Entinostat plus pembrolizumab shows efficacy in anti-PD-1-resistant melanoma
ATLANTA — The combination of the histone deacetylase inhibitor entinostat and the anti-PD-1 inhibitor pembrolizumab induced clinical responses and appeared well-tolerated among patients with melanoma that progressed on prior anti-PD-1 treatment, according to results from the single-arm ENCORE 601 phase 1b/phase 2 clinical trial presented at American Association of Cancer Research Annual Meeting.
Histone deacetylase (HDAC) inhibitors such as entinostat (SNDX-275, Syndax) may counteract resistance to checkpoint inhibition in two ways: by suppressing regulatory cells — including myeloid-derived suppressor cells and regulatory T cells — and by increasing antigen expression on cancer cells.
“HDAC inhibition has been shown to decrease the function of T-regulatory cells (T-regs) and myeloid-derived suppressor cells, and increase antigen expression in tumors,” Ryan J. Sullivan, MD, assistant professor of hematology and oncology at Massachusetts General Hospital Cancer Center, told HemOnc Today. “A number of PD-1/PD-L1 inhibitor resistance mechanisms have been described and/or proposed and include, although are not limited to, high activity of T-regs, expression of myeloid-derived suppressor cells, and down-modulation of tumor antigen expression. Thus, it seemed logical to combine an agent like entinostat with pembrolizumab in PD-1-resistant/refractory melanoma.”
Sullivan and colleagues of ENCORE 601 aim to evaluate the efficacy of adding entinostat to pembrolizumab (Keytruda, Merck) in patients with non-small cell lung cancer, melanoma and mismatch repair-proficient colorectal cancer that had progressed on prior PD-1 therapy.
“Even in melanoma, where durable benefit to immune checkpoint inhibitor therapy ranges from 30% to 40%, the great majority of patients will need another therapy,” Sullivan said. “Further, there is no standard approach to these patients, thus developing better therapies for this indication is an urgent unmet need.”
The current analysis includes 53 patients with metastatic melanoma that progressed during or following treatment with anti-PD-1 immunotherapy (median duration of prior treatment, 4.9 months). Sixty-six percent of patients received no additional therapy between prior anti-PD-1 treatment and trial enrollment (median time from last dose to study entry, 2.7 months).
Most patients (70%) previously received ipilimumab (Yervoy, Bristol-Myers Squibb), and 23% had been treated with BRAF/MEK inhibitors.
Patients received 5 mg entinostat weekly with 200 mg pembrolizumab once every 3 weeks.
Objective response rate served as the study’s primary endpoint.
Results showed an ORR of 19% (95% CI, 9-32), which included nine partial responses and one complete response. Median duration of response was 12.5 months (range, 4-18), with five responses ongoing at the time of the data cutoff.
Seven patients have had stable disease for longer than 6 months, resulting in a clinical benefit rate of 32% (95% CI, 20-46).
Median PFS was 4.2 months.
Sullivan said these response rates are in line with other clinical trials in this setting so, although he is not surprised by the results, he is “encouraged that a clear and significant minority of patients benefitting from this regimen.”
The most common grade 3 to grade 4 adverse events included neutropenia, fatigue and hyponatremia. Five patients (9%) experienced a grade 3 to grade 4 immune-related adverse event, including two patients with rash and one patient each with colitis, pneumonitis and autoimmune hepatitis.
Biomarkers will be a key area of future research to advance this combination, Sullivan told HemOnc Today.
“It is critical that we determine whether the 15% to 30% of patients receiving benefit to various regimens are the same 15% to 30% of patients, or whether there are biomarkers that can predict benefit to specific regimens,” he said. “If so, we may already have a number of regimens that can help up to 50-60% of patients in this setting.” – by Alexandra Todak
Sullivan RJ, et al. Abstract CT072. Presented at: AACR Annual Meeting; March 29-April 3, 2019; Atlanta.
Disclosures: Syndax sponsored this study. Sullivan reports pain consultant/advisory board roles with Amgen, Array, Bristol-Myers Squibb, Compugen, Merck, Novartis, Replimune and Syndax. Please see the abstract for all other authors’ relevant financial disclosures.