Entinostat Plus Pembrolizumab Produced Durable Responses in Metastatic Uveal Melanoma

A subset of patients with metastatic uveal melanoma achieved promising responses after treatment with entinostat and pembrolizumab.

The combination of entinostat (SNDX-275, MS-275) and pembrolizumab (Keytruda) yielded long-term responses in a subset of patients with metastatic uveal melanoma, according to findings from the phase 2 PEMDAC study (NCT02697630).

Patients who received the regimen experienced an overall response rate (ORR) of 14% (95% CI, 3.9%-31.7%), including 4 confirmed partial responses, meeting the primary end point of the trial. Additionally, investigators reported a clinical benefit rate of 28% at 18 weeks. Of the 4 responses that were reported, 3 were ongoing at the data cutoff.

“Here we show for the first time that combined epigenetic and immunotherapy can cause tumor regression in a small subset of patients with metastatic [uveal melanoma]. Low tumor burden (ctDNA and LDH), presence of the tumor suppressor BAP1, and an outlier tumor mutational burden in an iris melanoma correlated with response and/or survival, possibly highlighting how outcomes for patients with [uveal melanoma] metastases are highly dependent on the intrinsic tumor genetics and the tumor microenvironment,” the study investigators wrote. “Combined epigenetic and immunotherapy would be interesting to evaluate in a randomized trial compared with immunotherapy alone. This would also address whether BAP1 mutational status is predictive of immunotherapy response or only in combination with epigenetic therapy.”

In order to be eligible for the single arm, multicenter study, patients needed to be aged 18 years or older with histologically- and cytologically-confirmed metastatic uveal melanoma. Disease needed to be measurable by CT or MRI per RECIST 1.1 criteria and an ECOG performance status of 0 or 1 was required. Additionally, patients were able to receive any number of prior therapies with the exception of anticancer immunotherapy agents. Those with brain metastases, active autoimmune disease, immunodeficiency or treatment with systemic corticosteroids, treatment with other investigational agents within 4 weeks of study drug administration, and a life expectancy of less than 3 months were not able to enroll on the study.

Investigators enrolled 29 patients from February 2018 to December 2018, with a cut off of December 2019. The median patient age was 70 years (range, 34-83), with 90% of patients having liver metastases at baseline. In total, 41% of patients had not previously received treatment for their metastatic disease and 28% were given prior chemotherapy for uveal melanoma.

Those who enrolled on the study received 200 mg of pembrolizumab intravenously every 3 weeks plus 5 mg of oral entinostat once a week. Treatment continued until patients experienced documented disease progression, intolerable adverse effects (AEs), withdrawal of consent, or decision to end treatment by the physician.

Additional findings from the study indicated that entinostat and pembrolizumab yielded a median overall survival (OS) of 13.4 months, as well as a 1-year OS rate of 59%. Moreover, investigators reported a median progression-free survival (PFS) of 2.1 months, as well as a 1-year PFS rate of 17%.

A total of 79% of patients were eligible for PD-L1 and tumor-infiltrating lymphocyte evaluation. Tumor PD-L1 expression was present in 1 patient, although 9 patients had a PD-L1 tumor-modified percent score greater than 0. Those with PD-L1–positive disease had progressive disease as their best overall response. No significant association was noted between survival and PD-L1 score.

A total of 66% of patients developed AEs of grade 3 or higher and commonly included increased blood alkaline phosphatase levels, neutropenia, increased aspartate/alanine aminotransferases, and rash. Immune-related AEs (irAEs) of any grade occurred in 86% of patients, and 28% developed irAEs that were grade 3 or higher. Grade 3 irAEs included hepatitis, skin toxicity, colitis, and stomatitis, as well as 1 reported case of grade 4 hypophysis.

Reference

Ny L, Jespersen H, Karlsson J, et al. The PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma. Nat Comm. 2021;12(5155). doi:10.1038/s41467-021-25332-w