Roche’s Tecentriq was approved in May 2016 for the second-line treatment of locally advanced/metastatic urothelial cancer following prior failure on platinum-based doublet chemotherapy. With this approval, it became the only approved drug in this setting in the US, and thus, the standard of care (SOC). Since then, Roche has forged on in bladder cancer treatment development, announcing on January 9 that the FDA had accepted the company’s supplemental biologic license application (sBLA) and granted Priority Review for Tecentriq for the first-line treatment of cisplatin-ineligible, locally advanced/metastatic urothelial carcinoma. With the decision date set for April 30, 2017, Tecentriq will handily beat Merck & Co’s Keytruda to market. Yet cisplatin-ineligible patients represent less than half of total first-line, treatment-eligible metastatic patients, meaning over half of first-line patients are receiving the current SOC, cisplatin-based doublet chemotherapy.

Companies have cautiously targeted the cisplatin-ineligible patient population initially, knowing that replacing cisplatin-doublet chemotherapy in the first-line is a difficult task for various reasons. One is that chemotherapy can be curative in 10–15% of metastatic patients. In addition, chemotherapy has demonstrated an overall survival (OS) benefit in the first-line setting. Thus, the current strategy is to use monotherapy PD-1 checkpoint modulators for cisplatin-ineligible patients, and a combination of either PD-1 modulator  + chemotherapy (in the case of Tecentriq and Merck & Co.’s Keytruda) or PD-1 modulator + CTLA4 (in the case of AstraZeneca’s durvalumab + tremelimumab) for cisplatin-eligible patients.

The use of combinations is meant to improve response rates, which hover in the 10–20% range for PD-1 checkpoint monotherapy. In addition, it gives a better chance to best the comparator arm of chemotherapy alone in Phase III randomized trials. The PD-1 modulator + chemotherapy combination approach has seen success in lung cancer, while the PD-1 modulator + CTLA4 approach has been effective in melanoma. It remains to be seen which of these routes will prove more efficacious in metastatic bladder cancer.