Entinostat/Pembrolizumab Combo Shows Promise in NSCLC Subgroup

Matthew D. Hellmann, MD

Ongoing analyses suggest enhanced clinical benefit is derived from the combined use of entinostat and pembrolizumab (Keytruda) in a subgroup of patients with PD-1/PD-L1—refractory non–small cell lung cancer (NSCLC) who have high levels of peripheral blood monocytes.

Preliminary results indicated that PD-1/PD-L1—refractory patients with elevated baseline levels of monocytes ("high monocyte" subset, n = 14) had a confirmed objective response rate (ORR) of 29%, comprising 4 partial responses (PRs) and progression-free survival (PFS) of 5.4 months. Interim results of the phase II ENCORE-601 trial were presented at the 19th World Conference on Lung Cancer (WCLC).

“Entinostat is an oral class-I selective histone deacetylase inhibitor [that] leads to downregulation of immunosuppressive cell types in the tumor microenvironment,” said Matthew D. Hellmann, MD, medical oncologist, Memorial Sloan Kettering Cancer Center.

The open-label phase Ib/II trial is designed to evaluate the efficacy and safety of entinostat in combination with pembrolizumab across multiple cohorts of PD-1/PD-L1 treatment—naïve and pretreated cancers, including NSCLC, melanoma, and microsatellite stable colorectal cancer. Patients received 5 mg of oral entinostat weekly and 200 mg of IV pembrolizumab every 3 weeks.

ORR (RECIST) assessed by independent review served as the primary endpoint, and secondary endpoints included PFS, overall survival (OS), safety, and tolerability.

In addition, tumor biopsies and blood samples for immune correlates were taken prior to and during treatment in a subset of patients.

Overall, the PD-1/PD-L1-pretreated cohort included 76 patients, of whom 72 were evaluable for efficacy. The majority of the 76 patients were male (53%) and the median age was 67 years (range, 30-85). Only 1% of patients had a complete response to prior anti—PD-1/PD-L1 therapy, 7% had a PR, 45% had stable disease, and 37% had disease progression. The median duration of prior anti–PD-1/PD-L1 therapy was 5.3 months and the median time between last dose of prior therapy and first dose with the combination regimen was 2.2 months.

Durable responses were observed in the 72 evaluable patients, with an ORR of 10% (n = 7; 95% CI, 4%-19%). The median duration of response was 5.3 months. An additional 50% of patients achieved stable disease from the combination regimen. The researchers noted that responses were observed regardless of PD-L1 tumor level. The median PFS was 2.8 months (95% CI, 2.1-4.1).

Among 51 blood samples collected and analyzed, response appeared to be associated with a higher median baseline level of peripheral classical monocytes (CD14+CD16-HLA-DRhi) with 16.9% of total live peripheral blood mononuclear cells in responders compared with 8.2% in non-responders.

As mentioned, the 14 patients characterized by elevated baseline levels of monocytes had a confirmed ORR of 29% and a PFS of 5.4 months. In contrast, the subgroup of patients characterized by lower baseline levels of monocytes ("low monocyte" subset, n = 37) had a confirmed ORR of 5% (2 PRs) and a PFS of 2.5 months.

Grade 3/4 immune-related adverse events (AEs) occurred in 7 of 76 (9.2%), safety-evaluable patients, including pneumonitis (n = 3), colitis (n = 3), and hyperthyroidism (n = 1). In addition, 23 patients (30.3%) experienced other grade 3/4 related AEs, including fatigue, anemia, hypophosphatemia, and hyponatremia occurring in more than 1 patient.

Eleven patients discontinued treatment due to treatment-related AEs, and 13 patients required a dose reduction.

“Exploratory biomarker analysis is particularly critical in this population to guide development. We identified the baseline classification of monocyte may be associated with clinical benefit, although work is ongoing and needed to determine this as a prognostic or predictive association,” Hellmann said. “Overall, encouraged by the clinical activity here, future development plans for this combination are ongoing and will prospectively incorporate biomarker selection in this patient population.”

Hellmann M, Jänne P, Opyrchal M, et al. Efficacy/Safety of Entinostat (ENT) and Pembrolizumab (PEMBRO) in NSCLC Patients Previously Treated with Anti-PD-(L)1 Therapy. Presented at: the IASLC 19th World Conference on Lung Cancer; September 23-26; Toronto, Canada. Abstract OA05.01.