The KRAS G12C mutation is associated with worse overall survival in patients with colorectal cancer (CRC). Current first-line standard of care for KRAS G12C-positive advanced CRC includes 5-FU-based chemotherapy with irinotecan, oxaliplatin and/or capecitabine, but is limited by low tumour-specific selectivity and systemic toxicity. Several KRAS G12C inhibitors, including sotorasib, adagrasib, and divarasib are currently being investigated as a single agent and in combination with EGFR inhibitors.
In an ongoing phase Ib study, divarasib in combination with cetuximab demonstrated a manageable safety profile and promising clinical activity. The further improvements in antitumour activity demonstrated with the addition of cetuximab to divarasib may represent an effective strategy for overcoming resistance to KRAS G12C inhibitors according to Drs. Jayesh Desai of the Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, The University of Melbourne in Melbourne, Victoria, Australia, Sae-Won Han of the Seoul National University Hospital and Seoul National University Cancer Research Institute in Seoul, South Korea, and GO42144 Investigator and Study Group researchers, who published the findings on 5 December 2023 in The Nature Medicine.
Oncogenic KRAS G12C mutations occur in approximately 4% of patients with CRC and are associated with poor prognosis. Patients with CRC who have tumours harbouring a KRAS mutation, including KRAS G12C do not benefit from anti-EGFR-based therapies. Divarasib (GDC-6036) is an orally bioavailable, covalent KRAS G12C inhibitor that turns off its oncogenic signalling by irreversibly locking the protein in an inactive state.
In vitro studies have also shown that divarasib is 5 to 20 times as potent and up to 50 times as selective as compared to the KRAS G12C inhibitors sotorasib and adagrasib. Single-agent divarasib treatment at 400 mg achieved a confirmed objective response rate (ORR) of 56.4% in patients with non-small cell lung cancer and 35.9% in patients with CRC, with a median progression-free survival (PFS) of 13.1 and 6.9 months, respectively.
Despite the encouraging antitumour activity with single-agent divarasib in patients with CRC, adaptive feedback reactivation of RAS–MAPK signalling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC, occurs frequently and ultimately limits efficacy. Preclinical studies have identified EGFR as a major mediator of adaptive feedback, and concomitant blockade of EGFR has been shown to enhance the antitumour activity of KRAS G12C inhibition.
The combination of an EGFR inhibitor with a KRAS G12C inhibitor may more effectively inhibit the KRAS–MAPK pathway, prevent adaptive feedback and lead to more robust clinical responses. Clinical studies of other KRAS G12C inhibitors, such as sotorasib and adagrasib, support this hypothesis, with higher response rates observed when used in combination with an EGFR inhibitor compared to when used as single-agent treatment in patients with CRC.
Divarasib in combination with other anticancer therapies is currently being evaluated in an ongoing phase Ib study in patients with advanced or metastatic solid tumours harbouring a KRAS G12C mutation. In a latest article published in The Nature Medicine, the GO42144 investigators report results from arm C patients with CRC who received divarasib in combination with cetuximab. The primary objective of this study was to evaluate safety; secondary objectives included characterisation of preliminary antitumour activity and the pharmacokinetic profile, and exploratory objectives included the characterisation of biomarkers of response and resistance.
The authors report the findings on divarasib plus cetuximab in 29 patients with KRAS G12C-positive CRC enrolled into arm C of an ongoing phase Ib study. The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab. Treatment-related adverse events led to divarasib dose reductions in 4 patients (13.8%). There were no treatment withdrawals.
The ORR was 62.5% (95% confidence interval [CI] 40.6%, 81.2%) in 24 KRAS G12C inhibitor-naive patients. The median duration of response was 6.9 months. The median PFS was 8.1 months (95% CI 5.5, 12.3). Among the 5 patients who had received KRAS G12C inhibitors before enrolment, 3 (60.0%) had a partial response and 2 (40.0%) had stable disease as their best response.
The steady-state pharmacokinetic profile and RAUC0–24 of divarasib in combination with cetuximab were similar to single-agent divarasib.
As an exploratory objective in this study, retrospective ctDNA profiling was conducted. The study team observed a decline in KRAS G12C variant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance.
Difference in potency may explain the numerically higher ORRs and longer PFS with divarasib compared to sotorasib and adagrasib, as a single-agent and in combination with an EGFR inhibitor in patients with CRC. The authors concluded that manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRAS G12C-positive CRC.
Divarasib is continuing to be investigated with other anticancer therapies for patients with CRC in this study, including bevacizumab, GDC-1971 (a SHP2 inhibitor) and inavolisib (a PI3Kα inhibitor). Additionally, a study is ongoing to explore the effects of the combination of divarasib plus cetuximab with or without chemotherapy (FOLFOX or FOLFIRI) in patients with KRAS G12C-positive CRC.
This study was sponsored by Genentech.
Reference
Desai J, Alonso G, Hyun Kim S, … GO42144 Investigator and Study Group, Han S-W. Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial. Nature Medicine; Published online 5 December 2023. DOI: https://doi.org/10.1038/s41591-023-02696-8