Shares of Syndax Pharmaceuticals Inc. (NASDAQ:SNDX) fell 17.1 percent to $5.01 Friday on news that adding its HDAC inhibitor, entinostat, to an aromatase inhibitor failed to deliver a statistically significant improvement in the length of time women with hormone receptor-positive, HER2-negative breast cancer lived without worsening of their cancers. The outcome, from the ongoing phase III study E2112, dashed hopes of an early regulatory filing, putting the focus on the trial's other co-primary endpoint, overall survival (OS).

Interim data on OS are expected around May and then again six months after in November, unless the trial is stopped early for futility.

The ECOG-ACRIN Cancer Research Group, which led the trial, is confidentially holding the findings from the progression-free survival (PFS) analysis until reporting final OS results.

"It's important to remember that E2112 is primarily an OS trial," Syndax CEO Briggs Morrison told investors during a conference call held to discuss the update. Breakthrough status awarded to the candidate by the FDA was based on "the impressive OS results seen in our phase II trial," and Syndax's team remains "very confident" that the phase III "will be a positive OS trial," he said.

The randomized, placebo-controlled phase IIb study ENCORE 301 showed entinostat providing "a significant advantage to patients" when administered with the aromatase inhibitor exemestane, the company said. Median PFS in the midstage study nearly doubled to 4.3 months in the entinostat plus exemestane (EE) group vs. 2.3 months in the exemestane plus placebo (EP) group, with a statistically significant hazard ratio of 0.73; 95 percent confidence interval (CI), 0.50 to 1.07; P1-sided=0.055. Median OS improved to 28.1 months in the EE group vs. 19.8 months in the EP group, corresponding to a statistically significant hazard ratio of 0.59; 95 percent CI, 0.36 to 0.97; P1-sided=0.018.

In the National Cancer Institute-sponsored phase III E2112 study, fully enrolled with 605 patients, there was hope that the PFS data might reflect the phase II results, setting the stage for an early filing. That it didn't was "disappointing, though not entirely surprising," said Cowen and Co. analyst Chris Shibutani. "The bar for achieving the PFS endpoint was relatively high, although our expert consultants had predicted a 65 percent probability of success. The bar for achieving the OS endpoint is lower," he told clients in a report filed Friday.

Downplaying the phase III miss, Syndax used the occasion of the news to highlight a second program testing entinostat with Keytruda (pembrolizumab, Merck & Co. Inc.). Expected to start in the first half of next year, the trial is intended to support registration in non-small-cell lung cancer patients whose disease has progressed after both platinum-based combination chemotherapy and a PD-1 antagonist therapy. Waltham, Mass.-based Syndax now plans to initiate a randomized trial comparing the entinostat plus Keytruda to standard-of-care chemotherapy in high monocyte patients enrolled in the study. Following discussions with the FDA, the study is designed to validate peripheral classical monocytes as a marker of response to the pairing. The study is expected to enroll about 200 patients and to read out potentially by the second half of 2020.

Martin Edelman, chair of the Department of Hematology and Oncology and Deputy Cancer Center Director for Clinical Research at Fox Chase Cancer Center, also joined Syndax's conference call. He said that "it will be nice to have biomarkers for selection based upon good hypothesis or exploratory population. There are many practical issues of fragmentation of the [lung cancer] population. Too many questions and too many trials right now." Having a "robust, easily obtainable biomarker is a definite plus," he said.

If successful, the program could potentially position Syndax to be the first in the U.S. and Europe to serve those lung cancer patients whose needs aren't met with current therapies, addressing a second launch indication for entinostat following closely on the heels of breast cancer, enabling the company to "build out a very significant franchise."

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