Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up

Abstract

Background Novel second-line treatments are needed for patients with advanced urothelial cancer (UC). Interim analysis of the phase III KEYNOTE-045 study showed a superior overall survival (OS) benefit of pembrolizumab, a programmed death 1 inhibitor, versus chemotherapy in patients with advanced UC that progressed on platinum-based chemotherapy. Here we report the long-term safety and efficacy outcomes of KEYNOTE-045. Patients and methods Adult patients with histologically/cytologically confirmed UC whose disease progressed after first-line, platinum-containing chemotherapy were enrolled. Patients were randomly assigned 1 : 1 to receive pembrolizumab [200 mg every 3 weeks (Q3W)] or investigator’s choice of paclitaxel (175 mg/m 2 Q3W), docetaxel (75 mg/m 2 Q3W), or vinflunine (320 mg/m 2 Q3W). Primary end points were OS and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central radiology review (BICR). A key secondary end point was objective response rate per RECIST v1.1 by BICR. Results A total of 542 patients were enrolled (pembrolizumab, n = 270; chemotherapy, n = 272). Median follow-up as of 26 October 2017 was 27.7 months. Median 1- and 2-year OS rates were higher with pembrolizumab (44.2% and 26.9%, respectively) than chemotherapy (29.8% and 14.3%, respectively). PFS rates did not differ between treatment arms; however, 1- and 2-year PFS rates were higher with pembrolizumab. The objective response rate was also higher with pembrolizumab (21.1% versus 11.0%). Median duration of response to pembrolizumab was not reached (range 1.6+ to 30.0+ months) versus chemotherapy (4.4 months; range 1.4+ to 29.9+ months). Pembrolizumab had lower rates of any grade (62.0% versus 90.6%) and grade ≥3 (16.5% versus 50.2%) treatment-related adverse events than chemotherapy. Conclusions Long-term results (>2 years’ follow-up) were consistent with those of previously reported analyses, demonstrating continued clinical benefit of pembrolizumab over chemotherapy for efficacy and safety for treatment of locally advanced/metastatic, platinum-refractory UC. Trial registration ClinicalTrials.gov: NCT02256436.

Bladder Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology

“…135 Long-term results (.2 years' follow-up) from this same phase III trial were consistent with earlier reports, with longer 1-and 2-year OS and PFS results for pembrolizumab compared with chemotherapy. 136 The median DOR was not reached for pembrolizumab compared with 4.4 months for chemotherapy. Pembrolizumab also showed lower rates of any grade (62% vs 90.6%) and grade $3 AEs (16.5% vs 50.2%) compared with chemotherapy.…”

Neutralizing PD-L1 and PD-L2 Enhances the Efficacy of Immune Checkpoint Inhibitors in Ovarian Cancer

“…1C-E). In contrast, bladder cancers have a reported higher clinical response rate to ICB (27) and interestingly, the staining of bladder cancer TMAs show low PD-L2 expression, but predominant PD-L1 ligand expression in bladder cancer cells (n=208) ( Fig. 1D and 1E).…”

<p>Optimal Management of Upper Tract Urothelial Carcinoma: Current Perspectives</p>

“…Most of the patients included in these trials had urothelial carcinomas of bladder. Only Pembrolizumab 93,94 and Atezolizumab 95 have Phase III randomized data published (KEYNOTE 045 and IMVigor 211, respectively). Other checkpoint inhibitors have been evaluated with Phase II single-arm trials ( Table 3) with favorable objective response rates and toxicities profile.…”

“…[96][97][98][99] Within KEYNOTE 045 and IMVigor 211, it is important to note that up to 27% of the included trial population were diagnosed with UTUCs; however, no further published data exist for this sub-group yet. [93][94][95] As these immunotherapeutic agents are increasingly utilized, it is important to be familiar with associated toxicities associated. A systematic review and meta-analysis of treatment-related adverse events of PD-1 and PD-L1 inhibitors used in 125 clinical trials involving 20,128 patients 100 found that the most common all-grade adverse events were fatigue (18.26%; 95% CI, 16.49-20.11%), pruritus (10.61%; 95% CI, 9.46-11.83%), and diarrhea (9.47%; 95% CI, 8.43-10.58%), while the most common grade 3 or higher adverse events were fatigue (0.89%; 95% CI, 0.69-1.14%), anemia (0.78%; 95% CI, 0.59-1.02%), and aspartate aminotransferase increase (0.75%; 95% CI, 0.56-0.99%)…”