‘Truly Remarkable’ Response with Combination for Melanoma

Nick Mulcahy

May 15, 2013

Combination immunotherapy with ipilimumab (Yervoy, Bristol-Myers Squibb) and the investigational antibody drug nivolumab (Bristol-Myers Squibb) has broken new ground in the treatment of metastatic melanoma, producing durable tumor shrinkage in about half of patients, according to results from a phase I study.

The objective response rate with the concurrent use of the 2 therapies was higher than seen in earlier trials of the 2 drugs used alone, said lead author Jedd Wolchok, MD, PhD, of the Memorial Sloan-Kettering Cancer Center, in New York City.

He spoke at a press briefing that precedes the 2013 annual meeting of the American Society of Clinical Oncology (ASCO).

In the new, dose-escalation, multiarm trial, the maximum doses of ipilimumab (3 mg/kg per day) and nivolumab (1 mg/kg per day), when given concurrently, yielded an objective response rate of 53% among 17 patients.

In earlier published trials, objective response rates were 11% for ipilimumab and 41% for nivolumab. At ASCO last year, nivolumab was hailed for "breaking the ceiling" for response rates seen in the past with immune therapies for cancer.

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 in June 2013, Dr. Wolchok said.

A total of 52 of the 86 patients in the phase 1 trial were enrolled in concurrent therapy cohorts (of differing doses). Overall, 90% of these patients continued to have responses as of February 2013. All of the patients in the study, which is ongoing, have inoperable stage III and stage IV (metastatic) melanoma and had undergone up to 3 prior therapies.

The maximum dosage version of the concurrent therapy produced "rapid and profound" results, Dr. Wolchok said. A total of 7 of the 17 patients (41%) of these patients had > 80% tumor reduction at 3 months. Overall, about one third of all of the patients in concurrent treatment cohorts had > 80% tumor reduction.

"This is truly remarkable. This kind of response has not been seen with immunotherapy before," summarized Sandra Swain, MD, president of ASCO, who was not involved with the study but was a commentator at the press briefing. She is from the Washington Cancer Institute, in Washington, DC.

"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," she continued.

Dr. Swain's comments refer to the fact that this is the first time that 2 immunotherapies have been used together in melanoma. Both belong to a new class of drugs, which employ "immune checkpoint blockade," meaning that they target immune system gatekeepers on immune cells, and "release the brakes" on the immune system to combat cancer, Dr. Wolchok said. Ipilimumab blocks CTLA-4, while nivolumab targets the protein PD-1.

"By blocking both CDLA-4 and PD-1 you allow for more robust immune cell activation," Dr, Wolchok added.

The complete response rate was 17% among the patients who received the ipilimumab/nivolumab concurrent therapy at maximum doses. However, among all of the patients in the trial, including those who received sequential therapy, the complete response rate was about 10%, he said.

In either case, the complete response rates were better than seen when the 2 agents are used alone (less than 3% for both ipilimumab and nivolumab), Dr. Wolchok said.

Because there have not been enough events to report yet, there is no median time to relapse in the phase 1 study. Neither of these immunotherapies are plagued by the consistent problem of drug resistance seen in the new targeted therapies for melanoma such as vemurafenib, Dr. Wolchok said.

The combination of ipilimumab and nivolumab is also being tested in non-small cell lung cancer and renal cell carcinoma.

Adverse Events "Manageable"

For all doses, the study protocol called for patients in concurrent cohorts to receive nivolumab and ipilimumab every 3 weeks for 4 doses, followed by nivolumab every 3 weeks for 4 doses. Then, at week 24, one concurrent combination treatment is administered every 3 months.

Dr. Wolchok reported that grade 3-4 side effects due to drug treatment occurred in 28 of 53 patients (53%) in the concurrent treatment cohorts. The adverse events were mostly related to immune-related inflammation. The most common were asymptomatic lab abnormalities: elevations of lipase (13%) and the liver enzymes AST (13%) and ALT (11%).

In the sequenced treatment cohorts, the toxicity was less intense. Grade 3-4 side effects due to drug treatment occurred in 6 of 33 patients (18%). The most common was asymptomatic elevation of lipase (6%).

The side effects in both the concurrent and sequenced treatment cohorts were managed using "standard protocol algorithms," which included steroids, Dr. Wolchok said.

There were no treatment-related deaths.

Dr. Wolchok downplayed adverse events seen in the trial. "We weren't surprised by the severity of the side effects or by anything new," he said. The adverse events were "no worse, no more frequent" than when the drugs are given alone, he said.

The study was supported by Bristol-Myers Squibb.

Dr. Wolchok reports being a consultant to Bristol-Meyers Squibb and research funding from the company. Coauthors include company employees.

American Society of Clinical Oncology (ASCO) 2013 annual meeting. Abstract 9012. To be presented June 2, 2013.


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