Metastatic Colorectal Cancer Clinical Practice Guidelines Updates (NCCN) (2019)

National Comprehensive Cancer Network

This is a quick summary of the guidelines without analysis or commentary. For more information, go directly to the guidelines by clicking the link in the reference.

June 05, 2019

The National Comprehensive Cancer Network (NCCN) released updated recommendations on the management of metastatic colorectal cancer (CRC) in May 2019.[1]

The most significant changes in the NCCN Guidelines over the past year regarding the management of metastatic CRC were related to biomarkers and disease subsets. Updates included additional options for BRAF-mutated cancers, tissue-agnostic approval for the NTRK inhibitor larotrectinib, and some additional language regarding Lynch syndrome and testing.

Additional Treatment Options Based on BRAF/MEK and NTRK Fusion Targets

Updated treatment options for use in CRC included inhibitors of BRAF (BRAFi), MEK (MEKi), and NTRK (NTRKi).

Of the 13 already existing US Food and Drug Administration (FDA)-approved drugs for use in CRC, five are cytotoxic agents and eight are biologics or targeted agents. The five cytotoxic agents are 5-fluorouracil (5-FU), capecitabine, TAS-102 (trifluridine-tipiracil), irinotecan, and oxaliplatin.

The biologics/targeted agents comprise two epidermal growth factor receptor (EGFR) inhibitors (cetuximab, panitumumab), two programmed cell death protein-1 (PD-1) inhibitors (pembrolizumab, nivolumab), one vascular endothelial growth factor (VEGF) inhibitor (bevacizumab), and one VEGF receptor-2 (VEGFR-2) inhibitor (ramucirumab). The remaining two agents are a dummy VEGFR (ziv-aflibercept) and a tyrosine kinase inhibitor (regorafenib).

Modified FOLFOXIRI Plus an EGFR

An additional treatment option for unresectable stage IV metastatic CRC has been included: modified FOLFOXIRI (mFOLFOXIRI; 5-FU/
leucovorin/oxaliplatin/irinotecan) plus panitumumab. However, this update applies only to patients with KRAS/NRAS/BRAF wild-type and left-sided tumors.

Microsatellite Instability (MSI)/Mismatch Repair (MMR)

Recognizing the relationship between BRAF mutations and MSI is important: The presence of a BRAF mutation makes hereditary nonpolyposis CRC (HNPCC) or Lynch syndrome much less likely. However, MSI-high (MSI-H)/deficient MMR (dMMR) disease does not rule out Lynch syndrome (∼1% of these patients will have BRAF V600E).

Germline testing is now recommended if a family cancer history exists, as well as further explanation of MMR immunohistochemistry for the four known mutated genes in Lynch syndrome (MLH1, MSH2, MSH6, PMS2).


For patients with dMMR/MSI-H tumors but who are not eligible for cytotoxic combinations, new first-line immunotherapy options are nivolumab or pembrolizumab, or a combination of nivolumab and ipilimumab. Furthermore, nivolumab ± ipilimumab or pembrolizumab can be used in the second- and third-line treatment of patients with dMMR/MSI-H CRC.

Targeting NTRK

Larotrectinib is now included as a second-line treatment option for patients with metastatic CRC who have NTRK gene fusions (occurring in ∼1% of patients), regardless of tumor type.

In November 2018, the FDA granted tissue-agnostic approval for larotrectinib for adult and pediatric patients who (1) have solid tumors that harbor an NTRK gene fusion without a known acquired resistance mutation, (2) have metastatic disease or disease that has progressed after treatment, (3) are likely to experience severe morbidity as a result of surgery, and (4) lack alternative satisfactory treatments. NOTE: NTRK fusions can be hard to detect and are rare in CRC (∼1%).

Targeting BRAF-Mutated CRC

New options have been incorporated for combination therapy for patients with BRAF-mutated (V600E) CRC. As second-line therapy options, the guidelines now include the following:

  • Dabrafenib (BRAFi) plus trametinib (MEKi) plus cetuximab or panitumumab (EGFR monoclonal antibody), OR

  • Encorafenib (BRAFi) plus binimetinib (MEKi) plus cetuximab or panitumumab

For more information, please go to Colon Cancer and Rectal Cancer.

For more Clinical Practice Guidelines, please go to Guidelines.


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