ESMO GI Congress 2026

At the ESMO Gastrointestinal Cancers Congress 2026 held in Munich, Germany, Dr. Vittorio Studiale presented the results of a pooled analysis of five randomized clinical trials (FIRE-3, MACBETH, PANAMA, TRIPLETE, VALENTINO) that were conducted by the GONO GI and AIO cooperative groups.

The analysis focused on treatments after progression to first-line anti-EGFR-based therapy in pMMR, RAS/BRAF wild-type metastatic colorectal cancer (mCRC). The standard management for these patients is a second-line switch of both the chemotherapy backbone and the targeted agent. However, in the clinical practice, retreatment with the same anti-EGFR-based regimen is often considered in selected scenarios, especially after treatment holidays or secondary surgery. Robust evidence guiding the choice between these two strategies is lacking.

The study pooled individual data of RAS/BRAF mCRC patients who progressed after first-line chemotherapy + anti-EGFR. Patients were divided into two groups: retreatment (same CT + anti-EGFR, n = 209) and switch (switched CT + antiangiogenic, n = 196). To account for baseline imbalances, adjusted and propensity-score matching (PSM) analyses were performed. Treatment effect was explored according to the anti-EGFR-free interval (aEFI) between the first and second line, applying a 4-month cut-off based on the expected decay time of anti-EGFR resistant clones.

In the full cohort, PFS and ORR did not differ between the two groups. Importantly, a significant interaction emerged between aEFI duration and treatment effect for both parameters (PFS pint <0.001; ORR pint = 0.006). In particular, for patients with an aEFI ≥4 months, retreatment yielded significantly better PFS (aHR: 0.65, p = 0.002) and a trend toward higher ORR. Conversely, for patients with an aEFI <4 months, the switch strategy was superior for both PFS (aHR 1.57 for retreatment, p = 0.002) and ORR (aOR: 0.37, p = 0.011). Finally, OS was significantly longer for the retreatment group (25.8 vs 16.9 months, aHR 0.60, p <0.001), with the OS benefit maintained across both aEFI subgroups (pint = 0.831). These results were confirmed in the PSM cohort (n = 161 per group).

Despite the inherent limitations of a retrospective analysis, these data provide pragmatic evidence for the clinical practice: anti-EGFR retreatment may yield a significant OS benefit compared to a switch strategy in selected patients. Furthermore, the aEFI is an independent predictor of retreatment efficacy in terms of both PFS and ORR, and an anti-EGFR washout of at least 4 months identifies the optimal candidates to maximize the clinical benefit of this approach.