The FDA has assigned a priority review designation to Opdivo (nivolumab) as a treatment for previously untreated patients with unresectable or metastatic melanoma.
The FDA has assigned a priority review designation to Opdivo (nivolumab) 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 3 data from the CheckMate-066 trial, in which Opdivo significantly extended overall survival (OS) and progression-free survival (PFS) when compared with dacarbazine (chemotherapy) in patients with untreated BRAF wild-type advanced melanoma.
In CheckMate-066, treatment with Opdivo improved OS by 58 percent and PFS by 57 percent compared with dacarbazine. In PD-L1-positive patients, OS was improved by 70 percent and the objective response rate (ORR) was 52.7 percent versus 10.8 percent, for Opdivo and dacarbazine, respectively. Moreover, grade 3/4 side effects were less common in the Opdivo arm.
“The CheckMate-066 trial marked the first time that a PD-1 immune checkpoint inhibitor showed a survival benefit in a randomized phase 3 trial,” Michael Giordano, MD, senior vice president, head of Development, Oncology, Bristol-Myers Squibb (BMS), the developer of Opdivo, said in a statement.
CheckMate-066 randomized 418 patients in a 1:1 ratio to receive intravenous Opdivo 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 percent had stage M1c disease, 36.6 percent had an elevated lactate dehydrogenase level, and 35.4 percent were PD-L1 positive, which was defined as ≥5 percent 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 percent with Opdivo compared with 42.1 percent in the dacarbazine arm (HR = 0.42; 99.79 percent CI, 0.25-0.73; P <.001). The median PFS was 5.1 versus 2.2 months, in the Opdivo and dacarbazine arms, respectively (HR = 0.43; 95 percent CI, 0.34-0.56; P <.001). The ORR was 40 percent with Opdivo versus 13.9 percent with dacarbazine (odds ratio = 4.06; P <.001).
All-grade treatment-related adverse events occurred in 74.3 percent of patients with Opdivo versus 75.6 percent with dacarbazine. However, grade 3/4 adverse events were less common with Opdivo compared with dacarbazine (11.7 percent versus 17.6 percent, respectively). The most common Opdivo-related side effects were fatigue (19.9 percent), pruritus (17 percent), and nausea (16.5 percent).
Treatment with Opdivo 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 Opdivo. In those with PD-L1-negative disease, the HR for OS was 0.48. The median OS was not reached in patients treated with Opdivo. In the dacarbazine arm, patients with PD-L1-positive disease experienced a longer median OS, at 12.4 months versus 10.2 months.
Opdivo has FDA-approved indications for unresectable or metastatic melanoma following treatment with Yervoy (ipilimumab) 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 2 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 Opdivo to Yervoy delayed disease progression by 60 percent compared with Yervoy alone in treatment-naïve patients with advanced melanoma.
Discussing BMS’s plans for the current regulatory review of single-agent Opdivo in the frontline melanoma setting, Giordano says, “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.”