As part of our American Society of Clinical Oncology (ASCO) 2025 coverage, we asked Dr Frank Sinicrope (Mayo Clinic, Rochester, MN, USA) to share his perspective on the top three most promising clinical trial updates in colon cancer presented at the meeting, held on May 30 to June 3 2025 in Chicago, IL, USA.
Alliance N0147
Post-Surgery ctDNA Predicts Poor Outcomes in Stage III Colon Cancer
We presented new findings from the Alliance N0147 clinical trial (Abstract 3504), which investigated circulating tumour DNA (ctDNA) in patients with stage III colon cancer. We used a tissue-free assay – Guardant Reveal™ – and assessed outcomes in patients treated with FOLFOX chemotherapy with or without cetuximab, an anti-EGFR antibody. ctDNA was detected in approximately 20% of patients at a median of 42 days post-surgery, and its presence was highly prognostic, consistently associated with worse survival across all patient subgroups.
Two key findings stood out. First, patients who were considered low risk based on tumour (T) and nodal (N) staging – and who typically receive three months of adjuvant chemotherapy – had significantly worse outcomes if ctDNA was detected after surgery. Second, while ctDNA-negative patients had a three-year disease-free survival (DFS) rate of 89%, ctDNA-positive patients had a markedly lower DFS of 44.7%. This suggests that even those deemed low risk by conventional staging may in fact be at high risk of recurrence if ctDNA is present.
We also observed an unexpected result in patients with deficient mismatch repair (dMMR) tumours. ctDNA-positive patients in this subgroup had worse survival than ctDNA-positive patients with proficient mismatch repair (pMMR). The underlying reason for this finding remains unclear, but it may be related to BRAF V600E mutations – an area that warrants further investigation. This observation also highlights the potential role of immunotherapy in the dMMR population. Ongoing trials such as ATOMIC, which includes serial blood sampling, may help determine whether immunotherapy can effectively clear ctDNA in these patients.
BREAKWATER
First-Line Encorafenib + Cetuximab + mFOLFOX6 Doubles OS in BRAF V600E-Mutant mCRC
The phase III BREAKWATER study (Late-breaking Abstract LBA3500), evaluated first-line treatment with encorafenib plus cetuximab with or without mFOLFOX6 versus standard chemotherapy in patients with BRAF V600E-mutant metastatic colorectal cancer. The results were striking: the triplet regimen significantly improved both progression-free survival (median 12.8 vs 7.1 months; HR 0.53) and overall survival (median 30.3 vs 15.1 months; HR 0.49) compared to standard therapy.
The safety profile was consistent with what we’ve seen before, though serious adverse events occurred in 46% of patients receiving the triplet therapy. Nonetheless, these results support encorafenib + cetuximab + mFOLFOX6 as a potential new standard of care for this high-risk population. The survival outcomes were seen by many as unexpectedly high and may represent a true shift in frontline treatment for patients with BRAF-mutant tumours, who typically have a poor prognosis and limited options.
DYNAMIC-III
No Benefit from ctDNA-Guided Chemotherapy Escalation in Stage III Colon Cancer
Improving outcomes for ctDNA-positive patients remains a critical challenge. The DYNAMIC-III trial (Abstract 3503) explored whether escalating chemotherapy in ctDNA-positive patients using the FOLFOXIRI regimen could improve outcomes. Among 259 ctDNA-positive patients, those who received treatment escalation based on ctDNA results had a similar 2-year recurrence-free survival (RFS) to those who received standard adjuvant chemotherapy (52% vs 61%; HR 1.11, P = 0.6). In other words, intensified chemotherapy did not provide added benefit.
These results underscore the limitations of chemotherapy escalation in this context. While ctDNA is an effective tool for identifying high-risk patients, we clearly need alternative treatment strategies beyond simply intensifying existing regimens.
View full #ASCO25 coverage here!
Disclosures: Frank Sinicrope discloses employment at MedVal (I); stock and other ownership interests at Lilly; a consulting or advisory role with Guardant Health and Roche; institution research funding from Ventana Medical Systems; patents, royalties and other intellectual property: patent royalty related to immune markers in colon cancer. Patent jointly held between himself and Roche/Ventana Medical Systems (Institution).
This content has been developed independently by Touch Medical Media for touchONCOLOGY. It is not affiliated with the American Society of Clinical Oncology (ASCO). Views expressed are the speaker’s own and do not necessarily reflect the views of Touch Medical Media.
Cite: #ASCO25 highlights: Dr Frank Sinicrope highlights top colon cancer trial updates. touchONCOLOGY. June 24th, 2025.
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