Anuhya Kommalapati, MD

targeting driver mutations has revolutionized cancer care in the past decade. Targeted therapy has entered the world of colorectal cancer (CRC) research with the identification of mutations in

has a presence in various malignancies, such as thyroid, melanoma, hairy cell leukemia, and non small cell lung cancer. Similar to the story of the HER2 receptor in breast cancer,

mutations were thought to be an ominous prognostic sign in CRC, occurring in 5% to 10% of cases.

mutations, about 90% in CRC, are a missense mutation (thymine to adenine) at codon 600, resulting in the substitution of glutamic acid for valine (

This mutation is known to hyperactivate the kinase activity of BRAF, rendering it and the downstream mitogen- activated protein kinase pathway constitutively active, thus promoting tumor cell proliferation and potentiating the CRC tumorigenesis.

Prior studies have demonstrated a strong association of

V600E with right- sided colon cancers; female sex; poorly differentiated, mucinous pathology; and higher rates of peritoneal metastases.

V600E tumors have a high rate of microsatellite instability (MSI), tumor mutational burden, and DNA epigenetic modification and hyper- methylation.5 In contrast, other types of

mutations tend to be left-sided and low-grade tumors.

Earlier studies that evaluated the standard-of-care chemotherapy regimen fluoropyrimidine in combination with irinotecan or oxaliplatin in

-mutated CRC did not produce encouraging results, irrespective of the combinations used.2 However, a subgroup analysis of the TRIBE study showed the median overall survival (OS) in patients treated with fluorouracil/leucovorin/oxaliplatin/irinotecan (FOLFOXIRI) plus bevacizumab (Avastin) was 19.0 months compared with 10.7 months in the fluorouracil/leucovorin/irinotecan plus bevacizumab arm for patients with BRAF-mutant CRC.

Acknowledging the limitations of the small sample size in this study, FOLFOXIRI plus bevacizumab is an option for first-line treatment of

In terms of targeted therapies, single-agent anti-EGFR monoclonal antibodies cetuximab (Erbitux) and panitumumab (Vectibix) have had modest to no benefit in

-mutated CRC.7 Similar disappointing results were seen with BRAF-targeted therapies such as vemurafenib (Zelboraf ) and encorafenib (Braftovi) in

-mutated CRC despite promising results in

Preclinical studies demonstrated the alternate EGFR pathway activation as a possible mechanism of resistance to BRAF inhibitors. With this knowledge, a phase I trial evaluated vemurafenib in combination with cetuximab and irinotecan, with encouraging results showing a progression-free survival (PFS) benefit of 7.7 months.

The triplet therapy was later evaluated head-to-head with cetuximab and irinotecan doublet therapy in an open-label, randomized trial in patients with metastatic

-mutant CRC who failed first- and/ or second-line therapy. The triplet therapy resulted in a 67% disease control rate versus 22% in the doublet arm. Indeed, median PFS was significantly better in the cohort that received triplet therapy (4.4 vs 2.0 months,

Given these encouraging results, the triplet therapy, known as VIC therapy, is now currently recommended in the National Comprehensive Cancer Network Guideline and has become an option for second- or third-line therapy in

It is important to note that arthralgias, keratoacanthomas, and nausea are common adverse events (AEs) of the VIC regimen.

Another triplet therapy of agents encorafenib, binimetinib (Mektovi), and cetuximab targeting BRAF, MEK, and EGFR pathways, respectively, showed exciting results in terms of objective response rates (26% vs 2% with the control) and median OS (9.0 vs 5.4 months with the control) in the randomized phase III BEACON CRC trial involving 665 patients with

Even though the trial was not intended to compare the doublet regimen of encorafenib and cetuximab with the triplet regimen, median OS was 8.45 months for the doublet arm, which is similar to that observed with the triplet regimen. The doublet therapy had a marginally better safety profile compared with that of the triplet therapy, with 50% and 58% of patients, respectively, having grade for patients with

-mutant CRC >3 AEs. This shows that the doublet therapy may be a reasonable option in patients who cannot tolerate the triplet therapy.

-mutant CRC, resistance to the BRAF inhibitors will eventually occur. Therefore, better elucidation of the mechanisms of resistance has become an area of active investigation.

PI3K/AKT pathway activation has also been implicated as a possible resistance mechanism for

Thus, a combination of agents such as EGFR, MEK, and BRAF inhibitors that target all resistance pathways (EGFR, PI3K/mTOR) seems to be rational for overcoming resistance. However, one multi-institutional study that evaluated various combination regimens targeting BRAF, MEK, and EGFR pathways in

mutations developed in about half of the study cohort (48%), indicating that acquired resistance is still a concern.

What does this mean? This highlights the need for further research and understanding of resistance mechanisms and identification of agents that specifically target them. With scientific advancements such as next- generation sequencing and circulating tumor markers, we have come a long way. Given the association and overlap of

V600E mutations with a high number of MSI, DNA hyper- methylation, and epigenetic modifications,16 checkpoint inhibitors and histone deacetylase (HDAC) inhibitors may play a role in this CRC cohort. Preclinical rationale suggests that epigenetic targeting with DNA methyl- transferase inhibitors or HDAC inhibitors in combination with targeted therapy or immunotherapy may overcome BRAF resistance. In the end, it is important that we understand the interplay between the

V600E mutation and associated tumor biology, leading to trials that can identify the most effective, well-tolerated targeted therapeutic regimens.

mutational testing along with the standard MSI,

testing in patients with CRC helps determine the optimal therapeutic regimen. Future studies that evaluate the role of HDAC inhibitors or checkpoint inhibitors and other combination therapies detailed above will, hopefully, provide additional insight or options along with the combination therapies targeting EGFR, MEK, and BRAF in these less common but dismal variants of CRC.

De Roock W, Claes B, Bernasconi D, et al. Effects of

mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis.

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Articles

Precision and personalized medicine targeting driver mutations has revolutionized cancer care in the past decade. Targeted therapy has entered the world of colorectal cancer research with the identification of mutations in KRAS and BRAF genes.

Anuhya Kommalapati, MD | Authors

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Overcoming Resistance to Agents Treating BRAF Mutations in Colorectal Cancer