Phase II Randomized Study of Ramucirumab and Pembrolizumab Versus Standard of Care in Advanced Non–Small-Cell Lung Cancer Previously Treated With Immunotherapy—Lung-MAP S1800A

Abstract

PURPOSE Resistance to immune checkpoint inhibition (ICI) in advanced non–small-cell lung cancer (NSCLC) represents a major unmet need. Combining ICI with vascular endothelial growth factor (VEGF)/VEGF receptor inhibition has yielded promising results in multiple tumor types. METHODS In this randomized phase II Lung-MAP nonmatch substudy (S1800A), patients ineligible for a biomarker-matched substudy with NSCLC previously treated with ICI and platinum-based chemotherapy and progressive disease at least 84 days after initiation of ICI were randomly assigned to receive ramucirumab plus pembrolizumab (RP) or investigator's choice standard of care (SOC: docetaxel/ramucirumab, docetaxel, gemcitabine, and pemetrexed). With a goal of 130 eligible patients, the primary objective was to compare overall survival (OS) using a one-sided 10% level using the better of a standard log-rank (SLR) and weighted log-rank (WLR; G[rho = 0, gamma = 1]) test. Secondary end points included objective response, duration of response, investigator-assessed progression-free survival, and toxicity. RESULTS Of 166 patients enrolled, 136 were eligible (69 RP; 67 SOC). OS was significantly improved with RP (hazard ratio [80% CI]: 0.69 [0.51 to 0.92]; SLR one-sided P = .05; WLR one-sided P = .15). The median (80% CI) OS was 14.5 (13.9 to 16.1) months for RP and 11.6 (9.9 to 13.0) months for SOC. OS benefit for RP was seen in most subgroups. Investigator-assessed progression-free survival (hazard ratio [80% CI]: 0.86 [0.66 to 1.14]; one-sided SLR, P = .25 and .14 for WLR) and response rates (22% RP v 28% SOC, one-sided P = .19) were similar between arms. Grade ≥ 3 treatment-related adverse events occurred in 42% of patients in the RP group and 60% on SOC. CONCLUSION This randomized phase II trial demonstrated significantly improved OS with RP compared with SOC in patients with advanced NSCLC previously treated with ICI and chemotherapy. The safety was consistent with known toxicities of both drugs. These data warrant further evaluation.

Immunotherapy in NSCLC Patients with Brain Metastases

“…Interestingly, early results from studies investigating the combination of pembrolizumab and lenvatinib, a multi-tyrosine kinase inhibitor, have shown improved efficacy and response durability in several advanced solid tumors, including preliminary data for patients with treatment-refractory NSCLC [69]. More recently, promising results were also presented for the combination of pembrolizumab and ramucirumab, a VEGFR-2 antibody, in pre-treated patients with NSCLC, although the subgroup of patients with BMs was not explicitly evaluated [70]. Outcomes of patients with NSCLC and BMs treated with combination therapies are reported in Table 2.…”

Potential of VEGFR2 expression as a predictive marker of PD‑1 blockade in patients with advanced NSCLC

“…Bevacizumab + atezolizumab is a standard first-line treatment for patients with advanced hepatocellular carcinoma (5). Reckamp et al (26) performed a phase II study to evaluate the efficacy of ramucirumab + pembrolizumab compared with investigator's choice of care in patients with advanced NSCLC who previously received chemotherapy + PD-1 blockade. Even following resistance to prior ICI, ramucirumab with pembrolizumab improved OS compared with standard care, with ORR of 22% (26).…”

Treatment Considerations for Patients With Advanced Squamous Cell Carcinoma of the Lung

“…82 However, the recent Lung-MAP S1800A substudy indicated that the combination of ramucirumab plus pembrolizumab might be a promising approach following immunochemotherapy in patients with NSCLC, including SCC. 83 A total of 136 patients were randomized to receive ramucirumab plus pembrolizumab or investigator's choice of standard care (docetaxel ± ramucirumab, gemcitabine or pemetrexed). In the overall dataset, the combination significantly improved OS versus standard of care (median 14.5 vs. 11.6 months; HR 0.69 [80% CI, 0.51-0.92]).…”