Advanced melanoma patients benefited from immunotherapy combination

Advanced melanoma patients benefited from immunotherapy combination

20 Apr 2015

The combination of two immunotherapies for first-line treatment of advanced melanoma showed promising results in a Phase 2 clinical trial led by Ludwig Harvard's Stephen Hodi and Ludwig Memorial Sloan Kettering (MSK)'s Jedd Wolchok. In particular, it was found that patients had better responses and far longer progression-free survival with two immunotherapy drugs combined than with one of those drugs alone.

Furthermore, the combination was effective in the portion of melanoma patients -- the majority -- who currently have few effective treatment options.

"Rationally combined immunotherapies hold great promise for cancer treatment as long as their side effects can be managed." ," said Wolchok

Immunotherapy’s mechanisms of action and clinical design

Ipilimumab interferes with a process by which the immune system controls the activation of T cells that destroy diseased tissues. The antibody blocks CTLA-4, a protein switch on the surface of T cells that, when turned on, dampens their activation.

Nivolumab, meanwhile, is an antibody that targets a protein known as PD-1, which is also found on the T cell surface. PD-1 is often aberrantly engaged by tumor cells themselves to thwart T cell attack. Both drugs have been approved by the US Food and Drug Administration.

The Phase 2, double-blind trial enrolled 142 patients with advanced melanoma who had not received prior therapy. The tumors of 109 of these patients had the normal form of the gene BRAF, which is frequently mutated in melanoma. This is significant because while melanoma patients with the mutant BRAF gene can be treated with a targeted therapy, the majority whose tumors encode a normal BRAF have few effective treatment options.

Promising results, modest side effects and more research to be done

The results of the trial, which compared a combination of checkpoint inhibitors ipilimumab and nivolumab against ipilimumab alone in previously untreated patients, showed that:

• Patients whose tumors had a normal BRAF gene showed an overall objective response rate of 61%. This included a 22% complete response rate.
• Those with a normal BRAF who received only ipilimumab had a response rate of 11%, with no complete responses.
• Patients with BRAF mutations had similar outcomes for each of the therapies.
• The combination therapy also induced effects that continued well after the last administration of the therapy.
• Of those patients who died, 25 in the combination group (27%) and 17 in the monotherapy group (37%) died from progressive disease. Notably, three of the deaths in the combination group were determined to have been 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 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."

 

Source: Science Daily