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Immune-checkpoint Inhibition on the Rise - Rapidly Shifting Paradigms in the Treatment of Urothelial Carcinoma

21 Dec 2017
Genitourinary cancers
Christoph Oing

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 [1].

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 [2], 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) [3], nivolumab (Checkmate 275) [4] and avelumab [1], or the anti-PD-L1-antibodies atezolizumab (IMvigor 210) [5] and durvalumab [6]. 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 [7]. 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.


  1. Apolo AB, Infante JR, Balmanoukian A et al. Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study. J Clin Oncol 2017; JCO2016716795.
  2. Bellmunt J, Bajorin DF. Pembrolizumab for Advanced Urothelial Carcinoma. N Engl J Med 2017; 376: 2304.
  3. Plimack ER, Bellmunt J, Gupta S et al. Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study. Lancet Oncol 2017; 18: 212-220.
  4. Sharma P, Retz M, Siefker-Radtke A et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2017; 18: 312-322.
  5. Rosenberg JE, Hoffman-Censits J, Powles T et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016; 387: 1909-1920.
  6. Massard C, Gordon MS, Sharma S et al. Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer. J Clin Oncol 2016; 34: 3119-3125.
  7. Balar AV, Castellano D, O'Donnell PH et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol 2017; 18: 1483-1492.

Discussion questions

  1. Are the factors (apart from PD-L1 expression) to enhance response prediction and patient selection?
  2. Which mechanisms mediate primary and acquired checkpoint inhibitor resistance and how can repsonse rates be improved?
  3. Can we safely discontinue checkpoint-inhibitor treatment in responding patients at some point? When is that?
  4. How can treatment option for non-responders be improved? 
Last update: 21 Dec 2017

Christoph Oing declares no conflict of interest.

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