Systemic treatments for metastatic urothelial carcinoma

ABSTRACT

Introduction: Urothelial carcinoma is one of the most common cancers in the western world and, until recently, had limited therapeutic options. The contemporary advancement of immune checkpoint inhibitors (ICI) has heralded a new era for these patients and represents a major shift in the evolving treatment landscape.

Areas covered: This article provides a comprehensive summary of the currently available treatments for metastatic urothelial carcinoma (mUC). The authors also review ongoing, phase-III studies with novel therapeutic targets and highlight recent insights into tumor biology that may help better understand the disease.

Expert opinion: The treatment landscape for first-line therapy of mUC continues to include platinum-based chemotherapy for patients who are eligible. While the approval of ICI has changed the management in those who are post-platinum or platinum-ineligible, the wider use of ICI in the first-line setting requires further clarity given recent FDA announcements. Maintaining the remarkable progress in mUC may depend upon ongoing phase-III studies evaluating treatment options beyond ICI. Better prognostication and identification of those unlikely to respond to ICI remain important unanswered questions, particularly as this class of agents moves further along the disease spectrum of non-metastatic UC.

KEYWORDS:

• Bladder cancer
• chemotherapy
• immunotherapy
• PD-1/PD-L1 inhibitors
• Phase III
• targeted therapy
• Urothelial carcinoma

Article highlights

• Urothelial carcinoma (UC) is the sixth most common cancer in the United States. Platinum-based chemotherapy has been the cornerstone of front-line treatment of metastatic UC (mUC) and single-agent immune checkpoint inhibitors (ICI), such as anti-PD-1/PD-L1 antibodies, are the standard of care for patients following progression on chemotherapy. However, the vast majority of patients will not respond to single-agent ICI.

• Of the 5 approved PD-1/PD-L1 ICI in the post-platinum setting, only pembrolizumab has demonstrated an overall survival benefit in the phase-III setting. Recent attempts have been made to better prognosticate patients treated with ICI (ie models based on atezolizumab therapy), however, biomarkers that may predict those patients unlikely to respond to ICI remain an unmet, important need.

• A variety of combinations are being evaluated in the first-line mUC setting, including chemotherapy plus ICI, ICI with other ICI, or chemotherapy plus targeted therapy directed at, for example, VEGF. These studies, if positive, may further shift the treatment landscape of mUC and impact downstream treatment options in the subsequent line setting. Importantly, trials evaluating chemotherapy plus ICI in this space have been modified such that ICI monotherapy is only offered to those whose turmors are PD-L1 positive.

• Key targets being evaluated in the post-ICI setting, including inhibitors of the fibroblast growth factor receptor (FGFR) and antibodies to Nectin-4, are based on encouraging early-phase results. Pan-FGFR inhibitors Erdafitinib and Rogaratinib are being investigated in the THOR and FORT-1 trials and the anti-nectin-4-antibody enfortumab in the EV-301 study – all of which are phase-III evaluations with the clinically relevant end point of overall survival.

• The continued, expanding knowledge of tumor biology gleaned in the metastatic and non-metastatic settings has the potential to further refine our prognostication and inform future treatment options for patients with UC. Finding a place for newer targets, and combination strategies, may depend on better biomarkers to improve patient selection in this expanding treatment landscape.

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Declaration of interest

AA Lalani has received honoraria and consultancy fees from Pfizer Inc, Eisai, Roche, Ipsen and Merck & Co., while GP Sonpavde has received consultancy fees from Bristol-Myers Squibb, Exelixis, Bayer Healthcare, Sanofi, Pfizer Inc, Novartis, Eisai, Janssen Pharmaceuticals, Amgen Inc, AstraZeneca, Merck & Co., Genentech, EMD Serono and Astellas/Agensys. GP Sonpavde also has received institutional support from Bayer Healthcare, Amgen Inc, Boehringer-Ingelheim, Janssen Pharmaceuticals, Merck & Co, Sanofi and Pfizer Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.