Official Title: A Phase Ib Study Evaluating Cobimetinib Plus Atezolizumab in Patients With Advanced BRAF V600 Wild-Type Melanoma Who Have Progressed During or After Treatment With Anti−PD-1 Therapy and Atezolizumab Monotherapy in Patients With Previously Untreated Advanced BRAF V600 Wild-Type Melanoma NCT Number: NCT03178851 Document Date: Protocol Version 5: 26-October-2018 PROTOCOL TITLE: A PHASE IB STUDY EVALUATING COBIMETINIB PLUS ATEZOLIZUMAB IN PATIENTS WITH V600 ADVANCED BRAF WILD-TYPE MELANOMA WHO HAVE PROGRESSED DURING OR AFTER TREATMENT WITH ANTI−PD-1 THERAPY AND ATEZOLIZUMAB MONOTHERAPY IN PATIENTS WITH PREVIOUSLY UNTREATED ADVANCED V600 BRAF WILD-TYPE MELANOMA PROTOCOL NUMBER: CO39721 VERSION NUMBER: 5 EUDRACT NUMBER: 2016-004402-34 IND NUMBER: 135,717 TEST PRODUCTS: Cobimetinib (RO5514041) Atezolizumab (RO5541267) MEDICAL MONITOR: M.D. SPONSOR: F. Hoffmann-La Roche Ltd DATE FINAL: 14 December 2016 DATES AMENDED: Version 2: 23 June 2017 Version 3: 19 September 2017 Version 4: 3 February 2018 Version 5: See electronic date stamp below. PROTOCOL AMENDMENT APPROVAL Approver's Name Title Date and Time (UTC) Company Signatory 26-Oct-2018 10:19:14 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 The information contained in this document, especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as an investigator, potential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. Cobimetinib and Atezolizumab —F. Hoffmann-La Roche Ltd Protocol CO39721, Version 5 PROTOCOL AMENDMENT, VERSION 5 RATIONALE Protocol CO39721 has been amended primarily to update the primary analysis timelines and to align with current atezolizumab risk language. • The primary analysis will be conducted in Cohorts A and B approximately 24 weeks after the last patient is enrolled in Cohort A. At this time, Cohorts A and B will have a minimum follow up of approximately 24 weeks. The primary analysis for Cohort C may be analysed independently, with a minimum of 24 weeks follow up for patients in Cohort C (Section 6). • The list of risks associated with atezolizumab has been revised to align with current atezolizumab risk language (Section 5.1.2). • Guidelines for managing patients who experience atezolizumab-associated adverse events have been revised to include nephritis (Appendix 8). Additional changes to the protocol are summarized below: • Independent review committee (IRC)-assessed objective response rate (ORR), duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS) have been added as secondary efficacy endpoints for Cohort C (Table 1 in Section 2 and Sections 3.1 and 6.4.2). • Text has been added to clarify that the patient numbers for each cohort are approximate (Sections 3.1, 3.3.2.2, and 6.1). • The inclusion criterion that addresses female contraception has been modified to specify when women must refrain from donating eggs (Section 4.1.1.4). • The exclusion criterion related to treatment with immunosuppressive medication for patients who have received acute, low-dose systemic immunosuppressant medication (≤ 10 mg/day oral prednisone or equivalent) or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) has been revised, specifying that such patients are eligible for the study after Medical Monitor approval has been obtained (Section 4.1.2.6). • Denosumab has been removed from the list of prohibited therapies (Section 4.3.2). • Text stating that ophthalmologic examinations should be performed prior to dosing has been added, and the frequency of the examinations has been clarified (Table 3 in Section 4.4.7). • Text stating recurrent Grade 1 pneumonitis should be treated as a Grade 3 or 4 event has been removed (Table 6 in Section 5.1.3.3). • The Medical Monitor has been changed and updated contact information has been provided (Section 5.4.1). • Language has been added for consistency with Roche's current data retention policy and to accommodate more stringent local requirements (if applicable) (Section 7.5). Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 2/Protocol CO39721, Version 5 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. Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 3/Protocol CO39721, Version 5 TABLE OF CONTENTS PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12 PROTOCOL SYNOPSIS .................................................................................... 13 1. BACKGROUND ........................................................................................... 26 1.1 Background on Melanoma ..................................................... 26 1.1.1 Incidence and Pathogenesis .................................................. 26 1.1.2 Treatment Options for Melanoma .......................................... 26 1.2 Background on the Study Treatments ................................... 28 1.2.1 Cobimetinib ............................................................................ 28 1.2.2 Atezolizumab ......................................................................... 28 1.3 Study Rationale and Benefit-Risk Assessment ...................... 29 1.3.1 Rationale for Combining Cobimetinib and Atezolizumab for Advanced BRAFV600 Wild-Type Melanoma after Progression on Anti-PD-1 Therapy ................................................................................. 29 1.3.1.1 Rationale for Atezolizumab Monotherapy for Previously Untreated Patients with Advanced BRAFV600-Wild-Type Melanoma ............................................ 29 1.3.2 Activity of Atezolizumab in Advanced Melanoma .................. 30 1.3.2.1 Study PCD4989g: Atezolizumab Monotherapy ..................... 30 1.3.3 Activity of MEK Inhibitors in BRAFV600 Wild-Type Melanoma .............................................................................. 31 1.3.4 Effect of MAPK Inhibition on Tumor-Immune Contexture ............................................................................. 31 1.3.5 Clinical Data for Combination Treatment with Cobimetinib and Atezolizumab in Advanced Melanoma .............................................................................. 32 1.3.5.1 Study GP28363 ..................................................................... 32 1.3.6 Risk-Benefit Statement .......................................................... 36 2. OBJECTIVES AND ENDPOINTS ................................................................ 36 3. STUDY DESIGN .......................................................................................... 39 3.1 Description of the Study......................................................... 39 3.1.1 Biopsies and Archival Tissue ................................................. 42 3.1.1.1 Optional Biopsies (Cohort A) ................................................. 43 Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd 4/Protocol CO39721, Version 5 3.1.1.2 Mandatory Biopsies (Cohort B) .............................................. 43 3.1.1.3 Optional Biopsies (Cohort C) ................................................. 44 3.1.2 Dosing of Study Treatment beyond Disease Progression ........................................................................... 44 3.2 End of Study and Length of Study ......................................... 45 3.3 Rationale for Study Design .................................................... 45 3.3.1 Rationale for Cobimetinib plus Atezolizumab Dose and Schedule ............................................................... 45 3.3.1.1 Cohort A (Cobimetinib plus Atezolizumab with Concurrent Start) ................................................................... 45 3.3.1.2 Cohort B (Biopsy Cohort) ....................................................... 46 3.3.1.3 Cohort C (Atezolizumab Monotherapy Cohort) ...................... 46 3.3.2 Rationale for Patient Population and Cohorts ........................ 46 3.3.2.1 Cohort A (Cobimetinib plus Atezolizumab with Concurrent Start) ................................................................... 46 3.3.2.2 Cohort B (Biopsy Cohort) ....................................................... 46 3.3.2.3 Cohort C (Atezolizumab Monotherapy).................................. 47 3.3.3 Rationale for Primary Endpoint Selection .............................. 47 3.3.4 Rationale for Confirmation of Progressive Disease per RECIST v1.1 ...................................................... 48 3.3.5 Rationale for Biomarker Assessments ................................... 49 3.3.6 Rationale for Blood Sampling for Biomarker Assessments ......................................................................... 49 3.3.7 Rationale for Ophthalmologic Assessments (Cohorts A and B) .................................................................. 49 3.3.7.1 Rationale for Optional