Overcoming Resistance to Agents Treating BRAF Mutations in Colorectal Cancer

Anuhya Kommalapati, MD

Anuhya Kommalapati, MD

Precision and personalized medicinetargeting 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 inKRASandBRAFgenes.¹BRAFhas 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,BRAFmutations were thought to be an ominous prognostic sign in CRC, occurring in 5% to 10% of cases.²The majority ofBRAFmutations, about 90% in CRC, are a missense mutation (thymine to adenine) at codon 600, resulting in the substitution of glutamic acid for valine (BRAFV600E mutation).^3,4This 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.^2-4Prior studies have demonstrated a strong association ofBRAFV600E with right- sided colon cancers; female sex; poorly differentiated, mucinous pathology; and higher rates of peritoneal metastases.⁴In addition,BRAFV600E tumors have a high rate of microsatellite instability (MSI), tumor mutational burden, and DNA epigenetic modification and hyper- methylation.5 In contrast, other types ofBRAFmutations tend to be left-sided and low-grade tumors.⁴

Earlier studies that evaluated the standard-of-care chemotherapy regimen fluoropyrimidine in combination with irinotecan or oxaliplatin inBRAF-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.⁶Acknowledging the limitations of the small sample size in this study, FOLFOXIRI plus bevacizumab is an option for first-line treatment ofBRAF-mutated CRC.

In terms of targeted therapies, single-agent anti-EGFR monoclonal antibodies cetuximab (Erbitux) and panitumumab (Vectibix) have had modest to no benefit inBRAF-mutated CRC.7 Similar disappointing results were seen with BRAF-targeted therapies such as vemurafenib (Zelboraf ) and encorafenib (Braftovi) inBRAF-mutated CRC despite promising results inBRAF-mutated melanoma.^8,9Preclinical 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.¹⁰The triplet therapy was later evaluated head-to-head with cetuximab and irinotecan doublet therapy in an open-label, randomized trial in patients with metastaticBRAF-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,P<.001).¹¹Given 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 inBRAFV600E—mutated CRC.¹²It is important to note that arthralgias, keratoacanthomas, and nausea are common adverse events (AEs) of the VIC regimen.

Richard D. Kim, MD

Richard D. Kim, MD

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 withBRAFV600E—mutated CRC.¹³Even 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 withBRAF-mutant CRC >3 AEs. This shows that the doublet therapy may be a reasonable option in patients who cannot tolerate the triplet therapy.

Despite the progress in the treatment ofBRAF-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 forBRAF-targeted therapy.¹⁴Thus, 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 inBRAF-mutated CRC demonstrated that acquiredNRASandKRASmutations developed in about half of the study cohort (48%), indicating that acquired resistance is still a concern.¹⁵

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 ofBRAFV600E 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 theBRAFV600E mutation and associated tumor biology, leading to trials that can identify the most effective, well-tolerated targeted therapeutic regimens.

In summary, gettingBRAFmutational testing along with the standard MSI,NRAS, andKRAStesting 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.

References

1. De Roock W, Claes B, Bernasconi D, et al. Effects ofKRAS,BRAF,NRAS, andPIK3CAmutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis.Lancet Oncol.2010;11(8):753-762. doi: 10.1016/S1470-2045(10)70130-3.
2. Morris V, Overman MJ, Jiang ZQ, et al. Progression-free survival remains poor over sequential lines of systemic therapy in patients withBRAF-mutated colorectal cancer.Clin Colorectal Cancer.2014;13(3):164-171. doi: 10.1016/j.clcc.2014.06.001.
3. Michaloglou C, Vredeveld LC, Mooi WJ, Peeper DS. BRAF(E600) in benign and malignant human tumours.Oncogene.2008; 27(7):877-895. doi: 10.1038/sj.onc.1210704.
4. Luu L-J, Price TJ. BRAF mutation and its importance in colorectal cancer. In: Segelov E, ed. Advances in the Molecular Understanding of Colorectal Cancer. London, United Kingdom: IntechOpen; 2019. intechopen.com/books/advances-in-the-molecular-understanding- of-colorectal-cancer/braf-mutation-and-its-importance-in- colorectal-cancer. Accessed October 16, 2019.
5. Lee HM, Morris V, Napolitano S, Kopetz S. Evolving strategiesfor the management ofBRAF-mutant metastatic colorectal cancer.Oncology(Williston Park). 2019;33(6):206-211. cancernetwork.com/article/evolving-strategies-management- braf-mutant-metastatic-colorectal-cancer .
6. Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open- label, phase 3 TRIBE study.Lancet Oncol. 2015;16(13):1306-1315. doi: 10.1016/S1470-2045(15)00122-9.
7. Karapetis CS, Jonker D, Daneshmand M, et al; NCIC Clinical Trials Group and the Australasian Gastro-Intestinal Trials Group.PIK3CA,BRAF, and PTEN status and benefit from cetuximab in the treatment of advanced colorectal cancer—results from NCIC CTG/AGITG CO.17.Clin Cancer Res.2014;20(3):744-753. doi: 10.1158/1078-0432.CCR-13-0606.
8. Kopetz S, Desai J, Chan E, et al. Phase II pilot study of vemurafenib in patients with metastaticBRAF-mutated colorectal cancer.J Clin Oncol.2015;33(34):4032-4038. doi: 10.1200/JCO.2015.63.2497.
9. Gomez-Roca CA, Delord J, Robert C, et al. Encorafenib (LGX818), an oral BRAF inhibitor, in patients (pts) with BRAF V600E metastatic colorectal cancer (mCRC): results of dose expansion in an open-label, phase 1 study.Ann Oncol.2014;25(suppl 4; abstr 535P). doi: 10.1093/annonc/mdu333.38.
10. Hong DS, Morris VK, El Osta B, et al. Phase IB study of vemurafenib in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer withBRAFV600E mutation.Cancer Discov.2016;6(12):1352-1365. doi: 10.1158/2159-8290.CD-16-0050.
11. Kopetz S, McDonough SL, Lenz H-J, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406).J Clin Oncol.2017;35(suppl 15; abstr 3505). doi: 10.1200/ JCO.2017.35.15_suppl.3505.
12. NCCN Clinical Practice Guidelines in Oncology. Colon Cancer, version 3.2019. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/colon.pdf. Published September 26, 2019. Accessed October 16, 2019.
13. Kopetz S, Grothey A, Van Cutsem E, et al. BEACON CRC: a randomized, 3-arm, phase 3 study of encorafenib and cetuximab with or without binimetinib vs. choice of either irinotecan or FOLFIRI plus cetuximab in BRAF V600E—mutant metastatic colorectal cancer.Ann Oncol.2019;30(suppl 4; abstr LBA-006). doi: 10.1093/annonc/mdz183.004.
14. Mao M, Tian F, Mariadason JM, et al. Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents.Clin Cancer Res. 2013;19(3):657-667. doi: 10.1158/1078-0432.CCR-11-1446.
15. Corcoran RB, Andre T, Atreya CE, et al. Combined BRAF, EGFR, and MEK inhibition in patients with BRAF V600E- mutant colorectal cancer.Cancer Discov. 2018;8(4):428-443. doi: 10.1158/2159-8290.CD-17-1226. 16. Lochhead P, Kuchiba A, Imamura Y, et al. Microsatellite instability andBRAFmutation testing in colorectal cancer prognostication.J Natl Cancer Inst. 2013;105(15):1151-1156. doi: 10.1093/jnci/djt173.