*BRAF Mutation and Its Importance in Colorectal Cancer DOI: http://dx.doi.org/10.5772/intechopen.82571*

*Advances in the Molecular Understanding of Colorectal Cancer*

**Agents investigated Study** 

Encorafenib + cetuximab ±

FOLFOX + bevacizumab vs. FOLFOXIRI + bevacizumab

Dabrafenib + panitumumab vs. dabrafenib + trametinib + panitumumab

Dabrafenib + panitumumab

+ trametinib + panitumumab vs. 5-fluorouracil-based chemotherapy + monoclonal

Trametinib + panitumumab

Encorafenib + cetuximab

vs. dabrafenib

antibody

+ alpelisib

binimetinib

**design**

Phase 3, randomised, open label

Phase 3 open label

4 part phase 1/2, open label

Phase 1b/2, open label, dose escalation

Irinotecan + AZD1775 Phase 1b Recruiting

LGK974 ± PDR001 Phase 1 Recruiting

**Status**

Recruiting

Active, not recruiting

Active, not recruiting

Active, not recruiting

**Therapeutic strategy**

+ MEK inhibition

 + selective Wee 1 inhibitor

+ immunotherapy

agent + cytotoxic chemotherapy

+ MEK inhibition

+ PI3K inhibition

NCT02928224 BRAF + EGFR

NCT02906059 Chemotherapy

NCT01351103 PORCN inhibitor

NCT01640405 Antiangiogenesis

NCT01750918 BRAF + EGFR

NCT01719380 BRAF + EGFR

*Updated 7th November 2018.*

**Table 2.**

**ClinicalTrials. gov number**

Immunotherapy also plays a role in the management of metastatic CRC [36]. Pembrolizumab and nivolumab are immune check point inhibitors against programmed death 1 (PD-1) that have demonstrated significant activity against

MSI-high mCRC [72, 73]. Given the strong association between MSI-high and BRAF MT CRC, this represents a possible therapeutic option. The initial trial of pembrolizumab in MSI-high CRC did not include BRAF MT cases; however, a case report

Nivolumab and combination nivolumab with ipilimumab (cytotoxic T-lymphocyte associated protein 4 inhibitor) in MSI-high/dMMR CRC was examined in the phase 2 CheckMate 142 study [73, 75]. 12 of the 74 patients receiving nivolumab harboured a BRAF mutation. An objective response was seen in 3 patients (25%) and 9 patients achieved disease control for greater than 12 weeks. The ORR for combination immunotherapy was greater at 55% in patients with MSI-high BRAF MT CRC, and disease control rate of 79%. Safety data was not reported by mutation status, however, appeared manageable, with 32% experiencing a grade 3 or 4 adverse event, most commonly raised AST. Discontinuation due to a treatment related adverse event was 13%.

BRAF V600E mutations are present in 7–10% of CRC. It represents a population with poor prognosis and a particular clinical phenotype, being more prevalent in

does suggest activity in the MSI-high BRAF MT population [74].

*Ongoing studies investigating different treatment strategies for BRAF MT mCRC.*

**44**

**7. Conclusion**

women, older than 70 years of age, associated with poorly differentiated histology and right-sided tumours. Chemotherapy with the addition of anti-angiogenesis agent remains the current standard of care in the first line metastatic setting. More aggressive, triplet chemotherapy (FOLFOXIRI) may be appropriate in the selected patient. BRAF inhibition has been extensively investigated for second line therapy and beyond and when in combination with EGFR, MEK and PI3K inhibitors have increased response rates, however, PFS and OS remains poor. Ongoing research remains important to improve outcomes in BRAF MT CRC.
