Efficacy, Safety, and Influence on the Tumor Microenvironment of Neoadjuvant Pembrolizumab plus Ramucirumab for PD-L1–Positive NSCLC: A Phase II Trial (EAST ENERGY)

Abstract Purpose: Angiogenesis inhibitors are known to modify tumor immunity. Combination of angiogenesis inhibitors with immune checkpoint inhibitors has shown efficacy against many types of cancers, including non–small cell lung cancer (NSCLC). We investigated the feasibility of neoadjuvant therapy with pembrolizumab and ramucirumab, a VEGFR-2 antagonist for patients with PD-L1–positive NSCLC, and its influence on the tumor microenvironment. Patients and Methods: Patients with pathologically proven, PD-L1–positive, clinical stage IB to IIIA NSCLC were eligible. Patients received two cycles of pembrolizumab (200 mg/body) and ramucirumab (10 mg/kg) every 3 weeks. Surgery was scheduled 4 to 8 weeks after the last dose. The primary endpoint was the major pathologic response rate by a blinded independent pathologic review. The sample size was 24 patients. Exploratory endpoints were evaluated to elucidate the effects of neoadjuvant therapy on the tumor microenvironment. Results: The 24 eligible patients were enrolled between July 2019 and April 2022. The major pathologic response rate was 50.0% (90% confidence interval, 31.9%–68.1%). Six patients showed pathologic complete response. Grade 3 adverse events (AE) occurred in nine patients (37.5%), including three immune-related AEs (acute tubulointerstitial nephritis in two cases and polymyalgia rheumatica in one case). There were no grade 4 or 5 AEs. The transcriptome and multiplex IHC results suggested that tumors with greater CD8+ T-cell infiltration and higher expression of effector molecules at the baseline could show better sensitivity to treatment. Conclusions: This new neoadjuvant combination of pembrolizumab plus ramucirumab was feasible, and anti-VEGF agents may enhance the effects of immune checkpoint inhibitors.