Adjuvant immunotherapy for muscle-invasive urothelial carcinoma of the bladder

ABSTRACT

Introduction

There are substantial unmet needs with regards to adjuvant therapy for muscle-invasive urothelial carcinoma (UC) of the bladder, including patients with persistent disease histologically following neoadjuvant platinum-based therapy and radical resection, as well as patients who are not eligible for or refuse cytotoxic chemotherapy. As such, increased interest has been developed in advancing the use of systemic immunotherapy in the postoperative setting.

Areas covered

We begin by examining current uses of systemic immunotherapy in the treatment of advanced UC. We also review emerging neoadjuvant data and describe current adjuvant approaches. We then report and analyze data on adjuvant immunotherapy, including the recent randomized trials on adjuvant nivolumab and atezolizumab, and conclude with a discussion on the available evidence and likely directions of the field.

Expert opinion

Systemic immunotherapy can serve to enhance postoperative therapies for muscle-invasive bladder UC, as exemplified by the recent approval of nivolumab. Further research will serve to define optimal immunotherapy timing and combinations with other systemic therapies, as well as identify predictive biomarkers to allow effective tailoring of therapy for each patient.

KEYWORDS:

• Adjuvant
• immunotherapy
• bladder
• muscle-invasive
• urothelial
• carcinoma
• review

Article highlights

• In muscle-invasive urothelial carcinoma (UC) of the bladder, neoadjuvant platinum-based chemotherapy remains the standard of care. However, many patients have persistent disease histologically following neoadjuvant therapy and radical resection, or are not eligible for or refuse cytotoxic chemotherapy.

• Adjuvant cytotoxic chemotherapy has also not been demonstrated to concretely improve overall survival in muscle-invasive bladder UC.

• As such, increased interest has developed in advancing the use of systemic immunotherapy in the postoperative setting, given that it has shown substantial efficacy in the advanced setting as well as promising results from phase I/II studies in the neoadjuvant setting.

• The FDA recently approved nivolumab for adjuvant use for patients at high risk of recurrence after improvement in disease-free survival was noted in the randomized prospective Checkmate 274 study, which compared adjuvant nivolumab to placebo.

• However, the randomized IMvigor 010 study did not detect improved outcomes with adjuvant atezolizumab compared to observation, although a post-hoc stratification by circulating tumor DNA (ctDNA) reported a subgroup of patients that appeared to benefit from adjuvant immunotherapy.

• Further studies are currently focused on examining additional agents in this space as well as prospectively evaluating the utility of ctDNA as a predictive biomarker.

• Additional studies also expand the use of immunotherapy to the entire perioperative period and evaluate combinations of immunotherapy with other systemic therapies.

Declaration of interest

J Bellmunt has received honoraria from Pfizer, Merck & Co., BMS, AstraZeneca, Pierre Fabre, Takeda, MSD; has served in an advisory/consultancy role for Pfizer, Merck, BMS, AstraZeneca, Roche/Genentech, Pierre Fabre; has received research grants/funding from Takeda, Pfizer (institution); has received travel/accommodation expenses from Pfizer, and royalties from UpToDate. 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.

Conflict of interest

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