Induction Lorlatinib in Stage III Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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A prospective, single-arm, open-label phase 2 study that evaluates the efficacy and safety of induction Lorlatinib in stage III non-small cell lung cancer and explores the clinical feasibility of dynamic ctDNA and multidisciplinary assessment in guiding local treatments.

Detailed Description
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Simon two-stage was applied to estimate the required sample size for the study. Overall an estimated 43 patients were required and at least 12 patients achieved pathological complete response would be deemed as positive result. Patients will be provided 3 cycles induction Lorlatinib 100mg and then assessed whether patients would be eligible for radical surgery or local radiotherapy through multidisciplinary evaluation. After local intervention, patients could choose consolidation treatment of Lorlatinib for up to 2 years or adjuvant doublet chemotherapy for up to 4 cycles. Dynamic blood samples will be collected before and after induction Lorlatinib as well as consolidation treatment. The primary endpoints is pCR for patients who received radical surgery.

Official Title
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Induction Lorlatinib for ALK Fusion Locally Advanced Non-small Cell Lung Cancer: A Prospective, Single Arm, Open-label Phase 2 Study

Conditions
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Stage III NSCLC, Surgery

Intervention / Treatment
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* Drug: Lorlatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age :18 Years to 75 Years; ECOG physical score 0-2 points; expected survival time ≥ 1 year; Pathologically confirmed diagnosis with Stage III NSCLC which harbored ALK fusion detected by next generation sequencing (NGS) or immunohistochemistry (IHC) with or without FISH. Suspected N2 (station 2/4/7) for stage III disease should be confirmed by either mediastinoscopy or EBUS. At least one measurable target lesion according to the RECIST 1.1 standard; The main organ function meets the following criteria: 1) blood routine: absolute value of neutrophils ≥ 1.5 × 109 / L, platelets ≥ 75 × 109 / L, hemoglobin ≥ 80 g / L; 2) blood biochemistry: total bilirubin ≤ 1.5 times the upper limit of normal value, aspartate aminotransferase and alanine aminotransferase ≤ 2.5 times the upper limit of normal value (if liver metastasis, ≤ upper limit of normal value 5 times), serum creatinine ≤ 1.5 times the upper limit of normal; Subjects voluntarily joined the study and signed informed consent, with good compliance to follow-up. Exclusion Criteria: Stage I, stage II and metastatic stage IV NSCLC; Histologically confirmed small cell lung cancer (including lung cancer mixed with small cell lung cancer and non-small cell lung cancer); Patients who have previously used any other anti-tumor drugs or received surgery/radiotherapy; Patients with any underlying disease that investigators consider it may affect patient's prognosis including sever cardiovascular, pulmonary disease or serious infections. Clinically obvious gastrointestinal abnormalities, which may affect the intake, transport or absorption of drugs (such as inability to swallow, chronic diarrhea, intestinal obstruction, etc.), or patients with total gastrectomy; Pregnant or lactating women; those who have fertility are unwilling or unable to take effective contraceptive measures; Patients with low compliance or willingness to take the drugs and surveillance.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: A Simon two-stage design was applied. Primary endpoint for this study was pCR. The unacceptable response rate for pCR was less than 20% and desirable response rate was 40%. The error rate for alpha was set as 0.05 and 0.2 for beta. The Optimal assay was chosen and 43 patients were to be enrolled to meet adequate statical power. 13 patients would be enrolled in stage I and at least 3 patients achieved pCR were required to proceed stage II enrollment. Overall, if 12 patients achieved pCR, the study would be determined as positive. 10% drop-off rate should be considered and at least 48 patients should be enrolled.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>Patients will receive 12-week induction Lorlatinib followed by radical surgery or local radiotherapy or continue Lorlatinib through MDT and optional consolidation lorlatinib for up to 2 years. | Drug: Lorlatinib<br>* Patients were assigned to receive oral lorlatinib at a dose of 100 mg daily in a course of treatment that was measured in cycles of 28 days. 3 cycles of induction treatment will be required for the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Complete Response (pCR) | The pathological complete response is defined as the absence of residual tumor in both lung and regional lymph nodes after induction treatment and radical surgery. | After surgery (approximately 2 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | The period after initiation of induction treatment till the time of disease progress or any cause of death. | From date of induction treatment till the date of first documented disease progression or death, whichever came first, assessed up to 48 months | 
| Objective Response Rate (ORR) | ORR is the number of participants with a Complete Response (CR) and Partial Response (PR) divided by the total number of enrolled participants per arm, then multiplied by 100. Response is based on the Response Evaluation Criteria In Solid Tumors (RECIST 1.1) criteria. Complete Response (CR) was defined as the disappearance of all target lesions. Partial Response (PR) was defined as at least a 30% decrease in sum of longest diameter of target lesions compared to baseline or the complete disappearance of target lesions, with persistence of 1 or more nontarget lesion(s) and no new lesions. | After last dose of induction treatment (approximately 1 week) | 
| Event-free Survival (EFS) | The period after radical surgery till the time of disease relapse with either local recurrence or distant metastasis. | From date of radical surgery till the date of first documented disease relapse, assessed up to 48 months | 
| Dynamic ctDNA alteration | The exploratory ctDNA alteration will be stratified into three parts. 1) Induction period: overall ctDNA clearance rate (before and after induction treatment); 2) Posttreatment period: ctDNA clearance rate after local treatment; 3) Consolidation period: 1-year and 2-year ctDNA positive rate during consolidation treatment. | From induction treatment till completion of consolidation lorlatinib (approximately 2.5 years) | 
| Overall Survival (OS) | OS was assessed from initiation of treatment to death as a result of any cause. | From date of induction treatment till the date of death from any cause, assessed up to 60 months. | 
| Adverse Events (AEs) | Incidence of AE/SAE which has been confirmed correlation with Lorlatinib or local treatment. | From Initiation of induction treatment till treatment discontinuation, assessed up to 24 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lorlatinib, ALK fusion, Induction Treatment, Multidisciplinary, ctDNA