Nivolumab, ipilimumab combination improves PFS in advanced melanoma regardless of prognostic factors

Issue: November 25, 2015

The immunotherapeutic combination of nivolumab and ipilimumab prolonged PFS among patients with advanced melanoma regardless of age, presence of metastases or BRAF status, according to phase 3 study results presented at the European Cancer Congress.

Because nivolumab (Opdivo, Bristol-Myers Squibb) is a PD-1 inhibitor and ipilimumab (Yervoy, Bristol-Myers Squibb) is a CTLA-4 inhibitor, a combination of the agents activates the immune system on two different pathways. Previous data from CheckMate 067 showed the combination improved PFS in treatment-naive patients with melanoma. However, this subset analysis demonstrated for the first time that the combination improved outcomes regardless of patient age, BRAF status or the stage of the disease.

“Results from our large analysis of predefined subgroups of patients with advanced melanoma provide evidence that suggests the combination of the two drugs consistently improves PFS across a range of subgroups, including patients with poor prognostic factors, when compared with either nivolumab or ipilimumab alone,” James Larkin, MD, a consultant medical oncologist at The Royal Marsden in London, said in a press release.

Researchers randomly assigned 945 treatment-naive patients with melanoma from 20 countries 1:1:1 to nivolumab (3 mg/kg biweekly) plus placebo, ipilimumab (3 mg/kg every 3 weeks) plus placebo, or nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg every 3 weeks).

In the entire cohort, patients assigned the combination achieved a median PFS of 11.5 months (95% CI, 8.9-16.7), which represented a significant improvement compared with a 6.9-month (95% CI, 4.3-9.5) median PFS in the nivolumab arm (HR = 0.57; P < .00001) and 2.9-month (95% CI, 2.8-3.4) median PFS in the ipilimumab arm (HR = 0.42; P < .00001).

Researchers then conducted subset analyses based on prognostic factors.

In patients with wild-type BRAF V600 (n = 645), the median PFS was 11.2 months (95% CI, 8.3-not reached [NR]) in the combination cohort compared with 7.9 months (95% CI, 4.9-12.7) in the nivolumab alone cohort and 2.8 months (95% CI, 2.8-3.1) in the ipilimumab alone cohort.

Among patients with the BRAF V600 gene mutation (n = 300), the median PFS was 11.7 months (95% CI, 8.0-NR) for those assigned the combination compared with 5.6 months (95% CI, 2.8-9.5) for those assigned nivolumab alone and 4 months (95% CI, 2.8-5.5) for those assigned ipilimumab alone.

“These results provide evidence that the efficacy of the combination therapy is similar whether or not the tumors harbor BRAF mutations,” Larkin said in the release. “This has important practical implications for clinicians treating patients with melanoma.”

The data also indicated similar patterns regarding disease stage. Among patients with metastatic melanomas and a poor prognosis (stage M1c; n = 559), median PFS was 8.5 months (95% CI, 5.5-12.4) for those assigned the combination compared with 5.4 months (95% CI, 2.8-8.9) for nivolumab alone and 2.8 months (95% CI, 2.7-2.8) for ipilimumab alone.

Data appeared similar regarding age for the combination (age ˂ 65 years, 11.7 months; 95% CI, 7-NR; 65 to 75 years, 11.1 months; 95% CI, 8.3-14), nivolumab alone (age ˂ 65 years, 5.5 months; 95% CI, 3-8.3; 65 to 75 years, 12.7 months; 95% CI, 6.7-NR) and ipilimumab alone (age ˂ 65 years, 2.8 months; 95% CI, 2.8-3.1; 2.9 months; 95% CI, 2.7-3.9). Median PFS had not yet been reached for patients aged 75 years or older but was 5.3 months (95% CI, 2.6-NR) for nivolumab alone and 4 months (95% CI, 2.8-6.9) for ipilimumab alone.

The most common adverse events included diarrhea, colitis and increased levels of alanine aminotransferase. Grade 3 to grade 4 treatment-related adverse events occurred in 55% of the patients treated with the combination compared with 16% for nivolumab alone and 27% for ipilimumab alone. The incidence of adverse events appeared comparable to these figures in each of the subgroups.

“Although the CheckMate 067 study has already reported that a combination of two checkpoint inhibitors — nivolumab and ipilimumab — is superior to either drug alone, the results presented here … have important clinical implications,” Peter Naredi, MD, PhD, professor and chief physician in the department of surgery at Sahlgrenska Academy at University of Gothenburg in Sweden and the European Cancer Organization scientific co-chair of the Congress, said in a statement. “These drugs come with a substantial frequency of adverse effects for the patients and it is important to spare patients who will not benefit from the treatment.

“What Larkin [and colleagues] show is that bad prognostic indicators, such as BRAF mutations, metastatic pattern or increased age, do not negatively influence PFS. Therefore, more patients can be considered for treatment, and tolerance to the treatment becomes a more important factor.” – by Anthony SanFilippo

Reference: Larkin J, et al. Abstract 3303. Presented at: European Cancer Congress; Sept. 25-29, 2015; Vienna.

Disclosure: Larkin reports institutional research funding from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis and Pfizer. Please see the abstract for a list of all other researchers’ relevant financial disclosures.