Evaluation of Brigatinib Efficacy in ALK-Positive Non-Small Cell Lung Cancer via Liquid Biopsy: An Exploratory Study

Trial ID: 2024-511317-38-00
Sponsor: Fundacion GECP

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Diseases & Conditions

Non-small cell lung cancer stage IV

Objectives

The primary objective of this study is to evaluate the **Overall Response Rate (ORR)** of brigatinib in patients with **ALK+ non-small cell lung cancer**. The ORR will be assessed according to RECIST V1.1 criteria, which is clinically relevant as it provides a standardized measure of the drug's efficacy in reducing tumor size or achieving complete response. This is crucial for determining the potential of brigatinib as a therapeutic option for this patient population.

Secondary objectives include:

Evaluating the efficacy of brigatinib by assessing the **duration of response (DOR)** and time on treatment, both according to RECIST v1.1.
Assessing the **intracranial overall response rate (ORR)** and intracranial time to progression, which are important for understanding the drug's effect on brain metastases.
Evaluating the **Progression-Free Survival (PFS)** rate at 1 and 2 years, providing insights into the long-term benefits of the treatment.
Assessing the **Overall Survival (OS)** rate at 1 and 2 years, which is a critical endpoint for determining the impact of brigatinib on patient longevity.
Evaluating the safety and tolerability of brigatinib, ensuring that the treatment is not only effective but also safe for patients.

Participants

The clinical trial involves participants diagnosed with **ALK+ non-small cell lung cancer**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a normal QT interval on screening ECG evaluation and adequate hematologic and organ function. The trial does not involve a vulnerable population. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and a life expectancy of at least 3 months. The trial includes individuals with histologically or cytologically confirmed Stage IIIB or IV non-squamous NSCLC, with documented ALK rearrangement, and no prior treatment for Stage IIIB or IV disease. Untreated or treated CNS metastases are allowed if asymptomatic and neurologically stable. Participants must have at least one measurable lesion as defined by RECIST v1.1. The sponsor has not provided information regarding the total number of participants in the trial.

Plans and Procedures

The clinical trial is designed to evaluate the **overall response rate** (ORR) of **brigatinib** in patients with **ALK+ non-small cell lung cancer**. This is a Phase IV, randomized, double-blind, controlled study, with an estimated recruitment start date of February 27, 2024, and an estimated end date of February 26, 2027. The trial will assess the efficacy of brigatinib, administered as 30 mg film-coated tablets, with a maximum daily dose of 180 mg, taken orally. The primary endpoint is the overall response rate, while secondary endpoints include the duration of response, intracranial overall response rate, progression-free survival (PFS) rate at 1 and 2 years, overall survival (OS) rate at 1 and 2 years, and the safety and tolerability of brigatinib.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, **ECOG performance status**, and documented ALK rearrangement. The trial will include follow-up visits to monitor response and safety, with assessments conducted per RECIST V1.1 criteria. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 30 days, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include non-compliance with study procedures, adverse events, or withdrawal of consent.

Treatment

The clinical trial involves the administration of **Alunbrig** 30 mg film-coated tablets, which contain the active substance **brigatinib**. Brigatinib is a chemical compound classified under the ATC code L01XE43. The pharmaceutical form of the medication is a film-coated tablet, designed for **oral use**. The maximum daily dose of brigatinib is 180 mg, with a total maximum dose of 180 mg over a treatment period of 30 days. The medication is manufactured by Takeda Pharma A/S and is not a pediatric formulation. The trial aims to evaluate the overall response rate of brigatinib in patients with non-small cell lung cancer with EML4-ALK translocation, as assessed by RECIST V1.1 criteria.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The focus is solely on the administration of brigatinib to assess its clinical utility. Participant compliance with the dosing schedule will be monitored to ensure adherence to the prescribed regimen. The trial does not involve any additional medicinal products or devices, and the treatment is not classified as an orphan drug. The study is exploratory in nature, aiming to provide insights into the effectiveness of brigatinib in the specified patient population.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the **Overall Response Rate (ORR)** of brigatinib, as measured by investigators using the RECIST V1.1 criteria. This criterion is a standardized set of guidelines for evaluating changes in tumor size and response to treatment in solid tumors. The primary endpoint is the ORR, which will provide a measure of the proportion of patients who experience a predefined level of tumor size reduction.

Secondary endpoints include the **Duration of Response (DOR)**, **Intracranial Overall Response Rate**, **Progression-Free Survival (PFS) rate at 1 year and 2 years**, and **Overall Survival (OS) rate at 1 year and 2 years**. These endpoints will offer additional insights into the long-term efficacy and impact of brigatinib on patient outcomes. The safety and tolerability of brigatinib will also be evaluated as part of the secondary endpoints.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female, aged equal or greater ≥18 years old
ECOG performance status of 0-2
Histologically or cytologically confirmed, Stage IIIB or IV NSCLC
Patients who have documented locally ALK rearrangement
No prior treatment for Stage IIIB or IV non-squamous NSCLC.
Having a life expectancy ≥ 3 months
Patients who have received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy, or chemo-radiotherapy with curative intent for non-metastatic disease must have experienced a treatment-free interval of at least 6 months from enrollment since the last chemotherapy, radiotherapy, or chemo-radiotherapy.
Untreated or treated CNS metastases allowed, as long as asymptomatic and neurologically stable
Patients with at least 1 measurable lesion, as defined by RECIST v1.1
Normal QT interval (QT) on screening ECG evaluation, defined as QT interval corrected (Fridericia) (QTcF) of ≤ 450 milliseconds (msec) in males of ≤ 470 msec in females
Adequate hematologic and organ function
All patients are notified of the investigational nature of this study and signed a written informed consent in accordance with institutional and national guidelines, including the Declaration of Helsinki prior to any trial-related intervention.
Willingness and ability to comply with scheduled visits and study procedures
For female patients of childbearing potential, a negative pregnancy test must have been documented prior to enrollment (within 14 days prior to enrollment)

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Exclusion Criteria

Patients with a known sensitizing mutation in the epidermal growth factor receptor (EGFR) gene, STK-1 Ligand alteration, MDM2 amplification or ROS1 translocations.
Patients that received any prior TKI, including ALK-targeted TKIs or any systemic anticancer therapy for locally advanced or metastasic disease
Patients that have received chemotherapy or radiation within 14 days of first dose of study drug.
Symptomatic CNS metastases (parenchymal or leptomeningeal) that are neurologically unstable or required an increasing dose of corticosteroids within 7 days prior to first dose of study drug
Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). Patients with leptomeningeal disease and without cord compression is allowed.
Malignancies other than NSCLC within 3 years prior to enrollment
Women who are pregnant, lactating, or intending to become pregnant during the study
Patients that received monoclonal antibodies or had major surgery within 30 days of the first dose of brigatinib
History of idiopathic pulmonary fibrosis, pulmonary interstitial disease, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
Have uncontrolled hypertension
Positive test for HIV. A and patients with active hepatitis B or active tuberculosis
Severe infections within 2 weeks prior to be included in the study
Have significant, uncontrolled or active cardiovascular disease
Patients with illnesses or conditions that interfere with their capacity to understand follow and/or comply with study procedures