Phase 3 Randomized Open-Label Study of Lorlatinib Versus Crizotinib in First-Line Treatment of Advanced ALK-Positive Non-Small Cell Lung Cancer

Trial ID: 2023-509169-19-00
Protocol: B7461006
Sponsor: Pfizer Inc.

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Diseases & Conditions

Non-small cell lung cancer Non-small cell lung cancer stage IV Non-small cell lung cancer metastatic

Objectives

The primary objective of this study is to demonstrate that **lorlatinib** as a single agent (Arm A) is superior to **crizotinib** alone (Arm B) in prolonging **Progression Free Survival (PFS)** in participants with advanced **ALK positive non-small cell lung cancer (NSCLC)** who are treatment-naïve. This is clinically relevant as it aims to establish a more effective first-line treatment option for this specific patient population, potentially improving their prognosis and quality of life.

Secondary objectives include:

Comparing Arm A and Arm B with respect to **Overall Survival (OS)** in treatment-naïve advanced ALK positive NSCLC participants.
Evaluating the antitumor activity in each treatment arm.
Assessing the safety and tolerability in each treatment arm.
Evaluating participant-reported outcomes (PROs) concerning health-related quality of life, disease/treatment-related symptoms of lung cancer, and general health status for each treatment arm.
Evaluating candidate biomarkers of sensitivity or resistance to single-agent crizotinib or lorlatinib in pre-treatment tumor tissue and peripheral blood.

These secondary objectives aim to provide a comprehensive understanding of the treatment's efficacy, safety, and impact on patients' quality of life, as well as to identify potential biomarkers for treatment response.

Participants

The clinical trial involves a total of **188 participants** diagnosed with **advanced ALK positive non-small cell lung cancer**. The study population includes both male and female subjects, aged **18 years and older**, with no prior systemic treatment for advanced or metastatic disease. Participants were selected based on a confirmed diagnosis of locally advanced or metastatic ALK positive NSCLC, determined by an FDA-approved diagnostic test. The trial includes individuals with an Eastern Cooperative Oncology Group Performance Status of 0, 1, or 2, indicating they are ambulatory and capable of self-care. Participants must have adequate bone marrow, pancreatic, renal, and liver function, and any acute effects of prior radiotherapy must have resolved. The trial population is diverse, including vulnerable populations, and requires participants to comply with scheduled visits and procedures. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

Plans and Procedures

The clinical trial is a **Phase 3**, randomized, open-label study designed to evaluate the efficacy of **lorlatinib** monotherapy compared to crizotinib monotherapy in the first-line treatment of patients with advanced **ALK-positive non-small cell lung cancer** (NSCLC). The primary objective is to demonstrate the superiority of lorlatinib in prolonging progression-free survival (PFS) in treatment-naïve participants. The trial is expected to run from October 16, 2017, with an estimated end date of December 31, 2028.

Participants will be randomly assigned to one of two treatment arms: Arm A receiving lorlatinib and Arm B receiving crizotinib. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to have a histologically or cytologically confirmed diagnosis of locally advanced or metastatic ALK-positive NSCLC, with no prior systemic treatment for advanced disease. Participants must also meet specific laboratory and performance status criteria.

The expected duration of participant involvement in the study is determined by the progression of the disease or the occurrence of unacceptable toxicity. Participants may be withdrawn from the study early if they experience significant adverse events, disease progression, or if they are unable to comply with the study protocol. The primary endpoint is PFS based on blinded independent central review, while secondary endpoints include overall survival, investigator-assessed PFS, and various safety and efficacy measures. The study will also evaluate patient-reported outcomes and tumor tissue biomarkers.

Treatment

The clinical trial involves the administration of **LORLATINIB**, an experimental medication, as a monotherapy for the treatment of advanced ALK-positive non-small cell lung cancer (NSCLC). **LORLATINIB** is provided in the form of a tablet and is administered orally. The maximum daily dose is 100 mg, with the total dose not exceeding 100 mg per day. The treatment period is set for a maximum of 4 weeks. The active substance in **LORLATINIB** is of chemical origin, and the medication is identified by the sponsor product code PF-06463922. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

In addition to the experimental treatment, the study includes a comparator treatment with **CRIZOTINIB** monotherapy. **CRIZOTINIB** serves as the standard-of-care therapy against which the efficacy of **LORLATINIB** is evaluated. The trial is designed to assess the superiority of **LORLATINIB** in prolonging progression-free survival in treatment-naïve participants with advanced ALK-positive NSCLC. The study is conducted in an open-label format, allowing for direct comparison between the two treatment arms.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the measurement of **Progression Free Survival (PFS)**, as determined by a blinded independent central review (BICR) using RECIST v.1.1 criteria. Secondary efficacy endpoints include overall survival (OS), PFS based on the investigator's assessment, objective response (OR) based on both BICR and investigator's assessment, intracranial objective response (IC OR), intracranial time to progression (IC TTP), duration of response (DR) and intracranial duration of response (IC-DR), time to response (TTR) and intracranial time to response (IC-TTR), all evaluated by BICR using RECIST v.1.1, as well as PFS2. Additional assessments include IC-OR, IC-TTP, IC-DR, IC-TTR, and DR based on the investigator's assessment.

Patient-reported outcomes (PROs) will be evaluated using the EORTC QLC C30, EORTC QLQ LC13, and EQ 5D 5L instruments. Tumor tissue biomarkers, including ALK gene rearrangement and/or mutation, will be measured by next-generation sequencing (NGS) and/or immunohistochemistry (IHC). Peripheral blood cfDNA biomarkers, such as ALK gene rearrangement and/or ALK kinase domain mutations, will also be assessed. The schedule for these assessments will align with the trial's protocol, ensuring systematic data collection and analysis throughout the study duration.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Diagnosis: a. Study Population: Participants with histologically or cytologically confirmed diagnosis of locally advanced [(Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) by American Joint Committee on Cancer (AJCC) v 7.0] ALK positive NSCLC where ALK status is determined by the FDA approved (for use in US), CE (Conformité Européene) marked (for EU and other countries that accept CE marking), and PMDA(Pharmaceuticals and Medical Devices Agency) approved (for use in Japan) Ventana ALK (D5F3) Companion Diagnostic (CDx) IHC test performed on the Ventana ULTRA or XT platforms (refer to Section 6.1.1.1 for any prescreening activity related to ALK determination); b. Tumor Requirements: At least 1 extracranial measurable target lesion per RECIST v. 1.1 that has not been previously irradiated. CNS metastases are allowed if asymptomatic and: 1. Either untreated and not currently requiring corticosteroid treatment, or on a stable or decreasing dose of ≤10 mg QD prednisone or equivalent; or 2. Local treatment has been completed with full recovery from the acute effects of radiation therapy or surgery prior to randomization, and if corticosteroid treatment for these metastases has been withdrawn for at least 4 weeks with neurological stability; or 3. In case of leptomeningeal disease (LMD) or carcinomatous meningitis (CM) if visualized on magnetic resonance imaging (MRI), or if baseline CSF positive cytology is available. c. Tissue Requirements: All participants must have an archival formalin fixed, paraffin embedded (FFPE) tissue specimen available and collected prior to randomization. If archived tissue is unavailable, then a mandatory de novo biopsy must be performed.
No prior systemic NSCLC treatment for advanced (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) disease, including molecularly targeted agents (eg, ALK TKIs), angiogenesis inhibitors, immunotherapy, or chemotherapy. Prior treatment for earlier Stages of the NSCLC only allowed if completed more than 12 months prior to randomization.
Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0, 1, or 2.
Age ≥18 years (or ≥20 years as required by local regulation).
Adequate Bone Marrow Function, including: a. Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 or ≥1.5 x 109/L; b. Platelets ≥100,000/mm3 or ≥100 x 109/L; c. Hemoglobin ≥9 g/dL.
Adequate Pancreatic Function, including: a. Serum total amylase ≤1.5 x upper limit of normal (ULN)*; b. Serum lipase ≤1.5 x ULN. *if total amylase >1.5 x ULN, but pancreatic amylase is within the ULN, then participant may be enrolled.
Adequate Renal Function, including: a. Serum creatinine ≤1.5 x ULN or estimated creatinine clearance ≥60 mL/min as calculated using the method standard for the institution.
Adequate Liver Function, including: a. Total serum bilirubin ≤1.5 x ULN; b. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤2.5 x ULN (≤5.0 x ULN in case of liver metastases).
Acute effects of prior radiotherapy resolved to baseline severity or to CTCAE Grade ≤1 except for AEs that in the investigator’s judgment do not constitute a safety risk for the participant.
Serum pregnancy test (for females of childbearing potential) negative at screening. Female participants of non childbearing potential must meet at least 1 of the following criteria: • Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause (which may be confirmed with a serum follicle stimulating hormone [FSH] level confirming the postmenopausal state if appropriate); • Have undergone a documented hysterectomy and/or bilateral oophorectomy; • Have medically confirmed ovarian failure. All other female participants (including female participants with tubal ligations) are considered to be of childbearing potential.
Evidence of a personally signed and dated informed consent document indicating that the participant (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
Willing and able to comply with scheduled visits, treatment plans, laboratory tests and other procedures.

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Exclusion Criteria

Spinal cord compression unless the participant has good pain control attained through therapy, and there is stabilization or recovery of neurological function for the 4 weeks prior to randomization.
Major surgery within 4 weeks prior to randomization. Minor surgical procedures (eg, port insertion) are not excluded, but sufficient time should have passed for adequate wound healing.
Radiation therapy within 2 weeks prior to randomization, including stereotactic or partial brain irradiation. Participants who complete whole brain irradiation within 4 weeks prior to randomization or palliative radiation therapy outside of the CNS within 48 hours prior to randomization will also not be included in the study.
Gastrointestinal abnormalities, including inability to take oral medication; requirement for intravenous alimentation; prior surgical procedures affecting absorption including total gastric resection or lap band; active inflammatory gastrointestinal disease, chronic diarrhea, symptomatic diverticular disease; treatment for active peptic ulcer disease in the past 6 months; malabsorption syndromes.
Known prior or suspected severe hypersensitivity to study drugs or any component in their formulations.
Active and clinically significant bacterial, fungal, or viral infection including hepatitis B virus (HBV) or hepatitis C virus (HCV) (eg, in case of known HBsAg or HCV antibody positivity), known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS) related illness.
Clinically significant vascular (both arterial and venous) and non vascular cardiac conditions, (active or within 3 months prior to enrollment), which may include, but are not limited to: • Arterial disease such as cerebral vascular accident/stroke (including Transient Ischemic Attack TIA), myocardial infarction, unstable angina; • Venous diseases such as cerebral venous thrombosis, symptomatic pulmonary embolism; • Non vascular cardiac disease such as 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; or ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 bpm (unless participant is otherwise healthy such as long distance runners, etc.), machine read Electrocardiogram (ECG) with QTc >470 msec, or congenital long QT syndrome.
Participants with predisposing characteristics for acute pancreatitis according to investigator judgment (eg, uncontrolled hyperglycemia, current gallstone disease) 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 including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, and pulmonary fibrosis.
Evidence of active malignancy (other than NSCLC, non melanoma skin cancer, or localized prostate cancer or any in situ cancer which does not currently require treatment) within the last 3 years prior to randomization.
Concurrent use of any of the following food or drugs (consult the sponsor if in doubt whether a food or a drug falls into any of the below categories) within 12 days prior to the first dose of lorlatinib or crizotinib. a. Known strong CYP3A inhibitors (eg, strong CYP3A inhibitors: grapefruit juice or grapefruit/grapefruit related citrus fruits [eg, Seville oranges, pomelos], boceprevir, cobicistat, conivaptan, itraconazole, ketoconazole, posaconazole, ritonavir alone and with danoprevir or elvitegravir or indinavir or lopinavir or paritaprevir or ombitasvir or dasabuvir or saquinavir or tipranavir, telaprevir, troleandomycin, and voriconazole. The topical use of these medications (if applicable), such as 2% ketoconazole cream, is allowed. b. Known CYP3A substrates with narrow therapeutic index, such as astemizole*, terfenadine*, cisapride*, pimozide, quinidine, tacrolimus, cyclosporine, sirolimus, alfentanil, fentanyl (including transdermal patch) or ergot alkaloids (ergotamine, dihydroergotamine) (*withdrawn from US market). c. Known strong CYP3A inducers (eg, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s Wort). d. Known P gp substrates with a narrow therapeutic index (eg, digoxin).
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 participant inappropriate for entry into this study.
Participants who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or participants who are 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.
Pregnant female participants; breastfeeding female participants; fertile male participants and female participants of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 97 days, if male or 35 days if female, after the last dose of investigational product if under lorlatinib or 90 days if under crizotinib.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	16 Oct 2017	1
Czechia	Not Recruiting	16 Oct 2017	1
France	Not Recruiting	16 Oct 2017	6
Germany	Not Recruiting	16 Oct 2017	3
Italy	Not Recruiting	16 Oct 2017	12
The Netherlands	Not Recruiting	16 Oct 2017	—
Poland	Not Recruiting	16 Oct 2017	4
Spain	Not Recruiting	16 Oct 2017	5
Netherlands	—	—	1