Immunotherapies Take Center Stage in Treatment of Metastatic Melanoma

The promise of immunotherapy is coming to fruition with therapeutic advances in melanoma. In 1998, high-dose interleukin-2 (HD IL-2) became the first U.S. Food and Drug Administration (FDA)-approved immunotherapy for metastatic melanoma. But HD IL-2 is severely toxic and benefits only a small minority of patients. In 2011, ipilimumab became the second immunotherapy approved for metastatic melanoma.

“As a medical oncologist primarily taking care of patients with advanced melanoma for which surgery is not an option, one of the most important advances in treating melanoma has been the dramatic success of new therapies that boost the immune system to allow the body to fight off melanoma more effectively,” says Margaret Callahan, a medical oncologist and research fellow at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York.

Despite undeniable benefits, the introduction of melanoma immunotherapies has complicated treatment decisions for some patients. One major question for metastatic melanoma is how to treat patients with advanced disease whose tumors have mutations in the BRAF gene. Most melanoma patients are eligible to take ipilimumab, but those with BRAF mutations could also benefit from treatment with the BRAF-targeted oral medication vemurafenib.

At MSKCC, Callahan says, treatment decisions depend on many factors, including how quickly a patient’s cancer is progressing. For patients with a BRAF mutation, there are no formal guidelines or data from clinical trials to help doctors craft a treatment schedule that combines ipilimumab and vemurafenib.

“For [metastatic melanoma] patients who are BRAF wild type, we typically turn to ipilimumab as the first treatment,” Callahan says. However, “more studies looking at this question are needed.” Indeed, she is part of a treatment and research team at MSKCC that is working on novel immunotherapy approaches and combinations for melanoma. The team also includes Jedd Wolchok, a medical oncologist who helped develop ipilimumab.

Several, newer immune system-boosting drugs are currently in both early and later stages of clinical testing. Some are anti-PD-1 agents that, like the anti-CTLA-4 ipilimumab antibody, inhibit a brake of the immune system, resulting in a more robust immune system response to cancer.

“CTLA-4 and PD-1 are both molecules expressed on T cells that help regulate how T cell are activated, but the two act at different steps in the process of T cell activation so their roles are not redundant,” says Callahan.

The anti-PD1 antibody nivolumab (BMS-936558) is currently being tested in a phase III trial comparing it to chemotherapy for previously untreated metastatic melanoma. Another phase III trial is examining the efficacy of nivolumab in patients who have progressive metastatic melanoma despite previous treatment with ipilimumab or another anti-CTLA4 antibody.

Other anti-PD1 agents in development include MK-3475, CT-011, and two anti-PDL1 antibodies: BMS-936559 and MPDL3280A, that are in early-stage trials.

Nivolumab results have been particularly encouraging so far. In a phase I/II trial of just over 100 patients, response rates in advanced melanoma patients ranged from 19% to 41% depending on dosage. In comparison, ipilimumab response rates have been in the range of 10% to 15% in phase III trials. Another anti-PD1 antibody, MK-3475 is also promising, with a 51% response rate reported for 85 advanced melanoma patients at the Society for Melanoma Research meeting in November 2012.

“It is easy to see why there is great enthusiasm for this approach,” says Callahan. But the sample sizes of patients treated with developmental anti-PD1 drugs are small, and results of large phase III trials are needed for further validation. “It is too early to make a comparison between these agents and ipilimumab,” she says.

A small combination trial testing nivolumab plus ipilimumab is also underway at two centers, including MSKCC. “There is a clear rationale for combining these two drugs in the setting of a clinical trial,” says Callahan. This rationale stems from two observations: 1), nivolumab and ipilimumab both have activity against melanoma as monotherapies; and 2), CTLA-4 and PD-1 regulate immune responses in unique and non-redundant ways.

Preclinical studies testing the combination in mice have shown better antitumor effects compared to each antibody alone, says Callahan. “This is an important study and it was designed to carefully understand the potential benefits and potential risks of such a combination.”