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Found 1 Presentation For Request "541P"
541P - Derazantinib (DZB), an oral fibroblast growth factor receptor inhibitor (FGFRi), shows promising activity in PDX-tumour models with aberrations in FGFR1-3
- Paul M. Mcsheehy (Basel, Switzerland)
Abstract
Background
DZB is an FGFRi, also targeting CSF1R, with clinical activity in FGFR2-fusion cholangiocarcinoma. To explore DZB activity in other tumour types carrying FGFR-fusions, mutations and/or differing FGFR copy-number/expression levels, a screen in 46 PDX-derived tumour models of breast (BC, 5), colorectal (CRC, 2), head & neck (H&N, 6), lung (LC, 16), ovarian (OC, 3) and gastric (GC, 14) cancer was performed.
Methods
PDX-models characterized for FGFR genetic aberrations and expression were profiled for DZB response (qd, oral, 75 mg/kg, for 10-27 days) compared to vehicle control (n=4/group). Tumour volumes (TV) and body weights (BW) were monitored twice weekly. Efficacy and tolerability were quantified as dT/C (treated/control) and Pearson correlations made between RNASeq values of FGFR1-3 family members showing the highest value.
Results
Efficacy varied from no-response to 100% regression. Considering dT/C≤0.4 as a threshold, the overall response rate was 31%. According to histotype, GC (43%) and LC (19%) showed the highest response rates. Although in BC and H&N, 1 strong regression (dT/C= -0.73) and 1 tumour stasis (dT/C= 0.04) were observed, respectively. Across all models, high FGFR expression correlated significantly with efficacy (r2=0.22, p=0.001, n=46); a stronger relationship was found in LC/GC models (r2=0.42, p=0.0002, n=29). In GC models, known FGFR driver-mutations were associated with partial responses (best dT/C=0.42), however models carrying FGFR2-fusions (4/6 with FGFR fusions) were highly responsive leading to strong regressions. Moreover, a highly significant correlation between efficacy and FGFR expression was observed in all models with FGFR-fusions (r2=0.45, p=0.0024, n=18) but not in non-fusion containing models (r2=0.03, p=0.36, n=28) indicating a strong association of response rate with FGFR-fusion and high expression.
Conclusions
DZB had strong activity in PDX-models with FGFR-fusions and high FGFR expression, in particular in GC, where regressions were observed in all FGFR2-fusion models tested. A clinical trial is planned in patients with GC to investigate DZB as mono- and combination-therapy.
Legal entity responsible for the study
Basilea Pharmaceutica Limited.
Funding
Basilea Pharmaceutica AG.
Disclosure
P.M. Mcsheehy: Full/Part-time employment: Basilea Pharmaceutica AG.