Therapeutic Drug Monitoring-Guided Versus Standard Dosing of Alectinib in ALK-Positive Non-Small Cell Lung Cancer Patients

The primary objective of this study is to evaluate the **prolonged median progression-free survival (mPFS)** for the cohort receiving Therapeutic Drug Monitoring (TDM)-guided dosing of alectinib compared to the standard fixed dosing cohort. This is specifically assessed in patients with an alectinib minimum concentration (Cmin) below the threshold of 435 ng/mL. This objective is clinically relevant as it aims to optimize treatment efficacy in patients with ALK-positive non-small cell lung cancer by potentially extending the duration of disease control.

Secondary objectives include evaluating the following:

• Functioning and safety of TDM
• Overall response rates (ORR)
• Median overall survival (mOS)
• Intracranial progression-free survival (PFS)
• Physician adherence to the dosing protocol
• Toxicity, particularly in relation to alectinib plasma concentrations and dose increases
• Quality of life
• Cost-effectiveness of the treatment approach
• Alectinib M4-concentrations

These secondary objectives are crucial for understanding the broader impact of TDM-guided dosing on patient outcomes, safety, and healthcare resource utilization.

The clinical trial involves participants diagnosed with **ALK positive non-small cell lung cancer** (NSCLC), specifically those with locally advanced or metastatic stages (IIIB to IV) as per the AJCC 8th edition. The study population includes both male and female subjects aged 18 years and older, with an **ECOG Performance Status** ranging from 0 to 4. Participants must have histologically or cytologically confirmed NSCLC with documented ALK rearrangement based on an EMA-approved test. The trial allows for individuals who are either chemotherapy-naïve or have undergone one line of platinum-based chemotherapy. Additionally, patients with asymptomatic brain or leptomeningeal metastases that are clinically stable for at least two weeks without steroid treatment are eligible. The study does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants' lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **alectinib** in patients with **ALK positive non-small cell lung cancer**. This study employs a randomized, double-blind, controlled design to compare standard dosing of alectinib with a therapeutic drug monitoring (TDM) guided dosing approach. The primary objective is to assess whether TDM-guided dosing can prolong median progression-free survival (mPFS) in patients with alectinib minimum concentration (Cmin) below 435 ng/mL compared to a fixed dosing regimen. The trial is expected to run from March 23, 2022, to December 31, 2025, with recruitment having commenced on March 23, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and documented ALK rearrangement. Following randomization, participants will attend regular follow-up visits to monitor drug levels, assess response to treatment, and evaluate safety and tolerability. The end-of-study visit will occur upon completion of the treatment period or earlier if the participant experiences disease progression or unacceptable toxicity. The expected duration of participant involvement is up to 600 days, although early termination may occur due to adverse events, withdrawal of consent, or protocol non-compliance.

Key elements of the research methodology include the measurement of primary and secondary endpoints. The primary endpoint is the increase in progression-free survival according to RECIST v1.1 criteria. Secondary endpoints encompass feasibility and safety of TDM, overall response rates, median overall survival, intracranial progression-free survival, patient adherence, and quality of life assessments. The study will also evaluate the cost-effectiveness of the TDM approach and measure alectinib-M4 concentrations in plasma samples. Participants will be monitored for toxicity related to plasma concentration and dose increases, with adverse events being documented and analyzed.

The clinical trial involves the administration of **Alectinib**, marketed under the name Alecensa, in the form of 150 mg hard capsules. Alectinib is a chemical substance used as the active ingredient in this investigational product. The pharmaceutical form of the medication is a hard capsule, designed for oral administration. The maximum daily dose of Alectinib is set at 1800 mg, with a total maximum dose of 32,850,000 mg over the course of the treatment period. The treatment period is defined as a maximum of 600 days. The administration of Alectinib is conducted orally, and the dosing schedule is determined based on either standard fixed dosing or Therapeutic Drug Monitoring (TDM) guided dosing, as per the trial's protocol. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the prescribed treatment plan.

In this clinical trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the efficacy and safety of Alectinib in the specified dosing regimens. The trial aims to assess the primary objective of prolonging median progression-free survival (mPFS) in the TDM-guided dosing cohort compared to the standard fixed dosing cohort, specifically in patients with an Alectinib minimum concentration (Cmin) below the threshold of 435 ng/mL. The study is conducted under the authorization of the relevant regulatory bodies, with the product being authorized for use in the Netherlands. The trial is sponsored by Roche Registration GmbH, and the product is not classified as an orphan drug or a pediatric formulation.

Efficacy in the clinical trial titled "Standard dosed alectinib versus Therapeutic Drug Monitoring guided alectinib dosing: The Adapt Alec trial" will be assessed primarily through the measurement of **progression-free survival (PFS)**. The main endpoint is an increase in PFS, evaluated according to RECIST v1.1 criteria, in subgroups of patients with an alectinib Cmin threshold of less than 435 ng/mL in the TDM-guided dosing cohort compared to the same subgroup in the fixed dosing cohort. Secondary endpoints include the feasibility and safety of TDM, overall response rates (ORR), median overall survival (mOS), intracranial PFS, patient adherence, toxicity related to plasma concentration and dose increases, quality of life (QoL), cost-effectiveness, and alectinib-M4 concentrations.

Feasibility and safety of TDM will be measured by the percentage of successful TDM measures, defined as target attainment with manageable toxicity. Physician adherence to TDM advice will be assessed by the percentage of dose recommendations implemented by treating physicians. ORR will be defined as the percentage of partial or complete responses according to RECIST v1.1. mOS will be calculated from randomization to death from any cause, with patients who do not die or are lost to follow-up being censored at their last available date. Intracranial PFS will be measured from the start of treatment to progressive disease in the brain or death from any cause, with similar censoring criteria. Patient adherence will be estimated through pill counts and patient diaries. Toxicity will be evaluated in subgroups with Cmin below and above 435 ng/mL, and in patients with or without PK-guided dose increases. QoL will be assessed using the EORTC QLQ_LC13, QLQ-C30, and EQ-5D-5L questionnaires. Cost-effectiveness will be determined by the incremental cost-effectiveness ratio based on costs and quality-adjusted life-years (QALYs). Alectinib-M4 concentrations will be measured in plasma samples.