A Study Of Lorlatinib Versus Crizotinib In First Line Treatment Of Patients With ALK-Positive NSCLC

Study Overview
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Brief Summary
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A phase 3 study to demonstrate whether lorlatinib given as monotherapy is superior to crizotinib alone in prolonging the progression-free survival in advanced ALK-positive NSCLC patients who are treatment naïve and to compare lorlatinib to crizotinib with respect to overall survival in the same population

Official Title
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A PHASE 3, RANDOMIZED, OPEN-LABEL STUDY OF LORLATINIB (PF-06463922) MONOTHERAPY VERSUS CRIZOTINIB MONOTHERAPY IN THE FIRST-LINE TREATMENT OF PATIENTS WITH ADVANCED ALK-POSITIVE NON-SMALL CELL LUNG CANCER

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Lorlatinib
* Drug: Crizotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed diagnosis of locally advanced or metastatic ALK-positive NSCLC; at least 1 extracranial measurable target lesion not previously irradiated. CNS metastases allowed if asymptomatic and not currently requiring corticosteroid treatment. Availability of an archival FFPE tissue specimen. No prior systemic NSCLC treatment. ECOG PS 0, 1, or 2. Age ≥18 years . Adequate Bone Marrow, Liver, Renal, Pancreatic Function Negative pregnancy test for females of childbearing potential Exclusion Criteria: Spinal cord compression unless good pain control attained Major surgery within 4 weeks prior to randomization. Radiation therapy within 2 weeks prior to randomization, including stereotactic or partial brain irradiation. Whole brain irradiation within 4 weeks prior to randomization Active bacterial, fungal, or viral infection Clinically significant cardiovascular disease, active or within 3 months prior to enrollment. Ongoing cardiac dysrhythmias, uncontrolled atrial fibrillation, bradycardia or congenital long QT syndrome Predisposing characteristics for acute pancreatitis in the last month prior to randomization. History of extensive, disseminated, bilateral or presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease Active malignancy (other than NSCLC, non melanoma skin cancer, in situ cervical cancer, papillary thyroid cancer, LCIS/DCIS of the breast, or localized prostate cancer) within the last 3 years prior to randomization. Concurrent use of any of the following food or drugs within 12 days prior to the first dose of lorlatinib or crizotinib. known strong CYP3A inhibitors . known strong CYP3A inducers known P gp substrates with a narrow therapeutic index Concurrent use of CYP3A substrates with narrow therapeutic indices within 12 days prior to the first dose of lorlatinib or crizotinib. Other severe acute or chronic medical or psychiatric condition, including recent or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or interfere with the interpretation of study results Investigational site staff members directly involved in the conduct of the study and their family members, or Pfizer employees, including their family members, directly involved in the conduct of the study. Participation in other studies involving investigational drug(s) within 2 weeks prior to study entry and/or during study participation.

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lorlatinib<br>Lorlatinib single agent, 100 mg (4 x 25 mg) oral tables, QD, continuously | Drug: Lorlatinib<br>* ALK-positive NSCL treatment<br>* Other names: PF-06463922;|
| Active Comparator: Crizotinib<br>Crizotinib single agent, 250 mg (1 x 250) oral capsules, BID, continuously | Drug: Crizotinib<br>* ALK-positive NSCL treatment<br>* Other names: Xalkori;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) Based on Blinded Independent Central Review (BICR) Assessment | PFS was defined as the time from randomization to the date of the first documentation of progressive disease as assessed by the independent radiologist or death due to any cause, whichever occurred first. PFS (in months) was calculated as (date of event or censoring-randomization+1)/30.4375. Progressive disease is defined per RECIST version 1.1, as at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of the longest dimensions of the target lesions taking as a reference the smallest sum of the longest dimensions recorded since the treatment started, or the appearance of 1 or more new lesions. | From time of Study Start up to 33 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the time from randomization to the date of death due to any cause. OS (in months) was calculated as (date of death or censoring - start date +1)/30.4375. Participants last known to be alive were censored at date of last contact. | From time of Study Start up to 33 months | 
| Progression-Free Survival (PFS) Based on Investigator's Assessment | PFS was defined as the time from randomization to the date of the first documentation of progressive disease as assessed by investigator or death due to any cause, whichever occurred first. PFS (in months) was calculated as (date of event or censoring-randomization+1)/30.4375. Progressive disease is defined per RECIST version 1.1, as at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of the longest dimensions of the target lesions taking as a reference the smallest sum of the longest dimensions recorded since the treatment started, or the appearance of 1 or more new lesions. | From time of Study Start up to 33 months | 
| Objective Response Rate (ORR) - Percentage of Participants With Objective Response (OR) Based on BICR Assessment | ORR was the percentage of participants with objective response of complete response (CR) or partial response (PR) according to RECIST version 1.1 recorded from randomization until disease progression or start of new anti-cancer therapy. CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). PR was defined as at least a 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. | From time of Study Start up to 33 months | 
| Objective Response Rate (ORR) - Percentage of Participants With Objective Response (OR) Based on Investigator's Assessment | ORR was the percentage of participants with objective response of complete response (CR) or partial response (PR) according to RECIST version 1.1 recorded from randomization until disease progression or start of new anti-cancer therapy. CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). PR was defined as at least a 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. | From time of Study Start up to 33 months | 
| Intracranial Objective Response Rate (IC-ORR) - Percentage of Participants With Intracranial Objective Response (IC-OR) Based on BICR Assessment | IC-ORR was the percentage of participant with intracranial objective response of complete response (CR) or partial response (PR) based on intracranial disease in the subset of participants with at least 1 intracranial lesion per RECIST version 1.1 (modified) recorded from randomization until disease progression or start of new anti-cancer therapy. CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). PR was defined as at least a 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. | From time of Study Start up to 33 months | 
| Intracranial Time to Progression (IC-TTP) Based on BICR Assessment | IC-TTP based on BICR assessment was defined as the time from date of randomization to the date of the first documentation of progression of intracranial disease, based on either new brain metastases or progression of existing brain metastases. | From time of Study Start up to 33 months | 
| Duration of Response (DR) Based on BICR Assessment | DR was defined, for participants with a confirmed objective response (OR) of complete response (CR) or partial response (PR) per RECIST version 1.1, as the time from the first documentation of OR to the first documentation of progressive disease (PD) or death due to any cause, whichever occurred first. CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). PR was defined as at least a 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. PD was defined as at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of the longest dimensions of the target lesions taking as a reference the smallest sum of the longest dimensions recorded since the treatment started, or the appearance of 1 or more new lesions. | From time of Study Start up to 33 months | 
| Intracranial Duration of Response (IC-DR) Based on BICR Assessment | IC-DR was defined, for participants with a confirmed intracranial objective response (OR) of complete response (CR) or partial response (PR) per RECIST version 1.1, as the time from the first documentation of intracranial OR to the first documentation of intracranial progressive disease (PD) or death due to any cause, whichever occurred first. CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). PR was defined as at least a 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. PD was defined as at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of the longest dimensions of the target lesions taking as a reference the smallest sum of the longest dimensions recorded since the treatment started, or the appearance of 1 or more new lesions. | From time of Study Start up to 33 months | 
| Time to Tumor Response (TTR) Based on BICR Assessment | TTR based on BICR assessment was defined, for participants with a confirmed objective response, as the time from the date of randomization to the first documentation of objective response (complete response or partial response) which was subsequently confirmed. Complete response was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). Partial response was defined as at least a 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. | From time of Study Start up to 33 months | 
| Intracranial Time to Tumor Response (IC-TTR) Based on BICR Assessment | IC-TTR was defined, for participants with a confirmed intracranial objective response, as the time from the date of randomization to the first documentation of intracranial objective response (complete response or partial response) which was subsequently confirmed. Complete response was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). Partial response was defined as at least a 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. | From time of Study Start up to 33 months | 
| PFS2 Based on Investigator's Assessment | PFS2 was defined as the time from randomization to the date of progression of disease on first subsequent systemic anti-cancer therapy, or death from any cause, whichever occurred first | From time of Study Start up to 45 months | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs; All-Causality and Treatment-Related) | An AE was an untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes: death, life-threatening experience, initial or prolonged inpatient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. All AEs in the table below were treatment-emergent AEs. Grade 3 and 4 AEs in the table below indicated severe AE and life-threatening consequences respectively; Grade 5 indicated death due to AE. Treatment-related AEs were determined by investigators. | From time of Study Start up to 33 months | 
| Number of Participants With Changes in Hematology Laboratory Parameters From Baseline Maximum NCI-CTCAE Grade Lower Than 3 to Postbaseline Maximum Grade 3 or Grade 4 | Laboratory test results were graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grades 1 and 2 indicate mild and moderate AE, respectively; Grades 3 and 4 indicate severe AE and life-threatening consequences respectively; Grade 5 indicates death due to AE. Participants with laboratory test abnormalities were summarized according to the worst grade for each laboratory test result. All participants meeting the postbaseline grade criteria in the table below had baseline maximum grades lower than 3. | From Baseline up to 33 months | 
| Number of Participants With Changes in Chemistry Laboratory Parameters From Baseline Maximum NCI-CTCAE Grade Lower Than 3 to Postbaseline Maximum Grade 3 or Grade 4 | Laboratory test results were graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grades 1 and 2 indicate mild and moderate AE, respectively; Grades 3 and 4 indicate severe AE and life-threatening consequences respectively; Grade 5 indicates death due to AE. Participants with laboratory test abnormalities were summarized according to the worst grade for each laboratory test result. All participants meeting the postbaseline grade criteria in the table below had baseline maximum grades lower than 3. | From Baseline up to 33 months | 
| Number of Participants With Changes in Lipid Laboratory Parameters From Baseline Maximum NCI-CTCAE Grade Lower Than 3 to Postbaseline Maximum Grade 3 or Grade 4 | Laboratory test results were graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grades 1 and 2 indicate mild and moderate AE, respectively; Grades 3 and 4 indicate severe AE and life-threatening consequences respectively; Grade 5 indicates death due to AE. Participants with laboratory test abnormalities were summarized according to the worst grade for each laboratory test result. All participants meeting the postbaseline grade criteria in the table below had baseline maximum grades lower than 3. | From Baseline up to 33 months | 
| Number of Participant With Vital Signs and Body Weight Data Meeting Pre-defined Criteria | Vital signs data included pulse, systolic blood pressure, and diastolic blood pressure. Measurements were only provided once per timepoint. If multiple assessments were provided per timepoint, the maximum value were used for reporting. The pre-defined criteria of vital sign and body weight data were as follows: maximum pulse rate >120 beats per minute (bpm); minimum pulse rate <50 bpm; maximum increase in pulse rate ≥30 bpm; maximum decrease in pulse rate ≥30 bpm; increase in systolic blood Pressure ≥40 mmHg; decrease in systolic blood pressure ≥40 mmHg; decrease in systolic blood pressure ≥60 mmHg; increase in diastolic blood pressure ≥20 mmHg; decrease in diastolic blood pressure ≥20 mmHg; decrease in diastolic blood pressure ≥40 mmHg; increase in body weight ≥10%; increase in body weight ≥20%; decrease in body weight ≥10%. | From Baseline up to 33 months | 
| Number of Participant With Maximum Increase From Baseline in Electrocardiogram (ECG) Data Meeting Pre-defined Criteria | Baseline was defined as the last assessment performed on or prior to date of the first dose of study treatment. Triplicate ECGs were collected in the study and the average of the replicate assessments were used for summary analysis. The pre-defined criteria of ECG data were as follows: change from baseline in QTcF ≥60 msec, ≥30 msec but <60 msec, <30 msec; change from baseline in QTcB ≥60 msec, ≥30 msec but <60 msec, <30 msec; PR change ≥50% if absolute baseline value was <200 msec; PR change ≥25% if absolute baseline value was ≥200 msec; QRS change ≥50% if absolute baseline value was <100 msec; QRS change ≥25% if absolute baseline value was ≥100 msec. | From Baseline up to 33 months | 
| Number of Participants With Maximum Decrease From Baseline Greater Than or Equal to 20 Points in Left Ventricular Ejection Fraction (LVEF) Percentage | In this outcome measure, baseline was defined as the last assessment on or prior to the date of the first dose of study treatment. Decrease from baseline was an absolute difference between baseline and observed value. | From Baseline up to 33 months | 
| Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time | BDI-II (Mood Assessment) is a 21 item self-reported scale, with each item rated by participants on a 4-point scale (ranging from 0-3). The scale includes items capturing mood, (loss of pleasure, sadness, and irritability), suicidal ideation, and cognitive signs (punitive thoughts, self-criticism, self-dislike pessimism, poor concentration) as well as somatic signs (appetite, sleep, fatigue, libido). Scores were obtained by adding up the total points from the series of answers. The total score ranged from 0 to 63, with higher total scores indicating more severe depressive symptoms. The standardized cutoffs are as follows: 0-13: minimal depression; 14-19: mild depression; 20-28: moderate depression; 29-63: severe depression. | Baseline, Cycle 2 Day 1 (C2D1), C3D1, C4D1, C5D1, C6D1, C8D1, C10D1, C12D1, C14D1, C16D1, C18D1, C20D1, C22D1, C24D1, C26D1, C28D1, C30D1, C32D1, C34D1, C36D1, C38D1 and End of Treatment | 
| Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time | Suicidal ideation and behaviors were assessed by the Columbia Suicide Severity Rating Scale (C-SSRS). The C-SSRS is a unique, simple and short method of assessing both behavior and ideation that tracks all suicidal events and provides a summary of suicidality. It assesses the lethality of attempts and other features of ideation (frequency, duration, controllability, reasons for ideation, and deterrents), all of which are significantly predictive of completed suicide. | Baseline, Cycle 2 Day 1 (C2D1), C3D1, C4D1, C5D1, C6D1, C8D1, C10D1, C12D1, C14D1, C16D1, C18D1, C20D1, C22D1, C24D1, C26D1, C28D1, C30D1, C32D1, C34D1, C36D1, C38D1 and End of Treatment | 
| Change From Baseline in Global Quality of Life (QOL), Functional Scales and Symptoms Scales as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) During Overall Treatment | The EORTC QLQ C30 consists of 30 questions and includes 5 functional scales (physical, role, cognitive, emotional, and social); a global health status/global quality of life scale; 3 symptom scales (fatigue, pain, nausea and vomiting); and 6 single items that assess additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and financial impact. All scales and single item measures range in score from 0 to 100. Higher scores on the functional scales represent higher levels of functioning. Higher scores on the global health status/quality of life scale represent higher health status/quality of life. Higher scores on symptom scales/items represent a greater presence of symptoms. | From Baseline up to Cycle 38 Day 1 | 
| Change From Baseline in Lung Cancer Symptoms as Assessed by the EORTC Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13) During Overall Treatment | The EORTC QLQ LC13 consists of 13 questions and includes 1 multi-item scale and 9 single items assessing symptoms (dyspnea, cough, haemoptysis, and site-specific pain), side effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and pain medication use. The scale scores rang from 0 to 100, with higher scores indicating higher (worse) level of symptoms. | From Baseline up to Cycle 38 Day 1 | 
| Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time | The EuroQol EQ-5D-5L is a participant-completed questionnaire designed to assess health status. There are 2 components to the EuroQol EQ-5D-5L: a descriptive system in which individuals rate their level of problems (none, slight, moderate, severe, extreme/unable) in 5 areas (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a VAS. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state) and higher scores indicate better health state. | Baseline, Day 1 of all cycles from Cycle 2 to Cycle 38, and End of Treatment | 
| Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time | The EuroQol EQ-5D-5L is a participant-completed questionnaire designed to assess health status. There are 2 components to the EuroQol EQ-5D-5L: a descriptive system in which individuals rate their level of problems (none, slight, moderate, severe, extreme/unable) in 5 areas (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a VAS in which participants rate their overall health status from 0 (worst imaginable) to 100 (best imaginable). EQ-5D summary index is obtained with a formula that weights each level of the 5 dimensions. The index-based score is interpreted along a continuum of 0 (death) to 1 (perfect health). | Baseline, Day 1 of all cycles from Cycle 2 to Cycle 38, and End of Treatment | 
| Time to Deterioration (TTD) in Participant Reported Pain in Chest, Dyspnea, or Cough From QLQ-LC13 | The EORTC QLQ LC13 consists of 13 questions and includes 1 multi-item scale and 9 single items assessing symptoms (dyspnea, cough, haemoptysis, and site-specific pain), side effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and pain medication use. The scale scores rang from 0 to 100, with higher scores indicating higher (worse) level of symptoms. TTD in pain in chest, dyspnea, or cough was defined as the time from randomization to the first time the participant's score showed a 10 point or greater increase after baseline in any of the 3 symptoms. TTD in months was calculated as (date of deterioration or censoring - randomization date +1)/30.4375. | From Baseline up to 33 months | 
| Number of Participant With ALK Domain Mutation in Plasma Circulating Nucleic Acid (CNA) Analysis at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 | The analysis of anaplastic lymphoma kinase (ALK) domain mutation in plasma CNA was performed by next-generation sequencing (NGS) and the number of participants with one or more ALK mutations at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 is presented here. | at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 | 
| Number of Participant With ALK Fusion Variant in Plasma Circulating Nucleic Acid (CNA) Analysis at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 | The analysis of ALK fusion variant in plasma CNA was performed by NGS and the number of participants with fusion variants at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 is presented here. In the table below, EML4-ALK is the abbreviation of echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase. | at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ALK; anaplastic lymphoma kinase; Non-Small-Cell Lung cancer; NSCLC