A single arm phase Ib/II trial of first-line pembrolizumab, trastuzumab and chemotherapy for advanced HER2-positive gastric cancer

Abstract

In this multi-center phase II trial, we evaluated the efficacy and safety of a quadruplet regimen (pembrolizumab, trastuzumab, and doublet chemotherapy) as first-line therapy for unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC) (NCT02901301). The primary endpoints were recommended phase 2 dose (RP2D) for phase Ib and objective response rate (ORR) for phase II. The secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, time to response and safety. Without dose-limiting or unexpected toxicities, the starting dose in the phase Ib trial was selected as RP2D. In 43 patients, the primary endpoint was achieved: the objective response rate was 76.7% (95% confidence interval [CI]: 61.4–88.2), with complete and partial responses in 14% and 62.8% of patients, respectively. The median progression-free survival, overall survival, and duration of response were 8.6 months, 19.3 months, and 10.8 months, respectively. No patients discontinued pembrolizumab because of immune-related adverse events. Programmed death ligand-1 status was not related to survival. Post hoc analyses of pretreatment tumor specimens via targeted sequencing indicated that ERBB2 amplification, RTK/RAS pathway alterations, and high neoantigen load corrected by HLA-B were positively related to survival. The current quadruplet regimen shows durable efficacy and safety for patients with HER2-positive AGC.

Validation of a targeted sequencing panel with automatic analysis system for clinical decision support in cancer therapy

“…Our study demonstrated the panel's reliable accuracy and sensitivity in detecting genetic alterations, CNVs, EBV/HPV infections, and MSI status. Furthermore, we have recently reported translational data utilizing the CancerMaster for comprehensive genomic pro ling in solid tumors, providing further evidence of its signi cant clinical implications and further highlighting that it has potential to improve patient outcomes through personalized cancer treatment (C. K. Lee et al 2022). The panel's asynchronous and parallel analysis pipeline offers a seamless, one-stop solution for comprehensive and rapid reporting of clinically actionable variants while conserving limited tumor tissue.…”

Efficacy and survival of anti-PD-1 antibody in combination with trastuzumab and chemotherapy versus trastuzumab and chemotherapy as first-line treatment of HER2-positive metastasis gastric adenocarcinoma: a retrospective study

“…The mPFS was 8.6 months and mOS achieved 19.3 months. At the same time, they explored the molecular signatures of enrolled patients, and next-generation sequencing indicated that RTK/RAS pathway alterations were closely correlated with PFS ( 32 ). In our study, the OS of patients with HER2 FISH positive was different in two groups.…”

Breakthroughs in the Systemic Treatment of HER2-Positive Advanced/Metastatic Gastric Cancer: From Singlet Chemotherapy to Triple Combination

“…The scientific rationale for using this triple combination is to facilitate tumor responses via tumor targeting through cross-priming, chemotherapy-induced immunogenic cell death, or modification of the immunosuppressive microenvironment. Proof-of-concept data from two single-arm phase II trials of pembrolizumab in combination with chemotherapy plus trastuzumab have been reported [ 76 77 ]. Janjigian et al [ 76 ] reported an ORR of 91% (95% CI, 78–97), 13 months of PFS (95%CI, 8.6–not reached [NR]), and 27.3 months of OS (95% CI, 18.8–NR).…”

“…PFS was associated with HER2 plasma copy number but not with tissue HER2 copy number, suggesting that plasma copy number better reflected tumor heterogeneity. The PANTHERA trial ( NCT02901301 ) [ 77 ] reported a 95% tumor shrinkage rate and an ORR of 77% (95% CI, 61.4–88.2) with a PFS of 8.6 (95% CI, 7.2–16.4) and an OS of 19.3 (95% CI, 16.5–NR) months. Patients with HER2 amplification had longer PFS than patients without amplification (22.0 vs. 7.6 months: HR, 0.28; P=0.01).…”