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

PURPOSE: In metastatic colorectal cancer (mCRC), RAS mutations drive resistance to anti–epidermal growth factor receptor antibodies. It is unclear whether RAS mutations ever become clonally undetectable. METHODS: CO.26 was a phase II clinical trial that assessed durvalumab + tremelimumab in heavily pretreated mCRC. RAS mutation status was tracked over time using circulating tumor DNA (ctDNA) sequencing at baseline, week 8, and on progression. RESULTS: Among the 95 patients with KRAS/NRAS mutations in their archival tumor tissue, 6.3% (6/95) had undetectable RAS 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 RAS -wildtype (WT) possibly as low as 3.2% (3/95). Fewer patients in the neo- RAS -WT group (33%) had greater than four lesions at trial baseline compared with patients with persistent RAS mutations (75%), P =.046. The likelihood of synchronous metastases at cancer diagnosis (33% v 63%; P =.15) or liver metastases at trial baseline (50% v 68.5%; P =.17) was not significantly different between patients with disappearing versus persistent RAS mutations. Overall survival from stage IV diagnosis (hazard ratio, 0.77 [95% CI, 0.35 to 1.72]; P =.52) was not significantly different between those with disappearing versus persistent RAS mutations. The disappearance of RAS mutations was not associated with primary tumor sidedness (P =.41), archival BRAF/MEK/ERK -mutant status (P =.16/1.00/.09), nor baseline ctDNA HER2 amplifications (P = 1.00). CONCLUSION: We identified a 3.2%-6.3% prevalence of the neo- RAS -WT phenomenon in the CO.26 trial. However, 67% of apparent cases were transient with subsequent re-emergence. Serial ctDNA shows transience of neo-RAS-wildtype phenomenon in mCRC [CCTG CO26]. [ABSTRACT FROM AUTHOR]