Determinants of response of HER2+ gastric cancer (GC) vs gastroesophageal junction adenocarcinoma (GEJ) to margetuximab (M) plus pembrolizumab (P)...

Date 30 September 2019
Event ESMO 2019 Congress
Session Poster Discussion 2 – Immunotherapy of cancer
Presenter Haeseong Park
Citation Annals of Oncology (2019) 30 (suppl_5): v475-v532. 10.1093/annonc/mdz253
Authors H. Park1, H. Uronis2, Y. Kang3, M.C.H. Ng4, P. Enzinger5, K.W. Lee6, S. Rutella7, S.E. Church8, J. Nordstrom9, K. Knutson10, C. Erskine10, T. Wu11, J. Yen12, A. Franovic13, J. Muth9, M. Rosales14, J. Vadakekolathu15, J. Davidson-Moncada16, Y. Bang17, D.V. Catenacci18
  • 1Medical Oncology, Washington University Medical School, 63110 - St. Louis/US
  • 2Medical Oncology, Duke Cancer Center, Durham/US
  • 3Oncology Dept, Asan Medical Center, University of Ulsan College of Medicine, 138-931 - Seoul/KR
  • 4Division Of Medical Oncology, National Cancer Centre Singapore, 169610 - Singapore/SG
  • 5Center For Esophageal And Gastric Cancer, Gastrointestinal Malignancy Program, Dana-Farber Cancer Institute, Cambridge/US
  • 6Internal Medicine, Seoul National University Bundang Hospital, Seongnam/KR
  • 7John Van Geest Cancer Research Centre, Nottingham Trent University-Clifton Campus, NG1 18NS - Nottingham/GB
  • 8Mdx Development, Nanostring, Seattle/US
  • 9Research, MacroGenics, Inc., Rockville/US
  • 10Discovery And Translation Labs Cancer Research, Mayo Clinic, Jacksonville/US
  • 11Biostatistics, MacroGenics, Inc., Rockville/US
  • 12Bioinformatics, Guardant Health, Inc., Redwood City/US
  • 13Biopharm Collaborations, Guardant Health, Inc., Redwood City/US
  • 14Clinical, MacroGenics, Inc., 20850 - Rockville/US
  • 15School Of Science And Technology, Nottingham Trent University, NG14FQ - Nottingham/GB
  • 16Clinical Development, MacroGenics, Inc., 20850 - Rockville/US
  • 17Medical Oncology, Seoul National University Hospital, Seoul/KR
  • 18Gastrointestinal Oncology Program, University of Chicago, 60637 - Chicago/US

Abstract

Background

T + chemo is standard 1st line therapy for HER2+ gastroesophageal adenocarcinoma; however, patients (pts) tend to progress in 6-8 months. Up to 40% show loss of HER2 expression post T, likely underlying the lack of efficacy of anti-HER2 agents in 2nd line therapy. We report here a clinical update and biomarker analysis of an ongoing study in pts receiving M, an anti-HER2 Fc-optimized mAb, plus P in HER2+ GEA pts in post T, 2nd line, chemotherapy-free treatment.

Methods

Endpoints described herein are safety, objective response rate (ORR), disease control rate (DCR), archival HER2 IHC level and/or ERBB2 amplification (amp) status pre-M+P in cell free DNA (cfDNA) by NGS (Guardant360), PD-L1 CPS by IHC (22C3 pharmDx), anti-HER2 T- cell immunity by ELISPOT on PBMCs, and NanoString PanCancer IO360™ assay on archival FFPE biopsies.

Results

92 pts (66% GC, 34% GEJ) received 15 mg/kg M + 200 mg P Q3W. 99% were MSS and 43% were PD-L1 + (>1%). Related adverse events ≥grade 3 were 18.5%. Confirmed ORR was 19% with 54% DCR; interestingly, higher response rates occurred in GC vs GEJ (25% vs 7% ORR, p = 0.047 and 64% vs 33% DCR, p = 0.008). A higher proportion of GC vs GEJ cancers was HER2 3+ on archival IHC (90% vs 53%, p = 0.0075), furthermore, a 5.3-fold greater fraction of GC vs GEJ pts showed upregulated tumor ERBB2 RNA expression (p < 0.001). Pts with upregulated tumor ERBB2 RNA expression showed a 3-fold greater frequency of DCR (p = 0.003). While not statistically significant, more GC pts retained HER2+ status post T (62.5% vs 50%) or expressed PD-L1 by IHC (46.3% vs 31.8%); notably, however, the frequency of dual ERRB2 amplified plus PD-L1+ was >6-fold higher in GC vs GEJ (34.7% vs 5.5%, p = 0.03) and associated with 53% confirmed ORR and 82% DCR in GC. GC pts with higher baseline T-cell immunity toward HER2 (p59 class II peptide) had greater probability of ORR (p = 0.005).

Conclusions

In this study, M+P demonstrated tolerability and preliminary evidence of anti-tumor activity as a chemotherapy-free regimen in 2nd line HER2+ GC; biomarker analysis suggests an association with higher expression and retention of HER2 and PD-L1 together with pre-existing anti-HER2 immunity.

Clinical trial identification

NCT02689284.

Editorial acknowledgement

Legal entity responsible for the study

MacroGenics, Inc.

Funding

MacroGenics, Inc.

Disclosure

H. Park: Research grant / Funding (institution): Ambrx; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Gilead Sciences; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Puma Biotechnology; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Vertex. H. Uronis: Shareholder / Stockholder / Stock options, Full / Part-time employment: GeneCentric; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Research grant / Funding (institution): Advaxis; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Merck. Y. Kang: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): DAE HWA Pharmaceutical; Advisory / Consultancy: Lilly/Imclone; Advisory / Consultancy: Merck/Serano; Advisory / Consultancy: Ono Pharmaceutical; Advisory / Consultancy: Roche/Genentech; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): LSK Biopharma. M.C.H. Ng: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD Oncology; Honoraria (self), Travel / Accommodation / Expenses: Taiho Pharmaceutical; Advisory / Consultancy: Bristol-Myers Squibb; Research grant / Funding (institution): ASLAN Pharmaceuticals. P. Enzinger: Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: Merck; Advisory / Consultancy: Taiho Pharmaceutical. K.W. Lee: Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): ASLAN Pharmaceuticals; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Green Cross Corp; Research grant / Funding (institution): LSK BioPharma; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Merck KGaA; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Pharmacyclics; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Lilly; Research grant / Funding (institution): ALX Oncology. S. Rutella: Leadership role: Clinical & Biomarkers Data Sharing Subcommittee, Society for Immunotherapy of Cancer; Research grant / Funding (institution): John and Lucille van Geest Foundation. S.E. Church: Shareholder / Stockholder / Stock options, Full / Part-time employment: NanoString Technologies. J. Nordstrom: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. T. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. J. Yen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Guardant Health. A. Franovic: Shareholder / Stockholder / Stock options, Full / Part-time employment: Guardant Health. J. Muth: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. M. Rosales: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. J. Davidson-Moncada: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. Y. Bang: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/MedImmune; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Beigene; Advisory / Consultancy, Research grant / Funding (institution): Green Cross; Advisory / Consultancy: Hanmi; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy, Research grant / Funding (institution): MSD Oncology; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Samyang; Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): CKD; Research grant / Funding (institution): Curis; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Takeda. D.V. Catenacci: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self): Five Prime Therapeutics; Honoraria (self), Speaker Bureau / Expert testimony: Foundation Medicine; Honoraria (self), Advisory / Consultancy: Genentech/Roche; Honoraria (self): GenMab; Honoraria (self): Gritstone Oncology; Honoraria (self), Speaker Bureau / Expert testimony: Guardant Health; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self): Merck; Honoraria (self): NantOmics; Honoraria (self): OncoPlex Diagnostics; Honoraria (self), Advisory / Consultancy: Taiho Pharmaceutical; Advisory / Consultancy: Astellas Pharma. All other authors have declared no conflicts of interest.