As reported in The Lancet Oncology by Thomas Powles, MD, PhD, and colleagues, the phase III KEYNOTE-361 trial has shown no significant improvement in progression-free or overall survival with first-line pembrolizumab plus platinum-based chemotherapy vs chemotherapy alone in patients with advanced urothelial carcinoma. An exploratory analysis showed no overall survival difference with pembrolizumab alone vs chemotherapy.

Thomas Powles, MD, PhD

Study Details

The open-label trial included 1,010 patients with previously untreated, locally advanced, unresectable or metastatic disease from sites in 21 countries. They were randomly assigned 1:1:1 between October 2016 and June 2018 to receive pembrolizumab plus chemotherapy (n = 351), pembrolizumab monotherapy (n = 307), or chemotherapy alone (n = 352).

Pembrolizumab was given at 200 mg every 3 weeks for a maximum of 35 cycles. Chemotherapy consisted of gemcitabine at 1,000 mg/m² on days 1 and 8 and investigator’s choice of cisplatin at 70 mg/m² or carboplatin at AUC 5 on day 1 of every 3-week cycle for a maximum of six cycles.

Hypothesis testing was first performed for superiority of pembrolizumab plus chemotherapy vs chemotherapy in the total population for the dual primary endpoints of progression-free survival (P value boundary = .0019), assessed by masked independent central review, and overall survival (P value boundary = .0142). If these endpoints were met, testing of noninferiority and superiority in overall survival was to be performed for pembrolizumab monotherapy vs chemotherapy in the population with a PD-L1 combined positive score (CPS) ≥10 and in the total population.   

Progression-Free and Overall Survival

Median follow-up was 31.7 months (interquartile range = 27.7–36.0 months). Median progression-free survival was 8.3 months (95% confidence interval [CI] = 7.5–8.5 months) in the pembrolizumab plus chemotherapy group vs 7.1 months (95% CI = 6.4–7.9 months) in the chemotherapy group (hazard ratio [HR] = 0.78, 95% CI = 0.65–0.93, P = .0033; not meeting P = .0019 boundary for significance). Median overall survival was 17.0 months (95% CI = 14.5–19.5 months) in the pembrolizumab plus chemotherapy group vs 14.3 months (95% CI = 12.3–16.7 months) in the chemotherapy group (HR = 0.86, 95% CI = 0.72–1.02, P = .0407; not meeting P = .0142 boundary for significance). Due to the lack of significance, no further formal statistical hypothesis testing was performed.

In exploratory analysis, median overall survival was 15.6 months (95% CI = 12.1–17.9 months) in the pembrolizumab monotherapy group vs 14.3 months in the chemotherapy group (HR = 0.92, 95% CI = 0.77–1.11) in the total population. Rates were 16.1 months (95% CI = 13.6–19.9 months) with pembrolizumab vs 15.2 months (95% CI = 11.6-23.3 months) with chemotherapy (HR =  1.01, 95% CI =  0.77–1.32) among 160 patients (52% of group) vs 158 patients (45% of group) with CPS ≥ 10.

Adverse Events

Treatment-related grade ≥ 3 adverse events occurred in 75% of patients in the pembrolizumab plus chemotherapy group, 17% of the pembrolizumab monotherapy group, and 72% of the chemotherapy group; the most common were anemia in the pembrolizumab plus chemotherapy group (30%) and chemotherapy group (33%), and diarrhea, fatigue, and hyponatremia (1% each) in the pembrolizumab monotherapy group.

Treatment-related serious adverse events occurred in 31%, 16%, and 18% of patients, respectively, with the most common being anemia in the pembrolizumab plus chemotherapy group (3%) and chemotherapy group (4%) and pneumonitis in the pembrolizumab monotherapy group (1%). Adverse events led to discontinuation of any component of treatment in 31%, 16%, and 18% of patients, respectively.  

Treatment-related adverse events led to death in two patients in each group, with causes consisting of cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, cardiac failure and malignant neoplasm progression in the pembrolizumab group, and myocardial infarction and ischemic colitis in the chemotherapy group.

The investigators concluded, “The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma.”

Dr. Powles, of the Barts Cancer Institute, Queen Mary University of London, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Merck Sharp and Dohme, a subsidiary of Merck. For full disclosures of the study authors, visit thelancet.com.