Syndax claims biomarker predicts increased benefit of HDAC/PD-1 combination in NSCLC

Syndax Pharmaceuticals’ combination of its HDAC inhibitor entinostat with Merck’s anti-PD-1 therapy Keytruda may have posted small gains in an ongoing phase 1b/2 study in non-small cell lung cancer, but the company believes it has identified an enrichment biomarker that could predict increased clinical benefit overall.

In 57 patients that had progressed after chemotherapy and PD-1 treatments, six showed partial responses to the entinostat-Keytruda combination, for an 11% objective response rate. The median duration of response was 4.6 months, according to Syndax.

Blood samples identified a subset of patients with higher baseline levels of classical blood monocytes that appeared to fare better with the combination regimen: with an ORR of 29% and a progression-free survival of 5.4 months, the subset nearly doubled the 2.8-month benefit seen in historical NSCLC patients treated with third-line chemotherapy.

By comparison, patients with lower monocyte levels had an ORR of 5% and a PFS of 2.5 months, below the overall patient population’s 2.7.

“Monocyte levels may reflect the ability of the immune system to respond after elimination of immune suppression,” said Dmitry Gabrilovich, Christopher M. Davis Professor and leader of the immunology, microenvironment and metastasis program at The Wistar Institute. The company plans to present the study’s results at the annual meeting of the American Society of Clinical Oncology this June.

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On a conference call with investors, Syndax estimated about 30,000 patients would qualify annually under this biomarker, after progressing through first-, second- or third-line treatments including PD-1 and PD-L1 inhibitors.

The company plans to launch a registration trial by the end of this year, gathering data for possible submissions in both the biomarker-enriched and the wider, “all-comers” populations in NSCLC. Syndax will meet with FDA and European officials for guidance in protocol design, with results expected in 2020.

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The phase 1b/2 study also enrolled cohorts in melanoma and microsatellite stable colorectal cancer—and while objective responses were observed across all cohorts, the company’s future development plans in these areas remain uncertain.

In melanoma, an ORR of 18% has led Syndax to not consider a registration trial at this time, and instead continue biomarker analysis. The company said it would feel more comfortable with correlative data like it found in NSCLC.

In MSS-CRC, following discussions with Merck, Syndax plans to expand enrollment from 16 to 37 patients into the first stage of a two-stage study by the end of the second quarter. Three responses will be required to advance to the second stage, where an additional 47 patients would be enrolled, with that decision scheduled for the first half of next year.