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
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.
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