FDA Issues Complete Response Letter for Nivolumab in BRAF-Mutant Melanoma

The FDA has issued a complete response letter to Bristol-Myers Squibb informing the company that additional data were needed for its supplemental biologics license application (sBLA) for the use of single-agent nivolumab (Opdivo) in previously untreated patients with BRAF V600 mutation-positive advanced melanoma. The application was based on the CheckMate-066 trial and additional data for a BRAF-positive group.

In August 2015, an application for frontline nivolumab in patients with BRAF-wild type melanoma was delayed by 3 months, following the submission of data for the BRAF-mutant population. Following this delay, on November 23, 2015, the FDA approved nivolumab for the frontline BRAF wild-type indication; however, a decision was not handed down for the BRAF-positive group.

"As part of the complete response letter, the FDA indicated the need for additional data in the BRAF-mutated patient population," according to a statement released by the company. "Bristol-Myers Squibb is working to evaluate the request outlined by the FDA and will continue to work closely with the agency to determine whether additional data, currently under review, adequately addresses these comments."

A separate sBLA was also submitted for BRAF-mutant advanced melanoma, based on phase III data from the CheckMate-067 trial. This application was granted a priority review, with a decision deadline of January 23, 2016. "Data for Opdivo monotherapy in both BRAF wild-type and BRAF V600 mutation-positive advanced melanoma was included as part of this application," according to the company.

In the CheckMate-067 study, 945 patients with untreated unresectable or metastatic melanoma were randomized to receive nivolumab (n = 316), ipilimumab (n = 315), or nivolumab plus ipilimumab followed by nivolumab (n = 314). In this frontline study, approximately a third of patients were BRAF mutation-positive. The co-primary endpoints were progression-free survival (PFS) and overall survival (OS).

At ≥9 months of follow-up, the median PFS was 11.5 months for the combination and 6.9 months for nivolumab monotherapy compared with 2.9 months for single-agent ipilimumab. The combination reduced the risk of progression by 58% compared with ipilimumab (HR, 0.42; P <.0001). Single-agent nivolumab reduced the risk of progression by 43% versus ipilimumab (HR, 0.57; P <.00001).

Outcomes were similar regardless of BRAF mutation status. For those with BRAF-mutations treated with single-agent nivolumab (n = 98), the median PFS was 5.6 months compared with 4.0 months with single-agent ipilimumab (n = 100; HR, 0.77; 95% CI, 0.54-1.09). In those with wild-type BRAF melanoma treated with nivolumab (n = 218), the median PFS was 7.9 versus 2.8 months with ipilimumab (HR, 0.50; 95% CI, 0.39-0.63).

For those with BRAF mutations treated with the combination of nivolumab and ipilimumab (n = 102), the median PFS was 11.7 months, representing a 53% reduction in the risk of progression versus ipilimumab (HR, 0.47; 95% CI, 0.32-0.68). For patients with BRAF wild-type disease (n = 212), the median PFS with the combination was 11.2 months (HR versus ipilimumab, 0.41; 95% CI, 0.32-0.53).

“Nivolumab alone and nivolumab with ipilimumab significantly improved progression-free survival compared to ipilimumab alone in patients with previously untreated melanoma," lead author Jedd Wolchok, MD, PhD, chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center, said when the results were presented at the 2015 ASCO Annual Meeting.

Earlier this year, nivolumab was approved in combination with ipilimumab as a treatment for patients with BRAF V600 wild-type unresectable or metastatic 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).

"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 when nivolumab was approved for BRAF wild-type melanoma. “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.”

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 marked the sixth indication for nivolumab.

Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373:23-34.