PD-L1 has long been dismissed as a viable biomarker in advanced bladder cancer, given that numerous late-stage clinical trials of PD-1/L1 inhibitors in the disease have reported clinical benefit even in patients who have low or undetectable levels of the biomarker. For this and other reasons related to the consistency of PD-L1 measurement, experts interviewed by GlobalData have been unanimous in their opinions that PD-L1 is not suitable as a treatment selection tool in advanced bladder cancer. However, this idea is now being challenged, as the FDA recently issued a drug safety notification warning against the use of frontline PD-1/L1 monotherapy for patients with PD-L1-low tumors who are eligible to receive platinum-based chemotherapy based on preliminary data analysis of pivotal trials for Merck & Co.’s Keytruda and Roche’s Tecentriq. If these findings are confirmed in later analyses, the chances of PD-1/L1 drugs replacing chemotherapies in the frontline setting will be dramatically lower. Further, the companion diagnostic market for PD-L1 tests could expand to include bladder cancer patients in the near future.

The FDA warning was based on data from an assessment conducted by a data monitoring committee (DMC) for the Phase III KEYNOTE-361 study and the Phase III IMvigor 130 study. Both studies contain investigational arms of Keytruda and Tecentriq, respectively, as monotherapies as well as in combination with chemotherapy, and comparator arms of platinum-based chemotherapy. The DMC review found that PD-L1-low expressers in the PD-1/L1 monotherapy arms had decreased overall survival compared with patients in the chemotherapy comparator arms. Since Keytruda and Tecentriq were approved for use as monotherapies in the frontline, cisplatin-ineligible setting based on Phase II single arm trials, these are some of the first data available for comparison with the first-line standard of care, platinum-based chemotherapy.

If these findings bear out in subsequent analyses, this could put pressure on PD-1/L1 sales in bladder cancer, as the emphasis for sales growth in the first-line setting will have to shift from monotherapies to combination therapies. Tolerable monotherapy approaches are much preferred in bladder cancer, as patients tend to be elderly with a high incidence of comorbidities. With tolerability a top priority in the advanced bladder cancer patient population, the effectiveness of chemotherapy in prolonging overall survival in the frontline setting, and the success of monotherapy PD-1/L1 in the second-line setting following frontline chemotherapy failure, chemotherapy regimens will likely be entrenched in the bladder cancer treatment algorithm for the foreseeable future. However, all is not lost for PD-1/L1 developers, as the PD-L1 companion diagnostics market, which was previously predicted to be quite small in bladder cancer, could see significant expansion if PD-L1 testing becomes necessary to justify PD-1/L1 usage in the frontline setting.

For more insight and data, visit the GlobalData Report Store – Drug Development Technology is part of GlobalData Plc.

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