On May 18, the U.S. Food and Drug Administration approved the latest immunotherapeutic drug, atezolizumab (Tecentriq), from Roche’s California division, Genentech. The drug, a PD-L1 inhibitor, is the first product in its class to gain approval for a common form of bladder cancer, urothelial carcinoma — specifically for patients with advanced disease or those who have not been helped by platinum chemotherapy or surgery. Atezolizumab is the fourth checkpoint inhibitor to gain FDA approval, and the first to be approved in the bladder cancer indication. Along with the drug, the FDA also approved a “complementary” diagnostic test that measures a patient’s PD-L1 levels to help physicians determine which patients might benefit most from the therapy.
Once again, like the immunotherapeutic approvals before it, the data supporting atezolizumab in bladder cancer was fairly limited, but sufficient to gain a positive FDA decision in a difficult indication. The approval was based on an open-label 310 patient Phase 2 study in which all participants received the drug, with no placebo for comparison. The goal of the study was to show shrinkage of the patient’s tumors. According to FDA, 14.8 percent of the patients had at least a partial shrinkage; 26 percent of those classified as positive for PD-L1 expression had tumor shrinkage, while only 9.5 percent of patients classified as “low PD-L1” (below 5 percent expression) had a response. The FDA approval was conditional, and Genentech/Roche is continuing to study the drug in an on-going Phase 3 trial.
While the approval as second-line therapy is the first for an immuno-oncology drug in bladder cancer, Roche is unlikely to have this indication to themselves for long. Keytruda is already in a Phase 3 trial, Opdivo in Phase 2, a Pfizer drug in a Phase 3 trial as second-line therapy, and a drug combination from AstraZeneca is in Phase 3 as well.
Moreover, the response rate that gained this approval for Roche is the lowest response rate to do so in immuno-oncology since Yervoy was approved in melanoma. Bladder cancer is a tough indication, and drug combinations may be needed to make significant improvements. There are a number of Phase 1 combination trials underway that include bladder cancer as one of the indications of interest, and we look forward to seeing the results.
With respect to the diagnostic, notably Roche did not go for an approval based on a PD-L1 positive patient population in the end, and the biomarker diagnostic was approved as a complementary test, not as a companion diagnostic. Thus it is intended to provide additional information, but is not required for atezolizumab’s use. While we don’t know whether this resulted from a change in strategy by Roche, this “complementary” diagnostic approval appears to validate the word-of-mouth that, for now at least, biomarkers don’t really have a strong benefit in immuno-oncology. The question remains to what extent the complementary diagnostic will be used if it requires an additional step and additional cost?
Ultimately, however, we continue to believe that as technology evolves and more analytes are studied and data sets built, biomarker diagnostics will play an important role in guiding immuno-therapeutic use, driven not only by physicians seeking the right treatment for their patients but also by diagnostic companies and payers seeking indications of value in the drugs they reimburse.