FDA Approves Frontline Nivolumab for Advanced Melanoma

Jeffrey S. Weber, MD, PhD

The FDA has expanded the approval for single-agent nivolumab (Opdivo) to include the frontline treatment of patients with BRAF wild-type advanced melanoma, based on a substantial improvement in overall survival (OS) compared with dacarbazine in a phase III study.

In data from the CheckMate-066 trial assessed by the FDA, median OS with nivolumab was not reached versus 10.8 months for dacarbazine, representing a 58% reduction in the risk of death (HR, 0.42; 95% CI, 0.30-0.60; P <.0001). Median progression-free survival (PFS) with nivolumab was 5.1 versus 2.2 months for dacarbazine (HR, 0.43; 95% CI, 0.34-0.56; P <.0001).

"Advanced melanoma continues to be one of the deadliest and most challenging cancers to treat, and ongoing research in Immuno-Oncology from clinical trials like CheckMate -066 shows the potential to provide improved overall survival for newly diagnosed patients with BRAF wild-type metastatic melanoma,” Jeffrey S. Weber, MD, PhD, deputy director of the Laura and Isaac Perlmutter Cancer Center at the NYU Langone Medical Center, said in a statement. “This important news means that we now have another new option to offer patients with BRAF wild-type metastatic melanoma.”

In the phase III trial, 418 untreated patients were randomized in a 1:1 ratio to receive nivolumab at 3 mg/kg every 2 weeks (n = 210) or dacarbazine at 1000 mg/m² every 3 weeks (n = 208). Of the patients enrolled, 61% had stage M1c disease and 36.6% had an elevated lactate dehydrogenase level. The primary endpoint of the study was OS. Secondary endpoints included PFS, objective response rates (ORR), and quality of life.

In updated data presented at the 2015 Society for Melanoma Research Congress, the 2-year OS rate with frontline nivolumab was 57.7% compared with 26.7% for dacarbazine. After a minimum follow-up of 15.1 months, median OS was not yet reached for patients receiving nivolumab compared with 11.2 months in the dacarbazine arm (HR, 0.43; 95% CI, 0.33-0.57; P <.001). The 1-year OS rates were 70.7% and 46.3%, for nivolumab and dacarbazine, respectively.

Following a positive interim analysis by an independent data monitoring committee, the study was unblinded to allow those in the chemotherapy arm to receive the PD-1 inhibitor. Following progression in the dacarbazine arm, 13% of patients (n = 27) went on to receive nivolumab.

In the update data, the median PFS was 5.4 months with nivolumab versus 2.2 months for dacarbazine (HR, 0.42; 95% CI, 0.32-0.53; P <.001). With nivolumab, the 1- and 2-year PFS rates were consistent, at 44.3% and 39.2%, respectively.

The ORR was 42.9% with nivolumab versus 14.4% with dacarbazine. A complete response was achieved by 11% of patients with nivolumab compared with 1% for dacarbazine. At the analysis, 81% of responses in the nivolumab arm remained ongoing.

All-grade adverse events (AEs) were similar between each arm but grade ≥3 AEs were less common with nivolumab (13% vs 17%). The most frequently reported all-grade AEs in patients treated with nivolumab were pruritus (22%), diarrhea (18%), and rash (18%). Altogether, AEs led to discontinuation in just 6% of patients in the nivolumab arm.

"Our focused approach to Immuno-Oncology research is to deliver treatment options that have the potential to improve long-term survival outcomes for patients,” Michael Giordano, MD, senior vice president, head of Oncology Development, Bristol-Myers Squibb, said in a statement. “Opdivo has become a critical part of the treatment landscape for advanced melanoma patients and their physicians, both as a monotherapy and in combination, and we are committed to exploring opportunities for this treatment across stages of disease and lines of therapy.”

Earlier this year, nivolumab was also approved in combination with ipilimumab for patients with advanced melanoma. A number of studies continue to assess nivolumab in various combinations for patients with melanoma and other types of cancer. A phase I/II study is looking at nivolumab with the anti-CD27 antibody varlilumab (NCT02335918). Additionally, a phase II/III study is exploring nivolumab and ipilimumab with the GM-CSF agent sargramostim (NCT02339571).

In addition to melanoma, the FDA has approved nivolumab as a treatment for patients with metastatic non-small cell lung cancer following a platinum-based chemotherapy regardless of histology or PD-L1 status and for patients with renal cell carcinoma following frontline antiangiogenic therapy. The frontline monotherapy indication marks the sixth approval for nivolumab.

Two-Year Survival and Safety Update in Patients (pts) with Treatment-Naïve Advanced Melanoma (MEL) Receiving Nivolumab (NIVO) or Dacarbazine (DTIC) in CheckMate-066. Presented at the Society for Melanoma Research 2015 International Congress; November 18-21, 2015; San Francisco, CA.