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

Summary

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].

Research in context.

Evidence before this study

We conducted a PubMed search using the terms “MET TKI” AND “non-small-cell lung cancer”, focusing specifically on clinical trials (with no language restrictions). These searches identified targeted therapies for MET altered non-small-cell lung cancer (NSCLC), including the MET tyrosine kinase inhibitors (TKls): tepotinib, capmatinib, savolitinib, gumarontinib, vebreltinib, and crizotinib. These clinical data reveal that patients with METex14 NSCLC benefit from MET inhibitors. However, all currently approved agents are type Ib MET inhibitors, resulting in the inability for sequential use after TKI drug resistance, as well as the high incidence of identical adverse events (AE), such as peripheral edema. In this content, we have previously provided the first pre-clinical and preliminary clinical data regarding the encouraging anti-tumor activity of the novel type Ia MET inhibitor ensartinib in METex14 NSCLC.

Added value of this study

In this multi-center phase II trial, 225 mg ensartinib once daily has a promising anti-tumor activity and manageable safety in previously treated patients with METex14 positive lung cancer. The differentiated safety profile of ensartinib, including a lower incidence of peripheral edema, offers a better-tolerated option for elderly patients with METex14 mutations. There were also encouraging early indications that patients who develop resistance to ensartinib may still benefit from subsequent type Ib MET inhibitors, rendering the sequential treatment potential. Our study also emphasizes the role of circulating tumor DNA (ctDNA) monitoring in guiding therapeutic strategies, demonstrating that ctDNA clearance at four weeks correlates with improved treatment outcomes.

Implications of all the available evidence

The results indicate that type Ia MET inhibitor, ensartinib holds promise as an additional and differentiated therapeutic alternative within the METex14 treatment pipeline.

Introduction

Lung cancer remains the leading cause of cancer-related deaths globally, with nearly 2.5 million new cases diagnosed and over 1.8 million deaths annually.¹ The discovery of onco-driver genes and the development of targeted drugs have significantly improved the prognosis of patients with specific mutations in non-small-cell lung cancer (NSCLC).² Approximately 60% of advanced NSCLC patients may have specific driver genes suitable for targeted therapy.³

MET protooncogene (MET), a tyrosine kinase receptor, has been confirmed as an independent oncogenic driver gene. The activation of MET pathway could be observed in many cancers and is resulted from several aberration modes, including overexpression, amplification, exon 14 skipping mutations, and fusion.⁴ In NSCLC patients, METex14 is presented in about 2–4% NSCLC, predominantly in elderly patients, with poor prognosis.5, 6, 7 Current approved MET inhibitors, all categorized as type Ib agents, include capmatinib, savolitinib, gumarontinib and tepotinib.⁴ Previous studies reported 40.5–66% objective response rate (ORR) and median progression-free survival (mPFS) of 5.4–11 months as the second line treatment.8, 9, 10, 11 Notably, given the similar binding sites of these drugs, the inability for sequential use after drug resistance attracts great concern. Concomitantly, due to the high incidence of adverse events (AE) such as peripheral edema, 16.1%–54% of patients need to reduce or even interrupt treatment.^12,13 Therefore, new drugs are required to achieve the unmet clinical needs.

Ensartinib is a multi-kinase inhibitor that has been approved for front line Anaplastic Lymphoma Kinase (ALK) rearranged NSCLC in China and is just approved by Food and Drug Administration (FDA) in the United States. In patients with ALK-rearranged NSCLC who are resistant to crizotinib, the ORR of ensartinib is 52%, and mPFS is 9.6 months.¹⁴ Furthermore, as a first-line therapy, ensartinib demonstrates robust anti-tumor activity, with an mPFS of 31.3 months, together with encouraging intracranial activity.^15,16 In the field of MET altered cancers, we previously found that ensartinib, as a novel type Ia MET inhibitor,¹⁷ exhibited anti-tumor activity by inhibiting the phosphorylation of MET signaling. In an initial evaluation of ensartinib in METex14 NSCLC among 18 compassionate use patients, we observed an ORR of 69%, DCR of 94%.¹⁷

To further test the efficacy and safety of ensartinib for METex14 NSCLC, we conducted this single-arm, multicenter, phase II clinical trial (EMBRACE). We reported the preliminary outcomes of the Simon stage 1 data of this study,¹⁷ and herein, we presented the full set data for the entire phase II cohort. Also, we evaluated the correlation between circulating tumor DNA (ctDNA) clearance and treatment outcomes.

Methods

Study design and participants

This study is an open-label, multicenter, single-arm clinical trial (ChiCTR2100048767) conducted from July 2021 to April 2024, involving a total of 31 patients recruited from six centers in China, including the Second Affiliated Hospital of Zhejiang University School of Medicine, West China Hospital of Sichuan University, Peking University Cancer Hospital, Tongji Medical College of Huazhong University of Science and Technology Union Hospital, Handan Central Hospital, and Hunan Cancer Hospital (Supplementary Fig. S1). The detailed protocol is provided in Supplementary Appendix S1. All eligible patients were adults (aged ≥ 18 years) diagnosed with histologically/cytologically confirmed advanced or metastatic NSCLC harboring METex14, with wild-type Epidermal Growth Factor Receptor (EGFR)/ALK/ROS proto-oncogene 1, who had not previously received MET-TKI treatment; had at least one measurable lesion; had either progressed through at least one cycle of platinum-based chemotherapy and/or immunotherapy, or demonstrated intolerance/refractoriness to standard chemotherapy regimens; had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≤2; and had a predicted survival time of ≥3 months.

This study has obtained approval from the ethics review committees or independent ethics committees of each participating center, and written informed consent was obtained from all patients prior to enrollment. The study conformed to international guidelines, including the Declaration of Helsinki and the Good Clinical Practice guidelines.

Procedures

After a 28-day screening period, eligible patients received daily treatment with ensartinib at a dose of 225 mg for a consecutive 28-day cycle until disease progression, unacceptable adverse events occurred, patient decision to withdraw, loss to follow-up, or death. In case of AEs, the dose could be reduced by no more than two dose steps (200 mg/day or 150 mg/day). If persistent toxicity occurs despite dose reduction or if treatment interruption exceeds 4 weeks due to treatment-related toxicity, the patient is required to withdraw from the clinical trial.

Radiological assessment of tumors was performed at baseline, with patients scheduled for visits at weeks 4 and 8, followed by visits every 8 weeks thereafter until trial withdrawal. High-resolution chest computed tomography (CT), abdominal CT or ultrasound, and brain magnetic resonance imaging (MRI) were used for evaluation during screening and all subsequent assessments. Disease evaluation was conducted by investigators according to RECIST v1.1 criteria. Recorded initial responses were required to be confirmed again after 4 weeks. AEs were recorded and estimated based on Common Terminology Criteria for Adverse Events (CTCAE) v5.0. In addition, to explore the correlation between ctDNA clearance and treatment outcomes, at screening and week 4 of treatment, plasma samples were collected, and stored for dynamic monitoring of ctDNA.

Outcomes

The primary endpoint is the ORR assessed by the investigators and defined according to RECIST v1.1 as the proportion of patients with complete response (CR) or partial response (PR). Key secondary endpoints include the DCR, defined as the proportion of patients with CR, PR, or stable disease (SD); the duration of response (DoR), which is the time from the first recorded instance of CR or PR until the first occurrence of disease recurrence, progression, or death; and PFS, defined as the time from the start of treatment to the first occurrence of disease recurrence, progression, or death.

Plasma processing and sequencing

Peripheral blood collection was performed prior to initiating ensartinib treatment, and again at the fourth week of treatment. 10 ml Blood samples were obtained in EDTA tubes and underwent centrifugation at a speed ranging from 1100 to 1300 g to isolate plasma. Plasma was aliquoted and stored at −80 °C. DNA extraction, library preparation, sequencing and data analysis were performed as previously described.¹⁸ Briefly, DNA was extracted from frozen plasma specimens using the QIAamp Circulating Nucleic Acid kit (Qiagen, Hilden, Germany). Libraries were constructed using a KAPA Hyper Prep kit (Kapa Biosystems, Wilmington, MA, USA), target enrichment was performed using the SureSelect XT-HS System (Agilent Technologies, Santa Clara, CA, USA), employing a 212-gene panel (Repugene Technology, Hangzhou, China), and sequencing was carried out using the Illumina HiSeq-X10 platform (Illumina, San Diego, CA, USA), with average sequencing depths of approximately 20,000×.

Statistical analysis

The study employed Simon’s optimal two-stage design to minimize the expected sample size and estimate the required sample size.¹⁹ With NSCLC second-line chemotherapy, we set an ORR of 10% as the null hypothesis. As a second-line treatment for METex14 NSCLC, we hypothesized that ensartinib, when used as such, would achieve an ORR of 30%. Based on this assumption, we proceeded to calculate the required sample size. Assuming a one-sided α of 0.05 and a power of 80%, a total of 29 evaluable subjects are required. The trial is carried out in two stages. In stage I, a total number of 10 evaluable patients is accrued. If there are 1 or fewer responses among these 10 subjects, the study will be early stopped. Otherwise, additional 19 evaluable subjects will be accrued in stage II, resulting in a total number sample size of 29. If there are 6 or more responses among these 29 subjects, we reject the null hypothesis and claim that the treatment is promising. Considering a 5% dropout rate, a total of 31 subjects were needed to be enrolled. The lower dropout rate was based on several factors, including the rigorous selection criteria for participants, and the potential motivation of patients to participate in a trial offering a novel therapeutic option. Additionally, we have incorporated strategies to minimize dropout, such as regular follow-up and communication with participants, as well as addressing any concerns or issues promptly. The ORR, DCR, and their 95% CIs were determined using the Clopper-Pearson method, which is recommended for calculating 95% confidence intervals (CI) with small sample size and is considered to be conservative at times.²⁰ The Kaplan–Meier method was used to estimate PFS, DoR, and time to progression, and to estimate cumulative rates at specific time points, with 95% CIs calculated using the Brookmeyer and Crowley method.^21,22 A log-rank test was used for between-group comparisons of progression-free survival. Hazard ratio (HR) and corresponding 95% CIs were estimated using a Cox proportional hazards model. The assumption of proportionality was tested with the Schoenfeld residuals at a 5% level and by assessing the residuals plot. SAS v.9.4 and SPSS v.22.0 were used for all the analyses.

Role of funding source

The principal investigator designed the study. Data collection, statistical analyses and the writing of the manuscript were all conducted by the investigators. The funders had no role in the design of the study, the collection, management, or analysis of data, the preparation of the manuscript, or the decision to submit the manuscript for publication.

Results

Patients

Between July 2021 and April 2024, 31 patients with NSCLC carrying the METex14 were enrolled and received treatment of ensartinib (225 mg, once daily). One patient quit from the trail due to irregular follow-up, resulting in a final analysis of 30 patients (Fig. 1). The median age was 69.4 years (range, 47–83 years); 53.3% (16/30) were female, and 36.7% (11/30) had a history of smoking. Adenocarcinoma was present in 90% of patients, with two cases of squamous cell carcinoma and one case of not otherwise specified (NOS). Brain metastases were found in five patients at baseline (Table 1). The most common splice donor sites of METex14 accounted for 46.7%. Common concurrent mutations included TP53 (29%), NF1 (6%), MDM2 (6%), PIK3C3 (3%), GATA6 (3%), STK11 (3%), STAG2 (3%), BRD4 (3%), INPP4A (3%) and CDK4 (3%) (Fig. 2).

Fig. 1.

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

Table 1.

Characteristics of the patients at baseline.

Characteristics	Phase II Cohort (N = 30)
Age — yr (median)	69.4 (47–83)
Sex — no. (%)
Male	14 (46.7%)
Female	16 (53.3%)
Tumor Histology — no. (%)
Adenocarcinoma	27 (90.0%)
Squamous Cell Carcinoma	2 (6.7%)
Not Otherwise Specified (NOS)	1 (3.3%)
Smoking Status — no. (%)
Current & Former Smoker	11 (36.7%)
Non-Smoker	19 (63.3%)
ECOG Performance Status — no. (%)
1	24 (80.0%)
≥2	6 (20.0%)
Disease Stage at Baseline — no. (%)
Stage III	6 (20.0%)
Stage IV	24 (80.0%)
Brain Metastasis at Baseline — no. (%)
With Brain Metastasis	5 (16.7%)
Without Brain Metastasis	25 (83.3%)
Treatment Line — no. (%)
1	18 (60.0%)
≥2	12 (40.0%)
Prior Systemic Treatment — no. (%)
Surgery	5 (16.7%)
Chemotherapy	8 (26.7%)
Radiotherapy	3 (10.0%)
Immune Checkpoint Inhibitors (ICI)	3 (10.0%)

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.

Efficacy

The median follow-up time was 9.2 months. Among 30 evaluable patients, 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). The tumor shrinkage rate was 33% (95CI 24.7–41.4) (Fig. 2). Ensartinib elicited rapid drug response, and the median time to response was 0.93 months (95% CI 0.83–1.13) (Fig. 3A). As of the data-cutoff date, 5 patients with a response (16.7%) were continuing to receive treatment without disease progression. Changes in tumor size from baseline over time are shown in Fig. 3B. The overall mPFS was 6.0 months (95% CI, 3.0–8.8) (Fig. 4A), with a mDoR of 7.9 months (95% CI, 4.8–8.7) (Fig. 4B), and the median overall survival (mOS) was 11.8 months (95% CI, 7.1–16.5). Among 5 patients with baseline brain metastases, 4 (80%) achieved partial responses, mPFS was 9.5 months (95% CI 2.2–9.6), DoR was 8.5 months (95% CI 1.2–8.7) (Supplementary Fig. S2).

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.

Our findings revealed a notably lower ORR of 33.3% in patients harboring concurrent TP53 mutations, in contrast to an ORR of 61.9% observed in patients with wild-type TP53. Additionally, not only the ORR, but mPFS was comparable in patients older (19/30) and younger (11/30) than 70-year-old (Fig. 5). Further analysis of anti-tumor responses, depth of response, best efficacy assessment or PFS reported no statistical difference across different METex14 mutation sites. Out of the 30 patients evaluated, 2 were found to have MET amplification, and both patients achieved PR.

Fig. 5.

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

Association between circulating tumor DNA (ctDNA) status and therapeutic outcomes

Blood samples were obtained at baseline from 29 enrolled patients. CtDNA harboring MET exon 14 skipping mutations was detectable in 15 patients (52%). ORR among patients with detectable ctDNA was 53.3% (8/15), compared to 57.1% (8/14) in patients with undetectable ctDNA, and mPFS was 3.7 months (95% CI, 1.3–8.8) vs. 6.0 months (95% CI 4.1–9.6, p = 0.83) (Fig. 6A).

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.

Among the 29 patients, 17 patients provided paired blood samples at week 4 for ctDNA analysis. We investigated the association between ctDNA status and treatment efficacy. 10 patients (59%) showed a decline in ctDNA abundance, with 5 of them (29%) achieving complete clearance of ctDNA. Patients who achieved ctDNA clearance at 4-week (positive at baseline, and negative at week 4) showed a highest ORR (80.0%; 95% CI, 37.6–96.4), followed by patients with negative ctDNA at both baseline and week 4 (ORR 42.9%, 95% CI, 15.8–75.0). The worst ORR was observed in patients with ctDNA residual at 4-week (positive at both baseline and week 4) (ORR 20.0%, 95% CI, 3.6–62.5) (Fig. 6B). In concordance, the mPFS was 9.5 m (95% CI, 8.8–10.2) for patients with ctDNA clearance, 5.9 m (95% CI, 5.8–6.2) for those with consistently negative ctDNA, and 2.2 m (95% CI, 2.1–2.4) for those with ctDNA residual (Fig. 6C). The mPFS of patients who achieved ctDNA clearance at 4 weeks was significantly higher than that of other patients (HR 0.28, 95% CI 0.07–1.07, p = 0.062). The assumption of proportionality was tested with the Schoenfeld residuals at a 5% level and by assessing the residuals plot. The assumption was satisfied for PFS between-group comparisons.

Safety and adverse events

All 30 patients completed the prescribed treatment regimen. 80% (24/30) of patients reported AEs attributed to ensartinib. 23.3% (7/30) of patients encountered grade 3 AEs, no grade 4 or 5 AEs were reported. The most frequent AE was rash (14/30, 46.7%), followed by increased alanine transaminase (ALT) (7/30, 23.3%), increased aspartate transaminase (AST) (7/30, 23.3%), anemia (7/30, 23.3%), decreased appetite (6/30, 20%), peripheral edema (4/30, 13.3%), nausea (3/30, 10%), and increased serum creatinine (3/30, 10%). Rash was also the predominant grade 3 AE (4/30, 13.3%) (Table 2, Fig. 4C). Different from type Ib MET inhibitors, only 4 patients (13.3%) experienced peripheral edema, predominantly manifesting as Grade 1 adverse events. 2 patients experienced dose reduction due to increased creatinine during treatment, and 1 patient experienced a temporary treatment interruption owing to rash and edema of grade 3. All AEs resolved or significantly improved after dose reduction or discontinuation.

Table 2.

Treatment-related adverse events.

Event — no. (%)	All Grades	Grade 3	Grade 2	Grade 1
Rash	14 (46.7)	4 (13.3)	4 (13.3)	6 (20.0)
Anemia	7 (23.3)	1 (3.3)	3 (10.0)	3 (10.0)
ALT Increased	7 (23.3)	1 (3.3)	1 (3.3)	5 (16.7)
AST Increased	7 (23.3)	0	0	7 (23.3)
Pruritus	6 (20.0)	0	3 (10.0)	3 (10.0)
Decreased Appetite	6 (20.0)	0	2 (6.7)	4 (13.3)
Constipation	4 (13.3)	0	1 (3.3)	3 (10.0)
Peripheral Edema	4 (13.3)	0	0	4 (13.3)
Nausea	3 (10.0)	0	1 (3.3)	2 (6.7)
Creatinine Increased	3 (10.0)	0	0	3 (10.0)
Bilirubin Increased	2 (6.7)	1 (3.3)	1 (3.3)	0
Vomiting	2 (6.7)	0	2 (6.7)	0

Discussion

This is the first phase II clinical trial evaluating the novel type Ia MET inhibitor, ensartinib. Our observations indicate that ensartinib demonstrates promising antitumor activity in patients with locally advanced or metastatic METex14 NSCLC after failing platinum-based chemotherapy and/or immunotherapy. Ensartinib achieved an ORR of 53.3% and a mDoR of 7.9 months, accompanied by a safety profile that is distinct from type Ib MET inhibitors. These findings herald a novel and promising therapeutic avenue for the treatment of NSCLC patients with MET exon 14 skipping mutations.

The study disclosed that the ORR of ensartinib in NSCLC patients with METex14 was 53.3%, which was comparable to the reported ORRs of 45% for tepotinib and 41% for capmatinib in later-line treatments, slightly lower than the 60% reported for gumarontinib.^8,9,11 The mPFS and mDoR for ensartinib were 6.0 months and 7.9 months, respectively, while the mPFS for other drugs in later-line treatments ranged approximately from 5.4 to 11 months, and the mDoR ranged from 8.2 to 12.6 months.^8,9,11 Although ensartinib’s efficacy did not significantly surpass that of other agents, it exhibited a more favorable safety profile. Specifically, for capmatinib, tepotinib, and gumarontinib, the rates of grade 3 or higher treatment-related adverse events (AEs) were 37.6%, 34.8%, and 54%, with edema being a prominent adverse reaction in all three cases. In contrast, ensartinib demonstrated a lower rate of grade 3 or higher AEs at 23.3%, and notably, the incidence of edema was only 13.3%.^8,9,11 Notably, ensartinib displayed remarkable efficacy in patients presenting with baseline brain metastases, achieving an ORR of 80%, and an mPFS of 9.5 months. Of particular interest, four patients who experienced resistance to ensartinib subsequently received savolitinib in our study. The sequential application of savolitinib following ensartinib resistance still resulted in significant clinical benefits, with durations of treatment ranging from 7.1 to 17.3 months.

We observed TP53 mutation was the most prevalent concomitant genetic alteration, significantly affecting the treatment efficacy. Patients with mutated TP53 exhibited inferior ORR and mPFS compared to those with wild-type TP53, findings consistent with previous studies involving capmatinib and savolitinib.^9,10 For this subset of patients, a more aggressive treatment strategy may be necessary. An ongoing trial is currently investigating the potential benefits of combining amivantamab and capmatinib (NCT05488314). However, the toxicity profile associated with this combination remains a significant concern.

CtDNA, as a non-invasive biomarker, has gained widespread adoption in the clinical management of NSCLC. For osimertinib, the plasma clearance rate of mutated EGFR ctDNA has been shown to play a highly significant predictive role for both PFS and OS.^23,24 In our study, although the ORR was similar, mPFS displayed a trend toward prolongation in the baseline ctDNA-negative cohort compared to the ctDNA-positive cohort (3.7 m vs. 6.0 m). Furthermore, patients who demonstrated ctDNA clearance at week 4 exhibited greater ORR and PFS. It is important to emphasize that the ctDNA analysis conducted in our study was exploratory. These findings are consistent with previous investigations involving tepotinib and savolitinib,^25,26 affirming ctDNA’s role as a predictor of ensartinib treatment outcomes, highlighting its value as a dynamic biomarker for guiding therapeutic strategies.

The AEs spectrum of ensartinib exhibits marked dissimilarity compared with type Ib MET TKIs, potentially attributable to its status as a multi-kinase inhibitor. Rash was the most frequently reported treatment-related AE at 46.7% in the study, which might be attributed to higher skin concentrations. Mild rashes typically resolve spontaneously without intervention. For rashes of grade 2 to 3, effective management strategies include the application of topical corticosteroids, administration of oral steroids, or the use of oral doxycycline. Edema, a common AE associated with type Ib MET TKIs, occurs with an incidence ranging from 32% to 74%, with grade 3 or higher peripheral edema documented in 9%–21% of patients. By contrast, ensartinib exhibits a markedly lower incidence of edema, at just 13.3%. Given that patients with MET exon 14 skipping mutations tend to be of an older demographic and may possess reduced tolerability to adverse effects, the diverse toxicity profile of ensartinib may facilitate more treatment options for these patients.

Our study has several limitations that should be acknowledged. Firstly, it is a single-arm study, and we hope for the opportunity to conduct a randomized study to compare the efficacy of ensartinib vs. standard of care in the future. Secondly, the exclusive conduct of the study in China and its focus solely on Asian participants restricts the generalizability of the results to a broader, global population. Fortunately, ensartinib has been approved by the FDA for marketing in the United States, and we hope to collect the real-world data from North America to further refine our understanding of its role in METex14. Lastly, limiting participation to patients at second-line or later treatment stages confines the applicability of the findings to a wider patient cohort.

In summary, the outcomes of phase II clinical trial of ensartinib demonstrate encouraging and sustained clinical activity in locally advanced or metastatic METex14 NSCLC patients. Our study would add another promising therapeutic option to the METex14 pipeline.

Contributors

The authors conceived and designed the study: Y. Xia, W. Li, P.W. Tian; the authors collected and assembled the data: Y. Xia, P.W. Tian, M. Zhou, J. Zhao, Y. Jin, Z.Y. Guo, D. Miao, Y.F. Lu, W.T. Xu, Y.C. Zhang, X.Z. Li, W.N. Lu; the authors directed and performed the statistical analysis: Y. Xia, M. Zhou, D. Miao, Y.F. Lu, W.T. Xu, X.Z. Li, W.N. Lu; the authors recruited patients: Y. Xia, P.W. Tian, J. Zhao, Y. Jin, Z.Y. Guo, Y.C. Zhang. The first draft of the manuscript was written by Y. Xia and M. Zhou. All authors reviewed and edited the manuscript, and approved the final manuscript for publication. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Data sharing statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Editor note

The Lancet Group takes a neutral position with respect to territorial claims in published maps and institutional affiliations.

Declaration of interests

The authors have no potential conflict of interests.