OREANDA-NEWS. Bristol-Myers Squibb Company (NYSE:BMY) announced today that the European Commission (EC) has approved Opdivo in combination with Yervoy for the treatment of advanced (unresectable or metastatic) melanoma in adults, representing the first and only approved combination of two Immuno-Oncology agents in the European Union (EU). This approval allows for the marketing of the Opdivo + Yervoy Regimen in all 28 Member States of the EU. Approval was based on CheckMate -067, the first Phase 3, double-blind, randomized study, in which the Opdivo + Yervoy Regimen and Opdivo monotherapy demonstrated superior progression-free survival (PFS) and objective response rates (ORR) in patients with advanced melanoma, regardless of BRAF mutational status, versus Yervoy alone. The safety profile was consistent with previously reported studies evaluating the Opdivo + Yervoy Regimen, and most treatment-related adverse events were managed using established algorithms.

Dr. James Larkin, from The Royal Marsden and lead author on CheckMate - 067, the trial that led to this approval, commented, “Historically, advanced melanoma has been a very difficult-to-treat disease. Now, with this approval, patients in Europe will have a treatment option combining two Immuno-Oncology therapies, Opdivo and Yervoy, which in a Phase 3 randomized trial has shown its ability to deliver superior efficacy versus Yervoy monotherapy in progression-free survival and response. This is truly good news for healthcare providers and the patients they treat, as it represents an important new treatment option with the potential for improved outcomes.”

In study CheckMate -067, the Opdivo + Yervoy Regimen demonstrated a 58% reduction in the risk of disease progression versus Yervoy monotherapy in previously untreated patients with advanced melanoma (HR=0.42 [99.5% CI: 0.32-0.56; p<0.0001]), while Opdivo monotherapy demonstrated a 45% risk reduction versus Yervoy monotherapy (HR=0.55 [99.5% CI: 0.42-0.73; p<0.0001]). The median PFS for the Opdivo + Yervoy Regimen was 11.5 months (95% CI: 8.9-22.18) and 6.9 months (95% CI: 4.3-9.5) for Opdivo monotherapy versus 2.89 months (95% CI: 2.8-3.4) for Yervoy monotherapy, at a minimum follow-up of 18 months. The Opdivo + Yervoy Regimen and Opdivo monotherapy also demonstrated a higher ORR (ORR: 58% and 44%, p<0.0001, respectively) versus Yervoy monotherapy (19%). Median duration of response was not reached for the Opdivo + Yervoy Regimen and was 22.3 months for Opdivo monotherapy, versus 14.4 months for Yervoy alone.

Based on a pre-planned, descriptive analysis of data from CheckMate -067, the EC adopted the Committee for Medicinal Products for Human Use (CHMP) recommendation to add an informative statement to the broad indication that relative to Opdivo monotherapy, an increase in PFS for the combination of Opdivo with Yervoy is established only in patients with low tumor PD-L1 expression. In the study, overall response rates were higher for the combination of Opdivo and Yervoy relative to Opdivo monotherapy across tumor PD-L1 expression levels.

The approval was also based on supportive data from the Phase 2 study, CheckMate -069, in which the Opdivo + Yervoy Regimen demonstrated an ORR, the primary endpoint, of 61% (95% CI: 48.9-72.4) in patients with BRAF wild-type advanced melanoma, versus 11% (95% CI: 3-25.4) ORR in the Yervoy monotherapy arm, with a minimum follow-up of 11 months. The estimated 12- and 18-month overall survival (OS) rates were 79% (95% CI: 67, 87) and 73% (95% CI: 61, 82), respectively, for the Opdivo + Yervoy Regimen, and 62% (95% CI: 44, 75) and 56% (95% CI: 39, 70), respectively, for Yervoy monotherapy. The OS data are based on an exploratory, pre-planned analysis of patients with BRAF wild-type advanced melanoma.

Emmanuel Blin, senior vice president, Head of Commercialization, Policy and Operations, Bristol-Myers Squibb, commented, “Today’s approval of the Opdivo + Yervoy Regimen for advanced melanoma patients supports our goal of developing innovative treatment approaches that have the potential to improve patient outcomes. The Opdivo + Yervoy Regimen is the first and only approved Immuno-Oncology combination, and only Regimen to deliver superior efficacy compared to Yervoy, and we are thrilled to make this novel combination treatment available to patients with advanced melanoma in Europe.”

Approval Based on Superior Efficacy Demonstrated Versus Yervoy In Pivotal Phase 3 Study

CheckMate -067 is a Phase 3, double-blind, randomized study that evaluated the Opdivo + Yervoy Regimen or Opdivo monotherapy versus Yervoy alone in patients with previously untreated advanced melanoma, including both BRAF V600 mutation positive or BRAF wild-type advanced melanoma. A total of 945 patients were randomized to receive the Opdivo + Yervoy Regimen (Opdivo 1 mg/kg plus Yervoy 3 mg/kg every 3 weeks for 4 doses followed by Opdivo 3 mg/kg every 2 weeks thereafter; n=314), Opdivo monotherapy (Opdivo 3 mg/kg every 2 weeks; n=316) or Yervoy monotherapy (Yervoy 3 mg/kg every 3 weeks for 4 doses followed by placebo every 2 weeks; n=315). Randomization was stratified by PD-L1 expression (?5% vs. <5%), BRAF status, and M stage per the American Joint Committee on Cancer (AJCC) staging system. Patients were treated until progression or unacceptable toxicity. The co-primary endpoints were progression-free survival (PFS) and overall survival (OS); the study is ongoing and patients continue to be followed for OS. Objective response rate (ORR) and the duration of response were also assessed.

Results from the trial demonstrated a statistically significant improvement in PFS in patients with advanced melanoma treated with the Opdivo + Yervoy Regimen (p<0.0001) and with Opdivo as a single agent (p<0.0001) versus Yervoy monotherapy. At a minimum follow-up of 18 months, the Opdivo + Yervoy Regimen demonstrated a 58% reduction in the risk of disease progression versus Yervoy monotherapy in previously untreated patients with advanced melanoma (HR=0.42 [99.5% CI: 0.32-0.56; p<0.0001]), while Opdivo monotherapy demonstrated a 45% risk reduction versus Yervoy monotherapy (HR=0.55 [99.5% CI: 0.42-0.73; p<0.0001]). The median PFS for the Opdivo + Yervoy Regimen was 11.5 months (95% CI: 8.9-22.18) and 6.9 months (95% CI: 4.3-9.5) for Opdivo monotherapy versus 2.89 months (95% CI: 2.8-3.4) for Yervoy monotherapy, at a minimum follow-up of 18 months.

The Opdivo + Yervoy Regimen and Opdivo monotherapy also demonstrated a higher ORR (ORR: 58% and 44%, p<0.0001, respectively) versus Yervoy monotherapy (19%). There were 38 (12%) complete responses and 143 (46%) partial responses seen in patients treated with the Opdivo + Yervoy Regimen, and 31 (10%) complete responses and 107 (34%) partial responses seen in patients treated with Opdivo monotherapy, versus 7 (2%) complete responses and 53 (17%) partial responses seen in patients treated with Yervoy alone. Median duration of response was not reached (0+ - 24+ months) for the Opdivo + Yervoy Regimen and was 22.3 months (0+ - 23+) for Opdivo monotherapy, versus 14.4 months (1.4 - 22.3+) for Yervoy alone.

CheckMate -069 is a Phase 2, double-blind, randomized study evaluating the Opdivo + Yervoy Regimen versus Yervoy monotherapy in 142 patients with previously untreated unresectable or metastatic melanoma. The trial included patients with BRAF V600 mutation positive and BRAF wild-type advanced melanoma, and randomization was stratified by BRAF mutation status. The primary endpoint was ORR in patients with BRAF wild-type tumors. Secondary endpoints included PFS in patients with BRAF wild-type tumors, ORR in patients with BRAF V600 mutation positive tumors and safety. Overall survival was an exploratory endpoint. Treatment was continued until progression or unacceptable toxicity. In this study, the Opdivo + Yervoy Regimen demonstrated a response rate of 61% (95% CI: 48.9-72.4) in patients with BRAF wild-type advanced melanoma, versus 11% (95% CI: 3-25.4) ORR in the Yervoy monotherapy arm, with a minimum follow-up of 11 months. The estimated 12- and 18-month OS rates were 79% (95% CI: 67, 87) and 73% (95% CI: 61, 82), respectively, for the Opdivo + Yervoy Regimen, and 62% (95% CI: 44, 75) and 56% (95% CI: 39, 70), respectively, for Yervoy.

In a pooled dataset of the Opdivo + Yervoy Regimen, based on three studies of the combination, the most frequent adverse reactions (?10%) were rash (51%), fatigue (43%), diarrhea (42%), pruritus (35%), nausea (25%), pyrexia (19%), decreased appetite (15%), hypothyroidism (15%), vomiting (14%), colitis (14%), abdominal pain (13%), anthralgia (11%) and headache (11%). The majority of adverse reactions were mild to moderate (Grade 1 or 2). Among the patients treated with Opdivo in combination with Yervoy in CheckMate -067, 151/313 (48%) had the first onset of Grade 3 or 4 adverse reactions during the initial combination phase. Among the 147 patients in this group who continued treatment in the single-agent phase, 37 (25%) experienced at least one Grade 3 or 4 adverse reaction during the single-agent phase.

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. Melanoma is the ninth most common cancer in Europe, with an estimated 100,000 new cases diagnosed annually and more than 20,000 deaths.

Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, we have a vision for the future of cancer care that is focused on Immuno-Oncology, now considered a major treatment modality alongside surgery, radiation and chemotherapy for certain types of cancer.

We have a comprehensive clinical portfolio of investigational and approved Immuno-Oncology agents, many of which were discovered and developed by our scientists. We pioneered the research leading to the first regulatory approval for the combination of two Immuno-Oncology agents, and continue to study the role of combinations in cancer.

Our collaboration with academia, as well as small and large biotech companies is responsible for researching the potential of Immuno-Oncology and non-Immuno-Oncology combinations, with the goal of providing new treatment options in clinical practice.

At Bristol-Myers Squibb, we are committed to changing expectations in hard-to-treat cancers and the way patients live with cancer.

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 a PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 expressed on activated T-cells, and blocks the binding of PD-L1 and PD-L2, preventing the PD-1 pathway’s suppressive signaling on the immune system, including the interference with an anti-tumor immune response.

Opdivo’s broad global development program is based on Bristol-Myers Squibb’s understanding of the biology behind Immuno-Oncology. Our company is at the forefront of researching the potential of Immuno-Oncology to extend survival in hard-to-treat cancers. This scientific expertise serves as the basis for the Opdivo development program, which includes a broad range of Phase 3 clinical trials evaluating overall survival as the primary endpoint across a variety of tumor types. The Opdivo trials have also contributed toward the clinical and scientific understanding of the role of biomarkers and how patients may benefit from Opdivo across the continuum of PD-L1 expression. To date, the Opdivo clinical development program has enrolled more than 18,000 patients.

Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world in July 2014, and currently has regulatory approval in 50 countries including the United States, Japan, and in the European Union.

U.S. FDA APPROVED INDICATIONS

OPDIVO® (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.

OPDIVO® (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO® (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO® (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.