Nivolumab plus Ipilimumab Regimen Receives Expanded FDA Approval in Unresectable or Metastatic Melanoma Across BRAF Status

FDA also expands use of nivolumab as single-agent to include previously untreated BRAF mutation-positive advanced melanoma patients, based on accelerated approval

On 23 January, Bristol-Myers Squibb Company announced that the US Food and Drug Administration (FDA) has approved nivolumab (Opdivo) in combination with  ipilimumab (Yervoy) for the treatment of patients with BRAF V600 wild-type and BRAF V600 mutation-positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

This approval expands the original indication for the nivolumab plus ipilimumab regimen for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma to include patients, regardless of BRAF mutational status, based on data from the phase III CheckMate-067 trial, in which PFS and overall survival (OS) were co-primary endpoints. It is the first and only FDA-approved combination of immune checkpoint inhibitors.

The FDA also expanded the use of nivolumab as a single-agent to include previously untreated BRAF mutation-positive advanced melanoma patients. The use of nivolumab as a single-agent in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma is approved under accelerated approval based on PFS. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Nivolumab was approved by the FDA in November 2015, for use in previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma.

Expanded approval based on efficacy demonstrated in a phase III trial

CheckMate-067 is a phase III, double-blind, randomised study that evaluated the nivolumab plus ipilimumab regimen or nivolumab monotherapy vs. ipilimumab monotherapy in patients with previously untreated advanced melanoma. The trial evaluated previously untreated patients, including both BRAF V600 mutant and wild-type advanced melanoma, and enrolled 945 patients who were randomised to receive the nivolumab plus ipilimumab regimen (n=314), nivolumab monotherapy (n=316) or ipilimumab monotherapy (n=315).

Patients were treated until progression or unacceptable toxic effects. The median duration of exposure was 2.8 months (range: 1 day to 18.8 months) for patients in the combined regimen arm with a median of four doses (range: 1 to 39 for nivolumab, 1 to 4 for ipilimumab), and 6.6 months (range: 1 day to 17.3 months) duration for the nivolumab monotherapy arm with a median of 15 doses (range: 1 to 38). The co-primary endpoints were PFS and OS; the study is ongoing and patients continue to be followed for OS.

Results from the trial demonstrated a statistically significant improvement in PFS in patients with advanced melanoma treated with the nivolumab plus ipilimumab regimen (p<0.0001) and with nivolumab as a single-agent (p<0.0001) vs. ipilimumab monotherapy. Median PFS was 11.5 months for the nivolumab plus ipilimumab regimen and 6.9 months for nivolumab monotherapy, vs. 2.9 months for ipilimumab monotherapy. The combined regimen demonstrated a 58% reduction in the risk of disease progression vs. ipilimumab (HR: 0.42; p<0.0001), while nivolumab monotherapy demonstrated a 43% risk reduction vs. ipilimumab monotherapy (HR: 0.57; p<0.0001).

In addition, the nivolumab plus ipilimumab regimen and nivolumab monotherapy demonstrated higher confirmed objective response rates (ORR; 50% and 40%; p<0.0001, respectively) vs. ipilimumab monotherapy (14%). The percentage of patients with a complete response was 8.9%, 8.5% and 1.9%, favouring the combined regimen and nivolumab monotherapy over ipilimumab monotherapy. Partial responses were seen in 41% of patients treated with the nivolumab plus ipilimumab regimen, 31% of patients treated with nivolumab monotherapy, and 12% of patients treated with ipilimumab monotherapy. The nivolumab plus ipilimumab regimen delivered durable responses, with three of four (76%) patients experiencing an ongoing response of at least six months (range: 1.2+ to 15.8+). Of patients in the nivolumab monotherapy and ipilimumab monotherapy arms, 74% and 63% experienced an ongoing response of at least six months, respectively (ranges: 1.3+ to 14.6+; 1.0+ to 13.8+).

In CheckMate-067, serious adverse reactions (73% and 37%), adverse reactions leading to discontinuation (43% and 14%), or to dosing delays (55% and 28%), and grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the nivolumab plus ipilimumab arm relative to the nivolumab arm. No overall differences in safety or efficacy were reported between elderly and younger patients.

The most common adverse reactions leading to discontinuation of the nivolumab plus ipilimumab regimen relative to nivolumab as a single-agent were diarrhoea (8% and 1.9%), colitis (8% and 0.6%), increased ALT (4.8% and 1.3%), increased AST (4.5% and. 0.6%), and pneumonitis (1.9% and 0.3%).

The most frequent (≥10%) serious adverse reactions in the nivolumab plus ipilimumab arm and the nivolumab arm, respectively, were diarrhoea (13% and 2.6%), colitis (10% and 1.6%) and pyrexia (10% and 0.6%).

The most common adverse reactions (≥20%) reported in patients receiving the nivolumab plus ipilimumab regimen relative to nivolumab as a single-agent were fatigue (59% and 53%), rash (53% and 40%), diarrhoea (52% and 31%), and nausea (40% and 28%). Pyrexia (37%), vomiting (28%) and dyspnoea (20%) were also reported in ≥20% of patients receiving the nivolumab plus ipilimumab regimen.

Dual immune checkpoint inhibition

Nivolumab and ipilimumab are immune checkpoint inhibitors that target separate, distinct and complementary checkpoint pathways (PD-1 and CTLA-4). The mechanism of action involves dual immune checkpoint inhibition resulting in increased anti-tumour activity. Ipilimumab blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, while nivolumab restores the active T-cell response directed at the tumour. This may affect healthy cells and result in immune-mediated adverse reactions, which can be severe and potentially fatal.