New PD-1 immune checkpoint inhibitor Opdivo (nivolumab) first to demonstrate survival benefit in Phase 3 trial in treatment naïve advanced melanoma

Results of study conducted in Canada, Australia and Europe presented at Society for Melanoma Research and published in The New England Journal of Medicine show one-year survival rate of 73% in patients on Opdivo, versus 42% on dacarbazine and a 58% decrease in the risk of death (Hazard Ratio [HR] = 0.42, p<0.0001). 

MONTREAL, Nov. 19, 2014 /CNW/ - Results of a Phase 3 randomized double-blind study conducted in Canada, Australia and Europe show that Opdivo (nivolumab), an investigational PD-1 immune checkpoint inhibitor from Bristol-Myers Squibb Company, demonstrated superior overall survival compared 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). In patients treated with Opdivo, median overall survival was not reached (since more than half of patients survived the study period) and was 10.8 months for DTIC (95% CI 9.3­–12.1). The one-year survival rate for Opdivo was 73% (95% CI = 66-79) vs. 42% (95% CI = 33-51) 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, 99.79% CI = 0.25-0.73; P<0.0001). This survival advantage was observed in Opdivo-treated patients, independently of PD-L1 expression.

The CheckMate-066 study was stopped early, in June 2014, because an analysis conducted by the independent Data Monitoring Committee showed evidence of superior overall survival in patients receiving Opdivo compared to DTIC. Results were published this week in The New England Journal of Medicine and highlighted as a late-breaking presentation during an oral session at the Society for Melanoma Research 2014 International Congress in Zurich, Switzerland.

"The results from the CheckMate-066 study are significant for two reasons," said Dr. David Hogg, one of the study investigators and an oncologist and hematologist at Princess Margaret Hospital and Director of the Melanoma Oncology Site Group at University Health Network in Toronto. "First, nivolumab was clearly superior in first line treatment of melanoma to the chemotherapy control. This finding should change our approach to melanoma treatment. And second, response to nivolumab was seen in patients regardless of PD-L1 expression, meaning all melanoma patients should benefit from the drug."

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.

About the Checkmate-066 Trial Design
CheckMate-066 is a Phase 3 randomized, double-blind study of patients with previously untreated 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 on an acceptable level of toxicity. Thirty-eight per cent 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 overall survival. Secondary endpoints included progression free survival (PFS) and objective response rate (ORR) by RECIST v1.1 criteria and PD-L1 expression as a predictive biomarker of OS. PD-L1 positivity was defined bas at least 5% of tumor cells showing cell-surface PD-L1 staining.  

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 (95% CI, 3.5 to 10.8) and 2.2 months (95% CI, 2.1 to 2.4), 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).

About Opdivo
Cancer cells may exploit "regulatory" pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Opdivo 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.

Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumour types consisting of more than 35 trials – as monotherapy or in combination with other therapies – in which more than 7,000 patients have been enrolled worldwide. Among these are several potentially registrational trials in non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), head and neck cancer, glioblastoma and non-Hodgkin lymphoma.

About Advanced Melanoma
Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma is the deadliest form of the disease, and occurs when cancer spreads beyond the surface of the skin to the other organs, such as the lymph nodes, lungs, brain or other areas of the body. The incidence of melanoma has been increasing for at least 30 years. In 2012, an estimated 232,130 melanoma cases were diagnosed globally. Melanoma is mostly curable when treated in its early stages. However, in its late stages, the average survival rate has historically been just six months with a one-year mortality rate of 75 per cent, making it one of the most aggressive forms of cancer.

Immuno-Oncology at Bristol-Myers Squibb
Surgery, radiation, cytotoxic or targeted therapies have represented the mainstay of cancer treatment over the last several decades, but long-term survival and a positive quality of life have remained elusive for many patients with advanced disease.

To address this unmet medical need, Bristol-Myers Squibb is leading advances in the innovative field of immuno-oncology, which involves agents whose primary mechanism is to work directly with the body's immune system to fight cancer. The company is exploring a variety of compounds and immunotherapeutic approaches for patients with different types of cancer, including researching the potential of combining immuno-oncology agents that target different and complementary pathways in the treatment of cancer.

Bristol-Myers Squibb is committed to advancing the science of immuno-oncology, with the goal of changing survival expectations and the way patients live with cancer.

About Bristol-Myers Squibb Canada
Bristol-Myers Squibb Canada is an indirect wholly-owned subsidiary of Bristol-Myers Squibb Company, a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit www.bmscanada.ca.

SOURCE: Bristol-Myers Squibb Canada

Monica Flores, Senior Manager, Public Affairs, Bristol-Myers Squibb Canada, 514-333-3845, [email protected]