Targeting HER2 in combination with anti-PD-1 and chemotherapy confers a significant tumor shrinkage of gastric cancer: A multi-institutional phase Ib/II trial of first-line triplet regimen (pembrolizumab, trastuzumab, chemotherapy) for HER2-positive advanced gastric cancer (AGC).

Abstract

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]

Safety and efficacy of HER2 blockade by trastuzumab-based chemotherapy-containing combination strategies in HER2+ gastroesophageal adenocarcinoma

“…Checkpoint inhibitor therapy was administered in combination with trastuzumab and chemotherapy in four studies. [14][15][16][17]24 Three of these studies investigated pembrolizumab (including the phase III KEYNOTE-811 14 and the phase I/II PANTHERA 16,17 ), and one tested avelumab. 24 Overall, median follow-up across all studies ranged from 10 to 34 months (Table 2).…”

“…The treatment-related AEs of all grades occurring in !30% of patients in at least two studies were nausea (33%-84%), anemia (33%-81%), and diarrhea (30%-73%; Table 3). 15,17 Grade !3 treatmentrelated AEs occurring in !10% of patients in at least two studies were neutropenia (28%-42%), anemia (11%-16%), and thrombocytopenia (7%-11%; Table 3). 15,17,24 Analysis of a select type of TEAEs across the four studies [14][15][16][17]24 of regimens containing checkpoint inhibitors, trastuzumab, and chemotherapy reveals the following ranges (Table 4): fatigue (all grades: 24%-86%; grade !3: 0%-4%); nausea (all grades: 49%-84%; grade !3: 0%-5%); diarrhea (all grades: 53%-73%; grade !3: 2%-7%); neutropenia (all grades: 19%-47%; grade !3: 0%-42%); anemia (all grades: 33%-81%; grade !3: 9%-16%); peripheral neuropathy (all grades: 19%-97%; grade !3: 0%-3%); pneumonitis (all grades: 5%; grade !3: 1%); stomatitis (all grades: 23%-38%; grade !3: 2%-5%); and PPE/HFS (all grades: 22%-23%; grade !3: 0%).…”

“…10 PD-L1 positivity by combined positive score !1 is found in w60% of patients with gastric cancer and anti-PD-1/PD-L1 antibodies have shown encouraging clinical activity in advanced gastric or GEJ cancer. 11,12 Moreover, trastuzumab has been reported to increase PD-L1 expression on syngeneic mouse tumor cells; 13 therefore, the addition of the checkpoint inhibitor pembrolizumab to SOC trastuzumab/chemotherapy has been tested in clinical trials, [14][15][16][17] and recently led to the United States Food and Drug Administration approval of pembrolizumab in combination with trastuzumab, and fluoropyrimidine-and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2þ gastric or GEJ adenocarcinoma, 18 based on data from the phase III KEYNOTE-811 study (NCT03615326). 14 Therefore, in this narrative review, we summarize safety and efficacy of 23 studies, 20 primary studies, and 3 subgroup analyses of first-line trastuzumab plus doublet chemotherapy, with or without checkpoint inhibitors, conducted in patients with locally advanced unresectable or metastatic HER2þ GEA, including phase II/III, prospective, and retrospective observational real-world evidence studies, published in PubMed over the last 11 years.…”

First-Line Pembrolizumab/Placebo Plus Trastuzumab and Chemotherapy in Her2-Positive Advanced Gastric Cancer: KEYNOTE-811

“…Results from one of these trials (NCT02954536) showed that a combination of pembrolizumab, trastuzumab and chemotherapy (oxaliplatin or cisplatin) had a manageable safety profile and promising efficacy, with an ORR of 91% (95% CI: 78-97; 32 of 35 patients; six CRs) in patients with esophagogastric adenocarcinoma [30]. In another trial (NCT02901301), the ORR was 77% with pembrolizumab, trastuzumab, capecitabine and cisplatin as first-line therapy for HER-positive advanced gastric cancer [31]; the dosing schedule and patient population are similar to those of the KEYNOTE-811 trial.…”

Management of Non-Colorectal Digestive Cancers with Microsatellite Instability

“…Their success likely stems from a hot tumor microenvironment (TME) marked by MSI-H-, TMB-H- and PD-L1-positive tumors and pathological associations with Helicobacter pylori and EBV infections. In addition to chemotherapy, combining ICIs with targeted therapies such as inhibitors against the VEGF or HER-2 pathway that are capable of modulating the TME have produced encouraging results [ 92 , 93 ]. Sequential therapy from ICIs to chemotherapy is another promising strategy [ 94 ].…”