Phase III Multicenter Study Comparing Entrectinib and Crizotinib in Advanced ROS1-Positive Non-Small Cell Lung Cancer with CNS Metastases

The primary objective of this study is to evaluate the **efficacy** of entrectinib compared with crizotinib in patients with ROS1 rearrangement-positive non-small cell lung cancer (NSCLC) with central nervous system (CNS) metastases at baseline. This is clinically relevant as it addresses the treatment efficacy in a specific subset of NSCLC patients who present with CNS involvement, a condition that often complicates treatment and worsens prognosis.

Secondary objectives include: - Evaluating the efficacy of entrectinib compared with crizotinib in the entire study population of patients with ROS1 rearrangement-positive NSCLC. - Assessing the efficacy of entrectinib compared with crizotinib in patients with ROS1 rearrangement-positive NSCLC with CNS metastases at baseline. - Evaluating the safety of entrectinib compared with crizotinib in patients with ROS1 rearrangement-positive NSCLC. - Assessing health status utility scores of patients treated with entrectinib to inform pharmacoeconomic modeling using the EuroQol 5-Dimension Questionnaire (5-level version; EQ-5D-5L) index-based and Visual Analog Scale scores.

The clinical trial involves a total of **115 participants** diagnosed with **non-small cell lung cancer** (NSCLC) characterized by ROS1 gene rearrangements. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific criteria, including a histologically or cytologically confirmed diagnosis of advanced or recurrent NSCLC that is not amenable to radical treatment or is metastatic. The trial includes individuals with measurable systemic disease and CNS metastases, including leptomeningeal carcinomatosis, as per RECIST v1.1 guidelines. Prior treatment with a ROS1 tyrosine kinase inhibitor, chemotherapy, or other systemic therapies for advanced or recurrent NSCLC was not allowed, although prior radiotherapy was permissible if completed more than 14 days before randomization. Participants are required to have a life expectancy of at least 12 weeks. The trial population also includes vulnerable groups, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographics. Lifestyle factors such as diet and physical activity were not specified by the sponsor.

The clinical trial is designed as a **randomized**, open-label, multicenter, Phase III study to evaluate the efficacy and safety of **entrectinib** compared to **crizotinib** in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangements, with and without central nervous system (CNS) metastases. The trial aims to assess progression-free survival (PFS) in patients with CNS metastases at baseline, as well as other secondary endpoints such as overall response rate (ORR), duration of response (DOR), and overall survival (OS). The study is expected to run from December 15, 2021, to December 1, 2027, with a maximum treatment period of 361 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically or cytologically confirmed diagnosis of advanced or recurrent NSCLC with ROS1 gene rearrangement, and no prior treatment with a ROS1 tyrosine kinase inhibitor. Follow-up visits will be scheduled to monitor the participants' response to treatment and any adverse events, using criteria such as RECIST v1.1 for measurable systemic disease and CNS lesions. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any long-term effects of the treatment.

The expected length of participant involvement is up to 361 days, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The trial will adhere to rigorous scientific standards, with endpoints assessed by a blinded independent review committee (BIRC) and investigators, ensuring the reliability and validity of the results. The study will not include pediatric formulations, and all substances used are of chemical origin, administered orally in the form of hard capsules.

The clinical trial involves the administration of two experimental medications: **entrectinib** and **crizotinib**. **Entrectinib** is provided in the form of hard capsules under the brand name Rozlytrek. The active substance, entrectinib, is chemically synthesized and is administered orally. The maximum daily dose for entrectinib is 600 mg, with a total maximum dose of 1516 g over a treatment period of up to 361 days. The pharmaceutical form is consistent across all variations, ensuring uniformity in administration. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

**Crizotinib** is also administered in the form of hard capsules, marketed under the brand name XALKORI. The active substance, crizotinib, is chemically derived and administered orally. The maximum daily dose for crizotinib is 500 mg, with a total maximum dose of 1263 g over a treatment period of up to 361 days. The capsules are re-labeled specifically for clinical trial use to ensure proper identification and compliance. As with entrectinib, participant adherence to the dosing regimen is closely monitored throughout the trial.

Both medications are administered as part of a randomized, open-label, multicenter, Phase III study. The trial aims to evaluate the efficacy of entrectinib compared to crizotinib in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangements, with and without central nervous system metastases. No non-experimental treatments, such as standard-of-care therapy or placebo, are utilized in this study. The trial design ensures that all participants receive one of the two active treatments, allowing for a direct comparison of their therapeutic effects.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is **Progression-Free Survival (PFS)** in patients with Central Nervous System (CNS) metastases at baseline. This is defined as the time from randomization to the first documented disease progression, either extracranial or intracranial, or death from any cause, whichever occurs first. This will be determined by a blinded independent review committee (BIRC) using RECIST v1.1 criteria.

Secondary endpoints include several measures: **CNS Progression-Free Survival (CNS-PFS)**, which tracks the time from randomization to the first documented disease progression in the CNS or death; **Overall Response Rate (ORR)**, which is the percentage of patients achieving complete response (CR) or partial response (PR); and **Duration of Response (DOR)**, which measures the time from the first documented response to disease progression or death. Additionally, **Overall Survival (OS)** is defined as the time from randomization to death from any cause. The impact on functioning and quality of life will be assessed using the EORTC QLQ-C30, focusing on Global Health Status/Quality of Life (GHS/QoL), Physical Functioning (PF), and Role Function (RF) scores. The trial will also evaluate lung cancer-specific symptoms using the EORTC QLQ-LC13.

Other secondary endpoints include **Objective Response Rate in the CNS (CNS-ORR)** and **Duration of Response in the CNS (CNS-DOR)**, both determined by the BIRC per RECIST v1.1. The incidence, type, timing, relatedness, and severity of adverse events will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. Health utility will be evaluated using the EQ-5D-5L and a pharmacoeconomic model. These assessments will provide a comprehensive evaluation of the efficacy of entrectinib compared to crizotinib in patients with ROS1 rearrangement-positive Non-Small Cell Lung Cancer (NSCLC) with CNS metastases at baseline.