Clinical Trials

Date: 2018-06-04

Type of information: Presentation of results at a congress

phase: 1-2

Announcement: presentation of results at the American Society of Clinical Oncology (ASCO) annual meeting, in Chicago

Company: BMS (USA - NY) Incyte (USA - DE)

Product: epacadostat and nivolumab

Action mechanism:

• enzyme inhibitor/immunotherapy product/monoclonal antibody/immune checkpoint inhibitor.
• Nivolumab is a fully-human PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 (programmed death-1) expressed on activated T-cells. PD-1, a receptor expressed on the surface of lymphocytes, plays a role in a regulatory pathway that suppresses activated lymphocytes in the body. Available evidence suggests that cancer cells exploit this pathway to escape from immune responses. Opdivo® is thought to provide benefit by blocking PD-1-mediated negative regulation of lymphocytes (i.e., the interaction of PD-1 with its ligands PD-L1 and PD-L2), thereby enhancing the ability of the immune system to recognize cancer cells as foreign and eliminate them. Opdivo® is the world’s first approved drug targeting PD-1.
• This monoclonal antibody has been generated under a research collaboration entered into in May 2005 between Ono and Medarex. When Medarex was acquired by BMS in 2009, it also granted BMS its rights to develop and commercialize the anti-human PD-1 monoclonal antibody in North America. Through the collaboration agreement entered into in September 2011 between Ono and BMS, Ono granted BMS exclusive rights to develop and commercialize Opdivo® in the rest of the world, except in Japan, Korea and Taiwan where Ono has retained all rights to develop and commercialize the compound.
• 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.

Disease: advanced solid tumors and lymphomas, including melanoma (MEL), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), squamous cell carcinoma of the head and neck (SCCHN), ovarian cancer (OC), and B cell non-Hodgkin lymphoma ( NHL ) or Hodgkin lymphoma (HL)

Therapeutic area: Cancer - Oncology

Country: UK, USA

Trial details:

• The ECHO-204 study is a Phase 1/2 study evaluating the safety and efficacy of epacadostat, Incyte's selective IDO1 enzyme inhibitor, in combination with nivolumab in subjects with select advanced solid tumors and lymphomas, including melanoma (MEL), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), squamous cell carcinoma of the head and neck (SCCHN), ovarian cancer (OC), and B cell non-Hodgkin lymphoma ( NHL ) or Hodgkin lymphoma (HL) (in Phase 2, DLBCL was the only NHL sub-type permitted). Patients previously treated with anti-PD-1, PD-L1, anti-CTLA-4, or therapies specifically targeting T-cell co-stimulation were excluded from this trial (except for MEL subjects where prior first-line anti-CTLA-4 was permitted). Enrollment for the Phase 2 (epacadostat 100 or 300 mg BID + nivolumab 240 Q2W) tumor-specific cohorts is ongoing. (NCT02327078)

Latest news:

• • On June 4, 2018, updated data from the ongoing Phase 1/2 ECHO-204 trial evaluating the safety and efficacy of epacadostat, Incyte's investigational oral selective IDO1 enzyme inhibitor, in combination with Opdivo^® (nivolumab), Bristol-Myers Squibb's PD-1 immune checkpoint inhibitor, in multiple advanced solid tumors, have been highlighted in an abstract at the American Society of Clinical Oncology ( ASCO ) annual meeting in Chicago, Illinois. These data indicates that epacadostat and nivolumab continues to show promising antitumor activity in patients with advanced melanoma and is generally well tolerated. Epacadostat 100 mg BID is the selected dose for phase 3 studies in patients with advanced cancer.
• • On June 5, 2017, updated data from the ECHO-204 trial have been highlighted in an oral presentation at the American Society of Clinical Oncology ( ASCO ) annual meeting in Chicago, Illinois .
• Efficacy data in patients with squamous cell carcinoma of the head and neck (SCCHN), treatment-naïve advanced melanoma (MEL), ovarian cancer (OC), and colorectal cancer (CRC) have been presented. The data show that in patients with MEL treated with epacadostat (100 mg or 300 mg) plus nivolumab (n=40), the combined objective response rate (ORR) was 63 percent (25/40), including 2 complete responses (CRs) and 23 partial responses (PRs), and the combined disease control rate (DCR) was 88 percent (35/40). In previously-treated patients with SCCHN who were treated with epacadostat (100 mg or 300 mg) plus nivolumab (n=31), the combined ORR was 23 percent (7/31), including 1 CR and 6 PRs, and the combined DCR was 61 percent (19/31). Responses for MEL and SCCHN were observed regardless of PD-L1 expression and HPV status (in SCCHN), and all responses were ongoing at the data cutoff ( February 13, 2017).

ECHO-204 Objective Response Rates (ORR), Disease Control Rates (DCR) and Duration of Response (DoR)

in MEL and SCCHN

n/N (%)

MEL

SCCHN

All pts

Epacadostat Dose

All Pts

Epacadostat Dose

Total

100 mg BID

300 mg BID

Total

100 mg BID

300 mg BID

ORR

25/40 (63)

6/6 (100)

19/34 (56)

7/31 (23) 1 CR 6 PR

1/7 (14)

6/24 (25)

2 CR 23 PR

all PR

2 CR 17 PR

1 PR

1 CR 5 PR

DCR

35/40

6/6

29/34

19/31

2/7

17/24

(88)

(100)

(85)

(61)

(29)

(71)

DoR

25/25 responses ongoing

8/8 responses ongoing

range 1+ to 41+ weeks

range 8+ to 32+ weeks

• Epacadostat plus nivolumab did not demonstrate an efficacy signal in the unselected refractory OC and CRC patient populations.
• Epacadostat plus nivolumab was generally well-tolerated in patients with select advanced solid tumors. In Phase 1 (dose escalation), 36 patients were enrolled and no dose-limiting toxicities were observed. Among the 230 patients enrolled in Phase 2, the most frequent treatment-related adverse events (TRAEs) (=10 percent) in patients receiving epacadostat 100 mg BID (69/230) or 300 mg BID (161/230) and Opdivo were rash (35 percent and 32 percent, respectively), fatigue (23 percent and 38 percent, respectively), and nausea (19 percent and 21 percent, respectively). Rash was the most common Grade 3/4 TRAE (10 percent [epacadostat 100 mg BID] and 15 percent [epacadostat 300 mg BID]). TRAEs led to discontinuation in 6 percent (100 mg) and 12 percent (300 mg) of patients. There were no treatment-related deaths.

Is general: Yes