Panelists: John L. Marshall, MD, Georgetown University Hospital; Dirk Arnold, MD, PhD, Instituto CUF de Oncologia; University of Hamburg; Fortunato Ciardiello, MD, PhD, Seconda Università di Napoli; Paul R. Helft, MD, Indiana School of Medicine of the Indiana University Melvin and Bren Simon Cancer Center; Tanios Bekaii-Saab, MD, Mayo Clinic Cancer Center in Arizona
John L. Marshall, MD: Paul, you’ve progressed—rechallenged or not. Then it’s into second-line therapy. Let’s talk about biologics in the second-line setting. Let’s make it easy. Let’s make our case a RAS-mutated patient. What is the role of VEGF therapy in second-line therapy?
Paul R. Helft, MD: I continue bevacizumab therapy in almost every patient.
John L. Marshall, MD: There are 2 other drugs out there approved and you’re picking bevacizumab?
Paul R. Helft, MD: I haven’t used any of them to any large extent.
John L. Marshall, MD: Why not?
Paul R. Helft, MD: We don’t have 1 of them on formulary. We decided as a group not to use it at all, and I haven’t found any compelling reasons to switch.
John L. Marshall, MD: Would there be that sort of “blew through first-line therapy in the RAS-mutated patient, maybe you’d switch” case, or not really?
Paul R. Helft, MD: Well, in that patient who doesn’t have any other great options, who’s blowing through first-line therapy but who has a RAS mutation, I would generally continue them anyway because they don’t have any options.
John L. Marshall, MD: Right, you’d just keep them on therapy.
Tanios Bekaii-Saab, MD: And those are the patients that do extremely bad anyway.
Paul R. Helft, MD: Almost no matter what you do.
John L. Marshall, MD: That right-sided mutation.
Tanios Bekaii-Saab, MD: Absolutely.
John L. Marshall, MD: What’s the role of VEGF in second-line therapy for the RAS-mutated patient?
Fortunato Ciardiello, MD, PhD: In most patients, I will still treat them by switching with irinotecan or oxaliplatin and continue bevacizumab. Ramucirumab is not reimbursed in our country, so the only alternative is aflibercept. Aflibercept, it in our country, can only be given with FOLFIRI (folinic acid, fluorouracil, and irinotecan). But, if you did FOLFIRI in the first-line setting, you cannot do it. And, individually, aflibercept is more toxic than bevacizumab. So, unless I have a patient—and these are very rare patients—who, within 2, 3, or 4 months, has progressed on FOLFOX (folinic acid, fluorouracil, and oxaliplatin) or bevacizumab, where I think that everything should be changed—but there are very, very few patients like this—I will treat with aflibercept. But, for the other 95% of patients, I will still treat with bevacizumab.
John L. Marshall, MD: And the thing that I never thought I would say is, bevacizumab is cheaper than the others.
Fortunato Ciardiello, MD, PhD: Yes. The only reason aflibercept is on the market in Italy is because it is cheaper than bevacizumab. Otherwise it could not be on the market.
Tanios Bekaii-Saab, MD: As for the cost, they actually are about equivalent, now. Ramucirumab is still more expensive because it’s priced at the gastric level. But, if you really look at the cumulative data from VELOUR to RAISE to TML, there’s really not much of a difference. In fact, if anything, when you look at aflibercept and you isolate those 30% that have prior use with bevacizumab, they do even worse than the others. We’re talking toxicity. We’re talking cost. We’re talking very little benefit. If we really think about what VEGF beyond progression adds, it’s about 1.4 months across the board in terms of improvement in benefit.
John L. Marshall, MD: On average, right? There will be some people who benefit more, and some probably are not benefiting.
Tanios Bekaii-Saab, MD: Actually, the response rate is pretty dismal.
John L. Marshall, MD: What about 5-FU beyond progression? We certainly use a lot of that. So, if you start with FOLFIRI, you pretty much have to do 5-FU beyond progression, because oxaliplatin is not really active or is less active by itself. What if you start FOLFOX?
Tanios Bekaii-Saab, MD: The answer is yes.
John L. Marshall, MD: The answer is, you should continue.
Tanios Bekaii-Saab, MD: The answer is yes, and that comes from a series of studies in the past that did suggest that there is some level of additivity, and maybe even synergism, when you combine 5-FU with irinotecan even with prior 5-FU exposure. We’ve also seen that in a different setting in NAPOLI-1 with pancreas cancer: 5-FU and MM-398 did better than MM-398 or 5-FU. So, there is this level of additivity and perhaps synergism. I actually tend to continue 5-FU. As long as I can milk that 5-FU, I would continue it.
John L. Marshall, MD: It’s still our best drug, right?
Tanios Bekaii-Saab, MD: It is still our best drug.
John L. Marshall, MD: Sad to say, but it still is.
Tanios Bekaii-Saab, MD: The whole superfamily of fluoropyrimidines, right? That includes TAS-102 at some point.
John L. Marshall, MD: Yes. Let’s look at the other side of EGFR in second-line therapy. I think we know the mutation status. You need to know BRAF status, and you need to know RAS status, right? And sidedness—we said earlier that if you’re a right-sided colon cancer patient, in later lines of therapy, we are certainly going to consider starting an EGFR-targeted therapy. But, let’s look at that very controversial space of RAS wild-type, BRAF wild-type second-line therapy. Tell me about a patient that you would use an EGFR therapy for that you hadn’t used in frontline—Paul?
Paul R. Helft, MD: That would be appropriate for the patient who really had a very rapid progression through anti-VEGF therapy. In general, I would continue anti-VEGF therapy through the second-line setting in an average patient. For the patient who had rapid progression through first-line therapy, I would tend to switch if they had a wild-type tumor.
John L. Marshall, MD: Tony?
Tanios Bekaii-Saab, MD: Is it left-sided or right-sided?
John L. Marshall, MD: It’s the sweet spot patient.
Tanios Bekaii-Saab, MD: Left-sided.
John L. Marshall, MD: Left-sided, mutation wild-type.
Tanios Bekaii-Saab, MD: I actually use EGFR inhibitors in the second-line setting.
John L. Marshall, MD: So, small volume, asymptomatic, 3- to 1-cm pulmonary nodules, and a para-aortic lymph node? That’s their volume of disease?
Tanios Bekaii-Saab, MD: That’s progression.
John L. Marshall, MD: You’re going to give an EGFR in that setting?
Tanios Bekaii-Saab, MD: Yes. I go from FOLFIRI/bevacizumab to FOLFIRI/EGFR. I don’t change the chemotherapy backbone. I don’t change anything about the chemotherapy. Patients have gotten used to the toxicities and management of them. We go to an EGFR inhibitor.
John L. Marshall, MD: That’s a unique approach. I haven’t heard that.
Tanios Bekaii-Saab, MD: It’s not unique. It’s actually in the guidelines. The principle of the BOND study is that you can continue irinotecan beyond progression and just add the EGFR inhibitor. In fact, we had a study with this that’s being compiled. But, we see 20% to 30%, if not more, strong responses in the second-line setting—and that’s not without integrating all-RAS wild-type. If you look at the 181 study, the response rate goes, of note, to 50% in the second-line setting. Now, albeit, they didn’t receive FOLFIRI in the first-line setting, and, if you look at TML, the response rate with FOLFIRI/bevacizumab or FOLFOX/bevacizumab is 5% or less.
John L. Marshall, MD: I tend to save EGFR therapy until I need a response, because it’s all I’ve got left— more for the symptomatic or more bulky tumor patients. In a patient where EGFR was used in the frontline setting, do you maintain the EGFR and change the chemotherapy? Or what do you switch to?
Dirk Arnold, MD, PhD: No, we switch for second-line therapy—chemotherapy plus an anti-VEGF compound.
John L. Marshall, MD: Same idea?
Fortunato Ciardiello, MD, PhD: I do the same.
John L. Marshall, MD: OK. And if it’s bevacizumab, frontline, in the sweet spot patient—in the left-sided, RAS wild-type?
Dirk Arnold, MD, PhD: Continue with bevacizumab in second-line.
John L. Marshall, MD: In an asymptomatic patient?
Dirk Arnold, MD, PhD: In an asymptomatic patient.
John L. Marshall, MD: But, in Paul’s patient, you might switch?
Paul R. Helft, MD: Yes.
John L. Marshall, MD: Does everybody else do the same thing, or you don’t know?
Fortunato Ciardiello, MD, PhD: It depends on how well the patient performed in the first-line setting. If there was a rapid progression, you have to change therapy. If you have a very good benefit in first-line therapy, why change? In most of my patients—the real progressors—in 2 months, they are progressing. These are the really progressive patients.
Paul R. Helft, MD: Primary progressors.
Tanios Bekaii-Saab, MD: Here’s what I would say—anyone that progresses before the median is a patient who’s not doing too well. So, it’s really 10 months.
Paul R. Helft, MD: I guess I would disagree a little bit with that, Tony. There are people who get 8 months of benefit out of the drug who are not at the median.
Tanios Bekaii-Saab, MD: No, I understand, but those are the patients that do not get the better benefit from bevacizumab.
Paul R. Helft, MD: I’m really talking about a patient that, on their first scan 8 weeks later, has progression.
Tanios Bekaii-Saab, MD: That’s a terrible situation, and the patient is unlikely to respond to anything.
Paul R. Helft, MD: And, just to break it down a little bit further very quickly, there are some patients who have bulky liver metastasis where much of their disease is centrally dominant. You know that when they progress next time, they’re going to have obstructed their liver, and that will be “all she wrote.”
John L. Marshall, MD: That’s bad.
Paul R. Helft, MD: Right, that’s really bad. Those patients really need a response and deserve the best chance.
Dirk Arnold, MD, PhD: I Completely agree. We should stay with the published data, and the published data in the TML trial were not saying that there is a median or that there’s 5 months, 6 months, or 7 months. It was saying that they survived the 2-month regimen. They had a benefit, independent from treatment duration, in first-line therapy.
Tanios Bekaii-Saab, MD: I use a lot of the TML data in most of my patients because most of my patients are not going to be eligible for EGFR inhibitors. So, for the majority of the patients, we’re going with bevacizumab beyond progression. But, for that minority of patients that essentially is likely to respond extremely well to EGFR inhibitors, I actually would rather place it in the second-line setting.