Keytruda Shows Activity in Urothelial Cancer

Data from an ongoing trial showed that one fourth of patients with PD-1-positive advanced urothelial cancer had objective responses to treatment with the immune checkpoint inhibitor Keytruda (pembrolizumab).

Seven of 28 evaluable patients (25 percent) responded to treatment, including three complete responses (10.7 percent). Patients had durable responses that ranged from 16 weeks to more than a year. Additionally, Keytruda was generally well tolerated among patients with urothelial cancer, as reported at the 2015 American Urological Association (AUA) Annual Meeting.

“In this heavily pretreated population, Keytruda provided a median overall survival of 12.7 months and a 12-month overall survival of 54.7 percent,” says Shilpa Gupta, MD, a genitourinary oncologist at Moffitt Cancer Center in Tampa. “These results support the ongoing development of Keytruda for the treatment of urothelial cancer.”

Ongoing clinical development includes a phase 3 trial comparing Keytruda versus paclitaxel, docetaxel, or vinflunine in patients whose disease progressed or recurred following treatment with platinum-based chemotherapy. Additionally, a phase 2 trial is evaluating Keytruda in patients with advanced urothelial cancer ineligible for platinum chemotherapy.

The PD-1 receptor antagonist Keytruda received FDA approval in 2014 for unresectable or metastatic melanoma and progression following treatment with Yervoy (ipilimumab) and (if indicated) a BRAF inhibitor. The FDA approved dose of the drug in patients with melanoma is 2 mg/kg once every three weeks.

The KEYNOTE clinical development program has evaluated Keytruda in multiple types of solid tumors, including urothelial cancer. As part of the phase 1b KEYNOTE-012 study, investigators screened 95 patients with urothelial cancer, and 61 of the patients (64.2 percent) had tumors that tested positive for PD ligand 1 (PD-L1). Subsequently, 33 of the 61 patients were enrolled in KEYNOTE-012.

The primary objectives were to determine the safety and tolerability of Keytruda in patients with PD-L1 positive tumors, evaluate Keytruda activity by RECIST criteria, and evaluate progression-free and overall survival.

The patients had a median age of 70 and most were men (69.7 percent). Two thirds had visceral (liver metastases in 24 percent) or bone metastases, 73 percent had ECOG performance status 1, and half of the patients had received two or more prior therapies for advanced urothelial cancer.

Each patient received Keytruda at a dose of 10 mg/kg every two weeks, continued until disease progress, intolerable toxicity, discontinuation, withdrawal, or completion of two years of treatment.

Gupta reported data from a median follow-up of 13 months, at which time, four of the patients remained on Keytruda. The most common reason for discontinuation was progressive disease (17 patients).

Overall, two thirds of the patients (66.7 percent) had some degree of tumor shrinkage during treatment with Keytruda. In the 28 patients with measurable disease at enrollment, the objective response rate by RECIST v1.1 criteria was 25 percent. Median time to response was 10 weeks, and median response duration had yet to be reached (range of 16 to more than 50 weeks).

Three of seven objective responses met criteria for complete response, and the remaining four were partial responses, Gupta reported. Four patients had stable disease as best response (14.3 percent), 13 had progressive disease, and response assessment had not occurred in four patients.

The median progression-free survival (PFS) was 2.0 months and the 12-month PFS rate was 19.0 percent with Keytruda. The 12-month OS rate was 54.7 percent with a median of 12.7 months.

The safety analysis revealed treatment-related adverse events in 21 patients (63.6 percent), most often fatigue (six patients, 18.2 percent), peripheral edema (four patients, 12.1 percent), and nausea (three patients, 9.1 percent). Five patients (15.2 percent) had one or more grade 3-5 adverse events. One patient discontinued due to a grade 3 rhabdomyolysis.

Gupta S, O’Donnell P, Plimack ER, et al. A Phase 1b Study of Pembrolizumab (Pembro; MK-3475) for Advanced Urothelial Cancer. Presented at: 2015 AUA Annual Meeting; May 15-19, 2015; New Orleans, LA. Abstract MP68-11.