Clinical Pearls & Morning Reports
Published January 4, 2023
Yaeger et al. conducted a phase 1-2, open-label, nonrandomized clinical trial, which evaluated the use of adagrasib as monotherapy or in combination with cetuximab in patients with previously treated metastatic colorectal cancer with mutant KRAS G12C. Read the NEJM Original Article here.
Q: What percentage of patients with colorectal cancer have a KRAS mutation?
A: Kirsten rat sarcoma virus oncogene homologue (KRAS) is the most frequently mutated oncogene in human cancer and is one that drives oncogenesis in up to 50% of patients with colorectal cancer. The KRAS protein cycles between “on” states with guanosine triphosphate (GTP) binding and “off” states with guanosine diphosphate (GDP) binding, with a protein resynthesis half-life of 23 hours. The KRAS glycine-to-cysteine mutation at codon 12 (KRAS G12C) occurs in 3 to 4% of patients with colorectal cancer and impairs GTP hydrolysis, which shifts KRAS to the active GTP-binding state to drive protumorigenic effector signaling.
Q: Are many therapies available for patients who have colorectal cancer with KRAS G12C mutations?
A:KRAS mutations have historically been considered to be “undruggable,” and retrospective series of clinical data suggest that the presence of the KRAS G12C allele is associated with worse survival outcomes than other KRAS mutations in patients with colorectal cancer. However, recent progress has led to the development of small molecules that can occupy the KRAS switch II binding pocket and covalently bind to the mutant cysteine to prevent GTP binding. Currently, no therapies that specifically target KRAS G12C protein have been approved for the treatment of colorectal cancer. Adagrasib is an orally available, small-molecule covalent inhibitor of KRAS G12C that irreversibly and selectively binds the mutant in its inactive, GDP-bound state.
A: Although early data from a study of adagrasib monotherapy are promising, in patients with colorectal cancer with KRAS G12C mutations, reactivation may occur in the RAS-MAPK signaling pathway because of adaptive feedback mediated by epidermal growth factor receptor (EGFR). Preclinical studies have shown that combining an antibody against EGFR with a KRAS G12C inhibitor could be an effective clinical strategy to mitigate EGFR reactivation. Cetuximab is an anti-EGFR monoclonal antibody that is indicated for the treatment of RAS wild-type metastatic colorectal cancer, either as monotherapy or in combination with chemotherapy. Combining cetuximab with adagrasib may enhance the inhibition of KRAS-dependent signaling or overcome adaptive feedback to delay resistance and improve outcomes.
A: In this trial, the authors found that KRAS G12C can be targeted in metastatic colorectal cancer with activity observed for adagrasib as monotherapy and in combination with cetuximab in heavily pretreated patients (i.e., in those who had received a median of three previous lines of therapy, the majority of whom had disease that was resistant to previous therapies). In the trial, adagrasib monotherapy resulted in a response of 19% and a median response duration of 4.3 months. In addition, adagrasib monotherapy was associated with a median progression-free survival of 5.6 months and median overall survival of 19.8 months. The combination of adagrasib and cetuximab was associated with a response of 46% and median response duration of 7.6 months. In addition, combination therapy was associated with a median progression-free survival of 6.9 months, which suggests a potential for enhanced clinical benefit through a combination approach. Both treatments produced reversible toxic effects in the majority of patients and resulted in no new safety concerns.