zoligratinib (Debio 1347)

This compound indicates a higher potential for inhibiting FGFR2 than the control inhibitor, Zoligratinib...ADMET analysis showed promising pharmacokinetic potential of the screened compound. Overall, the findings indicate that the compound CID:507883 may have promising potential to serve as a lead candidate against FGFR2 and could be further exploited in therapeutic development.

Debio 1347 had manageable toxicity; however, the efficacy in patients with tumors harboring FGFR fusions did not support further clinical evaluation in this setting. Our transcriptomic-based analysis characterized in detail the incidence and nature of FGFR fusions across solid tumors.

Although FGFRi treatments suppressed tumor growth across CRPC phenotypes, our analyses did not identify a single pathway or biomarker that would identify tumor response to FGFRi. This is very likely due to the array of FGFR1-4 expression and tumor phenotypes present in CRPC. Nevertheless, our data nominate the FGFR pathway as a clinically actionable target that promotes tumor growth in diverse phenotypes of treatment-refractory metastatic CRPC.

In this study, seven pan-FGFR inhibitors (infigratinib, AZD4547, debio1347, erdafitinib, LY2874455, pemigatinib, and TAS-120) were evaluated for their brain penetration ability employing cassette dosing strategy with an aim to identify the optimal candidates for brain tumor targeting. The predictive parameters of brain penetration calculated based on physico-chemical properties have been estimated and shown not to correlate with the experimentally obtained neuro-pharmacokinetic values. In summary, our study provides comprehensive evaluation of neuro-pharmacokinetic behavior of seven FGFR inhibitors and delivers rationale for selection of most optimal candidates for future investigation in brain tumor clinical trials.

Forty two (42) patients with FGFR2 fusions and 9 patients with FGFR2 rearrangements received FGFR inhibitors: these include infigratinib (13), pemigatinib (17), futibatinib (14), derazantinib (5), and zoligratinib (2). The genomic evolution post-progression on FGFR inhibition involves acquired resistance in multiple pathways. Targeting co-alterations acquired post-progression with drug combination may overcome these resistance mechanisms and potentiate the efficacy of FGFR inhibition.

P1/2, N=10, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed

We review the FGFR pathway and discuss emerging issues including resistance to FGFR inhibitors. We end with a discussion on future considerations to optimize the potential of this class of therapeutics in advanced cholangiocarcinoma.

Three patients with FGFR2 EIDs were treated with Debio 1347, an oral FGFR-1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F FGFR2 kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal FGFR2 EIDs as an alternative mechanism of FGFR2 activation in IHCC that predict sensitivity to FGFR inhibitors in the clinic.

Similarly, dovitinib, AZD4547, CH5183284, infigratinib, lenvatinib, LY2874455, and lucitanib are type I½ inhibitors...Ponatinib binds to FGFR4 in a DFG-D conformation and is classified as a type II inhibitor. Futibatinib, roblitinib, H3B-6527, fisogatinib, and PRN1371 bind covalently to their FGFR target and are classified as type VI inhibitors. Nintedanib, pazopanib, pemigatinib, rogaratinib, fisogatinib, and PRN1371 are FGFR inhibitors lacking drug-enzyme crystal structures...The development of FGFR inhibitors has lagged behind those of other receptor protein-tyrosine kinases. However, the FDA approval of erdafitinib for the treatment of urinary bladder cancers may stimulate additional work targeting the many other FGFR-driven neoplasms.

P1/2, N=10, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Nov 2020 --> Nov 2021 | Trial primary completion date: Nov 2020 --> Nov 2021

Pts received an ATP-competitive, reversible FGFRi including infigratinib (19%), pemigatinib (5%), Debio1347 (2%), ponatinib (2%), or AZD4547 (2%), or the covalently-binding, irreversible inhibitor futibatinib (69%) as their first FGFRi. On-target resistance with acquired mutations in the FGFR2 kinase domain emerges over time in pts experiencing clinical benefit from FGFRi, suggesting FGFR pathway dependence in these patients. Only ~40% of pts on futibatinib developed FGFR2 KDmuts, suggesting that most may have off-target mechanisms of resistance. Mutation of the cysteine residue to which futibatinib binds was not a common mechanism of resistance in this small series.