Results from the KEYNOTE-028 trial show that pembrolizumab is well tolerated and improves clinical outcomes for patients with malignant pleural mesothelioma. Compared with second-line chemotherapy, the response rate achieved with this immune checkpoint inhibitor is considerably higher.

Results from the phase I multi-cohort KEYNOTE-028 trial assessing pembrolizumab (Keytruda; Merck) in 20 different solid tumors indicate that the drug improves clinical outcomes for patients with malignant pleural mesothelioma (MPM). The trial's MPM cohort data only were reported by Evan Alley, MD, PhD, codirector of the mesothelioma and pleural program at the University of Pennsylvania School of Medicine, at the American Association for Cancer Research Annual Meeting 2015 in Philadelphia, PA, April 18–22.

MPM originates in the pleura, a thin cell layer lining the lungs and chest wall. It is a rare malignancy; in the United States, approximately 3,000 cases are diagnosed every year, with asbestos exposure being the key culprit. The median survival with standard therapy, pemetrexed (Alimta; Eli Lilly) plus cisplatin, is only about 13 months.

“We usually prescribe gemcitabine [Gemzar; Eli Lilly] or vinorelbine as second-line therapy, but the response rates are 10% or less, so there's clearly a need for other options,” Alley said. Approximately 40% of patients with MPM express PD-L1—a ligand of pembrolizumab's target, PD-1—in their tumor cells, so Alley and his colleagues decided to investigate the potential of pitting the immune system against MPM.

KEYNOTE-028 enrolled 25 patients into its MPM cohort, all with advanced disease and PD-L1 expression in at least 1% of their tumor cells—determined by immunohistochemistry—who were unable to receive standard therapy or no longer responded to it. The response rate to pembrolizumab was 28%, and another 48% achieved stable disease. Tumor shrinkage in the responders was observed as early as 8 weeks after the first dose of the drug. Pembrolizumab was well tolerated, Alley reported, with relatively mild (grades 1-2) fatigue and nausea being the main side effects, while the chief immune-related adverse event was a grade 1 rash.

“The response rate we've seen with pembrolizumab is unprecedented, looking at historical data for second-line chemotherapy,” Alley remarked, “and we feel that this warrants its continued evaluation in patients with advanced MPM.”

“It's a reasonable conclusion, given the dearth of options for this disease,” said D. Ross Camidge, MD, PhD, director of the University of Colorado Comprehensive Cancer Center's thoracic oncology clinical program.

While acknowledging that drugs targeting the PD-1 receptor and its ligands are “a major therapeutic breakthrough, with dramatic activity in a subset of solid tumors,” Camidge emphasized that further research is needed to identify the patients most likely to benefit from the drug. PD-L1 expression in tumor cells may be a potential biomarker, but whether it truly predicts therapeutic benefit or is merely prognostic—providing information on disease outcome independent of therapy—remains to be established, he said.

Nonetheless, “just because we don't yet know who this immunotherapy actually works in doesn't mean it shouldn't be given at all, or given to everyone,” Camidge added. “Every cancer therapy has different chances of benefit in different situations; at each decision point, we prioritize the treatment with the greatest chance of success.”