Learning More about Checkpoint Blockades

Researchers are learning more about how to optimize the melanoma therapy ipilimumab, an FDA-approved drug made by Bristol-Myers Squibb and sold under the brand name Yervoy. In two studies presented at the American Society of Clinical Oncology's (ASCO) annual conference, held May 30–June 3 in Chicago, IL, they reported on new ways of using the only checkpoint blockade therapy that has so far won federal approval.

In a phase III study, researchers found that giving ipilimumab earlier in the disease course provides some benefit, but perhaps not enough to justify its risks. Led by Alexander Eggermont, MD, PhD, director general of the Gustave Roussy Cancer Campus Grand Paris in Villejuif, France, the study achieved its primary endpoint of progression-free survival by delaying melanoma recurrence for an average of 9 months.

“This is the first trial ever with a drug that had an improvement on overall survival in metastatic melanoma” in an adjuvant setting, Eggermont said.

However, one third of the 475 patients in the treatment arm suffered grade 3 adverse events, more than 5% endured grade 4 side effects, and five died.

Steven J. O'Day, MD, an immunologist and clinical associate professor of medicine at the University of Southern California Keck School of Medicine in Los Angeles, cautioned that the drug's effectiveness in more advanced disease compared with the risk of side effects might not justify its earlier use—particularly because interferon is roughly as effective as ipilimumab in preventing recurrence at this stage.

“We can salvage these patients in the metastatic setting, not just by improving their survival but by producing long-term survival/cure,” said O'Day. “So our tolerance for death or severe toxicity in the adjuvant setting is a different bar.”

An expanded phase I study involving patients with advanced melanoma who had received up to three prior therapies looked at combining ipilimumab with an experimental checkpoint blockade called nivolumab, also from Bristol-Myers Squibb.

Mario Sznol, MD, a professor of medical oncology at Yale University School of Medicine and Yale Cancer Center in New Haven, CT, updated figures presented at last year's ASCO meeting to show “unprecedented 1- and 2-year survival rates.” With the combination therapy, 79% of the initial 53 patients were still alive 2 years after their treatment. Activity of the combination was confirmed in a new cohort of 41 patients, with an overall response rate of 43%.

As with Eggermont's study, the burden of grade 3 and 4 side effects was also high, at 62%, with one treatment-related death. However, Sznol said he believes most of the side effects will be manageable.

O'Day said the results of these and other studies in melanoma reminded him of the survival curves of childhood leukemia, which was transformed from a death sentence into a largely survivable disease. “That's what's so palpably exciting about melanoma,” he added.

Researchers still need to work out the most effective sequencing of the drugs to minimize adverse events and maximize survival, O'Day and Sznol said. Phase III trials to answer that question are under way.