Urothelial cancer (UC) is the sixth most common cancer in the U.S. and will be responsible for an estimated 164,000 new cases in 2021 and 31,940 deaths.¹

Most patients with advanced UC have disease control in 65% to 85%, with first-line platinum-based chemotherapy, but progression-free survival (PFS) and overall survival (OS) are most often limited due to the emergence of chemotherapy resistance. Since M-VAC chemotherapy in 1989,² there were few achievements in the past 30 years aside from gemcitabine and cisplatin and HD M-VAC.^3,4 Until recently, only 25% to 55% of patients received second-line treatment with suboptimal outcomes due to rapid disease progression. This has changed considerably with the advent of immunotherapy and novel therapies.

UC has a high mutational burden, making it particularly responsive to immunotherapy.⁵

Five checkpoint inhibitors have been approved, but most recently atezolizumab and durvalumab have been taken off the US market in the second line setting based on non-confirmatory phase III trials in a different setting. No head-to-head studies have been conducted and direct comparisons cannot be made between these studies.

Keynote 45 is the only randomized phase III trial of pembrolizumab vs investigator’s choice of chemotherapy; paclitaxel, docetaxel or vinflunine in patients who had progressed after 1–2 lines of platinum-based chemotherapy. This trial has consistently shown an improvement in overall survival (OS) irrespective of PDL-1 status. The first data showed a 27% reduction in the risk of death in patients treated with pembrolizumab, irrespective of CPS score.⁶ Five-year data were consistent and updated at ASCO 2021. Immune checkpoint blockade with pembrolizumab and atezolizumab have also been approved as first line therapeutic options in either platinum or carboplatin ineligible patients whose tumors also express PDL-1

A number of first-line phase III trials of checkpoint inhibitors alone or in combination with chemotherapy in UC have been reported. The U.S. Food and Drug Administration (FDA) and European Medical Associations stopped accrual of patients on single-agent immunotherapy without positive PDL-1 status in the atezolizumab and pembrolizimab phase III trials. The results of these combination studies unfortunately have for the most part been largely disappointing. The trials are listed in the figure.

Figure. Combination studies with immunotherapy and chemotherapy.

IMVIGOR 130 evaluated gemcitabine and cisplatin or carboplatin ± atezolizumab vs atezolizumab. There was an improvement in PFS with the combination,⁷ as first reported, but ultimately no improvement in OS, as last reported at the American Association for Cancer Research meeting in 2021.

Keynote 361 was a global randomized open label phase 3 trial of pembrolizumab alone or combined with platinum-based chemotherapy versus chemotherapy as first line treatment in advanced UC. Patients were randomized 1:1:1 to pembrolizumab and chemotherapy (351) or pembrolizumab alone (307) or chemotherapy alone (352).⁸ Keynote 361 was a negative trial in terms of both end points of PFS and OS. The results of this trial were unexpected as pembrolizumab is approved in several settings including high risk non muscle invasive bladder cancer after bacillus Calmette-Guérin failure.

The Danube trial was a phase III randomized open label first-line study of durvalumab ± an anti-CTLA-4 inhibitor, tremilumimab vs chemotherapy in unresectable, locally advanced or metastatic UC.⁹ Patients were randomized 1:1:1 to durvalumab (346) or durvalumab plus tremelimumab for up to 4 doses (342) or gemcitabine + cisplatin or carboplatin (344.) The co-primary end points were OS between durvalumab and chemotherapy in patients with high PD-L1 expression in their tumors and OS between durvalumab + tremelimumab and chemotherapy in the entire intention-to-treat (ITT) population. DANUBE did not meet either of these co-primary end points of OS. Secondary analyses suggested that the combination of durvalumab + tremelimumab had activity that was enhanced in the subset of patients with tumors that had high PD-L1 expression, a suggestion that a biomarker strategy to enrich for patients likely to receive benefit may still be important.

Results have not yet been presented for Checkmate 901 with nivolumab and ipilimumab vs nivolumab and chemotherapy or standard platinum-based chemotherapy.

The JAVELIN Bladder 100 trial of switch maintenance evaluated 700 patients with locally advanced or metastatic UC not progressed following first-line, platinum-based chemotherapy.¹⁰ Patients had 4–6 cycles of chemotherapy, and those who had CR, PR or SD, were randomized to every 2-week avelumab vs best supportive care. The primary end point was OS (in all randomized patients and in patients with PD-L1+ tumors). The median OS was 21.4 months vs 11.3 months with HR 0.69, with 61% vs 44% alive at 18 months in favor of avelumab switch maintenance therapy. OS in the PD-L1+ population was not reached vs 17.1 months and HR 0.56 with 70% vs 48% at 18 months in favor of avelumab switch maintenance therapy.¹⁰ This is a landmark study that has changed clinical practice and has been incorporated into most practice guidelines.

Enfortumab vedotin (EV) is an antibody drug conjugate that targets Nectin-4, a protein highly expressed on the surface of most UC. This antibody is conjugated to the anti-microtubule agent monomethyl auristate E. Once the antibody binds the Nectin-4 expressing cell, the agent is internalized and the payload is released. EV can be considered both in advanced disease after immunotherapy and chemotherapy. The EV-301 phase III study demonstrated for the first time that a novel targeted agent improved survival in the refractory setting beyond immunotherapy and chemotherapy when compared to chemotherapy.¹¹ EV was granted accelerated FDA approval in 2019, prior to this phase III study. Combination trials with immunotherapy are promising and ongoing.

Sacituzumab Govitecan (SG) is another antibody drug conjugate directed against Trop-2, a cell surface antigen highly expressed UC. Its payload is SN-38, the active metabolite of irinotecan, a topoisomerase I inhibitor that blocks DNA replication. In April 2021, the FDA granted accelerated approval to SG for patients with locally advanced or metastatic UC who previously received platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor.¹²

In 2019, the FDA granted accelerated approval to erdafitinib for patients with locally advanced or metastatic UC, with susceptible FGFR3 or FGFR2 genetic alterations, that have progressed during or following platinum-containing chemotherapy. This occurred after the results of a multicenter, open-label, single-arm trial in 87 patients.¹³ These molecular alterations are more often found in upper tract tumors. Molecularly targeted therapy is an important breakthrough and hopefully many more targeted therapies will be discovered.