(UroToday.com) The 2024 Bladder Cancer Advocacy Network (BCAN) Bladder Cancer Think Tank held in San Diego, CA between August 7th and 9th, 2024 was host to a BCAN 2023 Patient-Centered Clinical Young Investigator Awardee session. Dr. Sean Clark-Garvey presented his group’s work exploring Fibroblast Growth Factor 3 (FGFR3) inhibition as a sensitizing agent to Nectin-4 antibody-drug conjugate (ADC) therapy in urothelial carcinoma.
Over the last decade, we have witnessed the emergence and approval of an FGFR inhibitor, erdafitinib, and an antibody-drug conjugate targeting Nectin-4, and enfortumab vedotin (EV).
The expression of the NECTIN4 gene has been shown to be heterogenous across molecular subtypes of bladder cancer and is significantly enriched in luminal subtypes. The downregulation of NECTIN4 leads to EV resistance.1
Notably, FGFR3 alterations were more common in the luminal subtype, compared to basal subtypes, thus suggesting that there may be a positive correlation between NECTIN4 expression and FGFR3 alterations.
Accordingly, Dr. Clark-Garvey and colleagues hypothesized that inhibition of FGFR3 will lead to a decrease in NECTIN4 expression.
On western blot analysis, they unexpectedly discovered that FGFR3 inhibition was associated with increased Nectin-4 expression in cell lines harboring FGFR3 alterations.
Furthermore, they demonstrated that the effect on Nectin-4 expression was specific to FGFR3 activity:
As demonstrated below, FGFR3 inhibition using erdafitinib was associated with increased Necitn-4 expression (blue curves below):
It appears that Nectin-4 upregulation is possibly mediated through an FGFR3/MEK axis:
Following these in vitro studies, Dr. Clark-Garvey’s team demonstrated that erdafitinib-induced Nectin-4 upregulation can be replicated in an in vivo setting:
Based on these results, it is hypothesized that the combination of erdafitinib and EV may have synergistic mechanisms of action. The results of a phase 1b trial of this combination in the post-platinum chemotherapy and PD-1/L-1 inhibitor setting for 9 patients with metastatic urothelial carcinoma and FGFR2/3 alterations was presented at ASCO GU 2024 and demonstrated an objective response rate of 100% (partial response: 8; complete response: 1).
- FGFR3 activating alterations and Nectin-4 expression are enriched in luminal subtypes of muscle-invasive and metastatic urothelial carcinoma and mUC, with expression positively correlated.
- Membranous Nectin-4 expression is upregulated in cell lines harboring activating FGFR3 alterations following treatment with erdafitinib, and the effect is specific to FGFR3 inhibition.
- This effect is possibly mediated by MAPK signaling.
- There is in vitro synergy between erdafitinib and enfortumab vedotin
Written by: Rashid Sayyid, MD, MSc – Robotic Urologic Oncology Fellow at The University of Southern California, @rksayyid on Twitter during the 2024 BCAN Bladder Cancer Think Tank held in San Diego, CA between August 7th and 9th, 2024
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