Grothey Highlights Biomarker Research in CRC

Axel Grothey, MD

Identifying biomarkers for patients with colorectal cancer (CRC) continues to be a topic of discussion among researchers in the field, according to Axel Grothey, MD.

“There are various biomarkers, such as RAS and BRAF. We also do microsatellite-instability (MSI)-high testing to select patients for immunotherapy,” said Grothey.

Additionally, tumor sidedness might impact response to treatment, he adds. Researchers are attempting to determine biological and genetic explanations for the inferiority of right-sided CRC.

“The European and the American guidelines have come to different conclusions. I believe there is a golden medium between those and we can utilize the sidedness data to help with improvements for treatment,” said Grothey.

OncLive: Please provide an overview of your presentation.

In an interview with OncLive^® at the 2017 State of the Science Summit^TM on GI Malignancies, Grothey, a medical oncologist at Mayo Clinic, discussed current first-line treatments for patients with CRC and highlighted the importance of developing biomarkers for this population.Grothey: I talked about first-line treatment for colorectal cancer. First of all, there is an abundance of new and established drugs that are available right now. The key question that we have is, “Which patient should receive which treatment?” There are some theories, but we are more interested in looking at biomarker-driven decisions.

We are also wondering how can the location of the tumor, whether it is left or right, help us to decide whether we use cetuximab (Erbitux) or a VEGF inhibitor like bevacizumab (Avastin) as part of the treatment plan for our patients. There are data right now that clearly indicates that right-sided tumors do not benefit from certain therapies. We should use bevacizumab in right-sided tumors.

Can you discuss available and potential biomarkers for these patients?

The European and the American guidelines have come to different conclusions. I believe there is a golden medium between those and we can utilize the sidedness data to help with improvements for treatment.There are various biomarkers, such as RAS and BRAF. We also do MSI testing to select patients for immunotherapy.

What is some ongoing research that you find promising?

We decided to use HER2 screening amplification, like in breast cancer and gastric cancer, for all patients with metastatic CRC because there are more data showing that HER2 amplification is associated with a negative predictive marker for panitumumab (Vectibix) and cetuximab. It can also help us select patients for HER2-targeted therapies, which are available but they are not necessarily approved yet. These potential targeted therapies are being investigated in clinical trials.First of all, there are several trials ongoing, which look at making tumors that are not yet immune responsive become immune responsive. Everyone is raving about immunotherapy, it’s everywhere. Unfortunately, in metastatic CRC it’s about 4% to 5% of patients who really benefit from immunotherapy as we know it now.

The addition of immunotherapy to chemotherapy might help us generally change the tumor type, meaning the tumor-immune cells get into the tumor itself by adding other agents to immunotherapy, such as MEK inhibitors or bi-specific antibodies. Those are ongoing experimental trial ideas.

How do we sequence these agents?

For the majority of patients right now, this will still take some time for all this research to materialize. The agents such as cetuximab, panitumumab, or bevacizumab will not go away.Sequencing of agents is important because eventually patients benefit from being exposed to all active agents. The first-line treatment determines the second-line and third-line treatments. There are some personal preferences that people have developed. There are some patient characteristics where you might want to avoid certain side effect profiles in certain drugs. Eventually though, patients will get exposed to mostly all agents and I believe they should be.

With chemotherapy, it is clear that we move from one therapy to another. For the biologics, like the VEGF inhibitors, the situation is not that clear because we know that these agents work even when patients have progression of disease. For instance, continuation of bevacizumab during progression is one of the established treatment options with survival benefits. This is an interesting phenomenon.

We are learning how to deal with markers of secondary resistance. For the majority of patients, the tumor might respond to the treatment initially but then stops responding. No patient will respond forever on these treatments, which is a problem.

Are there any other challenges that you think are important?

Ultimately, we need to figure out what happens in cancer that causes the tumor to stop responding. I believe things like circulating tumor DNA and liquid biopsies can help us see what is changing when tumors start to progress during treatment.First of all, metastatic CRC has improved in outcome over the last years but even though the vast majority of patients survive, we are still not curing cancer. We have seen some early evidence that immunotherapy can lead to long-term responses and potentially even cure select patients. We would like to identify these patients to determine what is the common denominator, learn from that, and move forward.

What are the main takeaways from your talk?

The other challenge is putting the right sequence in place. Which patient needs which drug? What is the preferred sequencing? It is not easy to find that out in prospective clinical trials because it’s very difficult to move patients forward from one line to another line. In the end, making sense of all the treatment options we have is a challenge.The art of oncology is to keep patients alive utilizing all these tools that we have and to preserve a patient’s quality of life. It takes a knowledge of molecular markers, patient factors, and tumor factors. You need experience with side effect management. It’s important to know when to pull back and when to escalate.

It’s not as simple as it was back when we only had 1 drug approved. It’s more complicated, but it is also a lot more rewarding when you eventually see the patients living a lot longer. We are now seeing patients living 3 times as long as they previously have.