Background: Gene rearrangements (fusions) and mutations in RET have the potential to be oncogenic drivers and have been observed in a variety of tumors types. Selective RET inhibitors selpercatinib and pralsetinib have been approved for patients with RET-altered cancers. FHND5071 is a novel kinase inhibitor which specifically targets RET activated forms and has unique pharmacokinetic profile.

Methods: The pharmacological profile of FHND5071 have been confirmed in in vitro and in vivo evaluations, including enzyme and cell-based assays, PK/PD study, and RET-dependent tumor models.

Results: In enzymatic assays, FHND5071 potently inhibited RET wild type, RET fusions and mutations with the IC50 of 4.47~19.26 nM and demonstrated 89-fold selectivity over KDR (VEGFR-2). FHND5071-M2, the active metabolite identified in pre-clinical pharmacokinetics, had the same potency as FHND5071. In cellular settings, FHND5071 inhibited the proliferation of Ba/F3 engineered cells (RET WT, RET V804M, RET M918T) and inhibited RET phosphorylation in HEK-293 engineered cells (WT, V804M, RET M918T, KIF5B-RET, CCDC6-RET) with the similar potency compared with selpercatinib. In PK/PD study (Ba/F3 KIF5B-RET allograft model), compared with selpercatinib, FHND5071 had longer Tmax and MRT in plasma and tumor tissue. FHND5071 preferred to be distributed into tissues. The exposure of FHND5071 in tumor tissue (AUC0-t) was ~28 times that of selpercatinib and the concentration of FHND5071 in brain tissue was ~33 times that of selpercatinib at 4 h after dosing. Meanwhile, after FHND5071 administration, RET phosphorylation and the downstream signaling protein (pAKT, pErk1/2) were significantly inhibited in tumor tissue and the inhibition was maintained for 24 h at least. But the duration of inhibition with selpercatinib was shorter than that of FHND5071. In tumor models, FHND5071 exhibited significant anti-tumor efficacy in Ba/F3 KIF5B-RET model at oral dose levels ≥3 mg/kg once daily (QD) without inducing significant toxicity. FHND5071 QD exhibited similar anti-tumor activity as selpercatinib administrated twice a day (BID) at 30 mg/kg. 30 mg/kg FHND5071 (QD) demonstrated significant anti-tumor efficacy with 100% TGI in patient-derived xenograft models (colorectal cancer with CCDC6-RET and ovarian cancer with NCOA4-RET). In CCDC6-RET intracranial xenograft model, 30 mg/kg FHND5071 (QD) significant prolonged life time of model mice. The median survival time was 56 days and the increase in life-span was 51% (p<0.005 compared with the vehicle group).

Conclusions: FHND5071 demonstrated excellent selectivity and anti-tumor efficacy. The unique pharmacokinetic profile of FHND5071 supported the frequency of once-a-day dosing and better efficacy in target organ and brain tumor in clinical. FHND5071 has received IND approval from NMPA and FDA. It is currently in the dose-escalation segment of a first-in-human phase 1 trial for patients with RET-driven solid tumors.

Citation Format: Yongqiang Zhu, Jia Wang, Minghong Shang. FHND5071: a selective RET inhibitor with unique pharmacokinetic profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB330.