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Grothey Grapples With Treatment Options in mCRC

Caroline Seymour
Published: Tuesday, Jun 26, 2018

Axel Grothey, MD
Axel Grothey, MD
It is still debatable which EGFR or VEGF inhibitors provide the greatest benefit when added to chemotherapy in the first-line setting of metastatic colorectal cancer (mCRC), but the identification of RAS, BRAF, and microsatellite instability (MSI) has helped physicians to refine treatment decisions.

Additionally, every patient with mCRC should undergo a mutational analysis for RAS and BRAF mutations, MSI-high (MSI-H) status, and HER2 amplification, explained Axel Grothey, MD.

Immunotherapy is another interest in the field of mCRC. In March 2018, the FDA granted a priority review designation to nivolumab (Opdivo) and ipilimumab (Yervoy) for patients with metastatic MSI-H/mismatch repair deficient (dMMR) CRC following progression on a fluoropyrimidine, oxaliplatin, and irinotecan. Single-agent nivolumab was also approved for this indication in August 2017.

In an interview during the 2018 OncLive® State of the Science Summit™, Grothey, an oncologist at Sanford Burnham Cancer Center, discussed sidedness and first- and second-line treatments for patients with mCRC.

OncLive: Please provide an overview of your presentation on mCRC.

Grothey: I spoke about how to integrate molecular markers into the choice for first-line treatment of patients with CRC. We all intuitively look at patient and tumor characteristics, as well as patient wishes when we choose first-line treatment and the intensity of treatment, but more molecular markers have become available. [We’re using markers] like RAS and BRAF mutation status and, more recently, mismatch repair deficiency or MSI-H status to select which treatments we should offer patients.

Over the last 2 or 3 years, we’ve also realized that independent of all these factors, cancer sidedness is important to make a treatment decision, particularly regarding the EGFR antibodies cetuximab (Erbitux) and panitumumab (Vectibix). [One of] the questions we have right now is, “Which targeted agents should be added to first-line chemotherapy? Is it the EGFR antibodies or is it the VEGF inhibitor bevacizumab (Avastin)?”

We have learned that the ideal candidate for EGFR-antibody therapy is limited to patients without RAS mutations, BRAF V600 mutations, and right-sided cancers. We’ve refined the patient population that can benefit from cetuximab and panitumumab. In my eyes, about 20% to 25% of patients with mCRC should receive EGFR antibodies added to a chemotherapy backbone in first-line treatment.

How often should a patient with CRC undergo a mutational analysis?

Every patient with mCRC should undergo mutational analysis for RAS and BRAF mutations with MSI testing and, in the future, likely HER2 amplification. When we look at where we are right now, it’s very easy to see that the next-generation sequencing (NGS) approach will likely be applied to the initial workup of the majority of patients in the United States.

Now, this might lead to some delays in therapy. When we subject every single patient with metastatic disease to NGS to find these molecular alterations, it is probably a 2- to 3-week delay before we know what mutations the tumor has. [At that point], we’ll feel more comfortable regarding choice of therapy. The turn-around time will be shortened over time. Five years from now, comprehensible testing will be part of the initial workup of patients with mCRC.

Are there any indications as to why the left side of the colon reacts differently than the right side?

There are differences in the molecular pathways that are activated. We know that right-sided cancers are more likely to be BRAF mutated and BRAF V600 mutations. There is a higher prevalence of DNA methylation in right-sided cancers. Even when we consider all of these factors, sidedness still remains an independent predictive and prognostic marker.


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