Phase 3 Randomized Trial of Adagrasib, Pembrolizumab, and Chemotherapy in KRAS G12C Mutant Advanced Non-Squamous NSCLC

The primary objective of this randomized, double-blind, Phase 3 trial is to evaluate the potential added benefit of **Adagrasib** when combined with the current standard of care treatment in patients with previously untreated, locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) harboring a **KRAS G12C mutation**. This objective is clinically relevant as it aims to improve treatment outcomes in a specific subset of lung cancer patients who have limited therapeutic options due to the presence of this mutation.

Secondary objectives include assessing further efficacy, safety, and the effects on quality of life. These evaluations are crucial for understanding the comprehensive impact of the treatment regimen on patient health and well-being, beyond the primary efficacy endpoints.

The clinical trial involves a total of **373 participants** diagnosed with **Locally Advanced or Metastatic Non-small Cell Lung Cancer**. The study population includes both male and female subjects, with an age range encompassing adults and older adults. Participants were selected based on specific criteria, including a histologically or cytologically confirmed diagnosis of non-squamous NSCLC, measurable disease via CT or MRI, and no prior systemic anti-cancer therapy for advanced or metastatic disease. The trial does not include a vulnerable population. Lifestyle considerations such as diet, physical activity, or habits are not specified. Key inclusion criteria allow for participants with brain metastases, provided they are asymptomatic and not in need of immediate local therapy. The trial aims to assess the potential added benefit of combining Adagrasib with the current standard of care treatment in patients with untreated advanced lung cancer with a KRAS G12C mutation.

The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the efficacy of **adagrasib** in combination with **pembrolizumab** and chemotherapy compared to a placebo with pembrolizumab and chemotherapy in patients with previously untreated, locally advanced or metastatic non-small cell lung cancer (NSCLC) with a KRAS G12C mutation. The trial aims to assess the potential added benefit of adagrasib when combined with the current standard of care treatment. The primary endpoints include progression-free survival (PFS) and overall survival (OS), while secondary endpoints focus on PFS per RECIST v1.1 according to blinded independent central review (BICR).

The trial is expected to commence recruitment on April 30, 2025, and is estimated to conclude by April 30, 2032. Participants will be involved in the study for a maximum treatment period of 24 months, depending on the specific treatment arm. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as histologically or cytologically confirmed diagnosis of non-squamous NSCLC, measurable disease, and no prior systemic anti-cancer therapy for advanced or metastatic disease. Follow-up visits will be scheduled to monitor the participants' response to treatment and any adverse events. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial will ensure that all procedures adhere to ethical standards and regulatory requirements, maintaining the integrity and scientific validity of the study. The investigational products, including **pemetrexed**, **cisplatin**, **carboplatin**, and **palonosetron**, will be administered via intravenous infusion, while adagrasib will be provided as an oral film-coated tablet. The trial will not include any pediatric formulations, and all substances involved are of chemical origin.

The clinical trial involves the administration of **Adagrasib**, a film-coated tablet with the active substance **ADAGRASIB**. It is administered orally, with a maximum daily dose of 9999 mg and a total dose not exceeding 9999 mg. The treatment period is set to a maximum of 9999 days. Adagrasib is a chemical compound developed by Mirati Therapeutics Inc, and it is identified by the sponsor product code MRTX849.

**Pembrolizumab** is used in the trial as a solution for infusion. The active substance, **PEMBROLIZUMAB**, is a protein-based compound administered via intravenous infusion. The maximum daily and total doses are both set at 9999 mg/ml, with a treatment period of up to 24 weeks. Pembrolizumab is a key component of the experimental treatment regimen.

**Pemetrexed** is included as a concentrate for solution for infusion, with the active substance **PEMETREXED**. It is administered through intravenous infusion, with a maximum daily and total dose of 9999 mg/ml. The treatment period is not specified, allowing for flexibility in administration as part of the chemotherapy regimen.

**Cisplatin** is another chemotherapy agent used in the trial, provided as a concentrate for solution for infusion. The active substance, **CISPLATIN**, is administered intravenously, with a maximum daily and total dose of 9999 mg/ml. The treatment duration is limited to 12 weeks, aligning with standard chemotherapy cycles.

**Carboplatin** is also utilized in the trial, available as a concentrate for solution for infusion. The active substance, **CARBOPLATIN**, is delivered via intravenous infusion, with a maximum daily and total dose of 9999 mg/ml. The treatment period is capped at 12 weeks, consistent with typical chemotherapy protocols.

**Palonosetron** is administered as a solution for injection, with the active substance **PALONOSETRON**. It is used to manage chemotherapy-induced nausea and vomiting, delivered through injection. The maximum daily and total dose is 9999 µg/ml, with no specified treatment period, allowing for administration as needed during chemotherapy cycles.

The trial also includes a placebo group, where participants receive a placebo in combination with pembrolizumab and chemotherapy. The placebo is administered in a manner consistent with the active treatments to maintain the double-blind nature of the study.

The efficacy of the clinical trial will be assessed using the primary endpoints of **Progression-Free Survival (PFS)** and **Overall Survival (OS)**. These endpoints will compare the combination of adagrasib, pembrolizumab, and chemotherapy against a placebo, pembrolizumab, and chemotherapy in participants with previously untreated, locally advanced or metastatic non-squamous non-small cell lung cancer with a KRAS G12C mutation. Secondary endpoints include PFS per RECIST v1.1 according to Blinded Independent Central Review (BICR).