A phase 1–2 clinical trial found that adagrasib combined with cetuximab in patients with KRAS G12C mutations can increase progression-free survival and overall survival in refractory colorectal cancer patients.
There is a pressing need for effective treatments for metastatic colorectal cancer, particularly for patients with the KRAS G12C mutation, a kind of colorectal cancer that is highly challenging to treat. For over two decades, fluoropyrimidine-based chemotherapy has been the cornerstone of therapy for metastatic colorectal cancer. Biologic therapies added to chemotherapy regimens have improved outcomes as first- and second-line treatments, but third-line options, such as regorafenib and trifluridine–tipiracil, have provided only modest improvements.
KRAS mutations, especially G12C, have been considered “undruggable” and associated with poorer survival outcomes. The KRYSTAL-1 trial, a phase 1–2 study published in the New England Journal of Medicine is focused on addressing this issue.
Adagrasib Emerges as a Viable Option
Adagrasib (MRTX849) is a small-molecule covalent inhibitor of KRAS G12C. Earlier studies have shown that the drug is effective against many cancers, including colorectal cancer. However, there have been concerns regarding the potential reactivation of the RAS–MAPK signaling pathway through adaptive feedback involving epidermal growth factor receptor (EGFR). Combining adagrasib with cetuximab, an anti-EGFR monoclonal antibody, emerged as a strategic approach to enhance inhibition and overcome adaptive feedback.
The KRYSTAL-1 phase 1–2 trial evaluated adagrasib’s efficacy as monotherapy or in combination with cetuximab in previously treated metastatic colorectal cancer patients with KRAS G12C mutations. The trial design was open-label and nonrandomized, emphasizing adagrasib’s potential in real-world scenarios. Eligible patients had advanced colorectal cancer with no curative treatment options.
In the monotherapy group, adagrasib demonstrated a 23% response rate, with a median duration of response of 4.3 months. The median progression-free survival and overall survival were 5.6 and 19.8 months, respectively. Adagrasib plus cetuximab showcased even better results, with a 46% objective response rate and a median duration of response of 7.6 months. The combination therapy exhibited a median progression-free survival of 6.9 months and an overall survival of 13.4 months.
Exploratory analyses included assessing ctDNA response, revealing both cohorts’ substantial plasma clearance of KRAS G12C. Safety assessments indicated manageable adverse events, with diarrhea and nausea being the most common. Adagrasib monotherapy had a 93% incidence of treatment-related adverse events, with 34% experiencing grade 3 or 4 events. In the combination therapy group, all patients reported treatment-related adverse events, with 16% experiencing grade 3 or 4 events.
The Bottom Line
The KRYSTAL-1 trial results are encouraging, especially for pretreated patients with metastatic colorectal cancer. The study demonstrated the safety and efficacy of adagrasib, either alone or in combination with cetuximab, for patients with KRAS G12C mutations. These results are particularly noteworthy considering that the median response was more than 6 months in a combination therapy group.
Source:
Yaeger, R., Weiss, J., Pelster, M. S., Spira, A. I., Barve, M., Ou, S.-H. I., Leal, T. A., Bekaii-Saab, T. S., Paweletz, C. P., Heavey, G. A., Christensen, J. G., Velastegui, K., Kheoh, T., Der-Torossian, H., & Klempner, S. J. (2023). Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C. New England Journal of Medicine, 388(1), 44–54. https://doi.org/10.1056/NEJMoa2212419
