Entinostat plus Pembrolizumab in Patients with Metastatic NSCLC Previously Treated with Anti-PD-(L)1 Therapy

Abstract

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-programmed cell death ligand-1 [PD-(L)1]-resistant/refractory NSCLC treated with pembrolizumab plus entinostat in ENCORE 601.

Patients and methods: 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 II expansion cohort is overall response rate (ORR); safety, tolerability, and exploratory endpoints are described.

Results: Of 76 treated patients, 71 were evaluable for efficacy. immune-regulated RECIST-assessed ORR was 9.2% [95% confidence interval (CI): 3.8-18.1], which did not meet the prespecified threshold for positivity. Median duration of response was 10.1 months (95% CI: 3.9-not estimable), progression-free survival (PFS) at 6 months was 22%, median PFS was 2.8 months (95% CI: 1.5-4.1), and median overall survival was 11.7 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 IFNγ gene expression were not associated with benefit. Treatment-related grade ≥3 adverse events occurred in 41% of patients.

Conclusions: In anti-PD-(L)1-experienced patients with NSCLC, 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.

Trial registration: ClinicalTrials.gov NCT02437136.

Figure 1.

Maximal tumor burden and change in tumor volume over time. A, Waterfall plot and B, Spider plot of change in lesions over time. C, Prior treatment and duration of treatment for responders. Responses were observed regardless of prior treatment history or PD-L1 status.

Figure 2.

Expression of acetylated lysine in peripheral immune cells after therapy. Flow cytometry was used to analyze levels of acetylated lysine in A, CD3+ T cells; B, CD19+ B cells; and C, CD14+ monocytes at Cycle 1, Day 1 (C1D1), Cycle 1, Day 15 (C1D15) and Cycle 2, Day 15 (C2D15). Error bars represent mean ± standard deviation. D, Acetyl-lysine expression in CD19+ B cells at C2D15 compared to baseline C1D1 values. E, Kaplan-Meier curve of PFS by increase or decrease in acetyl-lysine expression in CD19+ B cells from baseline to C2D15.

Figure 3.

Kaplan-Meier curve of PFS (A) and OS (B) by proportion of classical monocytes (CD14+/CD16-/HLA-DR_hi). Median PFS and median OS were increased in the monocyte high group (≥8.64%) versus the monocyte low group (<8.64%).

Figure 4.

Enrichment of MYC Hallmark gene sets V1 and V2 in pretreatment tumors from anti–PD-1 pretreated NSCLC patients responding to pembrolizumab plus entinostat.