Efficacy and Safety of GDC-6036 Versus Sotorasib or Adagrasib in KRAS G12C-Positive Advanced or Metastatic Non-Small Cell Lung Cancer

The primary objective of this study is to evaluate the **efficacy** of divarasib compared with KRAS G12C inhibitors (sotorasib or adagrasib) in terms of **progression-free survival** (PFS) in patients with previously treated KRAS G12C-positive advanced or metastatic non-small cell lung cancer (NSCLC). This is clinically relevant as PFS is a critical endpoint in cancer trials, indicating the length of time during and after treatment that a patient lives with the disease without it worsening.

Secondary objectives include: - Evaluating the efficacy of divarasib compared with KRAS G12C inhibitors with respect to overall survival (OS) and duration of response (DOR). - Assessing the safety and tolerability of divarasib compared with KRAS G12C inhibitors. - Evaluating, from the participant's perspective, the functioning and impact of key disease-related symptoms, as well as the quality of life of participants treated with divarasib compared with KRAS G12C inhibitors. These secondary objectives are important for understanding the broader impact of the treatment on patient health and well-being, beyond the primary endpoint of PFS.

The clinical trial involves a total of **78 participants** diagnosed with **KRAS G12C-Positive Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including the presence of a KRAS G12C mutation and measurable disease according to RECIST v1.1. The trial population is characterized by adequate hematologic and organ function, as well as negative tests for HIV, hepatitis B, and hepatitis C. Lifestyle factors such as diet and physical activity are not specified, but the inclusion of a vulnerable population is noted. The selection process ensures that participants have a representative formalin-fixed, paraffin-embedded tumor specimen available for analysis. The trial aims to evaluate the efficacy of divarasib compared to other KRAS G12C inhibitors in terms of progression-free survival.

The clinical trial is a **Phase III**, randomized, open-label, multicenter study designed to evaluate the efficacy and safety of divarasib compared to sotorasib or adagrasib in patients with previously treated **KRAS G12C-positive advanced or metastatic non-small cell lung cancer (NSCLC)**. The primary objective is to assess progression-free survival (PFS), while secondary endpoints include overall survival (OS), objective response, and the incidence and severity of adverse events, among others. The trial is expected to commence recruitment on September 12, 2024, and conclude by September 30, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as measurable disease per RECIST v1.1 and documentation of a **KRAS G12C mutation**. The screening will also include tests for **HIV**, **hepatitis B**, and **hepatitis C**, as well as assessments of hematologic and organ function. Following the screening, participants will be randomized to receive either divarasib or one of the comparator drugs, sotorasib or adagrasib. The trial will involve regular follow-up visits to monitor treatment efficacy and safety, with assessments including vital signs, ECG parameters, and clinical laboratory tests. The end-of-study visit will mark the completion of the participant's involvement, which is anticipated to last until the trial's estimated end date.

Participant involvement may be terminated early if they experience unacceptable toxicity, disease progression, or withdrawal of consent. The trial's design ensures rigorous monitoring and data collection to evaluate the primary and secondary endpoints effectively. The study's open-label nature allows for direct observation of treatment effects, while the multicenter approach facilitates a diverse participant pool, enhancing the generalizability of the findings.

The clinical trial involves the evaluation of several investigational medicinal products (IMPs) of chemical origin, specifically targeting **KRAS G12C-positive advanced or metastatic non-small cell lung cancer**. The primary experimental medication in this study is **Divarasib**, also known by its sponsor product code **RO7435846**. This compound is provided by **GENENTECH, INC.** and is characterized as an active substance of chemical origin. The pharmaceutical form, dosage, route, and frequency of administration for Divarasib are not specified in the provided data. However, it is noted that the product is not a pediatric formulation and has been relabeled for clinical trial use.

In addition to Divarasib, the trial includes comparator treatments, namely **Sotorasib** and **Adagrasib**, which are also **KRAS G12C inhibitors**. These comparator treatments are provided by **AMGEN EUROPE B.V.** and **MIRATI THERAPEUTICS B.V.**, respectively. Both Sotorasib and Adagrasib are investigational medicinal products of chemical origin, relabeled for clinical trial use. The pharmaceutical form, dosage, route, and frequency of administration for these comparator treatments are not detailed in the available data. These treatments are not pediatric formulations and are used to compare the efficacy and safety against Divarasib in the study.

Participant compliance with the dosing schedules will be monitored throughout the trial, although specific methods for compliance monitoring are not described in the provided information. The trial is designed to assess the efficacy of Divarasib in comparison to the established KRAS G12C inhibitors, focusing on progression-free survival as the primary endpoint. The study is conducted in an open-label, randomized, multicenter format, ensuring a robust evaluation of the investigational treatments.

The efficacy of the investigational product in this clinical trial will be assessed primarily through the measurement of **progression-free survival (PFS)**. This primary endpoint will evaluate the time from randomization until the first documented disease progression or death from any cause, whichever occurs first. Secondary endpoints include overall survival (OS), objective response, and time to confirmed deterioration (TTCD) on specific scales such as the EORTC QLQ-C30 and QLQ-LC13. Additional secondary endpoints involve the duration of response (DOR), incidence and severity of adverse events, and changes from baseline in selected vital signs, ECG parameters, and clinical laboratory test results.

Patient-reported outcomes will be assessed using the NCI PRO-CTCAE and EORTC Item List (IL46) to evaluate the presence, frequency, severity, and interference of symptomatic treatment toxicities. Changes from baseline in symptoms such as diarrhea, nausea, vomiting, and others will also be monitored. The frequency of participants' responses regarding the degree of trouble with treatment symptoms will be recorded. The trial will utilize validated scales and instruments to ensure accurate and reliable data collection. The schedule for measuring these endpoints will be aligned with the trial protocol, ensuring systematic data collection at predefined timepoints throughout the study duration.