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

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 IO360TM assay on archival FFPE biopsies. Results: 92 pts (66% GC, 34% GEJ) received 15 mg/kgM+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.