The Biology of Extending Survival in Advanced CRC - Episode 5

Frontline Decisions in RAS Wild-Type Left-Sided mCRC


John L. Marshall, MD: Let’s talk about the more controversial left-side colon cancers. Again, I want to make these patients BRAF wild-type, KRAS, all-RAS wild-type. We have a fairly clear difference of practice between the United States and Europe in this space.

Dirk, I’m going to let you go first on describing the rationale for using EGFR therapy. The way I see it, we used to give EGFR therapy to everybody. Then it was for RAS-mutant cancer, then BRAF, and now for left-sided cancer. When you look at the total number of patients who fit, it’s down to about 20% of the population. It’s a fairly low frequency of patients who now fit this pattern. But in that sweet spot, in that left-sided mutation wild-type disease, what are you doing?

Dirk Arnold, MD, PhD: If we can identify them, we can clearly give an anti-EGFR antibody as first-line treatment—coming from the better overall survival likelihood of these combined analyses, as from the individual trials in these patient groups, and also the better progression-free survival and overall response rate. So, there is some consistency. I think the recommendation is clear.

I also agree that the number is about 20% for those who really do benefit from this. Interestingly, we already saw this in the very first analyses of these anti-EGFR trials when we were comparing response rates between chemotherapy and chemotherapy plus anti-EGFR, and response rates were about 20% higher. It mirrors that this group of patients really does benefit from an anti-EGFR.

John L. Marshall, MD: In this patient population in your practice, you would not start treatment, or you wouldn’t start a biologic, until you knew the molecular profile of the patient?

Dirk Arnold, MD, PhD: Well, we would start treatment if the patient was symptomatic and needs treatment. We would give him/her treatment. We would go ahead with chemotherapy or whatever else. But as we do have information that this is left-sided, primary RAS and BRAF wild-type colon cancer, we would in any case. If there’s nothing against adverse events, for a patient with clear preference or whatever, all factors are important. But if this doesn’t speak against that, we would recommend the patient to be treated with an anti-EGFR antibody.

Fortunato Ciardiello, MD, PhD: In Italy, at least in 90% of cases in the big hospitals and the medium-sized hospitals, we have the testing of all-RAS and BRAF for, I would say, almost all patients before we start first-line therapy. Basically, this is part of our workout for disease detection and determining a prognosis, in terms of the right of the patients to know what their disease is about. And what we are trying to do—and maybe this will be a topic we will discuss later—is to also have the status of microsatellite instability. This is what we are trying to do.

John L. Marshall, MD: You’re going to want to know all that anyway.

Fortunato Ciardiello, MD, PhD: Yes.

John L. Marshall, MD: Why aren’t we? What is the counter to this? They do have these trials. These trials are hard to interpret, I think, because the PFS and all of those things are the same and it’s really after the fact that we see the tail on the curve. We have a lot of counter-arguments as to why we are not doing it. Tony, why do we tend to use the VEGF inhibitor, bevacizumab, in this setting?

Tanios Bekaii-Saab, MD: We’re simpler.

John L. Marshall, MD: Simpler.

Tanios Bekaii-Saab, MD: No, it’s a practical and pragmatic element. When you look at the cumulative data, it is very clear that EGFR inhibitors do not benefit patients, significantly, or not at all on the right side.

John L. Marshall, MD: I’m talking about the sweet spot.

Tanios Bekaii-Saab, MD: We’re talking about the sweet spot patients. On the left side, it’s less clear. The delta, at least from the United States-based studies, are not as significant on the left side between VEGF and EGFR inhibitors. If you look pragmatically at the cumulative studies, the thought is, “Why should I change my standard? My standard has been, forever since we started introducing these agents, chemotherapy plus bevacizumab. I haven’t seen that convincing data that suggests that on the left side, I need to change my standard.”

On the right side, it became clearer. Now, that does not say that EGFR inhibitors do not have a role in the first-line setting. In our practice, we moved these EGFR inhibitors, now, to the second-line setting, rather than waiting to use them later. And we’ll go through a couple of VEGF lines.

John L. Marshall, MD: Even though there are really no data in that window? There are no OS data in the second-line setting.

Tanios Bekaii-Saab, MD: Sure.

John L. Marshall, MD: There’s refractory in first-line.

Tanios Bekaii-Saab, MD: But just on that left side.

John L. Marshall, MD: Yes, in that patient. In the sweet spot.

Tanios Bekaii-Saab, MD: In the sweet spot patient, we’ve moved it closer to the first-line setting. But the evidence, at least in my mind, from the cumulative studies, is not that compelling.

John L. Marshall, MD: Paul, I want to hear what you want to say on this.

Paul R. Helft, MD: I’ll make a few comments, very quickly. One is that the CALGB/SWOG 80405 trial did not confirm the FIRE-3 data in the way that probably would have changed practice if it had aligned.

John L. Marshall, MD: I would like to express, here, a disappointment from the CALGB/SWOG 80405 trial. We wanted it to be positive, in some level, because this was molecularly targeted therapy—right gene, right patient.

Paul R. Helft, MD: Almost 40 months of survival. I would say that I’m deeply and personally conflicted about this because I have not converted to giving anti-EGFR therapy in the first-line setting, even in this 20% patient population who has a wild-type tumor on the left side. Another reason is, you are going to be on first-line therapy for a long time and you’re also going to get the most mileage, from an OS perspective, from first-line therapy. Patients are going to be on it, on average, for 10 or 11 months. Some of our patients are on first-line therapy, as you know, for 2 to 2.5 years. We consider the thought of being on EGFR therapy with a rash for that long, even though the rash tends to get better with long-term therapy.

John L. Marshall, MD: I did want to talk about the toxicity management because one of my counters is that—particularly in the city I live, in where looks matter—that rash and all that stuff. Patients have a brand new diagnosis and, now, I’m going to give them a visible toxicity. And it’s one more thing for the practice to have to do. It’s one more education step that you have to do.

Paul R. Helft, MD: Well, psychologically, this is only partially about vanity. It’s mostly about announcing that you have cancer, right? You have a lot of explaining to do once you have a rash.

John L. Marshall, MD: Once you show up at work with this new rash. Another argument I’ve heard—and I’d love to hear more on this—is that we, in the United States, tend to use more second-line biologics. But when you look at the studies, it does fall off more. Is that a valid argument?

Dirk Arnold, MD, PhD: No. Let me reply. Although the United States is disappointed about the CALGB/SWOG 80405 trial, we have now undertaken the endeavor to combine these trials to have the analysis for first-line therapies for the benefit of this left-sided wild-type cancer. And the hazard ratio of all of the data, together, is 0.78 for OS and 0.75 for PFS.

The majority of the data, including more than 2000 patients, clearly shows the benefit of this. The toxicity concern is there, I agree. However, I’m saying this also—for me as one who is working on the continuation of treatment in the maintenance trial and for me who is working on the TML trial on the strategy, really adhering to the long-term benefit of bevacizumab—that just keeping patients on treatment is not a benefit, per se. If keeping patients on treatment for a long time, without extra benefit, yes, if it doesn’t add, it doesn’t add. If these months of anti-EGFR provide these results, that’s likely a better treatment.

Transcript Edited for Clarity