**6.4 BRAF and EGFR inhibition**

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 observed adverse events.

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 has been included in treatment guidelines [36].

#### **6.5 BRAF and MEK inhibition**

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

**43**

*BRAF Mutation and Its Importance in Colorectal Cancer*

disease (56%). During-treatment biopsies in 9 patients showed reduced levels of ERK compared with pre-treatment biopsies. It is suggested that combination BRAF and MEK inhibition could be a potential therapeutic backbone for the addition of

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

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

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

Current therapeutic investigations in the BRAF MT mCRC field involve multiple

targeted therapies aimed at overcoming acquired resistance to MAPK pathway

One such combination is encorafenib, cetuximab and alpelisib. Alpelisib (BYL719) specifically inhibits the alpha subunit of PI3K. A phase 1b dose escalation study included 2 arms, encorafenib plus cetuximab vs. triplet therapy with encorafenib, cetuximab and alpelisib [69]. Triplet therapy was showed to be active with an ORR of 18% and impressively a disease control rate of 92.8%. This combination has been investigated further in a phase 2 trial [63]. 102 patients with refractory BRAF MT CRC were randomised to doublet or triplet therapy. Progression free survival was the primary endpoint. Interim data following 73 events were released and showed no statistical difference between doublet and triplet therapy with HR 0.69 (P = 0.064) and median PFS of 4.2 vs. 5.4 months. Grade 3 and 4 adverse events were higher in the triplet arm, including anaemia and hyperglycaemia. Further investigations with other PI3K inhibitors are currently underway; however, the efficacy of PI3K inhibition remains unclear

Other potential targets include BRAF and AKT inhibition [70], BRAF, EGFR and HER2 inhibition [55], ERK inhibition alone or in combination with BRAF inhibition [71] and Wnt/β-catenin pathway inhibition (NCT02278133) **Table 2**.

*DOI: http://dx.doi.org/10.5772/intechopen.82571*

other agents including EGFR inhibitors.

**6.6 BRAF, MEK and EGFR inhibition**

trametinib and panitumumab (n = 31) [67].

or the dabrafenib and panitumumab doublet.

**6.7 Other therapeutic strategies and current trials**

combination regimens.

(NCT01337765, NCT01363232).

inhibition.

disease (56%). During-treatment biopsies in 9 patients showed reduced levels of ERK compared with pre-treatment biopsies. It is suggested that combination BRAF and MEK inhibition could be a potential therapeutic backbone for the addition of other agents including EGFR inhibitors.
