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 

 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 

 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 

 G12C mutations, looking at targeting both EGFR and KRAS G12C, he concludes.

Videos

Jayesh Desai, MBBS, FRACP, discusses the evolution of divarasib, highlighting the rationale for combining the KRAS G12C inhibitor with cetuximab in patients with advanced colorectal cancer harboring KRAS G12C mutations in a phase 1b study.


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

Jayesh Desai, MD, honorary, Surgery, The Sir Peter MacCallum Department of Oncology, Clinical School-Austin Health, Royal Melbourne Hospital, discusses a phase Ia study exploring BGB-283 in patients with 

BGB-283 is a RAF dimer inhibitor and potential BRAF and EGFR inhibitor that acts on RAF dimerization, Desai explains. Additionally, it can target downstream 

-activated tumors. This could have potential in 

-mutant colorectal cancers, which has EGFR activation with BRAF inhibition.

Though this is an early phase study, results show that the agent can be administered safely. Next steps include moving BGB-283 into a larger phase Ib trial with a recommended phase II dose across 10 tumor types with molecular characteristics. Secondly, there is early evidence of activity with this agent in patients with select mutations in thyroid cancer, melanoma, endometrial cancer, and non—small cell lung cancer.

Jayesh Desai, MD, honorary, Surgery, The Sir Peter MacCallum Department of Oncology, Clinical School-Austin Health, Royal Melbourne Hospital, discusses a phase Ia study exploring BGB-283 in patients with BRAF- or KRAS/NRAS-mutated solid tumors.


Jayesh Desai, MD

Articles

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

Dr. Desai on BGB-283 in Patients With BRAF or KRAS/NRAS Solid Tumors