Margetuximab (M) + pembrolizumab (P) for treatment of patients (pts) with HER2+ gastroesophageal adenocarcinoma (GEA) post-trastuzumab (T): Survival analysis

Abstract

Background: Current standard of care (SOC) in 2L GEA, ramucirumab +taxane, has median progression free survival (mPFS) of 4.4 months (m) and median overall survival (mOS) of 9.6 m. Chemotherapy-backbone HER2-targeted agents tested in 2L HER2+ GEA TyTAN and GATSBY studies showed mPFS and mOS ranged 2.4-5.4 months (m), and 7.1-11.2 m. P, in 2L KN061, showed mPFS and mOS of 1.5mand 9.1 min GEA pts with PD-L1 CPS>1, and both were lower for PD-L1 all-comers.Mis an investigational anti-HER2 Fc-optimized monoclonal antibody that can coordinate activation between innate and adaptive immunity. In pts treated withM+P, we previously reported ORR of 33% in HER-2 IHC-3+ gastric cancer (GC) pts and over 50% in pts with HER-2+/PD-L1+tumors. Methods: HER2+ PD-L1 unselected 2L GEA pts (N=86) were enrolled post progression on T-based therapy (tx) and treated withM(15 mg/kg) and P (200 mg) IV Q3wk. We report mPFS and mOS in the overall expansion cohort and in biomarker subgroups including archival PD-L1 and HER2 IHC, ERRB2 ctDNA (prior to 2L tx), and tumor site (GC vs junction [GEJ]). Results: Median duration of tx was 3.8m(range 0.7-26.5), with median follow-up 11.3 m(range 1.6-28.6). Pt characteristics (n,%) included: GC 60 (70%), HER2 IHC3+ 68 (79%), PD-L1 CPS>1 32 (37%), ERBB2 ctDNA+ 46 (53%), and MSI-high 1 (1%). In overall GEA pts, mPFS was 3.5m(95% CI 1.64-4.76), and mOS was 13.9m(95% CI 9.26-16.82); OS rates at 6/12/18/24mwere 77/57/35/32%, respectively. In GEA HER2 IHC3+pts, mPFS was 4.5m(95%CI 2.7-7.5) and mOS was 16.8m(95%CI 12.23-not reached (NR)). OS rates at 6/12/18/24mwere 85/66/48/44%, respectively; IHC3+ GC (54 [63%]) showed mPFS of 4.7m(95% CI 2.73-7.49) and mOS NR (95% CI 12.25- NR). IHC3+/ctDNA+ confirmation GEA (38 [44%]) showed mPFS 7.5m(95% CI 3.5-12.4) and mOS NR (13.27-NR), and IHC3+/ctDNA+GC (31 [36%]) showed mPFS 5.6m(95% CI 2.73-8.34) and mOS NR (12.48 - NR). Median PFS and mOS were lower in GEJ: 1.5m(1.38, 4.34) and 9.2m(5.26, 15.41), respectively. Conclusions: In this study, M+P, a chemotherapy-free regimen, demonstrated acceptable tolerability in HER2+ GEA pts post-T, with extension of time-to-event endpoints compared to historical experience with SOC regimens, and checkpoint inhibitors alone.