MCRC: Future Directions for Molecular-Driven Treatment

Transcript: Scott Kopetz, MD, PhD: A fascinating and emerging area of our understanding of colorectal cancer is really how the tumors evolve over time. We’ve known for a while that under EGFR selective pressure, we can see development of clones of KRAS, NRAS, EGFR ectodomain mutations, or other MAP kinase signaling areas that can appear, especially on ctDNA [circulating tumor DNA]. And this really reflects the acquired mechanisms of resistance.

As we discussed a little bit before, these can indeed regress with time and can allow rechallenge strategies. There’s been some interest in asking the question of, does the tumor go the other direction? Does it ever go from a KRAS-mutated state to a KRAS wild-type state? And here, there’s an increasing amount of data that are being collected with ctDNA. And the prevalence of that is extraordinarily rare, and I’m not convinced that this is a real change that is of clinical relevance. As a result, and we don’t recommend re-biopsying KRAS-mutated patients for reassessing KRAS status.

Richard Kim, MD: In colon cancer, there are several predictive markers that we use in normal practice. Obviously, we could do a better job because, unfortunately, even with a predictive marker, it’s not 100%. Eventually, those patients develop resistance and some of the predictive markers we have are very rare, such that we could pick it up but it’s less than 1%. For most patients, it’s not very helpful. So this is where I think a serial biopsy plays some role. By doing a serial tissue biopsy, you’re able to actually capture a novel mutation or some of the mechanisms of resistance. The problem with serial biopsy is 2-fold. Number 1 is that it’s very inconvenient. We cannot biopsy patients every 2 to 3 months. This is not practical and it’s a very invasive procedure. Second is that it does not capture tumor heterogeneity. By doing a biopsy on 1 side, you’re capturing the molecular profile of that side only. Therefore, you may be missing other mutations.

This is where I think liquid biopsy will play a big role in the future. Now, liquid biopsy has several advantages. Number 1 is, it’s much easier to do. You draw the blood, you send it out, nothing very invasive. You’re able to capture tumor heterogeneity from the liquid biopsy. Third, in real time you’re able to capture the response the patient is getting or able to capture the resistance pattern that’s developing in those patients.

Therefore, even though in stage IV patients, liquid biopsy is not ready for prime time—we don’t do it on all patients—it is now being used in earlier disease, for stage II patients. By being able to detect minimal residual disease in stage II patients, it is able to predict which patients have a higher chance of recurrence. Therefore, in stage II patients, now it’s being done such that you are able to check the liquid biopsy to see if the patient has any circulating tumor DNA. And if it’s there, we know that those patients are at higher risk, and therefore, those patients probably should get some chemotherapy.

However, in the stage IV setting, once again, it’s not ready for prime time. However, with better sensitivity, better specificity, and better technique, I think in the future, hopefully it will become standard of care where we’ll be able to monitor the patients’ disease response and identify certain mutations and identify resistance patterns as well in real time.

Scott Kopetz, MD, PhD: We continue to try to understand how we can better treat patients, and there are a number of large basket efforts that are ongoing. The NCI [National Cancer Institute] has the MATCH study that is wrapping up that looked at single agent targeted therapies in a number of different molecularly defined subgroups. In colorectal cancer, there’s an effort that’s called COLOMATE that’s in a refractory, previously treated patient population where circulating tumor DNA is being used to assess the status of the patient’s tumor. And then a number of molecularly defined therapies can be applied, including what we call the PULSE study of EGFR rechallenge that is enrolling as well.

All of these are very hopeful ways to try to think of novel approaches that may be useful in the future.

The ComboMATCH study, which is one of the successors of the MATCH study, is really trying to understand, how do we take those single biomarker-defined subgroups and look at combinations of targeted therapies to try to improve upon the activity—the limited activity in many cases—seen with the single agent targeted therapies?

Transcript Edited for Clarity