Cases from the Community: Investigators Discuss Emerging Research and Actual Patients with Gastroesophageal Cancers (Part 2 of A

Cases from the Community: Investigators Discuss Emerging Research and Actual Patients with Gastroesophageal Cancers (Part 2 of a 3-Part Series) Thursday, February 4, 2021 5:00 PM – 6:30 PM ET Faculty Daniel Catenacci, MD Yelena Y Janjigian, MD Rutika Mehta, MD, MPH Zev Wainberg, MD, MSc Moderator Neil Love, MD Faculty

Daniel Catenacci, MD Rutika Mehta, MD, MPH Associate Professor, Department of Medicine Assistant Member in the Department of Section of Hematology and Oncology Gastrointestinal Oncology Director, Interdisciplinary Gastrointestinal Moffitt Cancer Center Oncology Program Assistant Professor in the Department of Assistant Director, Translational Research Oncologic Sciences Comprehensive Cancer Center University of South Florida The University of Chicago Medical Center and Tampa, Florida Biological Sciences Chicago, Illinois

Yelena Y Janjigian, MD Zev Wainberg, MD, MSc Associate Attending Physician Co-Director, GI Oncology Program Associate Professor, Weill Cornell Medical College Director of Early Phase Clinical Chief, Gastrointestinal Oncology Service Research Memorial Sloan Kettering Cancer Center Jonsson Comprehensive Cancer Center New York, New York UCLA School of Medicine Los Angeles, California Commercial Support

This activity is supported by educational grants from Astellas, AstraZeneca Pharmaceuticals LP, Daiichi Sankyo Inc, Five Prime Therapeutics Inc, Lilly and Taiho Oncology Inc. Dr Love — Disclosures

Dr Love is president and CEO of Research To Practice. Research To Practice receives funds in the form of educational grants to develop CME activities from the following commercial interests: AbbVie Inc, Acerta Pharma — A member of the AstraZeneca Group, Adaptive Biotechnologies Corporation, Agendia Inc, Agios Pharmaceuticals Inc, Amgen Inc, Array BioPharma Inc, a subsidiary of Pfizer Inc, Astellas, AstraZeneca Pharmaceuticals LP, Bayer HealthCare Pharmaceuticals, Biodesix Inc, bioTheranostics Inc, Blueprint Medicines, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Clovis Oncology, Daiichi Sankyo Inc, Dendreon Pharmaceuticals Inc, Eisai Inc, EMD Serono Inc, Epizyme Inc, Exact Sciences Inc, Exelixis Inc, Five Prime Therapeutics Inc, Foundation Medicine, Genentech, a member of the Roche Group, Genmab, Gilead Sciences Inc, GlaxoSmithKline, Grail Inc, Guardant Health, Halozyme Inc, Helsinn Healthcare SA, ImmunoGen Inc, Incyte Corporation, Infinity Pharmaceuticals Inc, Ipsen Biopharmaceuticals Inc, Janssen Biotech Inc, administered by Janssen Scientific Affairs LLC, Jazz Pharmaceuticals Inc, Karyopharm Therapeutics, Kite, A Gilead Company, Lexicon Pharmaceuticals Inc, Lilly, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company, Merck, Merrimack Pharmaceuticals Inc, Myriad Genetic Laboratories Inc, Natera Inc, Novartis, Novocure Inc, Oncopeptides, Pfizer Inc, Pharmacyclics LLC, an AbbVie Company, Prometheus Laboratories Inc, Puma Biotechnology Inc, Regeneron Pharmaceuticals Inc, Sandoz Inc, a Novartis Division, Sanofi Genzyme, Seagen Inc, Sirtex Medical Ltd, Spectrum Pharmaceuticals Inc, Sumitomo Dainippon Pharma Oncology Inc, Taiho Oncology Inc, Takeda Oncology, Tesaro, A GSK Company, Teva Oncology, Tokai Pharmaceuticals Inc and Verastem Inc. Research To Practice CME Planning Committee Members, Staff and Reviewers

Planners, scientific staff and independent reviewers for Research To Practice have no relevant conflicts of interest to disclose. Dr Catenacci — Disclosures

Advisory Committee Astellas, Merck, Seagen Inc, Tempus Amgen Inc, Archer Pharmaceuticals, Astellas, Bristol-Myers Squibb Company, Daiichi Sankyo Inc, Five Prime Therapeutics Inc, Foundation Medicine, Genentech, a member of the Roche Group, Consulting Agreements Gritstone Oncology, Guardant Health, Lilly, Merck, Natera Inc, Pieris Pharmaceuticals Inc, QED Therapeutics, Seagen Inc, Taiho Oncology Inc, Tempus, Zymeworks

Contracted Research Amgen Inc, Genentech, a member of the Roche Group

Data and Safety Board Genentech, a member of the Roche Group, Merck Serono

Genentech, a member of the Roche Group, Guardant Health, Lilly, Speakers Bureau Merck, Tempus Dr Janjigian — Disclosures

AstraZeneca Pharmaceuticals LP, Basilea Pharmaceutica Ltd, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb Company, Daiichi Consulting Agreements Sankyo Inc, Imugene, Lilly, Merck, Merck Serono, Pfizer Inc, Rgenix, Zymeworks Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim Contracted Research Pharmaceuticals Inc, Bristol-Myers Squibb Company, Genentech, a member of the Roche Group, Lilly, Merck, Rgenix Ownership Interest Rgenix (Stock Options) Dr Mehta — Disclosures

Advisory Committee Bristol-Myers Squibb Company, Taiho Oncology Inc

Consulting Agreement Lilly

Science Review Committee NCCN Dr Wainberg — Disclosures

Amgen Inc, AstraZeneca Pharmaceuticals LP, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb Company, Daiichi Sankyo Inc, Consulting Agreements Five Prime Therapeutics Inc, Gilead Sciences Inc, Ipsen Biopharmaceuticals Inc, Lilly, Merck, Molecular Templates

Contracted Research Arcus Biosciences, Five Prime Therapeutics Inc, Novartis, Plexxikon Inc

Data and Safety Monitoring Array BioPharma Inc, a subsidiary of Pfizer Inc, Pfizer Inc Board/Committee We Encourage Clinicians in Practice to Submit Questions

Feel free to submit questions now before the program begins and throughout the program. Familiarizing Yourself with the Zoom Interface How to answer poll questions

When a poll question pops up, click your answer choice from the available options. Results will be shown after everyone has answered.

Meet The Professor Management of Lung Cancer Friday, February 5, 2021 12:00 PM – 1:00 PM ET

Faculty Joshua Bauml, MD

Moderator Neil Love, MD Year in Review — Clinical Investigators Provide Perspectives on the Most Relevant New Publications, Data Sets and Advances in Oncology: Breast Cancer Tuesday, February 9, 2021 5:00 PM – 6:00 PM ET

Faculty Harold Burstein, MD Lisa Carey, MD Moderator Neil Love, MD Recent Advances in Hematologic Oncology: A 4-Part Live Webinar Series Reviewing Key Data and Presentations from the 62nd ASH Annual Meeting Part 3 — Multiple Myeloma Wednesday, February 10, 2021 5:00 PM – 6:00 PM ET Faculty Rafael Fonseca, MD Robert Z Orlowski, MD, PhD Edward A Stadtmauer, MD Moderator Neil Love, MD Cases from the Community: Investigators Discuss Emerging Research and Actual Patients with Colorectal Cancer (Part 3 of a 3-Part Series) Thursday, February 11, 2021 5:00 PM – 6:00 PM ET

Faculty Kristen K Ciombor, MD, MSCI Eric Van Cutsem, MD, PhD

Moderator Neil Love, MD

Current Concepts and Recent Advances in Oncology: A Daylong Clinical Summit Hosted in Partnership with North Carolina Oncology Association (NCOA) and South Carolina Oncology Society (SCOS) Saturday, February 13, 2021 8:30 AM – 4:30 PM ET Faculty Courtney D DiNardo, MD, MSCE John M Pagel, MD, PhD Mitchell R Smith, MD, PhD Robert Dreicer, MD, MS Alexander Perl, MD Eric Van Cutsem, MD, PhD Justin F Gainor, MD Daniel P Petrylak, MD Peter Voorhees, MD Sara Hurvitz, MD Philip A Philip, MD, PhD, FRCP Heather Wakelee, MD Ian E Krop, MD, PhD Paul G Richardson, MD Moderator Neil Love, MD Saturday, February 13, 2021 — 8:30 AM – 4:30 PM

CME credit information will be emailed to each participant within 3 business days.

Daniel Catenacci, MD Rutika Mehta, MD, MPH Associate Professor, Department of Medicine Assistant Member in the Department Section of Hematology and Oncology of Gastrointestinal Oncology Director, Interdisciplinary Gastrointestinal Moffitt Cancer Center Oncology Program Assistant Professor in the Department Assistant Director, Translational Research of Oncologic Sciences Comprehensive Cancer Center University of South Florida The University of Chicago Medical Center and Tampa, Florida Biological Sciences Chicago, Illinois

Yelena Y Janjigian, MD Zev Wainberg, MD, MSc Associate Attending Physician Co-Director, GI Oncology Program Associate Professor, Weill Cornell Medical College Director of Early Phase Clinical Research Chief, Gastrointestinal Oncology Service Jonsson Comprehensive Cancer Center Memorial Sloan Kettering Cancer Center UCLA School of Medicine New York, New York Los Angeles, California We Encourage Clinicians in Practice to Submit Questions

You may submit questions using the Zoom Chat option below

Feel free to submit questions now before the program begins and throughout the program. Familiarizing Yourself with the Zoom Interface How to answer poll questions

When a poll question pops up, click your answer choice from the available options. Results will be shown after everyone has answered.

Meet The Professor Management of Lung Cancer Friday, February 5, 2021 12:00 PM – 1:00 PM ET

Faculty Joshua Bauml, MD

Faculty Kristen K Ciombor, MD, MSCI Eric Van Cutsem, MD, PhD

Moderator Neil Love, MD

Chronic Lymphocytic Leukemia and Lymphomas: John Pagel, Mitchell Smith Multiple Myeloma: Paul Richardson, Peter Voorhees Genitourinary Cancers: Robert Dreicer, Daniel Petrylak Lung Cancer: Justin Gainor, Heather Wakelee Gastrointestinal Cancers: Philip Philip, Eric Van Cutsem Breast Cancer: Sara Hurvitz, Ian Krop Acute Myeloid Leukemia and Myelodysplastic Syndromes: Courtney DiNardo, Alexander Perl Cases from the Community: Investigators Discuss Emerging Research and Actual Patients with Gastroesophageal Cancers (Part 2 of a 3-Part Series) Thursday, February 4, 2021 5:00 PM – 6:30 PM ET Faculty Daniel Catenacci, MD Yelena Y Janjigian, MD Rutika Mehta, MD, MPH Zev Wainberg, MD, MSc Moderator Neil Love, MD Warren S Brenner, MD Lynn Cancer Institute Boca Raton, Florida

Maria Regina Flores, MD Physician Partner for Florida Cancer Specialists and Research Institute Orlando, Florida

Ranju Gupta, MD Attending Physician Co-Director, Cardio-Oncology program LVPG Hematology Oncology Associates Lehigh Valley Health Network Bethlehem, Pennsylvania Lowell L Hart, MD, FACP Scientific Director of Research Florida Cancer Specialists and Research Institute Associate Professor of Medicine, Hematology and Oncology Wake Forest University School of Medicine Winston-Salem, North Carolina Co-Director, Phase 1 Program Wake Forest Baptist Comprehensive Cancer Center Fort Myers, Florida

Laurie Matt-Amaral, MD, MPH Attending Physician Cleveland Clinic Akron General Medical Center Akron, Ohio

Neil Morganstein, MD Hematology Oncology Atlantic Health System Summit, New Jersey Agenda

Questions • What is the optimal first-line therapy for this patient? Would the faculty use an immune checkpoint inhibitor with chemotherapy? If so, what CPS is required? • What is the difference between TPS and CPS? How do we interpret and utilize that information as to if and when to use immunotherapies? • How would the faculty manage the brain metastases? Case Presentation – Dr Brenner: An 81-year-old man with MSS metastatic esophageal cancer – PD-L1 TPS 15

• 11/2018: Diagnosed with HER2 negative, MSS, PD-L1 positive Warren Brenner, MD (TPS = 15) disease • 12/2018: FOLFOX x 9 à infusional 5-FU maintenance • 3/2020: Recurrent disease with brain metastases treated with CyberKnife • 11/2020: Progressive lower esophageal disease • 12/2020: Dose modified FOLFOX; addition of nivolumab 1/2021

Questions • Where should we use immunotherapy? Should we administer it with frontline chemotherapy if PD-L1 >5? Should we use without chemo if PD-L1 >10? • Do we differentiate between squamous cell carcinoma and adenocarcinoma as it relates to PD-L1 and checkpoint inhibitor therapy? Regulatory and reimbursement issues aside, in which line of therapy if any would you generally recommend an anti-PD-1/PD-L1 antibody (with or without chemotherapy) for a 65-year-old patient with metastatic HER2-negative, MSS adenocarcinoma of the GEJ with a PD-L1 CPS of 0%?

1. First line 2. Second line 3. Third line 4. Beyond third line 5. I would not recommend an anti-PD-1/PD-L1 antibody Regulatory and reimbursement issues aside, in which line of therapy would you generally recommend an anti-PD-1/PD-L1 antibody (with or without chemotherapy) for a 65-year-old patient with metastatic HER2-negative, MSS adenocarcinoma of the GEJ with a PD-L1 CPS of 10%?

1. First line 2. Second line 3. Third line 4. Beyond third line 5. I would not recommend an anti-PD-1/PD-L1 antibody Regulatory and reimbursement issues aside, in which line of therapy if any would you generally recommend an anti-PD-1/PD-L1 antibody (with or without chemotherapy) for a 65-year-old patient with metastatic HER2-negative, MSS squamous cell carcinoma of the esophagus with a PD-L1 CPS of 0%?

1. First line 2. Second line 3. Third line 4. Beyond third line 5. I would not recommend an anti-PD-1/PD-L1 antibody Regulatory and reimbursement issues aside, what adjuvant systemic therapy would you currently recommend to a patient with HER2- negative, MSS adenocarcinoma of the GEJ (PD-1 >1) who receives neoadjuvant FLOT and has residual disease at surgery?

1. Anti-PD-1/PD-L1 monotherapy 2. Anti-PD-1/PD-L1 and anti-CTLA-4 combination 3. Chemotherapy 4. Chemotherapy followed by anti-PD-1/PD-L1 monotherapy 5. I would not recommend adjuvant systemic therapy 6. Other Slide 1

Presented By Zev Wainberg at 2021 Gastrointestinal Cancers Symposium Bemarituzumab is an IgG1 antibody specific for the FGFR2b Receptor

Presented By Zev Wainberg at 2021 Gastrointestinal Cancers Symposium FIGHT Trial Design

Presented By Zev Wainberg at 2021 Gastrointestinal Cancers Symposium Progression-Free Survival and Overall Survival: Intent to Treat

Presented By Zev Wainberg at 2021 Gastrointestinal Cancers Symposium Best % Change in Target Lesions from Baseline

Presented By Zev Wainberg at 2021 Gastrointestinal Cancers Symposium FIGHT: Corneal-Related Adverse Events

Trial required corneal evaluation at baseline and every 8 weeks until the end of treatment1

Bema (N = 76) Placebo (N = 77)

Corneal Adverse Events (SMQ)2 All Grade3 51 (67.1%) 8 (10.4%)

Corneal Adverse Events (SMQ) Grade 34 18 (23.7%) 0 16.1 11.6 Median time to onset to any grade, weeks (range) (0.1, 41.0) (6.0, 29.0) Corneal AE leading to bema/placebo 20 (26.3%) 0 discontinuation5 AE resolved 12 (60.0%) 0

AE not resolved as of 23 Sept 2020 8 (40.0%) 0 27.0 Median time to resolution, weeks (95%CI) NA (18.9, NR)

1 If any event reported, examinations were to continue every 8W until resolution, even if drug discontinued 2 SMQ = Standardised MedDRA Query 3 Most common: dry eye (26.3%), keratitis (15.8%), punctate keratitis (14.5%), vision blurred (15.0%), corneal epithelium defect (10.5%) 4 No ≥ grade 4 event reported 5 Most common: dry eye (n=4), keratitis (n=4), corneal disorder (n=2), eye disorder (n=2) limbal stem cell deficiency (n=2), punctate keratitis (n=2) Courtesy of Daniel Catenacci, MD Pembrolizumab plus Chemotherapy for Previously Untreated, HER2-Negative Unresectable or Metastatic Advanced Gastric or Gastroesophageal Junction (G/GEJ) Adenocarcinoma: KEYNOTE-859.

Tabernero J et al. Gastrointestinal Cancers Symposium 2021;Abstract TPS263. KEYNOTE-859: Study Design and Key Outcomes

Primary Outcomes: OS, PFS Secondary Outcomes: ORR, DoR, safety/tolerability

Tabernero J et al. Gastrointestinal Cancers Symposium 2021;Abstract TPS263. Courtesy of Yelena Y Janjigian, MD CheckMate 649 Overall survival: CheckMate 649

Primary endpoint (PD-L1 CPS ≥ 5)

NIVO + chemo Chemo 100 (n = 473) (n = 482) 12-mo rate Median OS, mo 14.4 11.1 80 (95% CI) (13.1–16.2) (10.0–12.1) HR (98.4% CI) 0.71 (0.59–0.86) P value < 0.0001 a 60 57%

OS (%) 46% NIVO + chemo 20 Chemo 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Months No. at risk NIVO + chemo 473 438 377 313 261 198 149 96 65 33 22 9 1 0 Chemo 482 421 350 271 211 138 98 56 34 19 8 2 0 0

• Superior OS, 29% reduction in the risk of death, and a 3.3-month improvement in median OS with NIVO + chemo versus chemo in patients whose tumors expressed PD-L1 CPS ≥ 5

aMinimum follow-up 12.1 months. Courtesy of Yelena Y Janjigian, MD KEY DIFFERENCES: KEYNOTE-062 VS. CheckMate 649

Courtesy of Yelena Y Janjigian, MD ATTRACTION-4: Progression-Free Survival (Interim Analysis)

Nivolumab + Placebo + chemotherapy chemotherapy N = 362 N = 362 Median PFS, 10.45 8.34 months (8.44-14.75) (6.97-9.40) (95% CI) Hazard ratio 0.68 (98.51% CI) (0.51 – 0.90) P value 0.0007 1yr PFS rate (%) 45.4 30.6

Cut off: 31 Oct 2018 for Interim analysis

• PFS was continuously longer in NIVO + Chemo than in Chemo at the final analysis (NIVO+Chemo vs. Chemo: HR 0.70; mPFS 10.9 vs. 8.4 mo)

Courtesy of Yelena Y Janjigian, MD Agenda

Module 1: Evolving Front-Line Management of Advanced Gastric/Gastroesophageal Junction (GEJ) Cancer Module 2: Localized and Advanced Esophageal Cancer; Novel Strategies with Immunotherapy in GEJ Cancer Module 3: Selection and Sequencing of Therapies for Relapsed Gastric/GEJ Cancer; Novel Investigational Approaches Module 4: Key Optimal Management of HER2-Positive Advanced Gastric/GEJ Cancer Case Presentation – Dr Gupta: A 63-year-old woman with MSS metastatic gastric cancer – TMB 19 mut/Mb, PD-L1 CPS 0 Ranju Gupta, MD • 2018: Diagnosed with T3, LN negative, proximal stomach adenocarcinoma • NGS: PD-L1 negative | TMB: 19 muts/Mb | CPS: 0 | MSS • FLOT x 4 à surgery à FLOT x 4 for residual disease • 8/2019: Developed peritoneal metastases • Ramucirumab/paclitaxel à disease progression 2 months later • Pembrolizumab x 2 cycles Questions • Could we have used first-line pembrolizumab here? Would the faculty have chosen a different second-line therapy give the TMB? What other treatment options would they consider if the patient experienced disease progression on pembrolizumab? • POLE gene variant as potential marker of ICI benefit? Case Presentation – Dr Flores: A 53-year-old Hispanic woman with gastric cancer Maria Flores, MD • Presented with ulcerated antral mass and 20-pound weight loss • Pathology indicates adenocarcinoma; molecular profiling is pending • Potential therapy: FLOT

Questions • What neoadjuvant chemotherapy would the faculty utilize? • If the patient develops metastatic disease, what is your approach if she were not a candidate for surgery? • Is there a difference in how you treat squamous cell esophageal cancer versus adenocarcinoma? Is there a difference as far as the role of immunotherapy or other therapies? CheckMate 577: Health-related quality of life in a randomized, double-blind phase 3 study of nivolumab versus placebo as adjuvant treatment in patients with resected esophageal cancer or gastroesophageal junction cancer

Presented By Eric Van Cutsem at 2021 Gastrointestinal Cancers Symposium Patient-Reported Outcome (PRO) Administration Schedule in CheckMate 577

Presented By Eric Van Cutsem at 2021 Gastrointestinal Cancers Symposium CheckMate 577: Adjuvant Nivolumab Following Neoadjuvant CRT/Resection in Esophageal/GEJ Cancer

§ Randomized phase III trial of adjuvant nivolumab vs placebo following neoadjuvant CRT + surgical resection* for pts with stage II/III esophageal/GEJ adenocarcinoma/SCC (N = 794) DFS (Primary Endpoint) Median DFS, Mos (95% CI) 100 Nivolumab (n = 532) 22.4 (16.6 – 34.0) Placebo (n = 262) 11.0 (8.3 – 14.3) 80 HR: 0.69 (96.4% CI: 0.56 – 0.86; P = .0003) 60 (%) Nivolumab

DFS 40 Placebo 20

0 0 3 6b 9 12 15 18 21 24 27 30 33 36 39 42 45 Months *Residual pathologic disease ≥ ypT1 or ≥ ypN1. Kelly. ESMO 2020. Abstr LBA9. Courtesy of Zev Wainberg, MD, MSc Conclusion

Presented By Eric Van Cutsem at 2021 Gastrointestinal Cancers Symposium Genomic pathway of gut microbiome to predict efficacy of nivolumab in advanced gastric cancer:
DELIVER trial (JACCRO GC-08)

Presented By Yu Sunakawa at 2021 Gastrointestinal Cancers Symposium Results:

Presented By Yu Sunakawa at 2021 Gastrointestinal Cancers Symposium LEAP-005: A Phase 2 Multicohort Study of Lenvatinib Plus Pembrolizumab in Patients With Previously Treated Selected Solid Tumors: Results From the Gastric Cancer Cohort

Presented By Hyun Chung at 2021 Gastrointestinal Cancers Symposium LEAP-005 (NCT03797326)
Gastric Cancer Cohort

Presented By Hyun Chung at 2021 Gastrointestinal Cancers Symposium Antitumor Activity
(Confirmed Objective Responses, RECIST v1.1 by BICR)

Presented By Hyun Chung at 2021 Gastrointestinal Cancers Symposium Health-Related Quality of Life of Pembrolizumab Plus Chemotherapy Versus Chemotherapy as First-Line Therapy in Patients With Advanced Esophageal Cancer: The Phase 3 KEYNOTE-590 Study

Presented By Wasat Mansoor at 2021 Gastrointestinal Cancers Symposium KEYNOTE-590 Study Design (NCT03189719) and Primary Study Results

Presented By Wasat Mansoor at 2021 Gastrointestinal Cancers Symposium KEYNOTE-590 – Overall Survival in All Patients

Kato K, et al. ESMO 2020. Abstract LBA8 Courtesy of Zev Wainberg, MD, MSc KEYNOTE-590 – Overall Survival in SCC Patients

Kato K, et al. ESMO 2020. Abstract LBA8 Courtesy of Zev Wainberg, MD, MSc Conclusions

Presented By Wasat Mansoor at 2021 Gastrointestinal Cancers Symposium Nivolumab in advanced esophageal squamous cell carcinoma (ATTRACTION-1/ONO-4538-07): Minimum
of 5-year follow-up

Presented By Ken Kato at 2021 Gastrointestinal Cancers Symposium ATTRACTION-1: Efficacy

Presented By Ken Kato at 2021 Gastrointestinal Cancers Symposium Conclusions

Presented By Ken Kato at 2021 Gastrointestinal Cancers Symposium Three-Year Follow-Up of ATTRACTION-3: A Phase III Study of Nivolumab (Nivo) in Patients with Advanced Esophageal Squamous Cell Carcinoma (ESCC) That Is Refractory or Intolerant to Previous Chemotherapy

Chin K et al. Gastrointestinal Cancers Symposium 2021;Abstract 204. ATTRACTION-3: Nivolumab in Esophageal Squamous Cell Carcinoma (ESCC)

Nivolumab Chemotherapy P value Overall Response Rate 19% 22% 0.63 Disease Control Rate 37% 63% Median Time to Response 2.6 months 1.5 months Duration of Response 6.9 months 3.9 months Treatment-Related Adverse Events 66% 95% Dose delays due to Adverse Events 39% 50%

Cho BC et al ESMO 2019 Annual Congress and Kato K et al Lancet Oncology 2019 Courtesy of Zev Wainberg, MD, MSc ATTRACTION-3: Overall Survival (3-Year Follow-Up)

• No new safety signal was identified with 3-years follow-up and no major late-onset select TRAEs were observed

Chin K et al. Gastrointestinal Cancers Symposium 2021;Abstract 204. ATTRACTION-3: OS Landmark Analysis at 4 Months by Best Overall Response – Stable Disease

Chin K et al. Gastrointestinal Cancers Symposium 2021;Abstract 204. ATTRACTION-3: OS Landmark Analysis at 4 Months by Best Overall Response – Progressive Disease

Chin K et al. Gastrointestinal Cancers Symposium 2021;Abstract 204. Neoadjuvant PD-1 Blockade in Combination with Chemotherapy for Patients with Resectable Esophageal Squamous Cell Carcinoma

Cheng C et al. Gastrointestinal Cancers Symposium 2021;Abstract 220. Radiographic Response: Neoadjuvant camrelizumab in combination with chemotherapy Agenda

Laurie Matt-Amaral, MD, MPH • 2017: History of Barrett's esophagus with dysplasia s/p resection - Non-compliant with follow-up • History of prostate cancer and coronary artery disease • Fall 2019: Presents with difficulty swallowing, 30 plus pound weight loss • Suspected Stage IV disease, mostly with liver metastases à FOLFOX • Potential plan: Liver-directed therapy

Questions • Do the faculty have a specific liver-directed therapy that they feel would be more beneficial for this patient given his medical history? Or is whatever is available or that insurance would cover appropriate? Regulatory and reimbursement issues aside, what would you currently recommend as second-line therapy for a patient with metastatic HER2-negative, MSS gastric adenocarcinoma who has experienced disease progression on first-line FOLFOX?

1. Ramucirumab 2. Ramucirumab/paclitaxel 3. Other chemotherapy 4. Test for PD-L1 CPS and administer pembrolizumab if ≥1 5. Test for PD-L1 CPS and administer pembrolizumab if ≥10 6. Pembrolizumab 7. Nivolumab 8. Other What is your usual third-line treatment for a younger patient (PS 0) with metastatic HER2-negative, MSS gastric cancer (PD-L1 CPS <1) who has experienced disease progression on FOLFOX and paclitaxel/ramucirumab?

1. TAS-102 2. Other chemotherapy 3. Nivolumab 4. Pembrolizumab 5. Palliative care 6. Other Trifluridine/Tipiracil Outcomes in Third or Later Lines versus Placebo in Metastatic Gastric Cancer Treatment: An Exploratory Subgroup Analysis from the TAGS Study

Tabernero J et al. Gastrointestinal Cancers Symposium 2021;Abstract 229. TAGS Exploratory Subgroup Analysis: Median OS in the ITT Population

Tabernero J et al. Gastrointestinal Cancers Symposium 2021;Abstract 229. A Phase Ib Multicenter Study of Trifluridine/Tipiracil (FTD/TPI) in Combination with Irinotecan (IRI) in Patients with Advanced Recurrent or Unresectable Gastric and Gastroesophageal Adenocarcinoma (Agec) After at Least One Line of Treatment with a Fluoropyrimidine and Platinum Containing Regimen

Dayyani F et al. Gastrointestinal Cancers Symposium 2021;Abstract TPS251. TAS-102 in Combination with Irinotecan: Ongoing Phase Ib Study Design and Objectives

Current Enrollment (n = 20)

Primary Objective: • Regimen feasibility and efficacy estimate

Secondary Objectives: • Overall survival • Overall response rate • Adverse events

Dayyani F et al. Gastrointestinal Cancers Symposium 2021;Abstract TPS251. A Phase I/II Trial of Trifluridine/Tipiracil in Combination with Irinotecan in Patients with Advanced Gastric Cancer Refractory to Fluoropyrimidine, Platinum, and Taxane

Hara H et al. Gastrointestinal Cancers Symposium 2021;Abstract 210. TAS-102 in Combination with Irinotecan: Results from a Phase I/II Study

Hara H et al. Gastrointestinal Cancers Symposium 2021;Abstract 210. Results of a Phase II Trial of Ramucirumab plus Irinotecan as Second-Line Treatment for Patients with Advanced Gastric Cancer (HGCSG 1603)

Kawamoto Y et al. Gastrointestinal Cancers Symposium 2021;Abstract 217. HGCSG 1603: Second-Line Ramucirumab plus Irinotecan

Kawamoto Y et al. Gastrointestinal Cancers Symposium 2021;Abstract 217. Rainbow-Asia: A Randomized, Multicenter, Double- Blind, Phase III Study of Ramucirumab plus Paclitaxel versus Placebo plus Paclitaxel in the Treatment of Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma Following Disease Progression on First-Line Chemotherapy with Platinum and Fluoropyrimidine

Xu R et al. Gastrointestinal Cancers Symposium 2021;Abstract 199. Xu R et al. Gastrointestinal Cancers Symposium 2021;Abstract 199. Xu R et al. Gastrointestinal Cancers Symposium 2021;Abstract 199. Phase II Study of Zolbetuximab plus Pembrolizumab in Claudin 18.2: Positive Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (G/GEJ) — ILUSTRO Cohort 3

Klempner SJ et al. Gastrointestinal Cancers Symposium 2021;Abstract TPS260. Zolbetuximab

• It is a first-in-class novel chimeric idealized IgG1 monoclonal antibody • Targets only tumor cells and has a lower toxicity profile than other anti-cancer monoclonal antibodies • It activates ADCC and complement-dependent cytotoxicity.

Courtesy of Rutika Mehta, MD, MPH ILUSTRO Study Design – Target Enrollment (n = 112)

Klempner SJ et al. Gastrointestinal Cancers Symposium 2021;Abstract TPS260. ILUSTRO Cohort 3 – Target Enrollment (n = 62)

Cohort 3A (safety cohort):

Primary Endpoint: • Safety/tolerability

Cohort 3B (expansion cohort):

Primary Endpoint: • Overall response rate (ORR) by IRC

Key Secondary Endpoints: • ORR by INV • Disease control rate • Duration of response • Progression-free survival • Overall survival

Klempner SJ et al. Gastrointestinal Cancers Symposium 2021;Abstract TPS260. Agenda

Questions • Should NGS be part of initial work-up? Role for (neo)adjuvant HER2 targeted agents? • Would you use a TKI at all in this setting or use a different one? • If the patient experiences progression, would you consider T-DXd? Case Presentation – Dr Brenner: An 84-year-old man with advanced MSI-high gastric cancer – HER2 activating mutation Warren Brenner, MD • 6/2020: Diagnosed with signet-ring disease with evidence of peritoneal disease and mesenteric lymph nodes • NGS: MSI-h | high TMB | HER2 and FGFR2 activating mutations | PD-L1 low • FOLFOX x 8 à disease progression • Single-agent pembrolizumab

Questions • Would it have been better to start the patient on a checkpoint inhibitor? • What is the significance of HER2 activating mutation? • Should we consider dual checkpoint inhibitor therapy? Regulatory and reimbursement issues aside, in which line of therapy would you generally recommend trastuzumab deruxtecan for a 65-year-old patient with metastatic HER2-positive, MSS adenocarcinoma of the GEJ?

1. First line 2. Second line 3. Third line 4. Beyond third line 5. I would not recommend an anti-PD-1/PD-L1 antibody A Phase Ib/II, Multicenter, Open-Label, Dose- Escalation, and Dose-Expansion Study Evaluating Trastuzumab Deruxtecan (T-DXd, DS-8201) Monotherapy and Combinations in Patients with HER2-Overexpressing Gastric Cancer (Destiny- Gastric03) Janjigian YY et al. Gastrointestinal Cancers Symposium 2021;Abstract TPS261. A Phase Ib/II, Multicenter, Open-Label, Dose-Escalation, and Dose-Expansion Study Evaluating Trastuzumab Deruxtecan

Janjigian YY et al. Gastrointestinal Cancers Symposium 2021;Abstract TPS261. A Phase Ib/II, Multicenter, Open-Label, Dose-Escalation, and Dose-Expansion Study Evaluating Trastuzumab Deruxtecan

Janjigian YY et al. Gastrointestinal Cancers Symposium 2021;Abstract TPS261. FDA Approves Trastuzumab Deruxtecan for HER2-Positive Advanced Gastric/GEJ Adenocarcinomas Press Release: January 15, 2021

• The FDA approved trastuzumab deruxtecan for adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen. • Efficacy was evaluated in a multicenter, open-label, randomized trial (DESTINY-Gastric01) for patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma who had progressed on at least two prior regimens, including trastuzumab, a fluoropyrimidine- and a platinum-containing chemotherapy.

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-fam-trastuzumab-deruxtecan-nxki-her2-positive-gastric- adenocarcinomas. Phase II DESTINY-Gastric01 Trial Design

T-DXd (n = 120) 6.4 mg/kg, 3-week cycle Physician’s choice (Irinotecan or paclitaxel) (n = 60)

Shitara K et al. ASCO 2020;Abstract 4513. DESTINY-Gastric01 Trial: Third Line – Trastuzumab Deruxtecan

N= 125 pts R 2:1 100% Asian

Irinotecan or paclitaxel

51%

14%

Shitara et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. NEJM 2020 Courtesy of Daniel Catenacci, MD DESTINY-Gastric01 Trial: Third Line – Trastuzumab Deruxtecan

Irinotecan or paclitaxel

Shitara et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. NEJM 2020 Courtesy of Daniel Catenacci, MD Ongoing Trials of Trastuzumab Deruxtecan (T-DXd) in HER2- Positive Gastric or GEJ Adenocarcinoma

Trial name Target accrual (Identifier) Phase (N) Setting Treatment Arms DESTINY-Gastric04 III 490 • Unresectable and/or metastatic • T-DXd • Progressed on or after a • Ramucirumab + paclitaxel (NCT04704934) trastuzumab-based regimen

DESTINY-Gastric03 II 220 • Locally advanced, unresectable Part 1 or metastatic • T-DXd + 5-FU ± oxaliplatin (NCT04379596) • Progression on or after at least 1 (Ox) prior trastuzumab-based regimen • T-DXd + Cape ± Ox – Part 1 • T-DXd + Durvalumab ± 5-FU • Previously untreated dx – Part 2 or cape Part 2 • Trastuzumab + 5-FU or Cape + Ox or Cisplatin • T-DXd monotherapy • T-DXd + 5-FU or cape ± Ox • T-DXd + 5-FU or Cape + Durvalumab

Janjigian YY et al. ESMO 2020;Abstract 1500TiP; Clinicaltrials.gov; Assessed January 2021 MOUNTAINEER-02: Phase II/III Study of Tucatinib, Trastuzumab, Ramucirumab, and Paclitaxel in Previously Treated HER2+ Gastric or Gastroesophageal Junction Adenocarcinoma — Trial in Progress

Strickler JH et al. Gastrointestinal Cancers Symposium 2021;Abstract TPS252. Strickler JH et al. Gastrointestinal Cancers Symposium 2021;Abstract TPS252. Meet The Professor Management of Lung Cancer Friday, February 5, 2021 12:00 PM – 1:00 PM ET

Faculty Joshua Bauml, MD

Moderator Neil Love, MD Current Concepts and Recent Advances in Oncology: A Daylong Clinical Summit Hosted in Partnership with North Carolina Oncology Association (NCOA) and South Carolina Oncology Society (SCOS) Saturday, February 13, 2021 8:30 AM – 4:30 PM ET Faculty Courtney D DiNardo, MD, MSCE John M Pagel, MD, PhD Mitchell R Smith, MD, PhD Robert Dreicer, MD, MS Alexander Perl, MD Eric Van Cutsem, MD, PhD Justin F Gainor, MD Daniel P Petrylak, MD Peter Voorhees, MD Sara Hurvitz, MD Philip A Philip, MD, PhD, FRCP Heather Wakelee, MD Ian E Krop, MD, PhD Paul G Richardson, MD Moderator Neil Love, MD Thank you for joining us!

CME credit information will be emailed to each participant within 3 business days.