The Hunt for Predictive Markers in Metastatic Colorectal Cancer - Episode 4

Combination Strategies in Frontline Metastatic CRC

Transcript: Alan Venook, MD: The results of CALGB/SWOG 80405 are still sort of percolating, but I think we’re close to getting an explanation for the sidedness question. Once we figure that out, I think it will make a big difference. In CALGB/SWOG 80405, as in other contemporary studies, we know that there is a population of patients who do poorly compared with everybody else. The patients who do well live for about 3 years, and the patients who don’t do well live for about 2 years or a little less. One of the big differences appears to be right-sided primary versus left-sided primary…

None of us have believed that it’s just right versus left. We assume that’s a surrogate for some underlying biology. We’ve been looking and looking, and so far, I’m not sure that we’ve found it. We will be presenting new data from CALGB/SWOG 80405 and sort of an artificial intelligence, machine-learning analysis of the data, which makes us think we have a handle on what’s causing it.

If we know that, we can figure out the real issue. We can take the patients who do poorly with standard therapy and design different treatments for those patients. The patients who we know will do well can probably stay on the standard therapy, just as we do now.

What we’ve learned over the past number of years is that many patients do well almost regardless of what you do. As long as you don’t mess up, they don’t have complications or get into trouble. And then there’s a population of patients who don’t do well. Those are the ones for whom we really have to figure out how to improve outcomes.

Right now, we’re not sure what the subsets are, but we’re close to figuring that out. Once we do, I think it’ll be very important. The so-called CMS [consensus molecular subtypes] subtypes, which there are 4 of, have been described by a consensus group. We don’t think those are exactly the right subtypes. We can score these patients and look at them, but as our analysis suggests, that’s not exactly the right way to characterize them, at least not yet.

John L. Marshall, MD: We have really learned a lot over the past 5 years about how colon cancer is different. When I trained a long time ago, it was 1 disease. Now we know it is multiple diseases. A couple of key clinical trials helped us uncover that, one of which is called FIRE-3. FIRE-3 was a European-based study that essentially compared 2 biologics, bevacizumab and cetuximab, in frontline metastatic disease. The findings of this suggested that in certain patients there was a significant improvement seen by using the EGFR [epidermal growth factor receptor] therapy, cetuximab, in the frontline setting. Further subset analyses helped explain this.

In left-sided colon cancers, we have no idea why. Left-sided colon cancers appeared to do better than right-sided colon cancers. And remember, this is regardless of RAS or BRAF status because all these patients were in the wild-type group.

FIRE-3 has really changed the way we think about this disease. It has also sparked one of the biggest debates between the United States and Europe. In Europe, they have taken these data and have said, “Frontline EGFR therapy is the right thing for, essentially, any patient who is RAS wild type, BRAF wild type.” In the United States, we’ve taken the same data and have said, “This really only applies to left-sided colon cancer.” So we’re having this debate on how to take these data and apply them to our patients today.

Richard Kim, MD: The primary endpoint of the FIRE-3 study was response rate, which was presented many years ago. It was a negative study when it first came out. The response rate was very similar in the FOLFIRI [folinic acid, fluorouracil, and irinotecan] plus bevacizumab arm versus the FOLFIRI plus cetuximab arm. However, when the imaging was reviewed centrally, the response rate for FOLFIRI/cetuximab was much higher than it was for FOLFIRI plus bevacizumab. It was, I believe, around 72% for FOLFIRI/cetuximab versus 58% in the FOLFIRI plus bevacizumab arm. Also, in the trial, patients who were randomized to the FOLFIRI/cetuximab arm had an early response and had more depth of response. That correlated with an overall survival benefit.

For certain patients who present at the beginning with a left-sided RAS wild-type tumor—if a patient has burden of disease and is symptomatic, or is someone whom you’re trying to downstage to undergo possible surgery—this is a case where the response rate may matter. If they have a RAS wild-type left-sided tumor, and you’re trying to make the patient feel better or possibly downstage the patient to go for surgery, this is where response rate matters. I would possibly use FOLFIRI plus cetuximab in that setting.

John L. Marshall, MD: In frontline metastatic disease, we’ve seen response rates in the 50%, 60%, 70% ranges. This is a bit dependent on sidedness, the regimen you’re using, and what the RAS status is. Of the 2 best response rates we have in the book, we’ve seen a 70% response rate and a very nice progression-free survival rate and overall survival rate with our 4-drug combination. But in the left-sided RAS wild type, patients who are BRAF wild type with chemotherapy plus cetuximab, we’ve also seen a very high response rate. And so when you need that frontline response rate, you have 2 choices depending on sidedness and molecular profile.

Transcript Edited for Clarity