Phase 3 Randomized Study of Adagrasib Versus Docetaxel in Previously Treated Advanced Non-Small Cell Lung Cancer with KRAS G12C Mutation

The primary objective of this Phase 3 study is to evaluate the **efficacy** of the investigational agent MRTX849, also known as Adagrasib, compared to docetaxel in patients with previously treated metastatic **non-small cell lung cancer** (NSCLC) harboring a KRAS G12C mutation. This objective is clinically relevant as it aims to determine the potential of MRTX849 to improve treatment outcomes in a patient population with limited therapeutic options.

Secondary objectives include:

• Evaluating secondary efficacy endpoints in the study population.
• Assessing the **safety** and tolerability of the treatments.
• Investigating the **pharmacokinetics** of MRTX849 when administered to the study population.
• Evaluating health-related quality of life and cancer-specific symptoms in the study population.

The clinical trial involves a total of **90 participants** diagnosed with **Advanced Non-Small Cell Lung Cancer** (NSCLC) characterized by a KRAS G12C mutation. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on a histologically or cytologically confirmed diagnosis of NSCLC with the specified mutation and their candidacy to receive treatment with docetaxel. The trial does not include a vulnerable population. Participants' general health status is indicated by an ECOG performance status of 0 to 2, suggesting they are ambulatory and capable of self-care. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data. The selection criteria ensure that the study population is appropriate for evaluating the efficacy of the investigational agent MRTX849 compared to docetaxel in this specific patient group.

The clinical trial is a **randomized**, **double-blind**, controlled Phase 3 study designed to evaluate the efficacy of the investigational agent **adagrasib** compared to **docetaxel** in patients with previously treated **advanced non-small cell lung cancer** (NSCLC) harboring a **KRAS G12C mutation**. The trial aims to assess progression-free survival (PFS) as the primary endpoint, with secondary endpoints including overall survival (OS), objective response rate (ORR), duration of response (DOR), and 1-year survival rate. Safety will be characterized by the type, incidence, severity, timing, seriousness, and relationship to study treatment of adverse events (AEs), laboratory abnormalities, and the number of patients discontinuing study treatment due to an adverse event. The study will also evaluate population pharmacokinetic (PK) parameters of adagrasib and patient-reported outcomes (PRO) using the Lung Cancer Symptom Scale (LCSS) and the European Quality of Life Five Dimensions Questionnaire (EQ-5D-5L).

The trial is expected to last until December 31, 2024, with recruitment having started on February 1, 2021. Participants will be involved in the study for the duration of their treatment period, which is determined by the progression of their disease or the occurrence of unacceptable toxicity. The study includes an initial screening visit to confirm eligibility based on criteria such as a histologically or cytologically confirmed diagnosis of NSCLC with a KRAS G12C mutation and candidacy to receive treatment with docetaxel. Follow-up visits will be conducted to monitor the participants' response to treatment and any adverse events. The end-of-study visit will occur after the completion of the treatment period or upon early termination from the study.

Participants may be withdrawn from the study early if they experience disease progression, unacceptable toxicity, or if they choose to withdraw consent. Additionally, evidence of RECIST 1.1 defined disease progression on docetaxel per blinded independent central review (BICR) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 are criteria for crossover inclusion. The trial is not categorized as low intervention and is conducted under the sponsorship of Mirati Therapeutics Inc. and Sanofi Winthrop Industrie, with adagrasib administered orally as a film-coated tablet and docetaxel administered intravenously as a solution for infusion.

The clinical trial involves the administration of **Adagrasib**, an investigational medication, in the form of a **film-coated tablet**. The active substance in Adagrasib is a chemical entity known as **adagrasib**, also referred to by its sponsor product code **MRTX849**. The tablets are administered **orally** with a maximum daily dose of **1200 mg**. The treatment period is not explicitly limited, allowing for a maximum total dose of **9999 mg**. Adagrasib is developed by Mirati Therapeutics Inc. and is not a pediatric formulation. Participant compliance with the dosing schedule will be monitored throughout the study.

The comparator treatment in this study is **TAXOTERE**, which contains the active substance **docetaxel**. TAXOTERE is provided as a **concentrate and solvent for solution for infusion**. The administration route is **intravenous**, with a maximum daily dose of **75 mg/m²**. Similar to Adagrasib, the treatment period for TAXOTERE is not explicitly limited, with a maximum total dose of **9999 mg/m²**. TAXOTERE is manufactured by Sanofi Winthrop Industrie and is also not a pediatric formulation. The administration of TAXOTERE will follow standard infusion protocols, and participant adherence to the treatment regimen will be closely monitored.

The efficacy of the investigational agent **MRTX849** (Adagrasib) will be assessed in a randomized Phase 3 clinical trial comparing it to docetaxel in patients with previously treated metastatic non-small cell lung cancer (NSCLC) harboring a KRAS G12C mutation. The primary endpoint for evaluating efficacy is **Progression-free Survival (PFS)**, defined as the time from randomization until disease progression or death from any cause, whichever occurs first. Secondary efficacy endpoints include **Overall Survival (OS)**, **Objective Response Rate (ORR)**, **Duration of Response (DOR)**, and the **1-Year Survival Rate**.

Additional assessments will include safety characterization through the type, incidence, severity, timing, seriousness, and relationship to study treatment of adverse events (AEs), laboratory abnormalities, and the number of patients discontinuing study treatment due to an adverse event. Population pharmacokinetic (PK) parameters of MRTX849 will also be evaluated. Patient-reported outcomes (PROs) will be measured using the Lung Cancer Symptom Scale (LCSS) and the European Quality of Life Five Dimensions Questionnaire (EQ-5D-5L). These efficacy parameters will be collected and analyzed at specified timepoints throughout the study to determine the comparative effectiveness of MRTX849 versus docetaxel in this patient population.