ESMO 2016: Pembrolizumab Trial Stops Early, Meets Primary Endpoint in Advanced Bladder Cancer

The immune checkpoint antibody pembrolizumab (Keytruda, Merck) improved survival in previously treated advanced urothelial cancer compared to chemotherapy, according to the manufacturer of the immunotherapy.

Merck announced that they stopped the phase III KEYNOTE-045 trial early, based on the recommendation of an independent Data Monitoring Committee (DMC), after it met its primary endpoint of improvement of overall survival based.

Pembrolizumab is an antibody that targets PD-1 (programmed death receptor 1), a receptor expressed on T cells and plays an important role in dampening the response of the immune system by preventing activation of T cells. The antibody is currently approved for treatment of metastatic melanoma and non-small cell lung cancer that expresses PD-L1, the ligand for PD-1, and who have progressed following platinum-containing chemotherapy.

Merck has not yet released any data from the KEYNOTE-045 trial, but indicates that the company plans to do so at a future medical meeting. “The results of KEYNOTE-045 represent a major breakthrough and will be welcome news for patients dealing with previously treated advanced urothelial cancer,” said Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories in a statement. “We look forward to sharing the findings from this study with the medical community and with regulatory authorities around the world.”

The phase III trial randomized 542 patients with metastatic or locally advanced or unresectable urothelial cancer that has recurred or progressed following platinum-based chemotherapy to pembrolizumab or investigator-choice chemotherapy (either paclitaxel, docetaxel, vinflunine) for the treatment of metastatic or locally advanced or unresectable urothelial cancer that has recurred or progressed following platinum-based chemotherapy. The co-primary endpoints are overall survival and progression-free survival (PFS). The secondary endpoints are overall response rate (ORR), duration of response (DOR), and safety. Patients received 200 mg of pembrolizumab every 3 weeks or paclitaxel (175 mg/m² every 3 weeks), docetaxel (75 mg/m² every 3 weeks), or vinflunine (320 mg/m² every 3 weeks).

Early this month, researchers presented interim results from the phase II KEYNOTE-052 trial of pembrolizumab as an upfront therapy for metastatic urothelial cancer who were ineligible for cisplatin at the European Society for Medical Oncology (ESMO) congress held  October 7-11, 2016, in Copenhagen, Denmark.

In an analysis of the first 100 patients enrolled in the trial, the objective response was 24% at a median follow up of 8 months. The median time to response was 2 months. Six patients had a complete response and 17 patients had a partial response.

The US Food and Drug Administration approved the first anti-PD-1 or anti-PD-L1 immune checkpoint antibody, atezolizumab (Tecentriq, Roche) for urothelial carcinoma on May 18, 2016. Atezolizumab was approved to treat patients with locally advanced or metastatic urothelial carcinoma whose disease has worsened during or following platinum-containing chemotherapy, or within 12 months of receiving platinum-containing chemotherapy.

Another anti-PD-1 antibody, nivolumab (Opdivo, BMS) is also being developed for metastatic bladder cancer. Also at the ESMO congress, researchers presented the phase II CheckMate-275 trial of 265 patients who had progressed following first line platinum-based chemotherapy. In the 265 patients evaluated, the objective response rate was 19.6%. The median duration of response has not yet been reached, with a median follow-up of 7 months.