erdafitinib

Overview

Oral pan-FGFR tyrosine kinase inhibitor targeting FGFR1/FGFR2/FGFR3/FGFR4; FDA-approved for FGFR2/3-altered metastatic urothelial carcinoma (PMID:37682528).

Evidence in the corpus

  • Real-world MSK cohort of 32 metastatic urothelial carcinoma patients treated 8/2019–7/2022: ORR 40% (12/30 evaluable), median PFS 2.8 months (95% CI 2.6–5.4), median OS 6.6 months (95% CI 4.6–17.3) — activity modest relative to BLC2001 (PMID:37682528).
  • Tolerability-limited: dose reductions in 38% (12/32), interruptions in 50% (16/32); TEAEs included hyperphosphatemia 84%, fatigue 59%, mucositis 47% (grade >=3 16%), PPE 38% (grade >=3 9%), dysgeusia 31% (PMID:37682528).
  • Archival primary vs metastatic FGFR3 status discordant in 26% (7/27) of paired cases, arguing for metastatic-site or cfDNA profiling to guide erdafitinib selection (PMID:37682528).
  • Baseline TP53 co-alteration associated with lower ORR (22%, 2/9) and enriched among primary progressors (PMID:37682528).
  • In a multi-site paired primary-metastasis WES study of bladder cancer (n=60 pairs), FGFR3 mutations/fusions were discordant in 9% of primary-metastasis pairs, and cfDNA detected acquired FGFR3 resistance mutations (N540S, K650E, V553M) during erdafitinib therapy; both tissue and cfDNA profiling recommended to assess erdafitinib eligibility PMID:36543146
  • Referenced as an FGFR inhibitor actionable in metastatic urothelial carcinoma with FGFR3 mutations (e.g., S249C hotspot); 69.3% of UC-GENOME patients had NGS-identified treatment options including erdafitinib, but only 5.0% received targeted therapy PMID:36333289
  • Cited in HCC context as an FGFR inhibitor relevant to FGF19/FGFR4-amplified tumors; part of discussion of FGFR-targeted therapy landscape PMID:24798001
  • Pan-FGFR tyrosine kinase inhibitors including erdafitinib are proposed as rational targeted therapy for luminal-papillary MIBC (35% of cohort), which is enriched for FGFR3 mutations (42/57, p<1e-9), FGFR3-TACC3 fusions (8/10), and FGFR3 amplification PMID:28988769

Resistance mechanisms

  • Acquired second-site FGFR3 kinase-domain mutations detected in serial cfDNA: V553M and N540S (plus K650M, R669G); in silico modeling supports V553M as a gatekeeper allele allosterically blocking erdafitinib binding (PMID:37682528).
  • In a paired primary-metastasis WES/cfDNA cohort of bladder cancer, convergent FGFR3 evolution was observed: one patient accumulated 4 distinct oncogenic FGFR3 alterations (3 hotspot mutations + FGFR3-TACC3 fusion) in cfDNA but only 1 in the metastatic biopsy, demonstrating clonal heterogeneity that complicates erdafitinib response prediction PMID:36543146.
  • Acquired TP53 mutations in 5/27 on-treatment cfDNA series as putative resistance driver (PMID:37682528).
  • Acquired activating AKT1 mutation in 1/27 as putative bypass resistance (PMID:37682528).

Cancer types (linked)

Sources

  • PMID:37682528

  • PMID:36543146 — Sfakianos et al. 2023; FGFR3 discordance between primary and metastatic bladder cancer; cfDNA resistance mutations during erdafitinib therapy.

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