Kinetic Profiling of <i>RAS</i> Mutations With Circulating Tumor DNA in the Canadian Cancer Trials Group CO.26 Trial Suggests the Loss of <i>RAS</i> Mutations in Neo-<i>RAS</i>-Wildtype Metastatic Colorectal Cancer Is Transient.

Abstract

In metastatic colorectal cancer (mCRC), <i>RAS</i> mutations drive resistance to anti-epidermal growth factor receptor antibodies. It is unclear whether <i>RAS</i> mutations ever become clonally undetectable. CO.26 was a phase II clinical trial that assessed durvalumab + tremelimumab in heavily pretreated mCRC. <i>RAS</i> mutation status was tracked over time using circulating tumor DNA (ctDNA) sequencing at baseline, week 8, and on progression. Among the 95 patients with <i>KRAS/NRAS</i> mutations in their archival tumor tissue, 6.3% (6/95) had undetectable <i>RAS</i> mutations in ctDNA collected at baseline or week 8 of the CO.26 study. Of these, 67% (4/6) of disappearances were transient, with the same mutation reappearing with progressive disease. In three cases, the simultaneous persistence of other preexisting CRC-associated truncal mutations could not be demonstrated, suggestive of low tumor shedding of ctDNA, leaving the incidence of true clonal reversion to <i>RAS</i>-wildtype (WT) possibly as low as 3.2% (3/95). Fewer patients in the neo-<i>RAS</i>-WT group (33%) had greater than four lesions at trial baseline compared with patients with persistent <i>RAS</i> mutations (75%), <i>P</i> = .046. The likelihood of synchronous metastases at cancer diagnosis (33% <i>v</i> 63%; <i>P</i> = .15) or liver metastases at trial baseline (50% <i>v</i> 68.5%; <i>P</i> = .17) was not significantly different between patients with disappearing versus persistent <i>RAS</i> mutations. Overall survival from stage IV diagnosis (hazard ratio, 0.77 [95% CI, 0.35 to 1.72]; <i>P</i> = .52) was not significantly different between those with disappearing versus persistent <i>RAS</i> mutations. The disappearance of <i>RAS</i> mutations was not associated with primary tumor sidedness (<i>P</i> = .41), archival <i>BRAF/MEK/ERK</i>-mutant status (<i>P</i> = .16/1.00/.09), nor baseline ctDNA <i>HER2</i> amplifications (<i>P</i> = 1.00). We identified a 3.2%-6.3% prevalence of the neo-<i>RAS</i>-WT phenomenon in the CO.26 trial. However, 67% of apparent cases were transient with subsequent re-emergence.