**6.6 BRAF, MEK and EGFR inhibition**

*Advances in the Molecular Understanding of Colorectal Cancer*

factor receptor (HER) 2 and HER3 [55].

opment when BRAF is inhibited [60].

**6.4 BRAF and EGFR inhibition**

observed adverse events.

has been included in treatment guidelines [36].

**6.5 BRAF and MEK inhibition**

mutations [59].

response.

More recently, it has been showed that BRAF inhibition can also lead to up regulation of other receptor tyrosine kinases including human epidermal growth

Activation of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway has also been implicated in BRAF inhibition resistance [56]. PI3K signalling is activated by direct mutational activation or amplification of PIK3CA and AKT1 or loss of PTEN [57]. Approximately 40% of CRC have been shown to have alterations in 1 of 8 PI3K pathway genes, which are almost always mutually exclusive to each other [58]. Genotyping of BRAF MT CRC has showed concomitant PI3KCA and PTEN

The Wnt/β-catenin pathway is also involved in cell proliferation, differentiation and survival and interacts with the RAS-RAF-MEK-ERK pathway at multiple points. It has been identified as an important step in tumourigenesis and alterations in the Wnt pathway have been identified more frequently in BRAF V600E MT CRC patient samples, potentially representing an alternative pathway of tumour devel-

Based on these findings, BRAF inhibition has been combined with a number

In the fore-mentioned phase II "basket" trial, the effect of vemurafenib and cetuximab evaluated in 27 patients with BRAF V600 MT mCRC. The result was marginally improved compared to single-agent treatment. One patient had a partial response (4% ORR) and 69% had stable disease. Median PFS was 3.7 months and median OS was 7.1 months. A pilot trial with combination panitumumab and vemurafenib included 15 patients with BRAF V600E mCRC who had received at least 1 prior line of therapy [61]. 2 patients had confirmed partial response and 6 patients had stable disease, including 2 patients with stability lasting over 6 months. The treatment was well tolerated with fatigue and rash being the most frequently

Other combinations of BRAF and EGFR inhibitors have also been investigated including vemurafenib plus erlotinib [62], encorafenib (LGX818, a highly selective ATP-competitive small molecule RAF kinase inhibitor) plus cetuximab [63] and dabrafenib (a small molecule kinase BRAF inhibitor) plus panitumumab [64]. Response rates in these trials range from 4 to 23%. To improve this outcome, the combination has been combined with chemotherapy in the randomised phase 2 SWOG 1406 study [65]. Interim results of this trial were presented in 2017. The combination of irinotecan and cetuximab with or without vemurafenib was examined in 106 patients. Median PFS was significantly improved with the addition of vemurafenib (4.4 vs. 2.0 months, P < 0.001). Response rate increased from 4 to 16% (P = 0.09). However, there was an increase in grade 3 and 4 adverse events including neutropenia, anaemia and nausea. It was noted that no new safety signals. The data on median OS was immature. Based on these findings, this treatment regime

BRAF and MEK inhibition has been combined in melanoma with greater efficacy and so has been evaluated in the BRAF MT mCRC population. 43 patients were treated with dabrafenib and trametinib [66]. 1 patient achieved a complete response

and 4 patients had a partial response (ORR 12%). 24 patients achieved stable

of different agents in order to attempt to overcome resistance and improve

**42**

Given the role of MEK and ERK in EGFR activation leading to BRAF inhibitor resistance, the triplet combination of BRAF, MEK and EGFR inhibitors have been investigated. Corcoran et al. reported on a trial involving 3 cohorts, dabrafenib and panitumumab (n = 20), dabrafenib, trametinib and panitumumab (n = 91), and trametinib and panitumumab (n = 31) [67].

The ORR for triplet therapy was 21%, compared with 0% with trametinib and panitumumab and 10% with dabrafenib and panitumumab. With the increase in response rate, there was also a corresponding increase in adverse events. 70% of patients on triplet therapy had a grade 3 or 4 adverse event. 18% of patients had an adverse event resulting in study discontinuation, 54% had an adverse event that resulted in dose reduction, and 71% of patients had an adverse event that led to dose interruption or delay. Skin toxicity including rash and dermatitis acneiform occurred in 90% of patients, with 21% having grade 3 or 4 adverse events. Paired pre-treatment and on-treatment biopsies demonstrated that triplet combination produced greater inhibition of ERK than the dabrafenib and panitumumab doublet or the dabrafenib and panitumumab doublet.

It has been suggested that BRAF inhibitors may offset the dermatologic toxicity resulting from MEK or EGFR inhibitors. Mondaca et al. reported on a case of BRAF V600E MT metastatic CRC on clinical trial with dabrafenib, trametinib and panitumumab [68]. Dabrafenib dose reductions for neutropenia were associated with increased skin toxicity, which subsequently improved with increasing the dose. This case highlights the importance of dose intensity of BRAF inhibitors with used in combination regimens.
