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Potential Innovative Breakthroughs for BRAF V600E Mutated Metastatic Colorectal Cancer: What Does the Future Hold?

Jane E. Rogers, PharmD BCOP
Pharmacy Clinical Service
University of Texas MD Anderson Cancer Center
Houston, TX


Overview of Metastatic Colorectal Cancer
Substantial improvements in localized and systemic treatment modalities have increased the overall survival (OS) of metastatic colorectal cancer (mCRC) to approximately 30 months.1-2 Despite these improvements, mCRC clearly remains a heterogeneous disease with a 5-year OS of only 13%.3 Publications continue to reveal additional heterogeneity to decipher outcome differences and recognize unmet needs. Recent distinctions in antineoplastic predictive outcomes and prognostic differences in age, mutational analysis, and primary tumor location are surfacing (Table 1-see PDF).2,4,5

Critical Intracellular Pathway: MAPK Pathway
The epidermal growth factor receptor (EGFR)–mediated mitogen-activated protein kinase (MAPK) signaling pathway plays a significant role in mCRC.6 The MAPK signaling pathway is activated by extracellular signals that initiate a downstream cascade of phosphorylation from one protein to the next, leading to transcription and cell proliferation.6,7 The downstream cascade consists of rat sarcoma (RAS)/rapid accelerated fibrosarcoma (RAF)/mitogen-activated protein (MEK)/extracellular signal-regulated kinase (ERK). Mutations present in these kinases, such as a BRAF V600E mutation, lead to constitutive activation that causes upregulated cell proliferation.

BRAF V600E Mutated mCRC: Current Practice and Knowledge
BRAF V600E mutations are a rare entity in mCRC, seen in 8%–12% of patients, compared to RAS mutations, which account for about 50%–60% of the mCRC population.2,6 Although the mutations are infrequent, patients who harbor BRAF V600E mCRC have shown dramatic differences in biology and prognosis compared to wild-type BRAF mCRC. BRAF V600E mutated CRC is a strong negative prognostic marker, correlating with high-risk clinicopathological characteristics such as advanced age, poorly differentiated histology, right-sided tumors, T4 tumors, mucinous histology, microsatellite instability, early relapse of oligometastic liver resection, peritoneal disease, and distant lymph node metastases.2, 8-11

With standard antineoplastic therapy, the median OS of BRAF V600E mutated mCRC is reported at approximately 12 months, with a lower probability reported of these patients receiving second-line therapy following front-line progression.1,6 5-Fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) with bevacizumab in phase-2 and phase-3 trials reveal promising outcomes for the BRAF mutated subset, with a median OS range of 19–24 months.6 Considering the historically low probability of second-line therapy and the improvement seen with this regimen in this challenging aggressive tumor population, bevacizumab plus FOLFOXIRI should be considered a front-line regimen for BRAF V600E mutated mCRC patients who have a suitable performance status.2

The predictive role of BRAF mutated mCRC for EGFR monoclonal antibodies (mAb) remains an area of uncertainty, given the rarity of BRAF and the retrospective nature of these evaluations. A BRAF mutation is understood to be constitutively active, and therefore the cell proliferation mechanism would bypass the inhibition target of these mAbs. Current guidelines recognize the issues surrounding this determination.2,4 The National Comprehensive Cancer Network4 has added wording to its guidelines indicating that a BRAF V600E mutation makes response to EGFR mAb therapy (as monotherapy or in combination with cytotoxic chemotherapy) highly unlikely, and the European Society of Medical Oncology2 lists RAS wild-type and BRAF wild-type for EGFR mAb options.

Heterogeneity Among BRAF mCRC Mutations
Current retrospective reviews evaluating non-V600 mutated mCRC have recently been presented. Jones and colleagues reviewed mCRC patients at the Mayo Clinic between 2013 and 2015 and found that 18.9% of BRAF mutations identified were non-V600 mutations.12 The authors found a more favorable profile (lower-grade tumors, left-sided tumors, and longer OS) than the comparator V600 mutated patients. Cremolini and colleagues retrospectively examined mCRC patients at three Italian institutions from 2006 to 2014.13 BRAF mutated codons 594 and 596 (n  = 10) were compared to V600E mutations (n = 77). Results showed a more favorable clinicopathological profile (left-sided tumors, nonmucinous subtype, an absence of peritoneal disease, and markedly longer OS) with the non-V600E mutated group. The evidence of the heterogeneity within this class of mutations is compelling, despite the rarity of non-V600 mutation occurrence (<1%).13

New Treatment Strategies for BRAF Mutated mCRC
BRAF inhibitors (vemurafenib or dabrafenib) given as monotherapy in mCRC BRAF mutated patients exposed disconcerting results of minimal activity (response rates [RRs] = 5%–11%), in dramatic contrast to BRAF mutated melanoma (RRs = approximately 50%–60%).14,15 A combination BRAF mCRC trial, following a similar pathway of blockade seen with melanoma, looked at dabrafenib in combination with trametinib, an MEK inhibitor.16 This combination showed a 12% RR, again exposing a distinction in BRAF mutated melanoma compared to mCRC. A breakthrough in the complex understanding of this population was the resistance-mechanism discovery of rapid feedback reactivation of EGFR when in the presence of BRAF blockade, allowing for continued cell proliferation.17,18

Dual blockade with EGFR and BRAF inhibition represented the next investigative step.19,20 Dual blockade revealed promising results, with slightly increased RRs and progression-free survival (PFS) than those seen with BRAF inhibitor monotherapy, while at the same time these trials revealed that continued improvement is necessary. Currently, the BRAF mutated mCRC trial design involves dual EGFR and BRAF blockade with the addition of a third agent (traditional cytotoxic, MEK inhibitor, or PI3K inhibitor).21-24 Recently presented, Kopetz and colleagues reported on a randomized trial of irinotecan + cetuximab +/- vemurabenib in BRAF mutated mCRC showing a statistically significant difference in median PFS, RR, and disease control rate in the triplet arm.23 The recent steps in treatment discovery in this poor prognostic population hold a promising outlook. Combination study results with EGFR and BRAF inhibition plus additional agents are eagerly awaited.

References

1. Schirripa M, Lenz HJ. Biomarker in colorectal cancer. Cancer J. 2016 May-Jun; 22(3):156-64.

2. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016 Aug; 27(8):1386-422.

3. National Cancer Institute. Surveillance, epidemiology, and end results program. SEER facts and figures. Colorectal cancer. https://seer.cancer.gov.statfacts/html/colorectal.html. Accessed April 14, 2017.

4. National Comprehensive Cancer Network. NCCN guidelines: colon cancer. Version 2.2017. Accessed April 14, 2017.

5. Lieu CH, Renfro LA, de Gramont A, et al. Association of age with survival in patients with metastatic colorectal cancer: analysis from the ARCAD clinical trials program. J Clin Oncol. 2014 Sep 20:32(27):2975-84.

6. Cohen R, Cervera P, Svrcek M, et al. BRAF-mutated colorectal cancer: what is the optimal strategy for treatment? Curr Treat Options Oncol. 2017 Feb;18(2):9.

7. Obaid NM, Bedard K, Huang WY. Strategies for overcoming resistance in tumours harboring BRAF mutations. Int J Mol Sci. 2017 Mar 8;18(3).

8. Korphaisarn K, Kopetz S. BRAF-directed therapy in metastatic colorectal cancer. Cancer J. 2016 May-Jun;22(3):175-78.

9. Tran B, Kopetz S, Tie J, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 2011 Oct 1;117(20):4623-32.

10. Chen D, Huang JF, Liu K, et al. BRAF V600E mutation and its association with clinicopathological features of colorectal cancer: a systematic review and meta-analysis. PLoS One. 2014 Mar 3:9(3):e90607.

11.    Clancy C, Burke JP, Kalady MF, et al. BRAF mutation is associated with distinct clinicopathological characteristics in colorectal cancer: a systematic review and meta-analysis. Colorectal Dis. 2013 Dec;15(12):e711-18.

12.    Jones JC, Kipp B, Leal AD, Voss JS, et al. Commonality and clinical, pathological, and prognostic characteristics of non-V600E BRAF mutations (BRAFMut) in metastatic colorectal cancers (mCRC) compared to V600 BRAFMut CRCs. 2016 ASCO Annual Meeting. J Clin Oncol. 34, 2016(suppl; abstr 3529).

13. Cremolini C, Di Bartolomeo M, Amatu A, et al. BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis. Ann Oncol. 2015 Oct; 26(10):2092-97.

14. Kopetz S, Desai J, Chan E, et al. Phase II pilot study of vemurafenib in patients with metastatic BRAF mutated colorectal cancer. J Clin Oncol. 2015 Dec 1;33(34):4032-38. Epub 2015 Oct 12.

15. Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose escalation. Lancet. 2012 May 19;379(9829):1893-901.

16. Corcoran RB, Atreya CE, Falchook GS, et al. Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer. J Clin Oncol. 2015 Dec 1;33(34):4023-31.

17. Corcoran RB, Ebi H, Turke AB, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012 Mar;2(3):227-35. Epub 2012 Jan 16.

18. Prahallad A, Sun C, Huang S, et al. Unresponsiveness of colon cancer to BRAF (V600E) inhibition through feedback activation of EGFR. Nature. 2012 Jan 26;483(7387):100-03.

19. Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015 Aug 20;373(8):726-36.

20. Yaeger RD, Cercek A, O’Reily EM, et al. Pilot study of vemurafenib and panitumumab combination therapy in patients with BRAF V600E mutated metastatic colorectal cancer. J Clin Oncol. 33, 2015 (suppl 3; abstr 611).

21. Van Geel RM, Tabernero J, Elez E, et al. A Phase 1b Dose-Escalation Study of Encorafenib (LGX818) and Cetuximab With or Without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer. Cancer Discov. 2017 Mar 31.

22. Atreya CE, Cutsem EV, Bendell JC, et al. Updated efficacy of the MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E mutated (BRAFm) metastatic colorectal cancer (mCRC). J Clin Oncol. 33, 2015 (suppl; abstr 103).

23. Kopetz S, McDonough SL, Morris VK, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). J Clin Oncol. 35, 2017 (suppl 4S; abstr 520).

24. Clinicaltrials.gov. https://www.clinicaltrials.gov/. Accessed April 14, 2017.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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