Molecular Markers Critical to Guiding Treatment in Newly Diagnosed mCRC

Andrea Cercek, MD

The advent of immunotherapy and targeted agents, as well as understanding the impact of tumor sidedness, have impacted treatment decisions for newly diagnosed patients with metastatic colorectal cancer (mCRC), explained Andrea Cercek, MD.

“It is important to think about what we should do when we first meet a newly diagnosed patient with mCRC,” said Cercek. “[This is important in not] only how we choose the lines of therapy, but what molecular markers guide our care in the first- and later-line settings.”

Knowing a patient’s microsatellite instability—high (MSI-H)/mismatch repair deficient (dMMR) status, for example, can determine their eligibility for immunotherapy, she added.

Meanwhile, research efforts in the CRC paradigm are focused on targeting BRAF-, HER2-, and KRAS-mutant tumors, among others. To conduct molecular testing upfront for newly diagnosed patients with CRC is critical, Cercek said.

In an interview during the 2020 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Cercek, a medical oncologist at Memorial Sloan Kettering Cancer Center, shared insight on treatment selection, the importance of molecular testing, and unanswered questions with tumor sidedness in patients with newly diagnosed mCRC.

OncLive: What questions remain with first-line treatment selection for patients with mCRC?

Cercek: In terms of first-line therapy, how do we choose between FOLFOX versus FOLFIRI? Is it based on toxicities? Can we add biologics, such as bevacizumab (Avastin), cetuximab (Erbitux), or panitumumab (Vectibix)? What are the data to support that?

How have targeted therapies impacted this space?

Molecular markers are a very important part of the landscape. Tumors with MSI-H/dMMR status could be linked to a hereditary syndrome, such as Lynch syndrome.

All patients should be tested for MSI-H/dMMR when starting treatment, or at least before starting second-line therapy; we have immunotherapy available that may cure a subset of these patients. Testing is critical.

What targeted agents have become available?

Targeted agents come into play in the frontline and relapsed/refractory settings. We have targeted therapy for RAS mutations, including KRAS, NRAS, BRAF, and more recently, HER2.

There has been a lot of development in BRAF-mutant tumors. BRAF V600E—mutated mCRC tends to be a more aggressive subtype, is associated with worse prognosis, and does not respond well to cytotoxic chemotherapy.

Recently, there have been advances in targeting BRAF, as well as other signaling molecules in that pathway and the EGFR pathway. [In my presentation at the State of the Science Summit™], I highlighted the BEACON study, in terms of outcomes [with the] triplet therapy, versus a doublet, [versus the control regimen]. In the BEACON study, the control arm was systemic chemotherapy with an anti-EGFR agent.

We are not sure both will be approved, which is the drawback. Although [the triplet performed] statistically significantly better than the control, we don't know about the doublet. [We do know] there is more toxicity with the triplet compared with the doublet. I honestly don't know if 1 will be better than the other, or, if they are, how to make that choice for our patients.

There is progress being made in other ongoing studies in BRAF-mutated CRC. It is critically important because it comprises about 10% of all [mCRC cases] and has a worse prognosis.

HER2 is an emerging target. Thus far, two studies have been reported, and there is an ongoing study [evaluating] the combination of tucatinib and trastuzumab (Herceptin) in the relapsed/refractory setting for patients with HER2-amplified tumors. Preliminary data presented at the 2019 ESMO Congress showed an improvement in response rate, progression-free survival, and OS with this combination.

How does tumor sidedness influence frontline treatment selection?

When starting treatment for a patient with newly diagnosed mCRC, the location of the tumor is important. Several retrospective analyses [have shown] that patients with right-sided tumors, even RAS wild-type tumors, do not benefit from anti-EGFR therapy. They do however, do well with anti-VEGF therapy in combination with cytotoxic therapy. Conversely, left-sided tumors do benefit from anti-EGFR therapy.

We don't know why right-sided, RAS wild-type tumors behave so differently in terms of aggressive biology and lack of response to targeted therapy than left-sided tumors.

We know a lot about the molecular landscape. We believe we understand why it is different; however, we don't know why these tumors with this signature behave differently. That is an important question that remains to be answered.

What are your thoughts on the emerging data with agents targeting KRAS?

It is critically importantly because KRAS mutations comprise about 50% of mCRC. [Those patients] have 1 less therapeutic option because we cannot give them anti-EGFR therapy. We have seen poor responses with certain treatments in the setting of KRAS-mutated tumors, so it is an important target for us to have an active drug.

I am excited to see those studies, and we are trying to enroll patients as often as possible to try and help this population. There are varying drugs targeting different subtypes of KRAS mutations. All of them are important as they may help our patients.

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