European expert panel consensus on the clinical management of BRAF^V600E-mutant metastatic colorectal cancer¹

Molecular targeted therapies and immune checkpoint inhibitors have changed the treatment landscape for BRAF^V600E-mutant metastatic colorectal cancer (mCRC). This review is based on a scientific literature search and analysis by a European expert panel. It provides consensus statements on management guidance and makes recommendations for treatment sequencing and clinical monitoring, as well as for future research priorities.

The literature search for original research as well as recent reviews and meta-analyses was conducted on PubMed. The analysis also included congress materials presented in 2021 and 2022.

The expert panel consisted of nine European medical oncologists. After meeting in person for discussions, consensus statements were drafted and hypothetical clinical scenarios representative of patients diagnosed with BRAF^V600E-mutant mCRC were developed. In the next step, the panellists voted anonymously and independently, rating their level of agreement or disagreement to the statements from 1 (completely disagree) to 5 (completely agree). They also rated the appropriateness of different treatment choices for each of the four clinical scenarios from 1 (entirely inappropriate) to 5 (completely appropriate). Final statements and scenarios were approved by all panellists.

Biomarker testing – consensus statements

• Molecular testing should be performed at diagnosis of metastatic disease
• At a minimum, this should include testing for KRAS/NRAS mutations, BRAF^V600E mutations and dMMR/MSI-H status
• The preferred method of mutational testing is genomic NGS, or PCR if NGS is unavailable
• Due to the lack of adequate validation methods for mutated RAS and RAF proteins, IHC is recommended only for MMR status testing
• If no tissue is available, liquid biopsy to assess ctDNA is an adequate option.

Surgical resection

Surgical resection may be beneficial for a subset of patients but prognosis is poor. The panel recommends that each case be evaluated at a multidisciplinary team meeting, keeping in mind the poor prognosis and potential consequences of stopping therapy to perform surgery.

Clinical monitoring

In this paper the authors propose the following: Patients with BRAF^V600E-mutant disease require monitoring at least every two months to evaluate treatment response, review treatment goals and, if necessary, discuss other treatment options. Monitoring includes physical examinations, radiological scans, and blood tests. This recommendation might differ compared to local National Guidelines

Clinical management – consensus statements

• Preferred first-line therapy for patients with MSI-H BRAF^V600E-mutant mCRC is an immune checkpoint inhibitor
• Preferred first-line therapy for patients with MSS BRAF^V600E-mutant mCRC is doublet chemotherapy ± bevacizumab, or triplet chemotherapy ± bevacizumab in selected cases (e.g. younger patients, patients with good performance status and/or potentially resectable disease with sufficient tumour shrinkage, and/or patients with right-sided tumours)
• Upon progression following first-line treatment, patients should be treated with encorafenib + cetuximab as soon as possible
• Radiological monitoring of patients under treatment for BRAF-mutant mCRC should be performed at least every two months to avoid unnecessary delays in detecting disease progression and the need for changing therapy.

Clinical management in hypothetical patients

Recommended first-line systemic therapy is either chemotherapy + bevacizumab or an immune checkpoint inhibitor. In all four cases, encorafenib+cetuximab is recommended after the first-line treatment.

Enrolment in a relevant clinical trial should be considered alongside the presented therapeutic options.

Scenario 1: Older patient with right-sided tumour and comorbidities
This 75-year-old man has cardiac and renal impairment, EGOC PS 2 and small, unresectable liver metastases.

1^st line: doublet chemotherapy + bevacizumab.
2^nd line: encorafenib + cetuximab (preferred), or doublet chemotherapy + bevacizumab
3^rd and 4^th line: trifluridine/tipiracil ± bevacizumab and regorafenib, assuming the patient’s condition does not deteriorate with time.

Scenario 2: Patient with MSI-H disease and unresectable metastases
A 72-year-old woman with no comorbidities and EGOC PS 2 who had a right-sided tumour removed six months ago, with no adjuvant therapy.

1^st line: immune checkpoint inhibitor, preferably pembrolizumab
2^nd line: encorafenib + cetuximab
3^rd and 4^th line: doublet chemotherapy + bevacizumab, or trifluridine/tipiracil ± bevacizumab
5^th and 6^th line: regorafenib, if the patient’s condition allows.

Scenario 3: Younger patient with asymptomatic primary tumour, potentially resectable metastases and good performance status
This 32-year-old woman has no comorbidities and EGOC PS 1, an asymptomatic left-sided tumour and a limited number of liver metastases that may become resectable with treatment.

1^st line: triplet (preferred) or doublet chemotherapy + bevacizumab
2^nd line: encorafenib + cetuximab
3^rd and 4^th line: trifluridine/tipiracil ± bevacizumab and regorafenib

Scenario 4: Younger patient with MSI-H disease, resectable primary tumour and potentially resectable peritoneal metastases
A 40-year-old woman with no comorbidities EGOC PS 2 who has a potentially resectable right-sided tumour and potentially resectable and peritoneal metastases.

1^st line: immune checkpoint inhibitor, preferably pembrolizumab, or nivolumab + ipilimumab 2nd line: encorafenib + cetuximab
3^rd line: doublet chemotherapy + bevacizumab
4^th and 5^th line: trifluridine/tipiracil ± bevacizumab and regorafenib.

Priorities for future research
Despite substantial and meaningful advances in the treatment of BRAF^V600E-mutant mCRC in the last few years, much remains to be done. Data from ongoing trials will be pivotal in informing the rational use of targeted and combined therapies.

In addition to developing new treatments and improving existing ones, critical areas of interest for future research include potential mechanisms of acquired resistance to targeted therapy and new predictive biomarkers to identify subpopulations that may benefit from specific treatments.

Abbreviations

BRAF, brain rapidly accelerated fibrosarcoma – a gene that encodes serine/threonine protein kinases; ctDNA, circulating tumour DNA; dMMR, deficient DNA mismatch repair; EGOC PS, performance status assessed by using ECOG (Eastern cooperative oncology group) score; IHC, immunohistochemistry; KRAS/NRAS, RAS oncogenes; MSI-H, microsatellite instability-high; MSS, microsatellite stable; NGS, next-generation sequencing; PCR, polymerase chain reaction