ESMO Congress 2026

The position of encorafenib plus cetuximab in BRAF V600E metastatic colorectal cancer was established by the BEACON CRC phase 3 trial: 665 patients who had progressed after one or two prior regimens were randomized to the triplet of encorafenib, binimetinib and cetuximab, the doublet of encorafenib plus cetuximab, or the investigators' choice control of cetuximab plus irinotecan or FOLFIRI, with overall survival (OS) and objective response rate (ORR) as primary endpoints ^[1]. Updated follow-up showed median OS of 9.3 months for the triplet versus 5.9 months for control, and both the doublet and triplet improved OS and ORR over control ^[4]; the ASCO guideline accordingly recommends encorafenib plus cetuximab for previously treated BRAF V600E mCRC ^[3]. Notably, BEACON's control arm itself was cetuximab combined with the irinotecan or FOLFIRI chemotherapy backbone ^[1], which provides a direct reference for this meeting's discussion of switching the chemo backbone while keeping the targeted pair.

What was reported at ESMO26 is the ECLYPse phase II trial: in BRAF V600E mCRC patients progressing on encorafenib plus cetuximab (EC), EC was continued beyond progression in combination with FOLFIRI. The numbers from the floor: median PFS 7.1 months, median OS not reached (NR), ORR 15%. Commentators called it an interesting signal to continue EC, while asking what drives the benefit and calling for more translational data. The lower-GI panel also raised a framing question: post-BREAKWATER, if a patient progresses on FOLFOX + EC, could we switch to FOLFIRI + EC or vice versa, that is, can changing the chemo backbone preserve the targeted benefit beyond progression.

A separate study mentioned in the same posts is BRICKET by GONO: re-treatment with encorafenib plus cetuximab in 16 ctDNA-selected BRAF V600E mCRC patients yielded a median PFS of only 2.9 months, with resistance ctDNA mutations detected in 11 of 30 patients, prompting the reminder that molecular selection alone may not be enough. This contrasts with ECLYPse: the former continues the targeted pair beyond progression with a new chemo backbone, while the latter is re-challenge without changing the backbone, two threads pointing to the same clinical question of how to preserve the value of the EC combination after resistance.

Relative to existing knowledge, ECLYPse advances the concept of continuing targeted therapy beyond EC progression from idea to phase II efficacy numbers: a median PFS of 7.1 months suggests the strategy deserves validation in larger samples, while BRICKET's 2.9 months suggests that simple re-challenge or ctDNA selection is insufficient to reproduce efficacy. The limitations are equally clear: ECLYPse is phase II, with sample size and design details undisclosed, OS immature, and ORR only 15%; moreover, BEACON's population had progressed after one or two prior regimens ^[1], which differs from ECLYPse's population progressing after EC therapy, so the numbers on either side cannot be compared directly, and the mechanism of benefit still awaits translational data.