Evaluating the Efficacy of GDC-6036 in Advanced Solid Tumors with KRAS G12C Mutation

The oral medication GDC-6036 is a highly potent and selective inhibitor of KRAS G12C, which has exhibited anti-tumor activity in individuals diagnosed with KRAS G12C-positive advanced solid tumors, such as CRC. As per the findings of Desai et. al. presented at ESMO 2022, GDC-6036 demonstrated a partial response or complete response in 35% (19/55) of patients in a single-agent cohort. The confirmed overall response rate (ORR) was observed to be 24% (13/55 patients) in patients with KRAS G12C-positive CRC. The inhibition of EGFR may result in increased sensitivity of tumors to KRAS G12C inhibition. In preclinical models, the combination of a KRAS G12C inhibitor and an anti-EGFR antibody (cetuximab) demonstrated superior anti-tumor activity compared to KRAS G12C inhibition alone (Amodio et. al., 2020). In a continuous Phase I clinical trial (NCT04449874), individuals diagnosed with advanced or metastatic KRAS G12C-positive colorectal cancer were subjected to GDC-6036 (200-400 mg orally once a day) in combination with cetuximab (400 mg/m2 intravenously initially, then 250 mg/m2 weekly) until the occurrence of intolerable toxicity or disease progression.

The endpoints encompassed safety per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5, pharmacokinetics, and initial anti-tumor activity as per the Response Evaluation Criteria in Solid Tumors version 1.1. Results: As of the clinical data cut-off date of November 21st, 2022, a total of 29 patients who were enrolled by October 7th, 2022, were administered GDC-6036 and cetuximab. The patient’s prior metastatic therapy had a median of 2 (range 1-8) median lines, while the median time on study treatment was 5.2 (range 1.4-11.2) months. All patients have reported experiencing at least one treatment-related adverse event (TRAE). The most frequently observed TRAEs (≥15%) include rash (grouped terms), diarrhea, nausea, vomiting, dry skin, and paronychia. Eleven patients (38%) experienced Grade 3-4 treatment-related adverse events (TRAEs). Five patients (17%) encountered a minimum of one severe adverse event (AE), none of which were related to the treatment. Among these, two patients succumbed to CRC progression during the safety follow-up. Adverse events (AEs) necessitated modifications (interruptions and/or reductions) of GDC-6036 in 13 (45%) patients, dose reduction in 3 (10%) patients, and no patients discontinued treatment due to AEs. Eleven patients were discontinued from the study treatment, with 10 due to disease progression and 1 due to the physician’s discretion.

The pharmacokinetic profile of GDC-6036 at a dosage of 400 mg administered once daily exhibited comparable results when used in conjunction with cetuximab as opposed to being used as a single agent. A confirmed objective response rate (ORR) of 62% (18/29 patients) was observed, with a partial response achieved in 66% (19/29) of patients. The combination of GDC-6036 and cetuximab exhibited a manageable safety profile and promising clinical activity. The aforementioned data provide evidence that incorporating anti-EGFR therapy into the GDC-6036 treatment regimen may result in significant clinical advantages for individuals diagnosed with KRAS G12C-positive colorectal cancer.

Source:https://www.abstractsonline.com/pp8/#!/10828/presentation/10277

Clinical Trial:https://clinicaltrials.gov/ct2/show/NCT04449874

Jayesh Desai, Sae-Won Han, Jong-Seok Lee, Einat Shacham-Shmueli, Erminia Massarelli, Andrés Cervantes, Elena Garralda, Alejandro Falcon, Wilson H. Miller Jr., Eelke Gort, Thomas Karasic, Salvatore Siena, Rafal Stec, Laura Medina, Luis Paz-Arez, Angelo Delmonte, Adrian Sacher, Hans Prenen, Martin Forster, Tae Won Kim, Matthew G. Krebs, Rasha Cosman, Yoonha Choi, Sandhya Mandlekar, Mark T. Lin, Kenneth K. Yau, Julie Chang, Stephanie Royer-Joo, Neekesh V. Dharia, Jennifer L. Schutzman, Manish Patel/Phase Ib study of GDC-6036 in combination with cetuximab in patients with colorectal cancer (CRC) with KRAS G12C mutation/(2020). Abstractsonline.com. https://www.abstractsonline.com/pp8/#