Efficacy Comparison of Brigatinib Versus Second-Generation TKIs in First-Line Treatment of Locally Advanced or Metastatic ALK-Positive NSCLC
- Trial ID
- 2024-513947-94-00
- Protocol
- ABP-2019
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **efficacy** of brigatinib as a first-line treatment to that of any other second-generation tyrosine kinase inhibitor (TKI) in patients with locally advanced or metastatic anaplastic lymphoma kinase positive non-small cell lung cancer (ALK+ NSCLC). This is assessed by progression-free survival (PFS) using RECIST v1.1 criteria. The clinical relevance of this objective lies in determining the most effective first-line treatment option for ALK+ NSCLC, potentially improving patient outcomes by delaying disease progression.
Secondary objectives include:
- Evaluating progression-free survival (PFS) in second-line treatment.
- Comparing the efficacy of brigatinib in first-line use to other TKIs based on time to next treatment (TNT) in both first and second lines, and overall survival.
- Assessing efficacy in the central nervous system (CNS) using RECIST v1.1 criteria.
- Evaluating patient-reported quality of life (QoL) using SF-12 and EORTC-QLQ-BN20.
- Assessing the safety and tolerability of brigatinib compared to other TKIs.
- Exploratory objectives include typing of ALK fusion variants, assessing TP53 mutation status, detecting acquired resistance mutations via next-generation sequencing, exploring treatment efficacy according to ALK fusion variant and TP53 status, and examining molecular resistance patterns after first-line failure. Additionally, the impact of second-line treatment after first-line failure and the clinical utility of cerebrospinal fluid ctDNA analysis in brain-only progression are explored.
Participants
The clinical trial involves participants diagnosed with **locally advanced (stage III) and not suitable for curative treatment, or metastatic (stage IV) ALK+ non-small cell lung cancer (NSCLC)**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria include histologically confirmed ALK+ NSCLC, with no prior therapy for metastatic ALK+ NSCLC, except for limited chemotherapy or immunotherapy. Participants must have adequate organ function and at least one measurable lesion per RECIST v1.1. The trial population was selected based on their willingness and ability to comply with scheduled visits and study procedures, as well as their consent to participate in accompanying research programs. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **brigatinib** in the first-line treatment of patients with locally advanced or metastatic anaplastic lymphoma kinase positive non-small cell lung cancer (ALK+ NSCLC). This is a randomized, double-blind, controlled trial comparing brigatinib to other second-generation tyrosine kinase inhibitors (TKIs). The trial is expected to last until January 16, 2026, with recruitment having started on June 16, 2020, and ending on May 16, 2023. The trial involves multiple study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, performance status, and organ function. Participants will undergo regular follow-up visits to monitor treatment efficacy and safety, with assessments based on RECIST v1.1 criteria. The end-of-study visit will conclude the participant's involvement, which is anticipated to last up to 68 weeks, depending on individual response and tolerance to the treatment.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The primary endpoint is progression-free survival (PFS) during first-line treatment, while secondary endpoints include PFS during second-line treatment, overall survival, and quality of life assessments. Safety and tolerability will be evaluated through the incidence and severity of adverse events. Exploratory endpoints will investigate molecular resistance patterns and the efficacy of treatment according to ALK fusion variant and TP53 status. The trial aims to provide comprehensive data on the comparative effectiveness of brigatinib and other TKIs in this patient population.
Treatment
The clinical trial involves the administration of **Alunbrig** (brigatinib) as the experimental medication. Alunbrig is provided in the form of film-coated tablets, each containing 30 mg of the active substance **brigatinib**. The medication is administered orally with a maximum daily dose of 180 mg. The treatment period is set for a maximum of 68 weeks. The primary packaging consists of round wide mouth high-density polyethylene (HDPE) bottles with child-resistant screw cap closures, and the tablets are labeled specifically for the study. Participant compliance is monitored throughout the trial to ensure adherence to the dosing schedule.
In addition to the experimental treatment, the study includes the use of **Zykadia** (ceritinib) as a comparator treatment. Zykadia is available in the form of hard capsules, each containing 150 mg of the active substance **ceritinib**. The administration route is oral, with a maximum daily dose of 450 mg. The treatment duration is also up to 68 weeks. The comparator treatment is used to evaluate the efficacy of brigatinib against another second-generation tyrosine kinase inhibitor (TKI) in patients with locally advanced or metastatic anaplastic lymphoma kinase positive non-small cell lung cancer (ALK+ NSCLC).
Another comparator treatment in the study is **Alectinib**, provided in the form of hard capsules. The active substance **alectinib** is administered orally with a maximum daily dose of 1200 mg. The treatment period for alectinib is consistent with the other treatments, lasting up to 68 weeks. The inclusion of alectinib as a comparator allows for a comprehensive assessment of brigatinib's efficacy in comparison to other available second-generation TKIs.
Efficacy
The efficacy of the clinical trial will be assessed by comparing the efficacy of **brigatinib** in the first-line use to that of any other second-generation tyrosine kinase inhibitor (TKI) in patients with locally advanced or metastatic anaplastic lymphoma kinase positive non-small cell lung cancer (ALK+ NSCLC). The primary endpoint for evaluating efficacy is the progression-free survival (PFS) of the first-line treatment, assessed by applying RECIST v1.1 criteria. Secondary endpoints include PFS for the second-line treatment, time-to-next treatment (TNT) for both first and second lines, overall survival (OS), and efficacy in the central nervous system (CNS) using RECIST v1.1 criteria. Quality of life (QoL) will be assessed with SF-12 and EORTC-QLQ-BN20 instruments.
Exploratory endpoints will capture ALK fusion variants, TP53 mutation status, and acquired resistance mutations via standardized NGS-based multiplex analysis. The efficacy of treatment according to ALK fusion variant and TP53 status, molecular resistance patterns after first-line failure, and the impact of second-line treatment after first-line failure will also be explored. Additionally, the clinical utility of cerebrospinal fluid ctDNA analysis in "brain-only" progression will be evaluated. The trial is designed to provide comprehensive insights into the efficacy of brigatinib and other TKIs in treating ALK+ NSCLC, with assessments scheduled throughout the treatment period.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Fully informed written consent and any locally-required authorization (EU Data Privacy Directive) given by the patien
- Male or female ≥ 18 years of age
- Histologically confirmed locally advanced (stage III) and not suitable for curative treatment, i.e. R0 operation or definitive chemo-/radiation, or metastatic (stage IV) ALK+ NSCLC NOTE: Documentation of ALK rearrangement by a positive result of any ALK assay approved in Germany [i.e. positivity for at least one of the three: immunohistochemistry (IHC), NGS, fluorescence in situ hybridisation (FISH)] must be available at baseline. Treatment can already be started based on a local ALK+ test result, but subsequent central testing of the baseline biopsy for molecular profiling, incl. determination of ALK variant and TP53 status, should be made possible for all patients.
- No prior therapy for metastatic ALK+ NSCLC including therapy with ALK inhibitors. However, 1 or 2 cycles of chemotherapy, chemo-immunotherapy or immunotherapy as well as cerebral irradiation before inclusion in the study will be allowed.
- At least 1 measurable (i.e., target) lesion per RECIST v1.1 or otherwise evaluable lesion (e.g. brain lesion with at least 5 mm of longest diameter if measured by high-resolution cMRT e.g. using 1 mm slices thickness and not planned for irradiation before the first response assessment).
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
- Have adequate organ function, as determined by: • Total bilirubin ≤1.5x the upper limit of the normal range (ULN) (< 3x the ULN if Gilbert’s disease is present) • Estimated glomerular filtration rate ≥30 mL/minute/1.73 m2 (calculated by MDRD or any other validated formula, see Appendix 13.4) • Alanine aminotransferase/aspartate aminotransferase ≤2.5x ULN NOTE: ≤5x ULN is acceptable if liver metastases are present. • Serum lipase or serum amylase ≤1.5x ULN • Platelet count ≥75x 109/L • Hemoglobin ≥9 g/dL • Absolute neutrophil count ≥1.5x 109/L
- Willingness and ability to comply with scheduled visit and study procedures
- Patient willing to participate in accompanying research program
- Collection of current biopsy during screening must be feasible
- Women of childbearing potential (WOCBP) must have a negative pregnancy test within 7 days prior to randomization. Women must not be breastfeeding.
- Female patients who: - are postmenopausal for at least 1 year before the screening visit, OR - are surgically sterile, OR - if they are of childbearing potential, agree to practice highly effective non-hormonal contraception from the time of signing the informed consent through at least 4 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse. Male patients, even if surgically sterilized (i.e., status post-vasectomy), who: - agree to practice effective barrier contraception during the entire study treatment period and through at least 3 months after the last dose of study drug, OR - agree to completely abstain from heterosexual intercourse.
Exclusion Criteria
- History or presence at baseline of pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis
- Uncontrolled hypertension, defined as hypertension treated* with anti-hypertensive drugs AND blood pressure ≥ 160 mmHg (systolic) or ≥ 100 mmHg (diastolic) in repeated measurements. Untreated elevated blood pressure is not an exclusion criterion and should receive adequate anti-hypertensive adjustment. *Please note: In case of treatment, at least 3 anti-hypertensive drugs should have been used with the intention to control hypertensive disease
- Systemic treatment with strong cytochrome P-450 (CYP) 3A inhibitors, strong CYP3A inducers, or moderate CYP3A inducers or treatment with any investigational systemic anticancer agents, chemotherapy or radiation therapy (except for stereotactic radiosurgery or stereotactic radiation therapy or palliative radiotherapy) within 14 days of randomization
- Treatment with antineoplastic monoclonal antibodies within 30 days of randomization
- Major surgery within 30 days of randomization. Minor surgical procedures, such as catheter placement or minimally invasive biopsies, are allowed.
- Current symptomatic spinal cord compression as confirmed by radiographic imaging. Patients with leptomeningeal disease without symptomatic cord compression are allowed.
- Significant or uncontrolled cardiovascular disease, defined as to the following: • If an acute myocardial infarction has ensued in the past 6 months, successful reperfusion has to be documented and the patient has to be free of symptoms • New York Heart Association Class III or IV heart failure (i.e. marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. walking short distances (20-100 m; comfortable only at rest) within 6 months prior to randomization • Any history of clinically significant ventricular arrhythmia, defined as ventricular tachycardia (VT), ventricular fibrillation (VF), or cardiac arrest
- Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose of study drug
- Malabsorption syndrome or other gastrointestinal illness or condition that could affect oral absorption of the study drug
- Active severe or uncontrolled chronic infection, including but not limited to, the requirement for intravenous antibiotics for longer than 2 weeks
- History of HIV infection. Testing is not required in the absence of history.
- Chronic hepatitis B (surface antigen-positive) or chronic active hepatitis C infection. Testing is not required in the absence of history.
- Any serious medical condition or psychiatric illness that could, in the investigator’s opinion, potentially compromise patient safety or interfere with the completion of treatment according to this protocol
- Known or suspected hypersensitivity to brigatinib or other TKI or their excipients
- Life-threatening illness unrelated to cancer
- Involvement in the planning and/or conduct of the study (applies to both Takeda staff and/or staff of sponsor and study site)
- Patient who might be dependent on the sponsor, site or the investigator
- Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities [in accordance with national regulations]
- Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [in accordance with national regulations]
- Legal incapacity or limited legal capacity
- Females who are pregnant or breastfeeding
- Patients who have symptomatic CNS metastases (parenchymal or leptomeningeal) at screening or asymptomatic disease requiring an increasing dose of corticosteroids to control symptoms within 7 days prior to randomization. NOTE: If a patient has worsening neurological symptoms or signs due to CNS metastasis, the patient needs to complete local therapy and be neurologically stable (with no requirement for an increasing dose of corticosteroids or use of anticonvulsants) for 7 days prior to randomization.
- Rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 16 Dec 2019 | 118 |
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 |
|---|---|---|---|---|---|---|
Alunbrig 30 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 180 | 68 | PRD6827999 |
CRIZOTINIB | Comparator | — | ORAL | 500 | 68 | SUB32267 |
LORLATINIB | Comparator | — | ORAL | 100 | 68 | SUB181272 |
Zykadia 150 mg hard capsules | Comparator | HARD CAPSULES | ORAL | 450 | 68 | PRD11417165 |
ALECTINIB | Comparator | — | ORAL | 1200 | 68 | SUB178557 |