Reference Detail

Ref Type

Abstract

PMID

Authors

Yongqiang Zhu; Jia Wang; Minghong Shang

Title

Abstract LB330: FHND5071: a selective RET inhibitor with unique pharmacokinetic profile

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer Research	83	8_Supplement	April 15, 2023

URL

https://aacrjournals.org/cancerres/article/83/8_Supplement/LB330/725305

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
FHND5071	FHND5071	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
FHND5071		FHND 5071\|FHND-5071	RET Inhibitor 52	FHND5071 inhibits RET, which decreases downstream signaling and potentially results in reduced cell proliferation and tumor growth (Cancer Res (2023) 83 (8_Supplement): LB330).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RET V804M	Advanced Solid Tumor	predicted - sensitive	FHND5071	Preclinical - Cell culture	Actionable	In a preclinical study, FHND5071 inhibited Ret phosphorylation and proliferation in cells expressing RET V804M in culture (Cancer Res (2023) 83 (8_Supplement): LB330).	detail...
RET M918T	Advanced Solid Tumor	predicted - sensitive	FHND5071	Preclinical - Cell culture	Actionable	In a preclinical study, FHND5071 inhibited Ret phosphorylation and proliferation in cells expressing RET M918T in culture (Cancer Res (2023) 83 (8_Supplement): LB330).	detail...