A new study recently published in The New England Journal of Medicine revealed that a specific combination of immunotherapies yielded promising results in patients with untreated advanced melanoma. The study was led by researchers at the Ludwig Center at Memorial Sloan Kettering Cancer Center, the Weill Cornell Medical College, New York and the Dana–Farber Cancer Institute, Boston and is entitled “Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma.”
Melanoma is the most dangerous form of skin cancer caused by damage to skin cells (usually by ultraviolet radiation from sunshine or tanning beds), which triggers mutations that are not repaired allowing cells to rapidly multiply and generate malignant tumors. When detected early, melanoma is curable, but the cancer can proliferate and spread (metastasize) to other parts of the body, becoming extremely difficult to treat.
Recent therapeutic strategies for metastatic melanoma are based on the stimulation of antitumor immunity by the blockade of specific immune checkpoints, namely the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and the programmed death 1 (PD-1) receptor. Drugs have been designed against these two elements. Ipilimumab is an anti-CTLA-4 antibody and nivolumab an anti–PD-1 antibody, both approved by the Food and Drug Administration (FDA) as they can to some extent improve overall health and survival in patients with advanced melanoma. Previous studies have indicated that dual blockade of the CTLA-4 and PD-1 immune checkpoints yields better antitumor responses than a single blockade.
Based on these studies, the research team assessed the combination of ipilimumab plus nivolumab as a first line therapy for advanced metastatic melanoma in comparison to the standard-of-care ipilimumab monotherapy. The team conducted a randomized, double-blind, Phase 2 clinical trial with 142 patients with advanced melanoma and no prior therapy. Of these, 109 patients had the normal form of the gene BRAF (a gene frequently found to me mutated in melanoma), which is known to have fewer effective therapeutic options.
Researchers found that among patients with a normal BRAF gene, 61% had an overall improvement in response rate, with 22% showing a complete response (the tumor could no longer be detected), while treatment with ipilimumab alone resulted in a response rate of 11%, with no complete responses. In patients with the BRAF gene mutated, both therapies yielded similar outcomes. “Preclinical studies suggested that this combination therapy would have better outcomes than those elicited by their individual or sequential administration,” said the study’s co-senior author Dr. F. Stephen Hodi from the Dana-Farber Cancer Institute in a news release. “It’s very encouraging to see that pattern reflected in this trial with previously untreated patients.”
Researchers reported side effects in both treatments, with 27% of the patients (25 individuals) given both drugs and 37% (17 individuals) given only ipilimumab died from progressive disease. Three of the deaths reported in the first group were found to be related to the combined therapy. “In general, and as might be expected, side effects were more prevalent in patients who received the combination therapy,” said Dr. Hodi. “This is something that will have to be studied further. But we also look forward to following up with the patients who benefitted from the combination therapy to assess the durability of the responses we have observed.”
The research team concluded that the combination of ipilimumab and nivolumab immunotherapies as a first-line treatment for advanced melanoma results in better outcome responses and longer progression-free survival than ipilimumab monotherapy. Importantly, the combination therapy was found to be effective in melanoma patients with a normal BRAF gene for whom few effective treatment options are available. Side effects of the treatment are, however, a problem that needs to be addressed. “Rationally combined immunotherapies hold great promise for cancer treatment as long as their side effects can be managed,” concluded the study’s co-senior author Dr. Jedd D.Wolchok from the Memorial Sloan Kettering Cancer Center.
