Pembrolizumab Shows Antitumor Activity in Advanced Urothelial Cancer

Pembrolizumab demonstrates durable antitumor activity in patients with advanced urothelial cancer, with a higher response rate seen in patients with programmed death-ligand 1 (PD-L1) expression, according to the updated results of a phase I, multi-cohort study presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 29 to June 2, in Chicago.

“In this heavily pretreated population, the overall response rate (ORR) was 28%, including a complete response (CR) rate of 10%. Response duration ranged from 8 to 64 weeks. Half of the patients were alive at 12 months,” said lead author Elizabeth R. Plimack, MD, director of genitourinary clinical research at Fox Chase Cancer Center in Philadelphia.

Previously, pembrolizumab, an anti–PD-1 antibody, has demonstrated antitumor activity and acceptable safety in patients with recurrent or metastatic PD-L1–positive urothelial cancer. Plimack presented updated efficacy and safety data for urothelial cancer patients, as well as an analysis of the relationship between PD-L1 expression and ORR.

The study (abstract 4502) enrolled 33 patients, median age 70 years, with recurrent, metastatic, or persistent urothelial cancer of the bladder, renal pelvis, ureter, or urethra who received pembrolizumab 10 mg/kg every 2 weeks until CR, progression, or unacceptable toxicity. One-third of the patients had three or more prior therapies, and two-thirds of them had osseous metastases.

After a median follow-up duration of 15 months, about two-thirds of the patients “experienced a reduction in the size of target lesions,” Plimack said. Of the 29 patients evaluable for response, the median time to response was 9 weeks. Three patients remain on therapy.

Responses include three CRs, five partial responses, and three patients with stable disease.

The median progression-free survival was 2 months with a 12-month PFS rate of 19%. Median overall survival (OS) was 12.7 months, with a 12-month OS rate of 52.9%.

In an exploratory analysis of predictive value of PD-L1 scoring, about 30% of patients with tumors positive for PD-L1 expression responded. “In order to maximize detecting responders while minimizing the false negative rate, scoring needs to take into account both PD-L1-positive tumor cells and PD-L1-positive tumor-associated inflammatory cells,” she said.

In addition, there was a suggestion of an association between clinical outcome and a previously defined gene expression signature related to T-cell signaling.

The majority of patients experienced mild or no adverse events. Grade 3/4 drug-related adverse events occurred in five (15%) patients. One patient discontinued due to treatment-related adverse events.

“The median OS of 12.7 months compares favorably to historical controls in the second-line setting,” Plimack said.

She noted that two ongoing, open clinical trials are investigating pembrolizumab in urothelial cancer.

ASCO discussant Noah M. Hahn, MD, associate professor of medicine at Johns Hopkins University, commented: “The impressive results for this population show more than a doubling of response rates than unselected patients in previous trials. Pembrolizumab was well-tolerated, with grade 3/4 adverse events much lower than cytotoxics. This agent expands our therapeutic options for urothelial cancer.”

There is a “clear message that PD-L1 does seem to be associated with improvement in tumor response,” Hahn said. “We need to look at PD-L1 agents independently.”