Combination Immunotherapy Shows Promise in Advanced Melanoma

Alice Goodman

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Combination therapy with ipilimumab and nivolumab achieved remarkable responses in a phase 1 trial of patients with aggressive advanced melanoma. Durable tumor shrinkage was observed in about half the patients.

“The complete and near-complete responses we are seeing are unprecedented for an immunotherapy in melanoma. We are particularly impressed that the drugs work together so well,” stated lead author Jedd D. Wolchok, MD, PhD, Memorial Sloan-Kettering Cancer Center, New York City. “This study shows that combining immunotherapies has the potential to improve upon single-agent immunotherapy,” he added.

Ipilimumab is a standard treatment option for advanced melanoma. Nivolumab is a novel PD-L1 antibody that has shown promising activity in melanoma and other cancers. Both drugs target immune system “checkpoints” – CTLA-4 in the case of ipilimumab and PD-L1 in the case of nivolumab – by releasing these “brakes” on the immune system, activating T cells to attack the cancer.

The average overall survival in metastatic melanoma is 10 to 14 months, Wolchok said. Previous studies showed an objective response rate of 11% with ipilimumab and 41% with nivolumab when used separately in advanced melanoma.

In this phase 1 trial, patients with inoperable stage III and IV melanoma treated with up to 3 prior lines of therapy were assigned to 6 different treatment arms. The results presented at a pre-ASCO press cast and then reported at the ASCO Annual Meeting were based on 3 arms in which concurrent treatment was given with the 2 drugs to 52 patients. Sequential treatment was used in 3 arms, and those responses were not reported.

The objective response rate, defined as a reduction of tumor volume of at least 50%, was 53% with concurrent treatment, which is substantially higher than with either drug alone. About 90% of responses continued as of February 2013. Wolchok said that melanoma was controlled in about 65% of patients if those with stable disease were included.

Combination therapy with the maximum dosages of both drugs achieved tumor shrinkage of ?80% at 3 months in 41% of patients.

Both treatments had side effects that were manageable with standard algorithms for each medication alone, Wolchok said.

Side effects were more frequent with the sequential therapy than with the concurrent therapy, he said. The most common adverse events were asymptomatic elevated enzymes in the liver and pancreas. Rare side effects included inflammation of the colon, eyes, or lungs, all of which were reversible.

Further studies of the concurrent regimen versus nivolumab versus ipilimumab are ongoing in advanced melanoma. The combination is also being studied in non–small cell lung cancer and renal cell carcinoma.

“This is an exciting study, showing great improvement and progress. The combination of 2 immunotherapies led to rapid and profound lasting tumor shrinkage. Ninety percent of responders are still responding. This has not been seen with immunotherapy before. This study of the combination of 2 drugs that release the brakes of the immune system is proof of principle that 2 immune agents can change the paradigm of treating melanoma,” said ASCO President Sandra Swain.

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