Encorafenib and cetuximab (EC) in combination with chemotherapy as first-line treatment for the first time

BRAFV600E mutations are found in approximately 10% of metastatic colorectal cancers. Although not common, they are related to a negative prognosis. Patients with them are generally resistant to therapies and rapidly develop resistance to treatments, and no substantial progress has been made in their treatment until recently. Preliminary data from safety lead-in has been presented on a new clinical trial, the BREAKWATER study, following on from the first BEACON trial, to assess safety, PK data, and anti-tumor activity in first-line treatment with a combination of encorafenib and cetuximab with chemotherapy improves the results of chemotherapy alone in these patients with BRAFV600E mutations.

In the 1L setting, the ORR of EC + mFOLFOX6 and EC + FOLFIRI was 68.4% and 66.7% in comparison with the 2L setting was 50% and 61.1%. EC + chemotherapy was generally tolerable, without new safety signals. For EC + mFOLFOX6, steady state encorafenib did not markedly alter oxaliplatin exposures. Preliminary promising antitumor activity was seen in participants EC + mFOLFOX6/FOLFIRI as 1L or 2L therapy for BRAFV600E mCRC, supporting the ongoing Phase III study. These results are particularly encouraging when compared with historical results of 1L chemotherapy for the treatment of BRAFV600E mCRC. Although the efficacy data is not complete, as it was not the objective of these first Phases of the study, it suggests there is sufficient promising anti-tumor activity in all patients who received the different drug combinations to justify continuing the phase III trial, which is now underway. The results are especially promising if compared to the historic results of chemotherapy as the first-line treatment for patients with metastatic colorectal cancer and a BRAFV600E mutation.

Conclusion- This BREAKWATER study seeks to answer whether a higher response rate will be observed in the frontline setting. Additionally, the trial will explore whether there is a similar synergy between cytotoxic and targeted therapies in this patient population as has been observed in other settings in CRC. One of the main conclusions of the study is that in general, the combination of encorafenib and cetuximab with chemotherapy was generally tolerable. And have also seen that encorafenib does not notably alter exposures to oxaliplatin when mFOLFOX6 is used giving potential coverage across all lines of therapies results from this BREAKWATER study will be crucial for Pfizer and help gain a stronghold in the CRC landscape.

Expert Opinion: “The most novel aspect of this study is that for the first time it assesses this combination as 1L treatment, as up to now, it has only been tried in more advanced stages of the disease when patients have progressed on to other treatments”.

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