The unprecedented and rapid market entry of five immune checkpoint inhibitors—Tecentriq, Opdivo, Keytruda, Imfinzi, and Bavencio— has revolutionized the treatment algorithm for previously treated unresectable locally advanced or metastatic bladder cancer, offering new treatment opportunities for this patient population.

However, not all patients respond to immune checkpoint inhibitors, and some responses are short-lived. So, what innovations are in the pipeline that may address the remaining unmet need in this indication?

While news around the immune checkpoint inhibitors overshadowed everything in bladder cancer last year, there are other innovative therapies with new mechanisms of action being developed for bladder cancer treatment that are beginning to come to the fore. The updated results from the early-phase trials of these innovative agents were presented at 2018 ASCO Annual Meeting (#ASCO18).

Will these innovations compete effectively against immunotherapies? Can their clinical activity and tolerability overpower immunotherapies' efficacy?

  • Erdafitinib, an FGFR inhibitor, yielded a robust response rate and was tolerable in patients with chemorefractory metastatic bladder cancer and FGFR alterations (mutations / aberrations); confirming a 40% ORR and 80% disease control rate (CR + PR + SD) in its Phase II study BLC2001; also showing a 59% ORR in the exploratory analysis of patients with FGFR alterations that had a poor response to prior immunotherapy (J Clin Oncol 36, 2018 (suppl; abstr 4504)). FGFR alterations are highly present in low-grade non-muscle-invasive tumors and appear in 15% to 20% of patients with metastatic disease, indeed, alterations in FGFR and the downstream RAS-MAPK pathway are implicated in contributing to the risk of bladder cancer development (Stewart BW, 2014; Knowles MA, 2015). Janssen’s Phase III THOR study of erdafitinib is comparing its OS with that of docetaxel, vinflunine, and Keytruda in patients with advanced urothelial cancer and selected FGFR gene aberrations who have received up to one prior systemic treatment. If positive, this trial could see Erdafitinib become the preferred treatment choice for those patients harbouring FGFR aberrations, and introduce FGFR as a biomarker to customize patients’ treatment. A potential next step for Janssen could be to explore the treatment of earlier stages of bladder cancer where FGFR alterations are much more frequent.

  • Enfortumab vedotin, an antibody-drug conjugate targeting Nectin-4 (a cell surface target overexpressed in bladder cancer [Challita-Eid PM, 2016]), provided encouraging results and was well tolerated in heavily pretreated – with chemotherapy or immunotherapy – patients with metastatic bladder cancer; showing a 41% ORR in all comers in this Phase I study EV-101 (J Clin Oncol 36, 2018 (suppl; abstr 4504)). Astellas Pharma and Seattle Genetics recently initiated their Phase III EV-301 trial to evaluate enfortumab vedotin versus chemotherapy in subjects with previously treated locally advanced or metastatic urothelial carcinoma. Enfortumab vedotin could therefore be poised to displace standard single chemotherapy agents (docetaxel, paclitaxel, vinflunine) frequently used as second- or later-lines of therapy.

While early-phase data such as these are based on a limited number of patients and therefore require validation in larger trials, the results are impressive so far, and both agents have already received breakthrough therapy designation by the FDA, an accolade previously only held by immune checkpoint inhibitors in this indication. In addition to offering a much-improved ORR that immunotherapy, the median OS of these agents is already over 12 months, will they become the new standards of care for metastatic bladder cancer?

Look out for Decision Resources Group’s upcoming Bladder Cancer Disease Landscape & Forecast, which will include information about these key emerging therapies and a 10-year market forecast, in unresectable locally advanced or metastatic urothelial carcinoma. For more insights on oncology drug development, follow @LauraVinuesaDRG

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