Pembrolizumab Combo Falls Short in Phase 3 Frontline Urothelial Carcinoma Trial

Roy Baynes, MD, PhD

Adding pembrolizumab (Keytruda) to chemotherapy did not lead to a statistically significant improvement in overall survival (OS) or progression-free survival (PFS) in patients with advanced or metastatic urothelial carcinoma, according to findings from the phase 3 KEYNOTE-361 trial.¹

Although there was a numerical improvement in OS and PFS with the combination versus standard chemotherapy, the difference did not achieve the threshold for statistical significance established in the trial design. There was also a single-agent pembrolizumab arm; however, since the primary OS or PFS end points were not met with the combination, the study design did not allow for formal testing of the monotherapy arm.

Merck (MSD), the manufacturer of pembrolizumab, reported in a press release that no new safety signals emerged with pembrolizumab in the trial. The company plans to present the study data at a future medical conference and communicate with regulatory authorities about the results.

“In this study, Keytruda in combination with chemotherapy in previously untreated patients with advanced or metastatic bladder cancer was rigorously tested against an active control of the current standard of care chemotherapy combination regimen,” Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, stated in the press release. “While we are disappointed in these study results, Keytruda has been established as an important option in the treatment of metastatic bladder cancer, and we are committed to continuing our research to help more patients with this disease. We are grateful to the patients and investigators for their participation in this study.”

The open-label, phase 3 KEYNOTE-361 trial (NCT02853305) randomized 1010 patients with advanced or metastatic urothelial carcinoma to frontline treatment with single-agent pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy alone. Chemotherapy consisted of cisplatin or carboplatin plus gemcitabine. The coprimary end points for the trial were OS and PFS. Secondary end points were response, disease control rate, and safety.

Pembrolizumab has 3 FDA-approved indications in bladder cancer: the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1or in patients who are not eligible for any platinum-containing chemotherapy regardless, of PD-L1 status;the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy; and the treatment of patients with Bacillus Calmette-Guerin–unresponsive, high-risk, non-muscle invasive bladder cancer

with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Positive data for pembrolizumab in urothelial carcinoma have been generated across several trials, including the phase 3 KEYNOTE-045 study of pembrolizumab in platinum-pretreated patients with urothelial carcinoma.² In this study, the median OS was 10.4 months with pembrolizumab compared with 7.4 months with chemotherapy (HR, 0.73; 95% CI, 0.59-0.91; P = .002). The objective response rate was 21.1% versus 11.4%, respectively.

References

1. Merck Provides Update on Phase 3 KEYNOTE-361 Trial Evaluating KEYTRUDA® (pembrolizumab) as Monotherapy and in Combination with Chemotherapy in Patients with Advanced or Metastatic Urothelial Carcinoma. Published June 10, 2020. https://bit.ly/3cQzLWe. Accessed June 10, 2020.
2. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376:1015-1026. doi: 10.1056/NEJMoa1613683