Cathy Eng, MD, FACP, FASCO from Vanderbilt-Ingram Cancer Center Vanderbilt University Medical Center speaks about the Editorial - BRAF Mutation in Colorectal Cancer: An Enigmatic Target.
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Cytotoxic chemotherapy combined with biologic agents such as antivascular endothelial growth factor or antiepidermal growth factor has been our normal strategy for all patients for over a decade.1-3 Since then, research has advanced, including the importance of genomic alterations as potential predictive and prognostic markers in the treatment of colorectal cancer (CRC).4,55
The BRAF gene encodes the critical mechanism in the carcinogenesis of multiple cancers for a serine or threonine-protein kinase associated with the mitogen-activated protein kinase pathway.6,7 The BRAF mutation (MT) results in the constitutive activation of downstream kinases, resulting in cell proliferation and survival. BRAF MT occurs in 60% of all melanomas but is present in < 10% of all CRCs. The V600E subtype, typically found in female and right-side colon cancers, accounts for more than 90% of all BRAF MTs.
Compared to their wild-type counterparts, the majority of patients with BRAFV600E MT metastatic CRC (mCRC) undergo decreased progression-free survival (PFS) and overall survival (OS). Researchers observed a decline in OS for BRAFV600E stage II-IV CRC as early as 2005.9 The predicted median OS (mOS) for colorectal stage IV cancer is approximately 29-30 months.10-12 Standard combination chemotherapy for BRAFV600E MT mCRC, in stark contrast, results in an mOS of 12-14 months.12,13
Individualized treatment should be given for advances in precision medicine, including the implementation of molecular testing and the development of novel targeted agents. Orally selective BRAFV600E inhibitors such as vemurafenib, dabrafenib, and encorafenib are licensed by the Food and Drug Administration (FDA) for use in surgically unresectable or metastatic melanoma.14-16 A pilot phase II trial of vemurafenib reporting a disappointing response rate (RR) of only 5% quickly dampened high expectations of similar gain in refractory BRAFV600E mCRC.17
In order to test this hypothesis, Corcoran et al18 developed a non-randomized three-arm phase I/II trial of dabrafenib(D)+panitumumab(P)+/−trametini In order to test this hypothesis, Corcoran et al18 developed a non-randomized three-arm phase I/II trial of dabrafenib(D)+panitumumab(P)+/−trametini. Dabrafenib-panitumumab resulted in a 10 percent RR and a 3.5-month PFS (95 percent CI, 2.8 to 5.8 months); dabrafenib-panitumumab-trametinib resulted in a 21 percent improved RR and a 4.2-month PFS (95 percent CI, 4.0 to 5.6 months). Correlatives showed a decrease in the radiographic response of the BRAFV600E stage, suggesting the position of serial cell-free DNA (cfDNA). Also mentioned was the clonal evolution of acquired Kristen-Ras (KRAS) mutations.
Kopetz et al22 published the results of S1406, the first phase II randomized National Clinical Trials Network analysis of irinotecan + cetuximab +/− vemurafenib (VIC) in refractory BRAFV600E MT mCRC, in the first article preceding this editorial. Microsatellite instability-high (MSI-H) tumors were not excluded in this trial because S1406 followed the FDA approval of immune checkpoint approval PFS was the primary endpoint, allowing patients on the control arm to crossover. For the VIC combination of 4.2 months versus 2.0 months, the investigators registered superior PFS. A non-statistical difference in OS in 42 percent of patients was due to the crossover. As a clinician, I find the dismal PFS of 2.0 months in the control arm of irinotecan + cetuximab in BRAFV600E mCRC to be the most striking result.
In order to detect the presence of somatic mutations, correlative work from S1406 included next-generation sequencing, serial plasma collection, and circulating tumor DNA (ctDNA). Challenges persisted, however, in the collection of tissue and blood. It was shown in Figure 3 of the publication that only 34 percent of patients supplied both baseline and first ctDNA restaging. S1406 reveals the difficulties that occur in current and potential BRAFV600E MT trials to obtain correlatives. Due to tissue acquisition limitations in this population, ctDNA would likely act as our best correlative resource as most patients will have surgically unresectable disease. Strict serial collection of plasma should be required from all participating sites as a result of the traditionally short PFS.
The BEACON trial is a global three-arm, phase III randomized trial of cetuximab + encorafenib (CE) +/− binimetinib (CEB) versus standard chemotherapy (irinotecan + cetuximab-based) in previously treated BRAFV600E mCRC patients.22 The trial included a safety run in 30 patients with an outstanding RR of 56%, 7.5-month PFS, and 19.0-month OS, resulting in the FDA breakthrough. OS for the CE arm relative to control, PFS, length of reaction, and protection were secondary endpoints; in particular, the study was not able to compare the two investigational weapons. The primary endpoint was met with the superior OS for CEB 9.0 months versus 5.4 months (HR = 0.52; 95 percent CI, 0.39 to 0.70) after a median follow-up of 7.8 months. As part of their descriptive analysis, it was noted that the CE arm provided CEB with identical Kaplan-Meier curves with a comparable OS (8.4 months v 5.4 months; HR = 0.60; 95% CI, 0.45 to 0.79). The investigators also noted that if given earlier in care, promoting RR with CEB (one prior line versus heavily pretreated: 34 percent v 26 percent ).