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Immunotherapy combination promising for untreated patients with advanced melanoma

Date:
April 20, 2015
Source:
Ludwig Cancer Research
Summary:
The combination of two immunotherapies for first-line treatment of advanced melanoma induces better responses and far longer progression-free survival than giving one of those drugs alone, new research shows. Further, the combination was effective in the portion of melanoma patients--the majority--who currently have few effective treatment options.
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A Phase 2 clinical trial led by Ludwig Harvard's Stephen Hodi and Ludwig Memorial Sloan Kettering (MSK)'s Jedd Wolchok has found that the combination of two immunotherapies for first-line treatment of advanced melanoma induces better responses and far longer progression-free survival than giving one of those drugs alone. Further, the combination was effective in the portion of melanoma patients -- the majority -- who currently have few effective treatment options. The results of the trial, which compared a combination of checkpoint inhibitors ipilimumab and nivolumab against ipilimumab alone in previously untreated patients, were presented today at the 2015 Annual Meeting of the American Association for Cancer Research and have been simultaneously published in the New England Journal of Medicine.

"Preclinical studies suggested that this combination therapy would have better outcomes than those elicited by their individual or sequential administration," said Hodi, who is also director of the Melanoma Center at the Dana-Farber Cancer Institute. "It's very encouraging to see that pattern reflected in this trial with previously untreated patients."

A Phase 1 study completed in 2013 led by Wolchok, who leads the Ludwig Collaborative Laboratory at MSK and is also the Chief of the Melanoma and Immunotherapeutics Service at MSK, found that the same concurrent combination of therapies generated notably positive responses in previously treated patients.

"It was apparent following that trial that the combination should be tested as a first line therapy for metastatic melanoma," said Wolchok. "Rationally combined immunotherapies hold great promise for cancer treatment as long as their side effects can be managed."

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. In this group of patients, 72 received ipilimumab plus nivolumab, followed by nivolumab alone, while 37 got ipilimumab plus placebo.

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."


Story Source:

Materials provided by Ludwig Cancer Research. Note: Content may be edited for style and length.


Journal Reference:

  1. Michael A. Postow, Jason Chesney, Anna C. Pavlick, Caroline Robert, Kenneth Grossmann, David McDermott, Gerald P. Linette, Nicolas Meyer, Jeffrey K. Giguere, Sanjiv S. Agarwala, Montaser Shaheen, Marc S. Ernstoff, David Minor, April K. Salama, Matthew Taylor, Patrick A. Ott, Linda M. Rollin, Christine Horak, Paul Gagnier, Jedd D. Wolchok, F. Stephen Hodi. Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma. New England Journal of Medicine, 2015; 150420053025009 DOI: 10.1056/NEJMoa1414428

Cite This Page:

Ludwig Cancer Research. "Immunotherapy combination promising for untreated patients with advanced melanoma." ScienceDaily. ScienceDaily, 20 April 2015. <www.sciencedaily.com/releases/2015/04/150420084537.htm>.
Ludwig Cancer Research. (2015, April 20). Immunotherapy combination promising for untreated patients with advanced melanoma. ScienceDaily. Retrieved May 23, 2017 from www.sciencedaily.com/releases/2015/04/150420084537.htm
Ludwig Cancer Research. "Immunotherapy combination promising for untreated patients with advanced melanoma." ScienceDaily. www.sciencedaily.com/releases/2015/04/150420084537.htm (accessed May 23, 2017).

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