Reversion of RAS mutations in metastatic colorectal cancer in the CCTG CO.26 clinical trial

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oregon; chiles


Background: RAS mutations in metastatic colorectal cancer (mCRC) drive resistance to anti-EGFR antibodies. It is unclear if RAS mutations are ever clonally lost, potentially uncovering a new therapeutic option for patients over time. Methods: We examined the temporal evolution of RAS mutation status among patients enrolled in CO.26 [NCT02870920] – a phase II clinical trial that assessed durvalumab + tremelimumab in patients with heavily pretreated mCRC – using whole exome sequencing (WES) of archival primary tumor tissue and circulating tumor DNA (ctDNA) sequencing of serial plasma samples that were taken at baseline, week 8 and on progression. Results: Six out of 95 (6.3%) patients diagnosed with KRAS/NRAS-mutated mCRC showed ‘neo-RAS-wildtype’ reversions at the time of baseline or week-8 ctDNA collection for the CO.26 trial. The majority (4/6) had falling tumor mutation burden (TMB) but stable or rising maximum mutation allele frequency (MAF) when reversions occurred. These were unlikely false negatives from non-secreting cancers as there were continued strong presence of other somatic clonal mutations (e.g., TP53, ATM). The majority (4/6) of reversions were transient, with mutations reappearing with progressive disease. ‘Neo-RAS-wildtype’ revertors had numerically longer median overall survival (OS) from date of cancer diagnosis to death compared those with persistent RAS mutations (7.7 vs. 4.2 yrs, HR = 0.65, 95% CI 0.31 to 1.36, log-rank P= 0.26). However, ‘neo-RAS-wildtype’ revertors were earlier-stage at diagnosis compared to those with persistent RAS mutations (33% vs. 63% had synchronous metastases, χ2 P= 0.15), and had lower disease burden upon enrollment (50% vs. 68.5% had liver metastases, P= 0.17; 33% vs. 75% had > 4 lesions, P= 0.03*). Survival from stage IV diagnosis to death did not differ between those with reverted vs. persistent RAS mutations (median 3.8 vs. 3.2 yrs, HR = 0.77, 95% CI 0.35 to 1.72, P= 0.52). ‘Neo-RAS-wildtype’ reversions were not associated with side of primary tumors (P= 0.41), archival BRAF/MEK/ERK-mutant status (P= 0.16, 1.00, 0.09), baseline HER2 amplifications (P= 1.00), or baseline TMB (P= 0.21). Conclusions: We identified a 6.3% prevalence of ‘neo-RAS-wildtype’ reversions in the CO.26 trial, however only 2.1% of patients had persistent loss when serial time points were considered. Further research is needed to understand if ‘neo-RAS-wildtype’ revertors may benefit from anti-EGFR therapy. Clinical trial information: NCT02870920.

Clinical Institute


Clinical Institute

Digestive Health






Wu F, Topham JT, O'Callaghan CJ, Feilotter H, Kennecke H, Banks KC, Renouf DJ, Jonker D, Tu D, Chen EY, Loree JM. ASCO Annual Meeting; June 2-6; Chicago, IL. 2023;41: 3567.

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