Podcast Roy S. Herbst, MD @DrRoyHerbstYale @YaleCancer #A...

Podcast Roy S. Herbst, MD @DrRoyHerbstYale @YaleCancer #ASCO22 Phase II S1800A Trial
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Roy S. Herbst, MD, PhD, Ensign Professor of Medicine (Medical Oncology) and Professor of Pharmacology; Director, Center for Thoracic Cancers; Deputy Director, Clinical Affairs; Assistant Dean for Translational Research, Office of the Dean, School of Medicine; Chief of Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital; Associate Cancer Center Director, Translational Science at Yale University. In this video, he speaks about the ASCO 2022 Late-Breaking Abstract - Overall survival from a phase II randomized study of ramucirumab plus pembrolizumab versus standard of care for advanced non–small cell lung cancer previously treated with immunotherapy: Lung-MAP nonmatched substudy S1800A. 


Most patients (pts) with advanced non-small cell lung cancer acquire resistance to immune checkpoint inhibitor (ICI) therapy (NSCLC). Tumors that acquire resistance to ICI represent a significant unmet need. Through immunological modulation, combined ICI and VEGF/VEGF receptor inhibition has proven efficacy in numerous tumor types. Under the auspices of Lung-MAP, a master protocol for patients with stage IV, previously treated NSCLC, we examined pembrolizumab plus ramucirumab (P+R) in advanced, ICI-exposed NSCLC. At ASCO 2021, pt features and treatment toxicities were presented.


S1800A was a randomized phase II trial for patients with acquired resistance to ICI defined as previous ICI therapy for at least 84 days with progressing disease (PD) on or after therapy who were ineligible for a biomarker-matched substudy. Prior platinum-based doublet therapy (sequential or in conjunction with ICI) and an ECOG PS of 0 were required for eligibility. Pts were stratified by PD-L1 expression, histology, and intent to receive ramucirumab in the standard of care (SOC) arm before being randomly assigned to P+R or SOC (investigator's choice of docetaxel, pemetrexed, and gemcitabine). The primary purpose was to compare overall survival (OS) between the arms using a 1-sided 10% level log-rank test after 90 deaths, with a goal of 144 total/130 eligible pts. Response, duration of response, investigator assessed-progression free survival, and toxicity were all secondary objectives.


Between May 17, 2019 and November 16, 2020, 166 patients were registered, with 137 of them being eligible (69 P+R; 68 SOC [45 +R, 23 w/o R]). Lack of PD on ICI or chemotherapy (6 SOC, 6 P+R), more than one line of ICI (2 P+R), ICI terminated due to toxicity (2 SOC), or lack of detectable illness (2 SOC, 1 P+R) were the most common reasons for ineligibility. OS improved considerably with P+R (HR: 0.61 [0.38-0.97], 1-sided p-value = 0.019; median [95 percent CI] OS of 15.0 (13.2-17) months (mo) for P+R and 11.6 (8.5-13.8) mo in the SOC arm). PFS did not differ across arms (HR: 0.86 [0.57-1.31], 1-sided p-value=0.25; median PFS (95 percent CI) of 4.5 (4.0-6.9) mo for P+R and 5.2 (4.0-6.6) mo for SOC). ORR did not differ between arms (p=0.28). P+R provided an OS improvement in the majority of subgroups. Survival analysis will be given based on genomic changes, tumor mutational burden, and PD-L1.


Pembrolizumab plus ramucirumab increased OS compared to SOC in patients with advanced NSCLC who had previously received chemotherapy and immunotherapy. Prior ICI trials have revealed discordance between ORR and PFS and OS (Rittmeyer et al. Lancet 2017). Using the Lung-MAP platform, this is the first trial in the 2nd line scenario without a chemotherapy backbone to reveal a possible survival benefit compared to SOC regimens comprising docetaxel and ramucirumab. NCT03971474 is the clinical trial number.