Novel Approaches, Individualization Needed in mCRC

Gina Columbus @ginacolumbusonc
Published: Thursday, Mar 16, 2017

Bert O’Neil, MD

Bert O’Neil, MD

While patients with metastatic colorectal cancer (CRC) may have a handful of treatment options in the second-line setting and beyond, experts say some of them overlap with one another and novel approaches are needed.

“Our current toolbox is good, and we can continue to refine how we use it with a better understanding of molecular features and individualization,” said Bert O’Neil, MD. “But, we’re going to run into this wall until we've identified completely new mechanisms of action.”

One such therapy is being explored in ongoing trials. At the 2017 Gastrointestinal Cancers Symposium, preliminary findings of a phase Ib/II trial showed that one-third of patients with treatment-resistant CRC attained objective responses with the stemness inhibitor napabucasin (BBI-608) plus chemotherapy with FOLFIRI with or without bevacizumab (Avastin). Additionally, disease-control rates in multiple subgroups reached as high as 93%.

O'Neil is 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. During the 2017 OncLive® State of the Science Summit on Gastrointestinal Malignancies, he gave a presentation on the paradigm of mCRC treatment. In an interview, he spoke to the need for novel treatments for these patients as well as why researchers need to develop a deeper understanding of tumor biology.

OncLive: What did you highlight regarding the landscape of mCRC?

O'Neil: I spoke on the treatment of mCRC that is initially diagnosed. What are the decisions that go into our first treatment for these patients? This tends to be the treatment that patients are on the longest, so this is a very important decision.

How we approach this decision is an evolution, from a time where we mostly treated patients similarly to 1 where we need to understand how to use molecular features to make different choices for different patients.

How has the frontline setting changed in recent years?

One of the biggest things we've seen is an evolution from using RAS mutation status, to decide about EGFR antibodies, to now a discovery that the site of origin of a tumor on the right or left side. It makes a big difference in terms of how a patient might respond to different biologics.

This really is new; it’s something that people need to be aware of, and is already starting to change how we make these decisions. As we kind of tease out the different molecular features of left-sided versus right-sided colon cancers, we know that this is really going to change how we practice medicine for these patients.

What are your thoughts on this sidedness data? What do we know about the underlying biology?

The right and left sides of the colon have different embryologic origins. It’s not a black and white thing; it’s not as if there is a true cutoff. There will probably be some overlap of features of some colon cancers that start on the right versus the left, but there does seem to be some powerful biology based on where the tumor started.

We are in the process of understanding this a little bit; I don’t think we understand it fully. One of the questions in many people's minds is, “Will this eventually be replaced by individual molecular features rather than side?” However, we'll start to see whether it’s sidedness that is important or whether it’s the molecular features that are the actual drivers of behavior.

How do you decide the sequence of agents beyond the first-line setting?

This is very complicated because after we get through a first-line setting, when patients have progressed, we actually now have quite a few options for second-line and beyond. For better or worse, a lot of these have overlapping mechanisms of action; the data are similar. It is very hard to know how to pick one versus the other. Can we sequence them? Is there a good sequence? For the most part, unfortunately, there’s not a lot of data to help make those kinds of decisions.

There are some differences between some of those treatments that might help you make some of those decisions but the reality is that at the moment, there are no solid data to give us guidance about what are the best choices to make for patients.

What does the future treatment landscape of mCRC look like to you?

In colon cancer, we are at a point where we have a lot of agents that target angiogenesis. We have several agents that target EGFR and not a lot of new mechanisms. Immunotherapy is one those new mechanisms but, at the moment, it looks like it might only apply to a small subset of these patients.

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