Safety and antitumor activity from the phase Ib study of ramucirumab plus pembrolizumab in treatment-naïve advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (JVDF)

Abstract

Introduction: Previous phase Ia study results confirmed the safety of combining ramucirumab (anti-VEGFR) plus pembrolizumab (anti-PD-1) in multiple tumor cohorts. Here we present final expansion cohort results from treatment-naïve patients with locally advanced and unresectable or metastatic G/GEJ adenocarcinoma. Clinicaltrials.gov NCT02443324. Methods: Patients with locally advanced unresectable or metastatic G/GEJ adenocarcinoma and ECOG PS of 0 or 1 eligible for first-line chemotherapy received ramucirumab (8 mg/kg day 1 and 8) plus pembrolizumab (200 mg day 1) every 3 weeks. This phase Ib study assessed safety according to NCI-CTCAE version 4.0, and preliminary efficacy: objective response rate (RECIST v1.1 and immune-related RECIST), disease control rate, duration of response, time to response, progression-free survival (PFS), and overall survival (OS). PD-L1 status was assessed with the DAKO PD-L1 22C3 IHC pharmDx assay using the combined positive score with ≥1 being positive. Association between tumor PD-L1-expression at baseline was correlated with clinical outcomes. Results: As of August 31, 2018, 28 treatment-naïve patients with locally advanced (n=1) or metastatic (n=27) G/GEJ adenocarcinoma were treated with ramucirumab plus pembrolizumab. The median age was 63 years, 75% were male, 57% had ECOG PS of 0, and 68% were PD-L1 positive. All grades treatment-related adverse events (TRAEs) occurred in 27 (96%) patients; TRAEs in ≥15% of patients were fatigue (36%), hypertension (29%), headache (21%), diarrhea (18%), nausea (18%), stomatitis (18%), increased alanine aminotransferase (18%), increased aspartate aminotransferase (18%), proteinuria (18%), and epistaxis (18%). Eighteen (64%) patients experienced grade 3 TRAEs, most commonly hypertension (14%), elevated alanine (11%) or aspartate (11%) aminotransferase, diarrhea (7%), and gastrointestinal hemorrhage (7%). No grade 4 or 5 TRAEs occurred. Objective response rate was 25% (7/28 patients) with complete and partial responses observed in 4% (1/28) and 21% (6/28), respectively. Of the 7 patients with an objective response, 6 were positive and 1 was negative for PD-L1. Disease control rate was 68%. Median time to response was 2.7 months (95% CI, 1.3-2.8) and median duration of response was not reached (95% CI, 9.7, not reached). Median PFS was 5.6 months (95% CI, 2.7-11.5). The 12-, 18-, and 24-month PFS rates were 30%, 21%, and 21%, respectively. Median OS was 14.6 months (95% CI, 5.4, not reached). The 12-, 18-, and 24-month OS rates were 54%, 41%, and 41%, respectively. The median OS in PD-L1 positive and negative patients were 17.3 months and 11.3 months, respectively. Conclusion: Final results from the cohort with G/GEJ adenocarcinoma demonstrate that a proportion of patients treated with ramucirumab and pembrolizumab in the first-line setting had prolonged disease control and survival, with no new safety signals from the combination.