Since the early 2000s, when Dana-Farber scientists discovered that many cancer cells carry “checkpoint” proteins that ward off an immune system attack on tumors, a great deal of research has focused on the development and testing of agents capable of blocking those proteins. In many patients, such agents have sent cancers into long-term remissions. A checkpoint protein called CTLA-4, which was discovered more than a decade earlier, however, has revolutionized the treatment of metastatic melanoma, one of the most stubborn of all cancers to treat.
In 1987, French researchers reported the discovery of CTLA-4 on the surface of immune system T cells, which specialize in identifying and destroying diseased and cancerous cells in the body. The role of CTLA-4, however, was a mystery until 1996, when scientists led by James Allison at the University of California at Berkeley showed that it acts as a brake on the T cell attack on certain cancer cells. These findings, confirmed by later studies, led to the development of ipilimumab, an antibody-based drug that targets CTLA-4. Dana-Farber’s F. Stephen Hodi, MD, director of the Melanoma Center and the Center for Immuno-Oncology, led a phase 3 clinical trial of the drug in patients with melanoma that had spread despite previous treatment.
The results, published in The New England Journal of Medicine in 2010, showed that patients who received the drug lived significantly longer than those who hadn’t—the first time any treatment had been shown to extend survival times for patients with metastatic melanoma. Some patients treated with the drug had a long-lasting benefit; one group of patients were apparently cured of their disease. Ipilimumab, marketed as Yervoy®, received approval by the Food and Drug Administration in 2011 for the treatment of patients with metastatic melanoma.
Hodi and his colleagues have worked to better understand which patients with melanoma are likely to be helped by ipilimumab, and to extend the drug’s benefits to a larger percentage of patients. In 2014 he published a study showing that patients with high blood levels of the protein VEGF tend to have a poor response to ipilimumab. The findings suggest that such patients may benefit from regimens that combine checkpoint inhibitors like ipilimumab with VEGF-blocking agents such as bevacizumab (Avastin®). Hodi’s team has launched a clinical trial of this combination in patients with advanced melanoma.
The success of ipilimumab in melanoma has prompted Hodi to organize an early-phase clinical trial of a drug that blocks another checkpoint protein—PD-1—on T cells. Last year, he and associates at Johns Hopkins University, Yale University, and other research centers published the results of a phase 1 study showing that the PD-1-blocking drug nivolumab (Opdivo) can drive metastatic melanoma into remission or hold it in check for more than two years in some patients. The study, published in the Journal of Clinical Oncology, provides the longest-term look to date at how melanoma patients have fared since receiving the drug.
Most recently, Hodi reported four-year follow-up results of a phase 3 trial, called CheckMate 067, in which patients with advanced melanoma were treated with a combination of ipilimumab and nivolumab. The combination was more effective than either drug alone when given as initial therapy for the disease. The response rate with the combination was 58 percent compared with ipilimumab (19 percent) or nivolumab (45 percent) alone. The combination eradicated all visible signs of the cancer—a “complete response” – in 21 percent of patients on the combination, versus 18 percent for nivolumab and 5 percent for ipilimumab.
The ipilimumab-nivolumab combination also reduced the risk of death in the long term, with more than half of the patients (53 percent) living past the four-year mark, compared with 46 percent for nivolumab or 30 percent for ipilimumab alone. “To the best of our knowledge, we have not seen a 53 percent overall survival rate with any available treatment at four years of follow-up in a randomized setting,” said Hodi.
Nearly all patients who received the two-drug combination experienced adverse events, such as diarrhea, colon inflammation, and high levels of lipase, a liver enzyme.
“Many are working on the next generation of anti-CTLA-4 drugs to try to improve efficacy and diminish toxicity,” Hodi said.