Clinical Trials

Date: 2017-09-09

Type of information: Presentation of results at a congress

phase: 3

Announcement: initiation of development program

Company: Incyte (USA - DE) Merck&Co (USA - NJ)

Product: epacadostat and Keytruda® (pembrolizumab)

Action mechanism:

• enzyme inhibitor/immunotherapy product/monoclonal antibody/immune checkpoint inhibitor. Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme that has been shown to induce regulatory T cell generation and activation, and allow tumors to escape immune surveillance. Epacadostat is an orally bioavailable small molecule inhibitor of IDO1 that has nanomolar potency in both biochemical and cellular assays and has demonstrated potent activity in enhancing T lymphocyte, dendritic cell and natural killer cell responses in vitro, with a high degree of selectivity. Epacadostat has shown proof-of-concept clinical data in patients with unresectable or metastatic melanoma in combination with the CTLA-4 inhibitor ipilimumab, and is currently in four proof-of-concept clinical trials with PD-1 and PD-L1 immune checkpoint inhibitors in a variety of cancer types.
• Keytruda® (pembrolizumab - MK-3475) is an highly selective monoclonal anti-PD-1 antibody designed to restore the natural ability of the immune system to recognize and target cancer cells by selectively achieving dual ligand blockade (PD-L1 and PD-L2) of the PD-1 protein. By blocking PD-1, pembrolizumab enables activation of the immune system’s T-cells that target cancer by essentially releasing a brake on the immune system.

Disease: melanoma

Therapeutic area: Cancer - Oncology

Country: Australia, Belgium, Canada, Chile, Denmark, France, Germany, Ireland, Israel, Italy, Republic of Korea, Mexico, The Netherlands, New Zealand, Poland, Russian Federation, South Africa, Spain, Sweden, Switzerland, UK, USA

Trial details:

• The ECHO clinical trial program was established to investigate the efficacy and safety of epacadostat as a core component of combination therapy in oncology. Ongoing Phase 1 and Phase 2 studies evaluating epacadostat in combination with PD-1 and PD-L1 inhibitors collectively plan to enroll over 900 patients in a broad range of solid tumor types as well as hematological malignancies.
• ECHO-301 (Keynote-252) is a phase 3 randomized, double-blind, placebo-controlled study to evaluate pembrolizumab in combination with epacadostat or placebo in patients with unresectable or metastatic melanoma. ECHO-301 will enroll 600 patients, randomized 1:1, who will be stratified by PD-L1 expression (positive versus negative/indeterminate) and BRAF mutation status (BRAF mutant who have received prior BRAF-directed treatment or BRAF mutant with no prior BRAF-directed treatment and BRAF wild type). The two primary endpoints of the study are progression-free survival and overall survival. Key secondary endpoints include objective response rate, safety and tolerability. ECHO-301 is co-sponsored by Incyte and Merck&Co. ECHO-301 was initiated in June 2016 and initial data from this study are expected to be available in 2018. (NCT02752074)
• ECHO-202 study  is evaluating the safety and efficacy of epacadostat in combination with Keytruda® . Patients previously treated with anti-PD-1 or anti-CTLA-4 therapies were excluded from this trial. Enrollment is complete for the Phase 1 dose escalation (epacadostat 25, 50, 100 mg BID + KEYTRUDA 2 mg/kg IV Q3W and epacadostat 300 mg BID + KEYTRUDA 200 mg IV Q3W) and Phase 1 dose expansion (epacadostat 50, 100, and 300 mg BID + KEYTRUDA 200 mg IV Q3W) portions of the trial. (NCT02178722)
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Latest news:

• • On September 9, 2017, Incyte and Merck&Co presented updated data from the ongoing Phase 1/2 ECHO-202 trial (KEYNOTE-037) evaluating epacadostat, Incyte’s selective IDO1 enzyme inhibitor, in combination with Keytruda®  (pembrolizumab), Merck’s anti-PD-1 therapy, in patients with advanced melanoma at the European Society for Medical Oncology (ESMO) 2017 Congres. Among all patients with advanced melanoma, including treatment-naïve and treatment-experienced, data showed an overall response rate (ORR) of 56 percent (n=35/63) in patients treated with the combination of epacadostat and Keytruda® ; median progression-free survival (PFS) was 12.4 months, with PFS rates of 65 percent at six months, 52 percent at 12 months, and 49 percent at 18 months. Results were generally consistent across dosing schedules of epacadostat combined with Keytruda®, including epacadostat 100 mg BID, the epacadostat dose being studied in the Phase 3 ECHO-301 trial.
• Data at ESMO (as of June 9, 2017) show an ORR of 56 percent among all patients with advanced melanoma treated with the combination of epacadostat and Keytruda®, with a complete response (CR) in nine patients (14%); partial response (PR) in 26 patients (41%); and stable disease (SD) in 10 patients (16%). Data also show a disease control rate (DCR) of 71 percent (n=45/63). Of the 35 responses to treatment, 30 were ongoing at the time of analysis; the median duration of response was 45 weeks (range: 1+ to 121+).
• The most common all grade treatment-related adverse events (TRAEs) were rash (46 percent), fatigue (43 percent), pruritus (29 percent), and arthralgia (17 percent). Grade ?3 TRAEs were observed in 20 percent of patients; the most common were increased lipase (6 percent) and rash (5 percent). Four patients (6 percent) discontinued for TRAEs. No treatment-related deaths occurred. The safety profile was consistent with previously reported Phase 1 findings, as well as the Phase 1/2 safety results in other tumor cohorts and pooled safety data from this study. In general, the safety profile of the combination was also consistent with Keytruda® (pembrolizumab) monotherapy.
• • On January 9, 2017, Incyte and Merck&Co announced the decision to advance the clinical development program investigating the combination of epacadostat with Keytruda® (pembrolizumab). With the expansion of the clinical development program, the companies plan to initiate pivotal studies of epacadostat in combination with Keytruda® in four additional tumors: non-small cell lung cancer, renal cell carcinoma, bladder cancer and squamous cell carcinoma of the head and neck. Presentations of data from the ongoing studies of epacadostat in combination with Keytruda®, which support this decision, are expected at upcoming medical meetings. • On June 22, 2016, Incyte announced that the first patient has been treated in the ECHO-301 study--a Phase 3 trial evaluating epacadostat, Incyte's oral IDO1 inhibitor, in combination with Keytruda® (pembrolizumab), Merck's anti-PD-1 therapy, as first-line treatment for patients with advanced or metastatic melanoma. Incyte expects initial data from the ECHO-301 study to be available in 2018.

Is general: Yes