Phase IB Study of GDC-6036 in Combination with Cetuximab in Patients With Colorectal Cancer (CRC) With KRAS G12C Mutation

Background: GDC-6036 is an oral, highly potent and selective KRAS G12C inhibitor that demonstrated anti-tumor activity in patients with KRAS G12C-positive advanced solid tumors, including CRC. In a previously reported single-agent cohort, GDC-6036 achieved a best response of partial response or complete response in 35% (19/55) of patients, with a confirmed overall response rate (ORR) of 24% (13/55 patients) in KRAS G12C-positive CRC patients (Desai et. al., ESMO 2022). EGFR blockade may sensitize tumors to KRAS G12C inhibition and the combination of an anti-EGFR antibody (cetuximab) with a KRAS G12C inhibitor showed greater anti-tumor activity than single-agent KRAS G12C inhibition in preclinical models (Amodio et. al., 2020).

Methods: In an ongoing Phase I study (NCT04449874), patients with advanced or metastatic KRAS G12C-positive CRC were administered GDC-6036 (200-400 mg orally once a day) with cetuximab (400 mg/m2 intravenously initially, then 250 mg/m2 weekly) until intolerable toxicity or disease progression. Endpoints included safety (NCI-CTCAE v5), pharmacokinetics (PK), and preliminary anti-tumor activity (RECIST v1.1).

Results: As of the clinical data cut-off date of 21 Nov 2022, 29 patients (enrolled by 07 Oct 2022) had received GDC-6036 and cetuximab. The median lines of prior metastatic therapy was 2 (range 1-8) and the median time on study treatment was 5.2 (range 1.4-11.2) months. All patients experienced at least one treatment-related adverse event (TRAE); the most common TRAEs (≥15%) were rash (grouped terms), diarrhea, nausea, vomiting, dry skin, and paronychia. Grade 3-4 TRAEs occurred in 11 patients (38%). Five patients (17%) experienced at least one serious AE, none of which were treatment-related (including 2 patients who died of CRC progression during the safety follow-up). AEs led to GDC-6036 modifications (interruptions and/or reductions) in 13 (45%) patients, dose reduction in 3 (10%) patients, and no patients discontinued due to AEs. Eleven patients discontinued from study treatment (10 due to disease progression and 1 due to physician’s discretion). The PK profile of GDC-6036 (400 mg once a day) was similar in combination with cetuximab when compared with single-agent. A partial response was achieved in 66% (19/29) of patients, with a confirmed ORR of 62% (18/29 patients).

Conclusions: GDC-6036 in combination with cetuximab demonstrated a manageable safety profile and promising clinical activity. These data support that the addition of anti-EGFR therapy to GDC-6036 may lead to robust clinical benefit in patients with KRAS G12C-positive CRC.