FDA Delays Decision on Frontline Nivolumab in Melanoma


The FDA has extended the review period for frontline nivolumab in patients with advanced melanoma by 3 months, to allow ample time to review additional data submitted by the PD-1 inhibitor's developer Bristol-Myers Squibb.

Michael Giordano, MD

The FDA has extended the review period for frontline nivolumab (Opdivo) in patients with advanced melanoma by 3 months, to allow ample time to review additional data submitted by the PD-1 inhibitor's developer Bristol-Myers Squibb (BMS). The updated action date for the new indication is November 27, 2015.

Nivolumab initially received a priority review designation for the new indication on April 30, 2015, based on the phase III CheckMate-066 trial that explored nivolumab in untreated patients with BRAF wild-type advanced melanoma. The new data hope to support an approval that is irrespective of BRAF status, BMS indicated.

“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, BMS, said when the FDA initially accepted the application. “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.”

In the CheckMate-066 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 overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rates (ORR), and quality of life.

According to findings published in The New England Journal of Medicine,1 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%).

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 PFS and OS.

At ≥9 months’ 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.2 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.

Wolchok noted that OS data from the CheckMate-067 trial are “not expected to be reported until 22 months of follow-up, so we’re quite a ways away from that.”

In late June 2015, the European Commission approved nivolumab as a treatment for patients with advanced melanoma in the first- and later-line settings regardless of BRAF mutation status, making it the first PD-1 inhibitor to gain approval in Europe. In the United States, nivolumab is currently FDA-approved for the treatment of patients with unresectable or metastatic melanoma following treatment with ipilimumab or a BRAF inhibitor.

In addition to melanoma, the FDA approved nivolumab in March 2015 as a treatment for patients with metastatic squamous non-small cell lung cancer (NSCLC) following a platinum-based chemotherapy, based on the open-label CheckMate-017 study. In addition to this indication, nivolumab improved OS by 27% in patients with non-squamous NSCLC in the CheckMate-057 study. An approval in this setting is anticipated.


  1. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320-330.
  2. 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.

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