Study comparing Opdivo (nivolumab) to chemotherapy in treatment naïve advanced melanoma patients marks first PD-1 immune checkpoint inhibitor to demonstrate a survival benefit in a Phase 3 trial

Bristol-Myers Squibb Company (NYSE:BMY) today 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 today 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.

“The results from CheckMate -066 are significant as they represent the first time a PD-1 immune checkpoint inhibitor has shown a survival benefit in a randomized Phase 3 trial,” said Prof. Caroline Robert, Professor of Dermatology, Head of the Dermatology Unit, Institute Gustave Roussy and lead author of the New England Journal of Medicine manuscript. “This represents a major milestone in the study of treatment naïve patients with wild-type BRAF advanced melanoma.”

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.

“Treatment naïve advanced melanoma patients who received nivolumab in this study had clinically important improvements in both overall survival and objective response rates compared to DTIC,” said Georgina V. Long, M.D., Ph.D., Melanoma Institute Australia & the University of Sydney and Mater Hospital and presenter of the results. “This study also confirms our hypothesis on the role of PD-L1 expression in advanced melanoma. In CheckMate -066, both PD-L1 positive and negative patients treated with nivolumab had a clear survival benefit.”

“Results from this Phase 3 Opdivo trial with a survival endpoint build upon the pioneering science that led to the introduction of Yervoy in 2011 and underscore our strategic commitment to provide more patients with the potential opportunity for long-term survival,” said Michael Giordano, senior vice president, head of Development, Oncology, Bristol-Myers Squibb. “And, we continue to develop our immuno-oncology portfolio across the continuum of melanoma and multiple other cancers as single agents and as part of combination regimens.”

Bristol-Myers Squibb has proposed the name Opdivo (pronounced op-dee-voh), which, if approved by health authorities, will serve as the trademark for nivolumab.

About the CheckMate -066 Trial Design

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 today are from the double-blind portion of the study before the amendment.

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.