Phase 2 and 3 Evaluation of Adagrasib and Pembrolizumab in Advanced NSCLC with KRAS G12C Mutation

The primary objective of this study is to evaluate the **efficacy** of **adagrasib** monotherapy and in combination with **pembrolizumab** in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring the **KRAS G12C mutation**. This is clinically relevant as it aims to determine the potential of adagrasib, alone or in combination, to improve treatment outcomes in a specific genetic subset of NSCLC, which is known for its poor prognosis and limited treatment options. Additionally, the study seeks to compare the efficacy of adagrasib combined with pembrolizumab versus pembrolizumab alone in patients with NSCLC with KRAS G12C mutation and PD-L1 expression ≥ 50%, which could inform treatment strategies for this patient population.

Secondary objectives include:

• Characterizing the safety and tolerability of the monotherapy and combination regimen in the selected population.
• Evaluating secondary efficacy endpoints using monotherapy and the combination regimen.
• Assessing the pharmacokinetics (PK) of adagrasib administered as monotherapy and in combination with pembrolizumab.
• Evaluating health-related quality of life (HRQOL) and lung cancer-specific symptoms in the study population.

The clinical trial involves a total of **419 participants** diagnosed with **Advanced Non-Small Cell Lung Cancer** (NSCLC) with a KRAS G12C mutation. The study population includes both male and female subjects, with an age range encompassing adults and older adults. Participants were selected based on specific inclusion criteria, such as a histologically confirmed diagnosis of NSCLC, the presence of measurable disease per RECIST version 1.1, and a known PD-L1 TPS score. The trial does not include a vulnerable population. Lifestyle factors such as diet and physical activity are not specified in the available data. The selection process ensures that participants are not candidates for definitive therapy, such as chemoradiation for locally advanced disease. The trial aims to evaluate the efficacy of adagrasib monotherapy and in combination with pembrolizumab in the first-line treatment setting for this patient population.

The clinical trial is designed to evaluate the efficacy and safety of **adagrasib** monotherapy and in combination with **pembrolizumab** in patients with advanced non-small cell lung cancer (NSCLC) with KRAS G12C mutation. The trial is structured in two phases: Phase 2 and Phase 3. Phase 2 aims to assess the efficacy of adagrasib as a monotherapy and in combination with pembrolizumab in a first-line treatment setting. Phase 3 is a randomized, double-blind, controlled study comparing the combination of adagrasib and pembrolizumab versus pembrolizumab alone in patients with NSCLC with KRAS G12C mutation and PD-L1 ≥ 50%. The trial is expected to conclude by July 2027, with recruitment having started in December 2020.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically confirmed diagnosis of NSCLC with KRAS G12C mutation and measurable disease per RECIST v1.1. Follow-up visits will be scheduled to monitor the primary endpoints, which include the objective response rate (ORR) for Phase 2 and progression-free survival (PFS) and overall survival (OS) for Phase 3. Secondary endpoints will assess safety, duration of response, pharmacokinetics, and patient-reported outcomes. The end-of-study visit will occur upon completion of the treatment period or if the participant discontinues the study.

The expected length of participant involvement varies, with a maximum treatment period of 24 months for pembrolizumab and an extended period for adagrasib. Conditions that may lead to early termination from the study include adverse events, disease progression, or withdrawal of consent. The trial is conducted under strict adherence to ethical guidelines and regulatory requirements to ensure the safety and well-being of all participants.

The clinical trial involves the administration of **pembrolizumab**, marketed under the name KEYTRUDA, which is a **concentrate for solution for infusion**. This experimental medication is of biological/biotechnological origin and is administered via **intravenous use**. The pharmaceutical form is a solution for infusion, with a concentration of 25 mg/mL. The maximum daily dose is 200 mg, with a total maximum dose of 4800 mg over a treatment period of up to 24 months. Pembrolizumab is a protein-based therapeutic agent, specifically designed to target and modulate immune responses in patients with advanced non-small cell lung cancer (NSCLC) with KRAS G12C mutation.

In addition to pembrolizumab, the trial also includes the administration of **adagrasib**, a chemical entity provided in the form of **film-coated tablets**. Adagrasib is administered orally, with a maximum daily dose of 1200 mg. The total maximum dose is not specified, but the treatment period can extend indefinitely, as indicated by the maximum treatment period of 9999 days. Adagrasib is a targeted therapy designed to inhibit specific molecular pathways associated with the KRAS G12C mutation in NSCLC. The trial evaluates adagrasib both as a monotherapy and in combination with pembrolizumab, comparing its efficacy against pembrolizumab alone in patients with advanced NSCLC.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. In Phase 2, the primary endpoint is the **Objective Response Rate (ORR)**, as defined by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), evaluated by the Investigator. For Phase 3, the dual primary endpoints include **Progression-Free Survival (PFS)**, assessed by Blinded Independent Central Review (BICR), and **Overall Survival (OS)**.

Secondary endpoints for Phase 2 include safety characterized by the type, incidence, severity, timing, seriousness, and relationship to study treatment of adverse events and laboratory abnormalities. Additionally, the **Duration of Response (DOR)**, PFS, 1-Year Survival rate, and OS will be evaluated. Pharmacokinetics (PK) will be assessed by measuring blood plasma concentrations of adagrasib and its potential metabolites. In Phase 3, secondary endpoints include PFS and ORR by both Investigator and BICR, DOR by both Investigator and BICR, safety assessments similar to Phase 2, population PK parameters of adagrasib, and patient-reported outcomes (PRO) to measure quality of life.