Reference Detail

Ref Type

Journal Article

PMID

(39489747)

Authors

Li W, Wang Y, Xiong A, Gao G, Song Z, Zhang Y, Huang D, Ye F, Wang Q, Li Z, Liu J, Xu C, Sun Y, Liu X, Zhou F, Zhou C

Title

First-in-human, phase 1 dose-escalation and dose-expansion study of a RET inhibitor SY-5007 in patients with advanced RET-altered solid tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Signal transduction and targeted therapy	9	1	2024 Nov 04	300	Signal Transduct Target Ther

URL

Abstract Text

Oncogenic RET alteration is an important, tissue-agnostic therapeutic target across diverse cancers. We conducted a first-in-human phase 1 study on SY-5007, a potent and selective RET inhibitor, in patients with RET-altered solid tumors. Primary endpoints were safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D). Secondary endpoints included pharmacokinetics and preliminary anti-tumor activity. A total of 122 patients were enrolled (17 in dose-escalation phase and 105 in dose-expansion phase), including 91 with non-small cell lung cancer, 23 with medullary thyroid cancer, 7 with papillary thyroid cancer and 1 with gastric cancer. Treatment-related adverse events (TRAEs) were reported in 96.7% of patients, with the most common grade ≥ 3 TRAEs being hypertension (22.1%), diarrhea (16.4%), hypertriglyceridemia (6.6%), and neutropenia (6.6%). The exposure to SY-5007 was dose proportional. Among the 116 efficacy-evaluable patients, the overall objective response rate (ORR) was 57.8%, with 70.0% in treatment-naïve patients and 51.3% in previously treated patients. The median progression-free survival (PFS) was 21.1 months. Efficacy was observed regardless of tumor types and previous therapies. Biomarker analysis of 61 patients with circulating tumor DNA (ctDNA)-detectable RET alterations showed an ORR of 57.4% and median PFS of 13.8 months. Rapid ctDNA clearance of RET alteration correlated with faster responses and improved outcomes. In relapsed patients, off-target induced resistance was observed in 57.1% (12/21), with no on-target RET alterations identified. In conclusion, SY-5007 was well-tolerated and showed promising efficacy in patients with RET-altered solid tumors. Serial ctDNA monitoring may unveil treatment response and potential resistance mechanisms (NCT05278364).

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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
SY-5007	SY-5007	3	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
SY-5007		SY5007\|SY 5007	RET Inhibitor 53	SY-5007 is a RET inhibitor with activity against resistance mutations including M918T, G810S, and V804M, which potentially decreases tumor cell proliferation and tumor growth (PMID: 39489747).

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 M918T	medullary thyroid carcinoma	sensitive	SY-5007	Phase I	Actionable	In a Phase I trial, SY-5007 treatment demonstrated safety and resulted in an objective response rate (ORR) of 57.8% (67/116, partial responses), a disease control rate (DCR) of 95.7% (111/116), and a median progression-free survival of 21.1 mo in advanced solid tumor patients harboring RET fusions or alterations, with an ORR of 52.2% (12/23) and DCR of 91.3% (21/23) at the phase II dose in medullary thyroid cancer patients harboring RET M918T (n=15) or other mutations (n=8) (PMID: 39489747; NCT05278364).	39489747
RET fusion	lung non-small cell carcinoma	sensitive	SY-5007	Phase I	Actionable	In a Phase I trial, SY-5007 therapy was tolerable and led to an objective response rate (ORR) of 57.8% (67/116, 67 partial responses), disease control rate (DCR) of 95.7% (111/116), and median progression-free survival of 21.1 mo in advanced solid tumor patients with RET fusions or alterations, and an ORR of 64.1% (41/64) and DCR of 96.9% (62/64) at the phase II dose in non-small cell lung cancer patients with KIF5B (n=51), CCDC6 (n=12), NCOA4 (n=1), or other RET fusions (n=4) (PMID: 39489747; NCT05278364).	39489747
RET C634W	Advanced Solid Tumor	sensitive	SY-5007	Preclinical - Cell culture	Actionable	In a preclinical study, SY-5007 inhibited proliferation in cells expressing RET C634W in culture (PMID: 39489747).	39489747