Efficacy and Safety of Ensartinib Combined With Anlotinib in Lorlatinib-Resistant ALK-Positive NSCLC

Efficacy and Safety of Ensartinib Combined With Anlotinib in Lorlatinib-Resistant ALK-Positive Non-small Cell Lung Cancer(NSCLC): An Exploratory Analysis

ALK TKIs, particularly second- and third-generation ALK TKIs, have significantly improved progression-free survival (PFS) in patients with advanced ALK-positive non-small cell lung cancer (NSCLC). However, patients continue to face challenges related to drug resistance and disease progression; in the CROWN study, 40% of patients still experienced disease progression within five years. There are currently no standard treatment recommendations for this patient population. This study retrospectively evaluated the efficacy and safety of ensartinib combined with anlotinib as a second-line treatment in patients who had developed resistance to lorlatinib. The inclusion criteria for data collection were patients aged ≥18 years with histologically confirmed stage IIIB-IV ALK-positive NSCLC who had developed resistance to lorlatinib; prior to lorlatinib treatment, patients could have received up to two other ALK-TKIs, excluding ensartinib.

Study Overview

• Status: Not yet recruiting
• Conditions: ALK-positive, Locally Advanced or Metastatic (TNM Stage IIIB-IV) Non-small Cell Lung Cancer That Has Developed Resistance to Prior Treatment With Lorlatinib
• Intervention / Treatment: Drug: Combined group of ensatinib and arotinib

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Qiming Wang Qiming Wang; Phone Number: 13783590691; Email: qimingwang1006@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Co-hort 1: Strict co-hort Inclusion criteria1：Histologically or cytologically confirmed stage IIIB-IV non-small cell lung cancer; Inclusion criteria2：Age ≥ 18 years at the time of signing the informed consent form; Inclusion criteria3：ALK-positive status confirmed by tissue samples or blood tests at each centre; Inclusion criteria4：History of resistance to lorlatinib treatment; prior use of ensartinib is not permitted; patients must have received a maximum of two other ALK-TKIs; prior receipt of ≤2 courses of chemotherapy is permitted; ECOG Performance Status (PS) score between 0 and 2, with no deterioration within 2 weeks prior to study entry;

Co-hort 2 (Compassionate Use Cohort):

Inclusion criteria1： Resistance to lorlatinib treatment; Inclusion criteria2： No restrictions on prior use of ensartinib or the number of prior lines of other ALK-TKIs and chemotherapy; Inclusion criteria3：Subjects with concomitant leptomeningeal metastases may be enrolled. For patients with leptomeningeal metastases (LM), diagnosis must be based on the three criteria outlined in the EANO-ESMO guidelines: clinical presentation, cranial imaging, and cerebrospinal fluid cytology. Tissue samples must not be derived from tumour sites that have previously undergone radiotherapy; however, new lesions arising after local treatment may be included; Inclusion criteria4：ECOG performance status of 0-4; Inclusion criteria5： Adequate organ system function, as determined by the investigator; Inclusion criteria6：All other inclusion criteria are consistent with items 1, 2 and 3 of Cohort 1.

Exclusion criteria1：Concurrent malignant tumours. Exclusion criteria2：Patients with leptomeningeal metastases (LM) who are unable to undergo contrast-enhanced MRI.

Exclusion criteria3：Patients who have undergone surgery within 4 weeks prior to treatment with the study drug, except for minor procedures deemed by the investigator not to preclude participation in the trial; or patients scheduled to undergo major surgery during the study period.

Exclusion criteria4：Patients who have experienced a marked deterioration in symptoms or signs within 2 weeks prior to screening and are deemed by the investigator to be unsuitable for participation in the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Strict Queue; Patients with a performance status (ECOG) score of 0-2 and brain parenchymal metastases were enrolled in Cohort 1.	Drug: Combined group of ensatinib and arotinib; Ensatinib is administered at a dose of 225 mg once daily, either on an empty stomach or with food; anlotinib is administered at a dose of 10 mg once daily, in 21-day cycles; treatment continues until disease progression, the occurrence of intolerable toxicity, withdrawal at the discretion of the investigator or the subject, loss to follow-up, initiation of other anticancer therapy, or death.
Other: Compassionate Use Cohort; Patients with a performance status (ECOG) score of 0-4 and leptomeningeal metastases were enrolled in Cohort 2 (compassionate use cohort).	Drug: Combined group of ensatinib and arotinib; Ensatinib is administered at a dose of 225 mg once daily, either on an empty stomach or with food; anlotinib is administered at a dose of 10 mg once daily, in 21-day cycles; treatment continues until disease progression, the occurrence of intolerable toxicity, withdrawal at the discretion of the investigator or the subject, loss to follow-up, initiation of other anticancer therapy, or death.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR)	If the patient has available imaging results from within 28 days prior to the first dose (bone scans may be accepted if performed within 2 months prior to the first dose), repeat imaging is not required. Tumour assessment should be performed every 6 weeks (±4 days) until tumour progression.	After the patients were enrolled according to the inclusion criteria, the tumor assessment will be conducted every 6 weeks, and the maximum duration of the assessment is 6 months until the patients have disease progression or cannot tolerate the treatmen

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary endpoints include progression-free survival (PFS)	Progression-free survival (PFS): defined as the time from randomisation to the first occurrence of objective tumour progression or death, whichever comes first.	The assessment was conducted every 2 cycles (6 weeks and 24 days), and the maximum duration of the assessment was 6 months until the patient's condition progressed or could not tolerate the treatment. As of June 2028, the follow-up work has been complete
Overall survival (OS)	Overall survival (OS): defined as the time from randomisation to the patient's death from any cause.	The assessment was conducted every 2 cycles (6 weeks and 24 days), and the maximum duration of the assessment was 6 months until the patient's condition progressed or could not tolerate the treatment. As of June 2028, the follow-up work has been complete
Duration of Response (DOR)	Duration of Response (DOR): Defined as the time from the first assessment of complete response (CR) or partial response (PR) until the first assessment of disease progression (PD) or death from any cause.	The assessment was conducted every 2 cycles (6 weeks and 24 days), and the maximum duration of the assessment was 6 months until the patient's condition progressed or could not tolerate the treatment. As of June 2028, the follow-up work has been complete
Disease Control Rate (DCR)	Disease Control Rate (DCR): Defined as the proportion of patients who achieve complete response (CR), partial response (PR) or stable disease (SD) following treatment and maintain this status for a certain period.	The assessment was conducted every 2 cycles (6 weeks and 24 days), and the maximum duration of the assessment was 6 months until the patient's condition progressed or could not tolerate the treatment. As of June 2028, the follow-up work has been complete
Safety assessment	Safety assessment: A summary of patients' physical examinations, electrocardiograms, ECOG scores, vital signs, adverse events and abnormal laboratory test results. All adverse events should be graded for severity in accordance with NCI CTCAE version 4.03.	At the end of the first cycle (24 days in each cycle), a safety follow-up (telephone follow-up) was conducted within 28 days after the last administration.

Collaborators and Investigators

• Sponsor: Qiming Wang
• Collaborators: Betta Pharmaceuticals Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: June 2, 2026
• First Submitted That Met QC Criteria: June 23, 2026
• First Posted (Actual): June 26, 2026

Study Record Updates

• Last Update Posted (Actual): June 26, 2026
• Last Update Submitted That Met QC Criteria: June 23, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Ensartinib; Anlotinib; Lorlatinib resistance; ALK-positive non-small cell lung cancer
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplastic Processes; Pathological Conditions, Signs and Symptoms; Neoplasm Metastasis
• Other Study ID Numbers: 2026-252

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No