Ensartinib for advanced or metastatic non-small-cell lung cancer with MET exon 14 skipping mutations (EMBRACE): a multi-center, single-arm, phase 2 trial

Abstract

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].

Keywords: Ensartinib; MET exon 14 skipping mutation; NSCLC.

Fig. 1

CONSORT flow chart of the trial. NSCLC: non-small-cell lung cancer; TKI: tyrosine kinase inhibitor.

Fig. 2

Efficacy of ensartinib therapy in NSCLC with METex14. Waterfall plot representing best change in target lesion size from baseline for 30 patients who had measurable disease.

Fig. 3

Antitumor activity and time on treatment for each patient. A: Swimmer plot showed time on treatment and best response for each patient; B: Spider plot showed the percentage change from baseline in the sum of the largest diameters of measurable tumors from baseline over time.

Fig. 4

Survival and adverse events. A: progression-free survival of 30 patients, and B showed the duration of response; C: the adverse events (AEs) of ensartinib in NSCLC patients with METex14. The severity grades of these AEs were distinctly represented using varying shades of color.

Fig. 5

Subgroup analysis of objective response rate (ORR). Forest plot representing the ORR for each subgroup.

Fig. 6

The association of ctDNA status and therapeutic outcomes. A: Kaplan–Meier estimates of progression-free survival according to ctDNA status at baseline, median progression-free survival (mPFS) exhibited a prolonged tendency for baseline ctDNA negative groups than positive ones. B: Difference in objective response rate (ORR) among the ctDNA residual, ctDNA negative and ctDNA clearance groups. C: Kaplan–Meier estimates of progression-free survival according to ctDNA status at 4-week. CR: complete response; PR: partial response; SD: stable disease.