ASCO 2015: Phase III Study Finds Nivolumab Improves Progression-Free Survival, Especially When Combined With Ipilimumab, in Advanced Melanoma


Key Points

  • Among patients with previously untreated melanoma, initial therapy with nivolumab alone more than doubled the median progression-free survival, to 6.9 months compared to 2.9 months for ipilimumab alone.
  • The benefit was even greater when the two agents were used together, resulting in a median progression-free survival of 11.5 months.
  • Response rates were also substantially higher in patients receiving the combination therapy (57.6%) or nivolumab alone (43.7%), as compared to ipilimumab alone (19%).
  • Overall survival has not yet been reached.

A randomized phase III trial among patients with previously untreated melanoma found that initial therapy with nivolumab (Opdivo) alone more than doubled the median progression-free survival compared with ipilimumab (Yervoy) alone (6.9 vs 2.9 months), and the benefit was even greater when the two agents were used together, resulting in a median progression-free survival of 11.5 months. The response rates were also substantially higher in patients receiving the combination therapy (57.6%) or nivolumab (43.7%) alone, as compared to ipilimumab alone (19%).

“Overall survival is not expected to be reported until 22 months of follow-up, so we are quite a way away from that,” lead study author Jedd Wolchok, MD, PhD, said at a press conference at the 2015 ASCO Annual Meeting. Dr. Wolchok, Chief of Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center in New York, also presented the study results at Sunday’s Plenary Session (Abstract LBA1).

Different Immune Checkpoints Targeted

Both nivolumab and ipilimumab are checkpoint inhibitors, but each blocks a different immune checkpoint; nivolumab blocks PD-L1, and ipilimumab blocks CTLA-4. These two checkpoints “represent distinct and complementary pathways that negatively regulate antitumor immunity, thus providing a rationale for simultaneous blockade of both targets,” Dr. Wolchok explained.

Both ipilimumab and nivolumab have been approved by the U.S. Food and Drug Administration for use as single agents in patients with unresectable or metastatic melanoma that no longer responds to other drugs.

Phase I and II studies of combined nivolumab and ipilimumab in advanced melanoma “showed an unexpectedly high response rate of about 53% in the phase I trial and 59% in the phase II trial, with 2-year overall survival rates ranging from 79% to 88%, depending on dose,” Dr. Wolchok noted.

The current study is the first phase III study to evaluate the combination in advanced melanoma. This study randomly assigned 945 patients with unresectable stage III or IV melanoma to receive ipilimumab, nivolumab, or a combination of the two.

Results Vary With PD-L1 Expression

Looking at the results stratified by PD-L1 expression, “in the group of patients who have tumors that have more than 5% PD-L1 expression, with the combination, the median progression-free survival is 14 months, with nivolumab alone, it is the same, 14 months, and with ipilimumab alone, it is 3.9 months,” Dr. Wolchok pointed out. In patients whose tumors have PD-L1 expression less than 5%, median progression-free survival was 11.2 with the combination, 5.3 months with nivolumab alone, and 2.8 months with ipilimumab alone.

“So based upon the available evidence, the combination represents a means to improve outcomes vs nivolumab alone, particularly for patients whose tumors have less than 5% PD-L1 expression,” Dr. Wolchok said.

Among all three treatment groups, the duration of response has not yet been reached, “which is very characteristic for any immunotherapy,” Dr. Wolchok noted. Median reductions in tumor burden were 51.9% with the combination and 34.5% with nivolumab alone. In contrast, patients who received ipilimumab alone experienced a 5.9% increase in tumor burden.

Responses Can Continue After Treatment Stops

“Importantly for safety, we actually saw no drug-related deaths in the combination group, which I think is a very important point because this trial was conducted at 137 sites globally, and the safety guidelines that were put in place along the way during development of both ipilimumab and nivolumab clearly were able to handle these side effects, as were investigators in a variety of different venues. So this treatment can be safely applied in a global setting,” Dr. Wolchok stated.

Grade 3/4 treatment-related adverse event rates were 55% for the combination group, 16.3 % for nivolumab alone, and 27.3% for ipilimumab alone. “The safety profile of the combination was consistent with earlier experience,” Dr. Wolchok said. “The majority of adverse events were managed and resolved with the established algorithms.”

Among the 36.4% of patients who discontinued treatment due to side effects, the response rate to treatment was nearly 68%, “with half of those responses occurring after the patient stopped treatment,” Dr. Wolchok noted. “So clearly these guidelines for when to stop treatment and how to manage side effects were very effective in establishing a good risk-benefit profile.”

Quality-of-ife data were collected on the study, and the analysis of those results will be reported at a later time.

Results Can Inform Conversations With Patients

“The most important thing this study shows is that we are beginning to define which patients may benefit from one drug and those who may benefit from both drugs. That will inform conversations about toxicity for patients and physicians as they decide their treatment course,” commented ASCO spokesperson Jyoti Patel, MD. Dr. Patel is Associate Professor of Medicine, Division of Hematology/Oncology at Northwestern University Feinberg School of Medicine, Chicago

Dr. Wolchok also saw the results “as a way to initiate meaningful conversations between patients and clinicians about whether the combination is the right fit for them vs nivolumab alone” and to talk about the value of risk vs benefit. “Ultimately, we are going to need the overall survival data, because response rate and progression-free survival are both surrogates for overall survival.”

If the survival at 2 or 3 years with the combination therapy “holds up at a high plateau compared to monotherapy, then it will be obvious what we need to do, but in the short term, this is an incredibly encouraging combination,” commented ASCO Expert Steven J. O'Day, MD. He is a Clinical Associate Professor of Medicine at the University of Southern California Keck School of Medicine, Director of the Los Angeles Skin Cancer Institute, and Director of Clinical Research at the Beverly Hills Cancer Center.

Asked by The ASCO Post how these results will affect the use of ipilimumab, Dr. O’Day, who was a key investigator in trials leading to ipilimumab's approval, replied that CTLA-4 “is a very important target” and ipilimumab “is a very important drug in the field of melanoma. It is not going away. It works differently. It tends to work to generate this army of T cells to go into battle,” he said, and anti–PD-L1 agents are “more about activating or resurrecting these tired T cells in the tumor microenvironment.” While different, the approaches are potentially synergistic, he added. “Both will be active. The question is what sequence or combination is the best, and this combination in melanoma is incredibly promising.” Dr. O’Day said.

This study received funding from Bristol-Myers Squibb. Dr. Wolchok reported consulting or advisory roles with Bristol-Myers Squibb, Merck, MedImmune, ZIOPHARM Oncology, Polynoma, Polaris, Jounce Therapeutics, and GlaxoSmithKline; travel, accommodations, and expenses from Bristol-Myers Squibb; patents, royalties, other intellectual property as a co-inventor on an issued patent for DNA vaccines for treatment of cancer in companion animals, stock and other ownership interests with Potenza Therapeutics and Vesuvius Pharmaceuticals; honoraria from EMD Serono and Janssen Oncology; research funding (institutional) from Bristol-Myers Squibb, MedImmune, GlaxoSmithKline, and Merck. For full disclosures of the study authors, view the study abstract at

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.