BRICKET

Based on the results of the phase III BEACON study, combination of encorafenib and cetuximab is currently the standard of care treatment for pre-treated patients with BRAF^V600E mutated mCRC.
Post-hoc analyses of this pivotal study recently described the MAPK pathway reactivation (i.e., gene mutation in KRAS, NRAS, and MAP2K1, and/or amplification of
MET, KRAS, BRAF and IGFR1) as the most common mechanism of acquired resistance to the dual BRAF and EGFR inhibition.
To date, after failure of encorafenib and cetuximab, subsequent conventional therapeutic options for patients with BRAF^V600E mutated mCRC are poorly effective and burdened by not negligible toxicities.
Moreover, retreatment strategies with anti-EGFR monoclonal antibodies are recognized as a valuable therapeutic option in patients who achieved benefit from a previous exposure to an anti-EGFR-based treatment and not bearing known mechanisms of acquired resistance to EGFR inhibition (i.e., RAS mutation) on ctDNA at the time of retreatment.
Drawing from these considerations, there is the potential for the encorafenib plus cetuximab regimen to be efficacious as a strategy of retreatment in patients with BRAF^V600E mutated mCRC, who experienced an initial benefit and then secondary resistance to this targeted treatment. After an intervening anti-BRAF and anti-EGFR free line of therapy, ctDNA analysis of known resistance alterations may guide the selection of patients more likely to benefit from an encorafenib plus cetuximab retreatment.
Accordingly, we designed the present proof-of-concept, multicenter, open-label, single arm one-stage phase II study of a ctDNA-guided retreatment strategy with encorafenib plus cetuximab in pre-treated BRAF^V600E mutated mCRC, with no detectable mutations in KRAS, NRAS, MAP2K1 and no amplification of MET gene on ctDNA at the time of retreatment.

Inclusion criteria

– BRAF^V600E mutated status of primary colorectal cancer and/or related metastasis, by local laboratory assessment according to standard procedures by means of molecular assay on genomic DNA;
– Previous treatment with encorafenib plus cetuximab with or without chemotherapy (i.e., ±FOLFOX/FOLFIRI) in any line, producing a RECIST 1.1 complete/partial response or disease stabilisation, with a PFS of this treatment lasting at least 6 months;
– Documentation of RECIST 1.1 disease progression during or after the end of the previous exposure to encorafenib plus cetuximab ± chemotherapy;
– One intervening line of treatment, not including any BRAF and EGFR inhibitor, between the end of first exposure to encorafenib plus cetuximab ± chemotherapy and the time of screening;
– At least 4 months elapsed between the end of the previous exposure to encorafenib plus cetuximab ± chemotherapy and the retreatment with encorafenib plus cetuximab;
– Previous treatment with immune checkpoint inhibitors (anti-PD-1/PD-L1 alone or in combination with anti-CTLA-4 agent), in the case of MSI-H or dMMR mCRC;
– BRAF^V600E mutated status of ctDNA at screening (central laboratory assessment by means of GUARDANT360 CDx, Guardant Health);
– KRAS, NRAS, MAP2K1 wild-type status and MET not amplified status on ctDNA at screening;

Exclusion criteria

– Discontinuation of previous treatment with encorafenib and/or cetuximab with or without chemotherapy due to encorafenib- and/or cetuximab-related adverse events;

The primary objective of this study is to evaluate the activity, in terms of best response
according to RECIST criteria 1.1 as assessed by the local investigator, of the ctDNA-guided retreatment with encorafenib plus cetuximab in BRAF^V600E mutated mCRC patients experiencing benefit from previous exposure to encorafenib plus cetuximab (+/- chemotherapy) and with BRAF^V600E mutated, KRAS, NRAS and MAP2K1 wild-type and MET not amplified status on ctDNA at the time of study entry.