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.
Background: Inhibitors of programmed death 1 (PD-1) and its ligand (PD-L1) have improved outcomes in patients (pts) with advanced melanoma, but treatment options for pts who progress on or after these therapies remain limited. In this group, we previously reported preliminary data that ENT, a class I selective histone deacetylase (HDAC) inhibitor, in combination with PEMBRO showed promising activity, through alteration of the immunosuppressive tumor microenvironment. Here we report the full cohort of patients enrolled. Methods: ENCORE-601 is an open-label study evaluating ENT (5 mg PO weekly) + PEMBRO (200 mg IV Q3W) in pts with unresectable or metastatic melanoma who were previously treated with a PD-1-blocking antibody and experienced progression on or after therapy. A Simon 2-stage design was utilized (Stage 1: 13 patients, Stage 2: 40 patients) and the primary endpoint was ORR as assessed by irRECIST. Tumor biopsies and blood samples for immune correlates were obtained pre- and on-treatment. Results: 53 patients were enrolled (the last patient entered April 2018, data cutoff is January 2018). The median duration of prior PD-1 therapy was 4.9 months and median time from last dose to study entry was 2.7 months (66% of patients had no intervening therapy between their prior PD-1 therapy and study enrollment). Additional baseline demographics are as follows: 55% were ECOG 0, 36% had elevated LDH, 70% pts had prior ipilimumab, and 23% had prior BRAF/MEK inhibitors. The confirmed objective response with ENT + PEMBRO is 19% (1 CR and 9 PRs; 95% CI: 9-32%); these results exceed the threshold for success based on the prespecified design. The median duration of response as of the cut-off date is 12.5 months (range 4-18 months) with 5 responders ongoing at the time of data cutoff. An additional 7 patients have had stable disease for > 6 months, resulting in a clinical benefit rate (CR, PR, SD > 6 months) of 32% (95% CI: 20%-46%). The median PFS is 4.2 months. Efficacy results in patients who received prior ipilimumab were consistent with the overall population. Among the responders, best response on prior PD-1 therapy were as follows: progression- 3 pts, stable disease- 5 pts, partial response- 1 pt, unknown- 1 pt. Grade 3/4 related AEs occurring in >5% of patients included neutropenia, fatigue, and hyponatraemia. 5 patients (9%) experienced a Grade 3/4 immune-related AE (2 events of rash, 1 each of colitis, pneumonitis, and autoimmune hepatitis). Additional correlative analyses to identify biomarkers of response, including whole exome sequencing and RNAseq, are in progress. Conclusions: In patients with melanoma who have progressed following treatment with prior PD-1 blockade, and both prior PD-1 and CTLA-4 blockade, ENT plus PEMBRO demonstrates significant clinical activity and acceptable safety. Citation Format: Ryan J. Sullivan, Stergios J. Moschos, Melissa L. Johnson, Mateusz Opyrchal, Peter Ordentlich, Susan Brouwer, Serap Sankoh, Michael L. Meyers, Sanjiv S. Agarwala. Efficacy and safety of entinostat (ENT) and pembrolizumab (PEMBRO) in patients with melanoma previously treated with anti-PD1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT072.
Background: Treatment options are limited for lung cancer patients whose disease has progressed on anti-PD-(L)1 therapy. HDAC inhibitors may synergize with PD-(L)1 inhibition to overcome resistance. We report the interim results of a Phase 2 trial of entinostat (ENT), a class I selective histone deacetylase (HDAC) inhibitor, plus pembrolizumab (PEMBRO) in patients with NSCLC previously treated with anti-PD-(L)1 therapy. Method: ENCORE-601 is an open-label study evaluating the combination of ENT + PEMBRO in patients with recurrent or metastatic NSCLC and prior progression on anti-PD-1/PD-L1 therapy. Patients were eligible irrespective of histology or baseline PD-L1 expression. Patients were treated with ENT 5 mg PO weekly and PEMBRO 200 mg IV Q3W. The primary endpoint was ORR as assessed by irRECIST. Tumor biopsies and blood samples for immune correlates were taken prior to and during treatment in a subset of patients. A total of 70 patients will be enrolled. Result: Of 57 patients with anti-PD-(L)1 resistant/refractory NSCLC, the confirmed objective response rate with ENT + PEMBRO was 11% (6 of 57, 95% CI: 4-21%). Of 49 patients with post-baseline tumor measurements, 47% had at least some reduction in tumor. Anti-PD-(L) 1 therapy was the most recent line of therapy in 38 of 57 patients, and the median time from last dose of prior anti-PD-(L)1 to study entry was 67 days. The median duration of response with ENT + PEMBRO was 5 months, with the longest over 14 months. Of the 6 responders, four were PD-L1 negative at study entry. Response was associated with a higher median baseline level of peripheral classical monocytes (CD14+CD16-HLA-DRhi) with 16.9% of total live PBMCs in responders (n¼6) compared to 8.2% in non-responders (n¼45). 5 patients (8.8%) experienced Grade 3/4 related irAEs (2 events each of pneumonitis and colitis, 1 event of hyperthyroidism). In addition, 19 patients (33.3%) experienced other Grade 3/4 related AEs with only fatigue, anemia, hypophosphatemia, and hyponatremia occurring in more than 1 patient. Additional correlative analyses to identify biomarkers of response, including whole exome sequencing and RNAseq, are in progress. Conclusion: ENT + PEMBRO demonstrated anti-tumor activity and acceptable safety in patients with NSCLC who have progressed on prior PD-(L)1 blockade. Ongoing analysis of immune correlates may identify strategies for effective patient selection.Background: Epacadostat (E) is a potent, highly selective inhibitor of the indoleamine 2, 3-dioxygenase 1 (IDO1) enzyme. ECHO-202/ KEYNOTE-037 is an open-label, phase 1/2 study of E + pembrolizumab (P) in patients (pts) with advanced tumors (NCT02178722). We report updated efficacy and safety data for the phase 1 and 2 non-small cell lung cancer (NSCLC) cohort as of 8 Jan 2018 data cutoff. Method: Adult pts with prior platinum-based therapy (tx), no prior immune checkpoint inhibitors, and those intolerant to EGFR-targeted therapy were eligible. Pts could receive E (25, 50, 100, or 300 mg twice daily [BID]) + P (2 mg/kg or 200 mg e...
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