1188PDMargetuximab (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 1.5 m and 9.1 m in GEA pts with PD-L1 CPS >1, and both were lower for PD-L1 all-comers. M is an investigational anti-HER2 Fc-optimized monoclonal antibody that can coordinate activation between innate and adaptive immunity. In pts treated with M+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 with M (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 3.8 m (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 3.5 m (95% CI 1.64-4.76), and mOS was 13.9 m (95% CI 9.26-16.82); OS rates at 6/12/18/24 m were 77/57/35/32%, respectively. In GEA HER2 IHC3+ pts, mPFS was 4.5 m (95%CI 2.7-7.5) and mOS was 16.8 m (95%CI 12.23-not reached (NR)). OS rates at 6/12/18/24 m were 85/66/48/44%, respectively; IHC3+ GC (54 [63%]) showed mPFS of 4.7 m (95% CI 2.73-7.49) and mOS NR (95% CI 12.25-NR). IHC3+/ctDNA+ confirmation GEA (38 [44%]) showed mPFS 7.5 m (95% CI 3.5-12.4) and mOS NR (13.27-NR), and IHC3+/ctDNA+ GC (31 [36%]) showed mPFS 5.6 m (95% CI 2.73-8.34) and mOS NR (12.48 – NR). Median PFS and mOS were lower in GEJ: 1.5 m (1.38, 4.34) and 9.2 m (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. Clinical trial identification NCT02689284. Legal entity responsible for the study MacroGenics, Inc. Funding MacroGenics, Inc. Disclosure D.V. Catenacci: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria