Activity of Targeted/Immune Therapy Approach in Patients with Advanced Urothelial Cancer

Prof. Thomas Powles of the Barts Cancer Institute, Queen Mary University of London, Barts Cancer Centre in London, UK and BISCAY investigators combined durvalumab with relevant targeted therapies in biomarker-selected chemotherapy-refractory advanced urothelial cancer populations. Their data support the clinical activity of fibroblast growth factor receptor (FGFR) inhibition and durvalumab monotherapy, but do not show increased activity for any of the combinations. The findings are published in a letter in the Nature Medicine on 3 May 2021.

The authors wrote in the background that durvalumab is a programmed death-ligand 1 (PD-L1) inhibitor with clinical activity in advanced urothelial cancer. Advanced urothelial cancer is also characterised by several recurrent targetable genomic alterations.

BISCAY is an open-label, randomised, multi-drug, biomarker-directed, phase Ib study conducted in patients with muscle invasive bladder cancer. The study team combined durvalumab with relevant targeted therapies in biomarker-selected chemotherapy-refractory advanced urothelial cancer populations including FGFR inhibitors in tumours with FGFR DNA alterations, PARP inhibitor in tumours with and without DNA homologous recombination repair deficiency and TORC1/2 inhibitors in tumours with DNA alteration to the mTOR/PI3K pathway.

This study adopted a new, biomarker-driven, multi-arm adaptive design. Safety, efficacy and relevant biomarkers were evaluated. Overall, 391 patients were screened of whom 135 were allocated to one of six study arms.

Response rates ranged from 9% to 36% across the study arms, which did not meet efficacy criteria for further development.

Overall survival and progression-free survival were similar in the combination arms and durvalumab monotherapy arm.

Biomarker analysis showed a correlation between circulating plasma-based DNA (ctDNA) and tissue for FGFR alterations. Sequential ctDNA analysis showed that changes to FGFR alterations correlated with clinical outcome.

The authors concluded that their data support the clinical activity of FGFR inhibition and durvalumab monotherapy, but do not show increased activity for any of the combinations. These findings are relevant in terms of the question about the targeted/immune therapy approach in advanced urothelial cancer.

The study was sponsored by AstraZeneca.

Reference

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. Nature Medicine; Published online 3 May 2021. DOI: https://doi.org/10.1038/s41591-021-01317-6

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