Efficacy and Safety of Lorlatinib Monotherapy in Advanced ROS1-Positive Non-Small Cell Lung Cancer Post First-Line TKI Failure
- Trial ID
- 2024-512028-12-00
- Protocol
- IFCT-2003
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of lorlatinib in molecular subgroups of patients with advanced ROS1-positive non-small cell lung cancer (NSCLC) following molecular analysis of disease progression on first-line treatment with crizotinib or entrectinib. This is clinically relevant as it aims to determine the potential of lorlatinib to provide therapeutic benefits in patients who have experienced progression on initial tyrosine kinase inhibitor therapy, thereby addressing a critical need for effective second-line treatment options in this patient population.
Secondary objectives include:
- Evaluating the efficacy of lorlatinib as measured by progression-free survival (PFS), time to progression (TTP), disease control rate (DCR), duration of response (DOR), overall survival (OS) as assessed by investigators, and objective response rate (ORR) as assessed by an independent reviewer.
- Assessing the efficacy of lorlatinib as measured by PFS, OS, and ORR by investigators in three different molecular subgroups.
- Evaluating the efficacy of lorlatinib on central nervous system (CNS) disease.
- Assessing the safety and tolerability of lorlatinib.
- Evaluating the efficacy of lorlatinib according to the type of tyrosine kinase inhibitor (TKI) prescribed in the first line, either crizotinib or entrectinib.
- Evaluating the quality of life of patients receiving lorlatinib.
Participants
The clinical trial involves participants diagnosed with **advanced ROS1-positive non-small cell lung cancer**. The study population includes both male and female subjects, aged 18 years and older, with a life expectancy of at least 12 weeks. Participants are required to have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 2 or less, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. The trial population was selected based on specific molecular subgroups, particularly those who have experienced disease progression on first-line treatment with crizotinib or entrectinib. Participants must have adequate bone marrow, pancreatic, renal, and liver function, and must have recovered from any treatment toxicities to a manageable level. The trial includes individuals with asymptomatic and neurologically stable CNS metastases. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information on the total number of participants involved in the study.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **lorlatinib** monotherapy in patients with advanced ROS1-positive non-small cell lung cancer (NSCLC) who have experienced disease progression following first-line treatment with tyrosine kinase inhibitors such as crizotinib or entrectinib. This is a phase II, single-group assignment, multicenter study. The trial employs a non-randomized, open-label design, focusing on a specific molecular subgroup of patients. The estimated duration of the trial is from January 15, 2021, to January 15, 2027, with a maximum treatment period of 72 weeks for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as adequate bone marrow, pancreatic, renal, and liver function, as well as a confirmed diagnosis of advanced ROS1-positive NSCLC. The screening visit will also include obtaining informed consent and ensuring compliance with the study protocol. Following the screening, participants will receive **lorlatinib** orally, with the dosage adjusted according to the study protocol. Regular follow-up visits will be scheduled to monitor the participants' response to treatment, assess any adverse events, and perform necessary laboratory tests. The primary endpoint is the objective response rate (ORR) at 8 weeks, with confirmation needed at 16 weeks, assessed by investigators using RECIST v1.1 criteria. Secondary endpoints include progression-free survival, time to progression, disease control rate, duration of response, overall survival, and CNS-specific outcomes.
The expected length of participant involvement is up to 72 weeks, with conditions for early termination including significant adverse events, disease progression, or withdrawal of consent. Participants must comply with scheduled visits, treatment plans, and laboratory tests throughout the study. The end-of-study visit will involve a final assessment of the participant's health status and documentation of any long-term effects of the treatment. The study aims to provide valuable insights into the efficacy of **lorlatinib** in this patient population, potentially informing future treatment strategies for advanced ROS1-positive NSCLC.
Treatment
The clinical trial involves the administration of **Lorlatinib**, marketed under the name Lorviqua, in two different dosages: 100 mg and 25 mg film-coated tablets. Lorlatinib is a chemical compound with the synonym PF-06463922, and it is classified under the ATC code L01ED05. The pharmaceutical form of the medication is a film-coated tablet, and it is intended for **oral use**. The maximum daily dose for participants is 100 mg, with a total treatment period not exceeding 72 weeks. The medication is manufactured by Pfizer Europe MA EEIG and is authorized for use in Iceland and Liechtenstein under the marketing authorization numbers EU/1/19/1355/002 and EU/1/19/1355/003, respectively.
In this study, Lorlatinib is administered as a monotherapy to evaluate its efficacy and safety in patients with advanced ROS1-positive non-small cell lung cancer (NSCLC) who have experienced disease progression after first-line treatment with tyrosine kinase inhibitors such as crizotinib or entrectinib. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen.
Efficacy
Efficacy in the clinical trial will be assessed using several parameters, with the primary endpoint being the **Objective Response Rate (ORR)** at 8 weeks, confirmed at 16 weeks. ORR is defined as the percentage of subjects achieving a confirmed complete response (CR) or partial response (PR) according to RECIST v1.1 criteria, as assessed by the investigators. Secondary endpoints include ORR at 8 weeks confirmed at 16 weeks by an independent reviewer committee, **Progression-Free Survival (PFS)**, **Time to Progression (TTP)**, **Disease Control Rate (DCR)** at 8 weeks confirmed at 16 weeks, **Duration of Response (DOR)**, **Overall Survival (OS)**, **CNS Objective Response Rate (C-ORR)**, **CNS Duration of Response (C-DOR)**, and **Time to CNS Progression** in patients without brain metastases at baseline. Additionally, changes from baseline in the EuroQol Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) will be evaluated at all scheduled time points.
The efficacy parameters will be measured and collected at specified intervals, with ORR assessments occurring at 8 and 16 weeks. PFS, TTP, DCR, DOR, and OS will be determined through investigator review or independent review of radiographic disease assessments per RECIST v1.1. OS will be specifically assessed at 12 and 24 months. The trial will utilize validated scales and criteria, such as RECIST v1.1, to ensure consistent and reliable measurement of efficacy outcomes. The analysis of these parameters will provide comprehensive insights into the efficacy of lorlatinib in patients with advanced ROS1-positive non-small cell lung cancer following progression on first-line treatment.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed Written Informed Consent: Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care. Subjects must be willing and able to comply with scheduled visits, treatment schedule, and laboratory testing
- Adequate Bone Marrow Function, including: Absolute Neutrophil Count (ANC) ≥1.5 x 109/L; Platelets ≥100 x 109/L; Hemoglobin ≥9 g/dL.
- Adequate Pancreatic Function, including: Serum lipase ≤1.5 x ULN.
- Renal Function, including: Serum creatinine ≤1.5 x ULN or estimated creatinine clearance ≥45 mL/min as calculated using the method standard for the institution.
- Adequate Liver Function, including: Total serum bilirubin ≤1.5 x ULN; Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤2.5 x ULN; ≤5.0 x ULN if there is liver metastases involvement.
- Participants must have recovered from treatment toxicities to CTCAE Grade ≤ 1 (for participants who have developed interstitial lung disease [ILD], they must have fully recovered) except for AEs that in the investigator’ judgment do not constitute a safety risk for the patient.
- Participants must have recovered from effects of any major surgery, or significant traumatic injury, at least 35 days before the first dose of lorlatinib.
- For all females of childbearing potential, a negative pregnancy test must be obtained within the screening period. A patient is of childbearing potential if, in the opinion of the investigator, she is biologically capable of having children and is sexually active. Additionally, all females of childbearing potential must provide an agreement to remain abstinent or use two adequate methods of contraception, including at least one method with a failure rate of < 1% per year, during the treatment period and for at least 90 days after the last dose of study drug.
- For men: agreement to remain abstinent or use an effective method of contraception (e.g., condom) during the treatment period and for at least 14 weeks after the last dose of study drug and agreement to refrain from donating sperm during this same period.
- Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
- Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests and other procedure.
- Patients with histologically or cytologically confirmed diagnosis of locally advanced not eligible to a local treatment or metastatic NSCLC (Stage IIIB or IIIC non irradiable or IV accordingly to 8th classification TNM, UICC 2015) that carries an ROS1 rearrangement, as determined by the molecular biology platform of the investigator by FISH assay or by Immunohistochemistry (IHC), or Next Generation Sequencing (NGS) or RNA sequencing approach. If the determination of ROS rearrangement was done by immunohistochemistry, a second method performed locally is required.
- Participant has national health insurance coverage.
- Washout period: if previous progression on ROS1-TKI: 7 days from last dose of the drug. The washout period may be shortened to 2 days at investigator discretion.
- Disease Status Requirements: Disease progression meeting RECISTv1.1 after one prior line of treatment with crizotinib or entrectinib (+ one line of chemotherapy with or without immunotherapy before TKI treatment). Note: patient with disease progression after treatment with another ROS1-TKI may still be eligible upon discussion with IFCT
- Tumor Requirements: All Patients must have at least one measurable target lesion according to RECIST v1.1. The radiological assessment has to be done within the timelines indicated. In addition, patients with asymptomatic and neurologically stable CNS metastases (including patients controlled with stable or decreasing steroid use within the last week prior to study entry) will be eligible. The brain metastases may be newly diagnosed after disease progression with crizotinib or entrectinib or be present as progressive disease after surgery, whole brain radiotherapy or stereotactic radiosurgery (see Exclusion Criterion for the lapsed time period required between the end of radiotherapy and study entry). Patients who have leptomeningeal disease (LM) or carcinomatous meningitis (CM) will be eligible if the LM/CM is visualized on MRI or if documented baseline cerebral spinal fluid (CSF) positive cytology is available and asymptomatic and neurologically stable (including patients controlled with stable or decreasing steroid use within the last week prior to study entry).
- Tumor Sample Requirement: Tumour biopsy sampling on fresh tissue (FFPE blocks required) obtained after progression on crizotinib or entrectinib. Tumour biopsy should be exploitable for molecular analysis. If the tumour biopsy is not exploitable, the inclusion will be allowed if two blood samples are provided for tumoral cfDNA analysis. The Sponsor will monitor a posteriori the exploitability of provided tumour biopsies and will investigate the impossibility to perform or repeat tissue tumor sampling.
- Age ≥18 years.
- Life expectancy of at least 12 weeks, in the opinion of the Investigator.
- Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 2
Exclusion Criteria
- Participants with disease progression on front-line treatment with TKI i.e. crizotinib or entrectinib limited to CNS or one non-CNS site (oligometastasis) and eligible to a local ablative treatment (surgery or stereotaxic radiotherapy).
- Histological transformation with neuro-endocrine differentiation.
- Spinal cord compression is excluded unless the patient demonstrates good pain control attained through therapy and there is stabilization or recovery of neurological function for the 4 weeks prior to study entry.
- Patients with symptomatic and neurologically instable CNS metastases or leptomeningeal metastasis (including patients that require increasing doses of steroids within one week prior to Day 0 of screening phase and during the screening phase to manage CNS symptoms).
- Major surgery within 35 days of study entry. Minor surgical procedures (eg, port insertion, mediastinoscopy, surgical procedure for re-sampling) are not excluded, but sufficient time at investigator discretion should have passed for wound healing.
- Radiation therapy within 2 weeks of study entry (except palliative to relieve bone pain). Palliative radiation (≤15 fractions) must have been completed at least 48 hours prior to study entry. Stereotactic or small field brain irradiation must have completed at least 2 weeks prior to study entry. Whole brain radiation must have completed at least 4 weeks prior to study entry.
- Active and clinically significant bacterial, fungal, or viral infection including hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS)-related illness.
- Clinically significant cardiovascular disease (that is, active or <3 months prior to enrollment): cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure (New York Heart Association Classification Class ≥ II), second-degree or third-degree AV block (unless paced) or any AV block with PR >220 msec.
- Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 bpm (unless patient is otherwise healthy such as long-distance runners, athletic patients etc.), machine-read ECG with QTc >470 msec, or congenital long QT syndrome.
- Patients with predisposing characteristics for acute pancreatitis according to investigator judgment (eg, uncontrolled hyperglycemia, current gallstone disease, alcoholism [more than 4 drinks on any day or 14 drinks per week where 1 drink is defined as the alcoholic beverage containing approximately 14 grams of pure alcohol, eg, 12 fl oz/360 mL regular beer or 5 fl oz/150 mL of wine] in the last month.
- History of bilateral or Grade 3 or 4 interstitial fibrosis or diffuse interstitial lung disease. Patients with history of prior radiation pneumonitis are not excluded.
- Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
- Evidence of active malignancy (other than current NSCLC, non-melanoma skin cancer, in situ cervical cancer, papillary thyroid cancer, DCIS of the breast or localized and presumed cured prostate cancer) within the last 3 years.
- Active inflammatory gastrointestinal disease, chronic diarrhea, symptomatic diverticular disease or previous gastric resection or lap band.
- Current use or anticipated need for food or drugs prohibited (see chapter 7.9.1 for details).
- Patients presenting with abnormal Left Ventricular Ejection Fraction (LVEF) by echocardiogram or Multi-Gated Acquisition Scan (MUGA) according to institutional lower limits.
- Breastfeeding female patients (including patients who intend to interrupt breastfeeding).
- Liver disease characterized by: ALT or AST level > 3 the upper normal limit (UNL) (≥ 5 x UNL for patients with liver metastases) confirmed on 2 consecutives measures OR impaired excretory function (e.g.. hyperbilirubinemia) or synthetic function or other conditions of decompensated liver disease e.g.: coagulopathy, Hepatic encephalopathy, hypoalbuminemia, ascites and bleeding from esophageal varices OR Acute viral or autoimmune or other types of hepatitis.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 01 Mar 2021 | 84 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Lorviqua 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 100 | 72 | PRD7271616 |
Lorviqua 25 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 100 | 72 | PRD7496623 |