Dual Immunotherapies Shrink Melanomas

Pairing a checkpoint inhibitor with an antibody that stimulates antigen-presenting cells shrank tumors in 27% of patients with metastatic melanoma, a new study finds.

Tumor cells defuse immune attacks by activating inhibitory receptors such as PD-1 and CTLA-4 on CD8+ T cells. Checkpoint inhibitors reverse this effect, but most patients don't respond to single checkpoint inhibitors. For example, ipilimumab (Yervoy; Bristol-Myers Squibb) targets CTLA-4, and the 2010 study that led to its approval showed an overall response rate of 10.9% in patients with metastatic melanoma. Thus, researchers have begun testing combinations of immunotherapies. Ipilimumab and a checkpoint inhibitor that blocks PD-1, nivolumab (Opdivo; Bristol-Myers Squibb), produced objective responses in 40% of patients with advanced melanoma, researchers reported 2 years ago.

David Bajor, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and colleagues tried a different strategy, combining the CTLA-4 blocker tremelimumab (AstraZeneca) with the antibody CP-870,893 (RO7009789; Roche). CP-870,893 is not a checkpoint inhibitor; it stimulates the CD40 receptor on antigen-presenting cells, boosting the immune response against the tumor. Bajor describes this approach as cutting the immune system's brakes while simultaneously stepping on its gas pedal.

On April 19 at the American Association for Cancer Research Annual Meeting 2015 in Philadelphia, Bajor presented the results of a phase I trial to test the strategy. Twenty-four patients with metastatic melanoma received CP-870,893 every 3 weeks and tremelimumab every 3 months for up to a year. Seventy-one percent of the patients had received prior treatments, including chemotherapy, but none had received treatments that target CTLA-4 or CD40.

Of 22 evaluable patients, tumors disappeared in two and diminished in four others, for an overall response rate of 27.3%. The median overall survival for the group was 26.1 months. The number of activated CD8+ T cells rose in patients who responded to the treatment, indicating that the combination can release the inhibition on these cells.

Three patients developed colitis, and 15 developed a side effect known as cytokine release syndrome, a surge in certain cytokines that can cause fever, muscle pain, and low blood pressure. However, the team could control the symptoms with over-the-counter medications and by slowing the drug infusion rate, Bajor says. Although one patient died early in the trial, the researchers think her death was caused by her cancer, not the treatment, he says.

The study indicates that the team's approach “can be safe and effective, and can activate the immune system,” says Bajor.

The objective response rate “is higher than [with] tremelimumab or ipilimumab alone,” notes Paul Chapman, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, who wasn't connected to the study. The approach “merits further testing,” he says.

The trial suggests other potential drug combinations. CD8+ T cells in the patients were inhibited by PD-1, implying that adding an antibody to block PD-1—or its activator, PD-L1—could improve the results. A phase I trial has started in Europe and Canada that will evaluate the combination of an anti–PD-L1 antibody and CP-870,893 in patients with solid tumors.

Meanwhile, Bajor and his colleagues plan to test the safety and effectiveness of combining CP-870,893 with chemotherapy in patients undergoing surgery for pancreatic cancer.