PROTOCOL TITLE: AN OPEN-LABEL, MULTICENTER, GLOBAL PHASE 2 BASKET STUDY OF ENTRECTINIB FOR THE TREATMENT OF PATIENTS WITH LOCALLY ADVANCED OR METASTATIC SOLID TUMORS THAT HARBOR NTRK1/2/3, ROS1, OR ALK GENE REARRANGEMENTS PROTOCOL NUMBER: GO40782 (RXDX-101-02) VERSION NUMBER: 5 EUDRACT NUMBER: 2015 003385 84

IND NUMBER: 120500,- 135124- TEST PRODUCT: Entrectinib MEDICAL MONITOR: Simonetta Mocci, M.D., Ph.D. SPONSOR: F. Hoffmann-La Roche Ltd DATE FINAL: Version 1: 30 July 2015 DATES AMENDED: Version 2: 2 November 2015 Version 3: 9 September 2016 Version 4: 3 August 2017 Version 5: See electronic date stamp below

PROTOCOL AMENDMENT APPROVAL

Approver's Name Title Date and Time (UTC) Reddy, Josina (josina) Company Signatory 28-Aug-2018 21:48:56

CONFIDENTIAL This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, including Genentech, Inc. in the United States. The information contained in this document, especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as an investigator, potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee or Institutional Review Board. It is understood that this information will not be disclosed to others without written authorization from Roche except to the extent necessary to obtain informed consent from persons to whom the drug may be administered.

Entrectinib—F. Hoffmann-La Roche Ltd Protocol GO40782 (RXDX-101-02), Version 5 PROTOCOL AMENDMENT, VERSION 5: RATIONALE Protocol GO40782 has been amended to reflect Roche as the new Sponsor of this study. Changes to the protocol, along with a rationale for each change, are summarized below: • The Sponsor and signatories have been updated to reflect Roche as the new Sponsor of this study. • Screening diagnostic testing has been updated throughout the protocol to reflect the change in laboratory from the Ignyta Pharos Lab to Foundation Medicine. • Section 6 has been updated to include the description of the foreseen commercial formulation of entrectinib, which may be introduced in the study at a later point in time. • Section 8 has been updated to remove urine collection from the study assessments, as it is no longer being analyzed. • Section 9.3 has been updated to align the immediate reporting requirements with Roche safety standards due to the Sponsor update. • Appendix 1 has been removed, as the Ignyta Pharos testing will no longer be used. Foundation Medicine testing information is located in the study laboratory manual. Subsequent appendices have been renumbered accordingly. • Reduced frequency of follow-up for patients after 1 year has been implemented in the schedule of assessments (previously Appendix 2, now Appendix 1) to align with tumor assessments and to reduce the impact on patients.

Additional minor changes have been made to improve clarity and consistency. Substantive new information appears in italics. This amendment represents cumulative changes to the original protocol.

Entrectinib—F. Hoffmann-La Roche Ltd 2/Protocol GO40782 (RXDX-101-02), Version 5

PROTOCOL AMENDMENT ACCEPTANCE FORM

TITLE: AN OPEN-LABEL, MULTICENTER, GLOBAL PHASE 2 BASKET STUDY OF ENTRECTINIB FOR THE TREATMENT OF PATIENTS WITH LOCALLY ADVANCED OR METASTATIC SOLID TUMORS THAT HARBOR NTRK1/2/3, ROS1, OR ALK GENE REARRANGEMENTS PROTOCOL NUMBER: GO40782 (RXDX-101-02) VERSION NUMBER: 5 EUDRACT NUMBER: 2015 003385 84

IND NUMBER: 120500,- 135124- TEST PRODUCT: Entrectinib MEDICAL MONITOR: Simonetta Mocci, M.D., Ph.D. SPONSOR: F. Hoffmann-La Roche Ltd

I agree to conduct the study in accordance with the current protocol.

Principal Investigator’s Name (print)

Principal Investigator’s Signature Date

Please retain the signed original of this form for your study files. Please provide a copy of this form to your local CRA at their next monitoring visit.

Entrectinib—F. Hoffmann-La Roche Ltd 3/Protocol GO40782 (RXDX-101-02), Version 5 PROTOCOL SYNOPSIS

TITLE: AN OPEN-LABEL, MULTICENTER, GLOBAL PHASE 2 BASKET STUDY OF ENTRECTINIB FOR THE TREATMENT OF PATIENTS WITH LOCALLY ADVANCED OR METASTATIC SOLID TUMORS THAT HARBOR NTRK1/2/3, ROS1, OR ALK GENE REARRANGEMENTS

PROTOCOL NUMBER: GO40782 (RXDX-101-02)

VERSION NUMBER: 5

EUDRACT NUMBER: 2015-003385-84

IND NUMBER: 120500, 135124

TEST PRODUCT: Entrectinib

PHASE: II

INDICATION: Locally Advanced or Metastatic Solid Tumors

SPONSOR: F. Hoffmann-La Roche Ltd

Rationale Entrectinib (RO7102122, previously known as RXDX-101) is a potent inhibitor of the tyrosine kinases TrkA (encoded by the gene NTRK1), TrkB (encoded by the gene NTRK2), TrkC (encoded by the gene NTRK3), ROS1 (encoded by the gene ROS1), and ALK (encoded by the gene ALK), with IC50 values for kinase inhibition in the low nanomolar range (1.7, 0.1, 0.1, 0.2, and 1.6 nM, respectively). While these enzymes play various roles in normal cellular function, gene rearrangements (fusions) in these target kinases have the potential to be oncogenic drivers, tend to be mutually exclusive, and are present in small percentages (< 10%; Vaishnavi et al., 2015) in a variety of tumor types, including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), salivary gland cancer, papillary thyroid cancer, melanoma, and sarcoma. As such, in the two Phase 1 clinical studies (Study GO40783 [ALKA- 372-001] and Study GO40784 [STARTRK-1]) that were conducted to determine the recommended Phase 2 dose (RP2D) of entrectinib, patients with locally advanced or metastatic solid tumors were enrolled irrespective of tumor type. Among 18 ALK-, ROS1-, or Trk-inhibitor- naïve patients (1 patient was ALK-inhibitor intolerant) with NTRK1/2/3, ROS1, or ALK gene rearrangements who were treated at or above the RP2D, a response rate of 72% (13/18; Siena et al., ECC 2015) was reported. Furthermore, when subset by molecular alteration and tumor type where antitumor activity was observed, these data suggest that patients with NSCLC, metastatic CRC (mCRC), renal cell carcinoma, melanoma, and salivary gland cancers that harbor NTRK1/2/3, ROS1, or ALK gene rearrangements may potentially benefit from treatment with entrectinib.

Entrectinib—F. Hoffmann-La Roche Ltd 4/Protocol GO40782 (RXDX-101-02), Version 5 In light of the potentially favorable preliminary benefit-risk profile for entrectinib combined with the low incidence of the targeted gene rearrangements and their presence across a variety of tumor types, this Phase 2 study was designed to demonstrate the efficacy of entrectinib by enrolling patients with any solid tumor that harbors NTRK1/2/3, ROS1, or ALK gene rearrangements, for whom no alternative effective standard therapy is available. Patients will be enrolled across multiple solid tumor “baskets” that will be individually analyzed as separate cohorts.

Study Design This is an open-label, multicenter, global Phase 2 basket study of entrectinib for the treatment of patients with solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement. NTRK1, NTRK2, and NTRK3 gene rearrangements will be treated as a combined NTRK1/2/3 gene rearrangement basket. An overview of the study design is provided in Figure 2 of the main protocol. In order to determine enrollment eligibility and assignment to a specific basket, patients will be screened for gene rearrangements at Foundation Medicine, Inc. laboratory in Cambridge, Massachusetts, USA. Alternatively, local testing using any nucleic acid-based diagnostic testing method that relies on direct assessment of gene rearrangements and is performed at a CLIA-certified or equivalently- accredited diagnostic laboratory will be accepted. Depending on each particular patient population basket, prior treatment will be allowed; however, prior treatment with Trk, ROS1, or ALK inhibitors (approved or investigational) will not be allowed in patients who have tumors that harbor those respective gene rearrangements, e.g., no prior ROS1-inhibitors will be allowed in patients with ROS1 gene rearrangements. The single exception is for patients with ALK- or ROS1-rearranged NSCLC who have been previously treated with crizotinib and have CNS-only progression. Note: The ALK-rearranged NSCLC basket for patients previously treated with crizotinib and presenting with CNS-only progression is closed for further enrollment. Entrectinib will be administered orally on a continuous daily dosing regimen, at a dose of 600 mg once-daily in repeated 4-week cycles. Safety will be assessed by monitoring of adverse events, clinical laboratory tests (hematology, biochemistry, coagulation, lipid panel, and urinalysis), and physician visits, including physical examination, eye exam, vital signs, and ECGs. Tumor assessments (computed tomography [CT] or magnetic resonance imaging [MRI]) of the chest, abdomen, pelvis (depending on tumor type), plus bone and/or brain as applicable, will be performed at the end of Cycle 1 and every 8 weeks thereafter. All CT and MRI scans will be read by a central independent imaging laboratory using the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and the Response Assessment in Neuro-Oncology Criteria (RANO) or RANO- Brain Metastases (RANO-BM), as applicable for patients with primary or secondary CNS disease, respectively. Patients will be followed for safety and efficacy as per the schedule of assessments and will remain on study treatment until documented Entrectinib—F. Hoffmann-La Roche Ltd 5/Protocol GO40782 (RXDX-101-02), Version 5 radiographic progression as assessed by blinded independent central review (BICR), development of unacceptable toxicity, or withdrawal of consent. At the discretion of the Investigator and with the Sponsor’s approval, patients may continue treatment with entrectinib after BICR- confirmed disease progression if the patient is perceived to be deriving clinical benefit. For these patients, tumor assessments will no longer be submitted for BICR, but Investigators are encouraged to evaluate patients following a similar 8-week schedule. Patients discontinuing study treatment due to documented radiographic progression will enter the survival follow-up period, where survival status and subsequent anticancer therapy information (including best response) will be collected every 3 months until death, loss of follow-up, or withdrawal of consent, whichever comes first. Patients discontinuing study treatment prior to documented radiographic progression will also enter the survival follow-up period, where they will continue to have scheduled disease assessments approximately every 8 weeks until BICR-confirmed disease progression, the start of a subsequent anticancer therapy, or decision to no longer treat (e.g., supportive care only), whichever is first. At that time, survival status (and subsequent anticancer therapy information, including best response, if appropriate) will be collected every 3 months until death, loss of follow-up, or withdrawal of consent, whichever comes first.

Primary Objective . To determine the objective response rate (ORR) of entrectinib, as assessed by BICR, in each patient population basket of solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement

Secondary . To determine the duration of response (DOR), time to response Objectives (TTR), and clinical benefit rate (CBR) of entrectinib, as assessed by BICR, in each patient population basket of solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement . To determine the intracranial tumor response of entrectinib and CNS progression-free survival (CNS-PFS) in patients presenting with measurable CNS disease at baseline, as assessed by BICR using RECIST v1.1 in addition to RANO-BM for patients with CNS metastases or RANO for primary CNS tumors, as applicable . To estimate the progression-free survival (PFS) and overall survival (OS) of patients with solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement treated with entrectinib . To evaluate the safety and tolerability of entrectinib when administered at the RP2D in patients with solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement . To assess the population pharmacokinetics (PK) of entrectinib and to explore correlations between PK, response, and/or safety findings in patients with NTRK1/2/3, ROS1, or ALK gene rearrangements . To evaluate the effect of entrectinib on ventricular repolarization . To assess treatment-related symptoms and general health status

Entrectinib—F. Hoffmann-La Roche Ltd 6/Protocol GO40782 (RXDX-101-02), Version 5 using validated instruments of patient reported outcomes

Exploratory . To assess for any potential differences in clinicopathologic Objectives presentation and response to entrectinib among the various tumor types harboring NTRK1/2/3, ROS1, or ALK gene rearrangements . To assess for any potential differences in clinicopathologic presentation and response to entrectinib among the various fusion partner variants of NTRK1/2/3, ROS1, or ALK gene rearrangements . To gain insights into potential mechanisms of resistance to entrectinib

Number of Patients . All baskets evaluable for the primary endpoint (excluding ROS1 fusion-positive, ROS1 inhibitor-naïve NSCLC): enrollment as per a 2-stage sequential testing design, with up to 62 patients in each basket as per histology and gene rearrangement combination . ROS1 fusion-positive, ROS1 inhibitor-naïve NSCLC: enrollment in 2 parts with approximately 150 patients total . “Non-evaluable for the primary endpoint” basket: This basket does not have a statistical objective as these patients will mainly contribute to assessment of safety, PK, and other secondary endpoints.

Enrollment Criteria Inclusion Criteria 1. Histologically- or cytologically-confirmed diagnosis of locally advanced or metastatic solid tumor that harbors an NTRK1/2/3, ROS1, or ALK gene rearrangement that is predicted to translate into a fusion protein with a functional TrkA/B/C, ROS1, or ALK kinase domain, respectively, without a concomitant second oncodriver (e.g., EGFR, KRAS), as determined by Foundation Medicine, Inc. laboratory or by any nucleic acid-based diagnostic testing method (please refer to Section 5.1) performed at a local CLIA-certified or equivalently-accredited diagnostic laboratory. Note: Patients diagnosed with anaplastic large cell lymphoma (ALCL) harboring a gene rearrangement of interest may be eligible provided they meet all other inclusion/exclusion criteria. US Only: Other hematological malignancies (e.g., acute leukemia, myeloma, etc.) are also known to potentially harbor a gene rearrangement of interest. Although these patients are not eligible for study enrollment, they may be eligible for treatment under a Single Patient Protocol. Please make all such requests directly to the Sponsor. 2. For patients enrolled via local molecular testing, an archival or fresh tumor tissue (unless medically contraindicated) is required to be submitted for independent central molecular testing at Foundation Medicine, Inc. laboratory post-enrollment 3. Measurable disease as assessed locally using RECIST v1.1. Note: Patients with non-measurable disease (evaluable disease only) will be eligible for enrollment in the “non-evaluable for the primary endpoint” basket and will mainly contribute to assessment

Entrectinib—F. Hoffmann-La Roche Ltd 7/Protocol GO40782 (RXDX-101-02), Version 5 of safety, PK, and other secondary endpoints. 4. Patients with CNS involvement, including leptomeningeal carcinomatosis, which is either asymptomatic or previously-treated and controlled, are allowed. The use of seizure prophylaxis is allowed as long as patients are taking non-enzyme-inducing anti- epileptic drugs (non-EIAEDs). If patients were previously on EIAEDs and these have been discontinued, they must have been discontinued for at least 2 weeks prior to the start of entrectinib treatment. If patients require an anti-epileptic medication, a CYP3A4 non-EIAED can be used such as levetiracetam, valproic acid, gabapentin, topiramate, or lacosamide. Moderate inducers of CYP450, such as dexamethasone or other glucocorticoids, may be used at the discretion of the Investigator. Patients requiring steroids must be at stable or decreasing doses for at least 2 weeks prior to the start of entrectinib treatment. 5. Prior anticancer therapy is allowed (excluding approved or investigational Trk, ROS1, or ALK (non-NSCLC patients only) inhibitors in patients who have tumors that harbor those respective gene rearrangements). Note: The ALK basket is closed to enrollment. 6. At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed after prior chemotherapy or small molecule targeted therapy, respectively, at the time of the start of entrectinib treatment. Note: For targeted therapies, there must be no signs of disease flare or accelerated disease progression after treatment discontinuation. 7. At least 4 weeks must have elapsed since completion of antibody- directed therapy at the time of the start of entrectinib treatment. 8. Prior radiotherapy is allowed if more than 14 days have elapsed since the end of treatment. Patients who received brain irradiation must have completed whole brain radiotherapy at least 14 days prior and/or stereotactic radiosurgery at least 7 days prior to the start of entrectinib treatment. 9. Age ≥ 18 years. 10. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and minimum life expectancy of at least 4 weeks. 11. Adequate liver function as defined by the following criteria: . Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase (SGOT)) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase (SGPT)) ≤ 3.0 × upper limit of normal (ULN); ≤ 5.0 × ULN if liver metastases are present . Total serum bilirubin ≤ 2.0 × ULN; patients with a known history of Gilbert’s syndrome and/or isolated elevations of indirect bilirubin are eligible 12. Females of childbearing potential must have a negative serum pregnancy test during Screening and must not be breastfeeding or intending to become pregnant during the study. Female patients will be considered to be of childbearing potential unless they have Entrectinib—F. Hoffmann-La Roche Ltd 8/Protocol GO40782 (RXDX-101-02), Version 5 undergone permanent contraception or are postmenopausal. Postmenopausal is defined as at least 12 months without menses with no other medical reasons (e.g., chemical menopause due to anticancer treatment). 13. Ability to swallow entrectinib intact without chewing, crushing, or opening the capsules. 14. Willingness to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. 15. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to the start of entrectinib treatment. Exclusion Criteria 1. Current participation in another therapeutic clinical trial. 2. Prior treatment with approved or investigational Trk, ROS1, or ALK inhibitors in patients who have tumors that harbor those respective gene rearrangements. Note: In cases where the patient was intolerant to prior Trk, ROS1, or ALK inhibitors, please discuss with the Sponsor. In addition, prior treatment with crizotinib is permitted ONLY in ALK- or ROS1-rearranged NSCLC patients presenting with CNS- only progression. Other ALK or ROS1 inhibitors are prohibited in that scenario. Note: The ALK-rearranged NSCLC basket for patients previously treated with crizotinib and presenting with CNS-only progression is closed for further enrollment. 3. History of other previous cancer that would interfere with the determination of safety or efficacy of entrectinib with respect to the qualifying solid tumor malignancy. Note: Patients presenting with dual primary cancers may enroll in the “non-evaluable for the primary endpoint” basket if at least one of the cancers harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement as per Inclusion Criterion 1. 4. Incomplete recovery from any surgery prior to the start of entrectinib treatment that would interfere with the determination of safety or efficacy of entrectinib. 5. Any condition (in the past 3 months) that would interfere with the determination of safety or efficacy of entrectinib: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, stroke, symptomatic bradycardia, or uncontrolled arrhythmias requiring medication. 6. History of non-pharmacologically induced prolonged QTc interval (e.g., repeated demonstration of a QTc interval > 500 milliseconds from ECGs performed at least 24 hours apart). 7. History of additional risk factors for torsade de pointes (e.g., family history of long QT syndrome).

Entrectinib—F. Hoffmann-La Roche Ltd 9/Protocol GO40782 (RXDX-101-02), Version 5 8. Peripheral sensory neuropathy Grade ≥ 2. 9. Known active infections that would interfere with the assessment of safety or efficacy of entrectinib (bacterial, fungal, or viral, including human immunodeficiency virus positive). 10. Active gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would reasonably impact drug absorption. 11. Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis. Note: Radiation-induced lung disorders are not included in this exclusion criterion. 12. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study or could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor.

Dose and Route of Entrectinib capsules will be administered orally on a continuous daily Administration dosing regimen, at a dose of 600 mg QD.

Safety Patients will be assessed for adverse events at each clinic visit while on Assessments the study. Adverse events will be graded according to the NCI CTCAE v4.0. Type, incidence, severity, timing, seriousness, and relatedness of adverse events and laboratory abnormalities will be reported.

Data Monitoring An independent third-party Data Monitoring Committee (DMC) will Committee monitor the safety of the patients, with periodic meetings to determine overall safety and benefit-risk assessment. Its membership and governance will be outlined in a separate charter that will define the rules for early termination, modification and continuation of the study, as well as how those recommendations will be made to the Sponsor. Periodic adverse event data review will also be performed by designated members of the Sponsor’s study team. Any safety issues of concern identified by the study team will be promptly reported to the DMC as described in the DMC Charter.

Pharmacokinetic Population PK analysis will utilize patient covariates to identify sub- Assessments populations where possible. The relationship of exposure to entrectinib (and its potential metabolites) to measures of safety and efficacy will be modeled to the greatest extent possible. In sites participating from Japan, at least 6 patients (3 male and 3 female) will undergo serial PK sample collection during Cycles 1 and 2 in order to provide the full PK profile of entrectinib in Japanese patients.

Entrectinib—F. Hoffmann-La Roche Ltd 10/Protocol GO40782 (RXDX-101-02), Version 5 Pharmacodynamic In all patients, additional tissue (at the time of progression, if clinically Studies feasible) as well as on-study blood samples (Day 1 of each treatment cycle and at the End of Treatment) will be collected to identify other relevant non-gene rearrangement molecular alterations that may predict activity of entrectinib and to gain insights into potential mechanisms of resistance. Mutational status of the NTRK1/2/3, ROS1, and ALK genes, among others, will be monitored in nucleic acids isolated from plasma using next generation sequencing and related techniques.

Efficacy Tumor assessments will be performed as scheduled according to the Assessments calendar, regardless of treatment delays resulting from toxicity. CT or MRI scans of the brain, chest, abdomen, +/- pelvis (depending on tumor type), plus a bone scan (if applicable) will be performed at baseline, end of Cycle 1, and at 8-week intervals thereafter until documented radiographic progression. For each patient, the same imaging modality should be used for baseline and on-study assessments throughout the study. All scans will be submitted for BICR to confirm responses and disease progression during the study.

Entrectinib—F. Hoffmann-La Roche Ltd 11/Protocol GO40782 (RXDX-101-02), Version 5 Endpoints All radiographic efficacy endpoints to be based on BICR using RECIST v1.1 (except RANO or RANO-BM, as noted): Primary Endpoint: . Objective Response Rate (ORR), defined as the proportion of patients with complete response (CR) or partial response (PR); a confirmed response is a response that persists on repeat-imaging (≥ 4 weeks after initial documentation of response) Secondary Endpoints: . Duration of Response (DOR), defined from the first date of objective response (either CR or PR) to first documentation of radiographic disease progression or death due to any cause, whichever occurs first . Time to Response (TTR), defined as the time from the first dose of entrectinib to the first documentation of objective response (either CR or PR) . Clinical Benefit Rate (CBR), defined as the proportion of patients with CR, PR, or stable disease (SD) at 6 months after the first dose of entrectinib . Intracranial tumor response rate in patients with measurable CNS disease, as determined by BICR using RANO or RANO-BM, as applicable . CNS Progression-Free Survival (CNS-PFS) in patients with measurable CNS disease, defined as the time from the first dose of entrectinib to first documentation of radiographic CNS progression (as determined by BICR using RANO or RANO-BM, as applicable) or death due to any cause, whichever occurs first . Progression-Free Survival (PFS), defined as the time from the first dose of entrectinib to first documentation of radiographic disease progression or death due to any cause, whichever occurs first . Overall Survival (OS), defined as the time from the first dose of entrectinib to the date of death due to any cause . Type, incidence, severity, timing, seriousness, and relatedness of adverse events and laboratory abnormalities . Population PK . Ventricular repolarization . Quality-of-life and health status Exploratory Endpoints . Analysis of potential differences in clinicopathologic presentation and response to entrectinib among the various tumor types harboring NTRK1/2/3, ROS1, or ALK gene rearrangements . Analysis of potential differences in clinicopathologic presentation and response to entrectinib among the various fusion partner variants of NTRK1/2/3, ROS1, or ALK gene rearrangements . Potential mechanisms of resistance to entrectinib

Entrectinib—F. Hoffmann-La Roche Ltd 12/Protocol GO40782 (RXDX-101-02), Version 5 Statistical Analysis All baskets evaluable for the primary endpoint (excluding ROS1 Plan and Rationale fusion-positive, ROS1 inhibitor-naïve NSCLC) for Number of In these baskets, for any particular tumor type and gene rearrangement Patients combination, patients will be enrolled under a 2-stage sequential testing design to determine whether entrectinib has sufficient anticancer activity to warrant further development of that specific patient population.

For each basket, a true response rate of 20% or less is considered insufficient to warrant further study, whereas a true response rate of 40% or more is considered worthy of further study. The number of patients evaluated in each stage and the minimum number of responders needed to meet the primary endpoint were determined based on a sequential testing technique with at least 80% power and 1- sided α = 0.025.

Based on the above design considerations, the first stage will enroll up to 13 patients per basket. Patients are enrolled sequentially and the stage is deemed successful on the 4th responder. If the first stage is not successful, then enrollment in that basket will be terminated.

Otherwise, up to an additional 49 patients will be enrolled into the second stage.

. If within a particular basket, the 14th responder is observed prior to the enrollment of the 49th response-evaluable patient in stage 2, the basket will be deemed as having met the primary endpoint (ruling out an objective response rate of 20%).

. In contrast, the basket will be deemed as not meeting the primary endpoint if the full complement of 49 response- evaluable patients have been enrolled in stage 2 and 14 responders have not been observed at 13 weeks post the date of Cycle 1 Day 1 for the 49th response evaluable patient.

. Under these conditions, if the true response rate is 20%, the probability of stopping enrollment during the first stage is 75%. Conversely, if the true response rate is 40%, then the probability that enrollment will be terminated during the first stage is equal to 17%. ROS1 fusion-positive, ROS1 inhibitor-naïve NSCLC basket For this basket, the primary objective will be assessed in 2 parts. In Part A, the statistical methods will continue to follow the 2-stage sequential testing design described above for all the other evaluable baskets, with up to 62 patients enrolled. In Part B, with 90 additional patients treated at the RP2D, there is at least 80% power to rule out a BICR-assessed ORR of ≤50% (null) when the true ORR is at least 65% at a 1-sided α = 0.025. The choice of a statistically significant observed response rate of >50% for this population is based on review of the literature of expected response rate to available targeted therapy, i.e., crizotinib [Shaw et al, NEJM 2014].

Entrectinib—F. Hoffmann-La Roche Ltd 13/Protocol GO40782 (RXDX-101-02), Version 5 In addition, a pooled analysis of safety and efficacy of Parts A and B will be performed: it is expected that approximately 150 ROS1 fusion- positive, ROS1 inhibitor-naïve NSCLC patients will be treated with entrectinib at the RP2D. With this sample size, the study has >90% power to rule out an ORR ≤ 50% at a 1-sided α = 0.025 when the true ORR is at least 65%. “Non-evaluable for the primary endpoint” basket This basket is considered exploratory and will consist of all patients who have an NTRK1/2/3, ROS1, or ALK gene rearrangement but do not meet all inclusion or exclusion criteria. These patients are not assessable for the primary endpoint. They will mainly contribute to assessment of safety, PK, and other secondary endpoints. Examples of such patients include, but are not limited to, those with ECOG performance status > 2, dual primary cancers where one cancer’s mutation status is unknown, or dual oncogenic drivers, e.g., ALK fusion and EGFR mutation. In addition, patients with extracranial solid tumors without RECIST v1.1-defined measurable disease will also be allowed to enroll in this basket. Planned Pooled Analyses: . All gene rearrangements: analysis of safety and efficacy after pooling of patients across tumor types that harbor the same gene rearrangement (e.g., pool all patients with ROS1 gene rearrangements, regardless of tumor type) . All patients presenting with measurable CNS disease at baseline: analysis of intracranial tumor response rate and CNS- PFS after pooling across all baskets, regardless of tumor type Planned Subset Analyses: . NTRK1/2/3 baskets: analysis of safety and efficacy by specific NTRK gene (NTRK1 vs. NTRK2 vs. NTRK3) . All gene rearrangements: analysis of safety and efficacy by specific fusion partner variants Planned Sensitivity Analyses: . For all baskets, analysis of safety and efficacy in patients that are treatment-naïve (i.e., no prior systemic therapy) vs. previously treated . For all baskets, analyses of the primary and secondary efficacy endpoints in patients enrolled based upon local vs. central molecular testing results . For all baskets, analyses of the primary and secondary efficacy endpoints including only patients who have BICR-confirmed measurable disease at baseline and have received at least one dose of entrectinib . For all baskets, analysis of concordance between BICR and Investigator-assessed primary and secondary efficacy endpoints . For all baskets, analysis of overall survival in patients that started new systemic anticancer therapy

Entrectinib—F. Hoffmann-La Roche Ltd 14/Protocol GO40782 (RXDX-101-02), Version 5 Duration of Patient Patients will remain on study treatment until BICR-confirmed Participation and radiographic disease progression, development of unacceptable Duration of Study toxicity, or withdrawal of consent. Patients discontinuing study treatment will enter the survival follow-up period and remain on study until death, loss of follow-up, or withdrawal of consent, whichever comes first. If the study is not terminated beforehand per the recommendation of the DMC, the end of trial in all participating countries will be defined as the time at which the secondary endpoint of OS has been met. At that time, the protocol may be amended to minimize the number of protocol assessments to only collection of safety data for those patients remaining on study.

Entrectinib—F. Hoffmann-La Roche Ltd 15/Protocol GO40782 (RXDX-101-02), Version 5 LIST OF ABBREVIATIONS

Abbreviation Definition AE adverse event ALCL anaplastic large cell lymphoma ALK anaplastic lymphoma kinase ALT alanine aminotransferase AST aspartate aminotransferase AUC area under the (plasma concentration versus time) curve BAL bronchoalveolar lavage BICR blinded independent central review BSA body surface area BUN blood urea nitrogen CAP College of American Pathologist CBR clinical benefit rate CFR Code of Federal Regulations CLIA Clinical Laboratory Improvement Amendments

Cmax maximal plasma concentration CNS central nervous system CR complete response CRC colorectal cancer CT computed tomography CTCAE Common Terminology Criteria for Adverse Events DLT dose-limiting toxicity DMC Data Monitoring Committee DOR duration of response ECG electrocardiogram ECOG Eastern Cooperative Oncology Group eCRF electronic case report form EIAEDs enzyme-inducing anti-epileptic drugs EORTC European Organization for Research and Treatment of Cancer FDA Food and Drug Administration FFPE formalin-fixed, paraffin-embedded GCP Good Clinical Practice GI gastrointestinal GLP Good Laboratory Practice

Entrectinib—F. Hoffmann-La Roche Ltd 16/Protocol GO40782 (RXDX-101-02), Version 5 h hour H&E hematoxylin and eosin HIPAA Health Insurance Portability and Accountability Act of 1996

IC50 inhibitory concentration at 50% ICH International Conference on Harmonisation IHC immunohistochemistry IRB Institutional Review Board IV intravenous mCRC metastatic colorectal cancer MRI magnetic resonance imaging MTD maximum tolerated dose NCI National Cancer Institute NGS next generation sequencing NSCLC non-small cell lung cancer ORR objective response rate OS overall survival PD progressive disease or pharmacodynamic PFS progression-free survival PK Pharmacokinetic PROs patient reported outcomes QLQ Quality of Life Questionnaire QOL quality of life QTc corrected QT interval RANO Response Assessment in Neuro-Oncology Criteria Response Assessment in Neuro-Oncology Criteria – Brain RANO-BM Metastases RECIST Response Evaluation Criteria in Solid Tumors ROW rest of the world RP2D recommended Phase 2 dose SAE serious adverse event SAP Statistical Analysis Plan SD stable disease SGOT serum glutamic oxaloacetic transaminase SGPT serum glutamate pyruvate transaminase SOC system organ class t1/2 plasma terminal half-life

Entrectinib—F. Hoffmann-La Roche Ltd 17/Protocol GO40782 (RXDX-101-02), Version 5 TKI tyrosine kinase inhibitor TTR time to response ULN upper limit of normal

Entrectinib—F. Hoffmann-La Roche Ltd 18/Protocol GO40782 (RXDX-101-02), Version 5 TABLE OF CONTENTS

PROTOCOL AMENDMENT ACCEPTANCE FORM...... 3 PROTOCOL SYNOPSIS ...... 4 1 BACKGROUND AND RATIONALE ...... 24 1.1 NSCLC...... 25 1.2 mCRC ...... 26 2 ENTRECTINIB...... 27 2.1 MOLECULAR FORMULA AND CHEMICAL CLASS ...... 27 2.2 PRE-CLINICAL OVERVIEW ...... 27 2.2.1 Safety Pharmacology ...... 27 2.2.2 Pharmacokinetics and Metabolism ...... 27 2.2.3 Toxicology...... 28 2.3 CLINICAL OVERVIEW...... 29 3 STUDY DESIGN...... 32 4 STUDY OBJECTIVES...... 35 4.1 PRIMARY OBJECTIVE ...... 35 4.2 SECONDARY OBJECTIVES...... 35 4.3 EXPLORATORY OBJECTIVES...... 35 5 PATIENT SELECTION ...... 36 5.1 MOLECULAR TESTING PROCESS...... 36 5.2 CLINICAL TRIAL ELIGIBILITY...... 37 5.2.1 Natural History Follow-Up...... 37 5.2.2 Inclusion Criteria ...... 37 5.2.3 Exclusion Criteria ...... 39 6 STUDY TREATMENT ...... 42 6.1 DRUG ADMINISTRATION...... 42 6.2 CYCLE MANAGEMENT...... 42 6.3 DOSE MODIFICATIONS...... 43 6.4 CONCOMITANT MEDICATIONS AND TREATMENTS...... 45 6.4.1 Seizure Prophylaxis ...... 45 6.4.2 Antiemetic and Antidiarrheal Support...... 45 6.4.3 Pneumonitis/Pneumonia ...... 46 6.4.4 Hematopoietic Support ...... 46 6.4.5 Antacids ...... 46 6.4.6 Cytochrome P450 Substrates ...... 47 6.4.7 Concomitant Radiotherapy ...... 47 6.4.8 Concomitant Surgery ...... 48 6.4.9 Other Anticancer or Experimental Therapy...... 48 6.4.10 Other Concomitant Medications...... 48 6.4.11 Lifestyle Guidelines...... 49 6.5 STUDY DRUG ACCOUNTABILITY AND TREATMENT COMPLIANCE ...... 49 7 STUDY PROCEDURES AND GUIDELINES...... 50 7.1 CLINICAL ASSESSMENTS ...... 50

Entrectinib—F. Hoffmann-La Roche Ltd 19/Protocol GO40782 (RXDX-101-02), Version 5 7.1.1 Demographics ...... 50 7.1.2 Medical History ...... 50 7.1.3 Physical Examination ...... 50 7.1.3.1 Eye Exam ...... 51 7.1.4 Vital Signs...... 51 7.1.5 Performance Status ...... 51 7.1.6 Adverse Events ...... 51 7.1.7 Concomitant Medications and Treatments ...... 51 7.1.8 Tumor Assessments ...... 52 7.1.9 Blinded Independent Central Review (BICR) ...... 52 7.2 CLINICAL LABORATORY ASSESSMENTS...... 53 7.3 ELECTROCARDIOGRAM (ECG)...... 53 7.3.1 ECG Collection Time Points ...... 54 7.4 PHARMACOKINETIC ASSESSMENTS ...... 55 7.4.1 PK Collection Time Points ...... 55 7.5 PHARMACODYNAMIC STUDIES...... 56 7.6 TUMOR MARKERS...... 56 7.7 PATIENT REPORTED OUTCOMES ...... 56 8 STUDY ASSESSMENTS BY VISIT...... 57 8.1 MOLECULAR TESTING PROCESS...... 57 8.2 SCREENING (WITHIN 30 DAYS OF THE FIRST DOSE OF STUDY DRUG) ...... 57 8.3 CYCLE 1 DAY 1...... 58 8.4 CYCLE 1 DAY 15 (+/- 2 DAYS)...... 59 8.5 CYCLE 2 DAY 1 (+/- 2 DAYS)...... 59 8.6 CYCLE 2 DAY 15 (+/- 2 DAYS) - OPTIONAL...... 60 8.7 CYCLE 3 DAY 1 (+/- 2 DAYS)...... 60 8.8 CYCLE 3 DAY 15 (+/- 2 DAYS) - OPTIONAL...... 61 8.9 DAY 1 OF CYCLE 4 AND EACH SUBSEQUENT TREATMENT CYCLE THEREAFTER (+/- 2 DAYS)...... 61 8.10 EVERY 8 WEEKS FROM CYCLE 2 DAY 1 (+/- 7 DAYS) ...... 62 8.11 END OF TREATMENT (APPROXIMATELY 7 DAYS POST THE LAST DOSE OF STUDY DRUG)...... 62 8.12 SAFETY FOLLOW-UP VISIT (APPROXIMATELY 30 DAYS POST THE LAST DOSE OF STUDY DRUG) ...... 63 8.13 SURVIVAL FOLLOW-UP (APPROXIMATELY 3 MONTHS FROM THE SAFETY FOLLOW-UP VISIT)...... 63 9 SAFETY ASSESSMENTS ...... 64 9.1 SAFETY PARAMETERS AND DEFINITIONS...... 64 9.1.1 Adverse Events ...... 64 9.1.2 Serious Adverse Events (Immediately Reportable to the Sponsor)...... 64 9.2 METHODS AND TIMING FOR CAPTURING AND ASSESSING SAFETY PARAMETERS ...... 65 9.2.1 Adverse Event Reporting Period ...... 65 9.2.2 Eliciting Adverse Event Information...... 66 9.2.3 Assessment of Severity of Adverse Events ...... 66 9.2.4 Assessment of Causality of Adverse Events...... 66

Entrectinib—F. Hoffmann-La Roche Ltd 20/Protocol GO40782 (RXDX-101-02), Version 5 9.2.5 Procedures for Recording Adverse Events ...... 67 9.2.5.1 Diagnosis versus Signs and Symptoms ...... 67 9.2.5.2 Adverse Events That Are Secondary to Other Events...... 68 9.2.5.3 Persistent or Recurrent Adverse Events ...... 68 9.2.5.4 Abnormal Laboratory Values...... 68 9.2.5.5 Abnormal Vital Sign Values ...... 69 9.2.5.6 Abnormal Liver Function Tests ...... 70 9.2.5.7 Deaths...... 70 9.2.5.8 Preexisting Medical Conditions ...... 70 9.2.5.9 Lack of Efficacy or Worsening of the Malignancy under Study...... 71 9.2.5.10 Hospitalization or Prolonged Hospitalization ...... 71 9.2.5.11 Adverse Events Associated with an Overdose or Incorrect Administration of Study Drug...... 71 9.3 IMMEDIATE REPORTING REQUIREMENTS FROM INVESTIGATOR TO SPONSOR...72 9.3.1 SAE Reporting...... 72 9.3.2 Reporting Requirements for Pregnancies ...... 73 9.3.2.1 Pregnancies in Female Patients ...... 73 9.3.2.2 Congenital Anomalies/Birth Defects and Abortions...... 73 9.4 FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS ...... 73 9.4.1 In vestigator Follow-Up...... 73 9.4.2 Sponsor Follow-Up...... 73 9.5 POST-STUDY ADVERSE EVENTS...... 74 9.6 EXPEDITED REPORTING TO HEALTH AUTHORITIES, INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND ETHICS COMMITTEES...... 74 10 PATIENT END OF TREATMENT...... 75 11 PROTOCOL VIOLATIONS ...... 76 12 DATA MONITORING COMMITTEE...... 76 13 STATISTICAL METHODS AND CONSIDERATIONS ...... 77 13.1 ANALYSIS POPULATIONS...... 77 13.2 EFFICACY ANALYSES...... 77 13.2.1 Analysis of Primary Endpoint...... 78 13.2.2 Analysis of Secondary Endpoints ...... 78 13.2.2.1 Duration of Response (DOR)...... 78 13.2.2.2 Time to Response (TTR)...... 78 13.2.2.3 Clinical Benefit Rate (CBR)...... 78 13.2.2.4 Intracranial Tumor Response Rate...... 78 13.2.2.5 CNS Progression-Free Survival ...... 79 13.2.2.6 Progression-Free Survival ...... 79 13.2.2.7 Overall Survival (OS)...... 80 13.2.3 Statistical Design and Sample Size Justification ...... 80 13.2.3.1 All baskets evaluable for the primary endpoint (excluding ROS1 fusion-positive, ROS1 inhibitor-naïve NSCLC) ...... 80 13.2.3.2 ROS1 fusion-positive, ROS1 inhibitor-naïve NSCLC basket ...... 81 13.2.3.3 “Non-ev aluable for the primary endpoint” basket...... 82 13.2.3.4 Planned secondary analyses ...... 82 13.3 SAFETY ANALYSES...... 83 13.3.1 Adverse Events ...... 83 13.3.2 Clinical Laboratory Results ...... 83

Entrectinib—F. Hoffmann-La Roche Ltd 21/Protocol GO40782 (RXDX-101-02), Version 5 13.3.3 Vital Signs...... 84 13.3.4 Concomitant Medications/Treatments...... 84 13.3.5 Ventricular Repolarization...... 84 13.4 POPULATION PHARMACOKINETIC (POP PK)...... 85 13.4.1 Japan PK Sub-Study ...... 85 13.5 PATIENT REPORTED OUTCOMES (PROS)...... 85 13.5.1 PRO Endpoints ...... 86 13.5.2 PRO Analyses...... 86 13.5.2.1 Change from Baseline Scores...... 87 13.5.2.2 Proportion of Patients Improved, Remained Stable, or Worsened...... 87 14 DATA COLLECTION, RETENTION AND MONITORING...... 87 14.1 DATA COLLECTION INSTRUMENTS...... 87 14.2 DATA MANAGEMENT PROCEDURES...... 87 14.3 DATA QUALITY CONTROL AND REPORTING ...... 87 14.4 DATA ARCHIVAL...... 88 14.5 AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS...... 88 14.6 MONITORING...... 88 14.7 PATIENT CONFIDENTIALITY ...... 88 15 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS...... 89 15.1 PROTOCOL AMENDMENTS ...... 89 15.2 INSTITUTIONAL REVIEW BOARDS/ETHICS COMMITTEES...... 89 15.2.1 Informed Consent Forms ...... 90 15.3 REPORTING OF SAFETY ISSUES AND SERIOUS BREACHES OF THE PROTOCOL OR ICH GCP ...... 91 15.4 END OF TRIAL IN ALL PARTICIPATING COUNTRIES ...... 91 15.5 SPONSOR DISCONTINUATION CRITERIA...... 91 15.6 PUBLICATIONS...... 91 16 REFERENCES...... 92 17 APPENDICES...... 96

Entrectinib—F. Hoffmann-La Roche Ltd 22/Protocol GO40782 (RXDX-101-02), Version 5 LIST OF TABLES AND FIGURES

Table 1 Most common, treatment-related, adverse events occurring in >10% of patients (as of 15 August 2015)...... 30 Figure 1 Entrectinib pharmacokinetics (continuous daily dosing) ...... 31 Figure 2 GO40782 (STARTRK-2) Basket Study Schema...... 34 Table 2 Dose Modifications for Entrectinib-Related Adverse Events ...... 44 Table 3 Enzyme-Inducing Anti-Epileptic Drugs (EIAEDs) and Non-EIAEDs ...... 45 Table 4 Cytochrome P450 CYP3A Inhibitors and Inducers...... 47 Table 5 Cytochrome P450 Enzyme-Specific Substrates ...... 47 Table 6 Concomitant Medications to be used with Caution...... 49 Table 7 Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTCAE v4.0 ...... 66 Table 8 Causal Attribution Guidance ...... 67

Entrectinib—F. Hoffmann-La Roche Ltd 23/Protocol GO40782 (RXDX-101-02), Version 5 1 BACKGROUND AND RATIONALE In recent years, there has been a paradigm shift in cancer treatment practices based on better understanding of oncogenic signaling processes. Molecular alterations in specific kinases can result in constitutive activity, which can drive the initiation and progression of malignancy. In light of this understanding, matching a patient's cancer with a therapy that targets the specific molecular alteration has become the cornerstone of precision oncology.

Chromosomal translocations/rearrangements are major drivers of tumorigenesis. Since the discovery of the BCR–ABL gene rearrangement in chronic myelogenous leukemia, other oncogenic fusion kinases have been identified in hematologic and epithelial malignancies, including anaplastic lymphoma kinase (ALK) rearrangements, RET rearrangements, and ROS1 rearrangements (Soda et al., 2007, Takeuchi et al., 2012). As a result, several small molecule inhibitors have been developed to treat tumors harboring these oncogenic fusion kinases, e.g., the ALK inhibitors crizotinib and ceritinib, which have demonstrated targeted activity against lung cancers harboring EML4–ALK gene rearrangements (Kwak et al., 2010, Shaw et al., 2014).

Entrectinib (also known as RXDX-101) is a potent inhibitor of the tyrosine kinases TrkA (encoded by the gene NTRK1), TrkB (encoded by the gene NTRK2), TrkC (encoded by the gene NTRK3), ROS1 (encoded by the gene ROS1), and ALK (encoded by the gene ALK), with IC50 values for kinase inhibition in the low nanomolar range (1.7, 0.1, 0.1, 0.2, and 1.6 nM, respectively). While these enzymes play various roles in normal cellular function, gene rearrangements in these target kinases have the potential to be oncogenic drivers, tend to be mutually exclusive, and are present in small percentages (< 10%; Vaishnavi et al., 2015) in a variety of tumor types, including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), salivary gland cancer, papillary thyroid cancer, melanoma, and sarcoma.

As such, in the two Phase 1 clinical studies (ALKA-372-001 and STARTRK-1) that were conducted to determine the recommended Phase 2 dose (RP2D) of entrectinib, patients with locally advanced or metastatic solid tumors were enrolled irrespective of tumor type. Among 18 ALK-, ROS1, or Trk-inhibitor-naïve patients (1 patient was ALK-inhibitor intolerant) with NTRK1/2/3, ROS1, or ALK gene rearrangements who were treated at or above the RP2D, a response rate of 72% (13/18; Siena et al., ECC 2015) was reported. Furthermore, when subset by molecular alteration and tumor type where antitumor activity was observed, these data suggest that patients with NSCLC, metastatic CRC (mCRC), renal cell carcinoma, melanoma, and salivary gland cancers that harbor NTRK1/2/3, ROS1, or ALK gene rearrangements may potentially benefit from treatment with entrectinib.

In light of the potentially favorable preliminary benefit-risk profile for entrectinib combined with the low incidence of the targeted gene rearrangements and their presence across a variety of tumor types, this Phase 2 study was designed to demonstrate the efficacy of entrectinib by enrolling patients with any solid tumor that harbors NTRK1/2/3, ROS1, or ALK gene rearrangements, for whom no alternative effective standard therapy is

Entrectinib—F. Hoffmann-La Roche Ltd 24/Protocol GO40782 (RXDX-101-02), Version 5 available. Patients will be enrolled across multiple solid tumor “baskets” that will be individually analyzed as separate cohorts.

1.1 NSCLC Lung cancer is one of the most common cancers in adult men and women and the leading cause of cancer-related death in developed countries with a total of 626,600 deaths in 2012 (Torre et al., 2015). If diagnosed early, lung cancer can be cured with surgical resection; however, the majority of patients have advanced disease at the time of their diagnosis (Davidson et al., 2013). Due in part to relatively ineffective methods for early detection and the lack of curative treatment for advanced disease, the prognosis for people with lung cancer is poor. NSCLC is the most common (80%) histological type of lung cancer. NSCLC is divided into 3 histological subtypes: squamous cell carcinoma, large cell carcinoma, and adenocarcinoma, with adenocarcinoma accounting for approximately 50% of all lung cancers (Pao and Girard, 2011).

Lung cancer has one of the highest rates of genetic aberrations in cancer and these aberrations have led to molecularly distinct diseases. The frequency of NTRK1/2/3 and ROS1 rearrangements in NSCLC patients is estimated at 1-2% for NTRK1/2/3 combined and 1-3% for ROS1 (Gerber et al., 2014); this frequency is approximately 5-fold lower than ALK rearrangements.

Targeted therapies offer both efficacy and safety advantages over general chemotherapy in the treatment of NSCLC. Clinical studies have been conducted that compared the effectiveness and safety of the orally administered epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) against chemotherapy in NSCLC patients who have tumors that harbor EGFR molecular alterations (Mok et al., 2009, Rosell et al., 2012, Sequist et al., 2013). In these studies, response rates were considerably higher, progression-free survival (PFS) was prolonged, and quality of life parameters were substantially superior with the targeted therapies. Similarly, the ALK TKI, crizotinib, had a PFS of 7.7 months, a 65% response rate, and a low degree of toxicity in ALK-positive patients compared to a 3.0-month PFS and 20% response rate in patients who received non-targeted chemotherapy (p < 0.001) (Shaw et al., 2013). Crizotinib is also approved for the treatment of ROS1-positive NSCLC: among 50 patients treated in an expansion cohort of the phase 1 study of crizotinib, the objective response rate was 72% with a median duration of response of 17.6 months (Shaw, Ou, et al., 2014). The safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC.

The promising findings with these targeted therapies have resulted in a bifurcation of the treatment approach in NSCLC; first-line therapy is now dependent on whether a relevant molecular driver has been identified. Clinical practice guidelines recommend that those NSCLC patients with advanced tumors that harbor the relevant molecular alteration first be treated with a corresponding EGFR, ALK (Davidson et al., 2013), or ROS1 inhibitor, while those who do not should receive four to six treatment cycles of platinum-based doublet chemotherapy. Chemotherapy usually includes cisplatin or carboplatin paired with another cytotoxic agent such as pemetrexed, gemcitabine, or paclitaxel. Treating beyond four to six cycles of chemotherapy has not been shown to improve overall survival (OS) and few patients can tolerate longer treatment durations. Entrectinib—F. Hoffmann-La Roche Ltd 25/Protocol GO40782 (RXDX-101-02), Version 5 Currently, there are no approved targeted therapies for NTRK1/2/3-rearranged NSCLC, thus making this a life-threatening medical condition with high unmet medical need.

1.2 mCRC In colorectal cancer, the mucosa of the colon or rectum changes from normal cells to adenomas, which in turn can progress from benign adenomatous polyps to adenocarcinoma (Markowitz and Bertagnolli 2009). These changes can be induced by inherited or somatic mutations involving oncogenes and tumor suppressor genes (Benson 2007, Binefa et al., 2014). Although CRC is considered to be a preventable disease by limiting risk factors such as high-fat diets and by performing routine screening in high- risk individuals (i.e., > 50 years of age, family history, etc.), it is the third most commonly diagnosed cancer in males and the second in females, with an estimated 1.4 million cases and 693,900 deaths occurring in 2012 (Torre et al., 2015).

If diagnosed early, e.g., Stages I and II, surgery alone can be highly curative. Unfortunately, many patients are not diagnosed until after their disease has metastasized, with over 20% of patients diagnosed when they present with Stage IV disease and another 20% to 25% of patients will experience metastases during the course of their disease (Benson, 2007). In the past decade, survival of metastatic colorectal cancer patients has approximately doubled. This significant improvement is mainly due to the development of new combinations of standard chemotherapy, including 5-fluorouracil, irinotecan, and oxaliplatin, and also to the introduction of new targeted therapies, such as monoclonal antibodies against EGFR or vascular endothelial growth factor. However, the addition of such targeted therapies to standard chemotherapy regimens results in increased toxicity and treatment costs, requiring clinicians to better select patients who are likely to benefit from these novel combination treatments. The chimeric IgG1 monoclonal antibody cetuximab has shown efficacy in irinotecan- resistant metastatic colorectal cancer expressing the EGFR (Cunningham et al., 2004). Cetuximab binds to EGFR with a high specificity and this binding results in inhibition of intracellular signaling pathways, such as the G protein K-ras, the protein kinase RAF (Ras/mitogen-activated protein kinase (MAPK) pathway), and phosphoinositide 3-kinase (PI3K/Akt pathway). Molecular alterations that activate a protein downstream of the inhibitor-targeted enzyme can greatly reduce that inhibitor’s efficacy (De Roock et al., 2010). As such, it is now known that wild type KRAS mCRC patients treated with cetuximab have a progression-free survival (PFS) that is twice as long as mutant KRAS mCRC patients (Karapetis et al., 2008).

NTRK1, ROS1, and ALK alterations have been detected in CRC (Aisner et al., 2013, Lin et al., 2009, Lipson et al., 2012), at low incidences on the order of 1-2%. Currently, there are no approved targeted therapies for NTRK1/2/3-, ROS1-, or ALK-rearranged mCRC, thus also making these life-threatening medical conditions with high unmet medical need.

Entrectinib—F. Hoffmann-La Roche Ltd 26/Protocol GO40782 (RXDX-101-02), Version 5 2 ENTRECTINIB A complete detailed summary of the pre-clinical and clinical development of entrectinib can be found in the latest edition of the Investigator’s Brochure, which is the safety reference document for this study.

2.1 Molecular Formula and Chemical Class

Chemical Name: N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4- methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4- ylamino)benzamide

Molecular Formula: C31H34F2N6O2

Molecular Weight: 560.65 Daltons

2.2 Pre-Clinical Overview Extensive in vitro and in vivo pharmacology studies were performed to characterize the anti-proliferative and antitumor activity in a variety of human tumor xenograft and allograft models dependent on Trk, ROS1, or ALK oncoproteins. Entrectinib was effective in both subcutaneous and disseminated anaplastic large cell lymphoma xenograft models, at doses that were well tolerated. Of note, in an intracranial NSCLC tumor model, magnetic resonance imaging analysis demonstrated tumor shrinkage, images consistent with tumor cell necrosis, prevention of intracranial edema, and ultimately, increased survival for entrectinib treatment in a dose-dependent manner. Collectively, these findings suggest that entrectinib has the potential to treat patients with tumors that harbor NTRK1/2/3, ROS1, or ALK gene rearrangements, including those patients with CNS disease.

2.2.1 Safety Pharmacology No functional changes in neurobehavioral or respiratory systems that are likely to be of importance in clinical testing of entrectinib were identified following acute oral administration of entrectinib. While the results of the hERG assay demonstrated concentration-dependent inhibition of IKr current, suggesting potential interferences on cardiac repolarization, telemetry studies conducted in dogs indicated no adverse hemodynamic or electrocardiographic effects of acute oral administration of entrectinib at dosages ≤ 300 mg/kg.

For additional information, please refer to the Investigator’s Brochure.

2.2.2 Pharmacokinetics and Metabolism

In pharmacokinetic and toxicokinetic studies, the exposure of entrectinib (Cmax and AUC) increased in a less than dose-proportional manner in the toxicology species (SD rats and Beagle dogs).

Higher exposures were observed in females than males at all doses tested in rats and at high doses in dogs; similarly, accumulation following multiple doses was more evident in

Entrectinib—F. Hoffmann-La Roche Ltd 27/Protocol GO40782 (RXDX-101-02), Version 5 rodents and at higher doses in dogs. In a food-effect study conducted in Beagle dogs, entrectinib exposure increased 2-fold in the fed state compared to the fasted state (ratio of 2.02 for mean values based on dose normalized AUC), and inter-animal variability was greatly reduced in the presence of food. In repeat-dose toxicokinetic studies, steady state was achieved within 4 days, consistent with a terminal half-life of less than 28 hours. Entrectinib demonstrated low to moderate clearance from plasma and moderate volume of distribution across species. Entrectinib was highly protein bound (99.4% - 99.5% bound) and readily crossed the blood-brain barrier (higher concentrations were measured in the brain than in plasma of dogs and in some rats in repeat-dose toxicology studies).

Incubations of entrectinib with recombinant CYP enzymes suggested that the enzymes CYP2C8, CYP2C9, CYP2C19, and CYP3A4, were capable of metabolizing entrectinib. In addition, entrectinib demonstrated potential to inhibit the metabolic activities of CYP2C9, CYP2D6, and CYP3A4 isoforms (IC50 values of 5.5, 5.6, and 2.8-6.3 µM, respectively) and to induce CYP3A4 (37% at 10 µM relative to positive control rifampin), suggesting the potential for drug interactions with drugs metabolized by these isoforms. Preliminary analysis of human samples suggest a dimethyl metabolite, M5, and a glucuronide are the main metabolites in humans.

For additional information, please refer to the Investigator’s Brochure.

2.2.3 Toxicology In single-dose toxicity studies in SD rats and a Beagle dog, the maximum tolerated dose (MTD) exceeded the highest doses tested (240 and 300 mg/kg, respectively). Exploratory and definitive repeat-dose toxicology studies have been conducted in SD rats and Beagle dogs. The exploratory studies included 7 consecutive days of dosing in dogs and 14 consecutive days of dosing in both species, while the definitive 4-week studies in both species were comprised of 2 treatment periods of 14 days of consecutive dosing separated by a 14-day rest period. Adverse CNS findings, such as incoordination and decreased activity, were observed following multiple doses of ≥ 200 mg/kg/day in rats and ≥ 60 mg/kg/day in dogs and were dose-limiting. These findings are consistent with the appreciable concentrations of entrectinib measured in the brain in both species. The CNS effects were reversible following cessation of dosing and not associated with morphological changes in the brain.

Additional toxicological findings common to rats and dogs in the repeat-dose toxicology studies were effects on the hemolymphopoietic system and changes in the liver. Slight hematological changes and spleen alterations were observed irrespective of dose administered. Dose-related elevations in transaminases were observed in both species, but were more pronounced, with histopathological correlates, in dogs. In dogs, a slight to moderate increase in alanine aminotransferase (ALT) activity (maximum 2.4-fold) was noted in animals administered 60 mg/kg/day of entrectinib, while a severe alteration in liver function parameters (2- to 29-fold increase) was observed in animals administered 120 mg/kg/day of entrectinib. The hemolymphopoietic changes were almost or completely resolved and all liver changes resolved completely by the end of a 4-week recovery period.

Entrectinib—F. Hoffmann-La Roche Ltd 28/Protocol GO40782 (RXDX-101-02), Version 5 QT/QTc interval prolongation was noted in dogs after repeated once-daily administration of 120 mg/kg/day in animals with high exposure levels (mean AUC0-24 of 147 to 159 μM·h). Similarly, QT/QTc interval prolongation was noted in the 7-day repeat-dose toxicology study at 120 mg/kg/day in 1 animal with an AUC0-24 value of 144 μM·h.

The MTDs in the definitive 4-week repeat-dose toxicology studies were 100 mg/kg/day in rats (AUC0-24 values of 54 and 111 μM·h in males and females, respectively) and 60 mg/kg/day in dogs (AUC0-24 values of 37 and 38 μM·h for males and females, respectively).

Entrectinib was negative for mutagenicity and clastogenicity in the Ames (GLP) and micronucleus or Comet assays (non-GLP), respectively. It induced transient irritation to the eye of New Zealand White rabbits, but was not irritating to the skin of the rabbits. Entrectinib was found to have phototoxic potential in an in vitro 3T3 study.

For additional information, please refer to the Investigator’s Brochure.

2.3 Clinical Overview Entrectinib was evaluated in two Phase 1 clinical studies (Study ALKA-372-001 and Study RXDX-101-01 [STARTRK-1]) designed to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of entrectinib in patients with advanced or metastatic solid tumors harboring NTRK1/2/3, ROS1, or ALK molecular alterations. Safety, pharmacokinetics, and antitumor activity were evaluated. The following dosing regimens were tested:

. Schedule A (ALKA-372-001 study): once-daily (fasted) 4 days on, 3 days off for 3 weeks followed by 1 week rest. Doses tested ranged from 100 to 1600 mg/m2 without dose-limiting toxicity (DLT). . Schedule B (ALKA-372-001 study): continuous daily dosing (fed) in 4-week cycles. Doses tested ranged from 100 to 400 mg/m2 and 600 mg fixed, without DLT. . Schedule C (ALKA-372-001 study): once-daily (fed) 4 days on, 3 days off in 4- week cycles. Doses tested ranged from 400 to 800 mg/m2 without DLT. . Continuous Daily Dosing (STARTRK-1 study): once-daily (fed) in 4-week cycles. Doses tested were 100 mg/m2, 200 mg/m2, 400 mg/m2, 600 mg fixed, and 800 mg fixed. Two DLTs were observed at the fixed 800 mg/day dose: one event of Grade 3 cognitive impairment and one event of Grade 3 fatigue. Both events were reversible upon study drug interruption.

Based upon these two DLTs, 400 mg/m2 administered once-daily on a fed regimen was selected as the BSA-based RP2D. Subsequently, additional expansion cohorts of patients were enrolled to further explore a fixed daily dosing regimen, and 600 mg/day was selected as the RP2D for future Phase 2 studies.

Entrectinib—F. Hoffmann-La Roche Ltd 29/Protocol GO40782 (RXDX-101-02), Version 5 A total of 92 patients have been enrolled across both studies. At doses ≥ RP2D, 24 patients have been treated at 400 mg/m2, 19 patients at 600 mg, and 12 patients at 800 mg; 9 patients have been treated > 6 months and 1 patient > 1 year.

The most common, treatment-related, adverse events (AEs) were fatigue/asthenia, dysgeusia, paresthesia, nausea, and myalgia (Table 1). Most of the AEs were Grades 1 and 2 as per NCI CTCAE v4.0; importantly, there was no evidence of cumulative toxicity. Four treatment-related serious adverse events (SAEs) were reported in the STARTRK-1 study: two SAEs occurred at 800 mg/day, the dose that exceeded the maximum tolerated dose (Grade 3 cognitive impairment and Grade 3 eosinophilic myocarditis) and two SAEs occurred at 600 mg/day (Grade 2 fatigue and fall and Grade 2 dysphagia). All resolved with study drug interruption and/or dose reduction. No treatment-related SAEs were reported in the ALKA-372-001 study.

There were no clinically significant trends in laboratory parameters across the various dosing regimens.

For the latest clinical safety data, refer to the Entrectinib Investigator’s Brochure.

Table 1 Most common, treatment-related, adverse events occurring in >10% of patients (as of 15 August 2015) ALKA-372-001 STARTRK-1 TOTAL Adverse Event Term (n=49) (n=43) (n=92) G1-G2 G3 G1-G2 G3 G1-G2 G3 Fatigue/Asthenia 16 (33) 1 (2) 19 (44) 3 (7) 35 (38) 4 (4) Dysgeusia 16 (33) 20 (47) 36 (39) Paresthesia 20 (41) 11 (26) 31 (34) Nausea 17 (35) 5 (12) 22 (24) Myalgia 16 (33) 5 (12) 21 (23) Diarrhea 10 (21) 7 (16) 1 (2) 17 (18) 1 (1) Dizziness 6 (12) 8 (19) 14 (15) Cognitive Disorder 3 (6) 5 (12) 2 (5) 8 (9) 2 (2) Vomiting 9 (18) 0 9 (10)

Exposures of entrectinib administered on a continuous daily dosing regimen increased in a dose-proportional manner and reached steady-state within a week of dosing. Based on accumulation, the plasma half-life was estimated to be approximately 20 to 24 hours. This estimate is consistent with that observed in healthy subjects (22 to 25 hours) following a single dose with 120-hour post-dose sampling, supporting once daily dosing of entrectinib. At both the BSA-based RP2D of 400 mg/m2 and fixed RP2D of 600 mg, the plasma protein binding-corrected mean Ctrough values are multiples above the concentrations required for complete tumor growth inhibition in animal models (Figure 1).

Entrectinib—F. Hoffmann-La Roche Ltd 30/Protocol GO40782 (RXDX-101-02), Version 5 Figure 1 Entrectinib pharmacokinetics (continuous daily dosing)

In both Phase 1 studies, tumor assessments were performed at the end of Cycle 1 and every 8 weeks thereafter. Among 18 ALK-, ROS1-, or Trk-inhibitor-naïve patients (1 patient was ALK-inhibitor intolerant) with NTRK1/2/3, ROS1, or ALK gene rearrangements that were treated at or above the RP2D, a response rate of 72% (13/18; Siena et al., ECC 2015) was reported.

For the latest clinical data, please refer to the Investigator’s Brochure.

Entrectinib—F. Hoffmann-La Roche Ltd 31/Protocol GO40782 (RXDX-101-02), Version 5 3 STUDY DESIGN This is an open-label, multicenter, global Phase 2 basket study of entrectinib for the treatment of patients with solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement (fusion). NTRK1, NTRK2, and NTRK3 gene rearrangements will be treated as a combined NTRK1/2/3 gene rearrangement basket.

An overview of the study design is provided in Figure 2.

In order to determine enrollment eligibility and assignment to a specific basket, patients will be screened for gene rearrangements at Foundation Medicine, Inc. laboratory in Cambridge, Massachusetts, USA. Alternatively, local testing using any nucleic acid- based diagnostic testing method that relies on direct assessment of gene rearrangements and is performed at a CLIA-certified or equivalently-accredited diagnostic laboratory will be accepted. If local molecular testing is performed for enrollment, tissue, preferably from the same block, must be submitted to Foundation Medicine, Inc. for central confirmation of biomarker status.

Depending on each particular patient population basket, prior treatment will be allowed; however, prior treatment with Trk, ROS1, or ALK inhibitors (approved or investigational) will not be allowed in patients who have tumors that harbor those respective gene rearrangements; e.g., no prior ROS1-inbibitors will be allowed in patients with ROS1 gene rearrangements. The single exception is for patients with ALK- or ROS1-rearranged NSCLC who have been previously treated with crizotinib and have CNS-only progression.

Note: The ALK-rearranged NSCLC basket for patients previously treated with crizotinib and presenting with CNS-only progression is closed for further enrollment.

Entrectinib will be administered orally on a continuous daily dosing regimen, at a dose of 600 mg once-daily in repeated 4-week cycles.

Safety will be assessed by monitoring of adverse events, clinical laboratory tests (hematology, biochemistry, coagulation, lipid panel, and urinalysis), and physician visits, including physical examination, eye exam, vital signs, and ECGs.

Tumor assessments (computed tomography (CT) or magnetic resonance imaging (MRI)) of the chest, abdomen, pelvis (depending on tumor type), plus bone and/or brain as applicable, will be performed at the end of Cycle 1 and every 8 weeks thereafter. All CT and MRI scans will be read by a central independent imaging laboratory using the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and the Response Assessment in Neuro-Oncology Criteria (RANO) or RANO - Brain Metastases (RANO- BM), as applicable, for patients with primary or secondary CNS disease, respectively.

Patients will be followed for safety and efficacy as per the schedule of assessments and will remain on study treatment until documented radiographic progression as assessed by blinded independent central review (BICR), development of unacceptable toxicity, or withdrawal of consent. At the discretion of the Investigator and with the Sponsor’s

Entrectinib—F. Hoffmann-La Roche Ltd 32/Protocol GO40782 (RXDX-101-02), Version 5 approval, patients may continue treatment with entrectinib after BICR-confirmed disease progression if the patient is perceived to be deriving clinical benefit. For these patients, tumor assessments will no longer be submitted for BICR, but Investigators are encouraged to continue to evaluate patients following a similar 8-week schedule.

Patients discontinuing study treatment due to documented radiographic progression will enter the survival follow-up period, where survival status and subsequent anticancer therapy information (including best response) will be collected every 3 months until death, loss of follow-up, or withdrawal of consent, whichever comes first.

Patients discontinuing study treatment prior to documented radiographic progression will also enter the survival follow-up period, where they will continue to have scheduled disease assessments approximately every 8 weeks until BICR-confirmed disease progression, the start of a subsequent anticancer therapy, or decision to no longer treat (e.g., supportive care only), whichever is first. At that time, survival status (and subsequent anticancer therapy information, including best response, if appropriate) will be collected every 3 months until death, loss of follow-up, or withdrawal of consent, whichever comes first.

Entrectinib—F. Hoffmann-La Roche Ltd 33/Protocol GO40782 (RXDX-101-02), Version 5 Figure 2 GO40782 (STARTRK-2) Basket Study Schema

Entrectinib—F. Hoffmann-La Roche Ltd 34/Protocol GO40782 (RXDX-101-02), Version 5 4 STUDY OBJECTIVES

4.1 Primary Objective . To determine the objective response rate (ORR) of entrectinib, as assessed by BICR, in each patient population basket of solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement.

4.2 Secondary Objectives . To determine the duration of response (DOR), time to response (TTR), and clinical benefit rate (CBR) of entrectinib, as assessed by BICR, in each patient population basket of solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement . To determine the intracranial tumor response of entrectinib and CNS progression- free survival (CNS-PFS) in patients presenting with measurable CNS disease at baseline, as assessed by BICR using RECIST v1.1 in addition to RANO-BM for patients with CNS metastases or RANO for primary CNS tumors, as applicable . To estimate the progression-free survival (PFS) and overall survival (OS) of patients with solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement treated with entrectinib . To evaluate the safety and tolerability of entrectinib when administered at the RP2D in patients with solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement . To assess the population pharmacokinetics (PK) of entrectinib and to explore correlations between PK, response, and/or safety findings in patients with NTRK1/2/3, ROS1, or ALK gene rearrangements . To evaluate the effect of entrectinib on ventricular repolarization . To assess treatment-related symptoms and general health status using validated instruments of patient reported outcomes

4.3 Exploratory Objectives . To assess for any potential differences in clinicopathologic presentation and response to entrectinib among the various tumor types harboring NTRK1/2/3, ROS1, or ALK gene rearrangements . To assess for any potential differences in clinicopathologic presentation and response to entrectinib among the various fusion partner variants of NTRK1/2/3, ROS1, or ALK gene rearrangements . To gain insights into potential mechanisms of resistance to entrectinib

Entrectinib—F. Hoffmann-La Roche Ltd 35/Protocol GO40782 (RXDX-101-02), Version 5 5 PATIENT SELECTION Enrollment into STARTRK-2 will be performed in two stages with two separate informed consent forms: initially, all potential patients will consent to undergo molecular testing either locally (local consent form as per the institution’s standard practice) or at Foundation Medicine, Inc. (molecular consent form).

Only when patients are determined to have tumors that harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement, will they proceed to the second stage in the enrollment process, consisting of a second consent form to screen for the clinical study (clinical trial consent form).

The two consent processes are independent of each other.

5.1 Molecular Testing Process Testing for enrollment eligibility may be performed in one of two ways:

1. A representative tumor tissue specimen may be submitted to Foundation Medicine, Inc. in Cambridge, Massachusetts, USA, to be tested for the presence or absence of target gene rearrangements (fusions) via next generation sequencing (NGS) (Appendix 1). A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (less than 3 years old) with greater than 20% tumor content is preferred. Alternatively, at least 10-15 slides containing unstained, freshly cut, serial sections plus one additional section at 5 µM thickness mounted for hematoxylin & eosin (H&E) staining is also acceptable. If archival tumor tissue is unavailable or is determined to be unsuitable for required testing, tumor tissue must be obtained from a biopsy performed at screening. Results of the NGS testing will determine enrollment eligibility and assignment to a specific basket. 2. Alternatively, patient specimens may be tested locally using any nucleic acid-based diagnostic testing method that relies on direct assessment of gene rearrangements and is performed in a CLIA-certified or equivalently-accredited diagnostic laboratory. Eligible patients must have a reported gene rearrangement involving NTRK1/2/3, ROS1, or ALK that is predicted to translate into a fusion protein with a functional TrkA/B/C, ROS1, or ALK kinase domain, respectively. NGS, Sanger, RT-PCR, NanoString, and EdgeSeq are examples of acceptable methods; FISH is not an acceptable method. Results of local testing will be used to determine enrollment eligibility and assignment to a specific basket. In cases of ambiguity, Roche may ask for additional analyses to confirm eligibility. All patients enrolled via local testing will still be required to provide tissue samples as described above in #1 (preferably from the same block and unless medically contraindicated) to Foundation Medicine, Inc. for independent central molecular NGS testing post-enrollment. Exception: In the case of ALK- or ROS1-rearranged NSCLC patients who were originally diagnosed via FISH (or IHC), had a confirmed RECIST response to crizotinib, but are now presenting with CNS-only progression, results of the Entrectinib—F. Hoffmann-La Roche Ltd 36/Protocol GO40782 (RXDX-101-02), Version 5 original local test can be used to determine enrollment eligibility. These patients will be enrolled in a separate basket for ALK- or ROS1-rearranged NSCLC patients previously treated with crizotinib and presenting with CNS-only progression. These patients will also be required to provide tissue samples (unless medically contraindicated) to Foundation Medicine, Inc. for independent central molecular NGS testing post-enrollment. Note: The ALK-rearranged NSCLC basket for patients previously treated with crizotinib and presenting with CNS-only progression is closed for further enrollment.

For detailed sampling procedures, storage conditions, and shipment instructions, see the laboratory manual. The turnaround time for analysis results is expected to be approximately 2-3 weeks from sample receipt by Foundation Medicine, Inc.

The Investigator may obtain results from these analyses by requesting a report directly from Foundation Medicine. If allowed by local laws, the Investigator may share and discuss the results with the patient, unless the patient chooses otherwise. The report is generated for research purposes and is not provided for the purpose of guiding future treatment decisions. Results may not be available for samples that do not meet criteria for testing.

At the discretion of the Investigator or treating physician, molecular testing may take place any time prior to being considered for enrollment into the clinical trial, even while the patient is still receiving other anticancer therapies.

5.2 Clinical Trial Eligibility The study can fulfill its objectives only if appropriate patients are enrolled. The following eligibility criteria were designed to maximize enrollment of these rare patient populations and to select patients for whom protocol treatment is considered appropriate. All relevant medical and non-medical conditions should be taken into consideration when deciding whether this protocol is suitable for a particular patient once he or she is determined to have a gene rearrangement of interest.

5.2.1 Natural History Follow-Up Patients who have an NTRK1/2/3, ROS1, or ALK rearrangement, but do not enroll in the clinical trial (e.g., do not meet the clinical trial eligibility criteria, choose not to enroll, or progress before they can be treated with entrectinib) will begin natural history follow-up to provide information regarding their alternate anticancer treatment(s) (including best response) and survival status every 3 months until death, loss of follow-up, or withdrawal of consent, whichever comes first.

5.2.2 Inclusion Criteria 1. Histologically- or cytologically-confirmed diagnosis of locally advanced or metastatic solid tumor that harbors an NTRK1/2/3, ROS1, or ALK gene rearrangement that is predicted to translate into a fusion protein with a functional TrkA/B/C, ROS1, or ALK kinase domain, respectively, without a concomitant Entrectinib—F. Hoffmann-La Roche Ltd 37/Protocol GO40782 (RXDX-101-02), Version 5 second oncodriver (e.g., EGFR, KRAS) as determined by Foundation Medicine, Inc. or by any nucleic acid-based diagnostic testing method (please refer to Section 5.1) performed at a local CLIA-certified or equivalently-accredited diagnostic laboratory. Note: Patients diagnosed with anaplastic large cell lymphoma (ALCL) harboring a gene rearrangement of interest may be eligible provided they meet all other inclusion/exclusion criteria. US Only: Other hematological malignancies (e.g., acute leukemia, myeloma, etc.) are also known to potentially harbor a gene rearrangement of interest. Although these patients are not eligible for study enrollment, they may be eligible for treatment under a Single Patient Protocol. Please make all such requests directly to the Sponsor. 2. For patients enrolled via local molecular testing, an archival or fresh tumor tissue (unless medically contraindicated) is required to be submitted for independent central molecular testing at Foundation Medicine, Inc. post-enrollment. 3. Measurable disease as assessed locally using RECIST v1.1. Note: Patients with non-measurable disease (evaluable disease only) will be eligible for enrollment in the “non-evaluable for the primary endpoint” basket and will mainly contribute to assessment of safety, PK, and other secondary endpoints. 4. Patients with CNS involvement, including leptomeningeal carcinomatosis, which is either asymptomatic or previously-treated and controlled, are allowed. The use of seizure prophylaxis is allowed as long as patients are taking non-enzyme- inducing anti-epileptic drugs (non-EIAEDs). If patients were previously on EIAEDs and these have been discontinued, they must have been discontinued for at least 2 weeks prior to the start of entrectinib treatment. If patients require an anti-epileptic medication, a CYP3A4 non-EIAED can be used such as levetiracetam, valproic acid, gabapentin, topiramate, or lacosamide. See Table 3 for a sample list of EIAEDs and non-EIAEDs. Moderate inducers of CYP450, such as dexamethasone or other glucocorticoids, may be used at the discretion of the Investigator. Patients requiring steroids must be at stable or decreasing doses for at least 2 weeks prior to the start of entrectinib treatment. 5. Prior anticancer therapy is allowed (excluding approved or investigational Trk, ROS1, or ALK (non-NSCLC patients only) inhibitors in patients who have tumors that harbor those respective gene rearrangements). Note: The ALK basket is closed to enrollment. 6. At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed after prior chemotherapy or small molecule targeted therapy, respectively, at the time of the start of entrectinib treatment. Note: For targeted therapies, there must be no signs of disease flare or accelerated disease progression after treatment discontinuation. 7. At least 4 weeks must have elapsed since completion of antibody-directed therapy at the time of the start of entrectinib treatment.

Entrectinib—F. Hoffmann-La Roche Ltd 38/Protocol GO40782 (RXDX-101-02), Version 5 8. Prior radiotherapy is allowed if more than 14 days have elapsed since the end of treatment. Patients who received brain irradiation must have completed whole brain radiotherapy at least 14 days prior and/or stereotactic radiosurgery at least 7 days prior to the start of entrectinib treatment. 9. Age ≥ 18 years. 10. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and minimum life expectancy of at least 4 weeks 11. Adequate liver function as defined by the following criteria: . Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase (SGOT)) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase (SGPT)) ≤ 3.0 × upper limit of normal (ULN); ≤ 5.0 × ULN if liver metastases are present . Total serum bilirubin ≤ 2.0 × ULN; patients with a known history of Gilbert’s syndrome and/or isolated elevations of indirect bilirubin are eligible 12. Females of childbearing potential must have a negative serum pregnancy test during Screening and must not be breastfeeding or intending to become pregnant during the study. Female patients will be considered to be of childbearing potential unless they have undergone permanent contraception or are postmenopausal. Postmenopausal is defined as at least 12 months without menses with no other medical reasons (e.g., chemical menopause due to anticancer treatment). 13. Ability to swallow entrectinib intact without chewing, crushing, or opening the capsules. 14. Willingness to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. 15. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to the start of entrectinib treatment.

5.2.3 Exclusion Criteria 1. Current participation in another therapeutic clinical trial.

2. Prior treatment with approved or investigational Trk, ROS1, or ALK inhibitors in patients who have tumors that harbor those respective gene rearrangements.

Note: In cases where the patient was intolerant to prior Trk, ROS1, or ALK inhibitors, please discuss with the Sponsor.

In addition, prior treatment with crizotinib is permitted ONLY in ALK- or ROS1- rearranged NSCLC patients presenting with radiographically-confirmed CNS- only progression. Other ALK or ROS1 inhibitors are prohibited in that scenario.

Entrectinib—F. Hoffmann-La Roche Ltd 39/Protocol GO40782 (RXDX-101-02), Version 5 Note: The ALK-rearranged NSCLC basket for patients previously treated with crizotinib and presenting with CNS-only progression is closed for further enrollment.

3. History of other previous cancer that would interfere with the determination of safety or efficacy of entrectinib with respect to the qualifying solid tumor malignancy.

Note: Patients presenting with dual primary cancers may enroll in the “non- evaluable for the primary endpoint” basket if at least one of the cancers harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement as per Inclusion Criterion 1.

4. Incomplete recovery from any surgery prior to the start of entrectinib treatment that would interfere with the determination of safety or efficacy of entrectinib.

5. Any condition (in the past 3 months) that would interfere with the determination of safety or efficacy of entrectinib: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, stroke, symptomatic bradycardia, or uncontrolled arrhythmias requiring medication.

6. History of non-pharmacologically induced prolonged QTc interval (e.g., repeated demonstration of a QTc interval > 500 milliseconds from ECGs performed at least 24 hours apart).

7. History of additional risk factors for torsade de pointes (e.g., family history of long QT syndrome).

8. Peripheral sensory neuropathy Grade ≥ 2.

9. Known active infections that would interfere with the assessment of safety or efficacy of entrectinib (bacterial, fungal, or viral, including human immunodeficiency virus positive).

10. Active gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would reasonably impact drug absorption.

11. Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis.

Note: Radiation-induced lung disorders are not included in this exclusion criterion.

12. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for

Entrectinib—F. Hoffmann-La Roche Ltd 40/Protocol GO40782 (RXDX-101-02), Version 5 entry into this study or could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor.

Entrectinib—F. Hoffmann-La Roche Ltd 41/Protocol GO40782 (RXDX-101-02), Version 5 6 STUDY TREATMENT Entrectinib is supplied as white 200-mg hard capsules.

The foreseen commercial entrectinib 200 mg formulation consists of orange hard capsules. The capsules are of the same size and composition as the white capsules, except for the addition of sunset yellow FCF (also known as E110, or FD&C Yellow #6), an azo coloring agent (which may cause allergic reactions), and a printing ink. The Sponsor will continue to supply white capsules to this clinical study, but at a later point in time may switch to the orange commercial formulation.

The study drug will be periodically tested and monitored for its acceptable shelf life. Any study drug that fails to comply with the manufactured specifications will be promptly removed from the clinical trial site and replaced with new supplies by the Sponsor (or designee).

Each bottle will be labeled with the required regulatory agency warning statement, the protocol number, the Sponsor’s name, and directions for patient use and storage. The Investigator should ensure that the study drug is stored in appropriate conditions in a secure location with controlled access.

For clinical formulation-specific and batch-specific storage instructions, see the packaging label.

6.1 Drug Administration Entrectinib will be self-administered orally at home (except on clinic days – see below), on a continuous daily dosing regimen at a dose of 600 mg per day (three 200-mg capsules per day). Entrectinib should be administered approximately at the same time each day. For patients experiencing fatigue, nausea, or other mild tolerability issues, an evening time administration is recommended. For more specific dosing instructions, please refer to the Pharmacy Manual.

On Day 1 clinic visit days, entrectinib should be taken at the clinic after all the pre-dose assessments have been conducted, at the direction of the study research nurse/treating physician. On Day 15 and other visits (e.g., scans), entrectinib should be taken at home prior to coming to the clinic, according to the patient’s daily routine.

6.2 Cycle Management A treatment cycle consists of 4 weeks (28 days).

It is anticipated that individual patients may occasionally forget to take a dose. In those cases, missed doses should be replaced only if the patient remembers within a 12-hour window. After that, patients should just take the next dose the following day, without compensating for the missed dose (including vomited doses).

Entrectinib—F. Hoffmann-La Roche Ltd 42/Protocol GO40782 (RXDX-101-02), Version 5 In the event of missed doses or dose delays due to transient toxicity, cycle visits and tumor assessments should remain on schedule (i.e., every 4 and 8 weeks, respectively) independent of missed doses or dose delays.

6.3 Dose Modifications Adverse events associated with entrectinib can often be managed with concomitant medications, supportive care (see Section 6.4), and/or dose modifications as per Table 2. Each treatment intervention should be clearly documented in the electronic Case Report Form (eCRF).

If an adverse event (AE) is considered unrelated to study treatment and results in dose interruption, treatment may resume at the initial dose after the AE stabilizes or resolves to Grade ≤ 1, as per the Investigator’s discretion.

If toxicities that are possibly related to entrectinib are not easily managed or corrected, and are not tolerable to the patient, or if there are adverse events that are not acceptable in the Investigator’s judgment, the patient should have study treatment interrupted until the AE resolves to Grade ≤ 1. If study treatment is interrupted, dose reduction (if mandated) should occur when study treatment is resumed. All dose reductions should be based on the most severe toxicity observed that is attributable to entrectinib.

If needed, dose reductions may occur in decrements of 200 mg and no more than 2 dose reductions will be allowed; therefore, the possible daily doses of entrectinib are:

Dose Level Dose (mg QD) RP2D 600 - 1 400 -2 200 Doses reduced for drug-related toxicity should generally not be re-escalated. However, intrapatient re-escalation back to the previous dose level may be permitted at the discretion of the Investigator after discussion with the Sponsor.

Entrectinib treatment may be interrupted for a maximum of 28 days to allow sufficient recovery from any toxicity if the patient is still deriving clinical benefit in the judgment of the Investigator.

Dose Escalation for CNS disease: CNS metastases are common in many solid tumors, such as lung, breast, colon, kidney, and malignant melanoma. Specifically, among ALK- positive NSCLC patients previously treated with crizotinib, the frequency of CNS metastases is approximately 60% (Ou et al, J Clin Oncol 2015). Recent studies with alectinib, a second-generation ALK inhibitor, suggest that dose intensification may be necessary to overcome incomplete ALK inhibition in the CNS and prolong the durability of responses in patients with CNS metastases, particularly those with leptomeningeal carcinomatosis (Gainor et al, J Thorac Oncol 2015). As such, for patients with CNS disease who have been on study for at least 2 cycles of treatment (i.e., 8 weeks) with a best response of Stable Disease (SD) per RECIST v1.1 AND without treatment-related Grade ≥ 2 adverse events, dose escalation to 800 mg QD will be allowed as per Investigator’s discretion after discussion with the Sponsor. Entrectinib—F. Hoffmann-La Roche Ltd 43/Protocol GO40782 (RXDX-101-02), Version 5 Table 2 Dose Modifications for Entrectinib-Related Adverse Events Toxicity* Grade 1 Grade 2 Grade 3 Grade 4 Non(treatm-hematologicent0- Continue at same Continue at same Withhold dose until Withhold dose until dose level dose level toxicity is ≤ G1 or has toxicity is ≤ G1 or has For prolonged or returned to baseline, returned to baseline, intolerable CNS then reduce by 1 dose then reduce by 1 dose toxicity, withhold level and resume level and resume dose until toxicity is treatment treatment; or ≤ G1 or has returned discontinue treatment as to baseline, then per the Investigator’s reduce by 1 dose discretion level and resume treatment Hematologic Continue at same Continue at same Withhold dose until Withhold dose until dose level dose level toxicity is ≤ G2, or has toxicity is ≤ G2, or has returned to baseline, returned to baseline, then resume treatment then reduce the dose by at the same dose level 1 dose level and resume or reduce by 1 dose treatment level as per the Grade 4 lymphopenia Investigator’s without other dose- discretion limiting events (e.g., Grade 3 lymphopenia opportunistic infection) without other dose- may continue study limiting events (e.g., treatment without opportunistic infection) interruption may continue study treatment without interruption Prolonged QTc Continue at same Interrupt entrectinib Interrupt entrectinib Discontinue treatment dose level until recovery to until recovery to permanently baseline baseline Assess and correct Assess and correct electrolytes and electrolytes and concomitant concomitant medications medications. Continue at same Reduce dose by 1 dose dose level level and resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Pneumonitis (in Withhold dose until Withhold dose until Discontinue treatment Discontinue treatment absence of disease toxicity is Grade 0, toxicity is Grade 0, permanently permanently progression, then resume treatment then resume pulmonary at same dose treatment at same embolism, positive Discontinue treatment dose cultures or permanently if Discontinue radiation effect) pneumonitis recurs treatment permanently if pneumonitis recurs *dose modifications to be based on worst toxicity grade as per NCI CTCAE v4.0

Entrectinib—F. Hoffmann-La Roche Ltd 44/Protocol GO40782 (RXDX-101-02), Version 5 6.4 Concomitant Medications and Treatments Patients are required to self-report concomitant medication use. Investigators are encouraged to employ best supportive care according to local institutional standards of care and the guidance provided below. All concomitant medications and treatments must be recorded on the eCRF.

6.4.1 Seizure Prophylaxis Seizure prophylaxis with non-enzyme-inducing anti-epileptic drugs (non-EIAEDs) is allowed during the study for patients with controlled asymptomatic CNS involvement.

EIAEDs are not allowed. Table 3 lists EIAEDs and non-EIAEDs.

Moderate inducers of CYP3A, CYP3A4, or CYP3A4/5, such as dexamethasone or other glucocorticoids, may be used at the discretion of the Investigator.

Table 3 Enzyme-Inducing Anti-Epileptic Drugs (EIAEDs) and Non-EIAEDs

EIAEDs (Prohibited) Non-EIAEDs (Allowed) Carbamazepine Levetiracetam Oxcarbazepine Valproic acid Phenytoin Lacosamide Fosphenytoin Gabapentin Phenobarbital Topiramate Primidone Lamotrigine Tiagabine Zonisamide Clonazepam Clobazam Pregabalin

6.4.2 Antiemetic and Antidiarrheal Support For nausea and emesis, treat with standard antiemetics; prophylactic antiemetics are permitted as necessary using institutional guidelines for treatment and/or published guidelines. Refer to Section 6.4.10 for concomitant medications that should be administered with caution.

Treatment with antidiarrheal drugs may be warranted and should follow institutional and/or published guidelines. If no guidelines exist, then the following recommendations may be instituted:

. For Grade 1 diarrhea, treat with loperamide (Imodium) if needed; no dose modification is necessary. . For Grade 2 diarrhea, treat with loperamide (4 mg at first onset, then 2 mg every 2-4 hours or after each loose stool, until symptom free for 12 hours). No dose modification is necessary unless the patient is intolerant or symptom is recurrent. Entrectinib—F. Hoffmann-La Roche Ltd 45/Protocol GO40782 (RXDX-101-02), Version 5 . For Grade ≥ 3 (despite use of loperamide), treatment should be withheld until recovery to Grade ≤ 1

6.4.3 Pneumonitis/Pneumonia Investigators must thoroughly evaluate patients who demonstrate potential signs/symptoms of pneumonitis/pneumonia. If a patient has a potential diagnosis of pneumonitis or drug-related lung injury, the following evaluations/procedures should be considered to assist or exclude the diagnosis of pneumonitis during this period:

. A sputum gram stain and culture (induced sputum if needed) for bacteria, viruses, fungi, protozoa, and mycobacteria . Blood culture for febrile patients . Thoracentesis if pleural fluid is present (examined for same pathogens as sputum) . Bronchoscopy with bronchoalveolar lavage (BAL), if appropriate. BAL fluid should be sent for culture and cytology (examined for same pathogens as sputum) . Lung biopsy (e.g., open or thorascopic preferable; bronchoscopy with transbronchial biopsy), if appropriate . A plasma sample for B-type natriuretic peptide to evaluate for evidence of congestive heart failure . For Asian patients, a blood sample for β-D-glucan to evaluate for the presence of protozoal pneumonia (e.g., Pneumocystis jiroveci) If clinically appropriate, high dose corticosteroid treatment should be initiated. Should the event be fatal, an autopsy is highly recommended to confirm/exclude the diagnosis. For any case of suspected pneumonitis, please contact the Sponsor. See Table 2 for appropriate dose modifications.

6.4.4 Hematopoietic Support Prophylactic use of G-CSF or initiation of erythropoietin may be instituted according to the American Society of Clinical Oncology guidelines in patients who are having difficulty with severe neutropenia or anemia. Patients who have been treated for > 4 weeks with erythropoietin prior to starting on study may continue on the existing treatment.

Patients with neutropenic fever or infection should be hospitalized promptly for IV antibiotic therapy and may receive therapeutic colony stimulating factors as appropriate.

Red blood cell and platelet transfusions should be administered as warranted.

6.4.5 Antacids Absorption of entrectinib may be pH sensitive. Patients requiring H2-receptor antagonist, proton pump inhibitors, and/or antacid should preferentially take only H2 receptor antagonists or antacids as the duration of action of these drugs is relatively transient in contrast to proton pump inhibitors, which have longer half-lives. These medications

Entrectinib—F. Hoffmann-La Roche Ltd 46/Protocol GO40782 (RXDX-101-02), Version 5 should be taken at a time point that is not proximal to entrectinib administration (at least 3-4 hours before or after administration during the day, or the night before) to minimize any potential effect on absorption of entrectinib.

6.4.6 Cytochrome P450 Substrates A study with recombinant human cytochrome P450 isoforms (CYP450) suggests that entrectinib is metabolized by multiple CYP450 isoforms. Entrectinib inhibited the activities of CYP2C9, CYP2D6, and CYP3A4 isoforms with IC50 values of 5.5, 5.6, and 2.8-6.3 µM, respectively. Entrectinib also exhibited the potential to induce CYP3A4, suggesting a potential for interactions with other drugs primarily metabolized by CYP3A4. Due to this potential, entrectinib should be administered with caution with the drugs listed in Table 4 and Table 5 below.

Table 4 Cytochrome P450 CYP3A Inhibitors and Inducers Strong Inhibitors Strong Inducers Boceprevir, clarithromycin, conivaptan, grapefruit Alfentanil, cyclosporine, dihydroergotamine, juice, indinavir, itraconazole, ketoconazole, ergotamine, fentanyl, pimozide, quinidine, sirolimus, lopinavir/ritonavir, mibefradil, nefazodone, tacrolimus nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole Table 5 Cytochrome P450 Enzyme-Specific Substrates CYP450 Sensitive Substrates Substrates with Narrow Therapeutic Range Enzyme CYP2C9 Celecoxib Warfarin CYP2D6 Atomoxetine, desipramine, Thioridazine, pimozide dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine CYP3A4 Alfentanil, aprepitant, budesonide, Alfentanil, cyclosporine, dihydroergotamine, buspirone, conivaptan, darifenacin, ergotamine, fentanyl, pimozide, quinidine, darunavir, dasatinib, dronedarone, sirolimus, tacrolimus eletriptan, eplerenone, everolimus, felodipine, indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, quetiapine, saquinavir, sildenafil, simvastatin, sirolimus, tolvaptan, tipranavir, triazolam, ticagrelor, vardenafil

6.4.7 Concomitant Radiotherapy In certain instances, palliative radiotherapy to specific sites is permitted if considered medically necessary by the Investigator. The Sponsor must be notified if palliative radiotherapy is started; however, the need for radiation therapy will generally be considered indicative of progressive disease.

It is recommended to avoid radiotherapy for at least 5 days after the last dose of entrectinib. The irradiated area should be as small as possible and < 25% of the bone marrow reserve. Entrectinib administration should be withheld during the period of irradiation and for 2 weeks thereafter. If radiation-related toxicities (other than

Entrectinib—F. Hoffmann-La Roche Ltd 47/Protocol GO40782 (RXDX-101-02), Version 5 xerostomia) have not normalized to pre-irradiation levels after 2 weeks of rest, the patient should be removed from the study.

6.4.8 Concomitant Surgery Entrectinib treatment has not been specifically observed to interfere with wound healing; therefore, caution is advised on theoretical grounds. Based upon pharmacokinetic considerations, stopping entrectinib treatment is recommended at least 5-7 days prior to major elective surgery and 2-3 days prior to minor surgical procedures. Postoperatively, the decision to reinitiate treatment with entrectinib should be based upon clinical assessment of satisfactory wound healing and recovery from surgery.

6.4.9 Other Anticancer or Experimental Therapy No other approved or investigational anticancer therapy is permitted during study participation, including chemotherapy, immunotherapy, biological response modifiers, and/or hormonal therapy.

Bone-sparing agents (e.g., bisphosphonates, denosumab) for palliation of bone metastases or for the treatment of osteoporosis/osteopenia are allowed, but initiation of such agents or modification of the pre-study bisphosphonate or denosumab treatment regimen require discussion with the Sponsor.

6.4.10 Other Concomitant Medications Therapies considered necessary for the patient’s well-being (e.g., therapies to manage concomitant chronic pathologies or therapies required for life-threatening medical conditions) may be administered as per the Investigator’s discretion. For seasonal flu shots, inactivated vaccines are allowed.

Use of concomitant medications that increase or possibly increase the risk of QTc prolongation and/or induce torsades de pointes ventricular arrhythmia must be used with caution or avoided if possible during study participation (Table 6).

Entrectinib—F. Hoffmann-La Roche Ltd 48/Protocol GO40782 (RXDX-101-02), Version 5 Table 6 Concomitant Medications to be used with Caution Antiarrhythmics Amiodarone (Cordarone) Procainamide (Pronestyl) Disopyramide (Norpace) Quinidine (Quinaglute) Dofetilide (Tikosyn) Sotalol (Betapace) Ibutilide (Corvert) Antipsychotics Chlorpromazine (Thorazine) Quetiapine (Seroquel) Clozapine (Clozaril) Risperidone (Risperdal) Haloperidol (Haldol) Thioridazine (Mellaril) Antibiotics Azithromycin (Zithromax) Ketoconazole (Nizoral) Ciprofloxacin (Cipro) Levofloxacin (Levaquin) Clarithromycin (Biaxin) Moxifloxacin (Avelox) Erythromycin (Erythrocin) Ofloxacin (Floxin) Fluconazole (Diflucan) Sparfloxacin (Zagam) Gatifloxacin (Tequin) Telithromycin (Ketek) Itraconazole (Sporanox) Trimethoprim-Sulfa (Bactrim) Antidepressants Amitriptyline (Elavil) Imipramine (Norfranil) Citalopram (Celexa) Nortriptyline (Pametor) Desipramine (Pertofrane) Paroxetine (Paxil) Doxepin (Sinequan) Sertraline (Zoloft) Fluoxetine (Prozac) Venlaxafine (Effexor) Antiemetics Ondansetron (Zofran) Prochlorperazine (Compazine)

6.4.11 Lifestyle Guidelines Patients of childbearing potential (males and females) must agree to practice at least 2 methods of effective contraception such as vasectomy, oral contraception, intrauterine device (IUD), diaphragm, or condoms, or maintaining sexual abstinence prior to entering into the study and for 3 months following the last dose of study drug. Abstinence is defined as true abstinence, when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception.

Use of herbal medications (e.g., St. John’s Wort) and consumption of grapefruit and/or grapefruit juice should be avoided during the treatment period.

Patients should take precautionary measures regarding sun exposure, with daily sunscreen use and wearing protective clothing, sunglasses, and hats when outdoors.

6.5 Study Drug Accountability and Treatment Compliance At each clinic visit, patients will be asked to return any remaining study drug from the previous dosing cycle as well as all used and unused study drug containers. The designated site staff will perform accountability as per each clinical site’s standard practice.

Treatment compliance will be defined as the number of capsules taken divided by the expected number of capsules and reported as percentage. In case of dose reductions, the expected number of capsules should reflect the new dose level. Designated site staff must thoroughly document and re-instruct the patient when significant noncompliance is noted.

Entrectinib—F. Hoffmann-La Roche Ltd 49/Protocol GO40782 (RXDX-101-02), Version 5 At the end of the study, the Sponsor will provide instructions as to the disposition of any unused study drug.

All records must be readily available for inspection by the Sponsor or its representatives and the U.S. Food and Drug Administration (FDA) or other regulatory authorities at any time. For further guidance, please refer to the Study Reference Manual.

7 STUDY PROCEDURES AND GUIDELINES The Schedule of Assessments representing the required testing procedures to be performed during the study is diagrammed in Appendix 1.

Prior to conducting any study-related activities, written informed consent and any other authorizations must be signed and dated by the patient or patient’s legal representative.

Every effort should be made to ensure that the protocol required tests and procedures are completed as described. However, it is anticipated that from time to time there may be circumstances outside of the control of the Investigator that may make it unfeasible to perform the test. In those cases, the Investigator should take all steps necessary to ensure the safety and wellbeing of the patient. When a protocol required test cannot be performed, the Investigator will document the reason for this and any corrective and preventive actions which he/she has taken to ensure that normal processes are adhered to as soon as possible. The Sponsor study team should be informed of these incidents in a timely fashion.

Unless indicated otherwise, scheduled clinic visits should occur within +/- 2 days of the specified dates; where this is not possible because of extenuating circumstances (e.g., holidays), the visit should take place as close to this window as possible.

7.1 Clinical Assessments 7.1.1 Demographics Demographic information (e.g., date of birth and race) will be recorded at Screening, as allowed per local country privacy law regulations.

7.1.2 Medical History Relevant medical history, including history of current disease and prior anticancer therapies, other pertinent clinical conditions, and information regarding underlying diseases will be recorded at Screening. In addition, if available, microsatellite instability (MSI) and programmed death-ligand 1 (PD-L1) expression results should be documented at baseline.

7.1.3 Physical Examination A complete physical examination will be performed by either the Investigator or a sub- Investigator at Screening. Qualified staff (e.g., nurses or physician assistants) may complete an abbreviated physical exam at all other visits. New abnormal physical exam

Entrectinib—F. Hoffmann-La Roche Ltd 50/Protocol GO40782 (RXDX-101-02), Version 5 findings must be documented and followed by the Investigator, sub-Investigator, or other qualified staff at the next scheduled visit.

The physical examination may include, but not be limited to, general appearance, skin, neck, eyes, ears, nose, throat, breast, lungs, heart, abdomen, back, lymph nodes, extremities, and nervous system, as well as examination of known and suspected sites of disease, as per tumor type and standard local medical practices.

In order to monitor for potential study drug-related toxicities that may require dose modifications, routine assessment of adverse events commonly associated with entrectinib is recommended (please refer to the Investigator’s Brochure). These may include, but not limited to: fatigue, myalgia and arthralgia, gastrointestinal disturbances, and peripheral (e.g., dysgeusia and paresthesias) and central (e.g., attention deficit, confusion, dizziness, gait disturbance, memory impairment) neurologic effects.

7.1.3.1 Eye Exam Entrectinib-related corneal toxicity has been reported in animal studies. In order to monitor for potential corneal-related visual disturbances during treatment with entrectinib, ophthalmologic exams including at least the visual acuity and slit-lamp tests (which may be performed by an optometrist) will be required at Screening, Cycle 2 Day 1, at the End of Treatment, and as clinically indicated.

7.1.4 Vital Signs Body temperature, blood pressure, pulse and respirations will be performed at Screening and at every clinic visit. Blood pressure and pulse can be assessed either in the supine or seated position.

Height will be recorded at Screening only. Body weight will be recorded at every clinic visit.

7.1.5 Performance Status The Eastern Cooperative Oncology Group (ECOG) performance status scale will be assessed at Screening and at every clinic visit (Appendix 2).

7.1.6 Adverse Events Assessment of adverse events will include type, incidence, severity (graded by the NCI CTCAE, v4.0; Appendix 3), timing, seriousness, and relatedness. Adverse events will be assessed at every clinic visit.

7.1.7 Concomitant Medications and Treatments All concomitant medication and concurrent treatments (e.g., radiation therapy) will be documented at Screening and at every clinic visit. The indication for administration and dates of medication or treatment will be captured.

Entrectinib—F. Hoffmann-La Roche Ltd 51/Protocol GO40782 (RXDX-101-02), Version 5 7.1.8 Tumor Assessments Tumor assessments will be performed at Screening, at the end of Cycle 1 (Cycle 2 Day 1 +/- 2 days), every 8 weeks (+/- 7 days) thereafter, regardless of treatment delays resulting from toxicity, and at the End of Treatment (if more than 4 weeks have passed since the last imaging assessment). Care must be taken in scheduling disease assessments to prevent introduction of bias based on treatment delays.

Imaging studies will include a CT or MRI scan of the chest, abdomen, +/- pelvis (depending on tumor type), plus brain and/or bone scan (if applicable).

1. At Screening, a CT/MRI of the brain should be obtained to rule out newly diagnosed, untreated brain metastases or to document stability of previously treated brain metastases. If brain metastases are documented at Screening, then CT/MRI brain scans should be performed at every on-study tumor assessment. If brain metastases are not documented at Screening, then CT/MRI brain scans should be performed as clinically indicated.

2. For patients diagnosed with primary brain tumors, only the CT/MRI of the brain will be required at Screening and during the study.

3. At Screening, a bone scan should be obtained if bone metastases are suspected. For patients without bone metastases at baseline, a bone scan should be performed only to confirm a complete response (CR) or for suspicion of new bone disease, if not confirmed by CT/MRI. Radiographic confirmation of objective tumor response or disease progression will be based on RECIST v1.1 and assessed both locally and by blinded independent central review (Section 7.1.9). The same imaging modality should be used at Screening and on study.

Intravenous (IV) contrast is required when not medically contraindicated. Patients who have a contraindication to IV contrast may have MRI exams of the brain, abdomen, and pelvis performed in lieu of CTs and a non-contrast CT of the chest. PET/CT may be used to document baseline and new disease, but the CT portion of a PET/CT may not be used in lieu of a diagnostic CT, unless it is performed with IV contrast.

For patients with CNS disease, radiographic confirmation of intracranial objective tumor response or disease progression will be based on RANO or RANO-BM, as applicable, and only assessed by blinded independent central review.

Additional requirements are provided in the Imaging Manual.

7.1.9 Blinded Independent Central Review (BICR) All scans will be submitted to a third-party core imaging laboratory for independent review of tumor response and disease progression during the study according to an Imaging Review Charter to be prepared by the core imaging laboratory in consultation with the Sponsor.

Entrectinib—F. Hoffmann-La Roche Ltd 52/Protocol GO40782 (RXDX-101-02), Version 5 It is important to the integrity of the study that all imaging studies are forwarded to the core imaging laboratory in a timely manner throughout the study, preferably within 1 week of collection. Further details can be found in the Imaging Manual.

7.2 Clinical Laboratory Assessments Blood will be collected and analyzed locally for hematology and biochemistry at Screening, Days 1 and 15 of Cycle 1, Day 1 of each subsequent treatment cycle thereafter, at the End of Treatment, and as clinically indicated.

Standard coagulation and lipid panels will be required at Screening and as clinically indicated on-study.

In addition, female patients with childbearing potential will have a serum pregnancy test performed at Screening, Day 1 of every cycle, at the End of Treatment, and as clinically indicated.

Appendix 4 lists all of the specific tests that should be performed; any other details can be found in the Study Reference Manual. For blood, serum or plasma analytes are acceptable as long as normal ranges are obtained in the same manner.

Investigators can also perform additional local laboratory tests for the purpose of planning treatment administration, dose modification, or following adverse events.

7.3 Electrocardiogram (ECG) ECGs will be collected according to geographical region.

In the US and Japan (at least 6 patients also participating in the PK Sub-Study – please see Section 7.4.1), patients will have triplicate ECGs recorded and analyzed centrally, while in the rest of the world (ROW), all patients will have single ECGs recorded and analyzed locally.

Entrectinib—F. Hoffmann-La Roche Ltd 53/Protocol GO40782 (RXDX-101-02), Version 5 7.3.1 ECG Collection Time Points . Screening . Cycle 1 Day 1 o pre-dose Triplicate 12-lead ECGs o 4 hours (+/- 15 minutes) post-dose Performed ~ 2 minutes apart . Cycle 2 Day 1 o pre-dose Post-dose recording to coincide with PK US o 4 hours (+/- 15 minutes) post-dose sampling (Section 7.4.1) . Cycle 3 Day 1 o pre-dose Central Assessment o 4 hours (+/- 15 minutes) post-dose . Cycle 4+ Day 1 (pre-dose) . End of Treatment . As clinically indicated Triplicate 12-lead ECGs . Screening Performed ~ 2 minutes apart . Cycle 1 Day 1 o pre-dose Post-dose recording to coincide with PK o 4 hours (+/- 15 minutes) post-dose sampling (Section 7.4.1) . Cycle 2 Day 1 Japan o pre-dose (≥ 6 patients) Central Assessment o 4 hours (+/- 15 minutes) post-dose . Cycle 3 Day 1 Note: After the PK sub-study is completed, all o pre-dose newly enrolled patients will only need triplicate o 4 hours (+/- 15 minutes) post-dose ECG assessments at Screening, Day 1 of each . Cycle 4+ Day 1 (pre-dose) treatment cycle (pre-dose), End of Treatment, and . End of Treatment as clinically indicated . As clinically indicated . Screening . Cycle 1 Day 1 o pre-dose o 4 hours (+/- 15 minutes) post-dose Single 12-lead ECG . Cycle 2 Day 1 o pre-dose Rest of World Local Assessment o 4 hours (+/- 15 minutes) post-dose (ROW) Post-dose recording to coincide with PK . Cycle 3 Day 1 sampling (Section 7.4.1) o pre-dose o 4 hours (+/- 15 minutes) post-dose . Cycle 4+ Day 1 (pre-dose) . End of Treatment . As clinically indicated ECGs should be collected after the patient has rested quietly and is awake in a fully supine (or semi-recumbent, if supine is not tolerated) position for 5 to 10 minutes, and prior to any blood draw collection.

In the event of QTc prolongation (Grade > 1), study drug should be interrupted as per

Table 2 and the patient should be followed more closely. In addition, the ECGs should be over read for confirmation and continuous ECG monitoring may be implemented as clinically indicated.

For more details regarding ECG assessments, please refer to the Study Reference Manual.

Entrectinib—F. Hoffmann-La Roche Ltd 54/Protocol GO40782 (RXDX-101-02), Version 5 7.4 Pharmacokinetic Assessments Pharmacokinetic (PK) samples will be collected according to geographical region.

In general, blood for determination of plasma concentrations of entrectinib (and its potential metabolites) will be collected at each treatment cycle and at the End of Treatment. Additionally, if clinically feasible, a PK sample should be obtained at the time of any serious and/or unusual adverse events that may be causally related to the study drug.

All samples will be assayed using validated bioanalytical method(s) for entrectinib (and its potential metabolites). For further details regarding sample collection and processing procedures, please refer to the Study Reference Manual.

7.4.1 PK Collection Time Points . Cycle 1 Day 1 o pre-dose o 4 hours (+/- 15 minutes) post-dose . Cycle 2 Day 1 o pre-dose o 4 hours (+/- 15 minutes) post-dose US . Cycle 3 Day 1 o pre-dose o 4 hours (+/- 15 minutes) post-dose . Cycle 4+ Day 1 (pre-dose) . End of Treatment . As clinically indicated Japan PK Sub-Study: At least 6 patients (3 male . Cycle 1 Day 1 and 3 female) enrolled in Japan will be required to o pre-dose participate in a PK Sub-Study in order to gather o 0.5, 1, 2 hours (+/- 5 minutes), 4*, 6, 8 hours (+/- preliminary information about the pharmacokinetics 15 minutes), and 24 hours (+/- 60 minutes) of entrectinib (and its potential metabolites) in . Cycle 2 Day 1 Japanese patients. These are the same 6 patients o pre-dose with triplicate ECGs in Section 7.3.1 o 0.5, 1, 2 hours (+/- 5 minutes), 4*, 6, 8 hours (+/- 15 minutes), and 24 hours (+/- 60 minutes) Note: After the PK sub-study is completed, all . Cycle 3 Day 1 newly enrolled patients will only need PK o pre-dose assessments on Day 1 of each treatment cycle (pre- o 4 hours (+/- 15 minutes) post-dose dose), End of Treatment, and as clinically indicated . Cycle 4+ Day 1 (pre-dose) . End of Treatment *The 4-hour post-dose sample should be collected . As clinically indicated after the triplicate ECGs have been recorded . Cycle 1 Day 1 o pre-dose o 4 hours (+/- 15 minutes) post-dose . Cycle 2 Day 1 o pre-dose o 4 hours (+/- 15 minutes) post-dose Rest of World (ROW) . Cycle 3 Day 1 o pre-dose o 4 hours (+/- 15 minutes) post-dose . Cycle 4+ Day 1 (pre-dose) . End of Treatment . As clinically indicated

Entrectinib—F. Hoffmann-La Roche Ltd 55/Protocol GO40782 (RXDX-101-02), Version 5 7.5 Pharmacodynamic Studies In all patients, additional tissue (at the time of progression, if clinically feasible and patient has consented to the biopsy) as well as on-study blood samples (Day 1 of each treatment cycle and at the End of Treatment) will be collected to identify other relevant non-gene rearrangement molecular alterations that may predict activity of entrectinib and to gain insights into potential mechanisms of resistance. Mutational status of the NTRK1/2/3, ROS1, and ALK genes, among others, will be monitored in nucleic acids isolated from plasma using next generation sequencing.

7.6 Tumor Markers In order to monitor response to treatment and assess disease recurrence, additional blood samples will be collected at Screening, Day 1 of each treatment cycle, and at the End of Treatment, to measure the following tumor markers in the relevant patient populations listed below:

. CEA (mCRC and breast cancer patients)

a. CA 15-3 (breast cancer patients)

b. CA 19-9 (pancreatic cancer patients)

c. CA 125 (ovarian cancer patients) For other tumor types, other tumor markers can be collected according to standard medical practice.

7.7 Patient Reported Outcomes Prior to the first dose of entrectinib on Cycle 1 Day 1, pre-dose on Day 1 of each subsequent treatment cycle thereafter, and at the End of Treatment, patients will be required to complete the following self-administered quality of life (QOL) instruments: the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30) (Appendix 5) and the Euro-QoL Group EQ-5D (Appendix 8) to assess health status.

In addition, NSCLC and mCRC patients will complete the lung cancer and colorectal cancer specific modules, QLQ-LC13 (Appendix 6) and QLQ-CR29 (Appendix 7), respectively.

Entrectinib—F. Hoffmann-La Roche Ltd 56/Protocol GO40782 (RXDX-101-02), Version 5 8 STUDY ASSESSMENTS BY VISIT

8.1 Molecular Testing Process . Perform molecular testing as per Section 5.1 . Once patient is determined to have a tumor that harbors an NTRK1/2/3, ROS1, or ALK gene rearrangement, the patient can be consented to the clinical trial. Molecular testing to determine eligibility can be performed in advance with no time limit; e.g., the patient can be tested while being treated on another anticancer therapy

8.2 Screening (within 30 days of the first dose of study drug) . Assessments that have been performed as part of standard of care, prior to obtaining informed consent AND that are within the past 7 days of Screening AND within 30 days of the first dose of study drug, may be used for Screening and do not have to be repeated. . Obtain written informed consent (clinical trial consent) . Perform tumor imaging (scans performed prior to consent for this study may be used as baseline if obtained within 30 days prior to the first dose of study drug and the scans are of adequate quality): o CT/MRI brain o CT/MRI chest, abdomen, +/- pelvis (depending on tumor type) o Bone scan (if applicable) . Record demographics data . Record medical history, including oncologic history, MSI and PD-L1 expression results (if available), and prior treatments . Record concomitant medications . Perform a complete physical examination . Perform eye exam . Record height . Perform and record vital signs, body weight, and ECOG performance status . Perform and record ECGs: o US: triplicate 12-lead ECGs approximately 2 minutes apart o Japan (same patients as those participating in the PK Sub-Study): triplicate 12-lead ECGs approximately 2 minutes apart o ROW: single 12-lead ECG . Collect blood for clinical laboratory assessments, coagulation panel, lipid panel, and tumor markers . Female patients with childbearing potential: Perform a serum pregnancy test . Serious adverse events related to study procedures must be reported from the time of signed clinical trial informed consent

Entrectinib—F. Hoffmann-La Roche Ltd 57/Protocol GO40782 (RXDX-101-02), Version 5 . For patients who enroll in the clinical trial based on local molecular testing, archival or fresh tumor tissue (unless medically contraindicated) is required to be submitted for independent central molecular testing at Foundation Medicine, Inc. within 28 days of enrollment. . Patients who do not enroll in the clinical trial will begin natural history follow-up to provide information regarding alternate anticancer treatment(s) (including best response) and survival status every 3 months until death, loss of follow-up, or withdrawal of consent, whichever comes first

8.3 Cycle 1 Day 1 . PRE-DOSE: . Administer quality of life questionnaires: o QLQ-C30 (all patients) o QLQ-LC13 (NSCLC patients only) o QLQ-CR29 (mCRC patients only) o EQ-5D (all patients) . Review concomitant medications . Record any serious adverse events . Perform a complete physical examination (optional if performed within the past 7 days) . Perform and record vital signs, body weight, and ECOG performance status (optional if performed within the past 7 days) . Perform and record pre-dose ECGs: o US: triplicate 12-lead ECGs approximately 2 minutes apart o Japan (same patients as the PK Sub-Study): triplicate 12-lead ECGs approximately 2 minutes apart o ROW: single 12-lead ECG . Collect blood for clinical laboratory assessments and tumor markers (optional if performed within the past 7 days) . Female patients with childbearing potential: Perform a serum pregnancy test (optional if performed within the past 7 days) . Collect blood for PD assessments . All patients: Collect a baseline pre-dose PK sample . ADMINISTER FIRST DOSE OF ENTRECTINIB IN CLINIC . US: At 4 hours (+/- 15 minutes) post-dose, record triplicate 12-lead ECGs approximately 2 minutes apart and collect a corresponding PK blood sample . Japan PK Sub-Study: Collect PK samples at 0.5, 1, 2 hours (+/- 5 minutes), 4 hours (prior to blood sample collection, record triplicate 12-lead ECGs approximately 2 minutes apart), 6 hours, 8 hours (+/- 15 minutes), and 24 hours (+/- 1 hour) post-dose

Entrectinib—F. Hoffmann-La Roche Ltd 58/Protocol GO40782 (RXDX-101-02), Version 5 . ROW: At 4 hours (+/- 15 minutes) post-dose, record a single 12-lead ECG and collect a corresponding PK blood sample . Dispense study medication for the next cycle of treatment . For patients who enroll in the clinical trial based on local molecular testing, submit archival or fresh tumor tissue (unless medically contraindicated) to Foundation Medicine, Inc.

8.4 Cycle 1 Day 15 (+/- 2 days) . Assess study drug compliance . Review concomitant medications . Record any adverse events . Perform abbreviated physical examination . Perform and record vital signs, body weight, and ECOG performance status . Collect blood for clinical laboratory assessments

8.5 Cycle 2 Day 1 (+/- 2 days) . PRE-DOSE: . Administer quality of life questionnaires: o QLQ-C30 (all patients) o QLQ-LC13 (NSCLC patients only) o QLQ-CR29 (mCRC patients only) o EQ-5D (all patients) . Assess study drug compliance . Review concomitant medications . Record any adverse events . Perform tumor imaging (using the same imaging modality as used during Screening): o CT/MRI brain (if CNS disease was present at baseline) o CT/MRI chest, abdomen, +/- pelvis (depending on tumor type) o Bone scan (as applicable) o Submit scans for BICR within 1 week o Evaluate tumor response as per RECIST v1.1 (local assessment) . Perform abbreviated physical examination . Perform eye exam . Perform and record vital signs, body weight, and ECOG performance status . Perform and record pre-dose ECGs: o US: triplicate 12-lead ECGs approximately 2 minutes apart o Japan (same patients as the PK Sub-Study): triplicate 12-lead ECGs approximately 2 minutes apart o ROW: single 12-lead ECG

Entrectinib—F. Hoffmann-La Roche Ltd 59/Protocol GO40782 (RXDX-101-02), Version 5 . Collect blood for clinical laboratory assessments, tumor markers, and PD assessments . Female patients with childbearing potential: Perform a serum pregnancy test . All patients: Collect a pre-dose PK sample . ADMINISTER DOSE OF ENTRECTINIB IN CLINIC . US: At 4 hours (+/- 15 minutes) post-dose, record triplicate 12-lead ECGs approximately 2 minutes apart and collect a corresponding PK blood sample . Japan PK Sub-Study: Collect PK samples at 0.5, 1, 2 hours (+/- 5 minutes), 4 hours (prior to blood sample collection, record triplicate 12-lead ECGs approximately 2 minutes apart), 6 hours, 8 hours (+/- 15 minutes), and 24 hours (+/- 1 hour) post-dose . ROW: At 4 hours (+/- 15 minutes) post-dose, record a single 12-lead ECG and collect a corresponding PK blood sample . Dispense study medication for the next cycle of treatment

8.6 Cycle 2 Day 15 (+/- 2 days) - OPTIONAL . As per the Investigator’s discretion, this visit is optional depending on the patient’s clinical status. A phone call may also be used in lieu of a clinic visit. . Assess study drug compliance . Review concomitant medications . Record any adverse events . Perform abbreviated physical examination, if clinically indicated . Perform and record vital signs, body weight, and ECOG performance status, if clinically indicated . Collect blood for clinical laboratory assessments, if clinically indicated

8.7 Cycle 3 Day 1 (+/- 2 days) . PRE-DOSE: . Administer quality of life questionnaires: o QLQ-C30 (all patients) o QLQ-LC13 (NSCLC patients only) o QLQ-CR29 (mCRC patients only) o EQ-5D (all patients) . Assess study drug compliance . Review concomitant medications . Record any adverse events . Perform abbreviated physical examination . Perform and record vital signs, body weight, and ECOG performance status . Perform and record pre-dose ECGs:

Entrectinib—F. Hoffmann-La Roche Ltd 60/Protocol GO40782 (RXDX-101-02), Version 5 o US: triplicate 12-lead ECGs approximately 2 minutes apart o Japan (same patients as the PK Sub-Study): triplicate 12-lead ECGs approximately 2 minutes apart o ROW: single 12-lead ECG . Collect blood for clinical laboratory assessments, tumor markers, and PD assessments . Female patients with childbearing potential: Perform a serum pregnancy test . All patients: Collect a pre-dose PK sample . ADMINISTER DOSE OF ENTRECTINIB IN CLINIC . US: At 4 hours (+/- 15 minutes) post-dose, record triplicate 12-lead ECGs approximately 2 minutes apart and collect a corresponding PK blood sample . Japan (same patients as the PK Sub-Study): At 4 hours (+/- 15 minutes) post- dose, record triplicate 12-lead ECGs approximately 2 minutes apart and collect a corresponding PK blood sample . ROW: At 4 hours (+/- 15 minutes) post-dose, record a single 12-lead ECG and collect a corresponding PK blood sample . Dispense study medication for the next cycle of treatment

8.8 Cycle 3 Day 15 (+/- 2 days) - OPTIONAL . As per the Investigator’s discretion, this visit is optional depending on the patient’s clinical status. A phone call may also be used in lieu of a clinic visit. . Assess study drug compliance . Review concomitant medications . Record any adverse events . Perform abbreviated physical examination, if clinically indicated . Perform and record vital signs, body weight, and ECOG performance status, if clinically indicated . Collect blood for clinical laboratory assessments, if clinically indicated

8.9 Day 1 of Cycle 4 and each subsequent treatment cycle thereafter (+/- 2 days) . PRE-DOSE: . Administer quality of life questionnaires: o QLQ-C30 (all patients) o QLQ-LC13 (NSCLC patients only) o QLQ-CR29 (mCRC patients only) o EQ-5D (all patients) . Assess study drug compliance . Review concomitant medications . Record any adverse events . Perform abbreviated physical examination Entrectinib—F. Hoffmann-La Roche Ltd 61/Protocol GO40782 (RXDX-101-02), Version 5 . Perform and record vital signs, body weight, and ECOG performance status . Perform and record pre-dose ECGs: o US: triplicate 12-lead ECGs approximately 2 minutes apart o Japan: triplicate 12-lead ECGs approximately 2 minutes apart o ROW: single 12-lead ECG . Collect blood for clinical laboratory assessments, tumor markers, and PK/PD assessments . Female patients with childbearing potential: Perform a serum pregnancy test . Dispense study medication for the next cycle of treatment and advise patient to take his/her dose of entrectinib following the clinic visit

8.10 Every 8 weeks from Cycle 2 Day 1 (+/- 7 days) . Perform tumor imaging (using the same imaging modality as used during Screening): o CT/MRI brain (if CNS disease was present at baseline) o CT/MRI chest, abdomen, +/- pelvis (depending on tumor type) o Bone scan (as applicable) o Submit scans for BICR within 1 week o Evaluate tumor response as per RECIST v1.1 (local assessment) . Scans should continue on schedule according to the calendar, regardless if a +/- 7-day window was used or if there were treatment delays resulting from toxicity

8.11 End of Treatment (approximately 7 days post the last dose of study drug) . Perform tumor biopsy (if clinically feasible and patient has consented to the biopsy) and send tissue to Foundation Medicine, Inc. . Administer quality of life questionnaires (optional if performed within the past 2 weeks): o QLQ-C30 (all patients) o QLQ-LC13 (NSCLC patients only) o QLQ-CR29 (mCRC patients only) o EQ-5D (all patients) . Assess study drug compliance (optional if performed at the time of the last dose) . The following assessments are optional if performed within the past week: o Review concomitant medications o Record any adverse events o Perform abbreviated physical examination o Perform eye exam o Perform and record vital signs, body weight, and ECOG performance status

Entrectinib—F. Hoffmann-La Roche Ltd 62/Protocol GO40782 (RXDX-101-02), Version 5 o Perform and record ECGs: o US: triplicate 12-lead ECGs approximately 2 minutes apart o Japan: triplicate 12-lead ECGs approximately 2 minutes apart o ROW: single 12-lead ECG o Collect blood for clinical laboratory assessments, tumor markers, and PK/PD assessments o Female patients with childbearing potential: Perform a serum pregnancy test . Perform tumor imaging, submit scans for BICR within 1 week, and assess locally as per RECIST v1.1 (optional if performed within the past 4 weeks)

8.12 Safety Follow-Up Visit (approximately 30 days post the last dose of study drug) . Review concomitant medications . Record any adverse events . Perform abbreviated physical examination, as clinically indicated . Perform and record vital signs, body weight, and ECOG performance status, as clinically indicated . Collect blood for clinical laboratory assessments, as clinically indicated

8.13 Survival Follow-Up (approximately 3 months from the safety follow-up visit) . For patients discontinuing the study treatment due to documented radiographic progression, obtain survival status via phone call or medical chart review, including information about subsequent anticancer therapies (including best response) every 3 months until death, loss of follow-up, or withdrawal of consent, whichever comes first . For patients discontinuing the study treatment prior to documented radiographic progression, tumor assessments should continue on schedule approximately every 8 weeks until BICR-confirmed disease progression, the start of a subsequent anticancer therapy, or decision to no longer treat (e.g., supportive care only), whichever is first. At that time, survival status (and subsequent anticancer therapy information, including best response, if appropriate) will be collected every 3 months until death, loss of follow-up, or withdrawal of consent, whichever comes first.

Entrectinib—F. Hoffmann-La Roche Ltd 63/Protocol GO40782 (RXDX-101-02), Version 5 9 SAFETY ASSESSMENTS

9.1 Safety Parameters and Definitions

Safety assessments will consist of monitoring and recording adverse events, including serious adverse events, measurement of protocol-specified clinical laboratory assessments and vital signs, and other protocol-specified tests that are deemed critical to the safety evaluation of the study.

Certain types of events require immediate reporting to the Sponsor, as outlined in Section 9.3.

9.1.1 Adverse Events

According to the ICH guideline for Good Clinical Practice, an adverse event is any untoward medical occurrence in a clinical investigation subject administered a medicinal product, regardless of causal attribution. An adverse event can therefore be any of the following: . Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product . Any new disease or exacerbation of an existing disease (a worsening in the character, frequency, or severity of a known condition), except as described in Section 9.2.5.9 . Recurrence of an intermittent medical condition (e.g., headache) not present at baseline . Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is associated with symptoms or leads to a change in study treatment or concomitant treatment or discontinuation from study drug . Adverse events that are related to a protocol-mandated intervention, including those that occur prior to assignment of study treatment (e.g., screening invasive procedures such as biopsies)

9.1.2 Serious Adverse Events (Immediately Reportable to the Sponsor)

A serious adverse event (SAE) is any adverse event that meets any of the following criteria: . Fatal (i.e., the adverse event actually causes or leads to death) . Life threatening (i.e., the adverse event, in the view of the Investigator, places the patient at immediate risk of death) o This does not include any adverse event that, had it occurred in a more severe form or was allowed to continue, might have caused death . Requires or prolongs inpatient hospitalization (see Section 9.2.5.10)

Entrectinib—F. Hoffmann-La Roche Ltd 64/Protocol GO40782 (RXDX-101-02), Version 5 . Results in persistent or significant disability/incapacity (i.e., the adverse event results in substantial disruption of the patient’s ability to conduct normal life functions) . Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug . Significant medical event in the Investigator's judgment (e.g., may jeopardize the patient or may require medical/surgical intervention to prevent one of the outcomes listed above)

The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; see Section 9.2.3); the event itself may be of relatively minor medical significance (such as severe headache without any further findings).

Severity and seriousness need to be independently assessed for each adverse event recorded on the eCRF.

Serious adverse events are required to be reported by the Investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see Section 9.3 for reporting instructions).

9.2 Methods and Timing for Capturing and Assessing Safety Parameters

The Investigator is responsible for ensuring that all adverse events are recorded on the Adverse Event eCRF and reported to the Sponsor.

For each adverse event recorded on the Adverse Event eCRF, the Investigator will make an assessment of seriousness (see Section 9.1.2 for seriousness criteria), severity (see Section 9.2.3), and causality (see Section 9.2.4).

9.2.1 Adverse Event Reporting Period

Investigators will seek information on adverse events at each patient contact. All adverse events, whether reported by the patient or noted by study personnel, will be recorded in the patient’s medical record and on the Adverse Event eCRF.

After informed consent for the clinical trial has been obtained but prior to initiation of study drug, only serious adverse events related to protocol-mandated assessments should be reported.

After initiation of study drug, all adverse events, regardless of relationship to study drug, will be reported until at least 30 days after the last dose of study treatment. Any SAEs occurring any time after the reporting period must be promptly reported if a causal relationship to the study drug is suspected.

Entrectinib—F. Hoffmann-La Roche Ltd 65/Protocol GO40782 (RXDX-101-02), Version 5 9.2.2 Eliciting Adverse Event Information

A consistent methodology of non-directive questioning should be adopted for eliciting adverse event information at all patient evaluation time points. Examples of non-directive questions include the following: "How have you felt since your last clinic visit?" "Have you had any new or changed health problems since you were last here?"

9.2.3 Assessment of Severity of Adverse Events

The adverse event severity grading scale for the NCI CTCAE v4.0 will be used for assessing adverse event severity. Table 7 will be used for assessing severity for adverse events that are not specifically listed in the NCI CTCAE. Table 7 Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTCAE v4.0

Grade Severity

1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated

2 Moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living a

3 Severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living b, c

4 Life-threatening consequences or urgent intervention indicated d

5 Death related to adverse event d a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. b Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, using the toilet, and taking medications, as performed by patients who are not bedridden. c If an event is assessed as a "significant medical event," it must be reported as a serious adverse event per the definition of serious adverse event. d Grade 4 and 5 events must be reported as serious adverse events per the definition of serious adverse event.

9.2.4 Assessment of Causality of Adverse Events

Investigators should use their knowledge of the patient, the circumstances surrounding the event, and an evaluation of any potential alternative causes to determine whether or not an adverse event is considered to be related to the study drug, indicating "yes" or "no" accordingly. The following guidance should be taken into consideration (see also Table 8): . Temporal relationship of event onset to the initiation of study drug

Entrectinib—F. Hoffmann-La Roche Ltd 66/Protocol GO40782 (RXDX-101-02), Version 5 . Course of the event, considering especially the effects of dose reduction, discontinuation of study drug, or reintroduction of study drug (as applicable) . Known association of the event with the study drug or with similar treatments . Known association of the event with the disease under study . Presence of risk factors in the patient or use of concomitant medications known to increase the occurrence of the event . Presence of non-treatment-related factors that are known to be associated with the occurrence of the event Table 8 Causal Attribution Guidance

Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, science-based rationales, and clinical judgment?

YES There is a plausible temporal relationship between the onset of the adverse event and administration of the study drug, and the adverse event cannot be readily explained by the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the adverse event follows a known pattern of response to the study drug; and/or the adverse event abates or resolves upon discontinuation of the study drug or dose reduction and, if applicable, reappears upon re-challenge.

NO Evidence exists that the adverse event has an etiology other than the study drug (e.g., preexisting medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or the adverse event has no plausible temporal relationship to administration of the study drug (e.g., cancer diagnosed 2 days after first dose of study drug).

9.2.5 Procedures for Recording Adverse Events

Investigators should use correct medical terminology/concepts when recording adverse events on the Adverse Event eCRF. Avoid colloquialisms and abbreviations. Only one adverse event term should be recorded in the event field on the Adverse Event eCRF. 9.2.5.1 Diagnosis versus Signs and Symptoms

A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than individual signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated transaminases). However, if a constellation of signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at the time of reporting, each individual event should be recorded on the Adverse Event eCRF. If a diagnosis is subsequently established, all previously reported adverse events based on signs and symptoms should be nullified and replaced by one adverse event report based on the single diagnosis, with a starting date that corresponds to the starting date of the first symptom of the eventual diagnosis.

Entrectinib—F. Hoffmann-La Roche Ltd 67/Protocol GO40782 (RXDX-101-02), Version 5 9.2.5.2 Adverse Events That Are Secondary to Other Events

In general, adverse events that are secondary to other events (e.g., cascade events or clinical sequelae) should be identified by their primary cause, with the exception of severe or serious secondary events. A medically significant secondary adverse event that is separated in time from the initiating event should be recorded as an independent event on the Adverse Event eCRF. For example: . If vomiting results in mild dehydration with no additional treatment in a healthy adult, then only vomiting should be reported on the eCRF . If vomiting results in severe dehydration, then both events should be reported separately on the eCRF . If a severe gastrointestinal hemorrhage leads to renal failure, then both events should be reported separately on the eCRF . If dizziness leads to a fall and consequent fracture, then all three events should be reported separately on the eCRF . If neutropenia is accompanied by an infection, then both events should be reported separately on the eCRF

All adverse events should be recorded separately on the Adverse Event eCRF if it is unclear as to whether the events are associated. 9.2.5.3 Persistent or Recurrent Adverse Events

A persistent adverse event is one that extends continuously, without resolution, across cycles. When this occurs, the initial severity (intensity or grade) of the event will be recorded at the time the event is first reported. If a persistent adverse event becomes more or less severe, the initial event should be closed and a new event with the new severity should be recorded on the Adverse Event eCRF. Similarly, if the event becomes serious, the initial event should be closed and a new event recorded on the Adverse Event eCRF, completing all data fields related to serious adverse events. The serious adverse event should be reported to the Sponsor immediately (i.e., no more than 24 hours after learning that the event became serious).

A recurrent adverse event is one that resolves between treatment cycles and subsequently recurs. Each recurrence of an adverse event should be recorded as a separate event on the Adverse Event eCRF. 9.2.5.4 Abnormal Laboratory Values

Not every laboratory abnormality qualifies as an adverse event. A laboratory test result must be reported as an adverse event if it meets any of the following criteria: . Accompanied by clinical symptoms . Results in a change in study treatment (e.g., dosage modification, treatment interruption, or treatment discontinuation)

Entrectinib—F. Hoffmann-La Roche Ltd 68/Protocol GO40782 (RXDX-101-02), Version 5 . Results in a medical intervention (e.g., potassium supplementation for hypokalemia) or a change in concomitant therapy . Results in more frequent follow-up assessments or further diagnostic investigation . Clinically significant in the Investigator’s judgment

It is the Investigator’s responsibility to review all laboratory findings. Medical and scientific judgment should be exercised in deciding whether an isolated laboratory abnormality should be classified as an adverse event.

If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., increased alkaline phosphatase and bilirubin at 5  ULN associated with cholestasis), only the diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.

If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the abnormality itself should be recorded on the Adverse Event eCRF, along with a descriptor indicating if the test result is above or below the normal range (e.g., "elevated potassium," as opposed to "abnormal potassium"). If the laboratory abnormality can be characterized by a precise clinical term per standard definitions, the clinical term should be recorded as the adverse event. For example, an elevated serum potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."

Observations of the same clinically significant laboratory abnormality from visit to visit should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology changes. The initial severity of the event should be recorded, and the severity or seriousness should be updated as described in Section 9.2.5.3. 9.2.5.5 Abnormal Vital Sign Values

Not every vital sign abnormality qualifies as an adverse event. A vital sign result must be reported as an adverse event if it meets any of the following criteria: . Accompanied by clinical symptoms . Results in a change in study treatment (e.g., dosage modification, treatment interruption, or treatment discontinuation) . Results in a medical intervention or a change in concomitant therapy . Clinically significant in the Investigator’s judgment

It is the Investigator’s responsibility to review all vital sign findings. Medical and scientific judgment should be exercised in deciding whether an isolated vital sign abnormality should be classified as an adverse event.

If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on the Adverse Event eCRF.

Entrectinib—F. Hoffmann-La Roche Ltd 69/Protocol GO40782 (RXDX-101-02), Version 5 Observations of the same clinically significant vital sign abnormality from visit to visit should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology changes. The initial severity of the event should be recorded, and the severity or seriousness should be updated as described in Section 9.2.5.3. 9.2.5.6 Abnormal Liver Function Tests

The finding of an elevated ALT or AST ( 3  baseline value) in combination with either an elevated total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury. Therefore, Investigators must report as an adverse event the occurrence of either of the following: . Treatment-emergent ALT or AST  3  baseline value in combination with total bilirubin  2  ULN (of which ≥ 35% is direct bilirubin) . Treatment-emergent ALT or AST  3  baseline value in combination with clinical jaundice

The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal laboratory values should be recorded on the Adverse Event eCRF (see Section 9.2.5.4) and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the event), as a serious adverse event. 9.2.5.7 Deaths

For the purposes of this study, deaths due to disease progression will not be considered a serious adverse event.

All deaths, regardless of relationship to study drug, must be recorded on the Death eCRF and on the Adverse Event eCRF only if it is considered related to an adverse event.

Death should be considered an outcome and not a distinct event. The event or condition that caused or contributed to the fatal outcome should be recorded as the single medical concept on the Adverse Event eCRF. Generally, only one such event should be reported. The term "sudden death" should be used only for the occurrence of an abrupt and unexpected death due to presumed cardiac causes in a patient with or without preexisting heart disease, within 1 hour after the onset of acute symptoms or, in the case of an unwitnessed death, within 24 hours after the patient was last seen alive and stable. If the cause of death is unknown and cannot be ascertained at the time of reporting, "unexplained death" should be recorded on the Adverse Event eCRF. If the cause of death later becomes available (e.g., after autopsy), "unexplained death" should be replaced by the established cause of death. 9.2.5.8 Preexisting Medical Conditions

A preexisting medical condition is one that is present at the screening visit for this study. Such conditions should be recorded on the Medical History eCRF.

Entrectinib—F. Hoffmann-La Roche Ltd 70/Protocol GO40782 (RXDX-101-02), Version 5 A preexisting medical condition should be recorded as an adverse event only if the frequency, severity, or character of the condition worsens during the study. When recording such events on the Adverse Event eCRF, it is important to convey the concept that the preexisting condition has changed by including applicable descriptors (e.g., "worsening headaches"). 9.2.5.9 Lack of Efficacy or Worsening of the Malignancy under Study

Events that are clearly consistent with the expected pattern of progression of the underlying disease should not be recorded as adverse events. These data will be captured as efficacy assessment data only. In most cases, the expected pattern of progression will be reflected as objective radiographic progression according to RECIST criteria. In rare cases, the determination of disease progression will be based predominantly on symptomatic deterioration. However, every effort should be made to document progression through use of objective criteria. If there is any uncertainty as to whether an event is due to disease progression, it should be reported as an adverse event. 9.2.5.10 Hospitalization or Prolonged Hospitalization

Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) or prolonged hospitalization should be documented and reported as a serious adverse event, except as outlined below. The following hospitalization scenarios are not considered to be adverse events: . Hospitalization for respite care or social admissions (e.g., lack of housing, economic inadequacy, family circumstances) . Hospitalization solely for coordination of care, including hospice arrangements . Hospitalization due solely to progression of the underlying cancer . Hospitalization that was necessary solely because of patient requirement for outpatient care outside of normal outpatient clinic operating hours . Planned hospitalization required by the protocol (e.g., for study drug administration or insertion of access device for study drug administration) . Hospitalization for a preexisting condition, provided that the hospitalization was planned prior to the study or was scheduled during the study when elective surgery became necessary because of the expected normal progression of the disease and the patient has not experienced an adverse event 9.2.5.11 Adverse Events Associated with an Overdose or Incorrect Administration of Study Drug

An overdose is the accidental or intentional use of a drug in an amount higher than the dose being studied. An overdose or incorrect administration of study treatment is not itself an adverse event, but it may result in an adverse event. All adverse events associated with an overdose or incorrect administration of study drug should be recorded on the Adverse Event eCRF. If the associated adverse event fulfills serious criteria, the event should be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the event). Entrectinib—F. Hoffmann-La Roche Ltd 71/Protocol GO40782 (RXDX-101-02), Version 5 9.3 Immediate Reporting Requirements from Investigator to Sponsor

Certain events require immediate reporting to allow the Sponsor to take appropriate measures to address potential new risks in a clinical trial. The Investigator must report such events to the Sponsor immediately; under no circumstances should reporting take place more than 24 hours after the Investigator learns of the event. The following is a list of events that the Investigator must report to the Sponsor within 24 hours after learning of the event, regardless of relationship to study drug: . Serious adverse events . Pregnancies . Suspected transmission of an infectious agent by the study treatment, as defined below: Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent. A transmission of an infectious agent may be suspected from clinical symptoms or laboratory findings that indicate an infection in a patient exposed to a medicinal product. This term applies only when a contamination of study treatment is suspected.

The Investigator must report new significant follow-up information for these events to the Sponsor immediately (i.e., no more than 24 hours after becoming aware of the information). New significant information includes the following: . New signs or symptoms or a change in the diagnosis . Significant new diagnostic test results . Change in causality based on new information . Change in the event’s outcome, including recovery . Additional narrative information on the clinical course of the event

Investigators must also comply with local requirements for reporting serious adverse events to the local health authority and IRB/EC.

9.3.1 SAE Reporting

After informed consent has been obtained but prior to initiation of study drug, only serious adverse events related to protocol-mandated procedures should be reported.

After initiation of study drug, serious adverse events will be reported until at least 30 days after the last dose of study drug.

Investigators should record all case details that can be gathered immediately (i.e., within 24 hours after learning of the event) on the SAE report form and submit the report via fax or email (please refer to the Study Reference Manual).

Entrectinib—F. Hoffmann-La Roche Ltd 72/Protocol GO40782 (RXDX-101-02), Version 5 9.3.2 Reporting Requirements for Pregnancies 9.3.2.1 Pregnancies in Female Patients

Female patients or partners of male patients of childbearing potential will be instructed to immediately inform the Investigator if they become pregnant during the study or within 3 months after the last dose of study drug. A Pregnancy report form should be completed by the Investigator no more than 24 hours after learning of the pregnancy and submitted using the same process as for SAEs.

The Investigator should discontinue study drug and counsel the patient or partner of a male patient, discussing the risks of the pregnancy and the possible effects on the fetus. Monitoring should continue until conclusion of the pregnancy. Any serious adverse events associated with the pregnancy (e.g., an event in the fetus, an event in the mother during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be reported and submitted within 24 hours. 9.3.2.2 Congenital Anomalies/Birth Defects and Abortions

Any congenital anomaly/birth defect in a child born to a female patient or partner of a male patient exposed to study drug should be classified as a serious adverse event and reported as such. Any spontaneous abortion or miscarriage should be reported in the same fashion (therapeutic abortions are excluded from expedited reporting and would be captured as pregnancy outcome information).

9.4 Follow-Up of Patients after Adverse Events 9.4.1 Investigator Follow-Up

The Investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the Investigator, the patient is lost to follow-up, or the patient withdraws consent. Every effort should be made to follow all serious adverse events considered to be related to study drug or trial-related procedures until a final outcome can be reported.

During the study period, resolution of adverse events (with dates) should be documented on the Adverse Event eCRF and in the patient’s medical record to facilitate source data verification.

All pregnancies reported during the study should be followed until pregnancy outcome.

9.4.2 Sponsor Follow-Up

For serious adverse events and pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a monitoring visit to obtain additional case details and outcome information (e.g., from hospital discharge summaries, consultant reports, autopsy reports) in order to perform an independent medical assessment of the reported case.

Entrectinib—F. Hoffmann-La Roche Ltd 73/Protocol GO40782 (RXDX-101-02), Version 5 9.5 Post-Study Adverse Events

The Sponsor should be notified if the Investigator becomes aware of any serious adverse event that occurs after the end of the adverse event reporting period (defined as 30 days after the last dose of study drug), if the event is believed to be related to the study drug.

The Investigator should report these events directly to the Sponsor or its designee using the SAE report form.

9.6 Expedited Reporting to Health Authorities, Investigators, Institutional Review Boards, and Ethics Committees

The Sponsor will promptly evaluate all serious adverse events against cumulative product experience to identify and expeditiously communicate possible new safety findings to Investigators, IRBs, ECs, and applicable health authorities based on applicable legislation.

To determine reporting requirements for single adverse event cases, the Sponsor will assess the expectedness of these events using the Investigator's Brochure.

The Sponsor will compare the severity of each event and the cumulative event frequency reported for the study with the severity and frequency reported in the applicable reference document.

Reporting requirements will also be based on the Investigator's assessment of causality and seriousness, with allowance for upgrading by the Sponsor as needed.

Entrectinib—F. Hoffmann-La Roche Ltd 74/Protocol GO40782 (RXDX-101-02), Version 5 10 PATIENT END OF TREATMENT

A patient may be discontinued from study treatment at any time if the patient, the Investigator, or the Sponsor feels that it is not in the patient’s best interest to continue on study. The following is a list of possible reasons for early discontinuation of study treatment: . Disease progression (unless there is reasonable evidence of clinical benefit to justify continuation on treatment – to be discussed with the Sponsor) o Patients should be highly encouraged to remain on study treatment until there is BICR-confirmed radiographic progression . Any adverse event that cannot be adequately managed with dose modifications, including dose interruption > 28 days (unless there is reasonable evidence of clinical benefit to justify continuation on the protocol – to be discussed with the Sponsor) . Protocol violation requiring discontinuation of study treatment . Patient is not compliant with study procedures . Lost to follow-up . Patient withdrawal of consent for further treatment . Sponsor’s early termination of study. Reasons for terminating the study may include, but are not limited to, the following: o All enrolled patients have discontinued study treatment o The incidence or severity of adverse events in this or other studies indicates a potential health hazard to patients o Patient enrollment is unsatisfactory

Data to be collected for the end of treatment visit are described in Section 8.11.

Patients will be followed for at least 30 calendar days after the last dose of study drug. If a patient is withdrawn from treatment due to an adverse event, the patient will be followed until the adverse event has resolved or stabilized as per Section 9.4.

Entrectinib—F. Hoffmann-La Roche Ltd 75/Protocol GO40782 (RXDX-101-02), Version 5 11 PROTOCOL VIOLATIONS

A protocol violation occurs when the patient or Investigator fails to adhere to significant protocol requirements affecting the inclusion, exclusion, patient safety or primary endpoint criteria. Protocol violations for this study include, but are not limited to, the following: . Failure to meet inclusion/exclusion criteria . Dose modifications (e.g., wrong treatment or incorrect dose) that are not within the protocol specifications . Use of a prohibited concomitant medication . Any other deviation that presents significant risk or safety concerns to the patient, e.g., pregnancy on study

Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol violation. The Sponsor, in consultation with the Investigator, will determine if a protocol violation should result in withdrawal of a patient.

When a protocol violation occurs, it will be discussed with the Investigator and appropriate forms detailing the violation will be generated. A copy of the form will be filed in the site’s regulatory binder and in the Sponsor’s files.

12 DATA MONITORING COMMITTEE

An independent third-party Data Monitoring Committee (DMC) will be established to ensure the overall integrity and conduct of the study.

The DMC will review the progress of the study and cumulative safety and efficacy data on a periodic basis (e.g., a minimum of 3 review meetings per year). In addition to the formal meetings, listings of serious adverse events will be provided to the DMC on a monthly basis.

Following each review meeting, the DMC will recommend to the Sponsor whether to continue the trial unchanged, modify the conduct of the study, or terminate the study early. Rules for early termination, modifications and/or continuation of the study, as well as how those recommendations will be made to the Sponsor or Health Authorities will be outlined in a separate DMC Charter.

The DMC will be composed of 3 external members (2 physicians and 1 biostatistician) not associated with the conduct of the study. The Sponsor’s biostatistician and data management team will prepare and provide study data to the DMC. Complete details regarding the composition and governance of the DMC will be outlined in the DMC Charter.

Periodic adverse event data review will also be performed by designated members of the Sponsor’s study team. Any safety issues of concern identified by the study team will be promptly reported to the DMC as described in the DMC Charter. Entrectinib—F. Hoffmann-La Roche Ltd 76/Protocol GO40782 (RXDX-101-02), Version 5 13 STATISTICAL METHODS AND CONSIDERATIONS

A detailed methodology for summary and statistical analyses of the data collected in this study will be documented in a Statistical Analysis Plan (SAP) that will be dated, version- controlled and maintained by the Sponsor.

13.1 Analysis Populations

Unless specifically stated otherwise, each basket cohort of patients will be treated as its own separate patient population with the following definitions: . Natural History Follow-Up Cohort: All gene rearrangement positive patients who were screened and were not enrolled into the study . Safety Analysis Population [SA]: All eligible patients who enroll into a defined basket and have received at least one dose of entrectinib will be the primary population for evaluating patient characteristics, treatment administration, and safety endpoints for each particular basket . Efficacy Analysis Population [EA]: The response-evaluable patient population will be defined as all patients in the SA who had measurable disease at baseline. The EA population will be used for the primary efficacy analyses . CNS Response Population [CRP]: CNS response population will be defined as all patients in the EA who had measurable CNS disease at baseline . Patient Report Outcomes Population [PRO]: All patients in the SA who completed the QLQ-C30 and EQ-5D questionnaires on Cycle 1 Day 1 and answered at least one question on an on-study time point thereafter o For NSCLC or mCRC baskets, the PRO population will include all NSCLC or mCRC patients who also completed the QLQ-LC13 or QLQ- CR29 questionnaires, respectively, on Cycle 1 Day 1 and answered at least one question on an on-study time point thereafter, in addition to the QLQ- C30 and EQ-5D questionnaires as described above . Population Pharmacokinetics Populations [POP-PK]: All patients in the SA who have at least one PK sample collected during the study o Japan PK Sub-Study Population [JPN-PK]: Subset of POP-PK patients who are Japanese patients treated at sites in Japan

13.2 Efficacy Analyses

The primary analysis of efficacy endpoints that are based on radiographic tumor assessments (ORR, DOR, TTR, CBR, intracranial tumor response rate, CNS-PFS, and PFS) will be based on the results of the blinded independent central review (BICR). Investigator assessments will be used for sensitivity analyses, as described in the Statistical Analysis Plan.

Entrectinib—F. Hoffmann-La Roche Ltd 77/Protocol GO40782 (RXDX-101-02), Version 5 13.2.1 Analysis of Primary Endpoint

The primary endpoint for the study is objective response rate (ORR), as assessed by BICR using RECIST v1.1, in each patient population basket of solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement.

ORR will be defined as the proportion of patients with confirmed complete response (CR) or partial response (PR); a confirmed response is a response that persists on repeat- imaging ≥ 4 weeks after initial documentation of response. Such patients with a confirmed objective response (CR or PR) will be referred to as responders. Non- responders will include the following: . Patients without a confirmed objective response . Patients without a post-baseline tumor assessment . Patients who receive at least one dose of entrectinib and who discontinue for any reason prior to undergoing one post-baseline response evaluation ORR will be reported as the proportion of responders along with the corresponding 2- sided 95% Clopper-Pearson exact confidence interval.

13.2.2 Analysis of Secondary Endpoints

13.2.2.1 Duration of Response (DOR)

DOR will be defined from the first date of objective response (either CR or PR) to first documentation of radiographic disease progression, as assessed by RECIST v1.1, or death due to any cause, whichever occurs first. Kaplan-Meier methods will be used to estimate median DOR. DOR will be censored at the last tumor assessment date for patients without disease progression who have not died within 30 days of the last dose of study treatment.

13.2.2.2 Time to Response (TTR)

TTR will be defined as the time from the first dose of entrectinib to the first documentation of objective response (either CR or PR), as assessed by RECIST v1.1.

Kaplan-Meier methods will be used to estimate median TTR.

13.2.2.3 Clinical Benefit Rate (CBR) CBR will be defined as the proportion of patients with CR, PR, or stable disease (SD) at 6 months after the first dose of entrectinib, as assessed by RECIST v1.1.

13.2.2.4 Intracranial Tumor Response Rate For patients who present with measurable CNS disease at baseline, the intracranial tumor response rate (best overall) will be a composite of radiographical CNS target and non- target lesion responses, corticosteroid use, and clinical status, according to RANO in

Entrectinib—F. Hoffmann-La Roche Ltd 78/Protocol GO40782 (RXDX-101-02), Version 5 CNS primary tumors or RECIST v1.1 and RANO-BM for CNS metastases, as applicable (Wen et al, 2010, Lin et al, 2015).

13.2.2.5 CNS Progression-Free Survival CNS progression-free survival (CNS-PFS) will be defined as the time from the first dose of entrectinib to first evidence of radiographic CNS disease progression according to RANO or RANO-BM, as applicable, or death due to any cause (whichever occurs first). Censoring rules will apply as per below.

13.2.2.6 Progression-Free Survival

Progression-free survival (PFS) will be defined as the time from the first dose of entrectinib to first documentation of radiographic disease progression or death due to any cause (whichever occurs first).

PFS data for patients without progression or death will be censored on the date of the last tumor assessment (or, if no tumor assessment was performed after the baseline visit, at the date of first dose of study drug). Additional censoring rules will vary according to whether the analysis is performed for US or ex-US regulatory purposes, as shown below; both results will be provided in the clinical study report. ex-US regulatory guidance Scenario US regulatory guidance (EMA/CHMP) Data from patients who are Censored on the date of the Time of progression will be lost to follow-up or whose last tumor assessment that determined using the first disease progression or death the patient was known to be date when there is occurs after 2 or more progression-free documented evidence of consecutively missing or progression or death unevaluable tumor (whichever occurs earlier) assessments regardless of missed or unevaluable tumor assessments

Patients that receive new Censored on the date of the Time of progression will be systemic anticancer therapy last tumor assessment prior determined using the first prior to documented disease to the start of the new date when there is progression or death systemic anticancer therapy documented evidence of progression or death (whichever occurs earlier) regardless of change of therapy

Kaplan-Meier methods will be used to estimate median PFS. As an additional analysis, the 1-year progression-free survival rate will also be estimated.

Entrectinib—F. Hoffmann-La Roche Ltd 79/Protocol GO40782 (RXDX-101-02), Version 5 13.2.2.7 Overall Survival (OS)

Overall survival (OS) will be defined as the time from the first dose of entrectinib to the date of death due to any cause. Patients who are alive at the time of the analysis will be censored on the last known date that they were alive. In addition, the following censoring rules will apply: Scenario Date of Censoring Patients with no post-baseline Censored on the date of the first dose information Patients who are lost to follow-up or Censored on the last known date that they who withdraw consent for further were alive follow-up Sensitivity Analysis: Patients that Censored on the day before the start date of receive new systemic anticancer the new systemic anticancer therapy therapy

Kaplan-Meier methods will be used to estimate median OS. As an additional analysis, the 1-year survival rate will also be estimated.

13.2.3 Statistical Design and Sample Size Justification

13.2.3.1 All baskets evaluable for the primary endpoint (excluding ROS1 fusion- positive, ROS1 inhibitor-naïve NSCLC) In these baskets, for any particular tumor type and gene rearrangement combination, patients will be enrolled under a 2-stage sequential testing design to determine whether entrectinib has sufficient anticancer activity to warrant further development of that specific patient population.

For each basket, a true response rate of 20% or less is considered insufficient to warrant further study, whereas a true response rate of 40% or more is considered worthy of further study. The number of patients evaluated in each stage and the minimum number of responders needed to meet the primary endpoint were determined based on a sequential testing technique with at least 80% power and 1-sided α = 0.025.

Based on the above design considerations, the first stage will enroll up to 13 patients per basket. Patients are enrolled sequentially and the stage is deemed successful on the 4th responder. If the first stage is not successful, then enrollment in that basket will be terminated.

Otherwise, up to an additional 49 patients will be enrolled into the second stage.

. If within a particular basket, the 14th responder is observed prior to the enrollment of the 49th response-evaluable patient in stage 2, the basket will be deemed as having met the primary endpoint (ruling out an objective response rate of 20%).

Entrectinib—F. Hoffmann-La Roche Ltd 80/Protocol GO40782 (RXDX-101-02), Version 5 . In contrast, the basket will be deemed as not meeting the primary endpoint if the full complement of 49 response-evaluable patients have been enrolled in stage 2 and 14 responders have not been observed at 13 weeks post the date of Cycle 1 Day 1 for the 49th response evaluable patient. . Under these conditions, if the true response rate is 20%, the probability of stopping enrollment during the first stage is 75%. Conversely, if the true response rate is 40%, then the probability that enrollment will be terminated during the first stage is equal to 17%. Further details can be found in the Statistical Analysis Plan.

The choice of a statistically significant observed response rate of > 20% for locally advanced or metastatic solid tumor gene rearrangement baskets is based upon a review of the literature of expected response rates to standard, non-targeted therapies in these diseases. For example:

NSCLC: In 2 randomized studies of docetaxel in patients previously treated with platinum-based chemotherapy, response rates ranged from 5.5 to 5.7% (Taxotere® product label). A separate meta-analysis of ten randomized trials that included NSCLC patients who were either EGFR mutation-positive or EGFR mutation-negative demonstrated a response rate of approximately 20% in the 1,920 patients treated with non-targeted, second line chemotherapy (Li et al., 2014). A more recent patient-level analysis of 14 trials, all randomized with active control, totaling 12,567 patients with advanced NSCLC receiving 1L or 2L+ treatment, reported ORRs ranging from 7 to 29% for the active control arm with the 2L+ studies all showing ORRs ≤ 20% (Blumenthal et al., 2015). Additionally, in a randomized, second-line chemotherapy study of crizotinib compared to conventional second-line chemotherapy (docetaxel or pemetrexed) in ALK- rearranged NSCLC patients, a response rate of 20% was seen with conventional second- line chemotherapy (Shaw et al., 2013).

Metastatic CRC: A large multicenter randomized trial of anti-VEGF therapy in combination with FOLFOX in 829 patients with mCRC for progression after 1L irinotecan and 5-FU demonstrated an 8.6% ORR in the chemotherapy-only arm. In a more recent randomized study of anti-VEGF therapy in combination with FOLFIRI for progression after first-line FOLFOX, the standard FOLFIRI regimen showed a response rate of 11.1% (Van Cutsem et al., 2012). In two large randomized trials of anti-EGFR therapy with FOLFIRI for progression after first-line FOLFOX showed response rates of 4.2% and 10%, respectively, in the FOLFIRI only arms (Sobrero et al., 2008 and Peeters et al., 2010).

13.2.3.2 ROS1 fusion-positive, ROS1 inhibitor-naïve NSCLC basket For this basket, the primary objective will be assessed in 2 parts. In Part A, the statistical methods will continue to follow the 2-stage sequential testing design described above for all the other evaluable baskets, with up to 62 patients enrolled. In Part B, with 90 additional patients treated at the RP2D, there is at least 80% power to rule out a BICR-assessed ORR of ≤50% (null) when the true ORR is at least 65% at a 1-

Entrectinib—F. Hoffmann-La Roche Ltd 81/Protocol GO40782 (RXDX-101-02), Version 5 sided α = 0.025. The choice of a statistically significant observed response rate of >50% for this population is based on review of the literature of expected response rate to available targeted therapy, i.e., crizotinib [Shaw et al, 2014]. In addition, a pooled analysis of safety and efficacy of Parts A and B will be performed: it is expected that approximately 150 ROS1 fusion-positive, ROS1 inhibitor-naïve NSCLC patients will be treated with entrectinib at the RP2D. With this sample size, the study has >90% power to rule out an ORR ≤ 50% at a 1-sided α = 0.025 when the true ORR is at least 65%.

13.2.3.3 “Non-evaluable for the primary endpoint” basket This basket is considered exploratory and will consist of all patients who are not assessable for the primary endpoint. They will mainly contribute to assessment of safety, PK, and other secondary endpoints. Examples of such patients include, but are not limited to those with ECOG performance status > 2, dual primary cancers where one cancer’s mutation status is unknown, or dual oncogenic drivers, e.g., ALK fusion and EGFR mutation. In addition, patients with extracranial solid tumors without RECIST v1.1-defined measurable disease will also be allowed to enroll in this basket.

13.2.3.4 Planned secondary analyses

The following secondary analyses will be performed. Details on the statistical methods can be found in the Statistical Analysis Plan. Planned Pooled Analyses: . All gene rearrangements: analysis of safety and efficacy after pooling of patients across tumor types that harbor the same gene rearrangement (e.g., pool all patients with ROS1 gene rearrangements, regardless of tumor type) . ROS1 fusion-positive, ROS1 inhibitor-naïve NSCLC: analysis of safety and efficacy after pooling of patients across Part A and Part B. Heterogeneity of objective response rates in Part A and Part B will be evaluated with Fisher’s Exact Test prior to performing the pooled analysis . All patients presenting with measurable CNS disease at baseline: analysis of intracranial tumor response rate and CNS-PFS after pooling across all baskets, regardless of tumor type Planned Subset Analyses: . NTRK1/2/3 baskets: analysis of safety and efficacy by specific NTRK gene (NTRK1 vs. NTRK2 vs. NTRK3) . All gene rearrangements: analysis of safety and efficacy by specific fusion partner variants Planned Sensitivity Analyses: . For all baskets, analysis of safety and efficacy in patients who are treatment-naïve (i.e., no prior systemic therapy) vs. previously treated

Entrectinib—F. Hoffmann-La Roche Ltd 82/Protocol GO40782 (RXDX-101-02), Version 5 . For all baskets, analyses of the primary and secondary efficacy endpoints in patients enrolled based upon local vs. central molecular testing results . For all baskets, analyses of the primary and secondary efficacy endpoints including only patients who have BICR-confirmed measurable disease at baseline and have received at least one dose of entrectinib . For all baskets, analysis of concordance between BICR and Investigator-assessed primary and secondary efficacy endpoints . For all baskets, analysis of overall survival in patients that started a new systemic anticancer therapy

13.3 Safety Analyses 13.3.1 Adverse Events

Adverse events will be graded according to the NCI CTCAE v4.0 and coded to preferred term and system organ class (SOC) using the most recent version of MedDRA.

All AEs reported during the AE reporting period (inclusive of the 30-day post last dose of study drug period) will be considered as treatment-emergent adverse events.

For each patient population basket, incidence rates will be summarized with frequency and percentage by MedDRA SOC and preferred term, with all patients treated in that particular basket as the denominator, unless otherwise specified. In addition, AE incidence rates will also be summarized by severity and relationship to study drug. Treatment-related AEs are those judged by the Investigator to be at least possibly related to the study drug. Patients with multiple occurrences of events will only be counted once at the maximum severity to study drug for each preferred team, SOC, and overall. Deaths that occur within 30 days after the last dose of study drug are defined as on-study deaths.

Summary tables and individual patient listings will be prepared as per the Statistical Analysis Plan.

13.3.2 Clinical Laboratory Results

Normal ranges will be used to identify values that are outside the normal ranges and abnormal laboratory results will be graded according to the NCI CTCAE v4.0. Descriptive statistics will be provided for each test result and for the change from baseline by visit.

A shift summary of baseline grade by maximum post-baseline CTCAE grade will be presented, as appropriate. For each laboratory parameter, the baseline laboratory value will be defined as the last laboratory value collected on or prior to the date of the first dose of study drug.

Patients who develop toxicities of Grade ≥ 3 will be summarized. Laboratory test results not having CTCAE grade will also be summarized. Parameters that have criteria

Entrectinib—F. Hoffmann-La Roche Ltd 83/Protocol GO40782 (RXDX-101-02), Version 5 available for both low and high values (e.g., hypercalcaemia versus hypocalcaemia) will be summarized for both criteria. Patients will only be counted once for each criterion.

13.3.3 Vital Signs

Each vital sign (temperature, blood pressure (systolic and diastolic), respiration rate, and heart rate) will be summarized and presented by study visit. Patients with clinically significant abnormalities as compared to baseline will be listed.

13.3.4 Concomitant Medications/Treatments

All medications and/or treatments received during the protocol treatment period will be considered as concomitant medications and/or concomitant treatments and will be coded by WHO medical dictionary; patients who received concomitant medications and/or treatments will be listed.

13.3.5 Ventricular Repolarization

For the US and Japan, all analyses to be performed centrally.

For the rest of the world (ROW), analyses will be based on local reads entered in the eCRF.

Standard ECG intervals RR and QT will be determined for each ECG recording. Corrected QT intervals (QTc) will be determined using Fridericia's formula. Changes in ECG intervals from baseline will be calculated (for triplicate ECGs, baseline is defined as the mean of the triplicate measurements collected during Screening).

Tables to be prepared include analysis of time-matched mean differences between baseline and post-dose assessments, and analysis of maximum change from baseline for each patient.

In addition, patient’s QTc (Fridericia) will be categorized based on ICH E14 guidance. Tables will present the number and percentage of patients meeting or exceeding the following categories: QTc interval prolongation . Absolute values > 450 to ≤ 480 msec . Absolute values > 480 to ≤ 500 msec . Absolute values > 500 msec QTc interval change from baseline . Increase from baseline > 30 to ≤ 60 msec . Increase from baseline > 60 msec

Entrectinib—F. Hoffmann-La Roche Ltd 84/Protocol GO40782 (RXDX-101-02), Version 5 13.4 Population Pharmacokinetic (Pop PK)

Population PK analysis will utilize patient covariates to identify sub-populations where possible. The relationship of exposure to entrectinib (and its potential metabolites) to measures of efficacy and adverse events will be modeled to the greatest extent possible.

Descriptive statistics, including mean and median values will be summarized. Concentrations below the lower limit of quantification of the assay will be excluded or assigned a numeric value based on the lower reporting limit of the assay. Plasma levels of entrectinib (and its potential metabolites) will be listed by patient and summarized descriptively (mean, standard deviation, percent coefficient of variation, minimum, maximum). Individual and mean concentration versus time plots will be presented on both linear and logarithmic scales where possible. Non-compartmental, compartmental, and population analysis methods will be utilized, as applicable.

Samples may also be used for metabolite identification, but the results of such analyses will be used for exploratory purposes and will not be included in the clinical study report. Selected samples may also be analyzed for concentrations of concurrent medications, and these data may be used to assess drug-drug interactions.

13.4.1 Japan PK Sub-Study

Entrectinib (and its potential metabolites) concentrations will be measured using a validated LC-MS/MS method; pharmacokinetic parameters will be calculated for each patient using non-compartmental methods.

Plasma samples that are left over after the main analyses may be used for qualitative metabolite identification.

13.5 Patient Reported Outcomes (PROs)

On a monthly basis, patients will be complete the following self-administered quality of life (QOL) instruments:

Instrument Definition QLQ-C301 Core Quality of Life Questionnaire: (Appendix 5) . Comprises 30 questions assessing global QOL, functioning, and symptoms of both multi-item and single-item measures . Developed to assess the quality of life of cancer patients (Aaronson et al., 1998) . Has been translated and validated into 81 languages and is used in more than 3,000 studies worldwide (http://groups.eortc.be/qol/eortc-qlq-c30) QLQ-LC131 Lung Cancer Module (NSCLC patients only) (Appendix 6) . Comprises 13 questions assessing lung cancer-specific symptoms (Bergman et al., 1994) QLQ-CR291 Colorectal cancer module (mCRC patients only)

Entrectinib—F. Hoffmann-La Roche Ltd 85/Protocol GO40782 (RXDX-101-02), Version 5 Instrument Definition (Appendix 7) . Comprises 29 questions assessing colorectal cancer-specific symptoms (Gujral et al., 2007) Euro-QoL Generic, non-cancer specific tool to assess general health status Group EQ-5D (http://www.euroqol.org/about-eq-5d.html), consisting of a (Appendix 8) descriptive system used to calculate the following: . A health utility index score . A visual analog scale (EQ-5D VAS) 1 Developed by European Organization for Research and Treatment of Cancer (EORTC)

13.5.1 PRO Endpoints All QOL instrument will be reported on a 0 to 100 scale. Raw scores for the EQ-5D Utility Index Score and EQ-5D visual analogue scores are reported from 0 (worst imaginable health) to 100 (best imaginable health). For the QLQ-C30, QLQ-13, and QLQ-29, respectively, each domain and item will be linear-transformed to standardize the raw score to a range from 0 to 100, with 100 representing the best possible function/QOL and highest symptom severity. The following analysis variables will be summarized for all QOL instruments, domains, and single items: . Mean change from baseline, by cycle and across cycle . Proportion of patients with improved, stable, and worsened outcomes, by cycle and across cycle

A 10-point change from baseline in an item or domain is established to be clinically meaningful (Osoba et al., 1998). Hence, for functioning domains and global QOL, a patient will be deemed: . Improved, if the change from baseline is a 10-points or greater increase . Worsened, if the change from baseline is 10-point or greater decrement . Stable otherwise

For analysis of symptom domains and single items, the opposite is true: . Improved, if the change from baseline is a 10-points or greater decrement . Worsened, if the change from baseline is 10-point or greater increase . Stable otherwise

13.5.2 PRO Analyses

For each patient population basket and using the PRO-evaluable population, the number and percentage of patients of the total number eligible at each cycle who completed each questionnaire will be summarized per time point. The questionnaire domains and items will be scored according to each questionnaire’s respective scoring algorithm. Analyses will include the mean change from baseline scores across cycles and the proportion of patients with improved, stable, or worsened outcomes.

Entrectinib—F. Hoffmann-La Roche Ltd 86/Protocol GO40782 (RXDX-101-02), Version 5 13.5.2.1 Change from Baseline Scores

Descriptive statistics (including 95% confidence intervals) of raw and change from baseline scores will be performed by cycle and across cycle for the QLQ- C30/LC13/CR29 items and domain, EQ-5D index, and EQ-5D VAS. In addition, results will be depicted graphically.

13.5.2.2 Proportion of Patients Improved, Remained Stable, or Worsened

The proportion of patients who improved, remained stable, or worsened will be reported by cycle and across cycle.

14 DATA COLLECTION, RETENTION AND MONITORING

14.1 Data Collection Instruments

The Investigator will prepare and maintain adequate and accurate source documents designed to record all observations and other pertinent data for each patient treated with the study drug.

Study personnel at each site will enter data from source documents corresponding to a patient’s visit into the protocol-specific electronic Case Report Form (eCRF) when the information corresponding to that visit is available. Patients will not be identified by name in the study database or on any study documents to be collected by the Sponsor (or designee), but will be identified by a site number, patient number and initials, as per local regulations.

If a correction is required for an eCRF, the time and date stamps track the person entering or updating eCRF data and creates an electronic audit trail.

The Investigator is responsible for reviewing all information collected on patients enrolled in this study for completeness and accuracy. A copy of the eCRF will remain at the Investigator’s site at the completion of the study.

14.2 Data Management Procedures

The data will be entered into a validated database. The Sponsor or designee-designated data management group will be responsible for data processing, in accordance with procedural documentation. Database lock will occur once quality assurance procedures have been completed.

All procedures for the handling and analysis of data will be conducted using good computing practices meeting FDA guidelines for the handling and analysis of data for clinical trials.

14.3 Data Quality Control and Reporting

After data have been entered into the study database, a system of computerized data validation checks will be implemented and applied to the database on a regular basis. Entrectinib—F. Hoffmann-La Roche Ltd 87/Protocol GO40782 (RXDX-101-02), Version 5 Queries are entered, tracked, and resolved through the EDC system directly. The study database will be updated in accordance with the resolved queries. All changes to the study database will be documented.

14.4 Data Archival

The database is safeguarded against unauthorized access by established security procedures; appropriate backup copies of the database and related software files will be maintained. Databases are backed up by the database administrator in conjunction with any updates or changes to the database.

At critical junctures of the protocol (e.g., production of interim and final reports), data for analysis is locked and cleaned per established procedures.

14.5 Availability and Retention of Investigational Records

To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator agrees to keep records, including the identity of all participating patients (sufficient information to link records, e.g., eCRFs and hospital records), all original signed informed consent forms, copies of all eCRFs, safety reporting forms, source documents, and detailed records of treatment disposition, and adequate documentation of relevant correspondence (e.g., letters, meeting minutes, telephone calls reports). The records should be retained by the Investigator according to ICH, local regulations, or as specified in the Clinical Trial Agreement, whichever is longer; but at a minimum, all study documentation must be retained for 2 years after the last marketing application approval in an ICH region or after at least 2 years have elapsed since formal discontinuation of clinical development of entrectinib.

If the Investigator becomes unable for any reason to continue to retain study records for the required period (e.g., retirement, relocation), then the Sponsor should be prospectively notified. The study records must be transferred to a designee acceptable to the Sponsor, such as another Investigator, another institution, or to the Sponsor itself. The Investigator must obtain the Sponsor’s written permission before disposing of any records, even if retention requirements have been met.

14.6 Monitoring

Monitoring visits will be conducted by authorized representatives of the Sponsor according to the U.S. CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6), as well as any applicable local, regional, and country laws. By signing this protocol, the Investigator grants permission to the Sponsor (or designee), the U.S. FDA, other regulatory agencies, IRB/ECs, and respective national or local health authorities to conduct on-site monitoring and/or auditing of all appropriate study documentation.

14.7 Patient Confidentiality

In order to maintain patient confidentiality, only a site number, patient number and/or patient initials will identify all study patients on eCRFs and other documentation

Entrectinib—F. Hoffmann-La Roche Ltd 88/Protocol GO40782 (RXDX-101-02), Version 5 submitted to the Sponsor. Additional patient confidentiality issues (if applicable) are covered in the Clinical Trial Agreement.

15 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS

This study will be conducted in accordance with the U.S. Food and Drug Administration (FDA) regulations, the International Conference on Harmonisation (ICH) E6 Guideline for Good Clinical Practice (GCP), and applicable local, state, and federal laws, as well as other applicable country laws.

To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records will be identified by a coded number and initials only. All study records will be kept in a locked file cabinet and code sheets linking a patient’s name to a patient identification number will be stored separately in another locked file cabinet. Clinical information will not be released without written permission of the patient, except as necessary for inspection by the FDA or other regulatory agencies, IRB/ECs and respective national or local health authorities. The Investigator must also comply with all applicable privacy regulations (e.g., Health Insurance Portability and Accountability Act of 1996).

15.1 Protocol Amendments

Any amendment to the protocol will be written by the Sponsor. Protocol amendments cannot be implemented without prior written IRB/EC approval except as necessary to eliminate immediate safety hazards to patients. A protocol amendment intended to eliminate an apparent immediate hazard to patients may be implemented immediately, provided the IRB/ECs are notified within five working days.

15.2 Institutional Review Boards/Ethics Committees

The protocol, Investigator’s Brochure, the consent forms, any information to be given to the patient (including patient recruitment materials) and relevant supporting information must be submitted to the IRB/EC by the Investigator for review and approval before the study is initiated. The IRB/EC’s unconditional approval statement will be transmitted by the Investigator to the Sponsor or designee prior to the shipment of study supplies to the site. This approval must refer to the study by exact protocol title and number and should identify the documents reviewed and the date of review.

Protocol and/or informed consent modifications or changes may not be initiated without prior written IRB/EC approval except when necessary to eliminate immediate hazards to the patients or when the change(s) involves only logistical or administrative aspects of the study. Such modifications will be submitted to the IRB/EC and written verification that the modification was submitted and subsequently approved should be obtained.

Investigators are required to promptly report to their respective IRB/EC all unanticipated problems involving risk to human patients. Some IRB/ECs may want prompt notification of all SAEs, whereas others require notification only about events that are serious, assessed to be related to study treatment, and are unexpected. Investigators may receive

Entrectinib—F. Hoffmann-La Roche Ltd 89/Protocol GO40782 (RXDX-101-02), Version 5 written IND safety reports or other safety-related communications from the Sponsor. Investigators are responsible for ensuring that such reports are reviewed and processed in accordance with regulatory requirements and with the policies and procedures established by their IRB/EC and archived in the site’s Study File.

Finally, the Investigator will keep the IRB/EC informed as to the progress of the study, revisions to documents originally submitted for review, annual updates and/or request for re-approvals, and when the study has been completed.

15.2.1 Informed Consent Forms

Informed consent will be obtained in accordance with ICH GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a, b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, if applicable), and local regulations. Either the local institution’s or Roche’s molecular testing consent form can be used to perform molecular testing in order to determine enrollment eligibility. For all patients, the Sponsor’s clinical trial informed consent model form will be used to customize the local clinical informed consent form. Sponsor or its designee must review and approve any proposed deviations from the sample ICFs or any alternate consent forms proposed by the site before IRB/EC submission. Patients must be re-consented to the most current version of the consent forms during their participation in the study. The final IRB/EC-approved consent forms must be provided to Sponsor for regulatory purposes.

The consent forms must be signed by the patient or the patient’s legal representative before his/her participation in the study. The case history for each patient shall document the informed consent process and that written informed consent was obtained prior to participation in the study. A copy of each signed consent form must be provided to the patient or the patient’s legal representative. If applicable, it will be provided in a certified translation of the local language.

All signed and dated clinical trial consent forms must remain in each patient’s study file and must be available for verification by study monitors at any time.

The clinical trial consent form should be revised whenever there are changes to procedures outlined in the informed consent or when new information becomes available that may affect the willingness of the patient to participate.

For any updated or revised consent forms, the case history for each patient shall document the informed consent process and that written informed consent was obtained for the updated/revised consent form for continued participation in the study. The final revised IRB/EC-approved informed consent form must be provided to Sponsor for regulatory purposes.

Entrectinib—F. Hoffmann-La Roche Ltd 90/Protocol GO40782 (RXDX-101-02), Version 5 15.3 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP

In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable Competent Authority in any area of the World, or if the Investigator is aware of any new information which might influence the evaluation of the benefits and risks of the investigational product, the Sponsor should be informed immediately.

In addition, the Investigator will inform the Sponsor immediately of any urgent safety measures taken by the Investigator to protect the study patients against any immediate hazard, and of any serious breaches of this protocol or of ICH GCP that the Investigator becomes aware of.

15.4 End of Trial in All Participating Countries Patients will remain on study treatment until BICR-confirmed radiographic disease progression, development of unacceptable toxicity, or withdrawal of consent. Patients discontinuing study treatment will enter the survival follow-up period and remain on study until death, loss of follow-up, or withdrawal of consent, whichever comes first. If the study is not terminated beforehand per the recommendation of the DMC, the end of trial in all participating countries will be defined as the time at which the secondary endpoint of OS has been met. At that time, the protocol may be amended to minimize the number of protocol assessments to only collection of safety data for those patients remaining on study.

15.5 Sponsor Discontinuation Criteria

Premature termination of this study may occur because of a regulatory authority decision, change in opinion of the IRB/EC, drug safety problems, or at the discretion of the Sponsor. In addition, the Sponsor retains the right to discontinue development of entrectinib at any time. . If a study is prematurely terminated or discontinued, then the Sponsor will promptly notify the Investigator. After notification, the Investigator must notify the respective IRB/EC, and contact all participating patients and the hospital pharmacy (if applicable) within a 4-week time period. As directed by the Sponsor, all study materials must be collected and all eCRFs completed to the greatest extent possible.

15.6 Publications

Publication of study results is discussed in the Clinical Trial Agreement. Details regarding production of manuscripts and conference presentations will adhere to the International Committee of Medical Journal Editors (ICMJE) requirements for authorship and contributorship.

http://www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-the- role-of-authors-and-contributors.html

Entrectinib—F. Hoffmann-La Roche Ltd 91/Protocol GO40782 (RXDX-101-02), Version 5 16 REFERENCES

Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365-76.

Aisner DL, Nguyen TT, Paskulin DD, et al. ROS1 and ALK Fusions in colorectal cancer, with evidence of intratumoral heterogeneity for molecular drivers. Mol Cancer Res 2014;12:111-8.

Benson AB. Epidemiology, disease progression, and economic burden of colorectal cancer. J Manag Care Pharm 2007;13:S5-18.

Bergman B, Aaronson NK, Ahmedzai S, et al. The EORTC QLQ-LC13: a modular supplement to the EORTC Core Quality of Life Questionnaire (QLQC30) for use in lung cancer clinical trials. EORTC Study Group on Quality of Life. Eur J Cancer 1994;30A:635-42.

Binefa G, Rodríguez-Moranta F, Teule A, et al. Colorectal cancer: from prevention to personalized medicine. World J Gastroenterol 2014;20:6786-6808.

Blumenthal GM, Karuri SW, Zhang H, et al. Overall response rate, progression-free survival, and overall survival with targeted and standard therapies in advanced non-small- cell lung cancer: US Food and Drug Administration trial-level and patient-level analyses. J Clin Oncol 2015;33:1008-14.

Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337-45.

Davidson MR, Gazdar AF, Clarke BE. The pivotal role of pathology in the management of lung cancer. J Thorac Dis 2013;5:S463-78.

De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy- refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncology 2010;11:753-62

Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.

EMA/CHMP Appendix 1 to the guideline on the evaluation of anticancer medicinal products in man: methodological consideration for using progression-free survival (PFS) or disease-free survival (DFS) in confirmatory trials. European Medicines Agency 2011; Doc. Ref. EMA/CHMP/27994/2008.

Entrectinib—F. Hoffmann-La Roche Ltd 92/Protocol GO40782 (RXDX-101-02), Version 5 Gainor JF, Sherman CA, Willoughby K, et al. Alectinib salvages CNS relapses in ALK- positive lung cancer patients previously treated with crizotinib and ceritinib. J Thorac Oncol. 2015;10:232-6.

Gerber DE, Gandhi L, Costa DB. Management and future directions in non-small cell lung cancer with known activating mutations. 2014 ASCO education book: e353-65.

Gujral S, Conroy T, Fleissner C, et al. Assessing quality of life in patients with colorectal cancer: an update of the EORTC quality of life questionnaire. Eur J Cancer 2007;43:1564-73.

Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359:1757-65.

Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non- small-cell lung cancer. N Engl J Med 2010;363:1693-1703.

Li N, Yang L, Ou W, et al. Meta-analysis of EGFR tyrosine kinase inhibitors compared with chemotherapy as second-line treatment in pretreated advanced non-small cell lung cancer. PLoS ONE 2014;9(7):e102777. doi:10.1371/journal.pone.0102777.

Lin E, Li L, Guan Y, et al. Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non small cell lung cancers. Mol Cancer Res 2009;7:1466-76.

Lin NU, Lee EQ, Aoyama H, et al. Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncology 2015;16:e270-8.

Lipson D, Capelletti M, Yelensky R, et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med 2012;18:382-4.

Markowitz SD and Bertagnolli MM. Molecular basis of colorectal cancer. N Engl J Med 2009;361:2449-60.

Mok TS, Wu YL, Thongprasert S, et al. Gefıtinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57. Murphy DA, Ely HA, Shoemaker R, et al. Detecting gene rearrangements in patient populations through a 2-step diagnostic test comprised of rapid IHC enrichment followed by sensitive Next-Generation Sequencing. Appl Immunohistochem Mol Morphol 2016;Mar 29 [epub ahead of print].

Osoba D, Rodrigues G, Myles J, et al. Interpreting the significant changes in health- related quality-of-life scores. J Clin Oncol 1998;16:139-144.

Ou SI, Ahn JS, De Petris L, et al. Alectinib in crizotinib-refractory ALK-rearranged non- small-cell lung cancer: a phase II global study. J Clin Oncol 2015;34:661-8.

Pao W and Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncology 2011;12:175-80.

Entrectinib—F. Hoffmann-La Roche Ltd 93/Protocol GO40782 (RXDX-101-02), Version 5 Peeter M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 2010;28:4706-13.

Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first- line treatment for European patients with advanced EGFR mutation-positive non-small- cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncology 2012;13:239-46.

Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014;370:1189-97.

Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368:2385-94.

Shaw AT, Ou SI, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 2014;371:1963-71.

Siena S, Drilon AE, Ou SI, et al. Entrectinib (RXDX-101), an oral pan-Trk, ROS1, and ALK inhibitor in patients with advanced solid tumors harboring gene rearrangements. European Cancer Congress 2015, Vienna, Austria.

Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10:1-10.

Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:2311-9.

Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448:561-6.

Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med 2012;18:378-81.

The EuroQol Group. EQ-5D-3L: A Measure of Health-Related Quality of Life Developed by the EuroQol Group: User Guide. Version 4.0, April 2011. Rotterdam: The EuroQol Group, 2011.

Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. Ca Cancer J Clin 2015;65:87-108.

Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov 2015;5:25-34.

Entrectinib—F. Hoffmann-La Roche Ltd 94/Protocol GO40782 (RXDX-101-02), Version 5 Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012;30:3499-506.

Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 2010;28:1963-72.

Entrectinib—F. Hoffmann-La Roche Ltd 95/Protocol GO40782 (RXDX-101-02), Version 5 17 APPENDICES APPENDIX 1 SCHEDULE OF ASSESSMENTS ...... 97 APPENDIX 2 ECOG PERFORMANCE STATUS...... 101 APPENDIX 3 NATIONAL CANCER INSTITUTE (NCI) COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE)...... 102 APPENDIX 4 REQUIRED LABORATORY TESTS...... 103 APPENDIX 5 EORTC QLQ-C30 ...... 104 APPENDIX 6 EORTC QLQ-LC13...... 106 APPENDIX 7 EORTC QLQ-CR29 ...... 107 APPENDIX 8 EQ-5D...... 109

Entrectinib—F. Hoffmann-La Roche Ltd 96/Protocol GO40782 (RXDX-101-02), Version 5 APPENDIX 1 SCHEDULE OF ASSESSMENTS

Cycles 2-3 Cycles 4+ >1 Year of End of Safety Survival Screening e Cycle 1 (+/- 2d) (+/- 2d) Treatment f Treatment c Follow-Up d Follow-Up ~7 days ~30 days ~ Every Treatment Day -30 to -1 1 a 15 1 15 b 1 1 after last dose after last dose 3 months Baseline Assessments Molecular testing informed consent 1 No time limit Tumor biopsy 2 (X) (X) Clinical trial informed consent 3 X Eligibility assessment 3 X Physical examination 4 X (X)XX (X) X X (X) (X) Eye exam 5 X C2 (X) Serum pregnancy test 6 X X X X X (X) Laboratory Studies US: Triplicate ECGs 7 XX X X X (X) JPN: Triplicate ECGs 8 XX X X X (X) ROW: Single ECG 9 XX X X X (X) Clinical laboratory assessments 10 X (X)XX (X) X X (X) (X) Coagulation and lipid panel 10 X PK samples 11 X X X X (X) a. JPN: PK Sub-Study 12 X X X X (X) PD samples 13 X X X X (X) Tumor Markers 14 X (X) X X X (X) Imaging Assessments (+/- 7 days) 15 CT/MRI brain X (C2) (q8w) (q8w) (X) (q8w) CT/MRI chest, abdomen, (pelvis) X C2 q8w q8w (X) (q8w) Bone scan (X) (C2) (q8w) (q8w) (X) (q8w) Other Clinical Assessments ECOG, body weight, and vital signs 16 X (X)XX (X) X X (X) (X) Adverse events and conmeds 17 XXXX (X) X X (X) X Entrectinib compliance assessment XX (X) X X (X) Entrectinib dispensing and dosing 18 X X X X Post-study survival status 19 X Patient Reported Outcomes Quality of life questionnaires 20 X X X X (X)

Entrectinib—F. Hoffmann-La Roche Ltd 101/Protocol GO40782 (RXDX-101-02), Version 5 APPENDIX 1 SCHEDULE OF ASSESSMENTS (CONT.)

Footnotes (X) = optional or as applicable

1. Molecular Testing Informed Consent: Pre-study participation consent to detect NTRK1/2/3, ROS1, or ALK gene rearrangements (test performed at Foundation Medicine, Inc.), Cambridge, MA, USA, or alternatively, local testing using any nucleic acid-based diagnostic testing method that relies on direct assessment of gene rearrangements and is performed at a CLIA-certified or equivalently-accredited diagnostic laboratory will be accepted) in order to determine eligibility to proceed to the clinical trial consent process. Local or central determination of gene rearrangements to determine eligibility can be performed in advance with no time limit, and molecular testing does not trigger the Screening window. For patients enrolled via local molecular testing, submission of patient tumor sample (archival or fresh tissue and preferably from the same block, unless medically contraindicated) is required for independent central molecular testing at Foundation Medicine.

2. Tumor Biopsy: Fresh biopsies may be performed during Screening for patients who enrolled via local molecular testing but do not have enough leftover tumor tissue to submit to Foundation Medicine. Also, if clinically feasible and patient has consented to the biopsy, additional tissue at the time of progression will be collected to gain insights into potential mechanisms of resistance.

3. Clinical Trial Informed Consent and Eligibility Assessment: Following central determination of an NTRK1/2/3, ROS1, or ALK gene rearrangement, patients can proceed to consent to the main study and perform Screening assessments, including a thorough review of their prior medical and oncologic history.

4. Physical Examination: During Screening, a complete physical examination of major body systems, including known and suspected sites of disease, should be performed. During subsequent visits, abbreviated physical exams will be sufficient.

5. Eye exam: Ophthalmologic exams including at least the visual acuity and slit-lamp tests (which may be performed by an optometrist) will be required at Screening, Cycle 2 Day 1, at the End of Treatment, and as clinically indicated.

6. Serum Pregnancy Test: To be performed in all female patients of child-bearing potential during Screening, Day 1 of every cycle, at the End of Treatment, and as clinically indicated.

7. ECG (US): Three consecutive 12-lead ECGs performed approximately 2 minutes apart will be collected during Screening, on Days 1 of Cycles 1-3 pre-dose and 4 hours (+/- 15 minutes) post-dose, only pre-dose on Days 1 of each treatment cycle thereafter, at the End of Treatment, and as clinically indicated.

8. ECG (JPN): In the same patients participating in the JPN PK Sub-Study12, three consecutive 12-lead ECGs performed approximately 2 minutes apart will be collected during Screening, on Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 3 Day 1 pre-dose and 4 hours (+/- 15 minutes) post-dose coinciding with the PK samples; thereafter, triplicate ECGs need to be collected only pre-dose on Days 1 of each treatment cycle, at the End of Treatment, and as clinically indicated. After the required number of patients have been enrolled in the Japan PK Sub-Study, all subsequent newly enrolled patients will only require triplicate ECGs performed approximately 2 minutes apart during Screening, pre-dose on Days 1 of each treatment cycle, at the End of Treatment, and as clinically indicated. The Sponsor will communicate appropriately when the Japan PK Sub-Study is completed.

9. ECG (ROW): A single 12-lead ECG should be performed during Screening, on Days 1 of Cycles 1-3 pre-dose and 4 hours (+/- 15 minutes) post-dose, only pre-dose on Days 1 of each treatment cycle, at the End of Treatment, and as clinically indicated.

10. Clinical laboratory Assessments: Hematology and biochemistry assessments will be performed during Screening, on Days 1 and 15 of Cycle 1, Day 1 of each subsequent treatment cycle thereafter, at the End of Treatment, and as clinically indicated. Standard coagulation and lipid panels will be required at Screening and as clinically indicated on-study.

Entrectinib—F. Hoffmann-La Roche Ltd 98/Protocol GO40782 (RXDX-101-02), Version 5 APPENDIX 1 SCHEDULE OF ASSESSMENTS (CONT.)

All laboratory assessments will be performed locally at each institution.

11. PK Samples: Blood samples for determination of population PK will be collected pre-dose on Day 1 of each treatment cycle and at the End of Treatment. Additionally, if clinically feasible, a PK sample should be obtained at the time of any serious and/or unusual adverse events that may be causally related to the study drug. US: After each set of triplicate ECGs collected on Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 3 Day 1, an additional PK blood sample will be collected at 4 hours (+/- 15 minutes) post-dose to match the time of the post-dose ECGs. ROW: After each set of ECGs are collected on Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 3 Day 1, an additional PK blood sample will be collected at 4 hours (+/- 15 minutes) post-dose to match the time of the post-dose ECGs

12. Japan PK Sub-Study: In at least 6 patients (3 male, 3 female), blood samples will be collected at 0 (pre-dose), 0.5, 1, 2 hours (+/- 5 minutes), 4 hours (prior to blood sample collection, record triplicate 12-lead ECGs approximately 2 minutes apart), 6 hours, 8 hours (+/- 15 minutes), and 24 hours (+/- 1 hour) post-dose on Cycle 1 Day 1 and on Cycle 2 Day 1. At Cycle 3 Day 1, an additional PK blood sample will be collected at 4 hours (+/- 15 minutes) post-dose to match the time of the post-dose ECGs. Thereafter, starting with Cycle 4, only pre- dose samples will be collected on Day 1 of each subsequent treatment cycle and at the End of Treatment. After the required number of patients have been enrolled in the Japan PK Sub-Study, all subsequent newly enrolled patients will only require pre-dose PK samples on Day 1 of each treatment cycle and at the End of Treatment. The Sponsor will communicate appropriately when the Japan PK Sub-Study is completed.

13. PD Samples: Blood samples for exploratory biomarker analyses will be collected along with the clinical laboratory samples on Day 1 of each treatment cycle and at the End of Treatment.

14. Tumor Markers: Blood samples should be collected as per Standard of Care (SOC) for each patient’s particular tumor type and recorded in the eCRF at Screening, on Day 1 of each treatment cycle, at the End of Treatment, and as clinically indicated.

15. Imaging Assessments: CT or MRI of the brain, chest, abdomen, +/- pelvis (depending on tumor type), as well as a bone scan* (if applicable) should be performed during Screening according to the standard of care for each particular tumor type, e.g., for NSCLC patients, only CT or MRI scans of the brain, chest and abdomen are expected. * Sodium fluoride (NaF) PET scan may also be performed; FDG PET or PET/CT can be used in NSCLC patients and other patients with PET-avid tumors, but the CT potion of a PET/CT may not be used in lieu of a diagnostic CT, unless it is performed with IV contrast. Please consult with the Imaging Manual for further details on required scans per tumor type. On treatment scans are to be performed at the end of Cycle 1 (Cycle 2 Day 1 +/- 2 days), then approximately every 8 weeks thereafter (+/- 7-days) and at End of Treatment (if more than 4 weeks have passed since the last imaging assessment). Tumor assessments may also be performed outside of the protocol-defined time points at the discretion of the Investigator. Patients with responding tumors (CR or PR) must have response confirmed at least 4 weeks after the first documentation of response. All anatomical areas that were scanned during Screening should be assessed at every on-study time point using the same imaging modality in order to determine tumor response as per RECIST v1.1. In addition to submitting all scans for BICR within 1 week of collection, local assessment of tumor response should also be performed by the Investigator.

16. Vital Signs: Blood pressure and pulse can be assessed either in the supine or seated position. Body weight should be collected at every clinic visit, while height is only required at Screening.

17. Adverse Events and Concomitant Medications/Treatments: Patients must be followed for adverse events from the first day of study treatment until at least 30 days after the last dose of study drug, or until all serious or study drug-related toxicities have resolved or are deemed “chronic” or “stable”, whichever is later. Only serious adverse events related to study procedures need to be reported from the time of the main informed consent. Concomitant medications and concurrent treatments should be documented at Screening and at every clinic visit.

18. Entrectinib Dispensing and Dosing: Entrectinib bottles will be dispensed at the start of each new cycle of treatment. Entrectinib will be self-administered orally at home (except on clinic days), on a continuous daily dosing regimen at a dose of 600 mg per day (three 200-mg capsules per day).

Entrectinib—F. Hoffmann-La Roche Ltd 99/Protocol GO40782 (RXDX-101-02), Version 5 APPENDIX 1 SCHEDULE OF ASSESSMENTS (CONT.)

On Day 1 clinic visit days, entrectinib should be taken at the clinic after all the pre-dose assessments have been conducted, at the direction of the study research nurse. On Day 15 and other visits (e.g., imaging days), entrectinib should be taken at home according to the patient’s daily routine.

19. Post-Study Survival Status: Patients discontinuing study treatment due to documented radiographic progression will enter the survival follow-up period, where survival status and subsequent anticancer therapy information (including best response) will be collected every 3 months until death, loss of follow-up, or withdrawal of consent, whichever comes first. Survival can be collected via telephone call or medical chart review. Patients discontinuing study treatment prior to documented radiographic progression will also enter the survival follow-up period, where they will continue to have schedule disease assessments approximately every 8 weeks until documentation of radiographic progression, the start of a subsequent anticancer therapy, or decision to no longer treat (e.g., supportive care), whichever is first. At that time, survival status (and subsequent anticancer therapy information, including best response, if appropriate) will be collected every 3 months until death, loss of follow-up, or withdrawal of consent, whichever comes first.

20. Patients Reported Outcomes: All patients will complete the QLQ-C30 and EQ-5D quality of life questionnaires at the clinic PRIOR to any other clinical activity on Cycle 1 Day 1, Day 1 of each subsequent treatment cycle thereafter, and at the End of Treatment. NSCLC and mCRC patients enrolled across all baskets will also complete the lung cancer and colorectal cancer specific modules, QLQ-LC13 and QLQ-CR29, respectively, along with the other 2 questionnaires. a. Cycle 1 Day 1 Assessments: Assessments in parenthesis (X) do not need to be completed if they have been performed during the Screening period within the past 7 days. b. Day 15 Assessments: These safety visits will be performed during Cycles 1-3 and are optional at Cycles 2 and 3 as per Investigator’s discretion. Starting at Cycle 4, patients will be seen in the clinic once a month, at the start of each new cycle of treatment. c. End of Treatment Assessments: Assessments in parenthesis (X) do not need to be completed if they have been performed within the past 7 days (within the last 2 weeks for patient reported outcomes and 4 weeks for tumor assessments, respectively). d. Safety Follow-Up: Patients should be evaluated in clinic approximately 30 days after the last dose of study drug. Physical examination (including ECOG and vitals) and clinical laboratory assessments should be performed as clinically indicated. Adverse events should be followed until all serious or study drug-related toxicities have resolved or are deemed “chronic” or “stable”, whichever is later. e. Screening Assessments: Assessments that have been performed as part of standard of care, prior to obtaining informed consent AND that are within the past 7 days of Screening AND within 30 days of the first dose of study drug, may be used for Screening and do not have to be repeated. f. Patients on treatment after 1 year: Patients on treatment greater than 1 year, at the investigator’s discretion, may have decreased study visits to every other month (aligning with scan dates).

Entrectinib—F. Hoffmann-La Roche Ltd 100/Protocol GO40782 (RXDX-101-02), Version 5 APPENDIX 2 ECOG PERFORMANCE STATUS

0 Fully active, able to carry on all pre-disease activities without restriction

1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work or office work

2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours

3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours

4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair

5 Dead

Entrectinib—F. Hoffmann-La Roche Ltd 101/Protocol GO40782 (RXDX-101-02), Version 5 APPENDIX 3 NATIONAL CANCER INSTITUTE (NCI) COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE)

The NCI CTCAE v4.0 may be reviewed on-line at the following NCI website: http://ctep.cancer.gov/reporting/ctc.html

Entrectinib—F. Hoffmann-La Roche Ltd 102/Protocol GO40782 (RXDX-101-02), Version 5 APPENDIX 4 REQUIRED LABORATORY TESTS

Hematology Chemistry Other Hemoglobin Total bilirubin Urinalysis (dipstick): Hematocrit Alanine transaminase (ALT) Specific gravity Platelet count Aspartate transaminase (AST) pH Red blood cell count Alkaline phosphatase Glucose White blood cell count Total protein Protein White blood cell differential Albumin Blood Sodium Microscopic, if clinically indicated: Potassium (RBC, WBC, casts and crystals) Chloride Calcium Coagulation panel (Screening and Phosphate (phosphorus) as clinically indicated only) Magnesium Blood urea nitrogen (BUN) or urea Lipid panel (Screening and as Creatinine clinically indicated only) Uric acid Glucose Tumor Markers (disease-specific) LDH PD Markers (exploratory blood samples)

Entrectinib—F. Hoffmann-La Roche Ltd 103/Protocol GO40782 (RXDX-101-02), Version 5 APPENDIX 5 EORTC QLQ-C30

Entrectinib—F. Hoffmann-La Roche Ltd 104/Protocol GO40782 (RXDX-101-02), Version 5 Entrectinib—F. Hoffmann-La Roche Ltd 105/Protocol GO40782 (RXDX-101-02), Version 5 APPENDIX 6 EORTC QLQ-LC13

Entrectinib—F. Hoffmann-La Roche Ltd 106/Protocol GO40782 (RXDX-101-02), Version 5 APPENDIX 7 EORTC QLQ-CR29

Entrectinib—F. Hoffmann-La Roche Ltd 107/Protocol GO40782 (RXDX-101-02), Version 5 Entrectinib—F. Hoffmann-La Roche Ltd 108/Protocol GO40782 (RXDX-101-02), Version 5 APPENDIX 8 EQ-5D

By placing a checkmark in one box in each group below, please indicate which statements best describe your own health state today.

Mobility

I have no problems in walking about 

I have some problems in walking about 

I am confined to bed 

Self-Care

I have no problems with self-care 

I have some problems washing or dressing myself 

I am unable to wash or dress myself 

Usual Activities (e.g., work, study, house work, family, or leisure activities)

I have no problems with performing my usual activities 

I have some problems with performing my usual activities 

I am unable to perform my usual activities 

Pain/Discomfort

I have no pain or discomfort 

I have moderate pain or discomfort 

I have extreme pain or discomfort 

Anxiety/Depression

I am not anxious or depressed 

I am moderately anxious or depressed 

I am extremely anxious or depressed 

Entrectinib—F. Hoffmann-La Roche Ltd 109/Protocol GO40782 (RXDX-101-02), Version 5 To help people say how good or bad a health state is, we have drawn a scale (rather like a thermometer) on which the best state you can imagine is marked 100 and the worst state you can imagine is marked 0.

We would like you to indicate on this scale how good or bad your own health is today, in your opinion. Please do this by drawing a line from the box below to whichever point on the scale indicates how good or bad your health state is today.

Your own health state today

Entrectinib—F. Hoffmann-La Roche Ltd 110/Protocol GO40782 (RXDX-101-02), Version 5