In the phase II Lung-MAP substudy S1800A presented at the 2022 ASCO Annual Meeting (Abstract 9004) and simultaneously reported in the Journal of Clinical Oncology, Karen L. Reckamp, MD, and colleagues found that the combination of ramucirumab and pembrolizumab improved overall survival vs investigator’s choice of standard-of-care treatment in patients with advanced non–small cell lung cancer (NSCLC) who experienced disease progression on prior immune checkpoint inhibitor therapy.

As stated by the investigators, “Resistance to immune checkpoint inhibition in advanced NSCLC represents a major unmet need. Combining immune checkpoint inhibition with vascular endothelial growth factor (VEGF)/VEGF receptor inhibition has yielded promising results in multiple tumor types.”

Karen L. Reckamp, MD

Study Details

The U.S. multicenter open-label trial included 136 eligible patients with stage IV or recurrent disease previously treated with an immune checkpoint inhibitor and platinum-based chemotherapy who had progressive disease at least 84 days after initiation of immune checkpoint inhibitor treatment. They were randomly assigned between May 2019 and November 2020 to receive ramucirumab plus pembrolizumab (n = 69) or investigator’s choice of standard-of-care treatment (n = 67). Patients had to be ineligible for a biomarker-matched substudy within the Lung-MAP trial. Treatment consisted of ramucirumab at 10 mg/kg plus pembrolizumab at 200 mg once every 21 days, with standard-of-care choices including docetaxel/ramucirumab (n = 45), docetaxel (n = 3), gemcitabine (n =12), or pemetrexed (n = 1); six patients in the standard-of-care group received no treatment. The primary objective was to compare overall survival using a one-sided 10% level using a standard log-rank (SLR) and weighted log-rank (WLR) test; if either P value was < .0972, the study was considered to have rejected the null hypothesis.

Overall Survival

Median follow-up among surviving patients was 17.9 months (range = 1–30 months). Median overall survival was 14.5 months (80% confidence interval [CI] = 13.9–16.1 months) in the ramucirumab/pembrolizumab group vs 11.6 months (80% CI = 9.9–13.0 months) in the standard-of-care group (hazard ratio [HR] = 0.69, 80% CI = 0.51–0.92, SLR P = .05, WLR P = .15).

Investigator-assessed median progression-free survival was 4.5 months (80% CI = 4.2–6.1 months) vs 5.2 months (80% CI = 4.2–5.7 months; HR = 0.86, 80% CI = 0.66–1.14, SLR P = .25, WLR P = .14). Objective response rates were 22% vs 28% (P = .19).

Adverse Events

Grade ≥ 3 treatment-related adverse events occurred in 42% of patients in the ramucirumab/pembrolizumab group and 60% of the standard-of-care group. Treatment-related grade 4 events occurred in 4 vs 15 patients. Treatment-related death occurred in three patients in the ramucirumab/pembrolizumab group, due to cardiac arrest, respiratory failure, and unknown cause, respectively. Treatment-related death occurred in four patients in the standard-of-care group: due to sepsis in one patient and respiratory failure in two patients receiving docetaxel/ramucirumab, and sepsis in one patient on single-agent chemotherapy.

The investigators concluded, “This randomized phase II trial demonstrated significantly improved overall survival with ramucirumab/pembrolizumab compared with standard of care in patients with advanced NSCLC previously treated with immune checkpoint inhibitors and chemotherapy. The safety was consistent with known toxicities of both drugs. These data warrant further evaluation.”

Dr. Reckamp, of Cedars-Sinai Medical Center, Los Angeles, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by grants from the National Cancer Institute and Foundation for the National Institutes of Health, and by Eli Lilly and Company and Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc. For full disclosures of the study authors, visit ascopubs.org.