Keytruda-Epacadostat Combo Fails Primary Goal in Phase 3 Trial for Melanoma, Companies Announce

Keytruda-Epacadostat Combo Fails Primary Goal in Phase 3 Trial for Melanoma, Companies Announce

A Phase 3 clinical trial evaluating a combination of Keytruda and epacadostat in metastatic melanoma patients will be stopped after the combo failed the study’s first primary goal, Incyte Corporation and Merck announced.

Keytruda (pembrolizumab), developed by Merck (known as MSD outside the U.S. and Canada), is an approved therapy for several cancers, including unresectable or metastatic melanoma. It is a monoclonal antibody designed to block the interaction between the PD-1 receptor and its ligands in T-cells — a type of white blood cell involved in the immune response.

This prevents T-cells from being deactivated by the PD-1 ligand (PD-L1) present at the surface of some tumor cells — a powerful immune evasion mechanism of cancer cells — thus increasing the body’s immune response.

Incyte’s lead cancer immunotherapy candidate epacadostat (INCB024360) is a potent, selective oral inhibitor of IDO1, an enzyme expressed in many cancers that suppresses T-cell response.

According to Incyte, earlier clinical studies showed that the combination of epacadostat and Keytruda improved the response rates of patients with several types of cancer, including unresectable or metastatic melanoma, compared with Keytruda alone.

Based on this, Incyte hoped the combo therapy of Keytruda with epacadostat would fight cancer more effectively than Keytruda alone. In collaboration with Merck, the company created a Phase 3 clinical trial (NCT02752074) to evaluate the effectiveness and safety of Keytruda and epacadostat in patients with unresectable or metastatic melanoma.

The study, also known as ECHO-301/KEYNOTE-252, classified each of the 706 participants by tumor PD-L1 expression and BRAF mutation status. Patients were randomized to receive either the combo therapy or Keytruda with a placebo.

Primary goals were improvement of progression-free survival (PFS) — how long a patient lives without disease progression — and overall survival. Secondary endpoints included objective response rate, safety, and tolerability.

However, the addition of epacadostat to Keytruda therapy failed to stop cancer progression (or improve PFS), compared with Keytruda alone. The companies noted that the combo therapy is also expected to miss its second primary endpoint of overall survival, which is not expected to reach statistical significance.

“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,” Steven Stein, MD, Incyte’s chief medical officer, said in a press release.

According to the companies, the investigators will be notified of the trial’s results, and they will work with them to conclude the study “in a manner consistent with the best interests of each patient.”

ECHO-301/KEYNOTE-252’s data will be analyzed and submitted for presentation at an upcoming scientific conference.

Besides melanoma, the Keytruda-epacadostat combo therapy is also being studied in non-small cell lung cancer (NSCLC), renal cancer, head and neck cancer, and bladder cancer, in pivotal Phase 3 trials.