Durable Benefit With Immunotherapy Combination in Advanced Melanoma

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For the BRAF wild-type patient population, the combination of ipilimumab and nivolumab significantly reduced the risk of progression or death by 65% vs ipilimumab alone. Similar results were seen for all randomized patients.

Michael A. Postow, MD

With the recent explosion in immunotherapies for advanced melanoma and other tumors, all eyes are on how best to sequence or combine these therapies. Initial reports of overall survival from the phase II randomized CheckMate 069 trial suggest that the combination of ipilimumab (Yervoy, an anti–CTLA-4 [cytotoxic T-lymphocyte–associated protein 4] immunotherapy) and nivolumab (Opdivo, an anti–PD-1 [programmed cell death protein 1] immunotherapy) is superior to ipilimumab alone in patients with advanced melanoma.1

At a minimum follow-up of 2 years, in BRAF wild-type patients, ipilimumab and nivolumab achieved significantly longer progression-free survival vs ipilimumab alone (P < .0001). An exploratory analysis found that 2-year overall survival was 69% for the combination vs 53% for ipilimumab alone.

“The combination of ipilimumab and nivolumab significantly reduced the risk of progression or death by 65% vs ipilimumab alone. The progression-free survival curve appears to plateau at 12 months. Responses have been remarkably durable. “Now with 2 years of follow-up, there were no new safety signals, no treatment-related deaths, and no increase in grades 3 and 4 adverse events for the combination, compared to the initially published report,” said lead author Michael A. Postow, MD, of Memorial Sloan-Kettering Cancer Center, New York, New York. “These are the first survival data on the combination from a randomized phase II trial. We eagerly await survival data from the phase III CheckMate 067 trial,” he noted.

Study Details

CheckMate 069 included 142 treatment-naive patients with inoperable stage III or IV melanoma. Patients were stratified according to BRAF status: 109 BRAF wild-type patients and 33 BRAF-mutated patients. Patients were randomized 2:1 in a double-blind fashion to the combination of ipilimumab and nivolumab followed by nivolumab alone vs ipilimumab followed by placebo, and treatment was continued until disease progression or death. Ipilimumab-treated patients were allowed to receive nivolumab at disease progression on an open-label basis.

The primary endpoint of the trial was objective response rate by RECIST (Response Evaluation Criteria in Solid Tumors) criteria. Overall survival was an exploratory endpoint analyzed at a minimum of 2 years of follow-up.

At baseline, both treatment arms were well balanced for demographic and disease characteristics. The majority had stage IV melanoma. Twenty-five percent had elevated lactate dehydrogenase levels, about 24% were PD-L1–positive, and about 22% were BRAF V600 mutation–positive.

Response Rates

For the primary endpoint, in the BRAF wild-type patients, at 11 months, the objective response rate was 61% in the combination arm vs 11% for ipilimumab monotherapy; complete response was observed in 22% vs 0%, respectively. Partial response was 39% vs 11%. Results were similar for all randomized patients, including the 33 BRAF-mutated patients.

At 2-year follow-up, the median change in tumor burden was a 70% reduction for the combination arm vs a 5% increase in the ipilimumab-alone arm. Median duration of response has not been reached in either arm. Median time to response was similar in both arms. “A number of responding patients discontinued treatment for various reasons but remain in response,” he said.

Survival Outcomes and Toxicity

Looking at progression-free survival in BRAF wild-type patients, median progression-free survival has not been reached for the combination arm vs 4.4 months for ipilimumab alone (P < .0001). One- and 2-year progression-free survival in the BRAF wild-type population for the combination arm was 55% and 54%, respectively. One- and 2-year progression-free survival in the BRAF wild-type population for ipilimumab alone was 17% and 11%.

Combination Immunotherapy vs Monotherapy in Advanced Melanoma

  • Two-year follow-up of the phase II randomized CheckMate 069 trial showed a continued progression-free survival benefit for patients randomized to the combination of ipilimumab plus nivolumab vs initial ipilimumab alone; an exploratory analysis also showed a trend toward higher overall survival rates associated with the combination.
  • No new toxicity concerns were raised with the combination treatment.
  • Going forward, it will be important to identify biomarkers that can select patients for combination immunotherapy vs monotherapy.

Median overall survival in BRAF wild-type patients has not yet been reached in the combination arm. Median overall survival was 24.8 months for patients with BRAF wild-type melanoma in the ipilimumab-alone arm. One-year and 2-year overall survival was 79% and 69%, respectively, for the combination arm and 62% and 53%, respectively, for ipilimumab alone. Results were similar for all randomized patients. Numeric differences were observed for subsequent therapies, with 35% of the combination arm vs 70% in the ipilimumab arm going on to any subsequent treatment after progression.

The most common toxicities with the combination were gastrointestinal and hepatic. More than 85% of treatment-related adverse events resolved, Dr. Postow said. ■

Disclosure: Dr. Postow is on the advisory board of Bristol Myers Squibb and has received honoraria from Bristol-Myers Squibb and Merck.


1. Postow M, Chesney J, Pavlick A, et al: Initial report of overall survival rates from a randomized phase II trial evaluating the combination of nivolumab and ipilimumab in patients with advanced melanoma. 2016 AACR Annual Meeting. Abstract CT002. Presented April 17, 2016.

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