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.

Fig. 1. Trial profile.

Diagram indicating participant numbers and disposition through the course of the trial.

Fig. 2. Tumor reduction in total lesions and tumor response.

a Maximum percentage change from baseline in the size of total (target + non-target) tumor lesions with the corresponding best responses based on RECIST 1.1 criteria and the PD-L1 CPS from baseline tissue in all patients. The lower dotted line represents a 30% tumor reduction (n = 43). b A swimmer plot showing outcomes in all patients from the start of treatment to either disease progression or the last follow-up (n = 43). Note that seven patients received treatment for 2 years. CPS, combined positive score; PD-L1, programmed death-ligand 1; RECIST, Response Evaluation Criteria in Solid Tumors.

Fig. 3. Progression-free survival and overall survival.

a Kaplan–Meier curves of progression-free survival for all patients. b Kaplan–Meier curves of overall survival for all patients. Crosses denote censored observation, and number at risk is indicated below the plots.

Fig. 4. Baseline genomic landscape in the enrolled patients with HER2-positive gastric cancer treated with the first-line quadruplet regimen.

a Baseline (pretreatment) tumor tissue-targeted DNA sequencing results grouped by the best response and related clinicopathologic features (n = 31). Curated pathways and selected genes altered in 6% or more of the patients are shown. Other pathways included those related to the cell cycle and the Hippo, MYC, and NRF2 pathways. Vertical dashed lines indicate groups by the best response. b–d Kaplan–Meier survival curves with PFS stratified by pretreatment ERBB2 amplification as determined via NGS (b n = 35), RTK-RAS pathway gene alterations (c n = 31), and HLA-B-corrected neoantigen load (d n = 31). In (b–d), two-sided P-values for survival associations were calculated using the log-rank tests. Hazard ratios and corresponding 95% CIs were estimated using Cox proportional hazard regression model. No adjustments for multiple comparisons were made. Crosses denote censored observation, and the number at risk is indicated below the plots. HER2, human epidermal receptor 2; ERBB2, Erb-B2 receptor tyrosine kinase 2; HLA, human leukocyte antigen; NGS, next-generation sequencing; PFS, progression-free survival; RTK, receptor tyrosine kinase.

Fig. 5. Genomic analyses from serial biopsy samples of HER2-positive gastric cancer patients treated with the first-line quadruplet regimen.

a Spider plot showing patients with HER2 mutations found in serial NGS analyses of primary tumor. Only cases with HER2 mutations and variant allele frequencies (VAFs) with the corresponding patient IDs are shown. b, c Sensitive (b) or resistant (c) sub-clones in which the sub-clone frequency changed over 2-fold in post-progression (Post-PD) samples (n = 10) or on-treatment (On-Tx) samples (n = 9) compared to paired baseline samples (n = 14) are selected per patient. Statistically significant enriched Reactome pathways with the multiple test correction (Benjamini-Hochberg procedure) were retained, and selected enriched Reactome pathways from sensitive or resistant sub-clone genes are also shown. All paired tissue samples are only from the primary tumor (stomach). Only hotspot gene mutations that appeared in more than two samples are shown in the sub-clone frequency graph. X-axis indicated –log10 adjusted P-values and statistical significance is indicated by the vertical dashed line. d, e Representative cases showing sub-clonal evolution by fish plot and corresponding clinicopathologic features and computed tomography or endoscopic images from paired tissue NGS from both primary tumor (stomach) and metastatic liver. Selected hotspot mutations are labeled. Representative case from good responders (n = 11, d) and poor responder (n = 1, e). HER2, human epidermal receptor 2; ERBB2, Erb-B2 receptor tyrosine kinase 2; NGS, next generation sequencing.