Genetic Testing Guides mCRC Treatment

Al B. Benson, MD

Genetic testing is a critical component of sequencing treatment and maximizing survival in patients with metastatic colorectal cancer (mCRC), explained Al B. Benson, MD.

“There is no question that we have made tremendous progress, particularly in patients with RAS wild-type tumors. Unmasking the biology of CRC has led to new treatments that have shown an impact on survival,” said Benson. “However, we have much work to do. That's why it’s so important to participate in clinical trials.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, Benson, professor of medicine, Hematology and Oncology, Northwestern University Feinberg School of Medicine, discussed personalized treatment strategies for patients with mCRC.

OncLive: Could you discuss the treatment of patients with newly diagnosed mCRC?

Benson: [In my presentation], I discussed what to do when a patient comes to you with mCRC, whether it’s synchronous or metachronous metastasis. It’s important to consider the concept of the continuum of care. When you meet an individual with mCRC, you need to think about the broad picture. You need to gather the most information possible in order to construct an initial treatment plan. You need to define the sites of disease and the patient's performance status, as well as the patient's wishes and treatment goals.

You must also understand the genomic characteristics of the tumor. To do this, you should test for microsatellite instability (MSI), RAS, NRAS, BRAF, and HER2. HER2 testing is reserved for individuals who have RAS wild-type tumors. We now have evidence that giving combination HER2-directed therapy can be effective in this subtype of patients. From there, you can begin to decide whether the patient falls into a certain subset; this might guide therapy down the line.

It’s also important to consider whether the patient has potentially resectable metastatic disease. In that situation, you should bring in a multidisciplinary team, so that the surgeon and the radiologist can weigh in on whether the tumor is resectable or not. At that point, you have to decide what your therapeutic strategy will be.

If a patient presents with resectable disease, it's advisable to give a more limited course of neoadjuvant therapy, which typically ranges between 2 and 4 months. You don't really need to shrink the tumor because it’s already resectable. By giving chemotherapy, you'll have a sense as to [the patient’s] chemosensitivity, which may help you with future treatment planning. Also, the drugs we use are potentially toxic to the liver, so you want to limit complications with surgical resection. The National Comprehensive Cancer Network guidelines and the CALGB/SWOG 80405 trial [have reinforced the use of chemotherapy in the newly diagnosed setting]. We can use FOLFOX, CAPOX, or FOLFIRI. Then, we have to consider what biologic to add. If a patient has a RAS mutation, you would consider using bevacizumab (Avastin). If the patient is RAS wild-type, you could consider either cetuximab (Erbitux) or panitumumab (Vectibix).

What are your recommendations for genomic testing?

I stress the importance of doing tumor testing to determine whether an individual has a certain alteration that might inform treatment decisions. MSI testing should be done in every patient with CRC. We also want to make sure that the patient doesn’t have a genetic component, such as Lynch syndrome. If the patient has an MSI-high (MSI-H) tumor, then they are a candidate for immunotherapy. Currently, immunotherapy is generally given after progression on first-line chemotherapy. However, ongoing clinical trials are evaluating first-line immunotherapy. We know that patients with MSI-H tumors respond to chemotherapy, and upon progression, immunotherapy. MSI testing is essential, regardless of the stage of disease.

It's also important to know whether the individual has a RAS-mutated or wild-type tumor. Extensive RAS and NRAS testing should be done, because if the individual has wild-type disease, we have [to consider] when to introduce anti-EGFR therapy with either cetuximab or panitumumab.

The most efficient way to test for these alterations is to order next-generation sequencing (NGS). [By doing that], you might pick up a rare alteration, such as an NTRK fusion, for which there are targeted therapies. You could also pick up a mutation that would qualify a patient for a clinical trial.

One way to truly maximize the number of options for patients with RAS wild-type disease is to begin with FOLFOX or CAPOX, with or without bevacizumab. Once they progress, they could receive an irinotecan-based regimen, which typically consists of FOLFIRI and bevacizumab. At the time of progression, we could consider irinotecan or FOLFIRI with cetuximab or panitumumab, or cetuximab or panitumumab alone.

However, response rates are higher when you combine anti-EGFR therapy with chemotherapy. As we move into fourth- and fifth-line therapy, we could consider TAS-102 (trifluridine/tipiracil; FTD/TPI; Lonsurf) or regorafenib (Stivarga). Notably, patients with RAS wild-type tumors appear to have the best survival [of all patients with mCRC]. We expect a median survival of at least 3 years in this group of patients. To achieve that, this sequence of therapy becomes very critical.

Could you expand on some of the ongoing research with immunotherapy in mCRC?

Currently, our research with immunotherapy is limited to patients with MSI-H tumors. Studies have demonstrated the efficacy of pembrolizumab (Keytruda) and nivolumab (Opdivo), and more recently, the combination of nivolumab and ipilimumab (Yervoy). One of the questions is whether we should use immunotherapy as a single agent or in combination. Part of the answer may come down to how urgent of a response is needed. Keep in mind, a patient with MSI-H mCRC has a worse prognosis. If you're looking at second-line therapy, your window of opportunity might not be terribly long. Therefore, you might choose a combination therapy.

There is interest in exploring immunotherapy in the adjuvant setting, as well. The challenge is [making this approach effective] for the majority of patients who are not MSI-H. We know that single-agent immunotherapy is not effective for this population. A variety of approaches have been explored, including combinations of immunotherapy with radiation, liver-directed therapy, chemotherapy, targeted agents, and vaccines. We will have to see how all of this unfolds over time. My hope is that there will be extensive biological correlates for these strategies, so that we can get additional clues as to how to integrate immunotherapy into treatment for patients [with microsatellite stable disease].