Most patients now receive either a combination of immunotherapy and chemotherapy or immunotherapy alone as part of the first-line treatment for advanced non-small cell lung cancer. We are also starting to use immunotherapy to treat early-stage non-small cell lung cancer. Therefore, most patients do become exposed to immune checkpoint inhibitors at some point during treatment. Although patients experience substantial benefit, most patients develop tumor progression and develop resistance to immune checkpoint inhibitors.
The combination of pembrolizumab and ramucirumab was evaluated in patients with stage IV, previously treated NSCLC and acquired resistance to ICIs in the Phase 2 Lung-MAP substudy S1800A. Acquired resistance in the study was defined as disease progression during or after prior ICI therapy for at least 84 days.
A total of 137 eligible patients were treated in the study. The primary endpoint evaluated was overall survival (OS), and secondary endpoints were response, duration of response, investigator-assessed progression-free survival, and toxicity. To assess outcomes, patients were stratified by PD-L1 expression, histology, and intention to receive ramucirumab in the standard of care (SOC) arm. The SOC combination is ramucirumab and docetaxel.
After demonstrating improved OS compared with SOC, S1800A becomes the second study without chemotherapy to show a potential survival benefit compared with standard treatment regimens using the Lung-MAP platform. The median OS observed with pembrolizumab + ramucirumab was 15.0 (95% CI, 13.2-17), and the SOC was 11.6 months (95% CI, 8.5-13.8). There were no differences in PFS between treatment groups. Median PFS was 4.5 months (95% CI, 4.0-6.9) in the ramucirumab/pembrolizumab group and 5.2 months (95% CI, 4.0-6.6) in the SOC group. There was also no difference in overall response rate between treatment groups. Overall, overall survival is a better indicator of efficacy, especially when using immunotherapy with in the second-line setting.
Overall survival outcomes were assessed by PD-L1 status and there were no differences based on PD-L1 status, with all patients receiving ramucirumab/pembrolizumab benefiting. We did see a trend toward increased benefit in patients with squamous cell or mixed histology based on performance status. But again all pathological subgroups benefited.
The combination of ramucirumab and docetaxel was approved around 2014. This is the only standard beyond single-agent chemotherapy for patients who develop tumor growth on chemotherapy and immune checkpoint inhibitor therapy. So we're really in a position where we need some new therapies, new combinations, and uniquely ramucirumab/pembrolizumab is a non-chemotherapy option for patients.
More importantly, this was a patient population who had received immune checkpoint inhibitor therapy for at least 84 days before experiencing tumor progression. Therefore, this is a population with acquired resistance. In this population, we are now seeing an overall survival benefit from the pembrolizumab + ramucirumab combination as a non-chemotherapy option and the next step is to advance this to a phase 3 trial to better understand this combination benefits.
