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

Abstract

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).

Fig. 1

Tumor response in patients with RET-altered solid tumors receiving SY-5007. a Waterfall plots of the maximum tumor size change in 114 efficacy-evaluable patients with measurable lesions in RET-altered solid tumors. b The change in tumor burden over time in patients for whom postbaseline tumor data were available. BID bis in die, DCR disease control rate, MTC medullary thyroid cancer, NSCLC non-small cell lung cancer, ORR objective response rate, PTC papillary thyroid carcinoma, QD quaque die

Fig. 2

Efficacy of SY-5007 in patients with RET-altered solid tumors. a The time to response, the duration of treatment, and patient status by the data cut-off date for all enrolled patients with RET-altered solid tumors, according to the dose of SY-5007. b, c Kaplan-Meier curve of the progression-free survival in all patients (b) and NSCLC patients at 160 mg BID (c). Data shown were determined by investigator assessments. d Landscape of gene alterations in ctDNA from patients with progressive disease. The figure illustrates concurrent gene alterations identified in plasma samples from patients at baseline and after disease progression. Each column represents an individual patient for whom data are available. Within each column, colored rectangles indicate specific gene alterations, categorized by alteration type. Newly acquired genetic alterations in patients with progressive disease are highlighted in red font. CI confidence interval, CN copy number, NE not evaluated, NSCLC non-small cell lung cancer, PFS progression-free survival, SNV single nucleotide variation