FGFR3 G370C

The MODAPLEX FGFR panel allows the stratification of bladder cancer patients by determination of the FGFR3 mutational and FGFR2/3 fusion status. The PCR-based FGFR assessment by MODAPLEX FGFR panel and therascreen FGFR kit is highly concordant (78/79). The MODAPLEX assays enable fast, local FGFR assessment in a multiplexed one-step approach within few hours.

Background: Interest in FGFR-targeted (FGFRi) therapies for UC or pan-tumor use is growing (ongoing clinical studies include erdafitinib (NCT05316155; NCT04172675; NCT03390504; NCT04083976), LOXO-435 (NCT05614739), and pemigatinib (NCT03914794) following accelerated approval of erdafitinib in locally advanced/metastatic (m) post-chemotherapy UC patients with FGFR2/3 (i.e., DNA mutations and fusions) alterations (ALT). FGFR-PRS (+) captured most ALT (+) tumors and an additional 2X more with similar FGFR pathway activation. FGFR-PRS (+) tumors were associated with gene enrichments for ontologies linked to FGFR3 signaling. The correlation of FGFR-PRS score with in vitro FGFRi activity provided initial utility of the signature, which is undergoing clinical evaluation in the ALAMANCE retrospective study of UC patients treated with FGFRi or other standard-of-care therapies.

Background: In view of the efficacy of FGFR targeting in early and advanced bladder cancer, as has been shown for erdafitinib in the THOR and NORSE trial, molecular testing of FGFR mutations and fusions will soon become clinical routine worldwide... PCR-based FGFR assessment by Therascreen and UroTyper is highly concordant and enables fast, local FGFR assessment within few hours. FGFR3 mutations are associated with increased TROP2 & NECTIN4 expression indicating potential synergistic options which warrants further exploration as part of molecularly stratified clinical trials.

The results showed a similar trend to previous studies, where FGFR GA was reported in approximately 20% of metastatic UC patients. No difference was found in the PFS and the estimated survival rate by FGFR2/3 GA-positive or -negative patients. Our data showed that treatment pressure did not alter the FGFR status commonly.

P2; Trial completion date: Aug 2023 --> Aug 2025 | Trial primary completion date: Aug 2023 --> Aug 2025

P1, N=169, Recruiting, Abbisko Therapeutics Co, Ltd | Not yet recruiting --> Recruiting | Initiation date: Dec 2022 --> Jun 2023

A positive somatic mutational status of the FGFR3 gene was statistically significantly more common in the group of papillary low-grade non-muscle-invasive BC, demonstrating basal p16 IHC staining. In the study sample, there was no statistically significant relationship between the FGFR3 status of BC and gender and age differences, TILs, MMR status, PD-L1 status (SP142 and 22C3), and p16 status. The results of the study indicate the need to determine the FGFR3 status in patients with BC for further prescription of personalized therapy.

P3; N=218 --> 39 | Trial completion date: Jan 2025 --> Jan 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jan 2024 --> Jan 2023; The sponsor has decided to close the study due to the discontinuation of infigratinib development. The discontinuation of the study was not due to safety reasons.

P1, N=169, Not yet recruiting, Abbisko Therapeutics Co, Ltd

Variant histology was appreciated in 76% of FGFR mutated cases, with the micropapillary pattern being the most prevalent (n=12 | 32%). The FGFR pathway is classically associated with low-grade papillary tumors, which, through additional mutations, can cause invasive, high-grade disease. It is speculated that the initial papillary architecture present in FGFR mutated lesions may be preserved, manifesting as the micropapillary pattern appreciated in some invasive lesions.

P3; Recruiting --> Active, not recruiting

Gemcitabine-platinum combinations were the backbone of choice in 93.7% of pts receiving combined chemotherapy. Pembrolizumab and atezolizumab were the chosen first-line agents for 10.3% and 4% of the treated pts, respectively... The prevalence of FGFR alterations in advanced UC in Latin America is similar to those described in other regions. Our data suggest limited access to FGFR inhibitors for the treatment of advanced UC in Latin America.

Among 174 pts with available FGFRalt data pre and post BCG, FGFRalt status was maintained post BCG for most (54 [31%] pts had FGFRalt pre vs 51 [29%] post BCG). Conclusions : Overall, 30.3% of pts with HR NMIBC had FGFR+ tumors and pts with HR NMIBC had similar outcomes post BCG regardless of FGFR status.

P2; Not yet recruiting --> Recruiting

Despite a better response to first line treatment, overall FGFR GA showed to be an independent risk factor in mUC. Thus, this determination should be included in new prognostic models. Univariable and multivariable analysis for overall survival in the first line treatment setting for mUC.

The mechanism of resistance was not dependent on receptor kinase activity. Further studies are ongoing to determine the biochemical mechanisms of FGFR3-mediated immunotherapy resistance in bladder cancer.

Targetable mutations were mainly detected in BLCA, and S249C, Y373C, G370C, and R248C were hotspot mutations that could be targeted by an FDA approved erdafitinib...FGFG3 abnormal expression and alterations exhibited clinical correlations with patient prognosis in several tumors. This work exhibited the full alteration spectrum of FGFR3 and indicated several new clues for their application as potential therapeutic targets and prognostic indicators.

P2; N=25; Not yet recruiting; Sponsor:Memorial Sloan Kettering Cancer Center

Food and Drug Administration (FDA) has approved Balversa (erdafitinib) for metastatic bladder cancer treatment, and more FGFR inhibitors are currently being evaluated clinically in many other cancer types, including lung cancer...Hopefully, more patients with other FGFR mutations may benefit from FGFR inhibitors as well, which needs further clinical investigation. Meanwhile, the exclusive relationship between druggable FGFR mutations and other actionable variations in lung cancers defines a unique molecular subtype, extending the number of patients who can benefit from targeted therapy.