Safety, efficacy, and pharmacokinetics of eratrectinib (VC004) in solid tumors with NTRK fusions: phase 1 results from a phase 1/2 study

BACKGROUND: Tropomyosin receptor kinases (TRK) tyrosine kinase inhibitors (TKIs) have demonstrated marked efficacy in neurotrophic receptor tyrosine kinase (NTRK) fusion positive tumors. However, resistance inevitably develops. Eratrectinib (VC004) is a next-generation selective TRK TKI which can overcome drug resistance. METHODS: In this phase 1 study, patients with locally advanced or metastatic solid tumors were enrolled in the dose-escalation part. A standard 3 + 3 design was adopted to sequentially assign patients at 25 mg twice daily (BID), 50 mg BID, 100 mg BID, and 200 mg BID dose levels of oral eratrectinib. After each dose had been established, we expanded specific dose cohorts in patients with NTRK fusion positive locally advanced or metastatic solid tumors to obtain adequate data for safety, pharmacokinetics (PK), and efficacy. The primary endpoints of this study were safety, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). RESULTS: Between December 4, 2020 and November 4, 2021, 16 patients were enrolled in the dose-escalation part and a dose of 100 mg BID was identified as MTD. Between May 8, 2021 and March 19, 2025, 75 patients were enrolled in the dose-expansion part at doses of eratrectinib 25 mg BID, 50 mg BID, and 75 mg BID. Treatment-emergent adverse events (TEAEs) occurred in 94.7% (71/75) of patients. The most common treatment-related adverse events (TRAEs) included dizziness (51/75, 68.0%), anaemia (28/75, 37.3%), weight increased (27/75, 36.0%), hypertriglyceridemia (25/75, 33.3%). ≥ grade 3 TRAEs occurred in 17.3% (13/75) of patients. No TRAEs led to death. The dose of 50 mg BID was chosen as RP2D based on the results of safety, PK, and efficacy. At the RP2D dose, objective response rate (ORR) was 70% (21/30, 95% confidence interval 50.6-85.3). CONLUSIONS: Eratrectinib demonstrated manageable safety profile and promising efficacy in patients with NTRK fusion positive solid tumors, representing a new treatment option for this patient population. Further studies to confirm the efficacy and safety of eratrectinib are ongoing. Trial registration NCT04614740 (ClinicalTrials.gov).