Nivolumab/Ipilimumab Combination Improves Survival Over Ipilimumab Alone in Patients With Melanoma

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The race is on to identify combinations of immune checkpoint inhibitors that can improve outcomes over the use of immune checkpoint inhibitor monotherapy. Updated results of the phase III CheckMate 067 trial found the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) improved survival in previously untreated advanced melanoma vs ipilimumab alone.1

A descriptive analysis suggested that the combination was more effective than nivolumab alone, but that comparison was not a prespecified endpoint of the study. The data also provided hints that patients with a BRAF mutation and those with elevated programmed cell death ligand 1 (PD-L1) expression might benefit more from the combination, but this evidence lacked statistical power.

Individualized Approach Recommended

At present, these data are observations from a phase III study, which are interesting but speculative. The evidence is not strong enough to use BRAF mutation status as a factor for choosing the [nivolumab/ipilimumab] combination in clinical practice.
— James Larkin, MD, PhD

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“The combination of nivolumab/ipilimumab significantly improved overall survival and progression-free survival vs ipilimumab alone in patients with untreated advanced melanoma,” said lead author James Larkin, MD, PhD, a Consultant Medical Oncologist at The Royal Marsden Hospital, London, who presented updated CheckMate 067 results at the 2017 American Association for Cancer Research (AACR) Annual Meeting. “Descriptive analysis suggested that the combination had numerically higher survival, progression-free survival, and response rates vs nivolumab alone. The combination did better across all relevant subgroups. Median duration of response and time to subsequent therapy are not yet reached for the combination. The safety profile was consistent with earlier reports,” he said.

Despite the generally favorable results for the combination of both immunotherapies, Dr. Larkin did not endorse using it in every patient. He cited cost considerations as well as toxicity and recommended an individualized approach for each patient when considering treatment.

The first survival results of CheckMate 067 reported in 2015 showed that nivolumab monotherapy and nivolumab/ipilimumab extended progression-free survival compared with ipilimumab alone.2 This led to approval of the combination by the European Medicines Agency and the U.S. Food and Drug Administration (FDA).

“A condition of the FDA accelerated approval was that it was necessary to show that the progression-free survival benefit translated into improved overall survival, and here we show that nivolumab alone or in combination with ipilimumab resulted in significantly improved overall survival,” Dr. Larkin stated.

Study Details

CheckMate 067 is the first phase III study to report survival outcomes with the combination of nivolumab and ipilimumab. The study randomized 945 patients with untreated advanced melanoma 1:1:1 to treatment with nivolumab/ipilimumab, nivolumab and ipilimumab-matched placebo, or ipilimumab with nivolumab-matched placebo. Treatment was continued until evidence of progressive disease or unacceptable toxicity emerged.

Patients were stratified according to the presence of BRAF mutation, M stage, and level of PD-L1 expression. The coprimary endpoints were progression-free survival and overall survival in an intent-to-treat analysis.

“The study design projected 644 deaths by September 2016, but the actual number by that date was 467—28% lower than was projected,” Dr. Larkin told the audience.

Key Findings

The updated analysis at a minimum of 28 months’ follow-up showed that median overall survival was 20 months for ipilimumab and not yet reached for nivolumab monotherapy and nivolu­mab/ipilimumab (P < .0001 for ipilimumab vs the combination). Subsequent systemic therapy was needed by 32% in the combination arm, 44% in the nivolumab monotherapy arm, and 62% in the ipilimumab arm. Two-year overall survival rates were 64% for the combination, 59% for nivolumab, and 46% for ipilimumab.

Median progression-free survival was 11.7 months, 6.9 months, and 2.9 months, respectively. Objective response rates were 58.9%, 44.6%, and 19%, respectively. Complete response rates were 12.1%, 9.8%, and 2.2%, respectively.

At 28 months’ follow-up, the median duration of response was “impressive,” according to Dr. Larkin. Median duration of response was not yet reached for the combination, 31.1 months for nivolumab, and 18.2 months for ipilimumab.

Looking at survival in patients with BRAF wild-type and BRAF-mutant tumors, median overall survival has not yet been reached for both the combination and nivolumab alone in both subgroups compared, with a median of 18.5 months for BRAF wild-type tumors and 24.6 months for BRAF-mutant tumors treated with ipilimumab.

Overall survival according to PD-L1 expression (< 5% vs > 5%) showed that median survival was not yet reached for the two nivolumab-containing arms in either subgroup and was 18.5 and 28.9 months, respectively, for ipilimumab.

“Regardless of PD-L1 expression, the combination was numerically superior for survival endpoints,” Dr. Larkin commented. “The data for PD-L1 are intriguing, but the role of PD-L1 as a biomarker is not established, and treatment selection should be made on an individualized basis,” he stated.

Major Toxicities

The safety profile was consistent with earlier experience using both drugs. The rate of grade 3 and 4 adverse events was higher with the combination: 58.5% vs 20.8% with nivolumab and 27.7% with ipilimumab. Most events were manageable. “The vast majority of events resolved within 3 to 4 weeks,” he said.

However, the combination was not easily tolerated, since close to 40% of patients on combination therapy stopped treatment due to adverse events. Cessation of treatment did not appear to compromise response, he continued. The objective response rate was 70% among those who discontinued combination therapy due to adverse events, and median overall survival was not reached in this group of patients.

Four treatment-related deaths were reported: 1 each in the nivolumab and ipilimumab arms, and 2 deaths in the combination arm more than 100 days after the last treatment.

Additional Commentary

Suzanne L. Topalian, MD

Suzanne L. Topalian, MD

Commenting on this study at a press briefing where these data were presented, press conference moderator Suzanne L. Topalian, MD, noted, “Nivolumab plus ipilimumab is the first immunotherapy combination to be approved for any cancer by the FDA. Immunotherapy combinations are an active area of research, with several hundred ongoing trials of various combinations.” Dr. Topalian is Professor of Surgery and Oncology, John Hopkins Medicine; Associate Director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins; and Melanoma Program Director at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore.

“This study showed that combining drugs that block two different immune checkpoints [ipilimumab blocks cytotoxic T-lymphocyte–associated protein 4, and nivolumab blocks programmed cell death protein 1] has a powerful antitumor effect in melanoma. However, the combination also increases the risk of toxicity,” she continued.

“We have to discuss with our patients the potential benefits and risks of any therapy. We would like to have biomarkers to select patients most likely to respond and least likely to incur side effects,” she said.

Dr. Topalian noted that patients with BRAF mutations and those with increased PD-L1 expression seemed to do better on the combination, and combination therapy may have an advantage in these subgroups, although further study is needed.

Patient Discussion

“What is your conversation like with a patient who has newly diagnosed stage IV melanoma?” she asked Dr. Larkin.

“Both the BRAF and PD-L1 data are intriguing, but we need to understand the biology underlying this. We don’t know if this is a real effect in BRAF-mutated melanoma from a biologic perspective. PD-L1 is not an ideal biomarker. It is not binary, like BRAF, and I’m not sure if there is a clinically useful cutoff for PD-L1,” Dr. Larkin replied.

“When I sit with a patient who has advanced melanoma, I consider a constellation of factors that I discuss when formulating a treatment. This includes fitness level and presence or absence of a BRAF mutation. There is no set route to go down [for choosing therapy],” he continued.

“At present, these data are observations from a phase III study, which are interesting but speculative. The evidence is not strong enough to use BRAF mutation status as a factor for choosing the combination in clinical practice. These are expensive drugs, and the combination has more toxicity. We all want robust biomarkers for efficacy, safety, and cost,” he stated. ■

Disclosure: The study was funded by Bristol-Myers Squibb. Dr. Larkin reported no potential conflicts of interest. Dr. Topalian has been a consultant for, received research support from, or owned stock in AbbVie, Bristol-Myers Squibb, Five Prime Therapeutics, Amgen, Compugen, Jounce Therapeutics, MedImmune, Merck, Pfizer, Potenza Therapeutics, and Tizona.


1. Larkin J, Chiarion-Sileni V, Gonzalez R, et al: Overall survival results from a phase III trial of nivolumab combined with ipilimumab in treatment-naive patients with advanced melanoma (CheckMate 067). 2017 AACR Annual Meeting. Abstract CT075. Presented April 3, 2017.

2. Wolchok JD, Chiarion-Sileni V, Gonzales R, et al: Efficacy and safety results from a phase III trial of nivolumab alone or combined with ipilimumab versus ipilimumab alone in treatment-naive patients with advanced melanoma (CheckMate 067). 2015 ASCO Annual Meeting. Abstract LBA1. Presented May 31, 2015.

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