Bristol-Myers Squibb Company (NYSE: BMY) today announced that Opdivo (nivolumab) 3 mg/kg plus Yervoy (ipilimumab) 1 mg/kg (injections for intravenous use) was approved by the U.S. Food and Drug Administration (FDA) as the first Immuno-Oncology combination therapy for previously untreated patients with intermediate- and poor-risk advanced renal cell carcinoma (RCC).1,2 In the Phase 3 CheckMate -214 clinical trial, the Opdivo + Yervoy combination demonstrated a significant and unprecedented increase in overall survival (OS) in this patient population compared to a current standard of care, sunitinib. An OS benefit was observed regardless of PD-L1 expression level.1,2,3 Opdivo + Yervoy also delivered durable responses, with a higher objective response rate (ORR) compared to sunitinib.1,2 Patients in the CheckMate -214 trial received four cycles of the Opdivo + low-dose Yervoy combination, followed by Opdivo maintenance therapy.1,2 In the combination arm of the trial, 79% of patients received all four doses of Opdivo + Yervoy and went on to the Opdivo monotherapy phase.4 Flexible dosing options are available during the Opdivo maintenance phase (480 mg infused every four weeks or 240 mg infused every two weeks).

“Our goal is to provide cancer patients with medicines that have the potential to extend their lives. As the first treatment option to increase overall survival for subgroups of patients with advanced RCC compared to sunitinib, the Opdivo plus low-dose Yervoy combination helps deliver on that promise,” said Johanna Mercier, head, U.S. Commercial, Bristol-Myers Squibb. “This approval demonstrates our commitment to bringing Immuno-Oncology treatments that may improve outcomes to a broader range of RCC patients.”

Opdivo is associated with the following Warnings and Precautions: immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion reactions; and embryo-fetal toxicity. Please see the Important Safety Information section below, including Boxed WARNING for Yervoy regarding immune-mediated adverse reactions.1,2

Results from the CheckMate -214 trial in patients with previously untreated intermediate- and poor-risk advanced RCC include:

Overall Survival: Opdivo + Yervoy reduced the risk of death by 37% versus sunitinib (hazard ratio [HR] 0.63; 99.8% confidence interval [CI]: 0.44 to 0.89; p<0.0001).1,2 The median OS was not yet reached for Opdivo + Yervoy (95% CI: 28.2 to not estimable [NE]) and was 25.9 months for sunitinib (95% CI: 22.1 to NE).1,2,3

Objective Response Rate: Opdivo + Yervoy was associated with a 41.6% ORR (95% CI: 36.9 to 46.5; p<0.0001; n=177/425) versus 26.5% for sunitinib (95% CI: 22.4 to 31.0; n=112/422).1,2

Complete and Partial Response Rates: The complete response (CR) rate was 9.4% for Opdivo + Yervoy (n=40/425) and 1.2% for sunitinib (n=5/422), and the partial response (PR) rate was 32.2% for Opdivo + Yervoy (n=137/425) and 25.4% for sunitinib (n=107/422).1,2

Duration of Response: Among patients who responded, median duration of response (durability) for Opdivo + Yervoy was not yet reached (95% CI: 21.8 to NE), compared to 18.2 months for sunitinib (95% CI: 14.8 to NE).1,2

Progression-Free Survival: Progression-free survival (PFS) was 11.6 months for the Opdivo + Yervoy combination, compared to 8.4 months for sunitinib (HR 0.82; 99.1% CI: 0.64 to 1.05; p=not significant), which did not reach statistical significance.1,2

Among those with advanced RCC, 75% to 80% have one or more risk factors and are considered intermediate- and poor-risk patients according to International Metastatic Renal Cell Carcinoma Database Consortium criteria.5,6 These patients historically had a poor prognosis, and although there have been a number of treatment advances over the past decade, additional options to improve overall survival are still needed.7,8 Currently, only 36% of patients with advanced RCC survive beyond one year, and only 8% will live past five years.7,9

“Physicians treating advanced RCC have had few options to help achieve the goal of improved survival,” said Robert J. Motzer, M.D., medical oncologist, Jack and Dorothy Byrne chair in clinical oncology, Memorial Sloan Kettering Cancer Center. “Data from the CheckMate -214 trial demonstrated superior overall survival with Opdivo + Yervoy, showing the potential for the combination to become a new standard of care for patients with intermediate- and poor-risk advanced RCC. What's more, the combination resulted in fewer overall Grade 3 and 4 adverse reactions compared to sunitinib. Because of these encouraging results, we now have a new treatment option for newly diagnosed advanced RCC patients across PD-L1 expression levels.”

In CheckMate -214, the combination was associated with fewer overall Grade 3 or 4 adverse events than sunitinib (65% versus 76%).1,2 Treatment discontinuation due to adverse events occurred in 31% of patients in the Opdivo + Yervoy arm, compared to 21% in the sunitinib arm. Fifty-four percent (54%) of patients receiving Opdivo + Yervoy and 43% of patients receiving sunitinib had a dose delay for an adverse reaction. In the sunitinib group, 53% of patients required a dose reduction, which was not permitted for patients treated with the Opdivo + Yervoy combination. Serious adverse reactions occurred in 59% of patients receiving Opdivo + Yervoy and in 43% of patients receiving sunitinib.1,2

“Kidney cancer is the deadliest of all urological cancers, and too many patients are faced with this grim diagnosis,” said Dena Battle, president, KCCure. “Today’s approval of Opdivo + Yervoy for advanced RCC has the potential to transform the first-line treatment landscape for kidney cancer. But for patients, it is more than just a new therapy option – it represents hope for a longer life.”

Approval Based on CheckMate -214 Trial: Demonstrating Superior Overall Survival and Objective Response Rate vs. Sunitinib

CheckMate -214 is a Phase 3, randomized, open-label study evaluating the combination of Opdivo + Yervoy versus sunitinib in patients with previously untreated advanced RCC. In the intermediate- and poor-risk study population, 425 patients received Opdivo 3 mg/kg plus Yervoy 1 mg/kg every three weeks for four doses, followed by Opdivo 3 mg/kg every two weeks, and 422 patients received sunitinib 50 mg once daily for four weeks, followed by two weeks off every cycle.1,2 The recommended dosing for the Opdivo + Yervoy combination is Opdivo 3 mg/kg followed by Yervoy 1 mg/kg each infused intravenously over 30 minutes on the same day every three weeks for four doses. After completing four doses of the combination, Opdivo should be administered intravenously 240 mg every two weeks or 480 mg every four weeks over 30 minutes until disease progression or unacceptable toxicity.1,2

The primary efficacy outcome measures of the trial were OS, ORR (CR+PR) and PFS as determined by an independent radiographic review committee (IRRC) in intermediate- and poor-risk patients. Patients were included regardless of their PD-L1 status.1,2 Data from CheckMate -214 were presented at the European Society for Medical Oncology Congress in September 2017 and the Society for Immunotherapy of Cancer Annual Meeting in November 2017 and were published in the New England Journal of Medicine in March 2018.3,10,11

Select Safety Profile for the CheckMate -214 Trial

The most frequent serious adverse reactions reported in at least 2% of patients receiving Opdivo + Yervoy were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency and colitis. The most common adverse reactions (≥20%) reported in patients receiving Opdivo + Yervoy were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%) and vomiting (20%).1,2