BRAF V600E-mutant colorectal cancer with CNS metastases treated successfully with encorafenib, binimetinib and cetuximab

Abstract

This report describes a case of BRAF V600E-mutated colorectal cancer with CNS metastases in which treatment with encorafenib, binimetinib and cetuximab was effective. There is limited information on the ability of encorafenib, binimetinib and cetuximab to enter the CNS.

The patient was a 53-year-old man was diagnosed with ascending colon cancer (cT3N3M1c stage IVc). BRAF V600E mutation was confirmed. FOLFOX was started, but CNS metastases soon appeared. Encorafenib, binimetinib and cetuximab were administered and had a favorable effect on the CNS lesions. The patient initially responded well, but his disease progressed 2 months later. Further research is needed to improve management strategies for BRAF V600E-mutated colorectal cancer with CNS metastases.

Executive summary

• A combination of encorafenib, binimetinib and cetuximab demonstrated effectiveness in BRAF V600E-mutated colorectal cancer with CNS metastases.

• Treating brain metastasis in colorectal cancer is challenging because of the limited ability of drugs to penetrate the CNS.

• Although an initial response was observed, early disease progression suggested the existence of mechanisms of resistance to EGFR/BRAF inhibitors.

• Further research is needed to establish the efficacy of this treatment and improve management strategies.

Keywords: :

• binimetinib
• BRAF V600E
• central nervous system
• cetuximab
• colorectal cancer
• encorafenib
• metastasis

1. Background

The frequency of CNS metastasis in colorectal cancer (CRC) is reported to be low, with metastasis to the brain occurring in only 0.6–3.2% of cases [1]. An increased risk of brain metastasis has been associated with young age, a primary tumor in the rectum, and the presence of lung metastasis [1]. A correlation between KRAS mutation and the risk of brain metastasis has also been observed (6.1 vs. 1.9% in patients with wild-type metastatic CRC) [2]. However, there are limited reports on the association between BRAF V600E mutation and CNS metastasis in CRC [3].

CRC can be classified into various subtypes based on molecular characteristics. The frequency of BRAF V600E mutation has been reported to be approximately 8% [4]. BRAF is a serine/threonine kinase with an important role in the activation of the MAPK pathway, which is involved in cell proliferation and other processes promoting cancer growth [5]. Given that median overall survival has been found to be longer in patients with BRAF wild-type than in those with mutant BRAF V600E (20.0 months vs 11.7 months) [6], BRAF V600E mutation is regarded as a poor prognostic factor in metastatic CRC [7].

Molecular targeting therapies have been developed and approved for BRAF V600E-mutated CRC in an effort to improve its dismal prognosis. In the BEACON CRC study, a triplet regimen containing encorafenib (a BRAF V600E inhibitor), binimetinib (an MEK inhibitor), and cetuximab (an inhibitor of feedback to EGFR) and a doublet regimen containing encorafenib and cetuximab demonstrated superiority over chemotherapy in unresectable BRAF V600E-mutated CRC [8]. However, the exclusion criteria for that study included symptomatic brain metastases and leptomeningeal disease, so the efficacy of the BEACON regimen in patients with CNS metastases remains unknown.

In this report, we describe our experience treating a patient with metastatic ascending colon cancer harboring a BRAF V600E mutation that had metastasized to the CNS using encorafenib, binimetinib and cetuximab.

2. Case report

In October 2022, a 53-year-old man who was experiencing abdominal pain visited a local healthcare facility and was referred to our hospital after a computed tomography scan revealed possible signs of cancer in the ascending colon and metastases in the liver, lungs and peritoneum. A colonoscopy was attempted but was unsuccessful because of stenosis caused by the tumor. Biopsy revealed moderately to well-differentiated adenocarcinoma in the ascending colon. Based on the above findings, the patient was diagnosed with ascending colon cancer, liver metastasis, lung metastasis and peritoneal dissemination (cT3N3M1c stage IVc). There was the possibility of a loss of ability to ingest food because of the stenosis. Therefore, laparoscopic right hemicolectomy and D3 dissection were performed for palliation of the symptoms of stenosis caused by the primary tumor. Biomarkers of the primary tumor were microsatellite stability, KRAS/NRAS wild-type and positive BRAF V600E mutation. Postoperatively, FOLFOX (oxaliplatin 85 mg/m², leucovorin 200 mg/m², and 5-fluorouracil 400 mg/m² as a bolus infusion followed by 2400 mg/m² as a continuous infusion, every 2 weeks) was initiated as systemic chemotherapy in February 2023. Bevacizumab was not administered because the patient had recently undergone surgery.

Two weeks after starting FOLFOX, the patient showed symptoms of disorientation and forgetfulness. Contrast-enhanced magnetic resonance imaging (MRI) of the brain revealed multiple brain metastases and leptomeningeal disease (Figure 1A). Progression of liver and lung metastases was also observed. FOLFOX therapy was deemed ineffective, and the patient was started on second-line therapy using encorafenib (300 mg/day), binimetinib (90 mg/day and cetuximab (400 mg/m² as an initial dose followed by 250 mg/m² weekly). One month later (April 2023), follow-up contrast-enhanced MRI revealed significant improvement in the brain metastases and leptomeningeal disease (Figure 1B). Given that the metastatic lesions in the liver and lung were also well controlled, treatment with encorafenib, binimetinib and cetuximab was continued. His CNS symptoms of disorientation and forgetfulness improved, and no other significant adverse events were observed except for grade 1 fatigue. Radiotherapy was not administered for the CNS metastases.

Figure 1. Contrast-enhanced magnetic resonance images of the head. (A) Brain metastasis in the right occipital lobe and leptomeningeal disease along the cerebellar sulci. (B) Disappearance of brain metastasis and leptomeningeal disease.

The red arrows indicate the metastatic areas.

A computed tomography scan performed 2 months later (June 2023) revealed a rapid increase in the size of the liver metastases. Furthermore, a brain MRI performed to investigate speech impairment revealed multiple brain infarctions and confirmed onset of Trousseau's syndrome (Figure 2) but no apparent worsening of the CNS metastases. Considering the inefficacy of chemotherapy and the patient's overall condition, the decision was made to switch to best supportive care. He died at home a month later.

Figure 2. Magnetic resonance images showing multiple brain infarctions (Trousseau's syndrome).

The red arrows indicate the metastatic areas.

3. Discussion

Metastases of CNS from CRC are uncommon but have a dismal prognosis with a median survival of only a few months [1]. In view of the presence of the blood–brain barrier (BBB), it is debatable whether systemic chemotherapy is effective for CRC with CNS metastases [9]. This report describes a patient with BRAF V600E-mutated CRC and CNS metastases in whom encorafenib, binimetinib and cetuximab showed significant efficacy. Limited information is available regarding the ability of these drugs to penetrate the CNS, but this case suggests the possibility of central penetration and therapeutic efficacy.

Dabrafenib plus trametinib has demonstrated efficacy in BRAF V600-mutated melanoma with CNS metastasis, indicating an ability to penetrate cerebrospinal fluid [10]. However, vemurafenib, another BRAF inhibitor, has a limited ability to cross the BBB, and no clear correlation between its concentrations in blood and cerebrospinal fluid has been found [11]. Furthermore, a murine study that examined the accumulation of encorafenib in the brain and the dynamics of this agent in the intestine found that penetration of encorafenib into the brain was low, suggesting limited effectiveness for malignant tumors located behind the BBB [12]. Mouse experiments have also shown that binimetinib, an MEK inhibitor, has limited ability to penetrate the brain and cerebrospinal fluid. On the other hand, there have been reports that encorafenib and binimetinib exhibited intracranial activity in metastatic melanoma, and although the duration was short, the objective response was satisfactory [^13-15].

Regarding the possibility of cetuximab crossing the BBB, it has been reported that this drug may occasionally cause aseptic meningitis [16], and radiolabeled cetuximab was shown to penetrate a brain lesion in a patient with non-small-cell lung cancer [17]; however, no definitive evidence has been established.

Based on the available information, it can be inferred that encorafenib, binimetinib and cetuximab have low penetration rates as a result of the BBB, making it difficult to achieve therapeutic efficacy. However, in this particular case, these three agents in combination were a transiently successful treatment for CNS metastasis. Another report suggested that trastuzumab, a monoclonal antibody targeting HER2, may have the potential to penetrate brain lesions [18]. Some researchers have attributed this increased penetration ability to disruption or impairment of the BBB at the site of brain metastasis caused by the metastatic tumor itself or treatment for cancer, such as radiotherapy [19]. Trastuzumab has a molecular weight of 148,000 [20] and cetuximab has a similar molecular weight of 151,800 [21], so may be able to infiltrate the CNS. Trastuzumab may be transported across the BBB by the Fc receptor of immunoglobulin G expressed on the vasculature in the brain [22]. Cetuximab may also be able to penetrate the CNS via the same mechanism.

In this case, although an early treatment response was achieved, the disease progressed after 2 months of treatment. Previous studies have found that the BEACON triplet regimen was associated with a short-lived response, with median progression-free survival of 5.4 months for second-line therapy and 5.8 months for first-line therapy [8,23]. However, disease progression was detected earlier than previously reported. Several genes, including KRAS, NRAS and PIK3CA, have been linked to resistance to EGFR/BRAF inhibitors in terms of both intrinsic and acquired resistance mechanisms [24]. Mechanisms of resistance are diverse, and in this case, resistance was likely acquired early on in the course of the disease. Performance status, CA19-9 and lactate dehydrogenase levels, the neutrophil to lymphocyte ratio and the presence of liver, lung, and lymph node metastases have also been reported to be prognostic factors in BRAF V600E-mutated CRC [25]. Our patient had multiple metastases and elevated lactate dehydrogenase and CA19-9 levels. Other novel biomarkers reported include transcriptome analysis from the BEACON trial, the presence of RNF43 mutations, and the prognostic value of BRAF allelic fractions, none of which were investigated in this paper [^26-28].

CNS metastasis in CRC is relatively uncommon and controlling and treating it remains challenging. In this case, treatment for BRAF V600E-mutated CRC with CNS metastases was successful, albeit for a brief period of time because of progression outside the CNS. Additional reports and findings will be needed to strengthen the evidence for the efficacy of treatment with a combination of encorafenib, binimetinib and cetuximab in patients with CRC and CNS metastases.

Author contributions

All listed authors participated in the writing of the manuscript and have read and approved the final version.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The Institutional Review Board of National Cancer Center Hospital, Japan approved the case report and its submission to the medical literature (2017-229).

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.