Precision Medicine Impact Grows in GI Cancer Paradigm

Bert O’Neil, MD

The development of molecular testing and next-generation sequencing throughout the oncology space has also been applied to gastrointestinal (GI) cancers management, in an effort to better identify molecular alterations and optimize treatment decisions.

“We are trying to get to a point where we no longer think of a cancer type based on where it came from, but rather what type of cancer it is genetically,” says Bert H. O’Neil, MD.

OncLive: You spoke on precision medicine in GI cancers as well as a specific focus on mCRC. How have you seen the GI cancers paradigm evolve?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, O’Neil, the Joseph W. and Jackie J. Cusick Professor of Oncology, professor of medicine, and director of the Phase I and Gastrointestinal Oncology Programs at Indiana University, discussed the role of molecular testing throughout GI cancers and highlighted the current and developing treatment landscape for patients with colorectal cancer (CRC).O’Neil: We are now well into this area of precision medicine, which involves genetic sequencing of tumors to look for treatment options that we might not have considered for patients with a particular tumor type in the past. It is an exciting time.

What are the differences between targeted and expanded testing and when might it be better to use one over the other?

Are liquid biopsies something that we are prioritizing in GI cancers?

This is a big paradigm shift for us. In my talk, we discussed the basics of testing, how we test, and what kinds of results are out there so far. This is an area that is going to keep evolving as we get more drugs and as we define more genetic abnormalities. There is a lot of potential for future growth and it is something that people are generally familiar with but is also a good area to learn the newest data. If you are early in the treatment of a disease where you know there is a defined set of options that work well, then a targeted panel of genes is what makes the most sense. In patients beyond that initial set of treatments, where we are starting to get into an area of limited options, then we want to look more broadly because we are “hunting” for something that we wouldn't normally think of. In a patient with refractory cancer—or you could almost argue in any type of cancer—it makes sense to do a broad panel to get as much information as possible to find a treatment choice for someone who may not have one. Liquid biopsies in GI cancers is an interesting area right now. Unlike lung cancer, we do not tend to have the problem of not having enough tissue. In some ways, I would argue that liquid biopsies are not as necessary as they are in lung cancer, where it is less safe to biopsy patients and take large pieces of tissue.

How else are we evolving with precision medicine in GI cancers?

Can you give an overview of your other presentation, which was on CRC?

On the other hand, we are starting to see interesting data when you follow the genetic mutations in the plasma as patients are being treated. We see new mutations arise and those may help us make decisions about future therapy. We are not quite there yet, as it is still an evolving area of research. However, its clinical applicability in GI cancers is still unclear. GI cancers are arguably tougher than the other cancer types in terms of finding usable genetic hits. That is probably because, from CRC, we know that there is a huge frequency of these mutations that we do not know what to do with, such as RAS and p53. Many of those mutations do not have tyrosine kinase inhibitors that we can use, so it is a challenge. We are at a point where we do not necessarily need to find the mutations, but we need to find the drugs for the mutations we already know about. We discussed where we are in terms of patient selection for second-line therapy. This includes clinical factors, such as RAS mutations, which is something we have known about for quite some time. We have talked about first-line data comparing EGFR-targeted antibodies and the VEGF-directed antibody strategies.

When you find a patient with a molecular target, do you approach the target first or still use chemotherapy?

Relatively new considerations are things like what side did the tumor arise on, what are some special populations, what first-line therapy should be given to patients with HER2-positive cancer, and what first-line therapy should be given for a microsatellite instability-high (MSI-H) cancer. These are smaller populations, but there are important questions of when we start intervening with targeted therapies. Second-line therapy choices have not changed much over the last few years.At the moment, we do well in the average patient with chemotherapy plus one of our core biologics, such as the VEGF inhibitor bevacizumab (Avastin) or the EGFR-targeted antibodies. We haven’t gotten to a place where we can replace those.

How have you seen the data related to tumor sidedness have an impact on clinical practice?

Looking ahead, what are some exciting ongoing trials this year in the first- and second-line settings?

What is it about napabucasin that would make it such a novel addition to the landscape?

Where we will almost certainly change our behavior in the near future is in the MSI-H population. We are going to incorporate immunotherapy early. It is almost bound to happen, but those studies still have to be completed. The one that is more unsure is HER2 amplification, and whether to give immunotherapy earlier versus later but we are still early in exploring that. For patients with BRAF mutations, we are unsure of whether to intervene in the first-, second-, or third-line setting. We are early in trying to figure out specific treatments for that population.I am starting to hear people talk about it more. We are at that point. It has been almost 2 years since those data were presented. This has caused it to sink in for physicians who are not possibly experiencing that data firsthand in the clinic. I am hearing a lot more of that than I did 1 year ago. The first-line setting is relatively slow other than the MSI-H population. In the second-line setting, one of the more interesting trials that is ongoing is with napabucasin (BBI-608), an oral stemness inhibitor, being combined with chemotherapy. That has some interesting phase I/II data to back it up so that is a study that I am keeping an eye on.It is always nice for us when a completely unique mechanism comes up. This is very different than anything we have tested in CRC. It was shown in preclinical data to inhibit stem cell growth. Its mechanism may have to do with inhibition of the transcription factor called STAT3, which is overexpressed and overactivated in a lot of cancers. It gets activated by many different mechanisms. It is nice when you can find something that is so important to target in a lot of situations. It may also affect the Wnt/β-catenin pathway, which is another area where we have been desperate for strategies to combat. Wnt/β-catenin activation is common in CRC and has been a barrier, like RAS, to us making progress in combatting CRC.