Phase 1/2 Evaluation of Zidesamtinib (NVL-520) in Advanced ROS1-Positive NSCLC and Solid Tumors

The primary objective of this study is to determine the recommended Phase 2 dose (**RP2D**) and, if applicable, the maximum tolerated dose (**MTD**) of **NVL-520** in patients with advanced **ROS1-positive** solid tumors during Phase 1. In Phase 2, the study aims to evaluate the objective response rate (**ORR**) of NVL-520 at the RP2D in patients with advanced ROS1-positive non-small cell lung cancer (**NSCLC**). These objectives are clinically relevant as they aim to establish the optimal dosing regimen and assess the therapeutic efficacy of NVL-520, a highly selective **ROS1** inhibitor, in targeting advanced ROS1-positive malignancies.

Secondary objectives include: Phase 1 - evaluating the overall safety and tolerability of NVL-520, characterizing its pharmacokinetic (**PK**) profile, and assessing preliminary antitumor activity in patients with advanced ROS1-positive solid tumors. Phase 2 - assessing additional measures of clinical efficacy in patients with ROS1-positive NSCLC, evaluating clinical efficacy in patients with non-NSCLC ROS1-positive solid tumors, and evaluating the intracranial antitumor activity of NVL-520 at the RP2D in patients with advanced ROS1-positive NSCLC and other solid tumors. Additionally, the study aims to characterize the safety and tolerability of NVL-520 at the RP2D, confirm its PK profile, and assess treatment-related symptoms and general health status using validated instruments of patient-reported outcomes (**PROs**) in patients treated with NVL-520.

The clinical trial involves a total of **294 participants** diagnosed with **advanced ROS1-positive non-small cell lung cancer (NSCLC)** and other advanced ROS1-positive solid tumors. The study population includes both male and female subjects, with an age range starting from 18 years and above, and for a specific cohort, participants aged 12 years and weighing more than 40 kg are included. Participants were selected based on histologically or cytologically confirmed locally advanced or metastatic solid tumors with documented ROS1 rearrangement. The trial includes a vulnerable population, indicating that special considerations are in place for their participation. The health status of participants is characterized by the presence of advanced ROS1-positive solid tumors, and they must have either evaluable or measurable disease according to RECIST 1.1 criteria. 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 and safety of **zidesamtinib**, a highly selective ROS1 inhibitor, in patients with advanced ROS1-positive non-small cell lung cancer (NSCLC) and other solid tumors. This study is structured as a Phase 1/2 trial, incorporating a randomized, double-blind, and controlled methodology to ensure robust and unbiased results. The trial is expected to span from September 2021 to October 2026, providing a comprehensive assessment of the investigational product over a significant period.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease status, and prior treatment history. The primary objective in Phase 1 is to determine the recommended Phase 2 dose (RP2D) and, if applicable, the maximum tolerated dose (MTD) of NVL-520. In Phase 2, the focus shifts to evaluating the overall response rate (ORR) at the RP2D in patients with advanced ROS1-positive NSCLC. Follow-up visits will be scheduled to monitor safety, pharmacokinetics, and pharmacodynamics, as well as to assess treatment-emergent adverse events (TEAEs) and changes in laboratory parameters. The end-of-study visit will conclude the participant's involvement, summarizing the overall safety profile and preliminary efficacy of the treatment.

Participant involvement is anticipated to last until the completion of the trial or until specific conditions necessitate early termination, such as the occurrence of dose-limiting toxicities (DLTs) or significant adverse events. The trial's design ensures that all data collected will contribute to a comprehensive understanding of the investigational product's potential benefits and risks, ultimately guiding future therapeutic strategies for patients with advanced ROS1-positive solid tumors.

The clinical trial involves the administration of the experimental medication **NVL-520**, which is a highly selective **ROS1 inhibitor**. The active substance in NVL-520 is **zidesamtinib**, a chemical compound developed by Nuvalent Inc. The pharmaceutical form of NVL-520 is a tablet, and it is administered orally. The specific dosage, frequency of administration, and maximum tolerated dose (MTD) are determined during the trial, with the aim of establishing the recommended Phase 2 dose (RP2D) for patients with advanced ROS1-positive solid tumors, including non-small cell lung cancer (NSCLC).

In this study, NVL-520 is the primary investigational product, and no additional non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial focuses on evaluating the objective response rate (ORR) of NVL-520 at the RP2D in patients with advanced ROS1-positive NSCLC. Participant compliance with the dosing schedule is monitored throughout the study to ensure accurate assessment of the drug's efficacy and safety profile.

Efficacy in the clinical trial of NVL-520, a highly selective ROS1 inhibitor, will be assessed through specific primary and secondary endpoints. In Phase 1, the primary endpoint is to determine the recommended Phase 2 dose (RP2D) and, if applicable, the maximum tolerated dose (MTD) based on the incidence of dose-limiting toxicities (DLTs) during Cycle 1, overall safety profile, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy. In Phase 2, the primary endpoint is the objective response rate (ORR) as per RECIST 1.1 criteria in patients with advanced ROS1-positive non-small cell lung cancer (NSCLC).

Secondary endpoints include the incidence and severity of treatment-emergent adverse events (TEAEs) and changes in clinically relevant laboratory parameters. Pharmacokinetic parameters of NVL-520 will also be evaluated, including maximum plasma concentration (Cmax), dose-normalized Cmax, plasma concentration at the end of the dosing interval (Ctau), average plasma concentration (Cavg), and time of maximum concentration (Tmax). These assessments will be conducted using validated scales and laboratory tests at specified timepoints throughout the trial. The trial is designed to provide comprehensive data on the efficacy and safety of NVL-520 in patients with advanced ROS1-positive solid tumors.