Divergent Resistant Mechanisms Found With Upfront anti-EGFR Therapy in mCRC

Analysis from the phase 3 CALGB/SWOG-80405 trial reveals that acquired genomic alterations in patients treated with cetuximab in combination with chemotherapy in the first-line were not common.

With upfront use of anti-EGFR plus chemotherapy, acquired genomic alterations (Acq-GAs) were shown to be rare in patients with metastatic colorectal cancer (mCRC), including RAS, BRAF, and EGFR-ectodomain mutations and ERBB2 and MET amplifications. These data indicate divergent resistance mechanisms, according to findings published in the Journal of Clinical Oncology.1

“Acq-GAs, classically associated with EGFR resistance in later lines, were rare with up-front use of anti–EGFR-Ab combined with highly active chemotherapy and comparable with non–anti-EGFR regimen, suggesting divergent mechanisms of acquired resistance subject to line of therapy and concomitant cytotoxic exposure,” wrote the study authors led by Kanwal Raghav, MD, of the University of Texas MD Anderson Cancer Center.

The findings suggest that more assessment should be done on the timing of EGFR therapy and the value of circulating tumor DNA (ctDNA)–guided anti-EGFR rechallenge in patients with mCRC. This is especially true for patients treated with EGFR inhibitors in the frontline setting, according to Raghav et al.

While studies have shown various Acq-GAs demonstrate resistance to later-line anti-EGFR-antibody therapy in mCRC, there is a lack of data regarding emergence of these Acq-GAs for first-line anti-EGFR-chemotherapy.

To examine this further, experts performed next-generation sequencing using Guardant360 on ctDNA, which were gathered from paired plasma samples of patients enrolled in the CALGB/SWOG-80405 trial (NCT00265850).

The randomized, phase 3, CALGB/SWOG-80405 trial was designed to evaluate the efficacy of chemotherapy with either cetuximab (Erbitux), bevacizumab (Avastin), or both, as first-line treatment for (KRAS-WT) mCRC. The primary end point of the trial was overall survival.2

In the study, patients were randomly assigned between first-line chemotherapy with cetuximab (anti-EGFR-chemotherapy) or bevacizumab (anti-VEGF-chemotherapy). Among the entire CALGB/SWOG-80405 population and the patients who underwent ctDNA testing, baseline characteristics were similar. Additionally, the clinical outcomes in this cohort were consistent with those observed in the primary 80405 analysis and of these patients, 130 met eligibility criteria for current biomarker sub study. These patients were equally distributed between cetuximab (n = 61) and bevacizumab (n = 69) arms.

Of the evaluable patients, baseline characteristics were comparable between treatment arms with the median age of those in the cetuximab arm vs bevacizumab arm at 60.8 and 60.0 and on both arms, the majority of patients were male (63.9% v 59.4%). Further, 4 of 61 patients treated with cetuximab-chemotherapy (6.6%) developed at least 1 Acq-GA of interest at progression, and this prevalence was similar to what was seen with bevacizumab-chemotherapy in 7 of 69 patients (odds ratio [OR] 0.62;95% CI, 0.20-2.11).

Between treatment arms, there was no meaningful difference in prevalence of key alterations as mutations were seen in RAS (4.9% vs 5.8%), KRAS (0% vs 4.4%), NRAS (4.9% vs 1.5%), BRAF (0% vs 1.5%), and EGFR-ectodomain (1.6% vs 1.5%). Amplifications we in ERBB2 (1.6% vs 2.9%) and MET (0% vs 2.9%). There were also no differences in key clinical characteristics between patients who had and did not have Acq-GAs.

The prevalence of all Acq-GAs for those given first-line cetuximab and chemotherapy was also shown to be lower than the pooled prevalence (n = 292) on prior studies which administered an anti-EGFR-Ab-based regimen in later lines of therapy (6.6% vs 62.0%; [OR 0.09; 95% CI, 0.03-0.23]).

No significant difference in overall survival among the eligible patients was found between each treatment arm with 30.0 months vs 29.0 months.

  1. Raghav K, Ou FS, Venook AP, et al. Acquired Genomic Alterations on First-Line Chemotherapy With Cetuximab in Advanced Colorectal Cancer: Circulating Tumor DNA Analysis of the CALGB/SWOG-80405 Trial (Alliance). J Clin Oncol. Published online September 6, 2022. doi:10.1200/JCO.22.00365
  2. Cetuximab and/or bevacizumab combined with combination chemotherapy in treating patients with metastatic colorectal cancer. ClinicalTrials.gov. Updated May 7, 2020. Accessed October 4, 2022. https://www.clinicaltrials.gov/ct2/show/NCT00265850