Melanoma, a malignancy that originates in the pigment-producing cells of the skin, is cured 98 percent of the time by simple surgery when it is caught early. But once it has spread, it is aggressive and can be highly resistant to therapy.
A team of researchers led by Ludwig Cancer Research scientist Stephen Hodi reported the results of the longest follow-up survival study conducted to date on patients with advanced melanoma who were treated with the PD-1 inhibitor nivolumab.
‘A subset of heavily-treated patients with advanced melanoma derive a significant long-term clinical benefit from treatment with nivolumab.’
Hodi and his colleagues announced at a press event during the American Association for Cancer Research Annual Meeting in New Orleans that 34 percent of the patients treated with this immunotherapy alone in a previous Phase 1 trial were still alive five years later.
"Our results show that a subset of heavily-treated patients with advanced melanoma derive a significant long-term clinical benefit from treatment with nivolumab," said Hodi, investigator at the Ludwig Center at Harvard. "These results give us an additional paradigm shift for how we treat patients with this cancer, and we are hopeful that these findings will hold true for other cancers as well."
The median survival time of patients diagnosed with advanced melanoma has historically been about 11 months. The therapy evaluated in this study, nivolumab, is an antibody made by Bristol-Myers Squibb (BMS) against a protein expressed on the surface of killer T cells, which target diseased and cancerous cells. PD-1's engagement by proteins named PD-L1 and PD-L2 found on the surface of other cells suppresses the T cell response. Many types of cancer cells have adapted to express those proteins at high levels to protect themselves from immune attack. Nivolumab binds PD-1 and disrupts its interaction with the PD-L proteins, and is known in industry parlance as a checkpoint inhibitor.
In the current study, 107 patients diagnosed with advanced melanoma who had received one to five prior systemic therapies for their cancer were treated with nivolumab at different doses (0.1, 0.3, 1, 3, or 10 mg/kg) every two weeks for a maximum of 96 weeks beginning in October 2008. Researchers continued to track their survival after treatment had ceased. They found that the median overall survival for patients receiving 3mgs/Kg of nivolumab was about 20.3 months. For all patients at all doses, it was found to be 17.3 months.
The proportion of surviving patients declined steadily from 63 percent after the first year to 42 percent by the third. At around four years, however, the survival rate appeared to level off around 34 percent. In a previous study, patients treated with another checkpoint inhibitor named ipilimumab-which targets another T cell protein named CTLA-4-were found in an analysis conducted by Ludwig scientist Jedd Wolchok and his colleagues to have a long term survival of about 21 percent at three years. In that case too, survival appeared to level off, though it did so after about three years.
Nivolumab and ipilimumab have been tested in combination for melanoma in a Phase 3 trial led by Wolchok and Hodi. That study, reported at last year's AACR Annual Meeting, led to the US Food and Drug Administration's approval of the combination therapy for treating advanced, inoperable melanoma. Overall survival data for this combination therapy continues to be collected by Hodi, Wolchok and other researchers involved in that trial. Stephen Hodi is also Director of the Melanoma Center and the Center for Immuno-Oncology at Dana-Farber/Brigham and Women's Cancer Center.