Entinostat plus pembrolizumab in patients with metastatic NSCLC previously treated with anti-PD-(L)1 therapy.

Purpose: New therapies are needed to treat immune checkpoint inhibitor-resistant non-small cell lung cancer (NSCLC) and identify biomarkers to personalize treatment. Epigenetic therapies, including histone deacetylase inhibitors, may synergize with programmed cell death-1 (PD-1)blockade to overcome resistance. We report outcomes in patients with anti-PD-(L)1-resistant/refractory NSCLC treated with pembrolizumab plus entinostat in ENCORE 601. Experimental Design: The expansion cohort of ENCORE 601 included patients with NSCLC who previously experienced disease progression with immune checkpoint inhibitors. The primary endpoint for the phase 2 expansion cohort is overall response rate (ORR); safety, tolerability, and exploratory endpoints are described. Results: Of 76 treated patients,71 were evaluable for efficacy. irRECIST-assessed ORRwas 9.2%(95% CI: 3.8-18.1), which did not meet the prespecified threshold for positivity. Median DOR was 10.1 months(95% CI: 3.9-NE),PFS at 6 months was 22%, median PFS was 2.8 months(95% CI: 1.5-4.1),and median OS was11.7 months (95% CI: 7.6-13.4). Benefit was enriched among patients with high levels of circulating classical monocytes at baseline. Baseline tumor PD-L1 expression and IFNγgene expression were not associated with benefit. Treatment-related Grade ≥3 adverse events occurred in 41% of patients. Conclusions: In anti-PD-(L)1-experienced NSCLC patients, entinostat plus pembrolizumab did not achieve the primary response rate endpoint but provided a clinically meaningful benefit with objective response in 9% of patients. No new toxicities, including immune-related adverse events, were seen for either drug. Future studies will continue to evaluate the association of monocyte levels and response.