Nivolumab Extends Survival in Phase III Melanoma Study

Caroline Robert, MD

Frontline treatment with nivolumab (Opdivo) significantly extended overall survival (OS) and progression-free survival (PFS), when compared with dacarbazine in patients with untreated BRAF wild-type advanced melanoma, according to the phase III CheckMate-066 study presented at the 2014 Society for Melanoma Research Congress.

In the 418-patient phase III study, 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 results from CheckMate-066 are significant as they represent the first time a PD-1 immune checkpoint inhibitor has shown a survival benefit in a randomized phase III trial,” Caroline Robert, MD, PhD, a professor of dermatology and the head of the Dermatology Unit at the Institute Gustave Roussy, said in a statement. “This represents a major milestone in the study of treatment naïve patients with wild-type BRAF advanced melanoma.”

In the phase III study, 418 patients were randomized in a 1:1 ratio to receive intravenous nivolumab at 3 mg/kg every two weeks (n = 210) or dacarbazine at 1000 mg/m2 IV every three 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.

"Treatment naïve advanced melanoma patients who received nivolumab in this study had clinically important improvements in both overall survival and objective response rates compared to dacarbazine,” Georgina V. Long, MD, PhD, from the Melanoma Institute Australia & the University of Sydney and Mater Hospital, said in a press release. “This study also confirms our hypothesis on the role of PD-L1 expression in advanced melanoma. In CheckMate-066, both PD-L1-positive and -negative patients treated with nivolumab had a clear survival benefit.”

Nivolumab is currently being explored as a monotherapy and in combination across a variety of tumor types. To date, according to the drug's manufacturer Bristol-Myers Squibb (BMS), more than 7,000 patients are receiving treatment with nivolumab in a clinical trial.

On September 26, 2014, the FDA granted a priority review designation to nivolumab as a potential therapy for pretreated patients with advanced melanoma. Under this review program, the FDA is scheduled to make a decision on the drug by March 30, 2015.

This application was based on findings from the CheckMate-037 trial that compared nivolumab to dacarbazine or carboplatin plus paclitaxel in previously treated patients with advanced melanoma. In this study, the ORR was 32% in the nivolumab arm versus 11% in the chemotherapy arm. With nivolumab, the complete response rate was 3%, partial response rate was 28%, and 23% of patients experienced stable disease.

In 2013, the FDA granted a fast track designation to nivolumab as a treatment for patients with non-small cell lung cancer (NSCLC). In April 2014, BMS announced that it planned to initiate a rolling submission for nivolumab as a third-line treatment for patients with squamous cell NSCLC. This submission is expected to be complete by the end of the year.