Nivolumab Effective in Metastatic Melanoma Regardless of Prior Treatment

Treatment with the PD-1 inhibitor nivolumab demonstrated similar efficacy regardless of prior treatment with a BRAF inhibitor or ipilimumab in patients with BRAF mutant or wild type metastatic melanoma.

James Larkin, MD, PhD

The PD-1 inhibitor nivolumab demonstrated similar efficacy regardless of prior treatment with a BRAF inhibitor or ipilimumab in patients withBRAFmutant or wild type metastatic melanoma, according to a pooled analysis of four studies published inJAMA Oncology.

"This pooled analysis represents the largest dataset available to date to evaluate the efficacy and safety of nivolumab in wild-type and mutantBRAFpatients with metastatic melanoma," James Larkin, MD, PhD, from the Royal Marsden Hospital, and colleagues wrote. "Within the limitations of this retrospective analysis, the data suggest that nivolumab has activity in patients with wild-typeBRAFand in patients with mutantBRAF, consistent with findings of previous retrospective analyses of ipilimumab monotherapy and a phase I study of concurrent nivolumab and ipilimumab."

The retrospective study analyzed data from 440 patients with unresectable stage III or stage IV melanoma from four pooled clinical trials. Overall, 334 patients wereBRAFwild type and 106 wereBRAF V600mutation-positive.

Across the studies, intravenous nivolumab was administered at doses of 0.1, 0.3, 1.0, 3.0, or 10.0 mg/kg every 2 weeks. Most patients (83%) received nivolumab at 3 mg/kg. In total, 62% of those withBRAFmutations were treated with a BRAF inhibitor and 65% of all patients had received prior ipilimumab.

In evaluable patients, the objective response rate (ORR) was 34.6% in those with wild-typeBRAFstatus (n = 217) and 29.7% in those withBRAFmutations (n = 74). In untreated patients withBRAF-positive tumors the ORR was 33.1% versus 24.5% in BRAF inhibitor-treated patients.

"Nivolumab monotherapy may be an effective treatment for mutantBRAFpatients regardless of whether they have previously received a BRAF inhibitor," the authors wrote.

The median duration of response was 14.8 months in patients with wild-typeBRAFmelanoma and 11.2 months forBRAF-positive tumors. The median time to a response was 2.2 months in both arms.

In patients withBRAFmutations, those treated with prior ipilimumab had an ORR of 25% compared with 38.9% in those who had not received ipilimumab. For those with wild-typeBRAFtumors, the ORR was 36% in ipilimumab-treated patients and 30.8% in untreated patients.

Patients in theBRAFwild-type and positive arms experienced responses with nivolumab, regardless of PD-L1 status. In those withBRAFwild-type PD-L1-positive tumors, the ORR was 53.8%. The lowest response (22.2%) was seen in patients withBRAFwild-type PD-L1-negative disease.

"The objective response rates did not seem to be affected by prior BRAF inhibitor therapy, prior ipilimumab therapy, or PD-L1 status of the tumor," the authors noted.

All-grade adverse events were apparent in 68.3% of patients with wild-typeBRAFtumors and in 58.5% of those in the mutantBRAFgroup. Grade 3/4 adverse events were less common those withBRAFmutations compared with those without (2.8% vs 11.7%).

"These findings may have implications for the sequencing of BRAF/MEK inhibitors with immune checkpoint inhibitors," the authors wrote. "Further prospective studies will be required to determine the optimal treatment schedule for BRAF/MEK inhibitors and immune checkpoint inhibitors in advanced melanoma."

Larkin J, Lao CD, Urba WJ, et al. Efficacy and Safety of Nivolumab in Patients With BRAF V600 Mutant and BRAF Wild-Type Advanced Melanoma: A Pooled Analysis of 4 Clinical Trials.JAMA Oncol. Published online May 21, 2015. doi:10.1001/jamaoncol.2015.1184.