Evaluation of Safety and Efficacy of Divarasib with Pembrolizumab and Chemotherapy in KRAS G12C Mutant Advanced Non-Small Cell Lung Cancer

The primary objective of this study is to evaluate the **safety** and **tolerability** of divarasib in combination with pembrolizumab (Cohort A) and divarasib in combination with pembrolizumab plus platinum-based chemotherapy and pemetrexed (Cohort B) in patients with untreated advanced or metastatic non-small cell lung cancer with a KRAS G12C mutation. This is clinically relevant as it aims to determine the potential of these combination therapies to be safely administered to patients, which is crucial for advancing treatment options for this specific cancer mutation.

Secondary objectives include:

• Evaluating the activity of divarasib in combination with pembrolizumab (Cohort A) and divarasib in combination with pembrolizumab plus platinum-based chemotherapy and pemetrexed (Cohort B).
• Assessing the tolerability of these combination regimens.
• Characterizing the pharmacokinetic (PK) profile of divarasib.
• Identifying a recommended dose of divarasib in combination regimens with pembrolizumab (Cohort A) and pembrolizumab plus platinum-based chemotherapy and pemetrexed (Cohort B).

The clinical trial involves a total of **124 participants** diagnosed with **untreated advanced or metastatic non-small cell lung cancer** (NSCLC). The study population includes both male and female subjects, with an age range corresponding to adults and older adults. Participants were selected based on specific criteria, including a histologically or cytologically documented locally advanced unresectable or metastatic non-squamous NSCLC, and no prior systemic treatment for advanced unresectable or metastatic NSCLC. The trial also requires confirmation of biomarker eligibility, including the presence of the KRAS G12C mutation and PD-L1 expression. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified. The selection process ensures that participants have measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

The clinical trial is designed as a **Phase Ib/II, open-label, multicenter study** to evaluate the safety, activity, and pharmacokinetics of **divarasib** in combination with other anti-cancer therapies in patients with previously untreated advanced or metastatic non-small cell lung cancer with a **KRAS G12C mutation**. The trial is structured into two cohorts: Cohort A, which involves divarasib in combination with **pembrolizumab**, and Cohort B, which includes divarasib in combination with pembrolizumab plus platinum-based chemotherapy and **pemetrexed**. The study is expected to commence recruitment on August 15, 2023, and conclude by July 30, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically or cytologically documented locally advanced unresectable or metastatic non-squamous NSCLC, no prior systemic treatment for advanced disease, and confirmation of biomarker eligibility, including the presence of the KRAS G12C mutation and PD-L1 expression. The trial will include regular follow-up visits to monitor safety parameters and assess the occurrence of adverse events, as well as changes from baseline in targeted safety parameters. The end-of-study visit will evaluate the primary and secondary endpoints, including objective response rate, duration of response, and progression-free survival.

The expected length of participant involvement will vary depending on individual response and tolerance to the treatment regimen. Conditions that may lead to early termination from the study include the occurrence of unacceptable adverse events, disease progression, or withdrawal of consent by the participant. The trial will adhere to rigorous scientific and ethical standards to ensure the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Pemetrexed Accord** is provided as a 25 mg/mL concentrate for solution for infusion. It is administered via **intravenous infusion**. The product is relabeled for clinical trial use and is of chemical origin. **Pemetrexed** is also available in a powder form for concentrate for solution for infusion, sourced from Eli Lilly Australia, and administered intravenously.

**Carboplatin** is utilized in multiple formulations, including **Carboplatine Accord** and **Carboplatin-GRY®**, both as solutions for infusion at a concentration of 10 mg/mL. These are administered via intravenous infusion and are relabeled for clinical trial use. **CARBO-cell®** is another formulation of carboplatin, also provided as a 10 mg/mL solution for infusion, administered intravenously.

**Divarasib** is administered orally in the form of film-coated tablets, with product codes RO 743-5846/F04, RO 743-5846/F06, and RO 743-5846/F07. These tablets are relabeled for clinical trial use and are of chemical origin.

**Cisplatin** is available as a concentrate for solution for infusion, with products such as **Cisplatin NeoCorp** and **Cisplatin Teva®**, both at a concentration of 1 mg/mL. These are administered via intravenous infusion and are relabeled for clinical trial use.

**Pembrolizumab**, marketed as **KEYTRUDA**, is provided as a 25 mg/mL concentrate for solution for infusion. It is administered via intravenous infusion and is relabeled for clinical trial use. Pembrolizumab is a protein-based therapeutic agent.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The trial aims to evaluate the safety and tolerability of these medications, particularly in combination therapies for patients with advanced or metastatic non-small cell lung cancer with a KRAS G12C mutation.

The efficacy of the clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoints focus on the occurrence of adverse events and changes from baseline in targeted safety parameters. Secondary endpoints include the objective response rate, duration of response, and progression-free survival. Additionally, the trial will evaluate the presence, frequency, severity, and impact on daily function of symptomatic side effects using the Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE). Changes from baseline in symptomatic side effects will also be assessed through PRO-CTCAE.

Further secondary endpoints involve the proportion of participants reporting "frequent" or "almost constant" diarrhea, and "severe" or "very severe" nausea or vomiting during the first three cycles of treatment, as per PRO-CTCAE criteria. The frequency of participants' responses regarding the degree of trouble with treatment symptoms will be evaluated using the European Organisation for Research and Treatment of Cancer (EORTC) Item List 46 (IL46). Plasma concentration of **divarasib** at specified timepoints will be measured, and the recommended dose of **divarasib** in combination with pembrolizumab or pembrolizumab plus platinum-based chemotherapy and pemetrexed will be determined based on safety, activity, and pharmacokinetic data.