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Molecular Markers Gaining Greater Influence in CRC Paradigm

Caroline Seymour
Published: Wednesday, Mar 27, 2019

Mohamed E. Salem, MD

Mohamed E. Salem, MD

The field of metastatic colorectal cancer (mCRC) is starting to shift away from a one-size-fits-all treatment approach due to the discovery and development of targeted therapies for patients with HER2 amplification, NTRK fusions, and BRAF mutations, said Mohamed E. Salem, MD.

“We’re moving toward an era of precision medicine and customized treatment, with which we hope to prolong survival and make colon cancer more of a chronic disease,” said Salem.

Most recently, updated results from the phase II MyPathway trial (NCT02091141) were published in Lancet Oncology, in which patients with refractory, HER2-amplified mCRC received the combination of trastuzumab (Herceptin) and pertuzumab (Perjeta). Among all 57 patients who enrolled in the trial and were eligible for evaluation, there was 1 complete response (CR) and 17 partial responses, translating to a 32% objective response rate (ORR) among the entire study cohort.

Moreover, the combination was found to be well tolerated, with no treatment-related deaths reported. However, grade 3/4 treatment-related adverse events occurred in 21 patients, the most common of which were hypokalaemia and abdominal pain.

If the combination progresses in development, it has the potential to join an increasingly expanding armamentarium of targeted therapies, which currently include larotrectinib (Vitrakvi) for patients with NTRK fusion–positive cancer. Additionally, the regimen of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) for those with BRAF V600E–mutant mCRC has been granted a breakthrough therapy designation.

Apart from these markers, microsatellite instability-high (MSI-H) and microsatellite stable (MSS) status must also be considered, as the presence of MSI-H can indicate potential for immunotherapy.

In an interview during the 2019 OncLive® State of the Science Summit™ on Gastrointestinal Malignancies, Salem, a medical oncologist at Levine Cancer Institute, Atrium Health, highlighted ongoing research efforts to potentially improve survival in patients with mCRC.

OncLive: How has the field of mCRC changed in recent years?

Salem: mCRC is a common disease. Until recently, we didn't have many treatment options available. Usually, we would give frontline FOLFOX or FOLFIRI plus a biologic agent to these patients. Once patients progressed on those regimens, we didn't have many options to offer them. In the last few years, we started to have more drugs. For example, regorafenib (Stivarga) was approved by the FDA in 2013. TAS-102 (trifluridine/tipiracil; Lonsurf) was FDA approved in 2014 and became available to patients who progressed on FOLFOX- and FOLFIRI-based regimens.

Another important aspect to remember is that we've started to understand the disease better. I used to tell my patients in the clinic that CRC is a family [disease], yet every patient has their own individual features that differentiate them from other [cases]. For example, we now know that right-sided CRC is biologically different from left-sided CRC. As such, choice of therapy will differ based on where the tumor arises.

CRC is also starting to be divided into patient subgroups. For example, MSI-H disease is sensitive to immunotherapy. Additionally, some of our patients have NTRK fusions and respond very well to NTRK inhibitors. We're also learning about BRAF-mutant CRC. We know that the combination of a MEK inhibitor, BRAF inhibitor, and EGFR inhibitor is linked to a better result than the use of traditional therapy. We also saw activity with an anti-HER2 agent in the refractory setting. Recently, results from the MyPathway trial were published in Lancet Oncology showing the activity of this agent.

What did the results of the MyPathway trial show?

We're learning from breast cancer. In [that space], we learned about HER2 as a physiology and how to target it. With advances made in technology and the ability of next-generation sequencing, we are able to find HER2 overexpression in about 3% to 5% of patients. This is important, because we have drugs that can be used to target HER2-amplified tumors. A few years ago, the HERACLES trial was presented at the ASCO Annual Meeting and demonstrated the activity of anti-HER2 therapy in the refractory setting.




View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: 2nd Annual International Congress on Oncology Pathology™Aug 31, 20191.5
Community Practice Connections™: 2nd Annual School of Nursing Oncology™Sep 28, 20191.5
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