**6.7 Other therapeutic strategies and current trials**

Current therapeutic investigations in the BRAF MT mCRC field involve multiple targeted therapies aimed at overcoming acquired resistance to MAPK pathway inhibition.

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 (NCT01337765, NCT01363232).

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**.


#### **Table 2.**

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

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

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%.
