Learning Objective

At the conclusion of the activity, participants will be able to:

• Analyze recent studies on first and second line therapies for treatment for advanced urothelial cancer.

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 methotrexate, vinblastine, adriamycin and cisplatin (M-VAC) chemotherapy in 1989,² there have been few achievements in the past 30 years aside from gemcitabine and cisplatin and high-dose M-VAC (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–atezolizumab, pembrolizumab, nivolumab, durvalumab and avelumab–have been approved in the U.S. in the second line setting based on phase I to phase III trials. 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 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 (American Society of Clinical Oncology) 2021. Immune checkpoint blockade with pembrolizumab and atezolizumab have also been approved as first line therapeutic options in either platinum ineligible patients or carboplatin eligible patients whose tumors also express PD-L1.

The SAUL study was designed to assess atezolizumab in a broader population of patients, including patients typically excluded from phase III trials because of comorbidities, autoimmune disease, poor performance, poor creatinine clearance etc. We often see these patients in our clinical practice but there is little or no information on outcomes in these patients.

The primary endpoint of SAUL was safety. Secondary endpoints included overall survival, response rate and duration of response. We enrolled 1,004 patients from 32 countries and found that it was possible to safely give immunotherapy to many of these patients who would otherwise have been excluded from this therapy.⁷

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 pembrolizumab 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.

IMVIGOR 130 evaluated gemcitabine and cisplatin or carboplatin ± atezolizumab vs atezolizumab. There was an improvement in progression-free survival with the combination,⁸ 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.⁹ Patients were randomized 1:1:1 to pembrolizumab and chemotherapy (351) or pembrolizumab alone (307) or chemotherapy alone (352). Keynote 361 was a negative trial in terms of both end points of progression-free survival 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, tremelimumab, vs chemotherapy in unresectable, locally advanced or metastatic UC.¹⁰ 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 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.

Figure. Combination studies with immunotherapy and 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.¹¹ Patients had 4–6 cycles of chemotherapy, and those who had complete response (CR), partial response (PR) or stable disease (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.

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 auristatin 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.¹² EV was granted accelerated FDA approval in 2019, prior to this phase III study. The multi-cohort EV-103 study evaluates the safety/activity of enfortumab vedotin and pembrolizumab; 93% of cisplatin-ineligible patients with locally advanced or mUC had tumor reduction.¹³ Combination trials with immunotherapy are promising and ongoing.

Sacituzumab Govitecan 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. The linker is hydrolysable, which helps to ensure that an active concentration of SN-38 is maintained in the tumor, while hydrolysis of the linker releases the cytotoxic payload intracellularly and in the tumor microenvironment to kill cells. The response rate with Sacituzumab Govitecan after platinum-based chemotherapy and immunotherapy was 27%.¹⁴ In April 2021, the FDA granted accelerated approval to Sacituzumab Govitecan for patients with locally advanced or metastatic UC who previously received platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor.

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 phase II trial in mUC in 99 patients with FGFR3 mutations or FGFR2/3 fusions.¹⁵ These molecular alterations are more often found in upper tact tumors. Molecularly targeted therapy is an important breakthrough and hopefully many more targeted therapies will be discovered.