Data from a novel, biomarker-directed platform study of durvalumab in combination with relevant targeted therapies support the clinical activity of fibroblast growth factor receptor (FGFR) inhibition and durvalumab monotherapy in biomarker-selected chemotherapy-refractory patients with advanced urothelial cancer (AUC), but the results did not show increased activity for any of the combinations tested. These study results were published in Nature Medicine.
Durvalumab is an immune checkpoint inhibitor targeting the programmed death-ligand 1 (PD-L1) that has shown clinical activity in AUC. AUC typically features numerous recurrent targetable genomic alterations. While the combination of targeted therapy with immune therapy is an attractive treatment strategy for AUC, delivery of personalized combination therapy is complex and can result in increased toxicity and cost, the study authors wrote.
BISCAY is a randomized, open-label phase 1b trial (ClinicalTrials.gov Identifier: NCT02546661) with a novel biomarker-driven, multiarm adaptive design and a personalized approach to rapidly identify active combinations in AUC.
Researchers sought to determine the safety and efficacy of the combination of durvalumab with biomarker-selected targeted therapy including a fibroblast growth factor receptor inhibitor (FGFRi) in tumors with FGFR DNA alterations, a poly-adenosine diphosphate-ribose polymerase (PARPi) in tumors with and without DNA homologous recombination repair deficiency, and a raptor-mTOR protein complex/rictor-mTOR protein complex inhibitor (TORC1/2i) in tumors with DNA alteration to the mTOR/PI3K pathway.
The study population included 135 patients with chemotherapy-refractory AUC. Treatment was assigned based on specific genomic alterations as assessed by Foundation Medicine analysis. The patients were assigned to 1 of the 6 treatment arms: durvalumab alone (29 patients), AZD4547 (FGFRi) alone (16 patients), AZD4547 plus durvalumab (21 patients), olaparib (PARPi) plus durvalumab selected (14 patients), olaparib plus durvalumab unselected (22 patients), and vistusertib (TORC1/2i) plus durvalumab (29 patients).
The response rates to anti-PD-L1 therapy in combination with the different targeted agents were found to be modest, ranging from 9% to 36% across the study arms, and did not meet the efficacy criteria for further development. The addition of targeted therapy to durvalumab did not seem to increase the duration of response and the progression-free survival (PFS). At 6 months, the PFS rates ranged from 20% to 43%, and the 1-year OS rates ranged from 42% to 56% across the study arms.
Biomarker analysis revealed a positive correlation between circulating plasma-based DNA and tumors with FGFR DNA alterations. Changes to FGFR DNA alterations correlated with the clinical outcome as assessed by sequential analysis of circulating tumor DNA.
Although the combination of immune therapy and targeted therapy in biomarker-driven populations did not seem to improve efficacy, the authors indicated that the study has implications for further drug development in urothelial cancer and beyond.
“This biomarker-directed, multi-arm study, combining durvalumab with  promising molecular targets, shows that this new design is feasible. The strong biomarker platform, including circulating biomarkers, helped reinforce efficacy signals, which further adds to the utility of this approach,” the study authors reported.
Disclosure: This research was supported by AstraZeneca. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Powles T, Carroll D, Chowdhury S, et al. An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer. Nat Med. 2021;27(5):793-801. doi:10.1038/s41591-021-01317-6