Sanjiv S. Agarwala, MD, chief of medical oncology and hematology, St. Luke’s Cancer Center, professor of medicine, Temple University School of Medicine, discusses the impact of entinostat for patients with melanoma who progress on a PD-1/PD-L1 blocking antibody.

Pembrolizumab (Keytruda) is a PD-1 inhibitor that has shown efficacy in melanoma, Agarwala says. Unfortunately, there are a number of patients who either don’t respond to immunotherapy or become refractory to treatment over time. One of the most common ongoing questions in oncology is to figure out how to make immunotherapy-refractory patients respond to this type of treatment again. There have been many combinations designed to do just that, with one of them including HDAC inhibitors like entinostat, which affect the tumor microenvironment.

The design of the study Agarwala presented at the 2018 ASCO Annual Meeting took patients with melanoma who became refractory to anti—PD-1/PD-L1 treatment and determine whether they would respond to pembrolizumab with the addition of entinostat.

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Dr. Agarwala on Entinostat for Patients with Melanoma Who Progress on PD-1/PD-L1 Blockade

Sanjiv S. Agarwala, MD, chief of medical oncology and hematology, St. Luke’s Cancer Center, professor of medicine, Temple University School of Medicine, discusses the impact of combining entinostat with pembrolizumab (Keytruda) across a number of tumor types.

In a phase Ib/II study, the small molecular inhibitor entinostat was paired with the PD-1 inhibitor pembrolizumab for the treatment of patients with non—small cell lung cancer, melanoma, and mismatch-repair proficient colorectal cancer. In all cases, these patients were refractory to pembrolizumab alone.

Data from the study, which were presented at the 2018 ASCO Annual Meeting, show that the addition of entinostat resulted in an 18% confirmed overall response rate. Agarwala adds that 29% of patients who had disease progression became stable under the combination. Primary endpoints of the study were safety and efficacy.

Dr. Agarwala on Impact of Combining Entinostat with Pembrolizumab

Sanjiv S. Agarwala, MD, chief of medical oncology and hematology, St. Luke’s Cancer Center, professor of Medicine, Temple University School of Medicine, discusses whether the overall survival (OS) justifies the toxicities demonstrated in the CheckMate-067 trial for patients with melanoma.

According to Agarwala, the OS results of CheckMate-067 that were recently presented at the 2017 AACR Annual Meeting, was slightly better but not significant. Response rates and progression-free survival remain better; however, the toxicities were significantly higher.

The use of the combination needs to be selective based on these data, explains Agarwala. The most important decision facing a clinician regarding immunotherapy is whether to use monotherapy or combinations.

PD-L1 testing may be helpful to determine whether combinations or monotherapy will be more beneficial, states Agarwala. Additionally, there were 2 subsets of patients who might benefit more from combinations. Those subsets include patients with high-LDH levels and 

Sanjiv S. Agarwala, MD, chief of medical oncology and hematology, St. Luke’s Cancer Center, professor of Medicine, Temple University School of Medicine, discusses whether the overall survival (OS) justifies the toxicities demonstrated in the CheckMate-067 trial for patients with melanoma. 

Dr. Agarwala on the Significance of OS and Toxicity Results in CheckMate-067

Sanjiv S. Agarwala, MD, Chief of Medical Oncology, Hematology, St. Luke's Cancer Center and Temple University, discusses the differences between cytokines and other types of immunotherapies.

Cytokines and newer immunotherapies such as checkpoint inhibitors have almost opposite mechanisms of action, explains Agarwala. Cytokines get the immune system going, while checkpoint inhibitors prevent the immune system’s natural breaks from kicking in. Taking the breaks off the immune system with drugs like checkpoint inhibitors clinically seems to be a more effective method, says Agarwala.

However, there may be benefit from combinations therapies that include both checkpoint inhibitors and cytokines, he says. Ongoing studies are examining the combination of pegylated interferon and pembrolizumab in melanoma. 

Sanjiv S. Agarwala, MD, Chief of Medical Oncology, Hematology, St. Luke's Cancer Center and Temple University, discusses the differences between cytokines and other types of immunotherapies. 

Sanjiv S. Agarwala, MD

Articles

Dr. Agarwala on Entinostat for Patients with Melanoma Who Progress on PD-1/PD-L1 Blockade

Dr. Agarwala on Impact of Combining Entinostat with Pembrolizumab

Dr. Agarwala on the Significance of OS and Toxicity Results in CheckMate-067

Dr. Agarwala on the Role of Cytokines in the Immunotherapy Landscape