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Shengyu Zhou¹, Changgong Zhang¹, Guowen Wang²

¹Department of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Experimental Hematology & Oncology

|June 26, 2026

Abstract

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).

Insights

Eratrectinib shows promise for treating NTRK fusion-positive solid tumors, overcoming resistance to earlier therapies. This next-generation tyrosine kinase inhibitor demonstrated a manageable safety profile and a 70% objective response rate in a Phase 1 study.

Area of Science:

Oncology
Pharmacology
Clinical Trials

Background:

Tropomyosin receptor kinase (TRK) tyrosine kinase inhibitors (TKIs) are effective against neurotrophic receptor tyrosine kinase (NTRK) fusion-positive tumors.
Drug resistance is a common challenge with existing TRK TKIs.
Eratrectinib (VC004) is a next-generation TRK TKI designed to overcome resistance.

Purpose of the Study:

To evaluate the safety, maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of oral eratrectinib.
To assess the pharmacokinetics (PK) and efficacy of eratrectinib in patients with advanced solid tumors.

Main Methods:

A Phase 1, open-label, dose-escalation study using a 3+3 design.
Patients received oral eratrectinib at doses ranging from 25 mg twice daily (BID) to 200 mg BID.
Dose expansion cohorts were enrolled to gather further safety, PK, and efficacy data, particularly in NTRK fusion-positive patients.

Main Results:

The MTD was determined to be 100 mg BID.
The RP2D was established as 50 mg BID.
At the RP2D, the objective response rate (ORR) was 70% (21/30) in NTRK fusion-positive patients. Common treatment-related adverse events included dizziness and anemia.

Conclusions:

Eratrectinib exhibits a manageable safety profile and promising efficacy in patients with NTRK fusion-positive solid tumors.
Eratrectinib represents a potential new treatment option for this patient population.
Further studies are underway to confirm these findings.

Read full analysis

Keywords:

Eratrectinib Neurotrophic receptor tyrosine kinase fusion Solid tumor Tropomyosin receptor kinases tyrosine kinase inhibitors VC004

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