Acquired Genomic Alterations on First-Line Chemotherapy With Cetuximab in Advanced Colorectal Cancer: Circulating Tumor DNA Analysis of the CALGB/SWOG-80405 Trial (Alliance)

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Acquired genomic alterations (Acq-GAs), 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 (mCRC). However, data regarding emergence of these Acq-GAs under the selective pressure of first-line anti-EGFR-chemotherapy are lacking. We performed next-generation sequencing (Guardant360) on circulating tumor DNA obtained from paired plasma samples (pretreatment and postprogression) from the CALGB/SWOG-80405 trial, which randomly assigned patients with mCRC between first-line chemotherapy with cetuximab (anti-EGFR-chemotherapy) or bevacizumab (anti-VEGF-chemotherapy). The primary objective was to determine the prevalence of Acq-GAs on anti-EGFR-chemotherapy and compare this to the prevalence with anti-VEGF-chemotherapy on trial and pooled estimates (N = 292) seen with later-line anti-EGFR-antibody therapy as reported in the literature. Among the 61 patients on anti-EGFR-chemotherapy, only four (6.6%) developed ≥ 1 Acq-GAs of interest compared with 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). Acq-GAs, classically associated with anti-EGFR-antibody resistance in later lines (RAS, BRAF, and EGFR-ectodomain mutations; ERBB2 and MET amplifications), were rare with up-front use of anti-EGFR-chemotherapy indicating divergent resistance mechanisms. These findings have critical translational relevance to timing and value of circulating tumor DNA-guided anti-EGFR rechallenge in patients with mCRC, especially those treated with anti-EGFR therapy upfront.

Trial registration: ClinicalTrials.gov NCT00265850.

FIG 1.

Schematic flow of patients and samples for ctDNA analysis of the CALGB/SWOG-80405 trial. Eligible patients for the current biomarker study included those who were randomly assigned, treated, and subsequently progressed on cetuximab or bevacizumab; had plasma samples (both baseline and postprogression end-of-protocol treatment) available for ctDNA testing; and had at least one detectable genomic alteration. RAS/BRAF status (mutant or wild type) was determined by the presence of clonal mutations (relative mutant allele frequency of ≥ 25% in the sample) in ctDNA, and only RAS/BRAF wild-type patients identified by ctDNA were included in current study. chemo, chemotherapy; ctDNA, circulating tumor DNA.

FIG 2.

Acquired genomic alterations (mutations and amplifications) in patients with mCRC on systemic therapy. (A) Comparison of acquired genomic alterations between cetuximab-chemotherapy (C_S) and bevacizumab-chemotherapy (B_S) treatment arms on CALGB/SWOG-80405 study and acquired genomic alterations on anti–EGFR-Ab–based therapy in later lines in mCRC as reported in the literature (E_L). The error bars on each represent 95% CIs of the proportion. (B) Key clinical characteristics of patients who acquired genomic alterations and comparisons of these characteristics with those patients who did not develop acquired genomic alterations. All P values reported are for exploratory purposes only and not powered for statistical hypothesis testing. ^aResponse per RECIST v1.1 (PR/SD/PD). Acq, acquired; anti–EGFR-Abs, antiepidermal growth factor receptor antibodies; bev, bevacizumab; cetux, cetuximab; chemo, chemotherapy; CR, complete response; GAs, genomic alterations; HR, hazard ratio; max MAF, maximum mutant allele frequency; mCRC, metastatic colorectal cancer; OR, odds ratio; PD, progressive disease; PR, partial response; SD, stable disease.