How would you treat metastatic colon CA with BRAF non-V600E mutation?

BRAF mutated metastatic colorectal cancer is about 7-10% of all metastatic colorectal cancer. When we discuss BRAF mutated metastatic colorectal cancer, we mainly/only focus on BRAF V600E mutated metastatic colorectal cancer, however, about 22% of BRAF mutations are Non-V600E which means about 2% of metastatic colorectal cancer [Dankner et al., PMID 29540830]. Given the large number of metastatic colorectal cancer patients, this is certainly something we see in the clinic from time to time and we should know about. 

BRAF mutations are classified into three classes which have different characteristics.

1. BRAF V600 mutations are class I and lead to RAS-independent active monomer. The BEACON regimen (Encorafenib and cetuximab) is the current standard of care in second line setting while ongoing BREAKWATER study will try to address the role of combination chemotherapy with BEACON regimen in the first line setting (NCT04607421) given the ANCHOR study did not show great PFS by first line BEACON regimen. 
2. Class 2 BRAF mutations are RAS-independent activated dimers.
3. Class 3 BRAF mutations are kinase impaired and their signaling pathway is RAS-dependent and in theory, should still respond to EGFR inhibitor. 

This paper has a nice table listed/classified all BRAF mutations (Yao et al., PMID 28783719).

There was a retrospective study reported in 2017 which showed patients with BRAF non-V600E mutated metastatic colorectal cancer had better clinical outcomes (even better than BRAF WT patients) (Jones et al., PMID 28486044). However, the study did not differentiate class II or class III so we are not sure if the better clinical outcome is mainly driven by class III mutations. 

In the clinical setting, there is very limited data to guide our targeted treatment for class 2 and class 3 BRAF mutated metastatic colorectal cancer patients. Systemic chemotherapy with bevacizumab would still be the treatment choice.

Study results regarding response to epithelial growth factor receptor inhibitor (EGFRi) have not been consistent. Some studies suggested class 3 mutations may still respond to EGFRi (Yao et al., PMID 28783719) (Yaeger et al., PMID 31515458) while some studies showed class 3 mutation did not respond to EGFRi (even in RAS WT patients) Johnson et al., PMID 32914034). 

When I see a non-V600E BRAF mutated metastatic colorectal cancer, I only use sytemic chemotherapy with bevacizumab for class 2 mutated patients. For class 3 mutated patients, usually their clinical outcome is quite good and I may consider EGFRi challenge as the last resort only if the tumor does not have concurrent RAS mutation. 

Given the small patient population with non-V600E BRAF mutated metastatic colorectal cancer, it is very difficult to get a large study so most of our knowledge is based on retrospective studies with limited patient numbers. Hopefully, we will be able to develop more effective treatments for these patients (medications targeting the WEE1, MAPK/ERK pathway could be something in the future).