[GET] Four actionable targets for metastatic colorectal cancer that APPs should know – Reviews

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Treatment options for patients with metastatic colorectal cancer are limited and, therefore, many clinicians and researchers are focused on identifying predictive and prognostic molecular targets for this disease.

Over the past 2 years, a few pivotal clinical trials have shaped the way we approach patients with metastatic colorectal cancer. This article identifies four actionable mutations — microsatellite instability (MSI), BRAF V600E, HER2 and neurotrophic tyrosine receptor kinase (NTRK) — that APPs should be aware of and incorporate into the evaluation and management of this patient population.

The incidence of cancers with these markers is variable to low among the metastatic colorectal cancer population, with 5% being MSI-high or mismatch repair deficient, approximately 10% harboring BRAF V600E mutations, 2% to 6% with HER2 mutations, and only 0.3% of solid tumors harboring a NTRK gene fusion.

Microsatellite instability

MSI-high and mismatch repair deficient (dMMR) status are well-known biomarkers for colon cancer and patients with Lynch syndrome.

Kristin Barber FNP-BC, AOCNP
Kristin Barber

The approval of pembrolizumab (Keytruda, Merck) in 2018 represented the landmark first tumor-agnostic FDA approval for previously treated patients who harbor a loss of any one of the four MSI proteins: MLH1, MSH2, PMS2 and MSH6. Ipilimumab (Yervoy, Bristol-Myers Squibb) plus nivolumab (Opdivo, Bristol-Myers Squibb) or single-agent pembrolizumab or nivolumab should be administered to this patient population per National Comprehensive Cancer Network guidelines.

Data presented at this year’s ASCO20 Virtual Scientific Program served as the basis for FDA approval of pembrolizumab in the first-line setting for patients with MSI-high or dMMR status.

André and colleagues of the KEYNOTE-177 study compared pembrolizumab with investigator’s-choice chemotherapy among 307 patients with MSI-high metastatic colorectal cancer. Results showed improved median PFS (16.5 months vs. 8.2 months; HR = 0.6; 95% CI, 0.45-0.8) and a higher overall response rate (43.8% vs. 33.1%) with pembrolizumab.


BRAF V600-positive colorectal cancer has been known to portray a poor prognosis, with lack of response to EGFR therapy and median OS of 4 to 6 months after failure of previous therapy.

Previous trials have looked at BRAF inhibitors alone but have not been successful in achieving a meaningful response rate. The rationale for this is that BRAF inhibition causes negative feedback in the EGFR to RAS-RAF-MAPK pathway, resulting in EGFR reactivation.

Evidence from the phase 3 BEACON CRC clinical trial showed dual and triple inhibition of the BRAF-EGFR or BRAF-EGFR-MEK pathway with targeted therapy induced clinically significantly improved results over chemotherapy with FOLFIRI in the second-line setting and beyond.


Updated results of the trial, presented during this year’s ASCO20 Virtual Scientific Program, showed OS of 9.3 months in the triplet arm of encorafenib (Braftovi, Pfizer Oncology), binimetinib (Mektovi, Pfizer Oncology) and cetuximab (Erbitux, Eli Lilly) compared with 5.9 months with cetuximab-irinotecan or cetuximab-FOLFIRI.

OS in the doublet arm was 9.3 months, which prompted the newest FDA approval of the two-drug targeted therapy combination of encorafenib and cetuximab for previously treated patients with BRAF V600E-mutant metastatic colorectal cancer.

We await data from the ANCHOR study, which is looking at this doublet regimen in the first-line setting.

HER2 amplification

A third target that now has an active evidence-based role in metastatic colorectal cancer is HER2 amplification or overexpression.

HER2 amplification typically is identified by next-generation sequencing or immunohistochemical testing.

Data coming out of the MyPathway trial have been promising. This basket trial identified activity of targeted therapies in nonindicated tumor types. Specifically, researchers evaluated pertuzumab (Perjeta, Genentech) in combination with trastuzumab for HER2-positive metastatic colorectal cancer.

Results showed a 32% objective response rate with these drugs among a previously heavily treated population with a median four prior lines of therapy. Median duration of response was 5.9 months, with some patients responding for longer than 12 months.

Of note, the patients most likely to respond to HER2 antibody therapy were those with KRAS wild-type disease.

NTRK fusion

The final actionable target is for the rare group of patients with metastatic colorectal cancer who harbor a NTRK fusion.

The FDA approved larotrectinib (Vitrakvi, Bayer) for patients with NTRK gene fusions based on data from Hong and colleagues showing an ORR of 79% and median duration of response of 35.2 months with this agent across solid tumors.

Alternatively, entrectinib (Rozlytrek, Genentech) — another potent inhibitor of tropomyosin receptor kinase — also is an option for NTRK gene fusion-positive metastatic colorectal cancer. Doebele and colleagues studied this agent in 10 different tumor types in the STAR-TREK-1 and STAR-TREK-2 trials and reported a 57% ORR with a 7% complete response rate.

Based on these data, the FDA approved entrectinib regardless of tumor type last August.

Tailoring treatment

Because of these highly active therapies, it is important APPs ensure that next-generation sequencing is completed on all our patients to check for the presence of large introns, like NTRK2 and NTRK3 fusions. Often RNA sequencing is better able to identify these rather than typical DNA sequencing, and these are often mutually exclusive mutations where other aberrations are less likely to coincide.

Cancer treatment is becoming more specific and tailored to each individual’s genetic expression. By adapting these new drugs for patients with metastatic colon cancer, APPs are able to offer not only effective therapy, but also tailored therapy. This should be our ultimate goal for all of our patients.



André T, et al. Abstract LBA4. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.

Doebele RC, et al. Lancet Oncol. 2019;doi:10.1016/S1470-2045(19)30691-6.

Hong DS, et al. Ann Oncol. 2019;doi:10.1093/annonc/mdy539.

Hong DS, et al. Lancet Oncol. 2020;doi:10.1016/S1470-2045(19)30856-3.

Kopetz S, et al. Abstract 4001. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.

Kopetz S, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1908075.

Meric-Bernstam F, et al. Lancet Oncol. 2019;doi:10.1016/S1470-2045(18)30904-5.

NCCN Guidelines. Colon Cancer Version 2.2020. (2020). Available at: www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed June 19, 2020.

For more information:

Kristin Barber FNP-BC, AOCNP, is the clinical educator outpatient advanced practice clinician and an advanced practice clinician in gastrointestinal oncology at University of Utah Huntsman Cancer Institute. She can be reached at kristin.barber@hci.utah.edu.

[GET] Four actionable targets for metastatic colorectal cancer that APPs should know – Reviews
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