A combination of Syndax‘s entinostat and Keytruda (pembrolizumab) has shown clinically meaningful activity in patients with non-small cell lung cancer (NSCLC) who received prior chemotherapy and a PD-1 or PD-L1 inhibitor, Phase 3 trial data shows.
The combination reduced tumor volume in one out of 10 NSCLC patients in the trial, and an additional 50% achieved stable disease status. Responses, however, were particularly better among those with high monocyte counts, suggesting that measuring these immune cells could help identify patients more likely to benefit from the treatment.
The findings were discussed recently at the International Association for the Study of Lung Cancer (IASLC) 19th World Conference on Lung Cancer, in Toronto, Canada.
The oral presentation, “Efficacy/Safety of Entinostat (ENT) and Pembrolizumab (PEMBRO) in NSCLC Patients Previously Treated with Anti-PD-(L)1 Therapy,” was presented by Matthew D. Hellman, MD, study investigator and medical oncologist at Memorial Sloan Kettering Cancer Center.
Entinostat is an oral inhibitor of HDAC (histone deacetylases) enzymes, which are critical for the function of immunosuppressive cells in tumors, including myeloid-derived suppressor cells and regulatory T-cells. By blocking these cells, entinostat boosts the body’s immune response to tumors.
The medicine appears to work well in combination with immune checkpoint inhibitors, which boost the immune system through distinct mechanisms. That led Syndax and Merck to study a combination of entinostat and Keytruda in several solid tumors for which Keytruda is already approved. (Merck is known as MSD outside the U.S. and Canada.)
The ENCORE 601 Phase 1/2 clinical trial (NCT02437136) was conducted in two parts. First, it assessed the safety and tolerability of the combination in NSCLC patients.
Then, it included three expansion groups for patients with NSCLC, melanoma, and colorectal cancer. To date, the NSCLC group included 76 patients who already had received a PD-1 or PD-L1-targeting agent. Some of these patients had responded or achieved stable disease after their prior immune checkpoint inhibitor but progressed later on. Others had failed to respond at all.
Among the 72 patients who were evaluated for responses, seven (10%) responded to the combination, which did not meet the goal for overall response rates (15%), but “may represent clinically meaningful activity,” researchers wrote. Half of patients also achieved stable disease.
Responses lasted a median of 5.3 months, and were particularly long-lasting among patients who had not responded to their prior PD-1/PD-L1 therapy. Overall, patients lived a median of 2.8 months without seeing signs of disease progression.
“The observation of durable responses seen with the entinostat-pembrolizumab combination in NSCLC patients previously treated with both chemotherapy and PD-L1 therapy is an important result, and we look forward to more fully characterizing patient selection tools to identify those who are most likely to respond,” Peter Ordentlich, PhD, co-founder and chief scientific officer of Syndax, said in a press release.
Responses were not associated with prior treatment history of PD-L1 status; six out of the seven patients who responded had low or no PD-L1 production in their tumor cells.
However, researchers found that higher numbers of blood monocytes (a type of immune cell) before treatment was associated with better outcomes. Response rates were three times higher among those with high monocyte levels — 21.1% vs. 6.5% — and these patients also lived longer without their disease progressing — 5.3 months vs. 2.7 months.
“The exploratory finding that baseline peripheral classical monocytes may predict clinical benefit to the combination provides an opportunity to potentially correlate a readily measurable circulating biomarker with the state of the tumor microenvironment and supports the use of this approach for patient selection in future studies,” Ordentlich said.
The combination was well-tolerated, with a manageable toxicity profile. Adverse side effects have been consistent with those previously reported, with the most common being fatigue, diarrhea, anemia, and decreased appetite. A total of 11 patients withdrew from the study due to treatment-related side effects, and 13 patients required a dose reduction of entinostat.
Syndax hopes to announce the future plans for entinostat as treatment for previously treated NSCLC patients during the fourth quarter of this year.
The company also is evaluating entinostat potential in combination with Genentech’s Tecentriq (atezolizumab) for the treatment of breast cancer (NCT02708680), and with Pfizer and Merck KGaA’s Bavencio (avelumab) for ovarian cancer (NCT02915523).