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Ensartinib for advanced or metastatic non-small-cell lung cancer with MET exon 14 skipping mutations (EMBRACE):
Yang Xia1,2, Panwen Tian3, Mo Zhou1,2
1Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Background:
MET exon14 skipping mutations (METex14) is an established actionable driver oncogene of non-small-cell lung cancer (NSCLC). While ensartinib is a known second-generation tyrosine kinase inhibitor with primary activity against ALK translocation, it is also classified as a type Ia MET inhibitor. We have previously shown anti-tumor activity against METex14 positive NSCLC both in vivo and in vitro. The EMBRACE trial aims to evaluate the clinical efficacy and safety of ensartinib for treatment of METex14 positive NSCLC.
Methods:
This is a multicenter single arm phase II investigator-initiated study that enrolled METex14 positive lung cancer after failing first line chemotherapy and/or immunotherapy. Eligible patients received ensartinib 225 mg orally once daily in a continuous 28-day treatment cycle until disease progression, unacceptable side effect, or death. Primary endpoint was investigator-assessed objective response rate (ORR), and the secondary end point included disease control rate (DCR), progression-free survival (PFS), duration of response (DoR) and safety profiles. The study was registered with the Chinese Clinical Trial Registry (ChiCTR2100048767).
Findings:
From July 2021 to February 2024, a total of 31 patients were enrolled and received ensartinib. Median follow-up time of the 30 evaluable patients was 9.2 months (95% Confidence Interval [CI], 6.3-not estimable). The ORR was 53.3% (16/30; 95% CI, 35.5-71.2) and DCR was 86.7% (26/30; 95% CI, 74.5-98.8). Median PFS was 6.0 months (95% CI, 3.0-8.8) and median DoR was 7.9 months (95% CI, 4.8-8.7). Adverse events (AEs) were reported in 24 patients (80%), with 7 (23.3%) of grade 3. The most common AEs were rash (14/30, 46.7%), followed by anemia (7/30, 23.3%), increased ALT (7/30, 23.3%), increased AST (7/30, 23.3%), and pruritus (6/30, 20%). No serious adverse events or treatment-related deaths occurred. Importantly, the exploratory ctDNA analysis indicates that clearance of circulating tumor DNA (ctDNA) at four weeks treatment was associated with more favorable treatment outcomes comparing with patients having positive ctDNA.
Interpretation:
Ensartinib has a promising anti-tumor activity and manageable safety in previously treated patients with METex14 positive lung cancer.
Funding:
This work was supported by the National Natural Science Foundation of China [82370028, 82422001] and the CSCO-MET Aberrant Solid Tumor Research Grant [Y-2022METAZMS-0066].
Insights
Ensartinib shows promising anti-tumor activity and a manageable safety profile in patients with MET exon 14 skipping mutations (METex14) non-small-cell lung cancer (NSCLC). This study evaluated its efficacy in previously treated NSCLC patients, demonstrating significant response rates and progression-free survival.
Area of Science:
- Oncology
- Medical Research
- Clinical Trials
Background:
- MET exon 14 skipping mutations (METex14) are actionable oncogenic drivers in non-small-cell lung cancer (NSCLC).
- Ensartinib, a type Ia MET inhibitor, has demonstrated preclinical anti-tumor activity against METex14-positive NSCLC.
- The EMBRACE trial investigates ensartinib's efficacy and safety in this patient population.
Purpose of the Study:
- To evaluate the clinical efficacy and safety of ensartinib in patients with METex14-positive NSCLC.
- To determine the objective response rate (ORR) as the primary endpoint.
- To assess secondary endpoints including disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), and safety profiles.
Main Methods:
- A multicenter, single-arm, Phase II investigator-initiated study.
- Enrolled patients with METex14-positive NSCLC who failed first-line chemotherapy and/or immunotherapy.
- Patients received ensartinib 225 mg orally once daily until disease progression, unacceptable side effects, or death.
Main Results:
- 31 patients were enrolled; 30 were evaluable with a median follow-up of 9.2 months.
- Objective Response Rate (ORR) was 53.3% (16/30), and Disease Control Rate (DCR) was 86.7% (26/30).
- Median Progression-Free Survival (PFS) was 6.0 months, and median Duration of Response (DoR) was 7.9 months. Common adverse events included rash and anemia; no serious adverse events or treatment-related deaths occurred.
Conclusions:
- Ensartinib demonstrates promising anti-tumor activity in previously treated patients with METex14-positive NSCLC.
- The safety profile of ensartinib is manageable in this patient population.
- Exploratory ctDNA analysis suggests that ctDNA clearance correlates with favorable treatment outcomes.
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