Reason for request

New indication

Key points

Favourable opinion for reimbursement in the treatment of adult patients with metastatic colorectal cancer with a BRAF V600E mutation, who have received prior systemic therapy.

What therapeutic improvement?

Therapeutic improvement compared to treatment with irinotecan/cetuximab or FOLFIRI/cetuximab.

Role in the care pathway?

Currently, in the absence of a specific treatment for BRAF mutation in metastatic colorectal cancer (mCRC), patients with a BRAF V600E mutation are treated with the same drugs as other mCRC cases with wild RAS status. The second-line treatment of these patients with wild RAS mCRC depends on the first-line treatments received. It is primarily based on chemotherapy, usually combined with targeted anti-VEGF or anti-EGFR therapy. The anti-VEGF therapies indicated in this situation are AVASTIN (bevacizumab, indicated in combination with fluoropyrimidine-based chemotherapy), ZALTRAP (aflibercept, indicated in combination with FOLFIRI chemotherapy in the treatment of resistant mCRC or that has progressed following oxaliplatin-based treatment) or CYRAMZA (ramucirumab) and the anti-EGFR therapies are ERBITUX (cetuximab) or VECTIBIX (panitumumab). In the event of non-eligibility for these medicinal products, the salvage therapies LONSURF (trifluridine/ tipiracil) or STIVARGA (regorafenib) may be considered. According to the ESMO 2016 European guidelines and the SNFGE 2020 French guidelines, for second-line therapy it is recommended to switch to a different chemotherapy protocol to that used during first-line therapy. Combination with bevacizumab (or aflibercept if the FOLFOX protocol was used during first-line therapy) is recommended in most situations. In the event of use of an anti-EGFR or bevacizumab during first-line therapy, anti-EGFR treatments are not recommended as second-line therapy. In the event of first-line treatment with the FOLFOXIRI protocol + bevacizumab (recommended in the case of BRAF mutation), treatment with cetuximab or panitumumab combined with irinotecan is recommended. Patients not treated with bevacizumab in the context of its combination with chemotherapy during first-line treatment may receive this drug in the event of disease progression if they are eligible for this targeted therapy.

Role of the medicinal product in the care pathway

The Committee considers that the encorafenib-cetuximab combination is a second and later-line treatment for metastatic colorectal cancer with a BRAF V600E mutation. In the absence of available data in patients with an ECOG score of 2 or more, the Committee recommends that the decision to initiate the treatment in these patients be discussed during a multidisciplinary team meeting. Regular dermatological monitoring is necessary during treatment.

Special recommendations

Given the important identified risk of the development of skin cancers under encorafenib-cetuximab treatment, the Committee recommends regular dermatological monitoring throughout treatment.

Clinical Benefit


The Committee deems that the clinical benefit of BRAFTOVI (encorafenib) in combination with cetuximab is substantial in the MA indication.

Clinical Added Value



  • demonstration, in an open-label phase 3 study, of the superiority of the encorafenib/cetuximab combination compared to irinotecan/cetuximab or FOLFIRI/cetuximab combinations in terms of overall survival and progression-free survival, with absolute improvements of 3 months and 2.7 months respectively (ranked secondary endpoints),
  • the favourable general safety profile compared to the comparator group,

but also:

  • the methodological limitations of the study, notably related to the population included and the comparator, considered to be non-optimal for all the study patients,
  • the reported toxicity in terms of increased risk of skin cancers under encorafenib/cetuximab (3.2% versus 0%),
  • the absence of robust quality of life data, the Committee considers that the encorafenib/cetuximab combination provides moderate clinical added value (CAV III) compared to treatment with irinotecan/cetuximab or FOLFIRI/cetuximab.

The Committee considers that the encorafenib/cetuximab combination provides moderate clinical added value (CAV III) compared to treatment with irinotecan/cetuximab or FOLFIRI/cetuximab.



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