A Phase III trial assessing the combination of Incyte’s lead cancer immunotherapy candidate epacadostat (INCB024360) and Merck & Co.’s marketed cancer drug Keytruda® (pembrolizumab) in melanoma will be halted after the combo therapy failed the pivotal study, the companies acknowledged today.

The epacadostat/Keytruda combination missed its first primary endpoint of improving progression-free survival in the overall population compared to Keytruda monotherapy in the Phase III ECHO-301/KEYNOTE-252 study (NCT02752074). The combination is also expected to miss its second primary endpoint of overall survival, which is not expected to reach statistical significance, Incyte and Merck said.

Epacadostat is an orally bioavailable small-molecule inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), under development in nine cancer indications, either in combinations with other cancer drugs or alone.

Keytruda is a humanized monoclonal antibody that works by blocking interaction between the programmed cell death protein 1 (PD-1) and its receptor ligands, PD-L1 and PD-L2, thus increasing the immune system’s ability to fight cancer. Keytruda is approved for numerous cancer indications including unresectable or metastatic melanoma, for which a fixed dose of 200 mg every three weeks is indicated until disease progression or unacceptable toxicity occurs.

Keytruda is a blockbuster drug, having generated $3.809 billion in 2017 sales—more than double its 2016 sales (171.6%) yet ranking number 21 for the year and thus not among GEN’s Top 15 Best-Selling Drugs of 2017.

“While we are disappointed that this study did not confirm the efficacy of epacadostat in combination with Keytruda in patients with unresectable or metastatic melanoma, data from ECHO-301/KEYNOTE-252, including analyses of an extensive biomarker panel, will contribute to our understanding of the role of IDO1 inhibition in combination with PD-1 antagonists, and may inform our broader epacadostat clinical-development program,” Incyte CMO Steven Stein, M.D., said in a statement.

Data from ECHO-301/KEYNOTE-252 will be analyzed and submitted for presentation at an unspecified upcoming scientific conference, the companies added.

“Hope and Optimism”

The results and statement contrast with the upbeat expectation expressed to GEN earlier this year by Lance Leopold, M.D., group vice president for immuno-oncology development at Incyte. He said the company had “hope and optimism” that the combination treatment would produce results superior to those obtained with Keytruda alone.

He noted that IDO1 is a regulator of immune-cell activity that is commonly expressed, and results in the depletion of a key nutrient required for T-cell activation and function, tryptophan. By inhibiting IDO1, Incyte reasoned, T-cell inhibition was expected to be reversed, facilitating immune surveillance and tumor destruction.

ECHO-301/KEYNOTE-252 enrolled 706 patients, randomized 1:1, and stratified by tumor PD-L1 expression (positive versus negative/indeterminate) and BRAF mutation status (BRAF mutant who have received prior BRAF-directed treatment, BRAF mutant with no prior BRAF-directed treatment, and BRAF wild-type). In addition to the primary endpoints, the study identified key secondary endpoints that included objective response rate, safety, and tolerability.

Incyte and Merck said they will notify investigators of the results of ECHO-301/KEYNOTE-252, and work with them to conclude the study “appropriately” and “in a manner consistent with the best interests of each patient.”

Investors responded to the failure announcement with a stock selloff that sent shares of Incyte falling nearly 22% in early market trading from yesterday’s close of $83.07 per share, to $65.00 as of 9:37 a.m.

Melanoma was one of five indications in which the epacadostat/Keytruda combination was being studied in pivotal trials. The other four indications are non-small cell lung cancer (NSCLC), renal cancer, head and neck cancer, and bladder cancer. Epacadostat is additionally being studied in combination with AstraZeneca’s marketed drug Imfinzi™ (durvalumab) in NSCLC; in combination with Bristol-Myers Squibb’s marketed drug Opdivo® (nivolumab) in NSCLC and head and neck cancer; and as a monotherapy in multiple tumor types.

According to Incyte, earlier clinical studies that assessed combinations of epacadostat with immune checkpoint inhibitors have shown proof-of-concept in patients with unresectable or metastatic melanoma, NSCLC, renal cell carcinoma, squamous cell carcinoma of the head and neck, and bladder cancer.

“$INCY didn't mention it in the press release, but you can imagine what this means for those other indications if it didn't work in melanoma,” Brad Loncar, CEO of Loncar Investments, who tracks developments in cancer immunotherapy, said in a Twitter tweet today at 7:40 a.m.

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