Date: 2015-04-20
Type of
information: Presentation of results at a congress
phase: 2
Announcement: presentation of results at the American Association for Cancer Research (AACR) Annual Meeting
Company: BMS (USA - NY)
Product: Opdivo® (nivolumab)+Yervoy® (ipilimumab)
Action
mechanism:
- monoclonal antibody/immune checkpoint inhibitor . Nivolumab is an investigational, 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.
- Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The mechanism of action of ipilimumab’s effect in patients with melanoma is indirect, possibly through T-cell mediated anti-tumor immune responses.
Disease: previously untreated advanced melanoma
Therapeutic
area: Cancer - Oncology
Country:
Trial
details:
- CheckMate -069 is a Phase II double-blind, randomized study that evaluated the Opdivo+Yervoy regimen in patients with previously untreated unresectable Stage 3 and 4 melanoma. The study included patients with both BRAF wild-type and BRAF mutation-positive melanoma. The trial enrolled 142 patients who were randomized to receive either the Opdivo+Yervoy (n=95) regimen or Yervoy (n=47) monotherapy. Randomization was stratified by BRAF mutation status (V600 wild-type tumors versus BRAF mutation-positive tumors as assessed by an FDA-approved test). Patients in the Opdivo+Yervoy regimen group received 1 mg/kg of Opdivo plus 3 mg/kg of Yervoy every 3 weeks for 4 doses followed by 3 mg/kg of Opdivo per every 2 weeks until progression or unacceptable toxic effects. In the Yervoy monotherapy group, patients were treated with the same dosing schedule plus matching placebo. The primary endpoint was ORR in patients with BRAF wild-type tumors. Secondary endpoints included progression-free survival (PFS) in BRAF wild type patients and ORR and PFS in BRAF V600 mutation-positive patients, along with safety.
Latest
news:
- • On April 20, 2015, BMS announced positive results from a Phase II trial (CheckMate -069), evaluating the Opdivo® (nivolumab)+Yervoy® (ipilimumab) regimen versus Yervoy® alone in patients with previously untreated advanced melanoma. Patients with BRAF wild-type mutation status treated with the Opdivo+Yervoy regimen experienced a higher objective response rate (ORR) of 61% (n=44/72) – the primary study endpoint – compared to 11% (n=4/37) for patients administered Yervoy monotherapy (P<0.001). Complete responses were also reported in 22% (n=16) of patients with BRAF wild-type mutation status administered the Opdivo+Yervoy regimen and in no patients who received Yervoy monotherapy. Similar results were also observed in BRAF mutation-positive patients. The safety profile was consistent with previously-reported studies evaluating the Opdivo+Yervoy regimen and included grade 3-4 colitis (17%), diarrhea (11%), and increased alanine aminotransferase (11%).
- Along with higher ORR and more complete responses, the regimen decreased risk of progression for BRAF mutant and wild-type patients (hazard ratios = 0.4 [95% CI: 0.23, 0.68; P<0.001] and 0.38 [95% CI: 0.15, 1.00], respectively), representing a 60-62% reduction of risk of progression or death. In BRAF wild-type patients, median PFS was not reached. In BRAF mutation-positive patients, median PFS was 8.5 months for the regimen and 2.7 months for Yervoy alone. In addition, ORR was independent of PD-L1 status: 58% among patients with PD-L1 positive tumors and 55% among those with and PD-L1 negative tumors. The minimum follow-up period after randomization was 11 months. The safety profile was consistent with that previously reported for the Opdivo+Yervoy regimen. The treatment-related adverse event rate was similar (91% for the Opdivo+Yervoy regimen versus 93% for Yervoy monotherapy). The incidence of grade 3/4 adverse events (drug-related AEs) was higher with the Opdivo+Yervoy regimen (54%) compared to 24% of patients who received Yervoy monotherapy and managed using established safety guidelines and the majority (approximately 80%) improved or resolved with appropriate monitoring and use of corticosteroids. The most common grade 3/4 AEs with the Opdivo+Yervoy regimen were colitis (17%), diarrhea (11%), and increased alanine aminotransferase (11%). The Opdivo+Yervoy regimen was discontinued due to adverse events in 47% of patients versus 17% for Yervoy monotherapy. Of those patients who discontinued due to adverse events, 68% continued to experience a complete or partial response. There were three drug-related deaths associated with the Opdivo+Yervoy regimen.
- These data have been presented at the American Association for Cancer Research (AACR) Annual Meeting and featured during a press briefing at 8:30 AM EDT [Abstract #2860]. The results will also be published in The New England Journal of Medicine (NEJM).
Is
general: Yes
