Invited discussant of the two studies, Elena Élez, MD, PhD, of the Colon Cancer Program, Vall d’Hebron Institute of Oncology, Barcelona, Spain, discussed the challenge of treating BRAF-mutant colorectal cancer and what the new data bring to that effort.

Dr. Élez noted: “BRAF V600E–mutant metastatic colorectal cancer constitutes an entity with particular clinical features, poor prognosis, and resistance to standard therapies…. Until recently, there was no particular treatment recommended beyond the identification of pathologic features and [microsatellite instability] status…. The introduction of targeted therapy has represented a paradigm change.”

BRAF-Targeting Clinical Trials

The previous BEACON trial found that BRAF-targeted therapy with encorafenib and cetuximab, or with the doublet plus binimetinib, yielded encouraging outcomes in previously treated patients. The results led to the development of a clinical trial in the front-line setting, the ANCHOR trial, presented at this Congress. The study met its primary endpoint, with a response rate of 47.8%.

The study also achieved “interesting” results in progression-free survival (median, 4.86 months) and overall survival (14.4 months), Dr. Élez commented. “However, these results do not seem superior to the results from other trials of recommended chemotherapy in the front-line setting…. This is why it is justified to develop the ongoing BREAKWATER study.”

BREAKWATER is an open-label multicenter phase III trial of first-line encorafenib plus cetuximab with chemotherapy (n = 290) or without chemotherapy (n = 290) vs physicians’ choice of standard-of-care chemotherapy (n = 290). The primary endpoint is progression-free survival by blinded independent review. “It will be of particular interest to have more data on the potential treatment sequencing of these patients,” she said.

Regarding the MODUL trial, which evaluated maintenance therapy with fluorouracil/leucovorin plus cetuximab and vemurafenib after induction in previously untreated patients, Dr. Élez felt the most interesting finding pertained to the translational studies. Plasma analysis revealed an enrichment at baseline of the RNF43 variant, third only to BRAF and TP53. This enrichment persisted at the end of treatment, at which time MAP2K1, TET2, and DNMT3a also appeared.

“Selective pressure of the treatment arm leads to acquired mutations that reactivate and converge in the MAPK pathway as drivers of resistance to targeted therapy,” she explained, suggesting these genetic findings should be further explored.

Molecular Analysis

Dr. Élez’s own work—research on a population of patients receiving encorafenib/cetuximab with or without binimetinib, presented at this meeting—has shown that enrichment of RNF43 mutations and, chromosome 7 polysomy, seem to be associated with clinical benefit to BRAF-targeted therapy.¹ She and her team also found that BRAF mutant allele fraction (MAF) in cell-free DNA may constitute an independent prognostic biomarker. Low MAF (baseline BRAF MAF < 5% vs > 5%) was associated with a 52% reduction in mortality (P = .02) and, in an expoloratory analysis, patients with more than 5% MAF exhibited a trend toward a particular benefit from the triplet vs the doublet. Although the analysis is limited by the sample size, it is an effect that deserves further evaluation, she said.

BEACON investigators have also looked for biomarkers and have found that tumors classified as the CMS4 molecular subtype and BM1 transcriptional subtype may benefit more from the triplet,² she added.

In other words, “the underlying molecular landscape of BRAF V600E–mutant metastatic colorectal cancer is complex and heterogeneous,” Dr. Élez said. “There may be predictive biomarkers beyond mutational status for patients with BRAF-mutant colorectal cancer.”

Liquid biopsy captures dynamic changes in the molecular landscape as they arise under biologic pressure from targeted agents, she added. “The incorporation of these techniques in prospective studies must be a priority to better understand and defeat this illness.” 

DISCLOSURE: Dr. Élez has received honoraria from Array BioPharma, Bristol Myers Squibb, Merck Serono, Roche, Sanofi/Aventis, and Servier; has received institutional honoraria from AbbVie/Genentech, Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, MSD, and Novartis; has served as a consultant or advisor to Amgen, Array BioPharma, Bayer, Bristol Myers Squibb, Merck Serono, Roche, Sanofi, and Servier; has received research funding from Amgen and Merck Serono; has received institutional research funding from Array BioPharma, Bristol Myers Squibb, MedImmune, Pierre Fabre, Roche, Sanofi/Aventis, and Servier; has been reimbursed for travel, accommodations, or other expenses by Amgen, Array BioPharma, Bristol Myers Squibb, Merck Serono, Roche, Sanofi, and Servier.

REFERENCES

1. Élez E, Ros J, Martini G, et al: Integrated analysis of cell free DNA (cfDNA) BRAF mutant allele fraction (MAF) and whole exome sequencing in BRAF V600E metastatic colorectal cancer treated with BRAF-antiEFGR +/- MEK Inhibitors. ESMO World Congress on Gastrointestinal Cancers 2021. Abstract LBA-3. Presented July 2, 2021.

2. Kopetz S, Murphy DA, Pu J, et al: Molecular correlates of clinical benefit in previously treated patients with BRAF V600E-mutant metastatic colorectal cancer from the BEACON study. J Clin Oncol 39(suppl):3513, 2021.