Enhancing PD-1 Blockade in Solid Tumors

Findings from a phase I study show that a two-agent combination—the investigational immunotherapy utomilumab (PF-2566; Pfizer) plus pembrolizumab (Keytruda; Merck)—is well tolerated, producing sustained responses in about a quarter of patients with various solid cancers. Anthony Tolcher, MD, director of clinical research at South Texas Accelerated Research Therapeutics in San Antonio, presented the findings at the annual meeting of the American Society of Clinical Oncology in Chicago, IL, June 3–7.

“Despite the transformative effect that PD-1–targeting therapies have had in many malignancies, the vast majority of patients who receive these drugs otherwise progress or fail to respond,” Tolcher said. “As such, combinations that might enhance antitumor effects where PD-1 blockade alone is insufficient are desperately needed.”

Utomilumab, a humanized monoclonal antibody, binds to the costimulatory immune checkpoint molecule CD137, also known as 4-1BB, ultimately resulting in enhanced cytotoxic T-cell activity. In preclinical studies with a mouse melanoma model and a colon carcinoma cell line, Pfizer researchers showed that targeting CD137 with an agonist antibody enhanced the antitumor immune effects of PD-1 blockade.

The phase I study enrolled 23 patients with a range of solid cancers, the majority being non–small cell lung cancer, renal cell carcinoma (RCC), and head and neck cancer—tumor types that have been responsive to PD-1 therapies, Tolcher said. All participants had advanced or metastatic disease that had progressed on prior therapy. Six patients achieved an objective response to utomilumab plus pembrolizumab, including two complete responses in small cell lung cancer and RCC. One patient with anaplastic thyroid carcinoma, a highly aggressive disease that lacks effective treatment options, achieved a “dramatic partial response” after only four cycles of combination therapy, Tolcher noted.

Overall, as seen in other trials of PD-1–targeting therapies, “if you do achieve a response, these seem to be durable,” Tolcher said. Of five ongoing responses, three have passed 12 months. The responders had increased numbers of activated cytotoxic T cells, he added, as well as higher levels of IFNγ, a common biomarker for T-cell activation.

Utomilumab plus pembrolizumab had a good safety profile, akin to that of PD-1 inhibitors, Tolcher reported—fatigue and rash were the main side effects, and no patients discontinued treatment due to adverse events. No synergistic or additive toxicities were evident with this combination, nor did it affect either drug's pharmacokinetic profile.

On the whole, this is “a notable study with very little in the way of limitations,” said David Spigel, MD, chief scientific officer and director of the lung cancer research program at Sarah Cannon Research Institute in Nashville, TN. “The sustained responses in patients with a variety of refractory tumors—and the safety profile of a novel immunotherapy combination—is very encouraging.” –Esther Landhuis