FDA Grants Priority Review to Frontline Nivolumab in Melanoma

The FDA has assigned a priority review designation to the PD-1 inhibitor nivolumab (Opdivo) as a treatment for previously untreated patients with unresectable or metastatic melanoma. Under the expedited process, the action date for the FDA’s decision is August 27, 2015.

The application was based on phase III data from the CheckMate-066 trial, in which nivolumab significantly extended overall survival (OS) and progression-free survival (PFS) when compared with dacarbazine in patients with untreated BRAF wild-type advanced melanoma.

In CheckMate-066, treatment with nivolumab improved OS by 58% and PFS by 57% compared with dacarbazine. In PD-L1-positive patients, OS was improved by 70% and the objective response rate (ORR) was 52.7% versus 10.8%, for nivolumab and dacarbazine, respectively. Moreover, grade 3/4 side effects were less common in the nivolumab arm.

“The CheckMate-066 trial marked the first time that a PD-1 immune checkpoint inhibitor showed a survival benefit in a randomized phase III trial,” Michael Giordano, MD, senior vice president, head of Development, Oncology, Bristol-Myers Squibb (BMS), the developer of nivolumab, said in a statement.

CheckMate-066 randomized 418 patients in a 1:1 ratio to receive intravenous nivolumab at 3 mg/kg every 2 weeks (n = 210) or dacarbazine at 1000 mg/m² IV every 3 weeks (n = 208). Of the patients enrolled, 61% had stage M1c disease, 36.6% had an elevated lactate dehydrogenase level, and 35.4% were PD-L1 positive, which was defined as ≥5% total membrane staining in tumor cells.

The primary endpoint of the study was OS, with secondary endpoints focused on PFS, ORR, quality of life, and whether PD-L1 expression was an effective predictive biomarker for OS. The study allowed investigators to continue treatment beyond initial progression in patients showing clinical benefit and tolerating therapy, to allow for pseudoprogression commonly seen with checkpoint inhibitors.

According to findings published in The New England Journal of Medicine, the 1-year OS rate was 72.9% with nivolumab compared with 42.1% in the dacarbazine arm (HR = 0.42; 99.79% CI, 0.25-0.73; P <.001). The median PFS was 5.1 versus 2.2 months, in the nivolumab and dacarbazine arms, respectively (HR = 0.43; 95% CI, 0.34-0.56; P <.001). The ORR was 40% with nivolumab versus 13.9% with dacarbazine (odds ratio = 4.06; P <.001).

All-grade treatment-related adverse events occurred in 74.3% of patients with nivolumab versus 75.6% with dacarbazine. However, grade 3/4 adverse events were less common with nivolumab compared with dacarbazine (11.7% versus 17.6%, respectively). The most common nivolumab-related side effects were fatigue (19.9%), pruritus (17%), and nausea (16.5%).

Treatment with nivolumab was found to extend OS, regardless of PD-L1 status. In patients with PD-L1-positive tumors, the HR for OS was 0.30, favoring nivolumab. In those with PD-L1-negative disease, the HR for OS was 0.48. The median OS was not reached in patients treated with nivolumab. In the dacarbazine arm, patients with PD-L1-positive disease experienced a longer median OS, at 12.4 months versus 10.2 months.

Nivolumab has FDA-approved indications for unresectable or metastatic melanoma following treatment with ipilimumab (Yervoy) or a BRAF inhibitor, as well as for advanced squamous non—small cell lung cancer that has progressed during or following platinum-based chemotherapy.

The PD-1 inhibitor has also shown promise as part of a combination regimen in the frontline melanoma setting. In results from the phase II CheckMate-069 trial, which were recently presented at the 2015 AACR Annual Meeting and simultaneously published online in The New England Journal of Medicine, adding nivolumab to ipilimumab delayed disease progression by 60% compared with ipilimumab alone in treatment-naïve patients with advanced melanoma.

Discussing BMS’s plans for the current regulatory review of single-agent nivolumab in the frontline melanoma setting, Giordano said, “We look forward to continuing to work with the FDA to ensure cancer patients are provided the latest clinical advances that have the potential for improved responses and long-term survival.”