First-Line Pembrolizumab With or Without Chemotherapy for Advanced Urothelial Carcinoma

This trial aimed to evaluate the outcomes of first-line pembrolizumab monotherapy or pembrolizumab combined with chemotherapy, compared to chemotherapy alone, for patients diagnosed with advanced urothelial carcinoma who had not received prior treatment. The KEYNOTE-361 study is a phase 3 randomized trial that includes adult patients with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma and an Eastern Cooperative Oncology Group performance status of up to 2. Enrollment of eligible patients was conducted across 201 medical centers in 21 countries. These patients were randomly assigned (1:1:1) through an interactive voice-web response system to receive intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles, combined with intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator’s choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone. Stratification was performed based on the choice of platinum therapy and PD-L1 combined positive score (CPS). The treatment assignment and CPS were not concealed from the patients or the investigators. Upon reaching the protocol-specified final analysis, sequential hypothesis testing was initiated. The first step involved evaluating the superiority of pembrolizumab in combination with chemotherapy compared to chemotherapy alone in the entire patient population. This was done for the dual primary endpoints of progression-free survival (PFS), assessed by masked, independent central review and overall survival (OS).

The P value boundary for PFS was set at 0.0019, while that for OS was at 0.0142. Following this, non-inferiority and superiority of OS for pembrolizumab versus chemotherapy were assessed in the patient population with CPS of at least 10 and in the total patient population, which were also primary endpoints. Safety was evaluated in the as-treated cohort, comprising all individuals administered at least one dose of the investigational therapy. During the period spanning from October 19, 2016, to June 29, 2018, a total of 1010 patients were registered and assigned to receive either pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). The median duration of follow-up was 31.7 months, with an interquartile range of 27.7 to 36.0 months. The administration of pembrolizumab in combination with chemotherapy did not result in a significant improvement in PFS, as evidenced by a median progression-free survival of 8.3 months (95% CI 7.5-8.5) in the pembrolizumab plus chemotherapy group compared to 7.1 months (6.4-7.9) in the chemotherapy group (hazard ratio [HR] 0.78, 95% CI 0.65-0.93; P=0.0033). Similarly, there was no significant difference in overall survival, with a median overall survival of 17.0 months (14.5-19.5) in the pembrolizumab plus chemotherapy group versus 14.3 months (12.3-16.7) in the chemotherapy group (0.86, 0.72-1.02; P=0.0407). No additional formal statistical hypothesis testing was conducted. The comparison of overall survival between pembrolizumab and chemotherapy was analyzed. The results, which were exploratory based on hierarchical statistical testing, showed no significant differences in OS between the two treatment groups. This was observed in the total population and the population with a CPS of at least 10. The median OS for pembrolizumab was 15.6 months (95% CI 12.1-17.9), and for chemotherapy was 14.3 months (12.3-16.7), with a hazard ratio of 0.92 (95% CI 0.77-1.11). For the population with CPS of at least 10, the median OS for pembrolizumab was 16.1 months (13.6-19.9), and for chemotherapy was 15.2 months (11.6-23.3), with a hazard ratio of 1.01 (0.77-1.32). The predominant grade 3 or 4 unfavorable occurrence linked to the study intervention was anemia in patients receiving pembrolizumab in combination with chemotherapy (30% of 349 patients) or chemotherapy alone (33% of 342 patients). In patients receiving pembrolizumab alone, diarrhea, fatigue, and hyponatremia were the most common adverse events, affecting 1% of 302 patients. A total of 1010 patients were observed, out of which six (1%) succumbed to an unfavorable event ascribed to the study treatment. The mortality rate was uniform across both treatment groups, with two patients each. There was one incidence of cardiac arrest and device-related sepsis in the group receiving pembrolizumab plus chemotherapy, one incidence of cardiac failure and malignant neoplasm progression in the group receiving pembrolizumab and one incidence of myocardial infarction and ischaemic colitis in the group receiving chemotherapy alone. Incorporating pembrolizumab into initial platinum-based chemotherapy did not yield a significant enhancement in effectiveness and, therefore, should not be broadly implemented for the management of progressive urothelial carcinoma.

Source: https://pubmed.ncbi.nlm.nih.gov/34051178/

Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT02853305

Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomized, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. doi: 10.1016/S1470-2045(21)00152-2. Epub 2021 May 26. PMID: 34051178.