Ensartinib Yields “Promising” Efficacy in Pretrated METex14–positive NSCLC

In the phase 2 EMBRACE trial, ensartinib demonstrated an ORR of 53.3%, a DCR of 86.7%, and a tumor shrinkage rate of 33.3% in patients with METex14-positive NSCLC.

Ensartinib (Ensacove) demonstrated promising anti-tumor activity and an acceptable safety profile in the treatment of patients with previously treated METex14–positive non–small cell lung cancer (NSCLC), as shown by results from the phase 2 EMBRACE trial (ChiCTR2100048767) published in eClinicalMedicine.

At a median follow-up of 9.2 months (95% CI 6.3-not estimable [NE]), ensartinib yielded an overall response rate (ORR) of 53.3% (95% CI, 35.5%-71.2%) and a disease control rate (DCR) of 86.7% (95% CI, 74.5%-98.8%); the tumor shrinkage rate was 33.0% (95% CI, 24.7%-41.4%). The median time to response was 0.93 months (95% CI, 0.83-1.13) and the median duration of response (DOR) was 7.9 months (95% CI, 4.8-8.7). The median progression-free survival (PFS) was 6.0 months (95% CI, 3.0-8.8) and the median overall survival (OS) was 11.8 months (95% CI, 7.1-16.5).

In patients with brain metastases at baseline (n = 5), 80% (n = 4) achieved partial responses, the median PFS was 9.5 months (95% CI, 2.2-9.6), and the median DOR was 8.5 months (95% CI, 1.2-8.7).

Additionally, patients with concurrent TP53 mutations had an ORR of 33.3% (95% CI, 7.5%-70.1%) vs 61.9% (95% CI, 38.4%-81.9%) in those with wild-type TP53.

“Our observations indicate that ensartinib demonstrates promising antitumor activity in patients with locally advanced or metastatic METex14 NSCLC after platinum-based chemotherapy and/or immunotherapy, [failed them]” lead study author Wen Li, of Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, China, and Zhejiang University Cancer Center, and coauthors wrote in the paper. “Our study would add another promising therapeutic option to the METex14 pipeline.”

EMBRACE was a multicenter, investigator-initiated trial that enrolled a total of 31 patients, all of whom received 225 mg of ensartinib daily for a consecutive 28-day treatment cycle.

The median age of patients was 69.4 years (range, 47-83), 53.3% were female, 90.0% had histology of adenocarcinoma, 63.3% were non-smokers, 80.0% had an ECOG performance status of 1, 80.0% had stage IV disease at baseline, 83.3% did not have brain metastasis at baseline, 60% received 1 prior line of treatment, and the most common prior systemic treatment was chemotherapy (26.7%).

Eligible patients were 18 years or older with histologically or cytologically confirmed advanced or metastatic NSCLC harboring METex14 and wild-type EGFR/ALK/ROS proto-oncogene 1 who did not previously receive MET-TKI treatment. Patients had at least 1 measurable lesion, progressed on at least 1 cycle of prior platinum-based chemotherapy and/or immunotherapy, had an ECOG performance status of 2 or less, and a life expectancy of at least 3 months.

The trial’s primary end point was ORR assessed by investigators. Secondary end points include DCR, DOR, and PFS.

Twenty-nine enrolled patients submitted blood samples at baseline and ctDNA harboring METex14 skipping mutations were detectable in 15 patients. The ORR in patients with detectable ctDNA was 53.3% (n = 8/15) vs 57.1% (n = 8/14) patients with undetectable ctDNA; median PFS was 3.7 months (95% CI, 1.3-8.8) vs 6.0 months (95% CI, 4.1-9.6), respectively (P = .83).

Also, 59% of patients who provided paired blood samples at week 4 showed a decline in ctDNA abundance; 29% of them achieved complete clearance of ctDNA. In patients with ctDNA clearance at week 4, the ORR was 80.0% (95% CI, 37.6%-96.4%); in patients with negative ctDNA at baseline and week 4, the ORR was 42.9% (95% CI, 15.8%-75.0%); and in patients with residual ctDNA at week 4, the ORR was 20.0% (95% CI, 3.6%-62.5%). The median PFS was 9.5 months (95% CI, 8.8-10.2), 5.9 months (95% CI, 5.8-6.2), and 2.2 months (95% CI, 2.1-2.4), respectively. Those who achieved ctDNA clearance at 4 weeks experienced a significantly greater PFS than any other group (HR, 0.28; 95% CI, 0.07-1.07; P = .062).

Regarding safety, 80% of patients experienced adverse events (AEs) due to ensartinib; 23.3% experienced AEs of grade 3, and there were no instances of grade 4 or 5 AEs reported. The most common treatment-related AEs of any grade were rash (46.7%), anemia (23.3%), alanine aminotransferase increased (23.3%), aspartate aminotransferase increased (23.3%), pruritus (20.0%), and decreased appetite (20.0%); the most common grade 3 AEs were rash (13.3%), anemia (3.3%), alanine aminotransferase increased (3.3%), and bilirubin increased (3.3%).

Dose reduction occurred in 2 patients due to increased creatinine during treatment and temporary treatment interruption occurred in 1 patient due to rash and edema of grade 3.All AEs were resolved or notably improved following dose reduction or discontinuation.

Reference

Yang X, Panwen T, Mo Z, et al. 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. eClinicalMedicine. 2025;81:103099. doi:10.1016/j.eclinm.2025.103099