Pembrolizumab Active in Advanced Urothelial Cancer

Shilpa Gupta, MD

A fourth of patients with PD-1-positive advanced urothelial cancer had objective responses to treatment with the immune checkpoint inhibitor pembrolizumab, data from an ongoing trial showed.

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

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

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

The PD-1 receptor antagonist pembrolizumab received FDA approval in 2014 for unresectable or metastatic melanoma and progression following treatment with ipilimumab and (if indicated) a BRAF inhibitor. The FDA approved dose of the drug in patients with melanoma is 2 mg/kg once every 3 weeks.

The KEYNOTE clinical development program has evaluated pembrolizumab in multiple types of solid tumors, including urothelial cancer. As part of the phase Ib KEYNOTE-012 study, investigators screened 95 patients with urothelial cancer, and 61 of the patients (64.2%) 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 pembrolizumab in patients with PD-L1 positive tumors, evaluate pembrolizumab 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%). Two thirds had visceral (liver metastases in 24%) or bone metastases, 73% had ECOG performance status 1, and half of the patients had received two or more prior therapies for advanced urothelial cancer.

Each patient received pembrolizumab at a dose of 10 mg/kg every two weeks, continued until disease progress, intolerable toxicity, discontinuation, withdrawal, or completion of 2 years of treatment.

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

Overall, two thirds of the patients (66.7%) had some degree of tumor shrinkage during treatment with pembrolizumab. In the 28 patients with measurable disease at enrollment, the objective response rate by RECIST v1.1 criteria was 25% (95% CI, 10.7-44.9). 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%), 13 had progressive disease, and response assessment had not occurred in four patients.

The median progression-free survival (PFS) was 2.0 months (95% CI, 1.7-4.0) and the 12-month PFS rate was 19.0% with pembrolizumab. The 12-month OS rate was 54.7% with a median of 12.7 months (95% CI, 5.0-not yet reached).

The safety analysis revealed treatment-related adverse events in 21 patients (63.6%), most often fatigue (6 patients, 18.2%), peripheral edema (4, 12.1%), and nausea (3, 9.1%). Five patients (15.2%) 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.

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