CME/MOC/CC/CNE Improving Outcomes in Patients With Molecularly Altered NSCLC Through Broad Implementation of Precision Testing and Treatment: Latest Evidence and Practical Guidance in the Context of a Changing Landscape

Chair Alexander Drilon, MD Memorial Sloan Kettering Cancer Center New York, New York

Co-Chair Benjamin Levy, MD Johns Hopkins School of Medicine Johns Hopkins Sidney Kimmel Cancer Center (SKCC) at Sibley Memorial Hospital Washington, DC

What’s Inside 3 MasterClass Module 1—Molecular Testing in Lung Cancer: Options, Evidence, and Recommendations

6 MasterClass Module 2—Treatment of Molecularly Altered NSCLC in the Context of Rapidly Emerging Evidence and a Shifting Treatment Landscape: Synthesizing the Latest Research and Implications for Practice

26 MasterClass Module 3—Practicalities and Challenges of Managing Patients With Molecularly Altered NSCLC

Participate in interactive questions, download activity slides, and obtain your instant CME/MOC/CC/CNE credit online. This CME/MOC/CC/CNE activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical PeerView.com/NPG900 Education. Activity Information

Media: Enduring Material Alexander Drilon, MD, has a financial interest/relationship or affiliation in the form of: Accredited Activity Release Date: April 30, 2020 Consultant and/or Advisor for AbbVie Inc.; Ariad/Millenium/Takeda Pharmaceutical Company Accredited Activity Expiration Date: April 29, 2021 Limited; AstraZeneca; Bayer; BeiGene; BerGenBio ASA; Blueprint Medicines Corporation; Time to Complete Activity: 60 minutes Boehringer Ingelheim Pharmaceuticals, Inc.; Eli Lilly and Company; Exelixis, Inc.; F. Hoffmann- La Roche Ltd/Ignyta/Genentech, Inc.; Helsinn Healthcare SA; Hengrui Therapeutics, Inc.; Loxo Activity Description Oncology; Merus; MORE Health; Pfizer, Inc.; Turning Point Therapeutics, Inc.; Tyra Biosciences; In this activity, thoracic oncology experts discuss the expanding role of molecular testing and and Verastem, Inc. targeted treatment selection for patients with non–small cell lung cancer (NSCLC). The roles of Grant/Research Support from Foundation Medicine. Associated research paid to institution from tissue- and blood-based biomarker testing for mutations and other molecular alterations are Exelixis, Inc.; GlaxoSmithKline; Pfizer, Inc.; PharmaMar; Taiho Oncology, Inc.; and Teva. explored, along with current data on the efficacy and safety of approved and investigational Honoraria from AbbVie Inc.; Ariad/Millenium/Takeda Pharmaceutical Company Limited; targeted therapies in newly diagnosed patients and those with acquired resistance. AstraZeneca; Bayer; BeiGene; BerGenBio ASA; Blueprint Medicines Corporation; Eli Lilly and Company; Exelixis, Inc.; F. Hoffmann-La Roche Ltd/Ignyta/Genentech, Inc.; Helsinn Healthcare Target Audience SA; Hengrui Therapeutics, Inc.; Loxo Oncology; MORE Health; Pfizer, Inc.; Turning Point This activity has been designed to meet the educational needs of oncologists, pathologists, Therapeutics, Inc.; Tyra Biosciences; and Verastem, Inc. interventional radiologists, pulmonologists, nurses, nurse practitioners, physician assistants, Other Financial or Material Support from Merck & Co., Inc. and Puma Biotechnology, Inc. for travel and other healthcare professionals involved in the care of patients with advanced/metastatic expenses. lung cancer. Co-Chair Educational Objectives Benjamin Levy, MD Upon completion of this activity, participants will be able to: Associate Professor, Johns Hopkins School of Medicine • Evaluate the evolving science and recommendations for molecular testing in lung cancer, Clinical Director, Johns Hopkins Sidney Kimmel Cancer Center (SKCC) at Sibley Memorial Hospital including the use of tissue- and blood-based biomarker testing for evaluation of mutations Medical Director, Thoracic Oncology Program, SKCC at Sibley and other molecular alterations in advanced/metastatic NSCLC in newly diagnosed patients Washington, DC and those with acquired resistance • Characterize the mechanisms of action, safety/efficacy profiles, and indications of the Benjamin Levy, MD, has a financial interest/relationship or affiliation in the form of: different approved and investigational targeted therapies for advanced NSCLC in different Honoraria from AstraZeneca; Celgene Corporation; Eli Lilly and Company; Genentech, Inc.; Merck patient populations & Co., Inc.; and Pfizer, Inc. • Integrate best practices related to molecular testing through the continuum of advanced NSCLC and interpretation of results to guide treatment selection Planning Committee Disclosures • Implement evidence-based, individualized, precision treatment plans for patients with Tracy L. Greene, MSN, RN, FNP-C, Nurse Planner, MLI, has nothing to disclose. advanced NSCLC based on results of molecular testing The planners from Medical Learning Institute, Inc., the accredited provider, and PeerView Providership, Credit, and Support Institute for Medical Education, the joint provider, do not have any financial relationships with This CME/MOC/CC/CNE activity is jointly provided by Medical Learning Institute, Inc. and PVI, an ACCME-defined commercial interest related to the content of this accredited activity during PeerView Institute for Medical Education. the past 12 months unless listed below.

This activity is supported through independent educational grants from AstraZeneca, Bayer Content/Peer Reviewer Disclosures Healthcare Pharmaceuticals, Inc., Genentech, and Loxo Oncology, Inc. The following Content/Peer Reviewers have nothing to disclose:

Physician Continuing Medical Education Stacy L. Sims, MSN, RN, CMCN This activity has been planned and implemented in accordance with the accreditation Natalie I. Vokes, MD requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Medical Learning Institute, Inc. Disclosure of Unlabeled Use and PVI, PeerView Institute for Medical Education. The Medical Learning Institute, Inc. is This educational activity may contain discussions of published and/or investigational uses of accredited by the ACCME to provide continuing medical education for physicians. agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational The Medical Learning Institute, Inc. designates this enduring material for a maximum of 1.0 AMA activity are those of the faculty and do not necessarily represent the views of the planners. PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of Please refer to the official prescribing information for each product for discussion of approved their participation in the activity. indications, contraindications, and warnings.

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Continuing Nursing Education About This CME/MOC/CC/CNE Activity Medical Learning Institute, Inc. is accredited as a provider of continuing nursing PVI, PeerView Institute for Medical Education, and Medical Learning Institute, Inc. are education by the American Nurses Credentialing Center's Commission on responsible for the selection of this activity’s topics, the preparation of editorial content, and Accreditation. the distribution of this activity. Our activities may contain references to unapproved products Successful completion of this continuing nursing education activity will be awarded 1.0 contact or uses of these products in certain jurisdictions. The preparation of PeerView activities is hour(s). supported by educational grants subject to written agreements that clearly stipulate and enforce the editorial independence of PVI and Medical Learning Institute, Inc. Faculty Disclosures Chair The materials presented here are used with the permission of the authors and/or other sources. Alexander Drilon, MD These materials do not necessarily reflect the views of PeerView or any of its partners, providers, Acting Chief of Early Drug Development and/or supporters. Memorial Sloan Kettering Cancer Center New York, New York

Go online to complete the post-test and evaluation for CME/MOC/CC/CNE credit PeerView.com/NPG900 2 Improving Outcomes in Patients With Molecularly Altered NSCLC Through Broad Implementation of Precision Testing and Treatment: Latest Evidence and Practical Guidance in the Context of a Changing Targeted Therapy Landscape

MasterClass Module 1—Molecular Pathologic Evaluation of Lung Cancer1

Testing in Lung Cancer: Options, Step 1: Distinguish between small cell lung cancer vs NSCLC There are now 7 genomic alterations occurring in NSCLC with FDA-approved Step 2: If NSCLC, determine subtype (squamous, targeted therapies, and there are many Evidence, and Recommendations adenocarcinoma, large cell) more coming Step 3: NCCN guideline recommendation: All patients • EGFR Alexander Drilon, MD with adenocarcinoma undergo molecular profiling to identify EGFR, ALK, ROS1, BRAF, RET, MET exon • ALK Benjamin Levy, MD 14 skipping • ROS1 • Other new/emerging actionable alterations to test: • BRAF V600E NTRK, HER2, KRAS G12C, EGFR exon 20, • NTRK NRG1, others Dr. Drilon: Hello, and welcome to this educational activity focused • MET exon 14 skipping (new) Step 4: If negative for targeted alterations/mutations, on the expanding role of precision testing and treatment of non– immunohistochemical testing for PD-L1 expression • RET (new) small cell lung cancer. I’m Dr. Alexander Drilon, the acting chief 1. NCCN Clinical Practice Guidelines in Oncology. Non–Small Cell Lung Cancer. Version 6.2020. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. of the Early Drug Development Service at the Memorial Sloan Kettering Cancer Center in New York. So, there are multiple steps involved in this. And we’re still trying to I’m joined today by Dr. Benjamin Levy, who is the clinical director better define the best practices for this. It’s evolving. of Medical Oncology at the Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital in Washington, DC. Thanks for But clearly, first, discerning small cell from non–small cell lung being here today, Ben. cancer is critical. The regimens are different for the two. And then, within non–small cell lung cancer, determining Dr. Levy: Thanks for having me, Alex. subtype: squamous cell versus adenocarcinoma and large cell.

Diagnostic Workup Then, as you mentioned in your intro, it is really looking at the genetic underpinnings—looking at the molecular features of the Accurate classification and staging of suspected advanced/metastatic NSCLC are tumor. essential to ensure patients receive the most appropriate and effective treatment possible

Goals of initial workup So I think we have to remember that PD-L1 testing also needs • Determine clinical and pathologic stage and presence/absence of metastatic disease to be done in conjunction, but we need to prioritize tissue, • Evaluate overall functioning/performance status of patient and molecular testing is critical for determining what the right • Classify NSCLC according to histopathologic, immunohistochemical, and molecular features treatment for the patient is.

NSCLC Is Complex and Heterogeneous

Molecular Subtyping of Adenocarcinoma1-3 n KRAS mutation n EGFR mutation n ALK fusion Dr. Drilon: So I thought we’d start today by talking about strategies n ROS1 fusion Other n RET fusion for molecular profiling in lung cancer. And maybe we’ll begin with 18% n NTRK1 fusion n BRAF mutation NSCLC 62% n MET exon 14 mutation the number of different potentially actionable operations that n HER2 mutation n PIK3CA mutation 20% we’ve identified in the last couple of years even. n HRAS mutation n NRAS mutation Squamous cell n Adenocarcinoma AKT mutation carcinoma n MAP3K1 mutation Dr. Levy: Yes, I think it’s never been a more critical time to consider n Unknown

molecular profiling for patients with lung cancer. Clearly, the 1. NCCN Clinical Practice Guidelines in Oncology. Non–Small Cell Lung Cancer. Version 5.2020. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. 2. Lindeman NI et al. J Thorac Oncol. 2018;13:323-358. 3. Kalemkerian GP et al. J Clin Oncol. 2018;36:911-919. movement has been that this is not a one-size-fits-all model. We need to discover underlying genomic underpinnings to drive treatment decisions. And, you know, importantly, for every And we’ve learned in non–small cell lung cancer, again, there patient, we need to think about clinical and pathological stage are multiple actionable mutations. We can define molecular first for patients, look at their overall performance status, and then subsets and, based on that molecular subset, wed that patient to obviously start to classify their non–small cell lung cancer, not only a particular targeted therapy. So I think that’s kind of a high-level histologically from an immunohistochemical standpoint, but then overview of molecular testing, and critical for our patients with looking at molecular features. non–small cell lung cancer.

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Dr. Drilon: And I think it’s important to point out that there are take 10 cc of blood, look at circulating tumor DNA—not circulating many different assays that you can use to interrogate someone’s tumor cells, but circulating tumor DNA—and be able to do genetic tumor for one of these drivers. And so most commonly, we use a interrogation off that platform and have very similar concordance DNA-based assay, right? And given that there’s a longer gene list with tissue testing from the same patient? than there was in the past, when we did single-gene testing, then obviously something that’s more cost-effective and efficient would Plasma ctDNA “Liquid Biopsies”: Rationale and Methods1 be the new comprehensive panel that gets everything that you

Circulating • Capture of ctDNA via a simple noninvasive blood test want. tumor cell Healthy tissue • Shedding of ctDNA is product of and necrosis, two relevant processes in cancer

Apoptosis • New, more sensitive diagnostic platforms have the capability However, given that a lot of these are DNA, we do need to or necrosis to genetically interrogate isolated DNA from the blood remember that in patients where your gut feel is that something’s • Circumvent the need for tissue biopsies Apoptosis sitting there, and you send off a next-generation DNA-based assay Technique Sensitivity, % Optimal Application Inflamed Sanger sequencing >10 Tumor tissue tissue and nothing comes back, there are some data showing that, if you Pyrosequencing 10 Tumor tissue NGS 2 Tumor tissue then do a pass looking at RNA, you might detect one or more of Healthy cell Quantitative PCR 1 Tumor tissue Phagocyte Blood plasma or Tumor cell ARMS 0.10 Tumor tissue serum sample containing ctDNA Mutation these different fusions or MET exon 14. BEAMing, PAP, ctDNA, rare variants Red blood cell ≤0.01 Endothelial cell digital PCR, TAm-Seq in tumor tissue Chromosome Dr. Levy: Yes, that’s critical. It really is. And, just to reinforce what 1. Diaz LA Jr, Bardelli A. J Clin Oncol. 2014;32:579-586. you just said, I think comprehensive genomic profiling is the way to go. The single-gene sequential testing really needs to be done So, plasma is reliable. I think what we know is that for stage IV non– away. small cell lung cancer patients, roughly 60% to 70% of patients will shed circulating tumor DNA. That shed is higher depending And again, the importance of identifying a genetic alteration that on metastatic load; if the patient has liver metastases or bone we can wed to targeted therapy. We see certainly in the EGFR space, metastases, they’re more likely to shed ctDNA. with , response rates as high as 70%, and the list goes on now. ALK, ROS1, BRAF V600E, HER2, RET, NTRK, [and MET exon 14 And what we know now is, obviously, we have multiple platforms skipping mutations]. All of these genetic alterations can be wedded that can capture circulating tumor DNA and do the genetic to targeted therapies that then can lead to improved outcomes for interrogation, and that it’s reliable. I think that it’s important. The our patients and, dare I say, better quality of life. I mean, that’s really concordance between plasma and tissue is quite high, so that a important. positive result is essentially ruling in the results.

Dr. Drilon: Absolutely. And the vast majority of our discussion High PPV for NGS Panel1 today will really tease out what the activity and safety of these new strategies are. • Method comparison 6,948 consecutive clinical NSCLC samples • Real-world database 4,961 without tissue genotyping reports • 7,000 consecutive samples 1,987 samples with submitted • Actionable driver mutations tissue testing reports Lung Cancer Genotyping: Tissue vs Plasma 1,453 without actionable variants or tissue QNS 543 matched samples with tissue genotyping reports • Tumor biopsies involve multiple steps:

IR: Pathologist: Oncologist: Molecular lab: 291 16 procedure pathology 181 37 26 5 3 prepare sample, EGFR EGFR tumor biopsy EGFR ALK/ROS1 KRAS BRAF MET exon scheduled and reviewed exon 19 exon 20 ordered perform assay L858R fusion mutations V600E 14 skipping performed and reported deletion insertion

PPV 98% 98% 100% 92% 100% 100% 100%

• Liquid biopsies (plasma genotyping) involve fewer steps: 1. Zill OA et al. J Clin Oncol. 2016;34(suppl 18). Abstract LBA11501.

Oncologist: Molecular lab: liquid biopsy ordered prepare sample, perform assay We’ve had a large body of data recently published looking at more than 500 patients that they did both plasma and tissue, and they show a high positive predictive value of identifying alterations in the plasma. But, backing up a little bit and talking about other tests that could be done, I’m sure there are patients where it may be challenging to And this is not just with EGFR. If you find an EGFR, it’s going to be in get a biopsy in the clinic. And can you talk about a complementary the tissue. But this is with other alterations, as well—BRAF, ALK and strategy that you might use for those situations? ROS1, KRAS, MET exon 14 skipping—again, suggesting that if you find an alteration in plasma that essentially rules in their genotype, Dr. Levy: I think in the past 5 to 10 years, we’ve really begun to and you can use that information to drive treatment decisions. understand the power of plasma and liquid biopsies. Who would’ve thought even 5, 10 years ago that this was possible, to be able to

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Clinical Implications of Plasma ctDNA Testing Dr. Drilon: Maybe one thing to point out is, there are also certain in Metastatic NSCLC1 events that you may not always pick up on plasma, like if someone

229 patients with NSCLC prospectively enrolleda progresses, maybe on a tyrosine kinase inhibitor and their cancer

128 concurrent plasma 101 plasma NGS only and tissue NGS (no tissue NGS possible) undergoes morphologic transformation to small cell, it’s not

79 DNA quality or 22 biopsy not something that you may typically pick up on a liquid biopsy test. quantity not sufficient technically possible

21 clinically relevant 54 clinically relevant 11 clinically relevant 38 clinically relevant 7 clinically relevant mutation detected in mutation detected in mutation detected in mutation detected in mutation detected in tissue only plasma & tissue plasma only plasma only plasma only

16 therapeutically 31 therapeutically 8 therapeutically 22 therapeutically 5 therapeutically targetable mutation targetable mutation detected targetable mutation targetable mutation targetable mutation detected in tissue only in plasma & tissue detected in plasma only detected in plasma only detected in plasma only

14 received indicated 20 received indicated 7 received indicated 18 received indicated 3 received indicated targeted therapy targeted therapy targeted therapy targeted therapy targeted therapy

47 therapeutically targetable mutations 35 additional therapeutically targetable 82 therapeutically targetable detected in tissue (20.5%) + mutations detected in plasma (15.3%) = mutations detected (35.8%)

a Patients were either enrolled at time of initial diagnosis or at disease progression. 1. Aggarwal C et al. JAMA Oncol. 2019;5:173-180.

I think one of the critical questions that’s being asked about plasma is, when should you do it? You know, we do tissue testing on all of our patients given all the reasons that we just went over—finding these molecular subsets that we can wed to targeted therapy. The question is, when should plasma play a role?

And we’ve got a couple of different trials now. One of the trials, Charu Aggarwal’s, looking at patients in which they did both plasma and tissue, and they found that, essentially in these patients, if you layered in the plasma with the tissue result, you enhanced your capture of alterations.

And it really, sort of, changed the algorithm.

In every patient who is treatment naïve who has a tissue biopsy, there should be a consideration to do a parallel plasma test.

Plasma ctDNA Testing in Treatment-Naïve Patients With Advanced NSCLC

• Plasma ctDNA has high positive predictive value but imperfect sensitivity, with up to 30% false-negative rate1 • Simultaneously adding plasma ctDNA analysis to tissue testing in treatment-naïve patients can enhance the chances of detecting a relevant actionable mutation2,3 • Plasma-based testing is indicated for all patients with advanced-stage, treatment-naïve lung cancer for whom tissue sampling may be infeasible or insufficient4 • Plasma-based testing should be considered for every patient with advanced-stage, treatment-naïve lung cancer who has a tissue biopsy

1. Oxnard GR et al. J Clin Oncol. 2016;34:3375-3382. 2. Aggarwal C et al. JAMA Oncol. 2019;5:173-180. 3. Leighl NB et al. Clin Cancer Res. 2019;25:4691-4700. 4. NCCN Clinical Practice Guidelines in Oncology. Non–Small Cell Lung Cancer. Version 3.2020. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.

Based on the data, I think we’ve seen that ordering plasma in conjunction with tissue will increase your chances of identifying an actionable mutation. A negative plasma test tells you nothing, essentially, because the false negative rate is 30%. But if it’s positive, you can act on that, and you can act on it quickly.

And one thing we also didn’t mention is the turnaround time of plasma. I mean, this is a test that you can order in your office, and you can get a result within 7 to 10 business days, so it’s pretty remarkable.

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MasterClass Module 2—Treatment But then there are other uncommon mutations that we’ll talk about that may or may not predict sensitivity in exon 18. And then exon of Molecularly Altered NSCLC in 20 EGFR mutations, we’re still trying to learn about these. Not all the Context of Rapidly Emerging exon 20 mutations are the same. Some exon 20 mutations may predict sensitivity to TKIs. The majority of them do not. Evidence and a Shifting Treatment Landscape: Synthesizing the EGFR: Clinical Context

PFS, mo Study Drugs RR, % PFS, HR Latest Research and Implications (EGFRmut) 71 9.5 IPASS 250 mg vs carboplatin + paclitaxel 0.48 47 6.3 for Practice 55 8.0 SIGNAL Gefitinib 250 mg vs cisplatin + gemcitabine 0.54 46 6.3 62 9.2 WJTOG 3405 Gefitinib 250 mg vs cisplatin + docetaxel 0.49 32 6.3 74 10.8 NEJ002 Gefitinib 250 mg vs carboplatin + paclitaxel 0.3 Alexander Drilon, MD 31 5.4 83 13.1 OPTIMAL 150 mg vs carboplatin + gemcitabine 0.16 Benjamin Levy, MD 36 4.6 58 9.7 EURTAC Erlotinib 150 mg vs platinum doublet of choice 0.37 15 5.2 56 11.1 LUX-Lung 3 40 mg vs cisplatin + pemetrexed 0.58 23 6.9 67 11.1 LUX-Lung 6 Afatinib 40 mg vs cisplatin + gemcitabine 0.28 23 5.6

Dr. Drilon: Absolutely. But maybe let’s start with the canonical exon 19 and L858R. What are the current strategies, and what do EGFR Inhibitors the trial data tell us about the frontline setting and which TKI to in NSCLC use?

Dr. Levy: Yes, I think we’ve come a long way. What we’ve seen in multiple studies is that first- or second- generation TKIs outperform chemotherapy in terms of response rate, in terms of progression-free survival. Not in terms of overall survival from the first trials, but probably due to the heavy Dr. Drilon: So let’s first start with probably the most popular gene crossover. in non–small cell lung cancer. That’s a driver oncogene. And these are EGFR mutations. Dr. Drilon: That’s right.

Complexity of EGFR Alterations in Lung Cancer Dr. Levy: But perhaps underrepresented in the literature, and just as important, is quality of life. I think that all of these studies initially EGF binding EGF binding TM Tyrosine kinase Autophosphorylation Exon 2 5 7 13 16 17 18-21 22-24 28 show that delivering frontline TKI improved outcomes: response Mutations associated with drug resistance T790M (50%) D770-N771 (ins NPG) D770-N771 (ins SVQ) EGFR D770-N771 (ins G), N771T rate, PFS, and quality of life. And that really changed the way we V769L Drug Names D761Y 5768I (5%) First generation Erlotinib, gefitinib

688 728 729 (<1%) 761 762 823 824 875 Second generation Afatinib, Exon 18 Exon 21 Exon 19 Exon 20 thought about treating EGFR, and really put EGFR testing on the (nucleotide-binding loop) (activation loop) Third generation Osimertinib (rociletinib), nazartinib

G719C ΔE746-A750 V765A L858R G719S ΔE746-T751 T783A N826S G719A ΔE746-A750 (ins RP) A839T map. (<1%) V689M ΔE746-T751 (ins A/I) K846R N700D ΔE746-T751 (ins VA) L861Q E709K/Q ΔE746-S752 (ins A/V) G863D S720P ΔL747-E749 (A750P) (40%-45%) ΔL747-A750 (ins P) (5%) A775, G776insYVMA (83%, 20/24) ΔL747-T751 G776>VC (8%, 2/24) ΔL747-T751 (ins P/S) V777_G778insCG (4%, 1/24) P780_Y781insGSP (4%, 1/24) ΔL747-S752 770 831 Mutations associated HER2 -E--A--Y--V--M--A--G--V--G--S--P--Y--V--S--R--L--L--G--I--C--L--T--//--A-K- ΔL747-752 (E746V) EGFR -E--A--Y--V--M--A--S--V--D--N--P--H--V--C--R--L--L--G--I--C--L--T--//--A-K- Dr. Drilon: Yes. with drug sensitivity 762 823 V774_C775insHV ΔL747-752 (P753S) A763_Y764insFHEA H773_V774insNPH A767_S768insTLA ΔL747-752 (ins Q) H773_V774insH V769_D770insASV H773_V774insPH ΔL747-P753 V769_D770insGE H773_V774insAH ΔL747-P753 (ins S) P772_H773insNPH ΔS752-I759 P772_H773insNP N771_P772insH D770_N771insSVD (45%) D770_N771insGT D770_N771insF D770_N771insY D770>GY ARCHER 1050: First-Line Dacomitinib vs Gefitinib1,2 • Most commonly encountered EGFR-activating mutations are exon 19 deletion and L858R • Many FDA-approved EGFR tyrosine kinase inhibitors (erlotinib, gefitinib, afatinib, dacomitinib, osimertinib)

Dacomitinib • Stage IIIb/IV NSCLC 45 mg once daily n = 227 • EGFR-activating mutation Ben, are all EGFR mutations the same? Stratified by: R • Race • ECOG PS 0/1 • EGFR mutation status (19 vs 21) Gefitinib Dr. Levy: The short answer is no. I think we’ve learned a lot about • N = 452 250 mg once daily n = 225 EGFR biology in the past 5 to 10 years. EGFR has been the leading Primary endpoint: PFSa edge of precision medicine in lung cancer. The two most common Secondary endpoints: OS, OS at 30 months, PFS by investigator assessment, response, sensitizing mutations that we see are exon 19 and the L858R. safety, and PROs

We know from multiple data sets that these mutations predict a Per blinded IRC review. HR ≤0.667 (50% increase). 1. https://clinicaltrials.gov/ct2/show/NCT01774721. 2. Mok T et al. ASCO 2017. Abstract LBA9007. sensitivity to tyrosine kinase inhibitors.

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Dr. Levy: I think more recently, we’ve had some head-to-head FLAURA: Frontline Osimertinib1 comparisons between next-generation TKIs and older TKIs. The first is the ARCHER 1050 study. This was a trial looking at patients Phase 3 study of osimertinib vs standard-of-care EGFR TKI as first-line treatment for with sensitizing, activating mutations, advanced-stage patients, EGFR mutation–positive, locally advanced, or metastatic NSCLC randomized 1:1 to gefitinib versus dacomitinib. Osimertinib • Advanced EGFR-mutated NSCLC R • N = 650 ARCHER 1050: Efficacy1-3 Erlotinib or gefitinib

PFS OS Dacomitinib Gefitinib Dacomitinib Gefitinib Primary endpoint: PFS (n = 227) (n = 225) (n = 227) (n = 225)

Events, n (%) 136 (59.9) 179 (79.6) Deaths, n 103 117 Key secondary endpoints: ORR, OS, and QoL 1.0 Median PFS (95% CI) 14.7 (11.1-16.6) 9.2 (9.1-11.0) 100 Median OS (95% CI), mo 34.1 (29.5-37.7) 26.8 (23.7-32.1) HR (95% CI) 0.59 (0.47-0.74); P < .0001 0.8 80 1. https://clinicaltrials.gov/ct2/show/NCT02296125. 0.6 60 PFS rate: 0.4 30.6% vs 9.6% 40 OS, % Censored 0.2 20 HR = 0.760 (95% CI, 0.582-0.993)

Probability of PFS P = .0438 Dr. Drilon: But are there other pills that were also tested in the 0 0 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42 48 Time, mo Time, mo same fashion? No. at Risk No. at Risk Dacomitinib 227 154 106 73 20 6 0 0 Dacomitinib 227 206 188 167 138 77 14 3 0 Gefitinib 225 155 69 34 7 1 0 0 Gefitinib 225 213 186 144 113 63 12 3 0 Dr. Levy: Yes, I think we have newer data with better-tolerated 1. Mok T et al. ASCO 2017. Abstract LBA9007. 2. Wu YL et al. Lancet Oncol. 2017;18:1454-1466. 3. Mok T et al. J Clin Oncol. 2018;36:2244-2250. next-generation TKIs. Of course, the FLAURA trial was practice changing. This was a large phase 3 trial, more than 600 patients We saw an improvement in progression-free survival with this next- with activating mutations, randomized 1:1 to osimertinib or to generation TKI versus gefitinib. We saw also an improvement in standard of care, which was erlotinib and gefitinib. overall survival. So I think that, really, this was the first trial we saw where you compared two TKIs, where we saw an improvement in FLAURA: Osimertinib PFS1 outcomes between the two arms. 1.0 PFS in Full Analysis Set 1.0 PFS: With CNS Metastases Osimertinib HR = 18.9 (95% CI, 15.2-21.4) Osimertinib HR = 15.2 (95% CI, 12.1-24.4) 0.8 SOC HR = 10.2 (95% CI, 9.6-11.1) 0.8 SOC HR = 9.6 (95% CI, 7.0-12.4) HR = 0.46 HR = 0.47 0.6 (95% CI, 0.37-0.57) 0.6 (95% CI, 0.30-0.74) P < .001 P < .001 ARCHER 1050: Safety1 0.4 0.4 0.2 0.2 Probability of PFS Probability of PFS 0 0 Adverse Events From Any Causea 0 3 6 9 12 15 18 21 24 27 0 3 6 9 12 15 18 21 24 27 No. at Risk Time Since Randomization, mo No. at Risk Time Since Randomization, mo Dacomitinib (n = 227) Gefitinib (n = 224) Osimertinib 279 262 233 210 178 139 71 26 4 0 Osimertinib 53 51 40 37 32 22 9 4 1 0 SOC 277 239 197 152 107 78 37 10 2 0 SOC 63 57 40 33 24 13 6 2 1 0 AE, n (%) Any Grade Grade 1 Grade 2 Grade 3/4/5 AE, n (%) Any Grade Grade 1 Grade 2 Grade 3/4/5 1.0 PFS: Without CNS Metastases

Diarrhea 198 (87.2) 113 (49.8) 65 (28.6) 19 (8.4)/0/1 (0.4) Diarrhea 125 (55.8) 103 (46.0) 20 (8.9) 2 (0.9)/0/0 0.8 Osimertinib HR = 19.1 (95% CI, 15.2-23.5) SOC HR = 10.9 (95% CI, 9.6-12.3) Paronychia 140 (61.7) 46 (20.3) 77 (33.9) 17 (7.5)/0/0 Paronychia 45 (20.1) 30 (13.4) 12 (5.4) 3 (1.3)/0/0 0.6 HR = 0.46 (95% CI, 0.36-0.59) Dermatitis Dermatitis 0.4 P < .001 111 (48.9) 37 (16.3) 43 (18.9) 31 (13.7)/0/0 64 (28.6) 43 (19.2) 21 (9.4) 0/0/0 acneiform acneiform 0.2 Probability of PFS Stomatitis 99 (43.6) 51 (22.5) 40 (17.6) 8 (3.5)/0/0 Stomatitis 40 (17.9) 33 (14.7) 6 (2.7) 1 (0.4)/0/0 0 0 3 6 9 12 15 18 21 24 27 ↓ Appetite 70 (30.8) 40 (17.6) 23 (10.1) 7 (3.1)/0/0 ↓ Appetite 55 (24.6) 48 (21.4) 6 (2.7) 1 (0.4)/0/0 Time Since Randomization, mo No. at Risk Dry skin 63 (27.8) 42 (18.5) 18 (7.9) 3 (1.3)/0/0 Dry skin 38 (17.0) 35 (15.6) 3 (1.3) 0/0/0 Osimertinib 226 211 193 173 146 117 62 22 3 0 SOC 214 182 157 119 83 65 31 8 1 0 ↓ Weight 58 (25.6) 31 (13.7) 22 (9.7) 5 (2.2)/0/0 ↓ Weight 37 (16.5) 22 (9.8) 14 (6.3) 1 (0.4)/0/0 1. Soria JC et al. N Engl J Med. 2018;378:113-125. Alopecia 53 (23.3) 41 (18.1) 11 (4.8) 1 (.04)/0/0 Alopecia 28 (12.5) 26 (11.6) 2 (0.9) 0/0/0 Cough 48 (21.1) 39 (17.2) 9 (4.0) 0/0/0 Cough 42 (18.8) 36 (16.1) 5 (2.2) 1 (0.4)/0/0 Pruritus 45 (19.8) 27 (11.9) 17 (7.5) 1 (0.4)/0/0 Pruritus 31 (13.8) 24 (10.7) 4 (1.8) 3 (1.3)/0/0 ↑ ALT 44 (19.4) 37 (16.3) 5 (2.2) 2 (0.9)/0/0 ↑ ALT 88 (39.3) 45 (20.1) 24 (10.7) 19 (8.5)/0/0 There was an improvement in PFS. I think the improvement was a AEs occurring in ≥15% of patients in either study group in the safety population. Events listed are in descending order of frequency in the dacomitinib group. 1. Mok T et al. ASCO 2017. Abstract LBA9007. both for patients with brain metastases, who were allowed on the trial, and those without brain metastases. I think, importantly, however, we have to look at toxicity of dacomitinib. And unfortunately, there was a high rate of FLAURA: Osimertinib OS1 diarrhea, paronychia, stomatitis. So I think that the drug, while 1.0 outperforming first-generation TKI, probably due to its toxicity has Median OS, mo (95% CI) 0.9 Osimertinib 38.6 (34.5-41.8) 0.8 very little uptake right now. Comparator EGFR TKI 31.8 (26.6-36.0) 0.7 0.6 Dr. Drilon: Yes. Quality of life, in my mind, can tend to go the other 0.5 Osimertinib 0.4 0.3

way. Probability of OS Comparator EGFR TKI 0.2 HR = 0.80 (95.05% CI, 0.64-1.00) 0.1 P = .046 0 And one other thing about the trial is that it didn’t include patients 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 Time Since Randomization, mo No. at Risk with brain metastases. Osimertinib 279 276 270 254 245 236 217 204 193 180 166 153 138 123 86 50 17 2 0 Comparator EGFR TKI 277 263 252 239 219 205 182 165 148 138 131 121 110 101 72 40 17 2 0

1. Ramalingam SS et al. N Engl J Med. 2020;382:41-50. Dr. Levy: Brain mets, right. Yes.

And then perhaps most important, what we like to see, that coveted space between two curves here. We saw that. We saw an OS advantage in FLAURA.

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FLAURA: Safety1,2 Acquired Drug Resistance1

• Most common all-grade AEs with osimertinib • We can now offer sequential targeted therapy to overcome drug resistance • Safety profile showed clear − Diarrhea: 58%; 2% grade ≥3 benefits to patients receiving − Acquired resistance to erlotinib/gefitinib is commonly caused by a secondary − Dry skin: 32%; <1% grade ≥3 osimertinib EGFR mutation, T790M • Most common all-grade AEs with comparator arm • Treatment was better tolerated − Diarrhea: 57%; 3% grade ≥3 and grade 3/4 all-cause events n HER2 8% − Dermatitis acneiform: 48%; 5% grade ≥3 were approximately 12% lower n HER2 + T790M 4% • AEs led to discontinuation for 13.3% of patients in vs SOC therapies n T790M 60% osimertinib arm vs 18.1% in comparator arm n MET + T790M 3% n Small cell + T790M 2% • Overall, 33.7% of patients experienced a grade ≥3 AE n Small cell 1% with osimertinib vs 44.8% with erlotinib and gefitinib n Small cell + MET 1% n MET amplification 3% n Unknown 18%

1. Ramalingam SS et al. 42nd European Society for Medical Oncology Congress (ESMO 2017). Abstract LBA2. 1. Yu HA et al. Clin Cancer Res. 2013;19:2240-2247. 2. Soria JC et al. N Engl J Med. 2018;378:113-125.

And the drug is exceptionally well tolerated in the context of other Dr. Drilon: And so once patients have had an upfront TKI, what drugs we have seen. We don’t see that rash. We don’t see diarrhea do we know about how these cancers evade targeted therapy like we do with first-generation TKIs. eventually—acquired resistance?

And I think because of FLAURA, really based on three things, its OS Dr. Levy: Yes, acquired resistance. We knew a lot about acquired benefit, its CNS penetration, showing a benefit with osimertinib resistance in the first-generation TKI. When patients were versus first-generation TKI, and then its safety profile—the low on erlotinib or gefitinib, we’d really ironed out some of the rates of AEs in the osimertinib arm—it really changed the calculus mechanisms of resistance in these patients. And roughly 50% to for us, I think. And it moved osimertinib—which was first thought 60% of these patients had a T790M mutation, and that’s where to be a T790M-directed therapy delivered upon EGFR first- osimertinib started. But we also had MET amplification, HER2, and generation TKI resistance—now moving into the frontline, I think then, importantly, small cell transformation that we saw. has changed the game for us.

Acquired Drug Resistance: Osimertinib1 Dr. Drilon: Yes. So, it definitely checked all of the boxes. • First-line osimertinib is still relatively new, and we are still learning the resistance mechanisms Resistance Mechanisms to First-Line Osimertinib C797X L718Q 1 EGFRamp Osimertinib in Uncommon Mutations G724S S768I

6%- METamp 7%-15% 15% 10% Acquired EGFR mutations • Data are n (%, 95% CI) or median (95% CI) 8%-17% Acquired amplifications HER2amp 1%-2% • Uncommon mutation categories overlap for those with common mutations, so individual SPTBN1–ALK Acquired oncogenic fusions 1%-8% RET fusions patients might appear in more than one category Acquired MAPK–PI3K mutations BRAF fusions Best Response to Osimertinib Acquired cell cycle gene alterations 40%-50% 13%-14% BRAF V600E 3% 60 G719A/C/D/S/X S768I Unknown PI3KCA 7% L861Q G719A/C/D/S/X + S768I KRAS 3%-4% Transformations (SCLC, SCC) HER2 1% 40 G719A/C/D/S/X + L861Q 10% Others 20 CCND1amp CCND2amp 0 Exon 18 deletion Exon 18:C.2158T>G: P.SER720AIA Exon 20 HIS 773_VAL774 DUPHIS CCNE1amp CDK4amp -20 CDK6amp 1. Leonetti A et al. Br J Cancer. 2019;121:725-737. -40 -60 Tumor Shrinkage, % -80 -100 We had a nice little pie graph and parsed out mechanisms of 1. Ahn MJ et al. J Clin Oncol. 2018;36(suppl 15):9050. resistance post–first-generation TKI. I think, now that osimertinib has moved frontline, we’re still trying to learn about mechanisms of But I think, going back to the very beginning of this discussion, resistance to osimertinib. we talked about how not all EGFR mutations are the same. And certainly, we know when we do these tests that sometimes you Dr. Drilon: Absolutely. might get an uncommon mutation that comes back. Are there strategies for dealing with those cases? Dr. Levy: And that’s important to inform treatment decisions and trial design. We, of course, have identified C797S as a potential Dr. Levy: Yes. I think that there are probably two strategies that mechanism of resistance. We look at MET amplification as a can be implemented for uncommon mutations. One is osimertinib. mechanism of resistance. We’re seeing KRAS mutations popping up We’ve got data now that osimertinib is active in uncommon EGFR from time to time, BRAF mutations popping up as mechanisms of mutations. resistance.

And we also have afatinib. Afatinib has also been shown—recently [in the] largest group of uncommon mutations that afatinib does elicit meaningful responses.

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Acquired Drug Resistance: Osimertinib1 (Cont’d) EGFR TKIs + in the First-Line Setting1-4

• Osimertinib resistance is the new emerging challenge • Phase 3 RELAY study: erlotinib + ramucirumab vs erlotinib alone – New EGFR-resistance mutations (C797S) are emerging in patients; not yet targetable – 40% reduction in the risk of progression or death with erlotinib + ramucirumab combination vs single-agent erlotinib – Novel resistance mechanisms, such as acquired KRAS mutations and ALK and RET – Median PFS with erlotinib + ramucirumab 19.4 mo vs 12.4 mo with erlotinib alone (HR = 0.59; 95% CI, fusions, are increasingly being identified 0.46-0.76; P < .0001) Start of osimertinib Biopsy date – OS data not yet mature 10,000 – More grade 3 or higher AEs with erlotinib plus ramucirumab (72%) vs erlotinib (54%); grade 3 hypertension and acneiform dermatitis more common in combination arm 1,000 EGFR exon 19 del May 29, 2020: The FDA approved ramucirumab in combination with erlotinib for the first-line treatment EGFR T790M 4 100 of metastatic EGFR mutation–positive NSCLC based on efficacy data from the RELAY trial KRAS Q61K

10 • Phase 2 TORG1833 study: evaluating osimertinib + ramucirumab vs osimertinib alone in the first-line Plasma, copies/mL N/D setting is under way 0 3 6 9 Time on Osimertinib, mo

1. Nakagawa K et al. ASCO 2019. Abstract 9000. 2. Nakagawa K et al. Lancet Oncol. 2019;20:1655-1669. 3. Nakahara Y et al. ASCO 2019. Abstract TPS9120. 1. Oxnard GR et al. JAMA Oncol. 2018;4:1527-1534. 4. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-ramucirumab-plus-erlotinib-first-line-metastatic-nsclc.

I think the largest body of data we have for mechanisms of And then we have RELAY, which is a randomized study to erlotinib resistance post–first-line osimertinib has been in plasma. So I think versus erlotinib plus ramucirumab, showing a robust benefit in we just have a nascent understanding of this right now. We’re just progression-free survival. at the ground floor, and it’ll be important to better define and characterize tumor biology post osimertinib as we move forward. And I will just say that ramucirumab plus erlotinib, the PFS is around 19.4 months, which is not that far off from what osimertinib Dr. Drilon: Absolutely. And sometimes we even see fusions pop up. provides.

Dr. Levy: Right. Dr. Drilon: Exactly.

Dr. Drilon: Like RET or ALK. Things we’re used to seeing in isolation Dr. Levy: So I think the antiangiogenesis story still is evolving—and pop up in the EGFR context. we’ll learn more. I think there’s a cooperative group trial looking at osimertinib plus ramucirumab versus osimertinib alone. So I think

Erlotinib + in the First-Line Setting we’ll learn more as we move forward.

• Phase 2 JO25567 study1,2 – 46% reduction in the risk of progression or death with erlotinib + bevacizumab combination vs Narrator: On May 29, 2020, the FDA approved ramucirumab in single-agent erlotinib – Median PFS with erlotinib + bevacizumab 16 mo vs 9.7 mo with erlotinib alone (HR = 0.54; 95% CI, combination with erlotinib for the first-line treatment of metastatic 0.36-0.79; P = .0015) – No difference in overall incidence of serious AEs between arms, but more grade 3 or higher AEs with EGFR mutation–positive NSCLC based on efficacy data from the erlotinib plus bevacizumab (90.7%) vs erlotinib (53.2%), primarily from grade 3 hypertension RELAY trial. • Phase 3 NEJ026 study3-5 – ORR with erlotinib + bevacizumab 72% vs 66% with erlotinib alone – Median PFS with erlotinib + bevacizumab 16.9 mo vs 13.3 mo with erlotinib alone (HR = 0.61; 95% CI, 0.42-0.88; P = .016) 1-3 – Median OS with erlotinib + bevacizumab 50.7 mo vs 46.2 mo with erlotinib alone (HR = 1.00; 95% CI, EGFR TKIs + Chemotherapy in the First-Line Setting 0.68-1.48) – Grade 3 or higher AEs more common with erlotinib plus bevacizumab (88%) vs erlotinib (46%) • Phase 3 NEJ009 study1 • Phase 3 BEVERLY study (NCT02633189) – ORR with gefitinib + carboplatin + pemetrexed 84% vs 67% with gefitinib alone – Evaluating erlotinib + bevacizumab vs erlotinib alone in the first-line setting is under way – Median PFS1 with gefitinib + chemo 21 mo vs 11 mo with gefitinib (HR = 0.49; P < .001); no difference 1. Seto T et al. Lancet Oncol. 2014;15:1236-1244. 2. Kato T et al. Drug Saf. 2018;41:229-237. 3. Furuya N et al. ASCO 2018. Abstract 9006. 4. Saito H et al. Lancet Oncol. 2019;20:625-635. 5. Maemondo M et al. ASCO 2020. Abstract 9506. in PFS2 between groups – Median OS with gefitinib + chemo 52 mo vs 39 mo with gefitinib alone (HR = 0.70; P = .013) – More grade 3 or higher AEs with gefitinib + chemo (65.1%) vs gefitinib (31.4%); hematologic toxicities more common with combination therapy • Phase 3 study comparing gefitinib + carboplatin + pemetrexed to gefitinib alone2 What do we know about combination therapies for EGFR-mutant – Included patients with PS = 2 lung cancers? – Radiologic RR 81% with combination vs 69% with gefitinib alone (P = .012) – Median PFS 16 mo with combination vs 8 mo with gefitinib (HR = 0.50; P < .001) – Median OS not reached with combination vs 18 mo with gefitinib alone (HR = 0.45; P < .001) – Clinically relevant grade ≥3 toxicities occurred in 51% vs 25% of patients receiving gefitinib Dr. Levy: Yes, I think it makes a lot of sense, now that TKIs have combination and gefitinib alone, respectively 3 defined their role in the EGFR space, that then we add certain • FLAURA2: osimertinib ± chemotherapy (NCT04035486) currently recruiting patients 1. Nakamura A et al. ASCO 2018. Abstract 9005. 2. Noronha V et al. ASCO 2019. Abstract 9001. 3. https://clinicaltrials.gov/ct2/show/NCT04035486. agents upfront. You know, there’s controversy. Should you add agents up front, or should you delve into the resistant setting? And they’re both going on. Dr. Drilon: And how about adding chemotherapy to a TKI?

But I think some of the data we have with bevacizumab continue Dr. Levy: And what we’ve learned from a Japanese study and to emerge. And what we’ve seen in a couple of studies from Asia an Indian study is, essentially, if you add chemotherapy to a is that adding bevacizumab to first-generation TKI does improve first-generation TKI compared with a first-generation TKI alone progression-free survival. in EGFR-mutant lung cancer patients, you do witness a marked improvement in overall survival.

Dr. Drilon: Yes.

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Dr. Levy: And that maybe speaks to tumor heterogeneity upfront, Mobocertinib (TAK-788) Shows Promise in NSCLC and knocking out the clones that aren’t sensitive to the TKI. With EGFR Exon 20 Mutations1

• Mobocertinib: “EXCLAIM” extension cohort 80 769_ASV 773_NPH Other exon 20 insertion Exact variant unknown (NCT02716116) 60 40 Confirmed ORR, 43% (n = 28) • Mobocertinib (ASCO 2019): observed activity PD I think what we don’t know is whether the same trend will hold true – 43% confirmed ORR and 7.33-month median PFS 20 0 in all patients, including those with baseline CNS SD SD -20 SD SD SD PD SD SD SD metastases SD PR -40 PR PR PR SD if we use osimertinib. Remember, the data we have with chemo » At R2PD dose of 160 mg by mouth once daily PR PR PR SD PR -60 PR » N = 28 patients -80 PR PR is with first-generation TKI. And we don’t know if chemo added • Responses observed regardless of Lesions, % Best Change in Target -100 – Treatment history (prior chemotherapy or ICI) PR Prior TKI N N N N Y N N N N N N N Y N N N N N N N N N Y Y N – Which specific exon 20 insertion variant Prior IO N Y Y N Y N N N N Y Y N Y Y N Y Y Y N N Y N Y Y Y to third-generation TKI compared with third-generation TKI alone – CNS involvement • Activity against intracranial metastases Exon 20 Confirmed Confirmed Patients, n will do anything. FLAURA2 is a trial that will look at this. So, that’s – 3 of 12 patients (25%) with brain metastases had Insertion Variant Responders, n ORR objective responses 769_ASV 5 2 40% • Most common AEs at 160 mg once daily exciting. I think that will enroll quickly, and we’ll have our answer – 96% had any AE; 63% had grade ≥3 AE 773_NPH 4 2 50% – Diarrhea: 85% any grade (18% grade ≥3) Exact variant 4 2 50% soon. – Nausea: 43% any grade unknown – Rash: 36% any grade Other 15 6 40% – Vomiting: 29% any grade 1. Riely G et al. International Association for the Study of Lung Cancer 2019 World Conference on Lung Cancer (WCLC 2019). P1.01-127. EGFR Exon 20: Why Do First-/Second-Generation EGFR TKIs Lack Efficacy?1

Wild-Type EGFR Wild-Type EGFR Key Clinical Trials in EGFR Exon 20 Insertion–Positive NSCLC Deletions Beyond that, there are drugs, like TAK-788 [mobocertinib]. And in Inhibitor Target Clinical Triala Key Results β3 β3 Retrospective analysis of Gefitinib/erlotinib EGFR PFS < 3 mo; RR 8%-27% clinical studies β4 β4 the EXCLAIM extension cohort, we actually saw a very encouraging PR for 1 patient Dacomitinib EGFR/HER2/HER4 NCT00225121 with D770delinsGY C-helix out C-helix in NCT00525148, NCT00949650, Afatinib EGFR/HER2/HER4 PFS 2.7 mo; RR 8.7% NCT01121393 Insertions response rate of north of 40%. Inactive Active EGFR/HER2/HER4 NCT00266877 RR, 0%

Osimertinib EGFR T790M NCT03414814 Ongoing Exon 19 Deletion Exon 20 Insertion Poziotinib EGFR/HER2 NCT03066206 Ongoing; RR 43% D770>GY patient + erlotinib EGFR NCT00895362 β3 with PFS 3.5 y β3 Preliminary report: 3 of 4 EGFR β4 Cetuximab + afatinib NCT03727724 ex20ins patients with PR; β4 PFS 5.4 mo Luminespib Hsp90 NCT01854034 PFS 2.9 mo; RR 17% Preclinical inhibition Active Active Tarloxotinib EGFR – of ex20ins EGFR Ongoing; preliminary antitumor Mobocertinib EGFR/HER2 ex20ins NCT02716116 activity reported Preclinical inhibition TAS6417 EGFR ex20ins – The active form of EGFR exon 20 insertion mutants of ex20ins EGFR not too dissimilar from that of wild-type EGFR Preclinical inhibition Compound 1A EGFR/HER2 ex20ins – of ex20ins EGFR → translates to narrower therapeutic window

a Details for trials with NCT numbers can be accessed at https://clinicaltrials.gov. 1. Vyse S, Huang PH et al. Signal Transduct Targeted Ther. 2019;4:5. ALK Inhibitors in NSCLC So, Alex, you were talking earlier about how not all EGFR mutations are the same. And exon 20 has been this EGFR mutation that we’ve had a hard time getting to and drugging. Do you want to talk a little bit about exon 20?

Dr. Drilon: Yes, for sure. So, it has been a very recalcitrant subtype of EGFR mutation. And it has a lot of parallels, actually, with HER2 So, why don’t we pivot now and talk about fusions? And we’ll start mutations that are also insertions/deletions, and we’ll look at that with one of the most common ones, ALK, that occurs in up to 4% of later on. patients. What do we know about targeted therapy?

But the thing about these mutations is that designing drugs tends ALK TKIs in NSCLC to be challenging because these kinase domain mutants sort of behave similarly to the wild type. So there’s a lower therapeutic window here. And that’ll inform what we’re seeing in terms of side effects. Next-generation ALK TKIs vs crizotinib FDA approved • More potent in preclinical models • Higher CNS activity But basically, there are a few different drugs that have been • Wider coverage of ALK resistance explored. There’s the drug poziotinib, which is an inhibitor of the Ensartinib ErbB family. And we’ve certainly seen responses in anywhere from 15% to 30% of cases, given the updated data.

Dr. Levy: Yes, it’s become a crowded space for ALK fusions. We started out with crizotinib, and then we’ve moved forward now with multiple other agents that are FDA approved. We have ceritinib, alectinib, brigatinib, and lorlatinib. And we have other ALK drugs that aren’t approved, ensartinib and entrectinib. Crowded space for a small niche, but nevertheless it’s an embarrassment of riches for us.

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I think that while we started out with crizotinib as the standard And so, I think both of these have been a win for patients with ALK- of care for patients with ALK rearrangements, we really have now rearranged lung cancer. Certainly, my standard of care for patients moved more towards next-generation ALK-directed therapy, similar that are ALK rearranged is alectinib. to the EGFR story. And we have, really, two trials that have shown that next-generation ALK drugs, either alectinib or brigatinib, have Narrator: On May 22, 2020, brigatinib received FDA approval for outperformed crizotinib. first-line treatment of ALK-positive NSCLC based on results from the ALTA-1L trial, which showed a progression-free survival hazard Dr. Drilon: Yes. ratio of 0.49, an objective response rate of 74%, and an intracranial response rate of 78%.

ALEX: Alectinib vs Crizotinib in First-Line ALK+ NSCLC1,2 CNS Response to ALK TKIs in Patients PFS (Investigator Assessed) OS With Measurable CNS Metastases1-4 100 Alectinib (n = 152) 100 Alectinib (n = 152) Crizotinib (n = 151) Crizotinib (n = 151) 80 HR = 0.43 (95% CI, 0.32-0.58) 80 + Censored ALK TKI ALK TKI Naïve Post Crizotinib 60 60

40 40 Alectinib 81% (ALEX) 54% (ALUR) 34.8 20 (17.7-NE) 20 Brigatinib PFS Estimate, % PFS Estimate, % 78% (ALTA-1L) 67% (ALTA) 10.9 90/180 (9.1-12.9) 0 0 0 6 12 18 24 30 36 0 6 12 18 24 30 36 42 48 54 60 Ceritinib 73% (ASCEND-4) 35% (ASCEND-5) Time, mo Time, mo Lorlatinib 53% (phase 2 cohort 2-5), Median follow-up: – 27.8 months (alectinib), 22.8 months (crizotinib) (phase 1 and 2) 42% (phase 1) Crizotinib 29% (ALTA-1L), 50% (ALEX) –

Chemotherapy 27% (ASCEND-4) – 1. Camidge et al. ASCO 2018. Abstract 9043. 2. Peters S et al. ASCO 2020. Abstract 9518.

1. Soria JC et al. Lancet. 2017;389:917-929 2. Peters S et al. N Engl J Med. 2017;377:829-838. 3. Soloman BJ et al. Lancet Oncol. 2018;19:1654-1667. 4. Camidge DR et al. N Engl J Med. 2018;379:2027-2039.

Dr. Levy: So the first trial, obviously, is ALEX. It’s randomized 1:1 to alectinib versus crizotinib, showing an improvement in response I think probably one of the most important things to talk about rate, an improvement in intracranial response rate, improvement with patients who are ALK rearranged is that they do have a in PFS. And interestingly, the median PFS in the alectinib arm is 34 propensity to metastasize to the brain. months. That’s PFS, not OS. That’s close to 3 years. And I think the old-school way of thinking is, when patients come Dr. Levy: So I think that trial really altered the therapeutic in with brain metastases, these patients should be referred to paradigm for patients with ALK-rearranged lung cancer. The safety radiation oncology. profile was reasonable with alectinib compared with crizotinib. I think we see some increases in LFTs, perhaps some nausea, some And this gets back to how important it is to do molecular testing, bilirubin elevations. But, overall, a real win for ALK-rearranged lung because if a patient has an ALK rearrangement and they do have cancer patients. brain metastases, the response rates to alectinib and brigatinib in the brain are north of 70%. And it really circumvents the need, I

ALTA-1L: Phase 3, Brigatinib vs Crizotinib (ALK TKI Naïve)1 think initially, for a radiation oncologist.

100 HR = 0.49 (95% CI, 0.35-0.68) P < .0001 And I don’t know if you have any different thoughts about this, or if 80 this has changed your practice pattern, but it’s been surprising how 60 well these drugs really work, how active they are in the CNS. Median PFS 2-Year PFS Events, n (%) PFS, % 40 (95% CI), mo (95% CI), % Brigantinib 63 (46) 24 (18.5-NR) 48 (39-57) 20 Brigantinib (n = 137) Crizotinib 87 (63) 11 (9.2-12.9) 26 (18-35) 1-3 Crizotinib (n = 138) Alectinib: CNS Efficacy 0 0 6 12 18 24 30 36 Time, mo 70 CNS Response With Measurable CNS Disease No. at Risk 60 Prior CNS radiation 50 Brigantinib 137 97 84 75 39 3 0 40 Yes (n = 34) • Majority of patients on later-line alectinib Crizotinib 138 80 49 37 17 2 0 30 No (n = 16) 20 had baseline CNS disease (60%); CNS 10 0 ORR was 43%, and CNS DCR was 85% May 22, 2020: Brigatinib received FDA approval for 1L treatment of ALK+ NSCLC based on -10 -20 ALTA-1L (brigatinib vs crizotinib) showing PFS HR = 0.49, ORR 74%, and intracranial RR 78% -30 • Among all patients, 17% had PD in CNS, -40 -50 11% with PD in CNS only, 8% in those 1. Camidge DR et al. ESMO Asia Congress 2019. Abstract LBA1. -60 -70 without baseline CNS disease

Decrease From Baseline), % -80 -90

Sum of Longest Diameter (Maximum -100 Patient • ALEX study looked at ALK TKIs as Incidence of CNS Progression first-line treatment (alectinib vs crizotinib), With Baseline Metastases Without Baseline Metastases with a mPFS of 25.7 vs 10.4 mo Crizotinib 12-month CIR = 58.3% (95% CI, 43.4-70.5) Crizotinib 12-month CIR = 31.5% (95% CI, 22.1-41.3) Alectinib 12-month CIR = 16.0% (95% CI, 8.2-26.2) Alectinib 12-month CIR = 4.6% (95% CI, 1.5-10.6) • In ALEX,a there was a longer time to More recently, we’ve got the ALTA-1L data, very similar design. 100 100 CNS PD with alectinib (HR = 0.18 with 80 80 baseline CNS metastases; HR = 0.14 Patients randomized to brigatinib, another next-generation ALK- 60 60 without baseline CNS metastases) 40 40 directed therapy, versus crizotinib, showing an improvement in 20 20 • Similar data with brigatinib and ceritinib 0 0 Cumulative Incidence, % 0 6 12 18 24 Cumulative Incidence, % 0 6 12 18 24 PFS, a hazard ratio of 0.49, and a proclivity for activity in the brain Time, mo Time, mo a ALEX study is the first to include prospective CNS assessments for all patients. compared with crizotinib. 1. Gadgeel S et al. J Clin Oncol. 2016;34:4079-4085. 2. Peters S et al. N Engl J Med. 2017;377:829-838. 3. Gadgeel S et al. Ann Oncol. 2018;29:2214-2222.

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Dr. Drilon: Yes, I agree 100%. And alectinib is also my preferred TKI upfront. And really, we’re seeing a parallel to what we saw with osimertinib—a good drug in the brain, addresses resistance. And we’re reaping the benefits in the frontline setting. ROS1 Inhibitors 1 Treating Resistance to ALK Inhibitors in NSCLC Cellular ALK Phosphorylation Mean IC50 (nmol/L) IC50 ≤ 50 nmol/L Mutation Status Crizotinib Ceritinib Alectinib Brigatinib Lorlatinib

Parental Ba/F3 763.9 885.7 890.1 2,274.0 11,293.8 50 nmol/L < IC50 < 200 nmol/L EML4–ALK V1 38.6 4.9 11.4 10.7 2.3 EML4–ALK 61.9 5.3 11.6 4.5 4.6 IC50 ≥ 200 nmol/L 61156Y EML4–ALK 130.1 8.2 397.7 26.1 49.0 I1171N EML4–ALK 94.1 3.8 177.0 17.8 30.4 I1171S EML4–ALK 51.4 1.7 33.6 6.1 11.5 I1171T • Each ALK mutation imparts differential EML4–ALK 115.0 38.0 27.0 18.0 8.0 F1174C sensitivities to ALK TKIs EML4–ALK 339.0 9.3 117.6 26.5 34.0 L119 6M EML4–ALK 0.4 196.2 42.3 13.9 14.8 • Lorlatinib is active against most acquired L1198F EML4–ALK ALK mutations, including the G1202R 381.6 124.4 706.6 129.5 49.9 G1202R mutation EML4–ALK 58.4 50.1 58.8 95.8 5.2 G1202del EML4–ALK 116.3 35.3 27.9 34.6 11.1 D1203N Dr. Levy: ROS1—yet another fusion that’s relevant in advanced EML4–ALK 42.8 5.8 31.6 24.0 1.7 E1201K EML4–ALK 117.0 0.4 25.0 ND 10.0 G1269A non–small cell lung cancer. EML4–ALK 338.8 237.8 75.1 123.4 69.8 D1203N + F1174C EML4–ALK 153.0 97.8 82.8 136.0 26.6 D1203N + E1210K 1. Gainor JF et al. Cancer Discov. 2016;6:1118-1133. ROS1 Fusion NSCLC (TKI-Naïve Patients)1-9

But let’s talk a little bit about resistance. What do we know about ORR, % PFS, mo OS, mo CNS Response Rate, % how these drugs develop on-target resistance to targeted TKIs, the Crizotinib 72 19.2 51.4 – early-generation TKIs? Ceritinib 62 19.3 24.0 25 Lorlatinib 62 21.0 NR 67 Dr. Levy: Yes, I think that we’ve got a lot of data now emerging with Entrectinib 77 19.0 NR 55 Entrectinib 80 26.3 NR – resistant patterns post alectinib. The one that is really front and without brain metastasis center is the G1202R, the solvent-front mutation—quite prevalent Repotrectinib 82 NR NR 100 post alectinib, based on the data we have, right? And that’s really • Crizotinib and entrectinib are FDA approved to treat ROS1-fusion NSCLC

1. Shaw AT et al. N Engl J Med. 2016;374:54-61. 2. Besse B et al. 42nd European Society for Medical Oncology Congress (ESMO 2017) Abstract 1308PD. one where we’re trying to learn how to best target. 3. Ou et al. WCLC 2018. Abstract OA02.01. 4. Solomon BJ et al. ESMO 2018. Abstract 1380PD. 5. Lim SM et al. J Clin Oncol. 2017;35:2613-2618. 6. Barlesi et al. European Lung Cancer Congress 2019 (ELCC 2019) Abstract 109O. 7. Shaw et al. ELCC 2019. Abstract 107O. 8. Cho et al. ASCO 2019. Abstract 9011. 9. Besse B et al. ASCO 2019. Abstract 9011.

Lorlatinib in Patients With Prior ALK TKI Treatment The data, of course, probably start with crizotinib. But we’ve got

• Lorlatinib in patients with ALK-positive NSCLC: results from a global phase 2 study1 newer agents that are coming down. Maybe you can just walk me

Previous Non-Crizotinib TKI ≥2 ALK TKIs through the movement that’s happening within ROS1 right now. (ORR: 32.1%) (ORR: 38.7%) 80 80 60 60

40 40 1 20 20 ROS1: Response to Crizotinib 0 0

-20 -20 OS by ROS1 Fusion Partner -40 -40 100 -60 -60 -80 -80 80 CD74 -100 -100 60 Change in Tumor Size From Baseline, % Change in Tumor 40 EZR 20

1. Solomon BJ et al. Lancet Oncol. 2018;19:1654-1667. 0 SDC4 -20 SLC34A2 -40 LIMA1 MSN -60 CR TPM3 Best Change From Baseline, % PR EML4–ALK -80 Dr. Drilon: And what we know from data with next-generation SD Negative PD -100 Failed drugs like lorlatinib, which can work very well against these Median PFS: 19.3 mo (95% CI, 15.2-39.1) 0 10 20 30 40 50 60 70 80 90 Time, mo kinase domain mutations—there was just a paper showing that 1. Shaw AT et al. Ann Oncol. 2019;30:1121-1126. in patients whose cancers actually harbor these mutations, the response rate seems to be higher than in patients who don’t. Dr. Drilon: Absolutely. So, as you said, the first agent to So, in a sense, it may be a way of selecting patients who are most demonstrate activity was crizotinib. Interestingly, also, in the likely to benefit from this therapy. But I would argue that even in PROFILE 1001 trial, you had an excellent response rate and, the absence of molecular profiling, with the overall profile of the interestingly, a median PFS that was about 19 months, so much drug with a response rate of north of 40%, pretty reasonable to just longer than we saw with ALK fusions for crizotinib. So it says go ahead and start. something biologically about these tumors.

But as you intimated, there are now two FDA-approved TKIs. The second one is entrectinib for ROS1 fusion–positive lung cancers.

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Ceritinib: Phase 2, Open-Label Trial1 Entrectinib in ROS1-Rearranged NSCLC: Time to CNS Progression1 1.0 All Patients Median PFS, mo Endpoint a All 9.3 mo (95% CI, 0-22) Integrated analysis of 53 patients with ROS1 fusion–positive NSCLC enrolled in ALKA-372-001, N = 32 0.8 Crizotinib naïve 19.3 mo (95% CI, 1-37) STARTRK-1, and STARTRK-2 ORR, % 62 0.6 100 9.3 (all) 80 mPFS, mo 0.4 19.3 (crizotinib naïve) 60 PFS, Proportion 0.2 All mDOR, mo 21.0 Crizotinib naïve 40 0 0 3 6 9 12 16 18 21 24 27 30 33 20

mOS, mo 24 Patients Free of

Time, mo CNS Progression, % 0 • The most common AEs (mostly grade 1 or 2) were diarrhea (78%), nausea (59%), and anorexia (56%); 0 6 12 18 24 30 0 0 grade 4/5 AEs included dyspnea, acute hepatitis, increased LFTs, hyperglycemia, and hyperuricemia Time, mo in 1 patient each, and pneumonia in 2 patients No. at Risk 53 42 38 33 30 18 11 7 7 6 5 3 2 1 (35) (31) (30) (28) (25) (15) (9) (7) (7) (6) (5) (3) (2) (1) a 32 patients with ROS1 rearrangement were treated with ceritinib in this trial: 30 were crizotinib naïve and 2 were previously treated. 1. Lim SM et al. J Clin Oncol. 2017;35:2613-2618. 1. Drilon et al. Lancet Oncol. 2020;21:261-270.

And actually, data on ceritinib, which is in the NCCN guidelines, but Dr. Levy: Yes, and as you mentioned, I think in the pooled analysis not FDA approved. from the STARTRK data, they did show, in the 50-something-odd patients, that there was a meaningful response in the brain. Very briefly, the data on ceritinib was from a phase 2 South Korean trial, where also we saw very good response rates and progression- Dr. Drilon: Correct. free survival that were comparable actually to what we saw with crizotinib. Dr. Levy: And I don’t think we’ve seen that with—at least reported data with—crizotinib.

Entrectinib in ROS1-Rearranged NSCLC: Overview and Integrated Dataset1 Dr. Drilon: Yes, you’re absolutely right. The PROFILE 1001 trial reported on zero patients with brain metastases. So there’s much • Multikinase inhibitor Integrated Dataset Endpoint more of a wealth of data on CNS activity with entrectinib. • Very potent against ROS1 (IC50 = 5 nM) (N = 53)

• Good CNS penetration ORR, % 77 Dr. Levy: Okay. So you’ve got crizotinib, ceritinib, and entrectinib. Common AEs of entrectinib reflect its mPFS, mo 19 effects on multiple targets, including mDOR 24.6 Do you ever revert back to crizotinib at any point—not after, but TRK-specific on-target effects such as dizziness, lightheadedness, issues Intracranial ORR, % 55 you said entrectinib is sort of your go-to solely based on the CNS with proprioception, paresthesia, mPFS in patients with activity, or are there cases where you would still use crizotinib and weight gain 13 brain metastases frontline for your ROS1 patients?

a Integrated analysis of data from the global multicenter trials (ALKA, STARTRK-1, STARTRK-2) in patients with ROS1 fusion–positive NSCLC previously untreated with an ROS1 TKI. 1. Doebele R et al. WCLC 2018. Abstract OA02.01. Dr. Drilon: I think in general, as long as there are no issues surrounding tolerability, I would just use entrectinib for all of my And then finally, moving back to entrectinib, which is different from patients that walk in the door. the other drugs in that it’s a multikinase inhibitor that also inhibits

TRK. And it was designed to have meaningful activity in the central Resistance to Crizotinib in ROS1-Rearranged NSCLC1 nervous system, something that, at least with crizotinib, we were worried about given the data in ALK. • Multiple mechanisms of resistance to crizotinib – Most common is acquisition of a secondary ROS1 mutation, especially ROS1 So what are we seeing? With the entrectinib data, there was a G2032R (25%-30% of patients) » Ceritinib and entrectinib cannot overcome this resistance mechanism pooled analysis of three different trials showing, again, a high – ROS1-independent resistance mechanisms response rate and a median progression-free survival that, in the » Alternative or bypassed signaling pathways that drive resistance as a secondary pathway overall population, wasn’t very different from crizotinib. However, • CNS progression if you take a deep dive and look at things like duration of response, then you are seeing the numbers get up into about the 25-month range. 1. Gainor JF et al. JCO Precis Oncol. 2017;2017.

So I think that even though the high-level data seem similar for entrectinib and crizotinib, if I had someone walk in during clinic, But it’s interesting, the question as to what to use next. And that’s today I tend to favor entrectinib, just because you might get the really informed by resistance patterns that we see with the early- activity of the drug in the CNS to prevent brain metastases. But, generation TKIs. Obviously, the most data that we have is with hopefully, also length in progression-free survival. crizotinib. But as we’ve talked about with ALK, you can see these cancers acquire ROS1 kinase domain mutations, like the G2032R solvent-front mutation, which is paralogous to the ALK G1202R.

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Dr. Levy: Right. Dr. Levy: Right.

ROS1 Fusion NSCLC in TKI-Pretreated Patients1-9 Repotrectinib in ROS1-Rearranged NSCLC1,2

• Multikinase inhibitor (ROS1, TRK, ALK) CNS Response Efficacy ORR, % PFS, mo OS, mo Rate, % Pretreated • Potent activity against ROS1 observed in phase 1 TRIDENT-1 trial – ORR = 91% in TKI-naïve ROS1 NSCLC Crizotinib 72 19.2 51.4 – – – ORR = 57% in ROS1 NSCLC after progression on first-line crizotinib Ceritinib 62 19.3 24.0 25 No • Designed specifically to overcome gatekeeper and solvent-front resistant mutations Entrectinib 77 19.0 NR 55 No (eg, G2032R)

Lorlatinib 62 21.0 NR 67 Yes (27%)

Repotrectinib 82 NR NR 100 Yes (39%)

1. Shaw AT et al. N Engl J Med. 2016;374:54-61. 2. Besse B et al. ESMO 2017. Abstract 1308PD. 3. Doebele R et al. WCLC 2018. Abstract OA02.01. 4. Solomon BJ et al. ESMO 2018. Abstract 1380PD. 5. Lim SM et al. J Clin Oncol. 2017;35:2613-2618. 6. Barlesi F et al. ELCC 2019. Abstract 109O. 7. Shaw A et al. ELCC 2019. Abstract 107O. 8. Cho BC et al. ASCO 2019. Abstract 9011. 9. Besse B et al. ASCO 2019. Abstract 9011. 1. Drilon AE et al. Cancer Discov. 2018;8:1227-1236. 2. Doebele RC et al. ASCO 2020. Abstract TPS9637.

Dr. Drilon: And fortunately, there are next-generation agents that Dr. Drilon: Thankfully, there is another drug called repotrectinib or have been explored after patients fail a first-generation pill. TPX-0005, which, in contrast to lorlatinib, was really meaningfully designed to hit these solvent-front mutations and the other kinase

Lorlatinib in ROS1-Rearranged NSCLC: Overview domain mutations.

• ALK/ROS1 TKI1,2 Lorlatinib is indicated for the treatment Preliminary Clinical Activity of Repotrectinib • High potency against ROS1 of patients with ALK-positive metastatic 1 2 Against ROS1 G2032R Solvent-Front Mutation (IC50 = 0.05 nM) NSCLC whose disease has progressed

1,2 on crizotinib and at least 1 other ALK • Good CNS penetration Overall Response • ROS1 G2032R identified by plasma cfDNA or tissue NGS inhibitor for metastatic disease; or 30 test in 5 patients who had prior crizotinib treatment • Preclinical activity against most known alectinib as the first ALK inhibitor 20 resistance mutations in ALK- or therapy for metastatic disease; or 10 80 160 240 160^ 160 • All 5 patients experienced tumor regressions on QD QD QD QD QD repotrectinib ROS1-rearranged NSCLC1 ceritinib as the first ALK inhibitor therapy 0 -10 for metastatic disease3 a • Confirmed ORR: 2/5 (40%) • Minimal activity against ROS1 G2032R -20 – 2/3 (67%) for 160 mg once daily and above with 1 prior -30 # TKI -40 a » 1 cPR at 160 mg once daily with food (DOR 1.0+ -50 c cPR months and remains on treatment at 3.0+ months) -60 b cPR 1 Prior TKI c » 1 cPR at 160 mg once daily (DOR 4.4+ months and -70 >1 Prior TKI

Size From Baseline, % remains on treatment at 18.6+ months) -80 ^ Dose with food 1. Lin JJ et al. J Thorac Oncol. 2017;12:1611-1625. 2. Shaw AT et al. Lancet Oncol. 2017;18:1590-1599. # SD Maximum Change in Tumor 3. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf. -90 PD -100 G2032R identified in (a) plasma cfDNA, (b) tumor tissue, (c) plasma cfDNA and tumor tissue

1. Cho BC et al. ASCO 2019. Abstract 9011. The first one we’ll talk about is lorlatinib, which we’ve heard about already, which is also a ROS1 inhibitor. The drug does have very good CNS activity and has a reported response rate in about the And in that data set—a drug that also has good CNS activity—we 30% to 40% range, after patients fail crizotinib or another TKI. are in contrast seeing responses in cancers that harbor solvent- front mutations in the ROS1 kinase domain.

Lorlatinib in NSCLC With ROS1 Gly2032Arga Mutations 1 Previously Treated With Crizotinib ROS1-Positive NSCLC: Summary

• No patients with the ROS1 resistance mutation, Gly2032Arg, achieved an objective response with lorlatinib 80 Crizotinib ROS1-positive Second-line ROS1 TKI Third-line (and beyond) Best overall response Ceritinib 60 NSCLC therapy ROS1 TKI therapy? Partial response Entrectinib 40 Stable response 20 Objective progression CNS disease 0 • First-in-human study of DS-6051b in patients with Resistance mutation Repotrectinib (TPX-0005) -20 advanced solid tumors conducted in the US; Lorlatinib -40 ROS1 kinase domain mutation TKI with high affinity for ROS1 and NTRK kinases: DS-6051b -60 cfDNA ORR = 33% (2/6 pts ROS+)1 Brigatinib Tumor tissue -80 Both cfDNA and tumor tissue Best Change From Baseline, % -100 • Global phase 2 study investigating the activity of repotrectinib in advanced solid tumors harboring ROS1 or NTRK1/2/3 rearrangements (TRIDENT-1); approximately 360 patients will be enrolled (265 ROS1 + 95 NTRK)2 Gly2032Arg Gly2032Arg Gly2032Arg Gly2032Arg Gly2032Arg Leu2026Met Leu2026Met Ser1986Phe Lys1991Glu • Phase 1 study of entrectinib (RXDX-101), a TRK, ROS1, and ALK inhibitor in children, Gly2032Arg, 3 a Gly2032Arg and G2032R are synonymous. Patients adolescents, and young adults with recurrent or refractory solid tumors 1 .Shaw AT et al. Lancet Oncol. 2019;20:1691-1701.

1. Papadopoulos KP et al. ASCO 2018. Abstract 2514. 2. Doebele RC et al. ASCO 2020. Abstract TPS9637. 3. Desai AV et al. ASCO 2018. Abstract 10536.

The one thing, though, about lorlatinib is that if you look at patients who have the G2032R solvent-front mutation, you’re not Dr. Levy: It’s exciting. So how do you sequence this out? What do really seeing meaningful responses there. You are seeing responses you do in your clinical practice? with other kinase domain mutations, but at least for that subset of patients, you don’t get as much activity as we had hoped to see. Dr. Drilon: I don’t think we have a really good algorithm yet. And I think more data will inform us. But what I do is, I start with a first-

Go online to complete the post-test and evaluation for CME/MOC/CC/CNE credit PeerView.com/NPG900 14 Improving Outcomes in Patients With Molecularly Altered NSCLC Through Broad Implementation of Precision Testing and Treatment: Latest Evidence and Practical Guidance in the Context of a Changing Targeted Therapy Landscape generation TKI, like entrectinib or crizotinib. When they’re resistant, front and test these patients. Do you want to talk a little bit about I transition to lorlatinib or repotrectinib. the evolution of NTRK and essentially the NTRK drugs that are currently coming or currently approved or coming down the pike But it brings up the question, can you then move these next- soon? generation agents into the first-line space, as we’ve spoken about for EGFR and ALK? And certainly both programs have actually Dr. Drilon: As you mentioned, it’s really championed the basket looked at ROS1 TKI-naïve patients. trial strategy, because the way I look at the frequency of these TRK fusions, they’re very common in four rare malignancies, like Interestingly, we’re seeing high response rates. But what you really secretory carcinoma of the salivary gland or breast, congenital want is a PFS readout. And we don’t have mature data yet. fibrosarcoma, and congenital mesoblastic nephroma. But also the second bucket is where you’re seeing them with much lower Dr. Levy: Well, it’ll be interesting to see if it, as you said, mirrors the frequencies in more common cancers, like lung cancer. ALK and EGFR, where drugs are moving up rather than waiting for second or third line. So if you prospectively sequence lung cancers, you’ll see that TRK fusions are found in about 0.2% of cases, recognizing that you’re Dr. Drilon: Right sequencing for a bunch of other things at the same time.

Dr. Levy: It’s an incredible time in precision medicine for lung TRK Inhibitors: Activity Across Tumor Types1,2 cancer. Entrectinib n n n Efficacy Population Baseline CNS Metastases 100 Sarcoma Prostate CRC n Salivary gland n Soft tissue sarcoma n Lung Parameter (n = 74) (n = 16) 80 n Melanoma n Thyroid n Cervix ORR, n (%) 47 (63.5) 10 (62.5) n Unknown primary n Cholangiocarcinoma n Appendix 95% CI 51.5-74.4 35.4-84.8 60 n GI stromal tumor n Pancreatic Dr. Drilon: Right, absolutely. n Bone sarcoma n Breast CR, n (%) 5 (6.8) 0 40 PR, n (%) 42 (56.8) 10 (62.5) 20 Patients with brain metastases SD, n (%) 9 (12.2) 4 (25.0) 0 PD, n (%) 6 (8.1) 1 (6.3) -20

Non-CR/PD, n (%) 3 (4.1) 0 -40

Missing or unevaluable, n (%) 9 (12.2) 1 (6.3) -60 -80 100 n Cholangiocarcinoma (n = 1) n Gynecological (n = 2) -100 n Neuroendocrine (n = 4) n Salivary MASC (n = 13) 75 n Sarcoma (n = 16) n Thyroid (n = 7) 50 n GI other (n = 1) n CRC (n = 7) Parameter All Patients (N = 116) Patients With CNS Metastases (n = 14) n Pancreatic (n = 3) n NSCLC (n = 13) 25 n Breast (n = 6) ORR (95% CI), % 71 (62-79) 71 (42-92) 0 CR, n (%) 12 (10) 0 -25 PR, n (%) 70 (60) 10 (71) -50 SD, n (%) 19 (16) 2 (14) Baseline in SLD, % -75 PD, n (%) 11 (9) 2 (14) Best Improvement From TRK Inhibitors Not determined 4 (3) 0 -100 in NSCLC 1. Rolfo CD et al. ASCO 2020. Abstract 3605. 2. Drilon AE et al. ASCO 2020. Abstract 3610.

But the topline data with the first-generation TRK inhibitors, which are larotrectinib or entrectinib, which we’ve already talked about for ROS1, is that you are seeing responses, and this is across cancer types. So many of those cancers went onto the basket trial regardless of what they looked like under the microscope, as long Dr. Levy: So let’s stay on the fusions and really, you obviously as they had the NTRK fusion of interest. championed the therapeutic landscape for the next fusion, NTRK fusions. TRK Inhibitors: Status of Selected Agents

Different NTRK Gene Fusion Partners Across Multiple Tumors1 Treatment of adult and pediatric patients with solid tumors that • Harbor an NTRK gene fusion without a known acquired resistance mutation Larotrectinib Lung ADC CC CC CC KD MPRIP–TRK1 • Are metastatic or where surgical resection is likely to result in severe morbidity Lung ADC TM TD TM KD CD74–NTRK1 Intrahepatic cholangiocarcinoma KD RABGAP1L–NTRK1 • Have no satisfactory alternative treatments or that have progressed following treatment Colon, PTC, pediatric gliomas, sarcoma, lung ADC CC TM KD TMP3–NTRK1 (TRK) PTC CC KD TPR–NTRK1 (TRKT–1/2) PTC CC KD TFG–NTRK1 (TRKT–3) PTC CC CC CC KD PPL–NTRK1 Treatment of adult and pediatric patients ≥12 years of age with solid tumors that Glioblastoma KD CHTOP–NTRK1 Glioblastoma CC CC KD ARHGEF2–NTRK1 Entrectinib • Harbor an NTRK fusion without a known acquired resistance mutation Glioblastoma IG-C2 IG-C2 IG-C2 IG-C2 IG-C2 IG-C2 KD NFASC–NTRK1 FDA accelerated approval Glioblastoma IG-V KD BCAN–NTRK1 August 2019 • Are metastatic or where surgical resection is likely to result in severe morbidity Spitzoid neoplasms Coil 1A Coil 1B KD LMNA–NTRK1 Spitzoid neoplasms OD TM KD TP53–NTRK1 • Progressed following treatment or have no satisfactory standard treatment Astrocytoma QUA1 TM KD QKI–NTRK2 Astrocytoma BTB TM KD NACC2–NTRK2 TM KD Selitrectinib Pediatric glioma VCL–NTRK2 • Phase 1 testing Pediatric glioma TM KD AGBL4–NTRK2 (BAY2731954; LOXO-195) Lung ADC ZFB ZFB CC KD TRIM24–NTRK2 HNSCC ZF CC KD PAN3–NTRK2 Low-grade glioma KD AFAP1–NTRK2 Repotrectinib • Phase 1 testing Low-grade glioma PB1 CC KD SQSTM1–NTRK2 AML, PTC, pediatric gliomas, 5’ partner protein domain secretory breast, CMN, MASC ETS KD ETV6–NTRK3 TM Transmembrane domain Pediatric gliomas BTB KD BTB1–NTRK3 KD TrkA/B/C kinase domain HNSCC KD LYN–NTRK3 Thyroid cancer KD RBPMS–NTRK3 • There are a number of known NTRK1 (blue), NTRK2 (red), and NTRK3 (green) fusions and tumor types in which they have been identified • It is important to note that not all gene fusions have been characterized functionally 1. Vaishnavi A et al. Cancer Discov. 2015;5:25-34. And the neat thing about the program is that it not only got both of these drugs FDA approved, and actually approved in other You know, this is a different type of fusion, because it can be found regulatory environments, but for the first time, looking at the in multiple tumor types, and we have a basket trial that has landed larotrectinib program, about a third of those cases were pediatric NTRK fusions on the map and put that into what we need to do up cases that went on. And we’ve leveraged a pediatric population

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F589L F617L G595R G639R F633L G623R The other thing is that, if you look very closely at the label, there G667C G709C G696A were cases on the larotrectinib trial of kids who had really bulky

Solvent Front (SF) xDFG Gatekeeper (GK) tumors that weren’t amenable to local therapy. They got targeted Acquired TRK kinase domain mutations in 3 recurrent motifs result therapy, tumor shrank nicely. They got a limb-sparing surgery and in on-target resistance to current generation of inhibitors Repotrectinib (TPX-0005)1,2 Selitrectinib (LOXO-195)3,4 • Designed to bind within ATP-binding boundary with high affinity • Investigational TRK inhibitor being studied in patients with solid a complete pathologic response. So actually, the label allows you and to target wild-type and mutant kinase tumors harboring an NTRK gene fusion who relapsed, became • Potently inhibited wild-type and mutant TRKs in vitro and in vivo, unresponsive, or were intolerant to a prior TRK inhibitor to give a TRK inhibitor in a neoadjuvant fashion for patients with especially the SF mutations that render common resistances to (NCT03215511) TRK inhibitors • Showed activity against acquired resistance mutations in • Phase 1/2 clinical trial is ongoing for TPX-0005 for cancer preclinical studies locally advanced disease. So, a lot of exciting stuff has happened in patients with solid tumors harboring ALK, ROS1, or NTRK fusion • Is thought to bind to TRK kinase domain, re-establishing genes (NCT03093116) blockage of downstream signaling pathways just the last 2 years. 1. Drilon A et al. Cancer Discov. 2018;8:1227-1236. 2. Drilon A et al. ESMO 2019. Abstract 444PD. 3. Cocco E et al. Nat Rev Clin Oncol. 2018;15:731-747. 4. Drilon A et al. Cancer Discov. 2017;7:400-409.

Entrectinib and Larotrectinib: Safety1,2 What we do know is that, similar to ALK and ROS1, resistance can Entrectinib Larotrectinib Expanded Safety-Evaluable Population Expanded Safety-Evaluable Population occur. And again, on-target resistance happens when you have Treatment-Related AEs (n = 355) (n = 260) Any Grade Grade 3/4 Any Grade Grade 3/4 these kinase domain mutations that either involve the solvent ALT increase 10 1 22 4 Anemia 12 5 10 2 front, the xDFG motif, or the gatekeeper. AST increase 11 1 20 <1 Constipation 24 <1 11 0 Diarrhea 23 1 6 0 Dizziness 25 <1 18 <1 Thankfully there now are, believe it or not, second-generation pills Fatigue 28 3 17 <1 Myalgia 15 <1 8 <1 that address resistance. The two of these are selitrectinib, or LOXO- Nausea 21 0 13 <1 Peripheral edema 14 <1 6 0 195, and repotrectinib, which we’ve already talked about for ROS1. Vomiting 14 0 9 0 And both of these drugs were designed to be smaller and fit better • Other AEs observed in 20% or more patients with entrectinib: dysgeusia (41% all grades and <1% grade 3/4); weight gain (20% all grades and 5% grade 3/4) into the ATP pocket and address resistance. 1. Demetri G. et al. ESMO 2018. Abstract LBA17. 2. Hyman DL et al. ESMO 2019. Abstract 445PD.

Selitrectinib and Repotrectinib: Efficacy1,2 Dr. Levy: And just a brief comment on toxicity of these drugs, because they have some interesting on-target side effects that we Selitrectinib (LOXO-195)1 Repotrectinib (TPX-0005)2 need to be mindful of. • 20 patients with identified TRK resistance mutation • 11 patients with TKI-naïve ROS1 fusion–positive NSCLC who had progressed on at least 1 prior TRKi – cORR = 91% – Overall ORR = 45% (9/20) – DOR ≥18 months = 65% – 14 with solvent front mutations: ORR = 50% (7/14) Dr. Drilon: That’s true, and that’s because the TRK pathway plays a – IC ORR in 3 of 3 patients – 4 with gatekeeper mutations: ORR = 25% (1/4) • 18 patients with 1 prior TKI and ROS1 fusion–positive very critical role in nervous system development and maintenance. – 2 with xDFG mutations: ORR = 50% (1/2) NSCLC So things you have to watch out for in your patients, which we’re • Patients who develop TRK-independent resistance – cORR = 39% are unlikely to benefit from selitrectinib not used to seeing, are things like weight gain, because the TRK – IC ORR = 75% • All patients with G2032R had tumor regression pathway modulates the appetite center. Things like pain flares, (ORR = 43%) if patients momentarily come off these drugs, because of, again, rewiring of your threshold for feeling pain. Patients can get dizzy. 1. Hyman D et al. 2019 American Association for Cancer Research Annual Meeting (AACR 2019). Abstract CT127. 2. Drilon A et al. ESMO 2019. Abstract 444PD. They’ll say that they get out of a car and they feel lightheaded, and that’s because the TRK pathway can control balance. And also, And we’ve seen clinical responses reported out for both programs. in line with these neurologic on-target side effects, sometimes you can see paresthesias that are perioral or like a sunburn-like In fact, the most data that we’ve seen has been with selitrectinib, sensation. or LOXO-195, where about 40% to 50% of cases with gatekeeper kinase domain mutations, solvent-front, or xDFGs will respond to But for the most part, I think even though we need to recognize therapy. So, very exciting times. these unique toxicities, these drugs are very well tolerated and are amenable to chronic dosing. Dr. Levy: It is. I mean, just to take one quick step back about identifying NTRK. These are fusions, not mutations, correct?

Dr. Drilon: Correct.

Dr. Levy: And we’re going to see some mutations on our NGS reports, and those do not predict efficacy to these drugs.

Dr. Drilon: That’s right. So the only situation where you may need to pay attention to mutation is when it pops up on top of a fusion, but not when it’s there by itself.

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Dr. Levy: Yes, an incredible story. First- and Second-Generation RET Inhibitors

RET

TK TKL STE Drug Names

First generation Alectinib, cabozantinib, MGC , CK1 Second generation ,

RET Inhibitors AGC in NSCLC CAMK Selpercatinib Pralsetinib (LOXO-292) (BLU-667)

So fortunately, in 2017, we saw the emergence or the entry of selective, clean RET inhibitors into the clinic, and there are two So let’s just finish off the fusions here with RET fusions— major ones. These are selpercatinib or pralsetinib, formerly known as LOXO-292 and BLU-667. Dr. Drilon: Let’s do it. But again, these are designed to be clean drugs that hit the target Dr. Levy: —another actionable alteration discovered in lung very potently, but also avoid these other kinases that result in off- cancer, with some really good drugs coming down. target toxicity.

RET Fusions in Lung Cancer1-8 New FDA Approval for RET Inhibitor Selpercatinib1

RET Fusions Non–small cell lung cancer (2%) • RET fusions are bona fide lung cancer drivers Thyroid cancers (10%-20%) – Mutually exclusive with other driver alterations1,2 Pancreatic cancer (<1%) – Transforming and actionable in vitro and in vivo3,4 May 8, 2020: The FDA granted accelerated approval to selpercatinib for the Salivary gland cancer (<1%) – Up to half of patients with advanced disease have treatment of adult patients with metastatic RET fusion–positive NSCLC Spitz tumors (<1%) brain metastases5 Colorectal cancer (<1%) Ovarian cancer (<1%) • Immunotherapy drugs (PD-1/PD-L1 inhibitors) • Line agnostic Myeloproliferative disorders (<1%) – May be less efficacious in driver-positive NSCLC Many others (<1%) patients, including RET fusions6,7 • Efficacy based on results of LIBRETTO-001 trial • Main outcome measures were ORR and response duration determined by a blinded

P P P P independent review committee using RECIST 1.1 Dimerization Kinase • Identification of RET gene alterations was prospectively determined in local laboratories P P P P using either next generation sequencing, polymerase chain reaction, or fluorescence in KIF5B (most common in lung cancer) CCDC6 or NCOA4 (most common in situ hybridization thyroid cancer)

1. Drilon A et al. Nat Rev Clin Oncol. 2018;15:151-167. 2. Wang R et al. J Clin Oncol. 2012;30:4352-4359. 3. Saito M et al. Carcinogenesis. 2014;35:2452-2456. 4. Takahashi M et al. Cell. 1985;42:581-588. 5. Drilon A et al. J Clin Oncol. 2017;35(suppl):9069. 6. Sabari JK et al. J Clin Oncol. 2018;36(suppl 15):9034. 1. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-selpercatinib-lung-and-thyroid-cancers-ret-gene-mutations-or-fusions. 7. Mazières J et al. J Clin Oncol. 2018;36(suppl 15):9010.

Do you want to talk a little bit about the relevance of RET Narrator: On May 8, 2020, the FDA granted accelerated approval rearrangements in lung cancer and what we can do and what the to selpercatinib for the treatment of adult patients with metastatic drugs are showing? RET fusion–positive NSCLC based on the efficacy results of the LIBRETTO-001 trial. Dr. Drilon: Yes, sure. Like ROS1 fusions, these are found in up to 1% to 2% of non–small cell lung cancers. And again, you’re looking for LIBRETTO-001: Selpercatinib in RET-Altered Cancers1 a fusion. Selpercatinib achieved marked and durable antitumor activity in patients with RET fusion–positive NSCLC and was well tolerated When we didn’t have great drugs, we tried older, dirtier drugs 40 Patients Pretreated With Platinum-based Chemotherapy Treatment-Naïve Patients 20 20 called the multikinase inhibitors, like cabozantinib, and the results 0 0 were modest. You know, we saw response rates anywhere from the -20 -20 -40 -40

-60 -60 high 20 percents to 50%. But these drugs came with a cost, that n Prior anti–PD-1/PD-L1 therapy n No prior anti–PD-1/PD-L1 therapy -80 -80 l Prior multitargeted kinase inhibitor Maximum Change in Tumor Size, % Maximum Change in Tumor these drugs resulted in a lot of side effects due to off-target toxicity. -100 Size, % Maximum Change in Tumor -100

In 105 previously treated patients: • ORR, 70% (95% CI, 60%-78%); responses did In 39 treatment-naïve patients: not differ by fusion partner or number or type of • ORR, 90% (95% CI, 76%-97%) prior therapies, including anti–PD-1/PD-L1 • Median DOR, NR with 27 of 33 (82%) confirmed agents and off-label multikinase inhibitor use responses ongoing at a median follow-up of 7.4 mo • Median DOR, 20.3 mo (95% CI, 15.6-24.0)

1. Goto K et al. ASCO 2020. Abstract 3584.

And what we’ve seen is in the topline data are that these drugs can work very well. Both drugs result in high response rates north of 60%.

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RET Inhibitor: Pralsetinib (ARROW Trial)1 Dr. Drilon: So kind of mirroring what we’ve seen with osimertinib in EGFR-mutant lung cancers with leptomeningeal disease. Response-Evaluable Population

All NSCLC Prior Platinum Treatment Naïve (N = 116)a (n = 80) (n = 26) 20 ORR, % 65b 61b 73 Dr. Levy: And what do we do if we have these drugs up front, or ** 0 95% CI, % 55-73 50-72 52-88 * * * * even in the treatment-refractory setting? What do we know about * * Best overall response -20 * * CR, % 6 5 12 ** * * mechanisms of resistance? Are there drugs that are coming down * * -40 * b b * * PR, % 59 56 62 * * ** ** * SD, % 28 34 15 the pike that may help out with this, similar to again the EGFR and ** -60 * * * ** * PD, % 7 5 12 in Target Lesion Diameter, % Lesion Diameter, in Target n Prior platinum treatment * -80 n Prior treatment other than platinum ** ALK story of sequencing TKIs? Maximum Reduction From Baseline NE, % 0 0 0 n Treatment naïve * * Prior anti–PD-1/PD-L1 therapy DCR (95% CI), % 93 (87-97) 95 (88-99) 88 (70-98) -100 * * * * * Dr. Drilon: Again, we benefit from seeing a lot of parallels with Clinical benefit rate 72 (62-80) 71 (60-81) 73 (52-88) (95% CI), % the other fusions. And certainly, there’s a recent report about the

a Includes 10 patients with prior treatment other than platinum. b Includes 2 patients still on treatment with PRs pending confirmation. solvent-front RET mutations and the G810Rs or other substitutions 1. Gainor J et al. ASCO 2020. Abstract 9515. that have emerged with these selective early-generation TKIs.

That’s not just in patients who have had chemotherapy, but also And so thankfully, there are agents being designed to address the in patients who have had a prior multikinase inhibitor or even in solvent-front mutations. One of them is a drug called TPX-0046 that treatment-naïve patients. And the last thing I’ll say about prior was presented in abstract fashion previously. So the hope, again, is treatment is that some of these patients also got , that we’ll see a sequential TKI paradigm for treatment in the future. and it didn’t seem to affect the likelihood of a response.

Selpercatinib and Pralsetinib: Safety1,2

Selpercatinib Pralsetinib Expanded Safety-Evaluable Expanded Safety-Evaluable Population Population Treatment-Related AEs (n = 531) (n = 120) Any Grade, % Grade 3/4, % Any Grade, % Grade 3/4, % BRAF/MEK Inhibitors ALT increase 21 7 13 2 AST increase 22 5 20 2 in NSCLC Constipation 11 <1 17 2 Diarrhea 16 1 9 – Dry Mouth 27 – 12 – Fatigue 14 <1 13 3 Hypertension 18 9 13 10 • Other AEs observed with pralsetinib in 20% or more (any grade) or 3% or more (grade 3/4) patients: neutropenia (26% all grades and 13% grade 3/4); anemia (11% all grades and 4% grade 3/4)

1. Drilon A et al. WCLC 2019. Abstract PL02.08. 2. Gainor J et al. ASCO 2019. Abstract 9008.

All right, Ben. We’re done with the fusions, and now we’re going to But the one other piece we’ll mention is that because these drugs jump back into the mutations, and we’re going to begin with BRAF. are cleaner, we definitely, in terms of an adverse event profile, are What do we know about BRAF mutations in lung cancer? seeing that these drugs are much better tolerated in the clinic compared with the multikinase inhibitors. BRAF Variants in NSCLC1

Dr. Levy: And having been an investigator participating in one of

D287Y G464V G466 G469 N581 D594 G596R L597 V600E K601E Class I Class II these drugs, I can tell you, I mean, as you know, it’s pretty incredible 155 227 457 714 Class III Ras-binding Protein kinase domain to see the impact they have not only on tumor shrinkage, but domain Class I Class II Class III Substitution 110 107 E quality of life. We’ve had several patients coming in and coughing V600 K601E L597 G596R D594 N581 100 V G464V G469 G466 D287Y 90 A 80 N and short of breath, and within 2 weeks of getting these drugs 70 R 60 51 S 50 G have marked improvement in their symptoms. 40 Patients, n Q V600E 30 25 19 Y 20 7 8 8 9 I 10 1 1 L 0 Dr. Drilon: One thing that we should note also is that these Patients, n drugs, both of them, have intracranial activity. So we’ve seen CNS p.D287p.G464p.G466p.G469p.N581p.D594p.G596p.L597p.V600p.K601 1. Dagogo-Jack I et al. Clin Cancer Res. 2018;25:158-165. metastases, brain metastases shrink nicely with these agents. And we just published a case, actually, with selpercatinib of a patient of mine with leptomeningeal disease, couldn’t get onto the trial, Dr. Levy: Yes, I think this is yet another relevant alteration. It occurs went on an FDA-approved single-patient use protocol and the in roughly 3% of patients with advanced non–small cell lung leptomeningeal disease responded. cancer. Similar to the EGFR story, not all BRAF mutations are the same. Dr. Levy: Yes. Dr. Drilon: Right.

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Dr. Levy: I think the ones that have become front and center and jury’s still out, but again, I tend to use targeted therapy first for relevant and actionable have been the BRAF V600E mutations. But these patients. there are also non-V600E mutations, and the question is how to really target those, and there are ongoing trials looking at targeted Dr. Drilon: That’s my approach, as well. therapies and combinations for non-V600E mutations. Dr. Levy: Yes. But it calls back the importance of looking at the molecular report. Not all BRAF mutations are the same. Some are actionable, some aren’t. Clearly, the V600E is the one that then can drive a treatment decision with targeted therapy.

BRAF V600–Mutant NSCLC Trials HER2 Inhibitors

Previously Treated Treatment Naïve VE-Basket Trial AcSé Trial BRF113928 BRF113928 BRF113928 in NSCLC Vemurafenib1 Vemurafenib2 Dabrafenib3 + trametinib4 Dabrafenib + trametinib4 (n = 62) (n = 101) (n = 78) (n = 57) (n = 36) Male 35 (56%) 50 (50%) 39 (50%) 29 (51%) 14 (39%) Never smoker 25 (40%) 32 (32%) 29 (37%) 16 (28%) 10 (28%) ORR, % (95% CI) 37 (25-50) 45 (35-55) 33 (23-45) 68.4% 63.9% Median PFS 6.5 (5.2-9.0) 5.2 (3.8-6.9) 5.5 (3.4-7.3) 10.2 (6.9-16.7) 10.9 (7.0-16.6) (95% CI), mo Median OS 15.4 (9.6-22.8) 9.3 12.7 (7.3-16.3) 18.2 (14.3-28.6) 17.3 (12.3-40.2) (95% CI), mo

Dabrafenib + mPFS Platinum-based CT Immunotherapy? (10.9 mo)

Dabrafenib + trametinib mPFS Dr. Drilon: Okay, Ben, moving on to another mutation, let’s talk Platinum-based CT Immunotherapy? (10.9 mo) about HER2. 1. Subbiah V et al. JCO Precision Oncol. 2019. DOI: 10.1200/PO.18.00266. 2. Mazieres J et al. ESMO 2018. Abstract 3902. 3. Planchard D et al. ASCO 2017. Abstract 9075. 4. Planchard D et al. ASCO 2020. Abstract 9593.

HER2 Alterations in Advanced NSCLC1 Dr. Drilon: And we know that the single-agent RAF inhibitors certainly are active in this space, with response rates in the order of Treatment Options • Chemotherapy 30% to 40%. But is that the best strategy for these tumors? Amplification Mutation • Immunotherapy • ISH • Sequencing • TKIs: afatinib, dacomitinib, • NGS • NGS Dr. Levy: Yes, I think what we’ve learned is that combo strategy neratinib, osimertinib, poziotinib, pyrotinib, mobocertinib, tarloxotinib with RAF and MEK inhibition has really elicited the most • Monoclonal antibodies/antibody meaningful responses, and— drug conjugates: , Overexpression pertuzamab, T-DM1, DS-8201a • IHC • Treatment combinations Dr. Drilon: Similar to melanoma, right?

Dr. Levy: Similar to melanoma. I think we’ve got now data both 1. Gkolfinopoulos S, Mountzios G. Ann Transl Med. 2018;6:142. in second-line and treatment-refractory patients and in frontline showing a response rate anywhere from 60% to 70% for BRAF Dr. Levy: Yes, this is another emerging target in which we may V600E and PFS ranges between the 10- and 11-month mark. have relevant therapies. I think there’s been a lot of confusion about HER2 in terms of what are the actual tests that drive You know, there are a lot of questions on whether you should treatment decision. Is it amplification? Is it overexpression by IHC? use your targeted therapy first or after treatment. I think what my Is it mutation sequencing by NGS? paradigm and my approach to these patients is, if you identify it and find that you should go ahead, that should trigger a targeted HER2 Mutations and Amplification Are Distinct Targets1-3 therapy decision with dabrafenib and trametinib. • HER2 is overexpressed, amplified, or mutated in a significant fraction of lung adenocarcinomas, with undefined prognostic significance Dr. Drilon: Absolutely. And because of the activity that you • HER2 dysregulation encompasses heterogeneous and distinct alterations – Lack of correlation between overexpression, amplification, and mutations mentioned, this combo’s actually FDA approved for these patients. – Considering HER2-deregulated NSCLC as a unique disease explains, in part, failure of initial clinical trials – Cohorts must be defined according to specific HER2 alteration present

Dr. Levy: Yes, I think it’s important. One other question that maybe HER2 Testing Most HER2-mutant Overlap HER2 responders to T-DM1 have we’ll talk about later is, you know, BRAF V600E mutations may HER2 Amplification HER Mutation Mutation and HER2 low HER2 expression and Amplification no HER2 amplification: be the one genotype that does okay with immunotherapy or HER2 mutation does not FISH (HER2/CEP17 ≥2) 4/145 = 3% 0/145 = 0% necessarily drive copy gains 3/175 = 3% immunotherapy combinations. And when you identify this, should 95% CI, 1%-7% 95% CI, 0%-3% of the mutant allele 95% CI, 1%-7% you use an immunotherapy or chemotherapy-immunotherapy 1. Li BT et al. J Thorac Oncol. 2016;11:414-419. 2. Li BT et al. WCLC 2017. Abstract OA14.05. 3. Li BT et al. J Clin Oncol. 2018;36:2532-2537. regimen, or a dabrafenib-trametinib combination? And I think the

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And I think, importantly, HER2 is overexpressed, amplified, or So I think that, clearly, this is a drug that may have meaningful mutated in a significant fraction of patients with lung cancer. And activity. You were part of the trial. Does toxicity [play a role], in there has been a lack of correlation between these—between terms of the things you witnessed in the study? overexpression, amplification, and mutations. I think what we’ve learned is that mutations may be the right alteration to look at as Dr. Drilon: I think it is exactly the same toxicity that you would we move forward. watch out for if you were giving this for breast cancer. So infusion reactions are something that you need to keep an eye on, and then Dr. Drilon: That’s right. of course moving forward serially, you need to watch the heart because a subset of patients may have cardiomyopathies.

Ado- (T-DM1)1-4 Dr. Levy: Yes. • Trastuzumab antibody conjugate O O to DM-1 (a maytansine derivative) N S N O O Me O O O Me CI • Maytansine potent microtubule Antibody-dependent N N OMe H 1 cellular cytotoxicity (ADCC) O Poziotinib Inhibits EGFR and HER2 Exon 20 Mutations In Vitro targeting agent O

O N OH • Antibody binds to cell internalized Immune H OMe effector HER2 Trastuzumab MCC DM1 (derivative of maytansine) and DM-1 released intracellularly cell Ba/F3 EGFR Exon 20 Ba/F3 HER2 Exon 20 HER3 (N = 20 cell lines) (N = 6 cell lines) • T-DM1 demonstrated activity in Fcү receptor T-DM1 NSCLC cell lines and xenograft ** *** 10000 ** ** P < .0001 10000 * *** P < .04 models Extracellular * *** , nM , nM 1000 ** * P < .01 1000 ** P < .001 50

50 *** • Case report of response in patient 100 ** 100 ** * P < .0001 Intracellular ** * with HER2-mutated NSCLC P P 10 10 1 1 Average IC Average

0.1 IC Average 0.1

Microtubule Lys-MCC-DM1 Lysosome

1. Lopus M et al. Mol Cancer Ther. 2010;9:2689-2699. 2. LoRusso PM et al. Clin Cancer Res. 2011;17:6437-6447. Afatinib Afatinib Erlotinib

3. Cretella D et al. Mol Cancer. 2014;13:143. 4. Weiler et al. J Thorac Oncol. 2015;10:e16-17. Pyrotinib Neratinib Neratinib Poziotinib Poziotinib Osimertinib Dacomitinib Dacomitinib Tarloxotinib TKI Tarloxotinib Tarloxotinib-TKI

Ratio IC Ratio IC 50 1,075 34.8 27.3 19.7 9.7 2.7 50 452 127 26.5 8.4 8.2 3.4 Dr. Levy: And we have some data on some new emerging drugs to Poziotinib to Poziotinib 1. Heymach J et al. WCLC 2018. Abstract 0A02.06. that have come out. One of the ones has been ado-trastuzumab, or T-DM1. You know, we know trastuzumab from the breast cancer literature. It’s an antibody conjugate to a potent microtubule- The other drug that I think has garnered a lot of attention has been targeting agent. The whole idea is that the antibody binds, it’s poziotinib. And this does inhibit both EGFR and HER2 exon 20 in internalized, and then the microtubule-directed agent is delivered vitro. to the cell.

Poziotinib Efficacy in HER2-Mutant NSCLC1 Ado-Trastuzumab Emtansine for Patient 1 With HER2-Mutant NSCLC 12 evaluable patients HER2 PFS ORR (best response): 50% (All Patients n = 13) ORR (confirmed): 42%

PD 100 Confirmed partial response 100 SD 30 SD PR Median PFS: 5.1 mo 75 PD 15 Response not confirmed/follow-up pending 50 0 ORR: 44% -15 25 50

-30 PFS, % 0 -45 Remains on treatment

Confirmed partial response From Baseline, % -25 Maximum Response -60 30% SD PD 0 Individual Patients -50 Ongoing 0 2 4 6 8 10 -75 Partial response start Time, mo G778dupGSP G778dupGSP G778dupGSP Y772dupYVMA Y772dupYVMA Y772dupYVMA Y772dupYVMA Y772dupYVMA Y772dupYVMA Y772dupYVMA Y772dupYVMA Y772dupYVMA Best Response Per RECIST v1.1, % -100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Patients, N Time on Treatment, mo 1. Heymach J et al. WCLC 2018. Abstract 0A02.06.

1. Li BT et al. J Clin Oncol. 2018;36:2532.

And we’ve seen activity with poziotinib specifically in the HER2- And we’ve seen activity with this agent, T-DM1, in non–small cell mutant cohort. The data we have so far show a response rate close cancer cell lines and in xenograft models. And the data we have I to 40% with patients with non–small cell lung cancer harboring think were presented by your colleague with ado-trastuzumab in HER2 mutations, a PFS around 5 months. patients with HER2-mutated non–small cell lung cancer. We’re participating in this trial. I think that this is meaningful Dr. Drilon: Right. activity. I think the challenge with poziotinib has certainly been its toxicity profile, and high rates of rash and diarrhea have been Dr. Levy: And it’s a small group of patients, a mix of patients that— there. I’m not sure if the toxicity is similar to the dacomitinib story, most of them were treatment refractory or had receded upon whether it will be like dacomitinib for EGFR and whether that will second or third line. And this drug did elicit meaningful responses. be prohibitive for really receiving wide uptake of the drug. But it The response rate was north of 40%, and also there was some nice clearly has some activity in HER2. duration of response in some of these patients.

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Dr. Drilon: Right. And one thing we should point out for the audience is that we’re seeing a lot of parallels in terms of therapeutic targeting between EGFR exon 20 insertions—where we have data for poziotinib—and these HER2 mutations. MET Inhibitors 1,2 Mobocertinib and Pyrotinib in HER2-Mutant NSCLC in NSCLC 35 Best response 80 EGFR exon 20 insertion mutation PR 60 HER2 mutation SD 0 PD 40 PD PD 20 SD PD Baseline, % -35

PD Change From SD SD 0 120 40 80 120 80 160 80 160 120 120 80 120 40 160 120 160 40 80 120 40 160 80 120 Dose, mg BID BID BID BID Mutation type SD SD -70 -20 SD PR A775_G776insYVMA SD SD SD SD SD threshold 25 P780_Y781insGSP -40 PR L755P PR PR PR 20 -60 G776 >IC PR 15 G776 >VC -80 G776C PR 10 Best Change in Target Lesions, % Best Change in Target

PR PFS, mo -100 CR 5 Progression-free survival Prior TKI N Y Y N Y N N N N N N Y Y N N N N N N N Y Y N Progression event 0 Prior IO N N N Y Y Y N N Y N Y Y N N Y Y N N N N Y Y N Ongoing A775_G776insYVMA Responses to Mobocertinib in NSCLC Patients With EGFR Exon 20 Insertions 80 mg QD; 120 mg QD; 80-160 mg 5-40 mg QD 160 mg QD PR (n = 12) 40 mg BID 60 mg BID (n = 6) Total Daily Dose So, Alex, let’s move to other relevant alterations. MET exon 14– (n = 9) (n = 9) (n = 24) SD PD Patients with ≥1 post-baseline scan n = 10 n = 9 n = 4 n = 5 n = 18 P780_Y781insGSP L755P ORR, n (%) 0 4 (44) 1 (25) 2 (40) 7 (39) G776 >VC G776C skipping mutations may be as prevalent as ALK rearrangements in CR, n (%) 0 0 1 (25) 0 1 (6) G776 >IC PR, n (%) 0 4 (44) 0 2 (40) 6 (33) 0 5 10 15 20 25 DCR, n (%) 3 (30) 8 (89) 4 (100) 5 (100) 17 (94) PFS, mo lung cancer. We need to remember that. 1. Neal JV et al. WCLC 2018. Abstract P1.13-44. 2. Wang Y et al. Ann Oncol. 2019;30:447-455.

MET Inhibitors in Clinical Trials1 And so other drugs like TAK-788, which we’ve discussed previously, and other multikinase agents, like pyrotinib, are also being Agent Other Molecular Targets IC50, nM explored in this space. Type I Crizotinib MET (type Ia), ALK, ROS1 <1 Capmatinib Selective MET (type Ib) 0.13 Selective MET (type Ib) 3 But then again, you still need to keep in mind that the therapeutic Selective MET (type Ib) 5 window may not be as large as you’re seeing with other paradigms Type II Cabozanitib MET (type II), VEGFR, RET, TIE2, AXL, FLT3, KIT 1.3 like sensitizing EGFR mutations. Merestinib MET (type II), MST1R, FLT3, MERTK, TEK, ROS1, DDR, NTRK, AXL 4.7

• Type I binds ATP-binding pocket in the active conformation; Ib more specific • Type II binds ATP-binding pocket in the inactive conformation; potency is more valuable [Fam-] (DS-8201) in HER2-Expressing or HER2-Mutated NSCLC1 1. Reungwtwattana T et al. Lung Cancer. 2017:103:27-37. Patients (N = 42) Confirmed ORR By ICR 61.9% (n = 26) CR (95% CI, 45.6%-76.4%) PR SD CR 2.4% (n = 1) Treatment continues PR 59.5% (n = 25) PD SD 28.6% (n = 12) Death PD 4.8% (n = 2) And we’ve got certainly some drugs that are newer. We have older NE 4.8% (n = 2) DCR NR (95% CI, 5.3 mo-NE) N = 42 drugs that you’ve recently reported on with crizotinib. So maybe DOR, median NR (95% CI, 5.3 mo-NE) PFS, median 14.0 mo (95% CI, 6.4-14.0 mo) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 we can start there, with crizotinib and the updated analysis, and Time, mo 100 100 80 80 then move to the newer drugs, tepotinib and . 60 60

PFS, % 40 40 PFS (N = 42)a OS (N = 42)

20 OS Probability 20 Median, 14.0 mo (95% CI, 6.4%-14.0%) Median, NR (95% CI, 11.8%-NE) 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Dr. Drilon: Yes, so with crizotinib, which is, in addition to being Time, mo Time, mo a Patients were censored if they discontinued treatment; the median is estimated by Kaplan–Meier analysis. Median follow-up, 8.0 months (1.4-14.2). an ALK and ROS1 inhibitor, is also a MET inhibitor. And it’s funny, Dashed lines indicate upper and lower 95% CI. 1. Smit EF et al. ASCO 2020. Abstract 9504. because the trial was initially designed to look at MET, and then found its way to the other two genes, and then we’re back to MET, But I think one thing that’s very encouraging is that we are seeing where we began. But certainly, an active drug. It’s in the NCCN the emergence of the utility of ADCs, or antibody–drug conjugates. guidelines with a response rate of about 30%. And if you look at the And certainly, the next-generation T-DM1 we know as trastuzumab waterfall plot, most of these patients have disease shrinkage with deruxtecan—very exciting data in the breast cancer literature. this agent. And this is an ADC that has a different payload. It’s an exatecan derivative compared with the T-DM1 maytansinoid that we talked But, as with ALK and ROS1, it is an earlier-generation drug, and about earlier. So, lots going on in this space. there are other type 1 inhibitors that are much more selective for MET, like capmatinib, savolitinib, and tepotinib, that are being Dr. Levy: Yes, it’s exciting to see. And again, yet another emerging explored. biomarker that has relevance. And I think we’ll iron out soon the therapeutic window, getting drugs that are active with fewer side Beyond that, there is a class of type 2 inhibitors that engage the effects. kinase domain in the inactive state and bind the hydrophobic back pocket that may result in activity after these type 1 drugs Dr. Drilon: Yes. fail in select situations. And so an example of a drug like that is cabozantinib. Dr. Levy: I think that’s the whole goal.

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MET TKI Efficacy in MET Exon 14 NSCLC1-4 Dr. Levy: Yes. And just a brief comment on MET exon 14–skipping mutations versus MET amplification. Is there any correlation Agent MET Testing n Brain Metastases, n ORR (95% CI), % DOR, mo PFS, mo between those two, and can you use MET amplification to drive 97 1L: 11.1 (5.55, NE) 1L: 3 1L: 67.9 (47.6 - 8 4.1) 1L: 9.7 (5.5-13.86) Capmatinib1 Tissue RT-PCR 1L: 28 2/3L: 9.7 2/3L: 11 2/3L: 40.6 (28.9-53.1) 2/3L: 5.4 (4.2-6.97) these treatment decisions, or is it really about the mutation similar 2/3L: 69 (5.55-12.98) Liquid: 50 (35.2, 64.8) to the story we were talking about with HER2? 1L: 58.8 (32.9–81.6) 2L: 53.3 (26.6-78.7) 73 Liquid (DNA based NGS) ≥3L: 37.5 (15.2-64.6) Liquid: 12.4 (5.8-NE) Liquid: 9.5 (6.7-NE) Tepotinib2 Liquid: 48 8 Tissue (RNA based NGS) Tissue: 45 (31.1-59.7) Tissue: 15.7 (9.0-NE) Tissue: 10.8 (6.9-NE) Tissue: 51 1L: 44.4 (21.5-69.2) 2L: 50 (26-74) Dr. Drilon: So I think it’s a different story here, because we know ≥3L: 40 (16.3-67.7) Tissue-local with the early PROFILE 1001 data that, if you have a highly MET- Crizotinib3 Prospective central tissue 65 – 32 (21-45) 9.1 (6.4 -12.7) 7.3 (5.4 - 9.1) and liquid ctDNA amplified cancer, crizotinib or other MET inhibitors can be active. Savolitinib4 Tissue 29 5 54.8 – –

1. Wolf J et al. ASCO 2019. Abstract 9004. 2. Paik PK et al. ASCO 2019. Abstract 9005 3. Drilon A et al. WCLC 2018. Abstract OA12.02. 1 4. Lu S et al. AACR 2019. Abstract CT031. MET-Amplified Inhibitor: Capmatinib (GEOMETRY mono-1 study)

Capmatinib Demonstrates Activity in a Subset of Patients With High-Level MET-Amplified (GCN ≥10) NSCLC Pretreated Patients Treatment-Naïve Patients 1.0 Cohort 1a (2/3L, GCN ≥10) (n = 69) 1.0 Cohort 5a (1L, GCN ≥10) (n = 15) BIRC Investigator BIRC Investigator 0.8 0.8 So we’ve seen a readout of these type 1b inhibitors, like tepotinib, Events, n (%) 58 (84.1) 58 (84.1) Events, n (%) 15 (100) 15 (100) Progression 47 (68.1) 52 (75.4) Progression 14 (93.3) 15 (100) 0.6 Death 11 (15.9) 6 (8.7) 0.6 Death 1 (6.7) 0 savolitinib, and capmatinib. The response rates have sort of Censored, n (%) 11 (15.9) 11 (15.9) Censored, n (%) 0 0 0.4 0.4 KM median 4.07 4.14 KM median 4.17 2.76 (95% CI), mo (2.86-4.83) (2.79-5.52) (95% CI), mo (1.45-6.87) (1.45-6.87) bounced around a little bit. So we’re seeing response rates PFS, Proportion 0.2 PFS, Proportion 0.2 0 0 0 4 8 12 16 20 24 28 32 36 0 4 8 12 16 20 24 28 32 36 anywhere from 30% to north of 60%. And that’s been done in Time, mo Time, mo various settings in treatment-naïve cases and also those that are Cohort 1a (2/3L) (n = 69) Cohort 5a (1L) (n = 15) BIRC Investigator BIRC Investigator pretreated. ORR, % (95% CI) 29 (18.7-41.2) 27.5 (17.5-39.6) 40 (16.3-67.7) 40 (16.3-67.7) DCR, % (95% CI) 71.0 (58.8-81.3) 60.9 (48.4-72.4) 66.7 (38.4-88.2) 73.3 (44.9-92.2) Median PFS, mo (95% CI) 4.07 (2.86-4.83) 4.14 (2.79-5.52) 4.17 (1.45-6.87) 2.76 (1.45-6.87) n = 20 n = 19 n = 6 n = 6 Median DOR, mo (95% CI) 8.31 (4.17-15.44) 6.80 (4.21-20.73) 7.54 (2.56-14.26) 9.66 (4.01-17.08)

New FDA Approval for MET Exon 14 Skipping Inhibitor 1. Wolf J et al. ASCO 2020. Abstract 9509. to Treat NSCLC1-3

May 6, 2020: Capmatinib received FDA approval for the treatment And it is a bit of a Venn diagram, because in about 15% to 20% of adult patients with metastatic MET exon 14 skipping NSCLC based on efficacy data from GEOMETRY trial of cases, you can have both MET exon 14 skipping and a MET

• The FDA also approved the FoundationOne CDx assay (F1CDx) as a companion diagnostic for amplification. So the way I think of it is that these are both capmatinib biomarkers of potential activity with MET-directed therapy, and • Primary efficacy outcome was ORR; secondary outcome was DOR • In 28 treatment-naïve patients: ORR, 68% (95% CI, 48%-84%) with a response duration of if you find one or the other or both, that would be an actionable 12.6 months (95% CI, 5.5-25.3) situation, still. • In 69 previously treated patients: ORR, 41% (95% CI, 29-53) with a response duration of 9.7 months (95% CI, 5.5-13.0)

1. https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-treat-aggressive-form-lung-cancer. 2. Wolf J et al. ASCO 2019. Dr. Levy: Yes, that’s good—still trying to sort out, again, the Abstract 9004. 3. https://www.targetedonc.com/news/fda-grants-priority-review-to-nda-for-capmatinib-in-met-exon-14-nsclc. alteration that makes most sense for our treatment decisions.

Narrator: On May 6, 2020, capmatinib received FDA approval for Dr. Drilon: Right. the treatment of adult patients with metastatic NSCLC harboring MET exon 14 skipping mutations based on the efficacy findings Dr. Levy: This is good clarity. from the GEOMETRY trial. This is the first approval of a targeted therapy for patients with MET-altered NSCLC. MET Exon 14 Skipping Inhibitor: Tepotinib (VISION Trial)1,2

Median Events, n VISION study design (N = up to 120) (95% CI), mo 1.0 Combined 8.5 1 • Stage IIIB/IV NSCLC 60 Capmatinib in MET Exon 14 Skipping NSCLC (n = 99) (6.7-11.0) Liquid biopsy group 8.5 – All histologies (including squamous 0.8 43 and sarcomatoid) (n = 66) (5.1-11.0) PFS and DOR Tumor Shrinkage Tissue biopsy group 11.0 0.6 32 Cohort 5b (1L) 25 – Exclusion of active brain metastases (n = 60) (5.7-17.1) Cohort 5b (1L) or brain as only measurable lesion Cohort A Tepotinib 0 0.4 • Tissue- or blood-based MET alterations METex14 500 mg daily

(21 day cycles PFS, Proportion (central lab testing) skipping -25 mutation until PD) 0.2 – METex14 skipping mutations detected Patient -50 Ø Plasma, LBx (DNA based) 0 n PFS 0 3 6 9 12 15 18 21 24 27 30 33 — DOR -75 Ø Tissue, TBx (RNA based) No. at Risk Time, mo – MET amplification only Combined 99 67 53 33 20 15 10 6 4 1 1 0

0 3 6 9 12 15 18 21 24 Best Change From Baseline, % -100 Liquid biopsy group 66 44 36 23 14 10 8 6 2 1 1 0 Time, mo • First-, second-, third-line therapy Tissue biopsy group 60 42 32 22 16 11 7 4 2 1 1 0 Cohort 4 (2/3L) 25 Cohort 4 (2/3L) – Prior anti-MET therapy was not allowed • In the combined group, median (95% CI) PFS was 8.5 (6.7-11.0) months by independent review 0 – Prior immunotherapy was allowed and 8.6 (6.7-11.2) months by investigator assessment • Median (95% CI) OS was 17.1 (12.0-26.8) months in the combined group,15.8 (9.5-NE) months -25 in the liquid biopsy group, and 22.3 (15.3-NE) months in the tissue biopsy group Patient -50 n PFS 1. Paik PK et al. ASCO 2019. Abstract 9005. 2. Le X, et al. ASCO 2020. Abstract 9556. — DOR -75

0 3 6 9 12 15 18 21 24 Time, mo Best Change From Baseline, % -100 1. Wolf J et al. ASCO 2019. Abstract 9004. And thankfully, these trials have also leveraged the fact that we can pick these up sometimes even more easily than fusions, if we do So, very interesting times. a plasma test and have put patients onto the trial with even just a plasma result in the absence of tissue sequencing.

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Dr. Levy: So the emerging KRAS inhibitor AMG 510 was evaluated in a small number of patients, 23 patients with KRAS G12C non– small cell lung cancer who had received two or more lines of therapy. KRAS Inhibitors a 1 in NSCLC NSCLC: Best Tumor Response (n = 10)

100 5 of 10 patients had PR • 4 are confirmed 80 • All 5 are still on treatment 60 40 20 SD 0 SD -20 SD SD -40 b PR PR c PR c -60 PR Change From Baseline in Longest Diameter, % in Longest Diameter, -80 Planned Dose 180 mg 360 mg 720 mg 960 mg PRb,d Dr. Drilon: Okay, Ben, last mutation of the day, and a mutation that -100 we did not think was druggable until recently. Let’s talk about KRAS. Patients Receiving AMG 510

a Based on local radiographic scans every 6 weeks using RESIST 1.1 criteria. One patient had clinical progression before week 6 and is not in this graph. b Confirmed response. c Two additional patients had confirmed PR post data cutoff. d Patient had a CR of the target lesions at week 18, post-data cutoff. 1. Govindan R et al. ESMO 2019. Abstract 446PD. AMG 510 Is a First-in-Class KRAS G12C Inhibitor

• KRAS is a GTP-binding protein that links activation to intracellular signaling1,2 And what we saw, incredibly, were response rates north of 40%, • Mutation of KRAS favors the GTP-bound active state and constitutive activation of downstream effects which is something that’s quite surprising. And so, I think we’re all (differentiation, proliferation, survival)3 very excited. Some of these responses that we saw were durable. • KRAS G12C mutation has been identified as an oncogenic driver of tumorigenesis The drug is fairly well tolerated. • KRAS G12C mutation is found in approximately 13% of lung cancer,4 3% of colorectal (CRC)5 and appendix cancer, and 1%-3% of other solid tumors Dr. Drilon: Yes. • Currently there is no approved therapy targeting this mutation GDP GTP KRAS G12C KRAS G12C

• AMG 510 is a novel, first in class, small molecule that AMG 510 Differentiation specifically and irreversibly inhibits KRAS G12C by Proliferation Survival Dr. Levy: Certainly, in the context of chemotherapy, it’s a welcome locking it in an inactive GDP-bound state change. 1. Prior IA et al. Cancer Res. 2012;72:2457-2467. 2. Ostrem JM et al. Nat Rev Drug Discov. 2016;15:771-785. 3. Biernacka A et al. Cancer Genet. 2016;209:195-198. 4. Neumann J et al. Pathol Res Prect. 2009;205:858-862. 5. Zhou L et al. Med Oncol. 2016;33:32.

MRTX849 Demonstrates Broad-Spectrum Tumor Regression Dr. Levy: Yes, so we’ve got new drugs specifically for KRAS G12C. in KRAS G12C Tumor Growth Models1

You know, KRAS is a GTP-binding protein. It alternates between the Tumor Assessment on Day 22 of Oral, Daily Dosing of MRTX849 (100 mg/kg) Non-G12C G12C inactive GDP and the active GTP state. And this drug specifically 100 Lung Colon Pancreas Cervix Lung PDX Colon PDX Pancreas PDX Esophagus and irreversibly binds, locking into the inactive GDP state. 50

Dr. Drilon: That’s right. 0

-50

Dr. Levy: And, you know, it’s a pretty incredible story, because -100

WT) H2122 LU99 H358 H1373 LU65 LU2512H2030PA1383 SW837SW756LU1147 HCC44LU5191LU5212 Calu-1 LU11693LU6405SW1573CR6256 CR6243LU11692 LU11554 LU5245 LU2529 this is probably another 12% to 15% of all non–small cell lung KRAS KYSE-410 MiaPaca-2 A549 (G12S) HCT116 (G13D) cancer patients that can be drugged with a specific target. It’s just NCI-H1299 ( 1. Papadopoulos K et al. ASCO 2019. Poster 3161. lessening the unknown slice of the pie.

Dr. Drilon: Yes. I think we have had other KRAS G12C drugs that are coming down the pike. One is MRTX849. And we’ve seen very early on in some

Emerging KRAS Inhibitor: AMG 5101 preclinical data that the drug is—has been active.

• 23 patients with NSCLC – ≥2 prior lines of therapy – KRAS G12C mutation

Efficacy Safety

• PR in 11 patients • 26 patients of 76 enrolled reported • SD in 11 patients TRAEs • PD in 1 patient who had early – 6 patients had grade 3+ progression • mDOR and mPFS are awaited

1. Govindan R et al. 2019 ESMO 2019. Abstract 446PD.

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Other Novel KRAS Inhibitors go back and look at the original next-generation sequencing report to see what subtype of KRAS they have, so that patients may be eligible for these trials or even drug approvals. • LY3499446: a selective, covalent KRAS G12C inhibitor – A phase 1/2 study is under way of LY3499446 administered to patients with advanced solid tumors (including NSCLC) with KRAS G12C mutation (NCT04165031) Dr. Drilon: I agree, absolutely. And I think it applies more broadly— • JNJ-74699157 – A first-in-human study of the safety, pharmacokinetics, pharmacodynamics, and you know, going back to the available menu of targeted therapies, preliminary antitumor activity of JNJ-74699157 in participants with advanced solid tumors harboring the KRAS G12C mutation (NCT04006301) every time you have to switch treatments.

So, one thing we didn’t touch on today is there are newer drivers like NRG1 fusions, for example, where there are now several clinical trials looking at the activity of these agents. So, like we’ve said over and over again, exciting times.

And there are others, as well, that are certainly going to, I think, Dr. Levy: Yes. make an impact. But, clearly, a very exciting time. Again, as you mentioned, KRAS was thought to be undruggable.

You know, we’ve got now a selective KRAS G12C inhibitor. I think the question for a lot of community providers, what about the non–KRAS G12C? Do these drugs have activity? And I don’t know, Alex, if you have any trials or are looking at some of these other IO vs Targeted types of KRAS to see if there’s activity with any of these drugs. Therapies

Dr. Drilon: Well, certainly, there are some direct inhibitors that are going for other mutations, like G13 substitutions. And one of these is a drug that’s early in its development, but unlike these other agents that you discussed, targets the active conformation—

Dr. Levy: Oh, okay. Yes. Dr. Drilon: All right, Ben, getting to the end here. We’ve discussed a lot of targeted therapies for these actionable drivers, but one thing Dr. Drilon: —versus the inactive. So we’ll see how that pans out. that might be on the minds of our viewers today is what the utility of immune therapy is for these patients. But for non–KRAS G12C mutations, there are other things that could be done, many ongoing trials. A lot of them may give Targeted Therapy for Actionable Drivers, combination therapies that target downstream pathways. And we Chemo/IO for Everyone Else1 have seen a few responses. But, hopefully, we are going to see an Progression-Free Survival According to Primary Oncogenic Driver From Initiation of ICI increase in these really selective direct inhibitors, because, as you Event/N Median PFS (95% Cl), mo 6-mo PFS (95% Cl) 12-mo PFS (95% Cl) pointed out, the toxicity profile is very favorable; KRAS G12C just KRAS 208/271 3.2 (2.7-4.5) 37.9 (32.1-49.8) 25.6 (20.2-31.3) doesn’t exist in the human body except in cancer. And so talking, EGFR 117/125 2.1 (1.8-2.7) 18.4 (12.1-25.6) 6.4 (2.7-12.1) BRAF 34/43 3.1 (1.8-4.6) 32.1 (18.3-46.6) 18.0 (7.2-32.7) again, about a therapeutic window, you’re seeing a very favorable HER2 23/29 2.5 (1.8-3.5) 22.7 (8.9-40.2) 13.6 (3.6-30.1) safety profile with these drugs. MET 26/36 3.4 (1.7-6.2) 36.5 (20.7-52.4) 23.4 (10.6-39.0) ALK 21/23 2.5 (1.5-3.7) 11.8 (2.2-30.2) 5.9 (0.4-23.0) Dr. Levy: Yeah. And just a reminder, as these drugs become ROS1 – – – – available in clinical trials, and as they potentially become available RET 15/16 2.1 (1.3-4.7) 14.1 (2.3-35.9) 7.0 (0.4-27.1) and approved by the FDA, I think we need to remind ourselves that 1. Mazieres J et al. Ann Oncol. 2019;30:1321-1328. some of our patients who are KRAS G12C who are on chemotherapy, you know, I’ve had to go back and look who’s KRAS G12C because I Dr. Levy: I think the data are starting to unfold. And really, we’ve tested, and I didn’t put it in the hard drive because I didn’t need to. dichotomized the science these days. There’s immunotherapy, and there’s targeted therapy within lung cancer. And there’s probably Dr. Drilon: Right. convergence that will happen at some point, and it’s starting to roll out in clinical trials. Dr. Levy: And they went on treatment, and now we have an AMG 510 trial, and I’ll have to look back and see, “Okay, wait, who had But one of the things that we’re starting to learn is that a KRAS G12C?” So it’s a reminder to the clinician that once you immunotherapy, at least as a single agent, may not be beneficial in ignored that KRAS—and you were right to do that—that it’s time to certain genotypes.

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We have a retrospective data set looking at a large number of Dr. Drilon: Yes. patients and looking at the role of single-agent immunotherapy for specific genotypes. And not surprisingly, immunotherapy Dr. Levy: The one responder from that trial ended up not having an is not that active as a single agent, at least in the EGFR and the EGFR mutation. So, clearly, there are efficacy concerns. ALK patients, even in the ROS1 and perhaps HER2 patients. But, you know, median PFS of single-agent immunotherapy in these Potentially Fatal Pneumonitis With Anti–PD-1 genotypes ranges anywhere from 3 to 5 months. Again, we and Subsequent EGFR TKI1 have to put these data in context, because these data looked at : Treatment-Related Adverse Events (TRAEs) Subsequent TKI: Treatment-Related Adverse Events (TRAEs) Any TRAE Any TRAE immunotherapy as third or fourth line for many of these patients. AE TRAE Grade 3-5 AE TRAE Grade 3-5 n = 11 (%) n = 11 (%) n = 7 (%) n = 7 (%)

Integument Integument Rash 3 (27.3%) 0 Rash 4 (57.1%) 0 Dr. Drilon: Right. Endocrine Respiratory Adrenal insufficiency 1 (9.1%) 0 Pneumonia 1 (14.3%) 1 (14.3%)

Gastrointestinal Gastrointestinal Diarrhea 2 (18.2%) 0 Diarrhea 2 (28.6%) 1 (14.3%)

Dr. Levy: But what we have learned, at least in the EGFR and Other Laboratory abnormalities Flu-like symptoms 2 (18.2%) 0 Transaminitis 1 (14.3%) 1 (14.3%) ALK space, single-agent immunotherapy usually does not elicit Chills 1 (9.1%) 0 Laboratory abnormalities ALT/AST increased 1 (9.1%) 1 (9.1%) meaningful responses or improvement in outcome. I think the ALP increased 1 (9.1%) 0 TSH decreased 1 (9.1%) 0 jury is still out, however, about the role of immunotherapy in combination with chemotherapy for these genotypes. 1. Lisberg AE et al. J Clin Oncol. 36(suppl 15):9014.

Dr. Drilon: Right. But there were also some toxicity concerns too for patients who then went on to receive TKI. There was a significant rate of adverse Dr. Levy: But, at least as single agent, it’s hard to believe that events for the sequencing strategy of getting an immunotherapy patients would derive a meaningful benefit as a second or third first followed by TKI. line. So I think because of this, I mean, it really prioritizes the importance

Pembrolizumab in PD-L1 >1%, EGFR-Mutated mNSCLC1 of genotyping your patient.

Dr. Drilon: Yes. Key eligibility criteria Postprogression • Advanced NSCLC Pembrolizumab Treat until progression • EGFR TKI • EGFR mutation 200 mg or total of 35 • Safety/efficacy • PD-L1 ≥1%a every 3 weeks study infusions analysis Dr. Levy: Patients who are EGFR positive, if you start them on • TKI naïve immunotherapy, and then you find out that they’re EGFR positive,

• Primary objective: ORR of pembrolizumab prior to TKI and then you sequence them to a TKI, there’s a real chance for • Secondary objectives: safety, PFS, OS of pembrolizumab; safety and efficacy toxicity. of subsequent EGFR TKI therapy

Dr. Drilon: Right.

a Performed with 22C3 assay in a Clinical Laboratory Improvement Amendments (CLIA)–approved laboratory. 1. Lisberg AE et al. ASCO 2018. Abstract 9014. Dr. Levy: And so I think it just calls in, again, the importance of rapidly genotyping your patient so that, one, you could deliver the You know, we have some prospective data, as well, looking at the best therapy to patients, and two, you can avoid toxicity. role of single-agent immunotherapy in treatment-naïve EGFR- positive patients. This was a small trial. It took patients who were And I don’t know if you’ve had any experience with the sequencing EGFR positive and had a PD-L1 expression of greater than 1%. And of immunotherapy followed by TKI and what can happen here. But instead of giving them a TKI, the trial mandated that they receive the data would suggest a pneumonitis rate close to 15% for these single-agent pembrolizumab. So it was asking the question, patients. essentially, how does single-agent immunotherapy do for EGFR patients who do also express PD-L1? Dr. Drilon: I think we’ve had a very parallel experience, and this is not only in EGFR. We’ve seen published reports of crizotinib, for The planned enrollment for this study was 25 patients. But only 11 example, after immune therapy for patients with an ALK fusion in patients enrolled. The trial was stopped due to futility, which I’ll talk their cancer, where you see higher rates of transaminitis. about. And I think across the board, even if we look at newer You know, of the 11 patients, eight patients had a PD-L1 expression investigational therapies, we do get the sense that there may be a greater than 50%. Incredibly, in patients—the majority of whom heightened level of toxicity after an immune checkpoint inhibitor, had a high PD-L1 expression greater than 50%—who received when someone gets a TKI. single-agent pembrolizumab, the response rate was zero.

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MasterClass Module 3— your best strategy from a tissue standpoint, I think is critical, because not all testing platforms are the same. But I think layering Practicalities and Challenges in a plasma test for patients is critical. I think, again, we’ve got of Managing Patients With good data now from Charu Aggarwal and good data from the NILE prospectively—a data set called NILE—suggesting, again, that Molecularly Altered NSCLC when we add plasma to the tissue testing, we increase our capture rate of potential actionable mutations. Alexander Drilon, MD Benjamin Levy, MD And so, I think my message here is that everyone who’s treatment naïve should be considered for a plasma test. And similar to tissue testing, there are different plasma platforms out there. And I think Best Practices For Molecular Testing in Patients you have to be selective on which ones you choose. But I think it’s With Advanced NSCLC really important that we consider that.

• Selecting an assay ü Make sure the test can detect gene fusions and other alterations in addition One other thing maybe we didn’t talk about in the beginning, to mutations ü When in doubt, consult with your pathologist but we’ve certainly layered in each of these genotype sections, is • When to perform molecular testing the role of retesting upon resistance. And is that the message for ü All treatment-naïve patients should be considered for a ctDNA plasma test providers out there, that patients who are on a targeted therapy in addition to tissue biopsy ü New tissue biopsy and/or plasma test needs to occur when patients develop who develop resistance or progression, we should be biopsying resistance/disease progression these patients? And if so, should it be tissue? Should it be plasma? • Communicate with colleagues who perform biopsies about the necessity of acquiring as much tissue as possible for DNA testing Should it be both?

I think that’s one of the main questions I get is, “Well, I did it upfront. Is there any role to doing it again for patients with specific Dr. Levy: So, Alex, we’ve talked a lot about the relevance of all genotypes?” these actionable mutations and the importance of precision medicine in lung cancer. And it’s probably a good idea just to Dr. Drilon: I think the answer to that is that there is a role. And go back where we started, which is the importance of molecular we certainly know that for each of the different genes that we testing. discussed that are next-generation therapies, and we know that the activity of some of these combinations or single-agent TKIs Maybe just some key bullet points to take home for both academic is really dependent on what the genomic signature looks like on and community oncologists to say, how do we best optimize progression. molecular testing? What are best practices, and how do we carry this out in the academic world, but also out in the real world and So, in my mind, if you don’t run into issues with payer coverage the community? and are able to do either plasma, tissue, or both, then it could certainly open up treatment options for your patients. And as we Dr. Drilon: I think, in terms of choosing best practices, one of the move into the future, if more of these next-generation therapies most critical issues is selecting the best test. And that, obviously, are approved, I can see how it’ll be easier to get molecular needs to come with the knowledge of the menu of different profiling covered at the onset of resistance. actionable drivers and making sure that the test that you choose is well poised to interrogate these different genomic signatures. Dr. Levy: Yes. One more question—and I’ll layer in my insight—is just how successful we really are at tissue testing. Is this a real I’ll say that many assays might actually have a gene list, and it challenge? This is the biggest challenge I hear going back to the might look like you have the gene of interest on the list, but it upfront testing. You know, we want to select the right platform. We may not be good at picking up things like MET exon 14 splice site want it to be comprehensive. We want it to identify alterations that alterations, which are very heterogeneous, or even fusions. Some include fusions, perhaps where there is an RNA platform, as well. of them are very hard to capture on DNA-based assays. But how often is tissue just not enough? And is this a real barrier at So, when in doubt, I think you need to talk to your pathologist, talk your institution, and one that you see out in the community? to your molecular diagnostics person, if you have one in house, and make sure that you very thoughtfully select a good assay for Dr. Drilon: Definitely, there are situations where tissue is the your patients. issue, and you can’t get enough of it. I think one thing we haven’t talked about is the concept of tissue storage and the dialogue Dr. Levy: Yes, I would say, on top of that again, just to pitch the between the medical oncologist and the pulmonologist, the idea for consideration of plasma on top of—you know, selecting interventional radiologist or the surgeon, and telling them that, if

Go online to complete the post-test and evaluation for CME/MOC/CC/CNE credit PeerView.com/NPG900 26 Improving Outcomes in Patients With Molecularly Altered NSCLC Through Broad Implementation of Precision Testing and Treatment: Latest Evidence and Practical Guidance in the Context of a Changing Targeted Therapy Landscape safe and feasible, acquire as much tissue as you can to maximize Dr. Drilon: Yes. the likelihood of getting enough DNA for an assay. Dr. Levy: So, you know, testing is one. But not hesitating to reach Dr. Levy: Yes. out to people who may be a little more versed in some of this is really important. Dr. Drilon: But it’s true. There are situations where a patient may be too frail to undergo a biopsy, or it’s just maybe in Dr. Drilon: Absolutely. And my final thoughts really go back to the bone, and there’s not a soft tissue component. And this is why therapeutic angle, that for many of these genes, as you’ve seen, complementary tests like plasma, those things are very critical. there are FDA-approved therapies, there are other therapies that are in the NCCN guidelines, and that helps get payer coverage. Dr. Levy: Yes. But beyond that, it’s also important to recognize that, while clinical

Final Thoughts trials may scare some patients, some of these newer agents are very promising and may achieve very high response rates and durable disease control. So, certainly, keep these in mind when • Leave no gene behind ü Do as much as possible to try to find a therapeutically actionable gene you’re considering therapies for your patient. in every patient with treatment-naïve NSCLC • When in doubt, reach out for expert advice Dr. Levy: Yes. • Check the NCCN guidelines for emerging therapies that are not FDA approved ü Can help with payer coverage • Consider clinical trials, as they may be your patient’s best option Dr. Drilon: And that concludes our discussion for today. Thank you very much, Dr. Levy, for joining us.

Dr. Levy: Thank you, Dr. Drilon.

Dr. Drilon: To those of you watching and listening, I hope you Dr. Drilon: We’re at the end of our discussion today, Ben, and this have found the program informative and useful to your practice. has been really great. And I think we’ll maybe leave our audience Thank you very much for participating. today with a couple of final thoughts. Narrator: This activity has been jointly provided by Medical Dr. Levy: Yeah, I think that it’s low-hanging fruit here, but, you Learning Institute, Inc. and PVI, PeerView Institute for Medical know, the importance of testing. And we’ve talked about not Education. just the approved targeted therapies, but the emerging ones. And there are probably more emerging targets than there are approved targets. And it’s going to get complicated.

And the first point I’ll say is, you know, it’s critical to do genotyping. And that has to be done with tissue and plasma, probably up front. But I’ve said this in talks before. Leave no gene behind. Do everything you can to try to find a gene that may be able to allow a patient to receive a genotype-directed therapy that could probably outpace chemotherapy. So I think that that’s the first thing that I’ll say.

The second thing is somewhat similar, which is, it’s getting really complicated. And having just recertified for my medical oncology boards, I can tell you that it is almost impossible to keep up with everything.

So my second call would be, don’t be afraid to reach out to an expert and say, “You know, I’m a little confused here. What would you do?” and partnering with other people in the community who may be disease specific or even academic folks who are disease specific to say, “Look, I have a patient. I’m not really sure what to do with this mutation, because the reports are confusing.”

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This CME/MOC/CC/CNE activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.

This activity is supported through independent educational grants from AstraZeneca, Bayer Healthcare Pharmaceuticals, Inc., Genentech, and Loxo Oncology, Inc.

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