Neoadjuvant Therapy With Ensartinib Combined With Chemotherapy for ALK-positive Non - Small Cell Lung Cancer (NSCLC)

The TD - ENSEMBLE Study: A Single - Arm, Multicenter Clinical Trial on Neoadjuvant Therapy with Ensartinib Combined with Chemotherapy for ALK - Positive NSCLC

Research Background

This is a clinical trial initiated by researchers. It aims to deeply analyze the current treatment landscape of non - small cell lung cancer (NSCLC), focusing on the unmet clinical needs of specific molecular subtype patient groups, and then conduct a study on the neoadjuvant therapy of ensartinib combined with chemotherapy for ALK - positive NSCLC.

Lung cancer is the leading cause of cancer - related deaths worldwide, and NSCLC accounts for approximately 80% of all lung cancer cases. For patients initially diagnosed with locally advanced (Stage II - III) NSCLC, surgical resection is a potentially curative treatment. However, even if the surgery is successful, the long - term survival rate of patients remains unsatisfactory. The 5 - year overall survival rate of patients with Stage II - IIIA NSCLC is about 36% to 60%. To improve the prognosis, platinum - based double - drug chemotherapy has become one of the standard treatment regimens for peri - operative (including neoadjuvant and adjuvant therapy) operable NSCLC. Large - scale meta - analyses have shown that compared with surgery alone, pre - operative neoadjuvant chemotherapy can increase the absolute 5 - year survival rate by about 5% and reduce the relative risk of death by 13%. However, the magnitude of this benefit is limited, indicating the need to explore more effective treatment strategies.

The study focuses on patients with NSCLC who have a positive anaplastic lymphoma kinase (ALK) fusion gene, which accounts for about 3% to 7% of all NSCLC cases. The development of ALK tyrosine kinase inhibitors (TKIs) has changed the treatment paradigm for advanced ALK - positive NSCLC. From the first - generation crizotinib to the subsequent second - and third - generation drugs, they have brought significant survival improvements for advanced patients. The study drug, ensartinib, is a second - generation ALK - TKI independently developed in China. It can not only strongly inhibit ALK but also has an inhibitory effect on the c - Met kinase. Clinical studies have shown that ensartinib has good efficacy in patients with advanced ALK - positive NSCLC who are resistant to crizotinib (the objective response rate (ORR) evaluated by independent review was 52%), and it has been approved for this indication. In the international multicenter Phase III eXalt3 study for first - line treatment, ensartinib significantly prolonged the median progression - free survival (mPFS was 31.3 months vs. 12.7 months) compared with crizotinib and has also been approved for first - line treatment.

Based on the excellent efficacy of ALK - TKIs in advanced diseases, applying them to the neoadjuvant treatment stage before surgery is a reasonable research direction. Some small - scale studies or case reports have explored the potential of ALK - TKIs for neoadjuvant treatment. For example, the SAKULA study (ceritinib), the NAUTIKA1 and ALNEO studies (alectinib), and the WILDERNESS study (brigatinib). These studies initially showed that ALK - TKI neoadjuvant treatment can achieve a relatively high major pathological response rate (MPR, about 42% - 66.7%) and pathological complete response rate (pCR, about 12% - 44.4%), and the safety is controllable. In addition, there are case reports of ensartinib achieving pCR in neoadjuvant treatment and retrospective analyses showing a trend of a high pCR rate of ensartinib combined with chemotherapy in neoadjuvant treatment.

Therefore, the TD - ENSEMBLE study aims to systematically evaluate the value of ensartinib (a targeted drug proven to be effective for advanced diseases) combined with a standardized chemotherapy regimen (pemetrexed + carboplatin) for the neoadjuvant treatment of operable early - stage (Stage II - IIIB, with N2 lymph node metastasis) ALK - positive lung adenocarcinoma patients.

Research Objectives and Evaluation Endpoints

* Primary Objective: To evaluate the pathological complete response rate (pCR) of the ensartinib - combined chemotherapy regimen. pCR is defined as the proportion of patients in whom no residual viable tumor cells are found in the resected primary tumor and metastatic lymph nodes after neoadjuvant treatment, as assessed by pathology. This is the gold standard for evaluating the depth of efficacy of neoadjuvant treatment. * Secondary Objectives: To evaluate a series of other efficacy and safety indicators. The efficacy indicators include the major pathological response rate (MPR, the proportion of patients with residual viable tumor cells ≤10%), the objective response rate (ORR, evaluated by imaging according to the RECIST 1.1 criteria), the R0 resection rate (no cancer residue at the microscopic margin), the event - free survival (EFS, from enrollment to disease progression that hinders surgery, post - operative recurrence, metastasis, or death from any cause), the overall survival (OS, from enrollment to death from any cause), and the 3 - year EFS rate, 5 - year OS rate, and 10 - year OS rate. The safety objective is to evaluate the occurrence of adverse events of the combined regimen. * Exploratory Objectives: To study potential biomarkers, including detecting the dynamic changes of minimal residual disease (MRD) before and after neoadjuvant treatment, analyzing the co - mutation status of other genes besides the ALK fusion at baseline, and analyzing the correlation between these factors and efficacy.

Study Design

* Study Type and Sample Size: A single - arm, multicenter, prospective, two - stage exploratory clinical study design is adopted. The planned total sample size is 20 patients, and the Simon's two - stage enrollment strategy is used. In the first stage, 5 patients are enrolled. After these 5 patients complete the neoadjuvant treatment and surgery, the safety data are reviewed by an independent data safety monitoring committee or the research team. If no special, unexpected, or serious adverse events (SAEs) related to ensartinib occur in these 5 patients during the neoadjuvant treatment, the study will proceed to the second stage, and the remaining 15 patients will be enrolled. If the above - mentioned safety problems occur, no new patients will be enrolled. The sample size calculation is based on the expected pCR rate of the primary endpoint. Referring to the previous pCR rate of approximately 4% in the general population with neoadjuvant chemotherapy, this study expects the ensartinib - combined chemotherapy to increase the pCR rate to 30%. Under the significance level (alpha = 0.025, one - sided) and test power (power = 90%), about 16 effective cases are required. Considering patient dropout, the final sample size is expanded to 20 to maintain sufficient statistical power. * Study Process

* Screening Period (within 28 days before enrollment): Potential subjects need to be strictly screened to confirm whether they meet the inclusion criteria and do not meet the exclusion criteria. Key screening steps include signing a written informed consent form; being histologically or cytologically diagnosed with lung adenocarcinoma through biopsy tissue (such as obtained by bronchoscopy or puncture); confirming the tumor to be ALK - fusion positive by methods recommended by the NCCN guidelines (such as PCR, FISH, IHC, or NGS); being confirmed as having operable Stage II - IIIB (N2) according to the AJCC 9th edition TNM staging system; having at least one measurable lesion that meets the RECIST 1.1 criteria confirmed by imaging (such as CT); having an ECOG performance status score of 0 or 1; undergoing comprehensive hematological, biochemical, and organ function tests to ensure the ability to tolerate treatment and surgery; evaluating cardiopulmonary function to confirm the feasibility of surgery; and conducting a pregnancy test for women of child - bearing potential. The protocol clearly defines detailed exclusion criteria, such as specific pathological types (squamous cell carcinoma, small cell carcinoma components), a history of previous anti - tumor treatment, active infections, severe or uncontrolled systemic diseases, a history of interstitial lung disease, specific cardiac criteria (such as QTc interval prolongation), pregnancy, or lactation. * Neoadjuvant Treatment Period (totaling 9 weeks): Enrolled patients receive a 9 - week neoadjuvant treatment. The treatment regimen is 225 mg of ensartinib taken orally once a day, combined with chemotherapy. Pemetrexed (500 mg/m²) and carboplatin (with the dose calculated according to the area under the blood - concentration - time curve (AUC) = 5 - 6) are administered intravenously on the first day of each 21 - day treatment cycle, for a total of 3 cycles. During this period, the safety and tolerability of patients are closely monitored. A blood routine test is performed once a week, and a blood biochemical test is performed once every 4 weeks (at the beginning of each cycle). At the end of the 9 - week treatment, patients undergo imaging evaluation (mainly enhanced chest CT) to assess the objective response of the tumor (ORR) according to the RECIST 1.1 criteria. * Surgical Period (within 4 weeks after the end of neoadjuvant treatment): A final imaging evaluation is performed 3 - 5 days after the completion of neoadjuvant treatment to determine the feasibility of surgery. After the evaluation, patients should undergo the planned surgical resection within 4 weeks, with the goal of achieving a complete R0 resection (no tumor cells at the microscopic margin). The resected tumor specimens are sent to the research center (such as the pathology department of the Second Affiliated Hospital of the Air Force Medical University, the leading unit, or the pathology departments of each sub - center) for standardized pathological processing and evaluation. Pathologists evaluate the proportion of residual viable tumor cells in the surgical specimens to determine the primary endpoint pCR and the secondary endpoint MPR. At the same time, surgical - related information, such as the surgical method and whether an R0 resection is achieved, is recorded. * Postoperative Follow - up Period

* Safety Follow - up: A dedicated 30 - day safety follow - up is conducted for all patients after the last dose of the study drug to monitor new adverse events. * Survival Follow - up: After surgery, a long - term survival follow - up is entered to monitor disease recurrence and patient survival status. The follow - up plan is detailed. In the first year after surgery, outpatient re - examinations are carried out every 3 months; in the second and third years, every 4 months; in the fourth and fifth years, every 6 months; and once a year after 5 years. The re - examination contents include chest CT, abdominal CT, and serum tumor marker tests. Head MRI examinations are scheduled in the 6th and 12th months of the first year after surgery, the 4th month of the second year, and the 4th month of the third year. Bone scans are performed as clinically needed. The follow - up continues until disease recurrence/progression is confirmed, the patient withdraws informed consent, death occurs, the patient is lost to follow - up, or the study is terminated. Through this follow - up, long - term efficacy data such as event - free survival (EFS) and overall survival (OS) are collected. * Efficacy Evaluation

* Primary Efficacy Endpoint: The pathological complete response rate (pCR), that is, the proportion of patients in whom no viable tumor cells are found in the resected primary tumor and all regional lymph nodes after neoadjuvant treatment. * Secondary Efficacy Endpoints: Include the major pathological response rate (MPR, residual viable tumor cells ≤10%), the objective response rate (ORR, imaging - evaluated complete response (CR) + partial response (PR)), the R0 resectio

• Major pathological response rate (MPR) [Time frame: From enrollment to the end of treatment at 9 weeks]
• Objective Response Rate (ORR) [Time frame: From enrollment to the end of treatment at 3 years]
• R0 Resection Rate [Time frame: Evaluated immediately after surgical intervention]
• 3-year EFS Rate [Time frame: Measured over a period of 3 years from study entry or treatment initiation]
• Event-Free Survival (EFS) [Time frame: From enrollment to the end of treatment at 5 years]
• 5-year OS Rate [Time frame: Measured over a period of 5 years from study entry or treatment initiation.]
• Overall Survival (OS) [Time frame: From enrollment to the end of treatment at 5 years]
• 10-year OS Rate [Time frame: Measured over a period of 10 years from study entry or treatment initiation.]
• Adverse events [Time frame: from date of enrollment until the end of the study, assessed up to 60 months]