Identifying New Treatment Mechanisms is a Key Next Step in mCRC, Expert Says


Bert O’Neil, MD, discusses the need for novel treatments for patients with metastatic colorectal cancer as well as why researchers need to develop a deeper understanding of tumor biology.

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. In an interview withTargeted Oncology, 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.

TARGETED ONCOLOGY:What did you highlight regarding the landscape of mCRC?


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.

TARGETED ONCOLOGY: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.

TARGETED ONCOLOGY: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.

TARGETED ONCOLOGY: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.

TARGETED ONCOLOGY: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.

We’re at a period where we are in need of identifying new treatment mechanisms. We kind of understand what the enemies are in terms of mutations, and there are a quite a few mutations that we don’t have answers for at the moment. We’re desperately searching for treatments forRAS-mutated tumors. We’re at a standstill with those right now. We are trying to understand what to do about p53, Wnt/β-catenin pathway, and the transforming growth factor beta (TGF-β) pathway.

We know that they're there, we just don’t have things we can do about them now.

TARGETED ONCOLOGY:What role could stemness inhibitors play in this field?


The stemness inhibitors are one of those areas that are really exciting. This does address the potential of Wnt/β-catenin; it’s a novel area of biology. It seems to be important, preclinically. We were part of a study with napabucasin (BBI-608) in CRC where there seemed to be some preliminary hints of activity, and that has moved onto phase III.

We have also seen some other inhibitors of the Wnt/β-catenin pathway, which look exciting, so that is definitely an area to keep an eye on. It is pretty early still, but it is promising and very exciting because it’s so different from the other treatment options we have.

TARGETED ONCOLOGY:What is the final message you hope community oncologists will take from your lecture?


For people who are caring for patients with colon cancer, they should go into all of their decision-making with all of the information they need to make an individual decision that’s best for the patient who is in front of them.

These days, that includes having all of your molecular information upfront before you've started on therapy. These things are going to be very important for how long patients are on therapies, how likely they are to respond to them, and perhaps how likely they are to have good outcomes, get them to surgery or, even for a subset of these patients, have a chance of cure. This is not a one-size-fits-all disease.


Bendell JC, O’Neil BH, Starodub A, et al. Cancer stemness inhibition and chemosensitization: Phase 1b/II study of cancer stemness inhibitor napabucasin (BBI-608) with FOLFIRI +/- bevacizumab (Bev) administered to colorectal cancer (CRC) patients (pts).J Clin Oncol. 2017;35 (suppl 4S; abstract 593).

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