 GDC-6036 is an oral, highly potent and selective KRAS G12C inhibitor that demonstrated anti-tumor activity in patients with 

-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 

-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).

 In an ongoing Phase I study (NCT04449874), patients with advanced or metastatic 

-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). 

 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).

 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 

Videos

Jayesh Desai, MBBS, FRACP, shares data from a phase IB study investigating KRAS G12C inhibitor GDC-6036, or divarasib, in combination with cetuximab for the treatment of patients with colorectal cancer.

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

Jayesh Desai, MBBS, FRACP, medical oncologist, associate professor, head, Phase I/Early Drug Development Program, associate director, Clinical Research, Peter MacCallum Cancer Centre, chair, the Sir Peter MacCallum Department of Oncology, the University of Melbourne, discusses efficacy data for the combination of divarasib (formerly GDC-6036) plus cetuximab (Erbitux) in patients with colorectal cancer (CRC) harboring a 

 G12C mutation from a phase 1B study (NCT04449874).

Findings presented at the 2023 AACR Annual Meeting

 showed that divarasib plus cetuximab elicited a confirmed objective response rate (ORR) of 62%. Notably, 5 of the 29 patients in the overall population received prior treatment with KRAS G12C inhibitor, and 3 of these 5 patients had a confirmed partial response with the divarasib-based combination, Desai says.

Previous data on divarasib monotherapy presented at the 2022 ESMO Congress showed that the KRAS G12C inhibitor had a good safety profile and was well managed in most patients, Desai says, adding that there was a low rate of patients requiring dose reductions or treatment discontinuation. In most instances, investigators were able to manage adverse effects with supportive care and other medications, Desai says.

Efficacy data with divarasib monotherapy showed that the ORR was 31% in patients who received the full 400-mg dose day within the CRC cohort (n = 39), and the ORR across all dose levels was 24%. Since those data were reported, the confirmed ORR in patients treated at 400 mg has risen to 36%, Desai says. Given the improved ORR for patients treated with the combination of divarasib plus cetuximab, these are exciting data for patients with 

Jayesh Desai, MBBS, FRACP, discusses efficacy data for the combination of divarasib plus cetuximab in patients with colorectal cancer harboring a KRAS G12C mutation from a phase 1B study.

Jayesh Desai, MBBS, FRACP

Articles

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

Dr Desai on the Efficacy of Divarasib Plus Cetuximab in KRAS G12C–Mutant CRC