Dr Desai on the Evolution of Divarasib in KRAS G12C-mutated CRC

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 the evolution of divarasib (formerly GDC-6036), highlighting the rationale for combining the KRAS G12C inhibitor with cetuximab (Erbitux) in patients with advanced colorectal cancer (CRC) harboring KRAS G12C mutations in a phase 1b study (NCT04449874).

Desai and colleagues presented findings from the phase 1b investigation at the 2023 AACR Annual Meeting, showing that divarasib plus cetuximab elicited a confirmed overall response rate (ORR) of 62%. Additionally, 5 of the 29 patients in the overall population received prior treatment with KRAS G12C inhibitor, and 3 of these patients achieved a confirmed partial response with the divarasib combination. 

Moreover, the unconfirmed ORR was 66% at the data cutoff of November 21, 2022. Although no patients discontinued treatment due to treatment-related adverse effects, 38% of patients discontinued treatment due to progressive disease (n = 10) or physician decision (n = 1). Previous data on the use of divarasib monotherapy presented at the 2022 ESMO Congress demonstrated that the KRAS G12C inhibitor appeared to have a good safety profile and was well managed in most patients.

Divarasib is a selective and potent KRAS G12C inhibitor, Desai says. The development of this inhibitor has been promising one, and the early data that emerged from the treatment of patients with CRC has led to the initiation of an expansion cohort within this patient population, Desai explains. The expansion cohort will evaluate divarasib in combination with cetuximab in evaluable patients with KRAS G12C mutations, looking at targeting both EGFR and KRAS G12C, he concludes.