Combining the PD-L1 inhibitor durvalumab with various targeted therapies does not change the response rate in patients with advanced urothelial cancer: a research letter published recently in Nature Medicine (https://www.nature.com/articles/s41591-021-01317-6) suggests that similar associations are not the optimal therapeutic strategy of this cancer type.
Durvalumab is a human monoclonal antibody directed against PD-L1, which has already been shown to be effective in advanced urothelial carcinoma and is approved in Italy for the treatment of non-small cell lung cancer; the BISCAY trial, coordinated by the Barts Cancer Center in London, investigated the combination of this immunotherapy with three different targeted therapies, because urothelial carcinoma is characterized by several recurrent targetable genomic alterations. The trial is the first biomarker-driven, adaptive design study in metastatic urothelial carcinoma; 391 patients who progressed on platinum-based chemotherapy and had not received immunotherapy underwent tumor DNA sequencing. One hundred and thirty-five of them were selected and subsequently allocated to treatments targeting specific alterations: a fibroblast growth factor receptor (FGFR) inhibitor (AZD4547) alone or in combination with durvalumab; the PARP inhibitor olaparib with durvalumab; the mTORC1 / 2 inhibitor seen with durvalumab. Those who did not have mutations on FGFR3, RICTOR, TSC1 or TSC2 or DNA damage response genes were randomized to receive durvalumab alone or durvalumab with olaparib.
Response rates ranged between 9 and 36% across study arms; notably, the response rate with durvalumab monotherapy was higher than predicted rates (28% vs 18%–20%), whereas the response to AZD4547 (31%) was lower than observed with the FDA-approved FGFR inhibitor, erdafitinib. No substantial improvements in response rates were observed between single-agent and combination therapy in any arm; the highest response rate was observed with the durvalumab/olaparib combination in patients with DNA damage response gene mutations (35.7%), but this result was not significantly higher than that observed with durvalumab monotherapy.
According to researchers, these data support clinical activity of FGFR inhibition and durvalumab monotherapy but do not show increased activity for any of the combinations, which did not display enough efficacy to warrant exploration in larger trials; despite this, the role for combined immunotherapy and targeted therapy in bladder cancer remains undefined because, for example, preliminary results of the ongoing NORSE trial, aimed at evaluating the effects of a combination of durvalumab and erdatifinib in a similar population of patients with metastatic urothelial carcinoma, are encouraging with a confirmed objective response rate of 55% and no patient exhibiting progression. Continued refinement of biomarkers predictive for response is critical to the identification of those patients most likely to respond to targeted agents, according to the authors; candidate biomarkers must also be investigated within the context of tumor heterogeneity, clonality, and the profile of co-altered genes within a given tumor during treatment selection.