In a circulating tumor DNA (ctDNA) substudy from the CALGB/SWOG-80405/Alliance trial reported in the Journal of Clinical Oncology, Kanwal Raghav, MD, MBBS, and colleagues found that first-line use of the anti-EGFR antibody cetuximab combined with chemotherapy was associated with only a small number of acquired genomic alterations associated with resistance to subsequent EGFR inhibition.
As stated by the investigators, “Acquired genomic alterations, specifically RAS, BRAF, and EGFR-ectodomain mutations and ERBB2 and MET amplifications, are recognized as major mechanisms of resistance to later-line anti-EGFR antibody therapy in metastatic colorectal cancer. However, data regarding emergence of these [alterations] under the selective pressure of first-line anti-EGFR/chemotherapy are lacking.”
Kanwal Raghav, MD, MBBS
Study Details
The primary analysis of the trial included 1,137 patients who were randomly assigned to first-line treatment with cetuximab plus chemotherapy or the anti-VEGF antibody bevacizumab plus chemotherapy. The current analysis included 61 patients in the cetuximab group and 69 patients in the bevacizumab group, with next-generation sequencing ctDNA analysis performed on paired pretreatment and postprogression plasma samples.
The primary objective of the analysis was to determine the prevalence of acquired genomic alterations of interest, prespecified as those implicated in anti-EGFR antibody resistance, on anti-EGFR treatment plus chemotherapy. Then, researchers worked to compare the prevalence with that seen with anti-VEGF treatment plus chemotherapy in these study patients, and with pooled estimated prevalence among 292 patients who received later-line anti-EGFR antibody therapy as reported in the literature.
Key Findings
Among 66 patients in the cetuximab/chemotherapy group, 4 (6.6%) developed at least one acquired genomic alteration of interest, compared with 7 (10.1%) of 69 patients in the bevacizumab/chemotherapy group (odds ratio [OR] = 0.62, 95% confidence interval [CI] = 0.20–2.11). In the cetuximab group vs bevacizumab group, alterations in RAS were observed in 4.9% vs 5.8%, KRAS in 0% vs 4.4%, NRAS in 4.9% vs 1.5%, BRAF in 0% vs 1.5%, and EGFR-ectodomain in 1.6% vs 1.5%. Amplifications were observed in 1.6% vs 4.3% of patients, including in ERBB2 in 1.6% vs 2.9% and in MET in 0% vs 2.9%.
The prevalence of alterations in the cetuximab/chemotherapy group was markedly lower than that among the cohort of 292 patients receiving later-line anti-EGFR antibody therapy: any alterations of interest were observed in 6.6% vs 62.0% (OR = 0.09, 95% CI = 0.03–0.23), with large differences in KRAS mutations (0% vs 44%, OR = 0.00, 95% CI = 0.00–0.08) and MET amplifications (0% vs 18%, OR = 0.00, 95% CI = 0.00–0.32). The prevalence of other alterations in the cohort receiving later-line treatment was 10% for NRAS, 4.0% for BRAF, 10% for EGFR-ectodomain mutations, and 7.0% for ERBB2 amplification.
The investigators stated, “Acquired genomic alterations classically associated with anti-EGFR antibody resistance in later lines (RAS, BRAF, and EGFR-ectodomain mutations; ERBB2 and MET amplifications) were rare with upfront use of anti-EGFR chemotherapy, indicating divergent resistance mechanisms. These findings have critical translational relevance to timing and value of ctDNA-guided anti-EGFR rechallenge in patients with metastatic colorectal cancer, especially those treated with anti-EGFR therapy upfront.”
Dr. Raghav, of the Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by grants from the National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.
