Clinical utility of checkpoint inhibitors against metastatic bladder cancer: overcoming challenges to find a way forward

ABSTRACT

Introduction

Cisplatin-based chemotherapy is currently considered the gold-standard treatment for metastatic urothelial carcinoma (mUC). Nevertheless, most mUC patients develop resistance to chemotherapy. Immune checkpoint inhibitors (ICI) have emerged as a therapeutic option for mUC. ICI are used as both first- and second-line therapy for patients with mUC but also for maintenance following chemotherapy and durable responses may be expected in these settings.

Areas covered

Patients with mUC who experience progression after platinum-based chemotherapy regimens, those who are cisplatin-ineligible and have positive PD-L1 expression, and those who are platinum-ineligible, regardless of PD-L1 status, are the target population. The role of ICI monotherapy or drug combinations and newer proposals for mUC therapy are reviewed. The current status of biomarkers to guide ICI treatments in mUC is also provided, focusing on PD-L1, tumor mutational load, and liquid biopsies using ctDNA.

Expert opinion

Current challenges to improve the role of ICI in mUC could be summarized as i) development of better drugs; ii) advances in drug-combinations schemes; iii) development of novel biomarkers and techniques to better select patients for this treatment; iv) providing the drugs in the optimal clinical setting; v) promoting trials covering more demographic and clinical heterogeneity (i.e. wider age range, gender, and diverse clinical representation).

KEYWORDS:

• Bladder cancer
• immune checkpoint inhibitor
• immunotherapy
• PD-1
• PD-L1
• biomarkers
• TMB
• ctDNA

Article highlights

• A potentially durable response is expected in metastatic urothelial carcinoma (mUC) treated with immune checkpoint inhibitors (ICI). This treatment is indicated as first-line for platinum-ineligible patients and cisplatin-ineligible patients with positive PD-L1 expression scores and second-line for those who experience progression after platinum-based chemotherapy regimens.

• The concept of long-term remission applies to patients that will maintain a response to therapy after discontinuing ICI therapy.

• Early disease control is better achieved with systemic chemotherapy than with immunotherapy in the frontline setting. The appearance of resistance soon after the treatment with chemotherapy represents a major limitation in achieving durable responses. The maintenance approach with ICI following initial control with chemotherapy is an attractive option.

• The PD-L1 biomarker in isolation is not considered a good biomarker. Other biomarkers, such as tumor mutational burden and T cell signatures, are promising. A PD-L1+/TMB^high signature usually predicts the response to immune checkpoint inhibitors.

Disclosure statement

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they serve on the speakers’ bureau of Astellas/SeaGen, BMS and Pfizer/EMD Serono and have received consultation fees from Merck, Immunomedics, AVEO, Exelixis and Janssen. Another reviewer on this manuscript has disclosed that they have been on the advisory boards for BMS, Genentech, EMD Serono, Merck, Sanofi, Seattle Genetics/Astellas, Astrazeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, G1 Therapeutics, Eli Lilly/Loxo Oncology, Infinity Pharmaceuticals, Lucence Health, IMV, Vial, Syapse and Tempus; acted as a consultant/scientific advisory board for Suba Therapeutics and Syapse; received research support to their institution from Sanofi (iaward), Astrazeneca, Gilead, Helsinn, Lucence, BMS, EMD Serono and Jazz Therapeutics; been a speaker for Informação Brasileira De Oncologia Ltda, OLE Forum (Mexico), Seagen, Gilead, Natera, Exelixis and Janssen; receive data safety monitoring committee honorarium from Mereo; their spouse is employed by Myriad and they have received writing/editor fees from Uptodate, Cancer Expert Now and PracticeUpdate Bladder Cancer Center of Excellence. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.