According to results from the open-label randomized phase III Keynote-045 study, the programmed death receptor 1 (PD-1) inhibitor pembrolizumab significantly improved overall survival (OS) compared to chemotherapy in patients with progressive advanced urothelial cancer regardless of PD-L1 expression status. Pembrolizumab is one of five PD-1/PD-L1 inhibitors that have been investigated for second-line treatment of urothelial cancer, but it is the first to demonstrate an OS benefit. Among these agents, atezolizumab and nivolumab gained accelerated approval in this setting based on results from nonrandomized phase II trials (IMvigor 210 and CheckMate-275)
Keynote-045 compared pembrolizumab 200 mg every three weeks to investigator’s choice chemotherapy (paclitaxel, docetaxel, or vinflunine) in 542 patients with advanced urothelial cancer that had recurred or progressed after platinum-based chemotherapy. At 14.1 months follow-up, pembrolizumab had significantly improved OS compared to chemotherapy (10.3 months vs 7.4 months; HR 0.73, P = .002). The one-year OS rate was 43.9% in patients receiving pembrolizumab versus 30.7% in patients receiving chemotherapy. The OS benefit was seen in all subgroups examined, including patients with a tumor PD-L1 combined positive score of less than 1%. In patients with a tumor PD-L1 combined positive score of 10% or more, OS was 8.0 months with pembrolizumab versus 5.2 months with chemotherapy (HR 0.57, P = .005). Of note, a relationship between smoking and benefit of pembrolizumab has been observed that may reflect high mutational load in current and former smokers. Overall there was no significant difference in progression-free survival (PFS) between the two treatment arms, either in the entire treatment population (HR 0.98) or in patients with a tumor combined PD-L1 score >10% (HR 0.89). However, beyond 6 months the PFS curves diverged in favor of pembrolizumab. More patients responded to pembrolizumab than to chemotherapy (21.1% vs 11.4%), and a greater proportion of responses to pembrolizumab were ongoing at data cut-off (72% vs 35%).
Importantly, patients treated with pembrolizumab experienced fewer treatment-related adverse events (AEs) of any grade (60.9% vs 90.2%) and grade 3 and higher (15% vs 49.4%) than patients receiving chemotherapy. The most common treatment related AEs of any grade associated with pembrolizumab were pruritus (19.5%), fatigue (13.9%), and nausea (10.9%). Four treatment-related deaths occurred in each arm, including one death due to pneumonitis in the pembrolizumab arm. The authors concluded that pembrolizumab is the first agent to demonstrate an OS benefit in patients with second-line advanced urothelial cancer, and that the durable nature of responses coupled with the low toxicity associated with pembrolizumab support the use of pembrolizumab in patients with advanced urothelial cancer who have progressed on first-line platinum-based chemotherapy.
In an accompanying editorial, Guru Sonpavde, MD (University of Alabama at Birmingham, Birmingham, Alabama, United States), called these results “practice-changing” and commented on the low toxicity and prolonged OS, particularly given the historic lack of agents to improve OS in this setting. Dr Sonpavde indicated that the efficacy of pembrolizumab along with nivolumab and atezolizumab in second-line urothelial cancer raises a number of questions, including which agent might be preferential (if any), how long PD-1/PD-L1 inhibition should continue, and if there are any biomarkers that might aid selection of patients, particularly considering the efficacy of these agents in patients with either low or no PD-L1 expression. In addition, he pointed out that these data support evaluation of immunotherapy in earlier disease settings. Currently, PD-1/PD-L1 inhibitors are being evaluated as monotherapy and in combination in first-line and adjuvant therapy.