3081 Background: Combining anti-PD-1 agent and trastuzumab has shown synergy in HER2 positive preclinical cancer models. We first report the result of a multi-institutional phase Ib/II trial of triple combination (pembrolizumab, trastuzumab, and chempotherapy) as first line therapy for HER2 positive AGC. (PANTHERA trial; NCT02901301). Methods: Pembrolizumab 200mg IV D1, Trastuzumab 6mg/kg (after 8mg/kg load) D1, Capecitabine 1000mg/m2 bid D1-14, and Cisplatin 80mg/m2 D1 every 3 weeks was selected as recommended phase II dose. The primary endpoint for phase II was ORR per RECIST v1.1. Secondary endpoints included PFS, OS, DoR, safety, and molecular analysis by targeted NGS. Results: Total of 43 patients were treated with median follow up of 16.1 months, and 11 pts remained on the treatment (treatment duration range: 1.4 to 24 months). There was significant tumor shrinkage of 95.3% with 54.6% median depth of response, with 76.7% ORR (CR 16.3%, PR 60.5%, conversion surgery 4.6%), and 97.7% DCR. Median PFS was 8.6 months (95% CI 7.2-22.0) and median OS was 18.4 months (95% CI 17.9-NA). Subsequent chemotherapy was given to 83.3% of 30 progressed pts. There were no MSI-H/dMMR or EBV-positive pts. PD-L1 status (57.1% of pts ≥ CPS 1 and 14.3% of pts ≥ CPS 10 among 35 pts), metastatic organ or baseline tumor burden was not related to the survival. Treatment-related AE (≥G3) occurred in 32 pts (74.4%) including 17 pts (39.5%) with neutropenia G3-4. Immune-related AEs (≥G3) occurred in 4 pts (10%). Ninety-six tumor tissues from 32 pts (paired tumor tissues from 25 pts) were analyzed with targeted NGS. TMB (median 12.7 mut/MB with range of 9.45-16.71) was not related to the PD-L1 expression or survival. Conclusions: First-line triplet regimen (Pembrolizumab, Trastuzumab, and Chemotherapy) confers a significant tumor shrinkage for HER2 positive AGC, regardless of PD-L1 status. Phase III Keynote-811 study (NCT03615326) is ongoing based on the protocol of this study. Clinical trial information: NCT02901301 . [Table: see text]

218 Background: We report the updated clinical data and molecular profiling results of a multi-institutional phase Ib/II trial of triple combination (pembrolizumab, trastuzumab, and chempotherapy) as first line therapy for HER2 positive advanced gastric and gastroesophageal junction (AGC/GEJ) cancer. (PANTHERA trial; NCT02901301). Methods: Pembrolizumab 200mg IV D1, Trastuzumab 6mg/kg (after 8mg/kg load) D1, Capecitabine 1000mg/m2 bid D1-14, and Cisplatin 80mg/m2 D1 every 3 weeks was selected as recommended phase II dose. The primary endpoint for phase II was ORR per RECIST v1.1. Secondary endpoints included PFS, OS, DOR, safety, and predictive biomarker analysis by targeted NGS. Results: At the time of data lock on Aug 31, 2020, total of 43 patients were treated with median follow up of 18.2 months, and 3 patients remained on the treatment, and 6 patients finished 2-year treatment without progression. ORR was 76.7% (CR 16.3%, PR 60.5%, conversion surgery 4.6%) with 26 pts (56.6%) showing more than 50% of tumor burden reduction. Median PFS was 8.6 months (95% CI 7.2-16.5) and median OS was 19.3 months (95% CI 16.5-NR). There were no MSI-H/dMMR or EBV-positive pts. No patient discontinued pembrolizumab because of immune-related adverse events. Clinical features including PD-L1 status (55.3% of pts ≥ CPS 1 and 13.2% of pts ≥ CPS 10 among available 38 pts), metastatic organ or baseline tumor burden was not related to the survival. Ninety-eight tumor tissues from 39 pts (paired tumor tissues from 22 pts) were analyzed with targeted NGS. Although every pts were HER2 IHC-positive, baseline HER2 amplification by NGS was related to the survival ( HER2 amp (n=8) vs HER2 non-amp (n=23); mPFS, not reached vs 7.7 months, P=0.0178; mOS, not reached vs 17.9 months, P=0.044) but no other signaling pathways predicted pts’ survival. HER2 mutations including L869R or D769H were related to the acquired resistance. High TMB showed a tendency toward better survival (mPFS; High (n=7) vs Low (n=24) TMB, 22.0 vs 8.2, P=0.2835) due to small number of patients. Updated immune markers and serial NGS analyses will be presented. Conclusions: First-line triplet regimen (Pembrolizumab, Trastuzumab, and Chemotherapy) showed promising efficacy based on HER2 amplification by NGS regardless of PD-L1 status in AGC/GEJ cancer. Correlative biomarkers found from NGS study need to be validated through on-going phase III Keynote-811 study. Clinical trial information: NCT02901301. [Table: see text]

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