Discuss Emerging Research and Actual Patients with

Cases from the Community: Investigators Discuss Emerging Research and Actual Patients

with Gastroesophageal Cancers (Part 2 of a 3-Part Series)

Thursday, February 4, 20215:00 PM – 6:30 PM ET

Daniel Catenacci, MDYelena Y Janjigian, MD

Rutika Mehta, MD, MPHZev Wainberg, MD, MSc

ModeratorNeil Love, MD

Faculty

Faculty

Daniel Catenacci, MDAssociate Professor, Department of MedicineSection of Hematology and OncologyDirector, Interdisciplinary Gastrointestinal Oncology ProgramAssistant Director, Translational ResearchComprehensive Cancer CenterThe University of Chicago Medical Center and Biological SciencesChicago, Illinois

Yelena Y Janjigian, MDAssociate Attending PhysicianAssociate Professor, Weill Cornell Medical CollegeChief, Gastrointestinal Oncology ServiceMemorial Sloan Kettering Cancer CenterNew York, New York

Rutika Mehta, MD, MPHAssistant Member in the Department of Gastrointestinal OncologyMoffitt Cancer CenterAssistant Professor in the Department of Oncologic SciencesUniversity of South FloridaTampa, Florida

Zev Wainberg, MD, MScCo-Director, GI Oncology ProgramDirector of Early Phase Clinical ResearchJonsson Comprehensive Cancer CenterUCLA School of MedicineLos 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

Consulting Agreements

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, 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

Speakers Bureau Genentech, a member of the Roche Group, Guardant Health, Lilly, Merck, Tempus

Dr Janjigian — Disclosures


AstraZeneca Pharmaceuticals LP, Basilea Pharmaceutica Ltd, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb Company, Daiichi Sankyo Inc, Imugene, Lilly, Merck, Merck Serono, Pfizer Inc, Rgenix, Zymeworks

Contracted ResearchBayer HealthCare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Genentech, a member of the Roche Group, Lilly, Merck, Rgenix

Ownership Interest (Stock Options) Rgenix

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, 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 Board/Committee Array BioPharma Inc, a subsidiary of Pfizer Inc, Pfizer Inc

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 InterfaceHow to answer poll questions

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Meet The ProfessorManagement of Lung Cancer

Friday, February 5, 202112:00 PM – 1:00 PM ET

Joshua Bauml, MD


Faculty

Year in Review — Clinical Investigators Provide Perspectives on the Most Relevant New

Publications, Data Sets and Advances in Oncology:Breast Cancer

Tuesday, February 9, 20215:00 PM – 6:00 PM ET

Harold Burstein, MDLisa Carey, MD


Faculty

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, 20215:00 PM – 6:00 PM ET

Rafael Fonseca, MDRobert Z Orlowski, MD, PhDEdward A Stadtmauer, MD


Faculty

Cases from the Community: Investigators Discuss Emerging Research and Actual Patients with Colorectal Cancer (Part 3 of a 3-Part Series)


Kristen K Ciombor, MD, MSCIEric Van Cutsem, MD, PhD


Faculty

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, 20218:30 AM – 4:30 PM ET


FacultyCourtney D DiNardo, MD, MSCE

Robert Dreicer, MD, MSJustin F Gainor, MD

Sara Hurvitz, MDIan E Krop, MD, PhD

John M Pagel, MD, PhDAlexander Perl, MD

Daniel P Petrylak, MDPhilip A Philip, MD, PhD, FRCP

Paul G Richardson, MD

Mitchell R Smith, MD, PhDEric Van Cutsem, MD, PhD

Peter Voorhees, MDHeather Wakelee, MD

Saturday, February 13, 2021 — 8:30 AM – 4:30 PM

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

Thank you for joining us!

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







Faculty

Faculty

Daniel Catenacci, MDAssociate Professor, Department of MedicineSection of Hematology and OncologyDirector, Interdisciplinary Gastrointestinal Oncology ProgramAssistant Director, Translational ResearchComprehensive Cancer CenterThe University of Chicago Medical Center and Biological SciencesChicago, Illinois

Yelena Y Janjigian, MDAssociate Attending PhysicianAssociate Professor, Weill Cornell Medical CollegeChief, Gastrointestinal Oncology ServiceMemorial Sloan Kettering Cancer CenterNew York, New York

Rutika Mehta, MD, MPHAssistant Member in the Department of Gastrointestinal OncologyMoffitt Cancer CenterAssistant Professor in the Department of Oncologic SciencesUniversity of South FloridaTampa, Florida

Zev Wainberg, MD, MScCo-Director, GI Oncology ProgramDirector of Early Phase Clinical ResearchJonsson Comprehensive Cancer CenterUCLA School of MedicineLos 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.

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



Joshua Bauml, MD


Faculty

Year in Review — Clinical Investigators Provide Perspectives on the Most Relevant New

Publications, Data Sets and Advances in Oncology:Breast Cancer

Tuesday, February 9, 20215:00 PM – 6:00 PM ET

Harold Burstein, MDLisa Carey, MD


Faculty

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, 20215:00 PM – 6:00 PM ET

Rafael Fonseca, MDRobert Z Orlowski, MD, PhDEdward A Stadtmauer, MD


Faculty

Cases from the Community: Investigators Discuss Emerging Research and Actual Patients with Colorectal Cancer (Part 3 of a 3-Part Series)


Kristen K Ciombor, MD, MSCIEric Van Cutsem, MD, PhD


Faculty













Saturday, February 13, 2021 — 8:30 AM – 4:30 PM

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







Faculty

Warren S Brenner, MDLynn Cancer InstituteBoca Raton, Florida

Ranju Gupta, MDAttending PhysicianCo-Director, Cardio-Oncology programLVPG Hematology Oncology AssociatesLehigh Valley Health Network Bethlehem, Pennsylvania

Maria Regina Flores, MDPhysician Partner for Florida Cancer Specialists and Research InstituteOrlando, Florida

Neil Morganstein, MDHematology OncologyAtlantic Health SystemSummit, New Jersey

Laurie Matt-Amaral, MD, MPHAttending PhysicianCleveland Clinic Akron General Medical CenterAkron, Ohio

Lowell L Hart, MD, FACPScientific Director of ResearchFlorida Cancer Specialists and Research InstituteAssociate Professor of Medicine, Hematology and OncologyWake Forest University School of MedicineWinston-Salem, North CarolinaCo-Director, Phase 1 ProgramWake Forest Baptist Comprehensive Cancer CenterFort Myers, Florida

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

Agenda





Case Presentation – Dr Morganstein: A 61-year-old man with MSS metastatic GEJ cancer – PD-L1 CPS = 2

• History of glioblastoma multiforme over 5 years ago- Long-term treatment with temozolomide - NED

• Presents with 20-pound weight loss- Diagnosed with widespread metastatic GEJ adenocarcinoma

• Undergoing CyberKnife® for three brain metastases

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?

Neil Morganstein, MD

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 (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?

Warren Brenner, MD

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 line2. Second line3. Third line4. Beyond third line5. 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%?


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, MSI-high adenocarcinoma of the GEJ?


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%?


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 squamous cell carcinoma of the esophagus with a PD-L1 CPS of 10%?


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 monotherapy2. Anti-PD-1/PD-L1 and anti-CTLA-4 combination 3. Chemotherapy 4. Chemotherapy followed by anti-PD-1/PD-L1 monotherapy5. I would not recommend adjuvant systemic therapy6. Other

Slide 1

Presented By Zev Wainberg at 2021 Gastrointestinal Cancers Symposium

Bemarituzumab is an IgG1 antibody specific for the FGFR2b Receptor


FIGHT Trial Design


Progression-Free Survival and Overall Survival: Intent to Treat


Best % Change in Target Lesions from Baseline


FIGHT: Corneal-Related Adverse Events

1 If any event reported, examinations were to continue every 8W until resolution, even if drug discontinued 2 SMQ = Standardised MedDRA Query3 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 reported5 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)

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

Median time to onset to any grade, weeks (range) 16.1(0.1, 41.0)

11.6(6.0, 29.0)

Corneal AE leading to bema/placebo discontinuation5 20 (26.3%) 0

AE resolved 12 (60.0%) 0

AE not resolved as of 23 Sept 2020 8 (40.0%) 0

Median time to resolution, weeks (95%CI) 27.0(18.9, NR) NA

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

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

Tabernero J et al. Gastrointestinal Cancers Symposium 2021;Abstract TPS263.

Primary Outcomes: OS, PFSSecondary Outcomes: ORR, DoR, safety/tolerability

Courtesy of Yelena Y Janjigian, MD

• 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

CheckMate 649

Overall survival: CheckMate 649

aMinimum follow-up 12.1 months.

Primary endpoint (PD-L1 CPS ≥ 5)

NIVO + chemo(n = 473)

Chemo(n = 482)

Median OS, mo 14.4 11.1

(95% CI) (13.1–16.2) (10.0–12.1)

HR (98.4% CI) 0.71 (0.59–0.86)

P value < 0.0001

OS

(%)a

NIVO + chemo

Chemo

MonthsNo. at riskNIVO + chemo 473 438 377 313 261 198 149 96 65 33 22 9 1 0Chemo 482 421 350 271 211 138 98 56 34 19 8 2 0 0

0

20

40

60

80

10012-morate

57%

46%

0 3 6 9 12 15 18 21 24 27 30 33 36 39


KEY DIFFERENCES: KEYNOTE-062 VS. CheckMate 649


ATTRACTION-4: Progression-Free Survival(Interim Analysis)

Cut off: 31 Oct 2018 for Interim analysis

Nivolumab + chemotherapy

N = 362

Placebo + chemotherapy

N = 362Median PFS, months(95% CI)

10.45(8.44-14.75)

8.34(6.97-9.40)

Hazard ratio(98.51% CI)

0.68(0.51 – 0.90)

P value 0.00071yr PFS rate (%) 45.4 30.6

• 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)


Agenda





Case Presentation – Dr Gupta: A 63-year-old woman with MSS metastatic gastric cancer – TMB 19 mut/Mb, PD-L1 CPS 0• 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?

Ranju Gupta, MD

Case Presentation – Dr Flores: A 53-year-old Hispanic woman with gastric cancer

• 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?

Maria Flores, MD

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


CheckMate 577: Adjuvant Nivolumab Following Neoadjuvant CRT/Resection in Esophageal/GEJ Cancer

Kelly. ESMO 2020. Abstr LBA9.

§ 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)

*Residual pathologic disease ≥ ypT1 or ≥ ypN1.

100

80

60

40

20

00 3 6b 9 12 15 18 21 24 27 30 33 36 39 42 45

Months

DFS(

%)

Nivolumab

Placebo

Median DFS, Mos (95% CI)Nivolumab (n = 532) 22.4 (16.6 – 34.0)Placebo (n = 262) 11.0 (8.3 – 14.3)HR: 0.69 (96.4% CI: 0.56 – 0.86; P = .0003)

Courtesy of Zev Wainberg, MD, MSc

Conclusion


Genomic pathway of gut microbiome to predict efficacy of nivolumab in advanced gastric cancer: <br />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)<br />Gastric Cancer Cohort


Antitumor Activity<br />(Confirmed Objective Responses, RECIST v1.1 by BICR)


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


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


Nivolumab in advanced esophageal squamous cell carcinoma (ATTRACTION-1/ONO-4538-07): Minimum<br />of 5-year follow-up

Presented By Ken Kato at 2021 Gastrointestinal Cancers Symposium

ATTRACTION-1: Efficacy


Conclusions


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.

Nivolumab Chemotherapy P valueOverall Response Rate 19% 22% 0.63Disease Control Rate 37% 63%Median Time to Response 2.6 months 1.5 monthsDuration of Response 6.9 months 3.9 monthsTreatment-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

ATTRACTION-3: Nivolumab in Esophageal Squamous Cell Carcinoma (ESCC)

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


ATTRACTION-3: OS Landmark Analysis at 4 Months by Best Overall Response – Progressive Disease


Neoadjuvant PD-1 Blockade in Combination with Chemotherapy for Patients with ResectableEsophageal Squamous Cell Carcinoma

Cheng C et al.Gastrointestinal Cancers Symposium 2021;Abstract 220.

Radiographic Response: Neoadjuvant camrelizumab in combination with chemotherapy

Agenda





Case Presentation – Dr Matt-Amaral: A 68-year-old man with metastatic esophageal cancer

• 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?

Laurie Matt-Amaral, MD, MPH

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. Ramucirumab2. Ramucirumab/paclitaxel 3. Other chemotherapy 4. Test for PD-L1 CPS and administer pembrolizumab if ≥15. Test for PD-L1 CPS and administer pembrolizumab if ≥10 6. Pembrolizumab 7. Nivolumab8. 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-1022. Other chemotherapy 3. Nivolumab4. Pembrolizumab5. Palliative care6. 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

Dayyani F et al. Gastrointestinal Cancers Symposium 2021;Abstract TPS251.

Current Enrollment (n = 20)

Primary Objective:• Regimen feasibility and efficacy

estimate

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

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)

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

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

Agenda





Case Presentation – Dr Hart: A 52-year-old man with gastric cancer with HER2 and HER3 mutations

• 11/2019: Presented with large 6 cm fungating mass in cardia and gastric fundus

• IHC: HER2 = 1+

• 3/2020: Neoadjuvant FLOT x 6 à total gastrectomy à residual disease

• 5/2050: Adjuvant FLOT

• NGS: ERBB2 and ERBB3 mutations

• 7/2020: FLOT discontinued due to worsening neuropathy; initiated lapatinib

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?

Lowell Hart, MD

Case Presentation – Dr Brenner: An 84-year-old man with advanced MSI-high gastric cancer – HER2 activating mutation

• 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?

Warren Brenner, MD

Regulatory and reimbursement issues aside, in which line of therapy would you generally recommend trastuzumab deruxtecanfor a 65-year-old patient with metastatic HER2-positive, MSS adenocarcinoma of the GEJ?


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.

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

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

Shitara K et al. ASCO 2020;Abstract 4513.

Physician’s choice(Irinotecan or paclitaxel) (n = 60)

T-DXd (n = 120)6.4 mg/kg, 3-week cycle

DESTINY-Gastric01 Trial: Third Line – Trastuzumab Deruxtecan

Shitara et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. NEJM 2020

Irinotecan or paclitaxel

N= 125 ptsR 2:1100% Asian

51%

14%


DESTINY-Gastric01 Trial: Third Line – Trastuzumab Deruxtecan

Shitara et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. NEJM 2020

Irinotecan or paclitaxel


Ongoing Trials of Trastuzumab Deruxtecan (T-DXd) in HER2-Positive Gastric or GEJ Adenocarcinoma

Janjigian YY et al. ESMO 2020;Abstract 1500TiP; Clinicaltrials.gov; Assessed January 2021

Trial name (Identifier) Phase

Target accrual (N) Setting Treatment Arms

DESTINY-Gastric04

(NCT04704934)

III 490 • Unresectable and/or metastatic• Progressed on or after a

trastuzumab-based regimen

• T-DXd• Ramucirumab + paclitaxel

DESTINY-Gastric03

(NCT04379596)

II 220 • Locally advanced, unresectable or metastatic

• Progression on or after at least 1 prior trastuzumab-based regimen – Part 1

• Previously untreated dx – Part 2

Part 1• T-DXd + 5-FU ± oxaliplatin

(Ox)• T-DXd + Cape ± Ox• T-DXd + Durvalumab ± 5-FU

or capePart 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

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.



Joshua Bauml, MD


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