SY-5007, a novel RET inhibitor, has demonstrated promising efficacy and manageable safety in a Phase 1 clinical trial involving patients with RET-altered solid tumors. The study, which enrolled 122 patients, showed significant anti-tumor activity across various RET alterations, including non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and papillary thyroid cancer (PTC). These findings suggest that SY-5007 could represent a valuable new treatment option for patients with these cancers.
Study Design and Patient Characteristics
The Phase 1 study enrolled patients between April 2021 and November 2023, with 17 patients in the dose-escalation phase and 105 in the dose-expansion phase. Among the participants, 91 had RET fusion-positive NSCLC, 23 had RET-mutant MTC, 7 had RET fusion-positive PTC, and 1 had RET-mutant gastric cancer. Prior treatments varied, with 36.1% of patients treatment-naïve and 63.9% previously treated with chemotherapy, MKIs, PD-1/PD-L1 inhibitors, or other systemic therapies. The most prevalent RET fusion partners were KIF5B (54.1%) and CCDC6 (15.6%), while the most common RET mutation was RET M918T (12.3%).
Safety and Tolerability
The safety analysis included all 122 patients who received at least one dose of SY-5007. No dose-limiting toxicity (DLT) was observed, and the maximum tolerated dose (MTD) was not reached. Treatment-related adverse events (TRAEs) were common, with 96.7% of patients experiencing at least one. The most frequent TRAEs (≥50%) included increased aspartate aminotransferase (AST, 69.7%), increased alanine aminotransferase (ALT, 56.6%), diarrhea (54.1%), and neutropenia (54.1%), all of which were reversible with appropriate management. Grade ≥3 TRAEs occurred in 57.4% of patients, with hypertension (22.1%), diarrhea (16.4%), hypertriglyceridemia (6.6%), and neutropenia (6.6%) being the most common.
Dose interruptions and reductions due to TRAEs were required in 45.9% and 23.8% of patients, respectively. Treatment discontinuation occurred in only 1.6% of patients due to adverse events. Treatment-related serious adverse events (TRSAEs) were reported in 10.7% of patients, with no treatment-related deaths.
Pharmacokinetics
Pharmacokinetic (PK) analysis included 43 evaluable patients. After single-dose administration, the mean time to maximum concentration (Tmax) ranged from 0.5 to 4.0 hours, and the mean elimination half-life (T1/2) ranged from 6.8 to 44.4 hours. SY-5007 exposure increased dose-proportionally from 20 mg to 160 mg, with saturation observed at higher doses. Multiple-dose administration showed significant increases in SY-5007 exposure with repeated dosing in the 20 mg to 160 mg range, with modest drug accumulation at steady state.
Efficacy Outcomes
Efficacy assessments were conducted on 116 patients. Overall, target tumor shrinkage was observed in 95.7% of patients. The objective response rate (ORR) was 57.8% (95% CI: 48.2-66.9%), and the disease control rate (DCR) was 95.7% (95% CI: 90.2-98.6%). SY-5007 induced rapid and durable responses, with a median time to first response (TTR) of 2.82 months (95% CI: 2.75-4.66) and a median duration of response (DoR) of 19.9 months (95% CI: 12.8-NE). The median progression-free survival (PFS) was 21.1 months (95% CI: 13.8-NE), with estimated 6-month and 12-month PFS rates of 86.1% and 68.9%, respectively.
In the dose-escalation phase, the ORR and DCR were 52.9% and 94.1%, respectively. In the dose-expansion phase, the ORR and DCR were 58.6% and 96.0%, respectively. For patients receiving SY-5007 at 160 mg BID or 200 mg BID, the ORRs were 58.9% and 60.0%, respectively, and DCRs were 94.7% and 100.0%, respectively.
Among treatment-naïve patients, the ORR and DCR were 70.0% and 95.0%, respectively. In previously treated patients, the ORR was 51.3% and the DCR was 96.1%. Based on these results, 160 mg BID of SY-5007 was selected as the recommended Phase 2 dose (RP2D).
Further analysis at the RP2D included 100 patients with NSCLC, MTC, and PTC. SY-5007 achieved an ORR of 64.1% and a DCR of 96.9% in evaluable NSCLC patients. The median TTR was 2.75 months, and the median DoR was 13.0 months. The median PFS was 15.4 months. In RET-mutant MTC patients and RET fusion-positive PTC patients, the ORRs were 52.2% and 42.9%, respectively, and DCRs were 91.3% and 100.0%, respectively.
SY-5007 also demonstrated intracranial anti-tumor efficacy in patients with baseline measurable central nervous system (CNS) metastases, with an intracranial ORR of 66.7% and DCR of 100.0%.
Biomarker Analysis
Retrospective analysis of circulating tumor DNA (ctDNA) profiling revealed that SY-5007 demonstrated significant anti-tumor efficacy in both patients with detectable and undetectable RET variations at baseline, achieving ORRs of 57.4% and 60.4%, respectively. Longitudinal analysis showed a rapid decline in the mean variant allele frequency (VAF) of RET alterations, with 21 patients achieving complete RET clearance. Patients with TP53 mutations showed numerically inferior efficacy compared to those without.
Comprehensive ctDNA profiling was conducted to elucidate potential mechanisms of resistance to SY-5007. No treatment-induced novel on-target RET alterations were identified, suggesting the potential significance of off-target induced resistance during the study period.
