A multi-institutional phase Ib/II trial of first-line triplet regimen (Pembrolizumab, Trastuzumab, Chemotherapy) for HER2-positive advanced gastric and gastroesophageal junction cancer (PANTHERA Trial): Molecular profiling and clinical update.

Abstract

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]

Immunotherapy Predictive Molecular Markers in Advanced Gastroesophageal Cancer: MSI and Beyond

“…Furthermore, the interim results of the PANTHERA trial reported the exploratory analysis of TMB in patients who received first line pembrolizumab plus chemotherapy with trastuzumab for HER-2-positive GEC. In this analysis, high TMB was associated with a nonsignificant tendency towards increased mPFS (22.0 vs. 8.6 months, p = 0.2835) [35]. These results suggest that TMB appears to have a potential as a biomarker of response to anti-PD-1 therapy in GEC.…”

“…The study demonstrated a six-month PFS of 70% (26/37), meeting its primary endpoint [34]. Additionally, a multicenter, single-arm phase Ib/II PANTHERA trial conducted in Korea recently reported in GI-ASCO 2021 a promising ORR of 76.7%, mPFS of 8.6 months, mOS of 19.3 months, and DOR of 10.8 months [35]. Based on these results, the KEYNOTE-811 trial is currently under way, comparing the addition of pembrolizumab versus placebo to trastuzumab and chemotherapy in untreated, HER-2 positive advanced GEC (NCT03615326).…”

Recent Advances in Systemic Treatments for HER-2 Positive Advanced Gastric Cancer

“…79 In the phase 1b/2 PANTHERA trial (NCT02901301), first-line triple therapy with pembrolizumab, trastuzumab and chemotherapy showed promising efficacy in the treatment of advanced HER2 amplified gastric cancer regardless of PD-L1 status. 80 The ORR was 77%, and patients with HER2 amplification per NGS (≥ 4 copy number) had a statistically significantly longer median PFS than those without HER2 amplification (median PFS, 22.0 months vs 7.7 months; P =0.03). The same trend was shown in patients with altered RTK/RAS pathways compared with wild-type RTK/RAS (median PFS, 13.8 months vs 4.9 months; P = 0.001).…”

Highlights from ASCO-GI 2021 from EORTC Gastrointestinal tract cancer group

“…Together with trastuzumab deruxtecan and margetuximab, zanidatamab appears to be a good candidate for integration with chemotherapy or immunotherapy in future for HER2 positive gastric cancer patients [5,6]. Considering HER2directed therapy plus immunotherapy, the results of triplet treatment of chemotherapy, trastuzumab and pembrolizumab in first-line advanced gastric cancer in the PANTERA study were also presented at ASCO-GI 2021 [7]. Radiological response rates of 76% were observed, with encouraging median OS of 19.3 months (95% CI, 16.5-NR).…”