Nick Mulcahy

June 02, 2013

CHICAGO — Giving experimental agents known as immune checkpoint blockers together or sequentially leads to improved outcomes in metastatic melanoma, according to the results of 2 studies published in the New England Journal of Medicine (NEJM) today.

The studies are both phase 1 trials, and therefore the outcomes are limited in their authority. However, the results are encouraging, especially the findings that the drug combinations did not result in a higher rate and severity of adverse events compared with the individual drugs alone, observes James Riley, PhD, of the Abramson Cancer Research Center at the University of Pennsylvania in Philadelphia. He wrote an editorial that accompanies the new studies.

The studies are also being presented here today at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO®).

"The future is all about combination therapies," said Jedd Wolchok, MD, PhD, a melanoma expert at the Memorial Sloan-Kettering Cancer Center in New York City. He spoke with Medscape Medical News in an interview. Dr. Wolchok said that melanoma will now go the way of other diseases such as tuberculosis and HIV, which have been increasingly successfully treated with the adoption of multiple drug regimens.

Dr. Wolchok is the lead author of one the new studies in NEJM, a phase 1 study combining the approved melanoma drug ipilimumab (Yervoy, Bristol-Myers Squibb Company) with the experimental nivolumab (BMS), both concurrently and sequentially. The results were first reported by Medscape Medical News in mid-May at an ASCO press conference that annually precedes the meeting.

Both ipilimumab and nivolumab are immune checkpoint blockers but have different targets (PD-1 and CTLA-4, respectively).

The investigators found that the maximum doses of ipilimumab (3 mg/kg/day) and nivolumab (1 mg/kg/day), when given concurrently, yielded an objective response rate of 53% among 17 patients.

Overall, the objective response rate with the concurrent use of the 2 therapies was 40% (n = 53 patients). Notably, this was higher than the response rate seen in earlier trials of the 2 drugs used alone; in earlier published trials, objective response rates were 11% for ipilimumab and 41% for nivolumab.

The ipilimumab/nivolumab concurrent regimen is now scheduled to be tested in phase 3 trials as a first-line treatment for patients with metastatic melanoma, starting this month.

Dr. Wolchok reported that grade 3-4 side effects of drug treatment occurred in 28 of 53 patients (53%) in the concurrent treatment cohorts. The adverse events were mostly related to immune-related inflammation. Dr. Wolchok and his coauthors write that the adverse events were "qualitatively similar to previous experience with monotherapy and were generally reversible."

Patients in the ipilimumab/nivolumab clinical trial who received sequential therapy had a much lower rate of grade 3-4 adverse events (18%). However, their response rate was also much lower (20%).

"This study is proof of principle that concurrent use of 2 immune checkpoint antibodies contains the treatment paradigm for advanced melanoma. It's very exciting," said Sandra Swain, MD, president of ASCO, who was not involved with the study but was a commentator at the press briefing in mid-May. She is from the Washington Cancer Institute, in Washington, DC.

Another New Anti-PD-1 Agent

In the second study in the NEJM, investigators report their findings on the experimental anti-PD-1 antibody MK-3475 (Merck & Co., Inc.) in patients with metastatic melanoma.

The intravenously administered agent works in a manner similar to nivolumab, which is also an anti-PD-1 antibody.

Overall, the objective response rate was 38% among all of the different dose cohorts (n = 135 patients), report the authors, led by Antoni Ribas, MD, of the University of California, Los Angeles.

The investigators found that the patients who received the 10 mg/kg dose every 2 weeks had the highest confirmed response rate (52%). This rate is on par with the rate seen when the ipilimumab/nivolumab regimen was used concurrently in the other phase 1 study reported. In both cases, the rates are unprecedented among immunotherapies for melanoma.

The responses with MK-3475 were "durable" in a majority of patients (median follow-up was 11 months among responders). The median progression-free survival among the 135 patients was 7 months.

Dr. Riley, in his editorial, believes that the success of ipilimumab/nivolumab and MK-3475 after failure on ipilimumab "opens the door" to using a wide variety of drug combinations in melanoma and other cancers — not just 2 immune checkpoint blockers. He proposes adding other immune modulators, cancer vaccines, or conventional therapies that target tumor survival and growth. "Such combinations may be required to effectively target the most treatment-resistant cancers, such as pancreatic cancer," he wrote.

Both nivoluzumab and MK-3475 are several years away from the market.

The ipilimumab/nivolumab study was supported by Bristol-Myers Squibb Company. Dr. Wolchok reports being a consultant to Bristol-Meyers Squibb and receiving research funding from the company. Coauthors include company employees. The MK-3475 study was supported by Merck & Co., Inc. Dr. Ribas reports financial ties to Plexxikon Inc. Coauthors include company employees.

2013 Annual Meeting of the American Society of Clinical Oncology. Abstracts 9009 and 9012. Presented June 2, 2013.

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