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

Purpose: In metastatic colorectal cancer (mCRC), mutations drive resistance to anti-epidermal growth factor receptor antibodies. It is unclear whether mutations ever become clonally undetectable.

Methods: CO.26 was a phase II clinical trial that assessed durvalumab + tremelimumab in heavily pretreated mCRC. 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 mutations in their archival tumor tissue, 6.3% (6/95) had undetectable 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 -wildtype (WT) possibly as low as 3.2% (3/95). Fewer patients in the neo--WT group (33%) had greater than four lesions at trial baseline compared with patients with persistent mutations (75%), = .046. The likelihood of synchronous metastases at cancer diagnosis (33% 63%; = .15) or liver metastases at trial baseline (50% 68.5%; = .17) was not significantly different between patients with disappearing versus persistent mutations. Overall survival from stage IV diagnosis (hazard ratio, 0.77 [95% CI, 0.35 to 1.72]; = .52) was not significantly different between those with disappearing versus persistent mutations. The disappearance of mutations was not associated with primary tumor sidedness ( = .41), archival -mutant status ( = .16/1.00/.09), nor baseline ctDNA amplifications ( = 1.00).

Conclusion: We identified a 3.2%-6.3% prevalence of the neo--WT phenomenon in the CO.26 trial. However, 67% of apparent cases were transient with subsequent re-emergence.