Pembrolizumab plus chemotherapy does not improve survival in advanced urothelial carcinoma

August 2021 Cancer trials Tobias Rawson
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Despite the fact that PD-1 and PD-L1 inhibitors were found to be active in metastatic urothelial carcinoma, little is known on the efficacy of their use as a first-line treatment option. Therefore, the phase III Keynote-361 study assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma.

Platinum-based chemotherapy has formed the basis of  standard of care (SoC) systemic therapy for advanced urothelial carcinoma for over 40 years. More recently, combinations of immune checkpoint inhibitors (ICIs) with chemotherapy have provided better survival outcomes for a variety of cancers. PD-1 and PD-L1 inhibitors were also found to be active in metastatic urothelial carcinoma, but positive randomised data supporting there use as a first-line treatment option are lacking. The KEYNOTE-361 trial is a phase III study that investigated the efficacy and safety of pembrolizumab alone or combined with chemotherapy versus chemotherapy in patients with previously untreated, advanced urothelial carcinoma.

This open-label, multicentre, phase III study enrolled 1,010 patients with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma with an ECOG PS score of 0-2. Patients were randomised (1:1:1) to receive either intravenous pembrolizumab for a maximum of 35 cycles (200 mg every 3 weeks), plus chemotherapy for a maximum of 6 cycles (gemcitabine 1,000 mg/m2 on days 1 and 8, plus cisplatin 70 mg/m2 or carboplatin [area under curve 5] on day 1 of every 3-week cycle) (N= 351), or pembrolizumab alone (N= 307), or chemotherapy alone (N= 352). Patients were stratified by choice of platinum chemotherapy and PD-L1 combined positive score. Following the emerging survival data for PD-(L)1 inhibitor monotherapy in patients with CPS of less than 10 in the IMvigor130 and KEYNOTE-361 trials, a protocol amendment limited randomisation of patients with CPS of less than 10 to the pembrolizumab plus chemotherapy or chemotherapy alone groups only. The dual-primary endpoints were PFS and overall survival (OS). Secondary endpoints included overall response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety.

Addition of pembrolizumab fails to improve OS and PFS

Patient demographics and baseline characteristics were well balanced across the three arms. The average age of study participants was 69 years of age, with approximately 75% being male. The majority of patients had an ECOG PS of 0-1 and a lower tract primary tumour site. Approximately 47% and 52% had a PD-L1 CPS ≥10 and <10, respectively. Before the protocol amendment on February 21, 2018, 82% of the 1,010 patients had already been randomly assigned. Therefore, the proportion of the population with PD-L1 CPS of at least 10 was slightly higher in the pembrolizumab group (52%) than in the pembrolizumab plus chemotherapy group (45%) and the chemotherapy group (45%).

At a median follow-up of 31.7 months, the combination of pembrolizumab plus chemotherapy failed to meet to prespecificed p-value boundary of 0.0019 for the final analysis. Median PFS by central review was 8.3 months in the pembrolizumab plus chemotherapy group vs. 7.1 months in the chemotherapy group (HR[95%CI]: 0.78[0.65-0.93], P= 0.0033). Median overall survival was 17.0 months in the pembrolizumab plus chemotherapy group versus 14.3 months in the chemotherapy group (HR[95%CI]: 0.86[0.72-1.02], P= 0.0407). The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve overall survival in the total population per the prespecified p-value boundary of 0.0142 for the final analysis. Hierarchical statistical testing ended following the non-significant results of both primary endpoints. In an exploratory analysis, the OS with pembrolizumab monotherapy was comparable to chemotherapy (15.6 months vs. 14.3 months; HR[95%CI]: 0.92[0.77-1.11]). Similar results were observed when testing median OS in the CPS ≥10 population (16.1 months vs. 15.2 months; HR[95%CI]: 1.01[0.77-1.31]). Despite these findings, in the overall population, an ORR of 54.7% was observed with the immunochemotherapy combination, compared to 30.3% with pembrolizumab alone, and 44.9% with chemotherapy only. These results were comparable to those in the PD-L1 CPS ≥10 population, with ORRs of 57.2%, 32.5% and 46.2%, respectively. Chemotherapy was associated with a greater number of initial responses, whereas pembrolizumab was associated with longer durations of response.

The most common grade ≥3 treatment-related adverse events (TRAEs) were anaemia with pembrolizumab plus chemo (30%) and chemotherapy-only (33%), and diarrhoea, fatigue and hyponatraemia with pembrolizumab alone (all 1%). The most common serious TRAE was anaemia in the pembrolizumab plus chemotherapy group (3%) and in the chemotherapy group (4%), and pneumonitis in the pembrolizumab group (1%). Six (1%) of all 1,010 patients died due to a TRAE; two patients in each treatment group. Of these deaths, one each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group.  


The KEYNOTE-361 trial did not meet the primary endpoints of superior progression-free survival and overall survival with first-line pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced urothelial carcinoma. Therefore, this regimen should not be widely adopted for treatment of advanced urothelial carcinoma.


Powles T, Csoszi T, Ozguroglu M, et al. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22:931-945.