Efficacy and safety of SY-5007, a highly potent and selective RET inhibitor, in Chinese patients with advanced RET-fusion positive non-small cell lung cancer (NSCLC): Results from a multicenter, single-arm, phase II study.

3106 Background: Lung cancer is the leading cause for all cancer-related death, with NSCLC accounting for 85% of all cases. The oncogenic RET-fusion is identified in 1-2% of NSCLC patients. Several RET inhibitors have been approved. This pivotal phase II study aimed to evaluate the efficacy and safety of SY-5007, a novel, highly selective RET inhibitor, in Chinese patients with advanced, positive RET NSCLC. Methods: This trial enrolled two cohorts of patients with RET-fusion positive NSCLC. Cohort 1 comprised treatment-naive patients, and cohort 2 included those previously treated with systemic therapy. Both cohorts received oral SY-5007 at 160 mg twice daily in a 28-day cycle. Primary endpoint was overall response rate (ORR) assessed by blinded independent central review (BICR) per RESICST v1.1. Secondary endpoints included ORR assessed by investigators, disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of the data cutoff date on January 16, 2024, the trial enrolled 105 patients, with a median follow-up of 4.57 months (95% confidence interval CI 0.2-10.3). The BICR-assessed overall ORR was 77.1% (95% CI 67.9-84.8) and DCR was 83.8% (95% CI 75.3-90.3). The investigator-assessed overall ORR was 77.1% (95% CI 67.9-84.8) and DCR was 90.5% (95% CI 83.2-95.3). In treatment-naive patients (cohort 1, n=56), SY-5007 showed an ORR of 83.9% (95% CI 71.4-92.4) and a DCR of 91.1% (95% CI 80.4-97.0). In pre-treated patients (cohort 2, n=49), SY-5007 exhibited an ORR of 69.4% (95% CI 54.6-81.7) and a DCR of 89.8% (95% CI 77.8-96.6). For 29 patients with baseline brain metastasis, the ORR and DCR were 69.0% (95% CI 49.2-84.7) and 86.2% (95% CI 68.3-96.1). Meanwhile, the ORR and DCR for 76 patients without baseline brain metastasis were 80.3% (95% CI 69.5-88.5) and 92.1% (95% CI 83.6-97.0). Among 10 patients with baseline intracranial target lesions, intracranial ORR and DCR were 80.0% (95% CI 44.4-97.5) and 100% (95% CI 47.8-100). Median PFS, DoR or OS were not reached. Treatment-related adverse events (TRAEs) were reported in 96.2% of patients, with common events (≥ 30%) including increased AST, increased ALT, decreased neutrophil count, decreased white blood cell count and decreased platelet count. Grade ≥ 3 TRAEs and treatment-related serious adverse events were observed in 42.9% and 10.5% of patients. TRAE-induced dose interruption and dose reduction occurred in 39.0% and 23.8% of patients, respectively. TRAEs led to SY-5007 discontinuation in two patients (1.9%), with no deaths due to TRAE. Conclusions: SY-5007 demonstrated promising efficacy and safety for advanced NSCLC with positive RET. Clinical trial information: NCT05278364 .