A New Standard of Care for Advanced Urothelial Carcinoma

Recent findings from the phase 3 Keynote-045 study demonstrate that Keytruda (pembrolizumab) should be the new standard of care to treat patients with advanced urothelial carcinoma who progressed during or after platinum-based therapy. According to results reported at the 19th European Cancer Congress (ECCO 2017), the PD-1 inhibitor significantly prolonged overall survival (OS) over investigators’ choice of chemotherapy in patients with recurrent advanced urothelial carcinoma.

Urothelial carcinoma is currently treated in the first-line setting with platinum-based chemotherapy, and there is no standard therapy for recurrent or progressive disease.

At a median follow-up of 14.1 months (range: 9.9-22.1), the median OS with Keytruda was 10.3 months compared with 7.4 months with standard chemotherapy. One-year OS rates were 43.9 percent with Keytruda versus 30.7 percent with chemotherapy.

The confirmed objective response rate was 21.1 percent with Keytruda compared to 11.4 percent with chemotherapy. Complete response (CR) was reported for 7 percent of patients, and partial response (PR) for 14.1 percent of patients treated with Keytruda, compared to a CR in 3.3 percent and a PR in 8.1 percent of patients receiving chemotherapy.

“Pembrolizumab is the first agent to demonstrate OS improvement compared with chemotherapy in patients with advanced urothelial carcinoma after failure of platinum-based chemotherapy,” said Andrea Necchi, Fondazione IRCCS Istituto Nazionale dei Tumori, in Milan, Italy. “This is the first immunotherapy to demonstrate OS benefit over an active comparator in urothelial carcinoma.”

In the KEYNOTE-045 trial, 270 patients with advanced urothelial carcinoma were randomized after the failure of platinum-based doublet chemotherapy to Keytruda at 200 mg every three weeks for 24 months, and 272 patients to receive the investigator's choice of paclitaxel at 175 mg/m², docetaxel at 75 mg/m², or vinflunine at 320 mg/m², each administered every three weeks. Randomization was stratified by ECOG performance status (0/1 versus 2), liver metastases (yes versus no), hemoglobin level (less than 10 versus more than 10 g/dL), and the time from last chemotherapy (less than three versus three or more months). The median patient age was 66 years, and nearly all patients had an ECOG performance status of 0 or 1.

There was no significant difference in progression-free survival (PFS); median PFS was 2.1 months with Keytruda compared with 3.3 months with chemotherapy.

“The objective response rate was significantly higher, and the response was more durable with pembrolizumab,” said Necchi.

For those receiving Keytruda, the median time to response was 2.1 months (range: 1.4-6.3) compared with 2.1 months (range: 1.7-4.9) with chemotherapy. The median duration of response (DoR) was not reached (range: 1.6-15.4+) with Keytruda, and 4.3 months (range: 1.4-15.4+) with chemotherapy.

A combined positive score was determined in patients with quantifiable PD-L1 expression on tumor and infiltrating immune cells; patients with high PD-L1 expression were described CPS 10 or greater.

In the CPS 10 or greater cohort 74 patients received Keytruda and 90 patients received chemotherapy. Median OS was eight months versus 5.2 months, and one-year OS rates were 39.8 percent with Keytruda versus 26.97 percent with chemotherapy. However, the ORR with Keytruda was 21.6 percent compared with 6.7 percent with chemotherapy.

“Pembrolizumab benefit was observed regardless of PD-L1 expression, “Necchi commented.

The KEYNOTE-045 investigators also performed a meta-analysis of OS in studies of second-line immunotherapy for advanced urothelial carcinoma that showed the median OS of 10.30 months demonstrated in this study was greater that the 9.7 months seen with Opdivo (nivolumab) in a phase 1/2 trial, the 8.74 months with Opdivo in a phase 2 trial and the 7.9-month OS shown with Tecentriq (atezolizumab) in a phase 2 trial.

The median exposure with Keytruda was 3.5 months (range, 0.03-20.0) with Keytruda compared to 1.5 months (range, 0.03-14.2) with chemotherapy.

Treatment-related adverse events (TRAEs) were less frequent with Keytruda compared with chemotherapy. The rates of all-grade TRAEs were 60.9 percent and 90.2 percent, and grade 3-5 TRAEs occurred in 15 percent of patients treated with Keytruda and 49.9 percent in patients treated with chemotherapy. TRAEs with Keytruda occurring at an incidence of 10 percent or more were pruritus (20 percent), fatigue (10 percent), nausea (10 percent) and diarrhea (10 percent).

Treatment discontinuation due to a TRAE was reported for 15 (5.6 percent) Keytruda patients compared to 28 (11 percent) of chemotherapy patients. Four deaths due to a TRAE occurred in each arm.

“The data from KEYNOTE-047 demonstrated that pembrolizumab treatment resulted in durable overall survival benefit with lower incidence of serious adverse events versus chemotherapy,” said Necchi. “Pembrolizumab should become the new standard of care for advanced urothelial carcinoma that progressed on or after platinum-based chemotherapy.”

The FDA approved Keytruda on Oct. 24, 2016, for the treatment of patients with metastatic non-small cell lung cancer whose tumors express PD-L1, as determined by an FDA-approved test.

Funding from Merck & Co. was reported.