FDA Grants Priority Review to Frontline Pembrolizumab for Urothelial Carcinoma

Arjun Balar, MD

The FDA has granted a priority review to pembrolizumab (Keytruda) as a treatment for cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma, according to Merck, the developer of the PD-1 inhibitor.

The priority review was based on data from the open-label phase II KEYNOTE-052 study, which was presented at the 2016 ESMO Congress. In first 100 patients enrolled in the study, the objective response rate (ORR) with pembrolizumab was 24%, which included a 6% complete response (CR) rate. After a median follow-up of 8 months, the median duration of response was not yet reached (range, 1.4+ to 9.8+ months), and 83% of patients responded to therapy for ≥6 months.

Under the priority review program, the FDA will make a decision on the supplemental biologics license application (sBLA) for pembrolizumab 4 months faster than a standard review. The deadline for the approval, under the Prescription Drug User Fee Act, is June 14, 2017, according to Merck.

“The activity that we’ve seen is clearly clinically meaningful, and there are durable responses that we are observing with these patients,” lead study author Arjun Balar, MD, from the NYU Langone Medical Center, told OncLive when he presented the results at the 2016 ESMO Congress. "I hope to see immunotherapy as a backbone upon which we develop other novel therapeutic approaches."

The phase II study enrolled 374 total patients, with an interim assessment for the first 100 participants. In the single-arm trial, pembrolizumab was administered at a flat 200 mg dose intravenously on day 1 of each 3-week cycle for up to 24 months. The median age for the first 100 patients was 75 years (range, 44-94), and 87% had visceral metastases at baseline. Patients had an ECOG performance status of 3 (1%), 2 (45%), 1 (30%), and 0 (24%).

The interim analysis of the study also assessed the impact of PD-L1 expression on response rates. PD-L1 was quantified using a combined positive score (CPS) on tumor and infiltrating immune cells. Of those assessable for this examination, 33 had a CPS of <1%, 33 had a CPS of ≥1% and <10%, and 30 had a CPS of ≥10%.

In those with expression of <1%, the ORR was 18% and the CR rate was 3% (95% CI, 0.1-16). In those with expression on ≥1% and <10%, the ORR was 15% (95% CI, 5-32) and there were no CRs. In those with a CPS of ≥10%, the ORR was 37% (95% CI, 20-56) and the CR rate was 13% (95% CI, 4-31).

"Using the CPS, we aimed to find a level of expression where we enriched greatly for responses but also minimized the false-negative rate," said Balar. "In essence, what we found was that the PD-L1 expression CPS cut point of 10% or greater, seemed to enrich for responses really well."

The adverse events (AEs) observed in the phase II study were consistent with prior trials exploring the PD-1 inhibitor. Overall, 5 patients discontinued treatment due to a treatment-related AE. There were no deaths attributed to treatment-related AEs.

All-grade treatment-related AEs were experienced by 67% of patients and included fatigue (14%), pruritus (12%), pyrexia (8%), decreased appetite (7%), diarrhea (7%), rash (7%), chills (6%), hypothyroidism (6%), and nausea (6%). Grade 3/4 treatment-related AEs were experienced by 16% of patients, and included fatigue (4%), muscle spasms (2%), decreased appetite (1%), and diarrhea (1%).

"We did see some notable immune-related adverse events, such as colitis, nephritis, and pneumonitis, in patients enrolled in this trial," said Balar. "But the overall frequency in the first 100 patients was very low, which means only 1 or 2 patients had developed each one of those toxicities."

In addition to the frontline indication, the FDA is also considering an sBLA for pembrolizumab as a second-line therapy for patients with urothelial carcinoma following a platinum-based agent. The deadline for this application is also June 14, 2017.

Outside of urothelial carcinoma, applications for pembrolizumab are also pending for the agent as a treatment for microsatellite instability-high cancer and Hodgkin lymphoma. The FDA has approved pembrolizumab for melanoma, lung cancer, and head and neck cancer.

Balar A, Bellmunt J, O’Donnell PH, et al. Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic urothelial cancer: Preliminary results from the phase II KEYNOTE-052 study. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA32.