Patients that are unfit for cisplatin-based chemotherapy represent 40-60% of patients with advanced urothelial cancer, however, there are widely accepted definitions for who is truly unfit, including (i) ECOG of 2 or greater, (ii) creatinine clearance ≤ 60 ml/min, (iii) grade 2 or greater peripheral neuropathy/hearing loss, (iv) NYHA class III heart failure. Taking into consideration all lines of therapy for standard of care for advanced urothelial carcinoma, the current landscape is as follows:
The KEYNOTE-052 trial was a multicenter, single-arm, Phase II study that assessed pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic disease.1 Dr. Dreicer highlights that 11% of these patients were ≥ 85 years of age, 42% had ECOG performance status 2, and 85% had visceral disease. Among 370 patients, the objective response rate was 29% (95% confidence interval [CI] 25-34%), including 7% (95% CI 25-34%) of patients with complete response, and 22% (95% CI 18-27%) with partial response.
First presented at the 2019 European Society of Medical Oncology (ESMO 2019) Annual Meeting, the IMvigor130 trial is a Phase III trial assessing atezolizumab as monotherapy or combined with platinum-based chemotherapy vs placebo + platinum-based chemotherapy in previously untreated locally advanced or metastatic urothelial carcinoma. This trial enrolled 1,213 platinum-based chemotherapy-eligible patients with metastatic urothelial carcinoma. Patients were randomized 1:1:1 to Arm A (atezolizumab + platinum-based chemotherapy [gemcitabine + either cisplatin or carboplatin]), Arm B (atezolizumab) or Arm C (placebo + platinum-based chemotherapy). The co-primary efficacy endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS) (Arm A vs C) and OS (Arm B vs C) per RECIST 1.1. The IMvigor130 trial design is as follows:
With a median follow-up of 11.8 months, the median PFS was 8.2 months in Arm A vs 6.3 months in Arm C (hazard ratio [HR] 0.82, 95% CI 0.70-0.96; p = 0.007). The PFS benefit of combination therapy was also robust across most subgroups. The comparison of OS did not cross the prespecified interim efficacy boundary, with a median of 16.0 months in Arm A and 13.4 months in Arm C (HR 0.83, 95% CI 0.69-1.00; p = 0.027). For Arm B vs C, the median OS was 15.7 months and 13.1 months, respectively (HR 1.02, 95% CI 0.83-1.24), for ITT patients and not estimable and 17.8 months, respectively (HR 0.68, 95% CI 0.43-1.08), for PD-L1 IC2/3 patients.
The KEYNOTE-361 trial was recently presented at the ESMO 2020 virtual meeting, a Phase III trial randomizing patients with advanced or metastatic disease 1:1:1 to pembrolizumab + gemcitabine + cisplatin or carboplatin versus pembrolizumab versus gemcitabine + cisplatin or carboplatin. The dual primary endpoints for this trial were PFS per RECIST v1.1 by blinded review and overall survival. Overall survival in the intention to treat population was 17.0 months (95% CI 14.5-19.5) in the pembrolizumab plus chemotherapy arm versus 14.3 months (95% CI 12.3-16.7) in the chemotherapy arm (HR 0.86, 95% CI 0.72-1.02, p=0.0407).
In arguably one of the most influential trials in the last year, the Phase III JAVELIN Bladder 100 trial showed that avelumab first-line maintenance plus best supportive care significantly prolonged overall survival (primary endpoint) versus best supportive care alone in patients with advanced urothelial carcinoma without disease progression with first-line induction chemotherapy (HR 0.69, 95% CI 0.56-0.86):2
Furthermore, in the PD-L1+ population median OS was not reached for avelumab plus best supportive care (95% CI 20.3 to not reached) versus 17.1 months (95% CI 13.5-23.7) for best supportive care alone (HR 0.56, 95% CI 0.40-0.79).
Shifting gears, Dr. Dreicer also discussed erdafitinib, a pan-fibroblast growth factor receptor (FGFR) inhibitor that is approved in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma and susceptible FGFR3/2 alterations following ≥ 1 line of platinum-based chemotherapy. Approval of erdafitinib was based on data from the primary analysis of the pivotal BLC2001 trial in adult patients with previously treated locally advanced or metastatic urothelial carcinoma and FGFR3/2 alterations.3 At the final analysis of the BLC2001 study, among all patients treated with the optimal schedule of erdafitinib, the objective response rate was 40%, median duration of response was 5.98 months, median progression-free survival was 5.5 months, and median overall survival was 11.3 months.
Enfortumab vedotin is an antibody-drug conjugate that is comprised of a fully human monoclonal antibody conjugated to the clinically validated microtubule-disrupting agent, monomethyl auristatin E (MMAE), via a protease-cleavable linker. Enfortumab vedotin targets Nectin-4, a transmembrane protein. In EV-101, a Phase I dose-escalation/expansion study n=155), enfortumab vedotin had a confirmed objective response rate of 43%, and duration of response of 7.4 months; median overall survival was 12.3 months, and the overall survival rate at 1 year was 51.8%.3 EV-301 is a global Phase III study of enfortumab vedotin versus physician choice of docetaxel/paclitaxel/vinflunine in patients previously treated with platinum and checkpoint inhibitors. In a press release on September 18, 2020, this trial was stopped early by the DMC as enfortumab vedotin significantly improved overall survival, with a 30% reduction in death (HR 0.70, 95% CI 0.56-0.89, p=0.001).
Dr. Dreicer concluded with several sequencing questions/comments in advanced urothelial cancer therapeutics:
- There is a relative wealth of therapeutic options, which creates challenges
- There is no data to support checkpoint inhibitor/chemotherapy combinations upfront
- The switch maintenance data is compelling
- There is data to support adjuvant therapy for high-risk patients with checkpoint inhibitor therapy
- Next-generation sequencing needs to become part of the management paradigm
- Single-agent “salvage” chemotherapy’s time is gone
- Novel non-chemotherapy combinations for upfront therapy are being evaluated in Phase III trials
Presented by: Robert Dreicer, MD, Section Head, Medical Oncology, Deputy Director, University of Virginia Cancer Center, University of Virginia, Charlottesville, Virginia
Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Augusta, Georgia, Twitter: @zklaassen_md at the 2020 Society of Urologic Oncology Annual Meeting – December 2-5, 2020 – Washington, DC
1. Balar, Arjun V., Daniel Castellano, Peter H. O'Donnell, Petros Grivas, Jacqueline Vuky, Thomas Powles, Elizabeth R. Plimack 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." The Lancet Oncology 18, no. 11 (2017): 1483-1492.
2. Powles, Thomas, Se Hoon Park, Eric Voog, Claudia Caserta, Begoña P. Valderrama, Howard Gurney, Haralabos Kalofonos et al. "Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma." New England Journal of Medicine 383, no. 13 (2020): 1218-1230.
3. Loriot, Yohann, Andrea Necchi, Se Hoon Park, Jesus Garcia-Donas, Robert Huddart, Earle Burgess, Mark Fleming et al. "Erdafitinib in locally advanced or metastatic urothelial carcinoma." New England Journal of Medicine 381, no. 4 (2019): 338-348.
4. Rosenberg, Jonathan, Srikala S. Sridhar, Jingsong Zhang, David Smith, Dean Ruether, Thomas W. Flaig, Joaquina Baranda et al. "EV-101: A Phase I Study of Single-Agent Enfortumab Vedotin in Patients With Nectin-4–Positive Solid Tumors, Including Metastatic Urothelial Carcinoma." Journal of Clinical Oncology 38, no. 10 (2020): 1041.