Immune Checkpoint Blockade and Targeted Agent Combos in Advanced Urothelial Cancer - Expert Commentary

Potentially actionable genomic alterations are common in advanced urothelial cancers (aUC). However, it is unclear if personalized treatment strategies based on each patient’s genomic profile will be effective in the clinic.


A recently published clinical trial, BISCAY, by Powles et al. in Nature Medicine, investigated the efficacy of durvalumab, an anti-PD-L1 inhibitor in combination with either an FGFR inhibitor (AZD4547), TORC1/2 inhibitor (vistusertib), or a PARP inhibitor (olaparib). The study was designed as a phase Ib trial with safety as the primary endpoint. However, the investigators used an adaptive design that allows expanding treatment arms that achieve objective response rates significantly higher than single-agent immune checkpoint blockade (15%-25%). The study included five treatment arms, including a control arm of durvalumab monotherapy. DNA, RNA, and serial circulating tumor DNA analysis were performed to select patients for targeted agents. The eligible patients have to harbor one of these molecular targets, FGFR1,2,3 mutations/fusions, homologous recombination repair (HRR), RICTOR, TSC1, and TSC2 gene alterations.

Out of 391 screened patients with aUC, 135 patients were allocated to the treatment arms. The response rates were similar across the treatment arms. The combinations did not achieve complete or durable responses. Similarly, the median progression-free survivals ranged between 20 and 43%. An important signal is that the AZD4547 showed single-agent anti-FGFR activity with an objective response rate of 31%. Taken together, the ICB-targeted agent combos did not outperform single-agent durvalumab. The highest incidence of grade 3 and 4 adverse effects (AEs) occurred in AZD4547 + durvalumab arm (48%). The discontinuation rate for AEs was relatively high and reached 33% for AZD4547 + durvalumab arm.

Tracking the FGFR genomic alterations showed a correlation between mutant allele frequency (AF) and the radiological response to therapy. Also, increasing the AF was observed on disease progression, suggesting a promising role of serial ctDNA tracking to monitor clinical response.

The efficacy findings from the BISCAY were limited by the phase Ib design and the sample size. Testing similar targeted agents in alternative disease settings, e.g., platinum-naïve or neoadjuvant, could demonstrate different efficacy profiles. Overall, the lack of added benefit to ICB in the BISCAY trial underscores a critical unmet need for developing robust biomarkers of benefit to ICB or other targeted therapies.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York

References:

  1. Powles T, Carroll D, Chowdhury S, Gravis G, Joly F, Carles J, 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. PMID: 33941921

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