Evaluation of Adagrasib Dosing Regimens in Previously Treated KRAS G12C-Mutant Non-Small Cell Lung Cancer Patients

The primary objective of this study is to evaluate the **efficacy** of two dosing regimens of **adagrasib** in patients with non-small cell lung cancer (NSCLC) harboring the KRAS G12C mutation. This evaluation is clinically relevant as it aims to determine the optimal dosing strategy for patients who have previously undergone treatment with a platinum-based regimen and immune checkpoint inhibitor therapy. Understanding the efficacy of these regimens could potentially improve treatment outcomes for this specific patient population.

Secondary objectives include:

• Evaluating secondary efficacy endpoints in the study population.
• Assessing the **safety** and tolerability of adagrasib in the study population.
• Investigating the **pharmacokinetics** (PK) of adagrasib when administered to the study population.
• Evaluating patient-reported symptoms during adagrasib administration.

The clinical trial involves a total of **154 participants** diagnosed with **non-small cell lung cancer** (NSCLC) characterized by the KRAS G12C mutation. The study population includes both male and female subjects, aged 18 years and older, who have previously undergone treatment with a platinum-based chemotherapy regimen and an immune checkpoint inhibitor. Participants are required to have advanced or metastatic NSCLC, indicating that the cancer has originated in the lungs and subsequently spread to other parts of the body. The selection process ensured that individuals had recovered from prior treatments and had blood test results within a safe range. The trial does not specify particular lifestyle considerations such as diet or physical activity. The inclusion of a vulnerable population is noted, although specific details are not provided. The trial aims to assess the efficacy of two dosing regimens of adagrasib, with the study population carefully selected to meet the outlined criteria.

The clinical trial is designed to evaluate the efficacy of two dosing regimens of **adagrasib** in patients with previously treated non-small cell lung cancer (NSCLC) harboring the KRAS G12C mutation. This is a randomized, double-blind, controlled trial, which will assess the administration of adagrasib at 600 mg twice daily without regard to food versus 400 mg twice daily with food. The trial is expected to commence recruitment on November 24, 2023, and is estimated to conclude by May 31, 2027. The primary endpoint is the Objective Response Rate (ORR) using RECIST 1.1 criteria, evaluated by blinded independent central review (BICR). Secondary endpoints include overall survival, progression-free survival, duration of response, safety assessments, and patient-reported outcomes.

Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, previous treatment history, and recovery from prior therapies. Follow-up visits will be scheduled to monitor treatment response, adverse events, and laboratory parameters. The end-of-study visit will occur after the last dose of adagrasib, with a follow-up period extending 28 days post-treatment to assess patient-reported symptoms. The expected length of participant involvement is from the date of randomization until the end-of-study visit, with conditions for early termination including significant adverse events or disease progression as per protocol-defined criteria.

The clinical trial involves the administration of **Adagrasib**, a chemical compound developed by Mirati Therapeutics Inc. Adagrasib is provided in the form of a **film-coated tablet** and is intended for **oral use**. The trial evaluates two dosing regimens: 600 mg administered twice daily (BID) without regard to food, and 400 mg BID taken with food. The maximum daily dose is set at 1200 mg, with no specified maximum treatment period. The active substance in Adagrasib is chemically synthesized and is identified by the chemical name 2-[(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile, also known as MRTX-849.

In this study, Adagrasib is being tested as a monotherapy for patients with previously treated **non-small cell lung cancer** (NSCLC) harboring the KRAS G12C mutation. Participants in the trial have previously received treatment with a platinum-based regimen and immune checkpoint inhibitor therapy. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Compliance with the dosing regimen is monitored throughout the study to ensure adherence to the prescribed treatment protocol.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the **Objective Response Rate (ORR)**, which will be evaluated using RECIST 1.1 criteria and completed per BICR review. This endpoint measures the proportion of subjects experiencing a confirmed complete response (CR) or partial response (PR) from the first dose of adagrasib until the last dose.

Secondary endpoints include Overall Survival (OS), defined as the time from randomization to death from any cause, and Progression-Free Survival (PFS), which is the time from randomization to the first progression per RECIST 1.1 or death from any cause. Duration of Response (DOR) will also be assessed, defined as the time from the first documentation of objective tumor response to the first documentation of either progressive disease (PD) or death. Safety will be evaluated by examining the type, incidence, severity, seriousness, and relationship of adverse events (AEs) to the study treatment, as well as laboratory abnormalities and the number of patients modifying or discontinuing treatment due to AEs.

Additional assessments include Population pharmacokinetic (PK) Model Derived AUC at Steady State (AUCtau,ss), with concentration data pooled from this and other studies to derive exposure parameters using population PK methods. Patient-reported outcomes (PROs) will be collected to assess symptomatic toxicity using the NCI PRO-CTCAE Measurement System, covering the period from the first dose of adagrasib to 28 days after the last dose.