Despite the given sensitivity of urothelial cancer against conventional cytotoxic treatment, long-term outcomes of locally advanced and/or metastatic disease is limited. After failure of first-line cisplatin-based combination chemotherapy, second- and further-line treatment commonly consisted of single-agent treatment with vinflunine, paclitaxel or docetaxel despite lacking high-level evidence of a meaningful overall survival (OS) benefit over best supportive care. Response rates did not exceed 10% and median OS was limited to 6-7 months .
During the last couple of years, immune-checkpoint inhibition by targeting Programmed-death-1 (PD-1) or its‘ ligand PD-L1 has fundamentally augmented the treatment options for patients with advanced and metastatic urothelial cancer.
For this Journal Club, I chose to introduce the phase III KEYNOTE-045 trial , which randomly compared the use of PD-1-inhibition with 200mg pembrolizumab IV every three weeks (arm A) to conventional single-agent chemotherapy (arm B; vinflunine, paclitaxel or docetaxel according to investigators‘ choice) in patients with urothelial cancer of different origins failing cisplatin-based first-line chemotherapy for advanced disease. Co-primary end points were OS and progression-free survival (PFS) in the total cohort and stratified by PD-L1 expression status (combined score) <10% vs. ≥10%. The treatment arms were well balanced with visceral metastatic disease in 89% (arm A) vs. 86% (arm B), liver metastases in 34% vs. 35%, and a positive PD-L1 expression score ≥10% in 28% vs. 34% for arms A and B, respectively.
After a median follow-up period of 14.1 months pembrolizumab significantly prolonged median OS by about 3 months to 10.3 months (HR 0.73; P = 0.002) with estimated 12-months OS rates of 43.9% (pembro) vs. 30.7% (chemo) irrespective of PD-L1.expression status. PFS did not differ significantly in both arms. Moreover, pembrolizumab significantly enhanced the objective response rate from 11.4% (chemo) to 21.1%. While time to response was 2.1 months in both arms, response duration was markedly longer for pembrolizumab (not reached vs. 4.3 months), and at the time of data cut-off 72% were still responding to pembrolizumab, but only 35% to chemotherapy. Of note, particularly patients with visceral metastasis had a dismal prognosis compared to patients with nodal metastasis only, irrespective of the treatment applied. Tolerability oft he checkpoint inhibitor was substantially better with grade 3-5 toxicities occuring in 15% (chemotherapy 49.4%). Immune-related adverse events grade 3-5 were reported in 4.5% of patients receiving pembrolizumab, of which pneumonitis and colitis were the most common.
The KEYNOTE-045 study was the first randomized phase III trial to report a substantial 3-months OS benefit accompanied by a doubled response rate and a much better tolerability compared to conventional chemotherapy as second-line treatment for urothelial cancer. KEYNOTE-045 impressively confirms the favorable results of recent non-randomised phase Ib / II trials evaluating either the anti-PD-1-antibodies pembroloziumab (KEYNOTE-012 trial) , nivolumab (Checkmate 275)  and avelumab , or the anti-PD-L1-antibodies atezolizumab (IMvigor 210)  and durvalumab . All agents achieved response rates of about 15-30% with a favorable toxicity profile. On the contrary, this means that still 70-85% of patients do not repsond to single-agent immune checkpoint inhibition. Moreover, in most of the studies, the responses were associated with PD-L1 expression in the tumor tissue, but as reported in the KEYNOTE-045 study, even patients lacking PD-L1 in the primary tumor tissue benefit from pembrolizumab treatment. Consequently, there is an urgent need for biomarkers apart from PD-L1 expression, to reliably predict response or resistance to immune checkpoint inhibitors.
Additionally, a single-arm phase II study (KEYNOTE-052) has recently reported clinically meaningful acitivity for pembrolizumab as first-line treatment in cisplatin-ineligible urothelial carcinoma patients, with an objective response rate of 24%, where patients with higher PD-L1 scores appeared to respond better . A phase III trial currently compares pembrolizumab mono to pembrolizumab plus platinum-based combination chemotherapy or platinum-based chemotherapy alone in the first-line setting (KEYNOTE-361; NCT02853305).
Based on the results of both trials, the phase III KEYNOTE-045 and the phase II KEYNOTE-052, the European Medicines Agency approved the use Pembrolizumab for the treatment of advanced urothelial cancer (i) after failure of platinum-based chemotherapy and/or (ii) as first-line treatment in cisplatin-ineligible patients in fall 2017.
In general, the older age and comorbidities have often limited the applicability of chemotherapy in these patients and despite the given chemosensitivity long-term remissions were rarely achieved by chemotherapy alone. In this regard, immune checkpoint inhibition has already fundamentally changed the treatment of urothelial cancer patients. But still many open questions remain.
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- Are the factors (apart from PD-L1 expression) to enhance response prediction and patient selection?
- Which mechanisms mediate primary and acquired checkpoint inhibitor resistance and how can repsonse rates be improved?
- Can we safely discontinue checkpoint-inhibitor treatment in responding patients at some point? When is that?
- How can treatment option for non-responders be improved?
Christoph Oing declares no conflict of interest.