NCCN Guidelines Updates: Management of Metastatic Colorectal Cancer

In the last year, several impactful updates have been added to the NCCN Guidelines for Colorectal Cancer (CRC) for the management of metastatic disease, including additional options for BRAF-mutated advanced CRC and the inclusion of combination immunotherapy (PD-1 and CTLA-4) for deficient mismatch repair/microsatellite instability (MSI)–high advanced CRC. According to Dr. Wells A. Messersmith, targeted therapies (ie, VEGFR, EGFR, multitargeted tyrosine kinase inhibitors) play an important role in CRC management, but none of them have been successful in the adjuvant setting (although checkpoint inhibition is now being tested in MSI-high stage III CRC). Reliable predictive biomarkers for most agents are still greatly lacking, highlighting the importance of investing in CRC biomarker studies.

Abstract

In the last year, several impactful updates have been added to the NCCN Guidelines for Colorectal Cancer (CRC) for the management of metastatic disease, including additional options for BRAF-mutated advanced CRC and the inclusion of combination immunotherapy (PD-1 and CTLA-4) for deficient mismatch repair/microsatellite instability (MSI)–high advanced CRC. According to Dr. Wells A. Messersmith, targeted therapies (ie, VEGFR, EGFR, multitargeted tyrosine kinase inhibitors) play an important role in CRC management, but none of them have been successful in the adjuvant setting (although checkpoint inhibition is now being tested in MSI-high stage III CRC). Reliable predictive biomarkers for most agents are still greatly lacking, highlighting the importance of investing in CRC biomarker studies.

In the past year, the most significant changes to the management of metastatic disease in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colorectal Cancer (CRC) were related to biomarkers and subsets of the disease, according to Wells A. Messersmith, MD, Professor of Medicine and Head, Division of Medical Oncology, University of Colorado School of Medicine.

“I’d say the biggest updates are the additional options for BRAF-mutated cancers, tissue-agnostic approval for the NTRK inhibitor larotrectinib, and some additional language regarding Lynch syndrome and testing, both in terms of expression of the markers and the fact that a BRAF mutation doesn’t rule out Lynch syndrome,” he said at the NCCN 2019 Annual Conference, where he presented revisions to the CRC guidelines. “These, to me, are the 3 biggest headliners.”

CRC is the third most common cancer in the United States, with a 5-year survival of approximately 11% in the metastatic setting.1 According to Dr. Messersmith, there are still major gaps in the understanding of metastatic CRC and there are questions to answer: Why do targeted therapies not work in the adjuvant setting? What are the predictive biomarkers for VEGR inhibitors? Why do left- and right-sided tumors behave differently? Why does immunotherapy not work in most cases? He maintains that additional treatment options, as well as additional detection and prevention options, are still badly needed.

Consensus Molecular Subtypes

There are 4 consensus molecular subtypes (CMS) of CRC, classified as CMS1, CMS2, CMS3, and CMS4, which are associated with varying lengths of overall survival (OS). For example, in an analysis of patients in the CALGB/SWOG 80405 study,2 patients with a CMS2 subtype had an OS of 40 months compared with 15 months for those with CMS1. “This makes a really meaningful difference,” said Dr. Messersmith. “These [subtypes] are seemingly important in terms of survival, but right now they're not really predictive for specific drugs.”

Currently, there are 13 FDA-approved drugs for use in CRC, but, until recently, only 4 of these were biomarker-driven (Figure 1). Major 2019 updates include the addition of treatment options based on BRAF/MEK and NTRK fusion targets.

Figure 1.
Figure 1.

FDA-approved drugs for use in colorectal cancer.

Abbreviations: EGFR, epidermal growth factor receptor; TAS-102, trifluridine-tipiracil; VEGF, vascular endothelial growth factor.

aVEGFR, BRAF, and others.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 5.5; 10.6004/jnccn.2019.5014

The issue of cost remains a major concern in the treatment of CRC, and as OS has increased, the price of treatment has risen substantially. According to data from the University of Colorado Pharmacy, depending on biomarkers and specific therapies used, 24 to 30 months of combination therapy for metastatic CRC can exceed $300,000. According to Dr. Messersmith, investing in biomarker studies is preferable to spending billions on ineffective or harmful drugs, which could potentially lower costs.

Modified FOLFOXIRI Plus an EGFR

The regimen of modified FOLFOXIRI (mFOLFOXIRI; 5-FU/leucovorin/oxaliplatin/irinotecan) plus an EGFR monoclonal antibody led to very high response rates in the phase II VOLFI trial of 96 patients with RAS wild-type metastatic CRC.3 Patients were randomized 2:1 to mFOLFOXIRI plus the EGFR inhibitor panitumumab (n=63) or to mFOLFOXIRI alone (n=33). The objective response rate in the combination arm was 85.7% versus 54.5% for mFOLFOXIRI. Based on these data, an additional treatment option of mFOLFOXIRI + panitumumab was added to the NCCN Guidelines for unresectable stage IV metastatic CRC. This update applies only to patients with KRAS/NRAS/BRAF wild-type and left-sided tumors.

Microsatellite Instability/Mismatch Repair

Microsatellite instability (MSI) and deficient mismatch repair (dMMR) are typically acquired, rather than inherited, such as in cases of hereditary nonpolyposis CRC (HNPCC) or Lynch syndrome. According to Dr. Messersmith, it is important to recognize the relationship between BRAF mutations and MSI: the presence of a BRAF mutation makes HNPCC or Lynch syndrome much less likely.

However, the updated NCCN Guidelines added a cautionary note that although MSI-high (MSI-H)/dMMR associated with BRAF V600E is usually due to epigenetic mechanisms and is not inherited, it does not rule out Lynch syndrome (∼1% of these patients will have BRAF V600E). The guidelines now recommend germline testing if there is a family history of cancer, as well as further explanation of MMR immunohistochemistry for the 4 genes known to be mutated in Lynch syndrome (MLH1, MSH2, MSH6, PMS2).

Immunotherapy

Initial results from the literature on use of PD-1 in CRC show response rates of essentially zero among the general population of patients with CRC, but improved response rates were seen in patients with MSI-H disease.4

“More importantly, and this is where it’s very different from other potential treatments used, we saw a nice duration of response,” he reported. “We have some patients in our center who have been on these trials for 4 to 5 years, and they’re still doing well. The question now is when we can take them off.”

The NCCN Guidelines have included new immunotherapy options for use in the first-line setting: nivolumab or pembrolizumab, or a combination of nivolumab and ipilimumab, are listed as category 2B recommendations for patients with dMMR/MSI-H tumors but who are not eligible for cytotoxic combinations. The guidelines also indicate that nivolumab ± ipilimumab or pembrolizumab can be used in the second- and third-line treatment of patients with dMMR/MSI-H CRC.

Targeting NTRK

Another major update to the guidelines was the addition of larotrectinib as a second-line treatment option for patients with metastatic CRC who have NTRK gene fusions (occurring in ∼1% of patients). This recommendation was added based on CRC results from a pivotal 2018 paper published in The New England Journal of Medicine.5 In that study, patients with NTRK gene fusions had an 80% response rate, but only 4 of the 55 study patients were diagnosed with CRC. “But it didn’t seem to matter which tumor type [they had],” Dr. Messersmith reported. “They seem to respond very well.”

For that reason, the FDA granted tissue-agnostic approval for larotrectinib in November 2018 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. It should be noted that NTRK fusions can be hard to detect and are rare in CRC (∼1%).

Targeting BRAF-Mutated CRC

Approximately 8% to 15% of patients with CRC also have a BRAF mutation. This is an early event in carcinogenesis and is typically associated with older age and right-sided tumors. This subset of patients is difficult to treat because their cancer tends to be more aggressive; patients with BRAF mutations live approximately half as long as those with other types. BRAF mutations are also associated with MSI-H, thought to be due to hypermethylation of MLH1. BRAF inhibitor monotherapy has historically been disappointing in clinical trials of CRC,6 but combination approaches have shown much more promise.

The phase III BEACON CRC trial assessed combining a BRAF, an MEK, and an EGFR inhibitor (encorafenib, binimetinib, and cetuximab, respectively) in metastatic CRC.7 According to Dr. Messersmith, results from the safety lead-in phase of the trial showed that the combination of upstream inhibition with an EGFR inhibitor and downstream inhibition with BRAF and MEK inhibitors was able to target these patients and produce higher response rates. In 30 patients with BRAF V600E–mutant metastatic CRC, the estimated median progression-free survival with encorafenib/binimetinib + cetuximab was 8 months and the estimated median OS was 15.3 months, with a median duration of follow-up of 18.2 months. The overall response rate was 48%, with 3 patients achieving a complete response.

As a major update to the NCCN Guidelines, the panel incorporated new options for combination treatment for patients with BRAF-mutated (V600E) CRC. As second-line therapy options, the guidelines now include dabrafenib (BRAF inhibitor) + trametinib (MEK inhibitor) + cetuximab or panitumumab (EGFR antibody), or encorafenib (BRAF inhibitor) + binimetinib (MEK inhibitor) + cetuximab or panitumumab (Figure 2).

Figure 2.
Figure 2.

Update to the NCCN Guidelines regarding BRAF.

Abbreviation: mAb, monoclonal antibody.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 5.5; 10.6004/jnccn.2019.5014

Disclosures: Dr. Messersmith has disclosed that he receives institutional grant/research support from Alexo Therapeutics, Inc.; D3 Pharma; Genentech, Inc.; Immunomedics; Incyte; Millennium Pharmaceuticals, Inc.; OncoMed Pharmaceuticals; Pfizer Inc.; Roche Laboratories, Inc.; and Tanabe Research Labs USA Inc. He also serves on Data Safety Monitoring Committees for FivePrime Therapeutics and Gilead.

References

  • 1.

    American Cancer Society. Cancer Facts & Figures 2018. Atlanta GA: American Cancer Society; 2018.

  • 2.

    Lenz HJOu SFVenook AP Impact of consensus molecular subtyping (CMS) on overall survival (OS) and progression free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance) [abstract]. J Clin Oncol 2017;35(Suppl):Abstract 3511.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Geissler MRiera-Knorrenschild JTannapfel A mFOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild- type metastatic colorectal cancer m(CRC): a randomized phase II VOLFI trial of the AIO (AIO- KRK0109) [abstract]. J Clin Oncol 2018;36(Suppl):Abstract 3509.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Le DTUram JNWang H PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:25092520.

  • 5.

    Drilon ALaetsch TWKummar S Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 2018;378:731739.

  • 6.

    Atreya CEVan Custem EBendell JC Phase 1/2 Study of the MEK inhibitor trametinib, BRAF inhibitor dabrafenib, and anti-EGFR antibody panitumumab in patients with BRAF V600E-mutated metastatic colorectal cancer [abstract]. J Clin Oncol 2015:33(Suppl):Abstract 103.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Kopetz SGrothey AYaeger R Updated results of the BEACON CRC safety lead-in: encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) for BRAFV600E-mutant metastatic colorectal cancer (mCRC) [abstract]. J Clin Oncol 2019;37(Suppl):Abstract 688.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Corcoran RBAndré TAtreya CE Combined BRAF, EGFR, and MEK inhibition in patients with BRAFV600E-mutant colorectal cancer. Cancer Discov 2018;8:428443.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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Correspondence: Wells A. Messersmith, MD, Gastrointestinal Medical Oncology Program, University of Colorado School of Medicine, 12801 East 17th Avenue, L18-8124, Mail Stop 8117, Aurora, CO 80045. Email: wells.messersmith@ucdenver.edu

Article Sections

Figures

  • View in gallery

    FDA-approved drugs for use in colorectal cancer.

    Abbreviations: EGFR, epidermal growth factor receptor; TAS-102, trifluridine-tipiracil; VEGF, vascular endothelial growth factor.

    aVEGFR, BRAF, and others.

  • View in gallery

    Update to the NCCN Guidelines regarding BRAF.

    Abbreviation: mAb, monoclonal antibody.

References

  • 1.

    American Cancer Society. Cancer Facts & Figures 2018. Atlanta GA: American Cancer Society; 2018.

  • 2.

    Lenz HJOu SFVenook AP Impact of consensus molecular subtyping (CMS) on overall survival (OS) and progression free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance) [abstract]. J Clin Oncol 2017;35(Suppl):Abstract 3511.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Geissler MRiera-Knorrenschild JTannapfel A mFOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild- type metastatic colorectal cancer m(CRC): a randomized phase II VOLFI trial of the AIO (AIO- KRK0109) [abstract]. J Clin Oncol 2018;36(Suppl):Abstract 3509.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Le DTUram JNWang H PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:25092520.

  • 5.

    Drilon ALaetsch TWKummar S Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 2018;378:731739.

  • 6.

    Atreya CEVan Custem EBendell JC Phase 1/2 Study of the MEK inhibitor trametinib, BRAF inhibitor dabrafenib, and anti-EGFR antibody panitumumab in patients with BRAF V600E-mutated metastatic colorectal cancer [abstract]. J Clin Oncol 2015:33(Suppl):Abstract 103.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Kopetz SGrothey AYaeger R Updated results of the BEACON CRC safety lead-in: encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) for BRAFV600E-mutant metastatic colorectal cancer (mCRC) [abstract]. J Clin Oncol 2019;37(Suppl):Abstract 688.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Corcoran RBAndré TAtreya CE Combined BRAF, EGFR, and MEK inhibition in patients with BRAFV600E-mutant colorectal cancer. Cancer Discov 2018;8:428443.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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