Phase 3 Multicenter Trial Comparing Repotrectinib and Crizotinib in TKI-naïve ROS1-positive Advanced Non-Small Cell Lung Cancer

The primary objective of this study is to compare the **Progression Free Survival (PFS)** per Blinded Independent Central Review (BICR) between **repotrectinib** and **crizotinib** in participants with locally advanced or metastatic Tyrosine Kinase Inhibitor (TKI)-naïve ROS1-positive Non-Small Cell Lung Cancer (NSCLC). This objective is clinically relevant as it aims to determine the efficacy of repotrectinib in delaying disease progression compared to crizotinib, which could potentially lead to improved treatment strategies for NSCLC patients.

Secondary objectives include:

• Overall Survival (OS) of repotrectinib and crizotinib.
• Tumor response of repotrectinib and crizotinib.
• PFS per investigator of repotrectinib and crizotinib.
• Time to intracranial progression of repotrectinib and crizotinib.
• Safety of repotrectinib and crizotinib.
• Disease-related symptoms for repotrectinib and crizotinib.

These secondary objectives are crucial for evaluating the comprehensive clinical benefits and safety profile of repotrectinib compared to crizotinib, providing insights into overall survival, tumor response, and management of disease-related symptoms in NSCLC patients.

The clinical trial involves a total of **302 participants** diagnosed with **non-small cell lung cancer (NSCLC)**. 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 locally advanced or metastatic NSCLC and the presence of a ROS1 gene rearrangement/fusion. The trial population includes individuals who have not been previously exposed to tyrosine kinase inhibitors (TKIs) that demonstrate activity in ROS1-positive NSCLC, and up to one prior line of systemic treatment for NSCLC is permitted. The general health status of participants is assessed with an 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 also includes a vulnerable population, although specific lifestyle considerations such as diet or physical activity are not detailed in the provided data.

The clinical trial is a **randomized**, open-label, multicenter, Phase 3 study designed to compare the efficacy of **repotrectinib** versus **crizotinib** in participants with locally advanced or metastatic **tyrosine kinase inhibitor** (TKI)-naïve **ROS1-positive non-small cell lung cancer** (NSCLC). The primary objective is to evaluate the **progression-free survival** (PFS) per Blinded Independent Central Review (BICR) according to RECIST v1.1 criteria. Secondary endpoints include overall survival, objective response rate, duration of response, time to response, and incidence of adverse events, among others. The trial is expected to commence recruitment on November 10, 2023, and conclude by July 25, 2031.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as a histologically or cytologically confirmed diagnosis of NSCLC, presence of a ROS1 gene rearrangement, and an ECOG performance status of ≤ 2. The trial will include multiple follow-up visits to monitor treatment response and safety, with assessments conducted according to RECIST v1.1 guidelines. The end-of-study visit will mark the completion of the participant's involvement in the trial, which is anticipated to last until the study's estimated end date, unless early termination criteria are met.

Participant involvement is expected to last for the duration of the trial, with conditions for early termination including the occurrence of serious adverse events, disease progression, or withdrawal of consent. The trial will utilize oral administration of the investigational products, with **repotrectinib** and **crizotinib** provided in hard capsule form. The maximum daily dose for repotrectinib is 320 mg, while for crizotinib, it is 500 mg. The study aims to provide valuable insights into the comparative effectiveness of these treatments in the specified patient population.

The clinical trial involves the administration of **Repotrectinib (TPX-0005)**, an investigational medication developed by Bristol-Myers Squibb International Corporation. This medication is provided in the form of a hard capsule and is administered orally. The active substance in Repotrectinib is of chemical origin and is classified as an antineoplastic agent and protein kinase inhibitor. The maximum daily dose for Repotrectinib is 320 mg, with a total dose limit of 9999 mg over the treatment period. The dosing schedule is designed to ensure participant compliance, with regular monitoring to assess adherence to the prescribed regimen.

In addition to Repotrectinib, the trial includes the use of **Crizotinib**, marketed under the name XALKORI, which serves as a comparator treatment. Crizotinib is available in two dosages: 250 mg and 200 mg hard capsules, both of which are administered orally. The active substance, Crizotinib, is also of chemical origin and functions as an antineoplastic agent and protein kinase inhibitor. The maximum daily dose for Crizotinib is 500 mg, with a total dose limit of 9999 mg over the treatment period. Participant compliance with Crizotinib administration is similarly monitored to ensure adherence to the treatment protocol.

The efficacy of the clinical trial will be assessed by comparing the **Progression Free Survival (PFS)** of participants treated with repotrectinib versus crizotinib. This primary endpoint will be evaluated per Blinded Independent Central Review (BICR) according to RECIST v1.1 criteria. Secondary endpoints include Overall Survival, Objective Response Rate (ORR), Duration of Response (DOR), and Time to Response (TTR) per BICR and per investigator, also according to RECIST v1.1. Additional secondary endpoints involve PFS per investigator, Time to intracranial progression per BICR, and various safety assessments such as the incidence of Adverse Events (AEs), Serious Adverse Events (SAEs), AEs leading to study intervention discontinuation, drug-related AEs, and deaths. The proportion of participants without meaningful symptom deterioration will be measured using the NSCLC-SAQ total score.