May 31, 2015, Chicago, Ill.—A Phase 3, multicenter clinical trial led by Ludwig Cancer Research investigators Jedd Wolchok and Stephen Hodi shows that the combination of two immunotherapies—ipilimumab and nivolumab—induces more frequent responses and considerably longer progression-free survival in patients with advanced melanoma than the administration of either of them alone. The results of the trial, which confirm those of a smaller study similarly conducted in previously untreated patients by the same Ludwig scientists, were presented today at the 2015 American Society for Clinical Oncology Annual Meeting and published online later today in the New England Journal of Medicine.
“Both the basic immunology and earlier clinical trials suggest this combination of drugs should have additional activity in patients with advanced melanoma,” says Wolchok, who has a dual role as director of the Ludwig Collaborative Laboratory and associate director of the Ludwig Center at Memorial Sloan Kettering. “It is at once comforting and exciting to have that expectation confirmed in a large, Phase 3 trial involving patients with this very aggressive cancer.”
The international team of researchers found that, for ipilimumab alone, the median overall progression-free survival (PFS)—the length of time following treatment before the cancer resumed its growth—was 2.9 months. Patients treated with nivolumab alone had a median PFS of 6.9 months, while the combination of the two induced a PFS of 11.5 months. The data required to measure overall survival of the patients in each arm of the study are still being gathered by the researchers. But the PFS data confirm the results of previous studies of each drug used alone and in combination to treat metastatic melanoma.
Also consistent with previous trials was the finding that 19% of patients treated with ipilimumab alone and 43.7% treated with nivolumab had an objective response, measured as a significant reduction in tumor size, to each therapy. The response rate for the combination therapy was 57.6%.
“The results of the trial confirm the effects of combining immune checkpoints seen in previous studies while setting an additional option for patients with melanoma,” says Hodi, who is an investigator at the Ludwig Center at Harvard University. Ipilimumab is an antibody that targets CTLA-4—a protein found on T cells, which can destroy cancerous and diseased cells. When switched on, it tamps down T cell activity. Nivolumab, meanwhile, binds and blocks a protein known as PD-1, also found on T cells. PD-1 is engaged by a protein known as PD-L1, which some tumor cells express to thwart T cell attack. Both drugs, often referred to as checkpoint inhibitors, have been approved by the US Food and Drug Administration.
To pin down a possibly important determinant of response, the researchers examined the tumors of all patients for PD-L1 expression. They found that patients whose tumors expressed PD-L1 had a PFS of 14 months, whether they were given nivolumab or the combination therapy. In those with PD-L1 negative tumors, the PFS for nivolumab alone was 5.3 months; for the combination therapy, it was 11.2 months.
“This is a very interesting result,” says Wolchok. “It allows a physician to carefully consider whom to offer the treatment that has a greater likelihood of inducing toxicity, and to do so knowing the expected difference in benefit. So with the caveat that we’ve only reported progression-free survival here, and not overall survival, this means that if a patient’s tumor is PD-L1 positive and if the patient is risk averse, you can offer nivolumab alone—and feel OK about it. If it turns out that the tumor is PD-L1 negative, you have a very strong rationale for offering the combination.”
In addition to their affiliations as Ludwig investigators, Jedd Wolchok is the chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering and Steve Hodi is the director of the Melanoma Center at the Dana-Farber Cancer Institute.
The trial was supported by Bristol-Myers Squibb.
About Ludwig Cancer Research
Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for more than 40 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested more than $2.5 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers.