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.

FIG 1.

CONSORT diagram of patient disposition. ^aOf the 84 patients randomly assigned to the SOC arm, 17 patients were not eligible because of the following reasons: not progressing from platinum-based chemotherapy (four), not receiving or progressing from anti–PD-1/PD-L1 therapy per protocol-specified timeframe (two), permanent discontinuation of prior anti–PD-1/PD-L1 therapy because of toxicity (two), baseline scans for measurable disease not performed within the protocol timeframe (two), brain metastases requiring continued steroid treatment beyond the time of registration (two), not receiving and progressing on all SOC–targeted therapies for an oncogenic driver alteration, no measurable disease identified before registration, baseline blood pressure outside of protocol-specified range, receiving more than one line of anti–PD-1/PD-L1 therapy, and baseline scans for measurable disease not of diagnostic quality (one patient each). Of the 82 patients randomly assigned to the investigational arm, 13 patients were not eligible because of the following reasons: not receiving or progressing from anti–PD-1/PD-L1 therapy per protocol-specified timeframe (four), receiving more than one line of anti–PD-1/PD-L1 therapy (two), not progressing from platinum-based chemotherapy (two), no measurable disease identified before registration, receiving systemic therapy within 21 days before random assignment, not receiving platinum-based chemotherapy, receiving radiation therapy within 14 days before random assignmentand inadequate renal function, and receiving corticosteroids for brain metastasis within 7 days before random assignment (one patient each). ^bOf the 55 on the RP arm with reported progression, 41 (75%) went off-RP at the time of progression (PD), four (7%) discontinued treatment before PD, and 10 received treatment after PD. Of the 10, durations were four for < 1 month, two for 1-3 months, one for 3-6 months, and two 6-18 months, and one remains on treatment as of last follow-up at 2.1 months after PD. AE, adverse event; PD, progression of disease; PD-1, programmed death 1; PD-L1, programmed death ligand 1; RP, ramucirumab plus pembrolizumab; SOC, standard of care.

FIG 2.

(A) Overall survival and (B) PFS. P values from the standard log-rank test. HR, hazard ratio; PFS, progression-free survival; RP, ramucirumab plus pembrolizumab; SOC, standard of care.

FIG 3.

Subgroup analysis of (A) overall survival and (B) Progression-free survival. One-sided P values from the standard log-rank test. HR, hazard ratio; IO, immuno-oncology; PD-L1, programmed death ligand 1; PS, performance status; RP, ramucirumab plus pembrolizumab; SOC, standard of care; TMB, tumor mutational burden.