Does the emergence of resistance to cetuximab mean ineffectiveness of all anti-EGFR antibodies?
Colorectal cancer (CRC) cells respond to targeted therapy in different ways. Besides the desired outcome of cell death, CRC cells can adapt and survive through changes in their genome. It is important to recognize that the developed resistance to targeted therapy may, but does not necessarily, apply uniformly across a class of drugs or a single mechanism of action.
Dynamic Evolution of Tumor Cell Genomes
Changes in the molecular profile of tumors during therapy are intensely studied in the context of targeted therapies for various cancer diagnoses. For example, during anti-EGFR targeted therapy for CRC with initially wild-type KRAS gene, clones of cells with mutations in this gene are formed, leading to resistance to anti-EGFR therapy. After the withdrawal of the therapy, these acquired mutations tend to disappear since their contribution to cell survival ceases and they may even become a burden to the cell. Monitoring mutations can help identify relapse risk and guide the choice of subsequent lines of therapy. The disappearance of acquired mutations supports the idea of therapeutic rechallenge, i.e., administering a different drug from the same class even if the patient previously developed resistance or relapsed while on it.
Cetuximab and Panitumumab
An example of rechallenge could be the use of panitumumab following cetuximab failure. Both drugs are comparable in terms of efficacy for metastatic CRC (mCRC) treatment, as evidenced by the ASPECCT clinical trial involving nearly 1000 mCRC patients refractory to chemotherapy with wild-type exon 2 of the KRAS gene. The study showed that both drugs prolonged overall survival (OS) to a comparable extent.
A previously described acquired S492R mutation in the epidermal growth factor receptor (EGFR) leads to resistance to cetuximab in preclinical models and patients. This mutation, which structurally alters the extracellular domain where cetuximab binds, was first reported in 2012. Because panitumumab binds to a different region on the EGFR, its efficacy is likely maintained even with the S492R mutation.
Frequency and Impact of S492R Mutation
An international team led by Prof. Timothy Price from the University of Adelaide investigated the significance of this mutation. Researchers retrospectively analyzed tumor DNA data from peripheral blood samples of 546 ASPECCT study participants at the beginning of the study and 4 weeks after the last dose of cetuximab or panitumumab. No S492R mutations were identified at the start of the study. Post-therapy, it was found in 1.1% of panitumumab-treated patients and 16.1% of cetuximab-treated patients (p < 0.0001).
Although survival analysis showed no significant statistical differences in progression-free survival (PFS) and OS between patients with and without the mutation, Kaplan-Meier curves present an interesting pattern. Initially, cetuximab-treated patients who later developed the S492R mutation seemed to fare better than those without the mutation. After 12 months of treatment, however, the survival advantages faded, and the mutation-carrying population fared worse. A similar trend was observed with PFS curves.
No definitive conclusions can be drawn from this data. The timing of mutation development in ASPECCT study patients is unclear, and its contribution to disease progression or survival reduction remains unknown. Additionally, it could not be determined whether the mutation affected panitumumab treatment, as it was identified only in samples from 3 patients treated with this anti-EGFR antibody.
Conclusion
The authors confirmed that a portion of mCRC patients treated with cetuximab develop the S492R mutation, leading to treatment resistance. This mutation occurs significantly less frequently in panitumumab-treated patients. Prospective studies tracking the development of the S492R mutation and determining whether switching from cetuximab to panitumumab after mutation development can improve long-term clinical outcomes by circumventing resistance would be insightful.
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Source: Price T., Ang A., Boedigheimer M. et al. Frequency of S492R mutations in the epidermal growth factor receptor: analysis of plasma DNA from patients with metastatic colorectal cancer treated with panitumumab or cetuximab monotherapy. Cancer Biol Ther 2020; 21 (10): 891–898, doi: 10.1080/15384047.2020.1798695.
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