Bristol-Myers Squibb Company announced that the US Food and Drug Administration (FDA) has approved Opdivo (nivolumab) in combination with Yervoy (ipilimumab) for the treatment of patients with BRAF V600 wild-type and BRAF V600 mutation-positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

This approval expands the original indication for the Opdivo + Yervoy regimen for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma to include patients, regardless of BRAF mutational status, based on data from the phase 3 CheckMate -067 trial, in which PFS and overall survival (OS) were co-primary endpoints.

Opdivo is associated with immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, rash, encephalitis, other adverse reactions; infusion reactions; and embryofetal toxicity.

“For nearly a decade, our researchers have worked tirelessly to find treatment options that could improve outcomes for patients with late-stage melanoma, a particularly aggressive cancer, and we are incredibly proud of today’s approval to expand the use of the Opdivo + Yervoy regimen to include patients with BRAF mutation-positive unresectable or metastatic melanoma. CheckMate -067 is the first phase 3 study to observe the efficacy and safety of both Opdivo as a single-agent as well as in combination with Yervoy versus Yervoy alone,” said Chris Boerner, head of US commercial, Bristol-Myers Squibb. “To make this treatment option available to more patients is truly a milestone in the fight against this deadly disease.”

Opdivo was approved by the FDA in November 2015, for use in previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma.

“Patients with metastatic melanoma historically have a very challenging disease. Recent advances in our understanding of the immune response to cancer has yielded therapies which provide meaningful responses and hope. The combination of two Immuno-Oncology treatments, nivolumab and ipilimumab, has been shown to provide these patients with a much needed improvement in progression-free survival and response rates,” said Jedd D. Wolchok, MD, PhD, chief, Melanoma and Immunotherapeutics Service, Department of Medicine and Ludwig Center at Memorial Sloan Kettering Cancer Center. “This expanded approval for the nivolumab and ipilimumab regimen provides more advanced melanoma patients with an Immuno-Oncology combination treatment, and the potential for improved outcomes.”

CheckMate -067 is a phase 3, double-blind, randomized study that evaluated the Opdivo + Yervoy regimen or Opdivo monotherapy vs. Yervoy monotherapy in patients with previously untreated advanced melanoma. The trial evaluated previously untreated patients, including both BRAF V600 mutant and wild-type advanced melanoma, and enrolled 945 patients who 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). Patients were treated until progression or unacceptable toxic effects.1 The median duration of exposure was 2.8 months (range: 1 day to 18.8 months) for patients in the Opdivo + Yervoy Regimen arm with a median of four doses (range: 1 to 39 for Opdivo; 1 to 4 for Yervoy), and 6.6 months (range: 1 day to 17.3 months) duration for the Opdivo monotherapy arm with a median of 15 doses (range: 1 to 38).1,2 The co-primary endpoints were PFS and OS; the study is ongoing and patients continue to be followed for OS.

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) vs. Yervoy monotherapy.1 Median PFS was 11.5 months (95 per cent CI: 8.9-16.7) for the Opdivo + Yervoy Regimen and 6.9 months (95 per cent CI: 4.3-9.5) for Opdivo monotherapy, vs. 2.9 months (95 per cent CI: 2.8-3.4) for Yervoy monotherapy. The Opdivo + Yervoy regimen demonstrated a 58 per cent reduction in the risk of disease progression vs. Yervoy (HR: 0.42; 95 per cent CI: 0.34-0.51; p<0.0001), while Opdivo monotherapy demonstrated a 43 per cent risk reduction vs. Yervoy monotherapy (HR: 0.57; 95 per cent CI: 0.47-0.69; p<0.0001).

In addition, the Opdivo + Yervoy regimen and Opdivo monotherapy demonstrated higher confirmed objective response rates (ORR; 50 per cent and 40 per cent; p<0.0001, respectively) vs. Yervoy monotherapy (14 per cent). The percentage of patients with a complete response was 8.9 per cent, 8.5 per cent and 1.9 per cent, favouring the Regimen and Opdivo monotherapy over Yervoy monotherapy. Partial responses were seen in 41 per cent of patients treated with the Opdivo + Yervoy Regimen, 31 per cent of patients treated with Opdivo monotherapy, and 12 per cent of patients treated with Yervoy monotherapy. The Opdivo + Yervoy Regimen delivered durable responses, with three of four (76 per cent) patients experiencing an ongoing response of at least six months (range: 1.2+ to 15.8+). Of patients in the Opdivo monotherapy and Yervoy monotherapy arms, 74 per cent and 63 per cent experienced an ongoing response of at least six months, respectively (ranges: 1.3+ to 14.6+; 1.0+ to 13.8+).

“The melanoma community is excited to see the ongoing developments in research from the pharmaceutical industry, including Bristol-Myers Squibb, who made the first approved combination of two Immuno-Oncology treatments available to more patients fighting this disease,” said Tim Turnham, executive director, Melanoma Research Foundation. “Today’s expanded approvals continue to bring new treatment options to patients, and demonstrate the ongoing impact of Immuno-Oncology research.”

In CheckMate -067, serious adverse reactions (73 per cent and 37 per cent), adverse reactions leading to discontinuation (43 per cent and 14 per cent), or to dosing delays (55 per cent and 28 per cent), and Grade 3 or 4 adverse reactions (72 per cent and 44 per cent) all occurred more frequently in the Opdivo + Yervoy arm relative to the Opdivo arm. No overall differences in safety or efficacy were reported between elderly and younger patients. The most common adverse reactions leading to discontinuation of the Opdivo + Yervoy regimen relative to Opdivo as a single-agent were diarrhea (8 per cent and 1.9 per cent), colitis (8 per cent and 0.6 per cent), increased ALT (4.8 per cent and 1.3 per cent), increased AST (4.5 per cent and. 0.6 per cent), and pneumonitis (1.9 per cent and 0.3 per cent). The most frequent (=10 per cent) serious adverse reactions in the Opdivo + Yervoy arm and the Opdivo arm, respectively, were diarrhea (13 per cent and 2.6 per cent), colitis (10 per cent and 1.6 per cent) and pyrexia (10 per cent and 0.6 per cent). The most common adverse reactions (=20 per cent) reported in patients receiving the Opdivo + Yervoy Regimen relative to Opdivo as a single-agent were fatigue (59 per cent and 53 per cent), rash (53 per cent and 40 per cent), diarrhea (52 per cent and 31 per cent), and nausea (40 per cent and 28 per cent). Pyrexia (37 per cent), vomiting (28 per cent) and dyspnea (20 per cent) were also reported in =20 per cent of patients receiving the Opdivo + Yervoy Regimen.

The scientific rationale for targeting the immune system via dual immune checkpoint inhibition in cancer has formed the basis of a novel approach to the treatment of metastatic melanoma.

Cancer cells may exploit “regulatory” pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Opdivo and Yervoy are immune checkpoint inhibitors that target separate, distinct and complementary checkpoint pathways (PD-1 and CTLA-4).1 The mechanism of action involves dual immune checkpoint inhibition resulting in increased anti-tumor activity. Yervoy blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, while Opdivo restores the active T-cell response directed at the tumour. This may affect healthy cells and result in immune-mediated adverse reactions, which can be severe and potentially fatal.

Bristol-Myers Squibb has a broad, global development programme to study the combination of Opdivo and Yervoy consisting of more than 14 trials in which more than 2,000 patients have been enrolled worldwide through September 2015. To date, the Opdivo clinical development programme 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 46 countries including the United States, Japan, and in the European Union.

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 other organs. The incidence of melanoma has been increasing for at least 30 years. Approximately 73,870 melanoma cases were estimated to be diagnosed in the US in 2015. Melanoma is mostly curable when treated in its early stages. However, in its late stages, 5-year and 10-year survival rates in the US average 15-20 per cent and 10-15 per cent, respectively.