Novel data support the use of liquid biopsy to guide cetuximab rechallenge in metastatic colorectal cancer

Using comprehensive genomic profiling (CGP) with plasma circulating tumour DNA (ctDNA) to identify ‘negative hyperselected’ metastatic colorectal cancer (mCRC) tumours (containing no pathogenic variants for resistance) is being investigated as a promising strategy for maximising efficacy and optimising the use of anti-EGFR therapies in RAS/BRAF wild type (WT) mCRC.

The single-arm, phase II CAPRI-2 GOIM trial was designed to evaluate the efficacy of three sequential lines of cetuximab-based therapy – first-line FOLFIRI plus cetuximab, second-line FOLFOX plus cetuximab and third-line irinotecan plus cetuximab – in patients with RAS/BRAF WT mCRC, with treatment defined by liquid biopsy-CGP at baseline of each line of therapy (ESMO Open. 2025;10:104511).

At the ESMO Gastrointestinal Cancers Congress 2026 (Munich, 1–4 July), novel data were presented comparing the three cetuximab-based therapies in 182 patients with RAS/BRAF V600E WT, microsatellite stable disease who received first-line FOLFIRI plus cetuximab (Abstract 2RO). At least one pathogenic variant for anti-EGFR drug resistance genes was identified by ctDNA in 50 patients (‘positive hyperselected’ cases). During first-line therapy, compared with positive hyperselected patients, negative patients achieved a greater objective response rate (ORR; 78% versus 54%) and a longer median progression-free survival (PFS; 13.8 months versus 9.6 months; hazard ratio [HR] 0.55; 95% confidence interval [CI] 0.39–0.78; p=0.001).

At first-line progression, 75 patients with RAS/BRAF V600E WT ctDNA (55 negative, 20 positive hyperselected) received second-line FOLFOX plus cetuximab. ORR (28% versus 20%) and median PFS (8.3 months versus 5.3 months; HR 0.54; 95% CI 0.31–0.94; p=0.021) were again improved in negative versus positive hyperselected patients. Median OS was 27.4 months in negative patients compared with 15.9 months in positive cases (HR 0.60; 95% CI 0.29–1.24; p=0.170).

For the 182 patients enrolled in the study, the median OS was 39.0 months overall, and when analysed by negative and positive hyperselection, it was not reached in the negative cases and 22.4 months in the positive cases (HR 0.47; 95% CI 0.30–0.73; p=0.001).

“Some tumours clearly remained dependent on EGFR signalling even after radiological progression in carefully selected patients with no clear molecular mechanism of EGFR resistance,” notes Dr Juan Manuel O’Connor from the Instituto Alexander Fleming, Buenos Aires, Argentina. “However, the findings should be interpreted with caution, given the non-randomised design of the study.”

A growing body of evidence suggests that anti-EGFR sensitivity is dynamic rather than permanently lost. For example, the phase II CRICKET study provides early proof of concept that third-line cetuximab plus irinotecan rechallenge may be active in patients with RAS and BRAF WT mCRC who initially responded and then became resistant to the regimen in the first-line (JAMA Oncol. 2019;5:343–350). Similarly, the phase II CHRONOS trial that prospectively investigated the use of ctDNA to guide chemotherapy-free panitumumab rechallenge in patients with RAS WT mCRC, reported a 30% ORR after excluding patients with ≥1 anti-EGFR resistance mutation, suggesting that an interventional liquid biopsy strategy may feasibly be used to guide treatment (Nat Med. 2022;28:1612–1618). More recently, the phase II PARERE trial, which randomised patients with RAS and BRAF WT mCRC to re-treatment with panitumumab followed by regorafenib after progression or the reverse sequence, demonstrated a higher ORR and longer PFS with panitumumab re-treatment compared with regorafenib, regardless of the sequence (Ann Oncol. 2026;37:79–91). Finally, the randomised phase III FIRE-4 study failed to demonstrate an OS benefit with cetuximab rechallenge compared with physician’s choice treatment in patients with RAS WT mCRC who previously responded to first-line cetuximab plus FOLFIRI (J Clin Oncol. 2025;43(Suppl 16):3513). “This suggests that RAS WT status alone may be insufficient to identify patients most likely to respond to rechallenge, and broader molecular profiling, as performed in the CAPRI-2 study, may improve patient selection,” O’Connor concludes.