Date: 2014-11-15
Type of
information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the Society for Melanoma Research 2014 International Congress in Zurich, Switzerland
Company: BMS (USA - NY)
Product: Opdivo® (nivolumab)
Action
mechanism:
- monoclonal antibody/immune checkpoint inhibitorr. 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.
Disease: naïve BRAF wild-type advanced melanoma
Therapeutic
area: Cancer - Oncology
Country:
Trial
details:
- CheckMate -066 is a Phase 3 randomized, double-blind study of patients with treatment naïve BRAF wild-type unresectable Stage III and IV melanoma. The trial enrolled 418 patients who were randomized to receive either Opdivo® 3 mg/kg every two weeks (n=210) or DTIC 1000 mg/m2 every three weeks (n=208). Treatment continued until there was disease progression or an unacceptable level of toxicity. Thirty-eight percent of patients in the DTIC arm received Yervoy® (ipilimumab) after stopping study treatment. All randomized patients were followed for up to 16.7 months at the time of database lock. The primary endpoint was OS. Secondary endpoints included progression free survival (PFS), objective response rate (ORR) by RECIST v1.1 criteria and PD-L1 expression as a predictive biomarker of OS. PD-L1 positivity was defined as at least 5% of tumor cells showing cell-surface PD-L1 staining. The study, which was designed in consultation with the Committee for Medicinal Products for Human Use (CHMP), was primarily conducted in countries where DTIC is a commonly-used treatment in the first-line setting, including Canada, Europe and Australia, but not at U.S. trial sites. On June 24, 2014, Bristol-Myers Squibb announced that CheckMate -066 was stopped early because an analysis conducted by the independent Data Monitoring Committee showed evidence of superior OS in patients receiving Opdivo® compared to the control arm, DTIC. As a result, patients in the trial were unblinded and allowed to receive Opdivo®. However, the results reported hereare from the double-blind portion of the study before the amendment.
Latest
news:
- • On November 15, 2014, BMS announced results from CheckMate -066, a Phase 3 randomized double blind study, comparing Opdivo®, an investigational PD-1 immune checkpoint inhibitor, to the chemotherapy dacarbazine (DTIC) in patients with treatment naïve BRAF wild-type advanced melanoma (n=418). The study met the primary endpoint of overall survival (OS) with the median OS not reached for Opdivo® vs. 10.8 months for DTIC. The one-year survival rate was 73% for Opdivo vs. 42% for DTIC and there was a 58% decrease in the risk of death for patients treated with Opdivo® (Hazard Ratio for death [HR]: 0.42, P<0.0001). This survival advantage was also observed in Opdivo®-treated patients in both PD-L1 positive and PD-L1 negative patients. Findings from CheckMate -066 were published in The New England Journal of Medicine and presented during an oral session at the Society for Melanoma Research 2014 International Congress in Zurich, Switzerland.
Safety was reported in all patients treated in the Opdivo® and DTIC arms. Fewer discontinuations were observed with Opdivo® than DTIC (6.8% vs. 11.7%) as well as for treatment-related Grade 3/4 adverse events (AEs) (11.7% vs. 17.6%), which were managed using established safety algorithms. The most common Opdivo® treatment-related AEs were fatigue (20%), pruritus (17%), and nausea (16.5%). Common adverse events in the DTIC arm were consistent with those in previous reports and included nausea (41.5%), vomiting (21%), fatigue (15%), diarrhea (15%) and hematological toxicities. No deaths were attributed to study drug toxicity in either arm.
- Detailed Study Results: Median OS was not reached for patients treated with Opdivo® and was 10.8 months for DTIC (95% CI 9.3–12.1). The one-year survival rate was 73% for Opdivo (95% CI = 66-79) vs. 42% for DTIC (95% CI = 33-51). There was a 58% decrease in the risk of death for patients treated with Opdivo® (Hazard Ratio for death [HR]: 0.42; 99.79% CI = 0.25-0.73; P<0.0001). Median PFS was 5.1 months and 2.2 months, respectively (HR: 0.43; 95% CI = 0.34–0.56; P < 0.0001).
- ORR was also significantly higher for Opdivo® than DTIC (40% vs. 14%, p<0.0001). Complete responses were observed in 7.6% of Opdivo®-treated patients vs. 1% for DTIC. Median duration of response was not reached for Opdivo® responders and was six months for DTIC (95% CI, 3.0–not estimable). Responses were ongoing in 86% of Opdivo responders compared to 51% for DTIC responders.
- In both the PD-L1 positive and PD-L1 negative/indeterminate subgroups, Opdivo®-treated patients had improved OS vs. DTIC (unstratified HR 0.30, 95% CI, 0.15-0.60 in PD-L1 positive patients; 0.48, 95% CI 0.32-0.71 in PD-L1 negative/indeterminate patients). Median OS was not reached in either PD-L1 subgroup in the Opdivo® arm. In the DTIC arm, mOS was slightly longer in the PD-L1 positive subgroup (12 vs. 10 months).
- Safety was reported in all patients treated in the Opdivo and DTIC arms. The incidence of any-grade treatment-related AEs was similar between the Opdivo® and DTIC groups (74.3% and 75.6%, respectively). However, fewer treatment-related Grade 3/4 AEs were observed with Opdivo® than DTIC (11.7% vs. 17.6%), which were managed using established safety algorithms, and there were fewer treatment discontinuations (6.8% vs. 11.7%). The frequency of Grade 3/4 treatment-related serious AEs was similar between the Opdivo and DTIC group (5.8% and 5.9%, respectively). The most common Opdivo treatment-related AEs were fatigue (20%), pruritus (17%), and nausea (16.5%). Common AEs in the DTIC arm were consistent with those in previous reports and included nausea (41.5%), vomiting (21%), fatigue (15%), diarrhea (15%) and hematological toxicities. No deaths were attributed to study drug toxicity in either arm.
Is
general: Yes
