KEY TAKEAWAYS
- Phase 3 trial CALGB/SWOG 80405 and NCT00265850 studied resistance mechanisms in mCRC.
- The primary aim was to determine the prevalence of (Acq-GAs) with anti-EGFR chemotherapy.
- Only 6.6% of patients on anti-EGFR-chemotherapy developed ≥ 1 Acq-GAs of interest, compared with 10.1% on anti-VEGF-chemotherapy and 62.0% on later-line anti-EGFR-antibody therapy.
- Findings have critical translational relevance to the timing and value of circulating tumor DNA–guided anti-EGFR rechallenge in patients with mCRC, especially those treated with anti-EGFR therapy upfront.
In metastatic colorectal cancer(mCRC), acquired genomic alterations (Acq-GAs) such as RAS, BRAF, and EGFR-ectodomain mutations and ERBB2 and MET amplifications are recognized as significant resistance mechanisms to later-line anti-EGFR-antibody therapy.
However, information on how these Acq-GAs manifest themselves in response to the selective pressure of frontline anti-EGFR-chemotherapy still needs to be made available. Researchers used next-generation sequencing (Guardant360) to analyze ctDNA isolated from plasma samples taken before and after progression in a randomized clinical trial comparing the efficacy of first-line cetuximab (anti-EGFR-chemotherapy) and bevacizumab treatment for metastatic colorectal cancer (mCRC) (anti–VEGF-chemotherapy). The primary goal was to compare the reported prevalence of Acq-GAs on later-line anti-EGFR-antibody therapy with the reported prevalence of Acq-GAs on trial and pooled estimates (N = 292) anti-VEGF-chemotherapy.
As compared to 10.1% (7) on anti-VEGF-chemotherapy (odds ratio, 0.62; 95% CI, 0.20 to 2.11) and 62.0% on anti-EGFR-antibody therapy in later lines (odds ratio, 0.09; 95% CI, 0.03 to 0.23), only four (6.6%) of the 61 patients on anti-EGFR-chemotherapy developed 1 Acq-GA of interest. However, acq-GAs are typically associated with anti-EGFR-antibody resistance in later lines (RAS, BRAF, and EGFR-ectodomain mutations; ERBB2 and MET amplifications), were uncommon when anti-EGFR-chemotherapy was administered initially, suggesting different mechanisms of resistance. These results have significant clinical implications for the timing and value of anti-EGFR rechallenge in patients with mCRC, particularly those pretreated with anti-EGFR therapy.
Source Link:https://ascopubs.org/doi/full/10.1200/JCO.22.00365
Clinical Link:https://clinicaltrials.gov/ct2/show/NCT00265850
Kanwal Raghav, Fang-Shu Ou, Alan P. Venook, Federico Innocenti, Ryan Sun, Heinz-Josef Lenz , and Scott Kopetz-Acquired Genomic Alterations on First-Line Chemotherapy With Cetuximab in Advanced Colorectal Cancer: Circulating Tumor DNA Analysis of the CALGB/SWOG-80405 Trial (Alliance)/Journal of Clinical Oncology, 41(3), 472–478. https://doi.org/10.1200/jco.22.00365
