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Use of VEGF-Targeted Tyrosine Kinase Inhibitors

Panelists:Johanna C. Bendell, MD, Sarah Cannon Research Institute; Edward Garon, MD, Jonsson Comprehensive Cancer Center at UCLA; Roy Herbst, MD, Yale School of Medicine; Yelena Y. Janjigian, MD, Memorial Sloan Kettering Cancer Center; Manish Shah, MD, Weill Cornell Medical College; Mark Socinski, MD, University of Pittsburgh
Published: Tuesday, Jul 12, 2016


Transcript:

Mark A. Socinski, MD:
Let’s switch gears from the antibodies to the TKIs (tyrosine kinase inhibitors). We mentioned regorafenib earlier. What’s its role in colon cancer? What are the data?

Manish A. Shah, MD: So, there was a very important study run by Axel Grothey that demonstrated the benefit of regorafenib versus best supportive care. Historically, actually, that’s very interesting because before that study, many investigators and companies felt that the United States wouldn’t be able to do a placebo-controlled trial. But in fact it was very rapidly accruing, and it demonstrated a benefit over best supportive care. And Yelena mentioned earlier, the selected population, that was a very selected population with a performance status of zero. And patients—who in their third line, after all standard therapies—were able to get on regorafenib or placebo. There was a modest improvement and benefit.

The biggest issue with regorafenib is the dosing and the toxicity. The standard dosing in the trial was 160 mg a day. You can get significant hand-foot syndrome and fatigue. So, many patients actually end up tolerating a lower dose, and many physicians start a lower dose because of that toxicity.

Mark A. Socinski, MD: Is a lower dose acceptable in terms of activity? Do we know that or no?

Johanna Bendell, MD: That’s the big question, and actually that’s being looked at in the trial now. I think Tony saw it as well as Axel, and both are looking at doing alternative dosing regimens of regorafenib. I think what’s happened though is when we first started using regorafenib, you would give the patients 160 mg. They’d come back a week later, throw the bottle at you, and walk out the door because it made people sick. There were very few patients that could really tolerate the 160 mg. So, that’s been an education on our part as practitioners to really do education and close follow-up with the patients. If you’re going to start at 160 mg, make sure they know potential toxicities and to call you early with them so you can either hold the drug or dose reduce early. There’s also a number of practitioners now that will start at 120 mg or even start at 80 mg to see how patients are going to tolerate it, and then maybe dose escalate. And that’s what Tony’s trial was looking at, starting at the lower dose and then escalate it.

Mark A. Socinski, MD: So, what about biomarkers for the TKIs?

Yelena Y. Janjigian, MD: It’s a very interesting point. We had a phase II of sorafenib, which is an earlier cousin of regorafenib. And although a majority of the patients sort of stayed on the trial for 4 months, and then progressed—this treated esophageal and gastric patients—a handful of people had a dramatic benefit. Either patient had a complete response to treatment—to single agent sorafenib—and in the search of this biomarker, I’ve sequenced their tumor, including whole exon sequencing. And I can tell you there was not one obvious biomarker. You’re probably familiar with the case series in lung, where there’s a complete responder to sorafenib with BRAF mutation. We didn’t see that. So, again, my sense that even for TKIs, this will be a secretory biomarker.

Building on the sorafenib data now, we just completed a phase II FOLFOX regorafenib data. And there we used regorafenib with alternate weeks. So, instead of a 3 weeks on, 1 week off schedule at full doses in combination with 5-FU—as you know, it causes hand-foot syndrome similar to regorafenib—this dosing was actually quite well- tolerated. And, again, out of 37 patients, there is I would say probably—and this data are still not published—a robust group of people who are on it with first-line disease for a long time. A dramatic response in combination of chemotherapy. And, so now what we’re doing is we’re sequencing all of their tumors, and we have some blood samples again to try to identify and narrow down. My sense is that patients with RTK activation, so the chromosomal unstable subtype of G junction tumors, tend to benefit more from the TKI. But, again, small subset, and it’s just very sort of anecdotal data.

Mark A. Socinski, MD: So, Roy, we have a number of these VEGF receptor TKIs, all of which have been studied for the most part in lung cancer, but not an FDA-approved agent. They all seem to have some degree of activity, but they’ve all failed phase III testing. What’s your perspective? Is this a dead strategy in lung cancer?

Roy S. Herbst, MD, PhD: No, I don’t think so. You know clearly they’ve all shown some activity, but again, it’s not hitting that bar. In fact one, vandetanib that we had studied…

Mark A. Socinski, MD: It did hit the bar.

Roy S. Herbst, MD, PhD: Actually it did hit the bar, but that was one where it was determined it wasn’t clinically significant enough to move forward. The drug is approved for medullary thyroid cancer. So, I think it’s just small molecules, as we said earlier, have the complexity of if they hit the target but they also hit other targets. Then you get additional side effects than you might get with the antibody. And then if the benefit’s not that great and you haven’t identified the population, you’re going to be seeing a small therapeutic window. I think again—you know as we’ve talked about today—these agents do have possibilities for use in combination regimens now. And one of the backbones are going to be now in these different tumors, certainly in lung. We’re getting to a world now where we’ll probably see immunotherapy move to the front-line setting. Again, benefitting some but not all. And there will be other immune checkpoints too, by the way, so I think PD-L1 is just the first of several. I think that’s an area where we can see some of these agents used. You know we always thought maintenance would be a good idea, right?

Mark A. Socinski, MD: Yes.

Roy S. Herbst, MD, PhD: And, again, it’s hard to go to maintenance or adjuvant therapies when you don’t really know who it works best in. And I think we’re seeing that in some of the trials. So, I think it’s a matter of keep an eye on these in lung cancer, but as of yet, they’re still looking hard for their niche.

Edward Garon, MD: One thing that I would just clarify for those who are tuning in from Europe, that they may be questioning why we’re saying that none of them have hit the bar. Because from European regulatory agencies, nintedanib has hit the bar. And to get into the details of it is probably beyond the scope of what we’re talking about today, and really would be better for a biostatistician than a medical oncologist. But in adenocarcinoma population, nintedanib did show a survival benefit. And, in Europe, there’s approval along with docetaxel in that setting, whereas that approval is not the case in the United States, and it isn’t really an available option.

Mark A. Socinski, MD: But the drug is approved for a pulmonary hypertension.

Edward Garon, MD: That is correct. It’s approved, just not for that indication.

Roy S. Herbst, MD, PhD: That’s what I was going to say. That’s another interesting aspect of this, again, having effects as we would expect on vasculature. I think we need more creative trials, different endpoints. I think, Yelena, you said it earlier, we’re getting more sophisticated in what we can study and how we can measure it. So, stay tuned.

Yelena Y. Janjigian, MD: That’s right. And nintedanib is very well-tolerated. We have a phase II trial in gastric they’re almost done with, and I can tell you it’s an easy drug to use. So, I think it has length.

Roy S. Herbst, MD, PhD: I can say one thing. You know, we’re constantly looking for new drugs. One project that’s been on my mind the last 2 years is this thing called Lung Map, which is the Lung Master Protocol—and Mark, of course, you’re involved with it very closely, too. And in squamous lung cancer we’re looking in the refractory setting for drugs that might have activity, and the premise is to have a biomarker, but we realize many patients won’t have a biomarker so we have non-matched arms, too. I can tell you that we have to be creative now. Trying to find drug or drug combinations is not easy. So, I think the drugs we’re talking about today all have possibilities—at least in lung, and it sounds like in the other tumor types as well—to look at combinations. We just need trial designs where we don’t have to study 300 patients before we do make a decision. You have to figure out how to do it in the first 20 or 30 using more novel imaging techniques, surrogate biomarkers still to be defined.

Transcript Edited for Clarity
Slider Left
Slider Right


Transcript:

Mark A. Socinski, MD:
Let’s switch gears from the antibodies to the TKIs (tyrosine kinase inhibitors). We mentioned regorafenib earlier. What’s its role in colon cancer? What are the data?

Manish A. Shah, MD: So, there was a very important study run by Axel Grothey that demonstrated the benefit of regorafenib versus best supportive care. Historically, actually, that’s very interesting because before that study, many investigators and companies felt that the United States wouldn’t be able to do a placebo-controlled trial. But in fact it was very rapidly accruing, and it demonstrated a benefit over best supportive care. And Yelena mentioned earlier, the selected population, that was a very selected population with a performance status of zero. And patients—who in their third line, after all standard therapies—were able to get on regorafenib or placebo. There was a modest improvement and benefit.

The biggest issue with regorafenib is the dosing and the toxicity. The standard dosing in the trial was 160 mg a day. You can get significant hand-foot syndrome and fatigue. So, many patients actually end up tolerating a lower dose, and many physicians start a lower dose because of that toxicity.

Mark A. Socinski, MD: Is a lower dose acceptable in terms of activity? Do we know that or no?

Johanna Bendell, MD: That’s the big question, and actually that’s being looked at in the trial now. I think Tony saw it as well as Axel, and both are looking at doing alternative dosing regimens of regorafenib. I think what’s happened though is when we first started using regorafenib, you would give the patients 160 mg. They’d come back a week later, throw the bottle at you, and walk out the door because it made people sick. There were very few patients that could really tolerate the 160 mg. So, that’s been an education on our part as practitioners to really do education and close follow-up with the patients. If you’re going to start at 160 mg, make sure they know potential toxicities and to call you early with them so you can either hold the drug or dose reduce early. There’s also a number of practitioners now that will start at 120 mg or even start at 80 mg to see how patients are going to tolerate it, and then maybe dose escalate. And that’s what Tony’s trial was looking at, starting at the lower dose and then escalate it.

Mark A. Socinski, MD: So, what about biomarkers for the TKIs?

Yelena Y. Janjigian, MD: It’s a very interesting point. We had a phase II of sorafenib, which is an earlier cousin of regorafenib. And although a majority of the patients sort of stayed on the trial for 4 months, and then progressed—this treated esophageal and gastric patients—a handful of people had a dramatic benefit. Either patient had a complete response to treatment—to single agent sorafenib—and in the search of this biomarker, I’ve sequenced their tumor, including whole exon sequencing. And I can tell you there was not one obvious biomarker. You’re probably familiar with the case series in lung, where there’s a complete responder to sorafenib with BRAF mutation. We didn’t see that. So, again, my sense that even for TKIs, this will be a secretory biomarker.

Building on the sorafenib data now, we just completed a phase II FOLFOX regorafenib data. And there we used regorafenib with alternate weeks. So, instead of a 3 weeks on, 1 week off schedule at full doses in combination with 5-FU—as you know, it causes hand-foot syndrome similar to regorafenib—this dosing was actually quite well- tolerated. And, again, out of 37 patients, there is I would say probably—and this data are still not published—a robust group of people who are on it with first-line disease for a long time. A dramatic response in combination of chemotherapy. And, so now what we’re doing is we’re sequencing all of their tumors, and we have some blood samples again to try to identify and narrow down. My sense is that patients with RTK activation, so the chromosomal unstable subtype of G junction tumors, tend to benefit more from the TKI. But, again, small subset, and it’s just very sort of anecdotal data.

Mark A. Socinski, MD: So, Roy, we have a number of these VEGF receptor TKIs, all of which have been studied for the most part in lung cancer, but not an FDA-approved agent. They all seem to have some degree of activity, but they’ve all failed phase III testing. What’s your perspective? Is this a dead strategy in lung cancer?

Roy S. Herbst, MD, PhD: No, I don’t think so. You know clearly they’ve all shown some activity, but again, it’s not hitting that bar. In fact one, vandetanib that we had studied…

Mark A. Socinski, MD: It did hit the bar.

Roy S. Herbst, MD, PhD: Actually it did hit the bar, but that was one where it was determined it wasn’t clinically significant enough to move forward. The drug is approved for medullary thyroid cancer. So, I think it’s just small molecules, as we said earlier, have the complexity of if they hit the target but they also hit other targets. Then you get additional side effects than you might get with the antibody. And then if the benefit’s not that great and you haven’t identified the population, you’re going to be seeing a small therapeutic window. I think again—you know as we’ve talked about today—these agents do have possibilities for use in combination regimens now. And one of the backbones are going to be now in these different tumors, certainly in lung. We’re getting to a world now where we’ll probably see immunotherapy move to the front-line setting. Again, benefitting some but not all. And there will be other immune checkpoints too, by the way, so I think PD-L1 is just the first of several. I think that’s an area where we can see some of these agents used. You know we always thought maintenance would be a good idea, right?

Mark A. Socinski, MD: Yes.

Roy S. Herbst, MD, PhD: And, again, it’s hard to go to maintenance or adjuvant therapies when you don’t really know who it works best in. And I think we’re seeing that in some of the trials. So, I think it’s a matter of keep an eye on these in lung cancer, but as of yet, they’re still looking hard for their niche.

Edward Garon, MD: One thing that I would just clarify for those who are tuning in from Europe, that they may be questioning why we’re saying that none of them have hit the bar. Because from European regulatory agencies, nintedanib has hit the bar. And to get into the details of it is probably beyond the scope of what we’re talking about today, and really would be better for a biostatistician than a medical oncologist. But in adenocarcinoma population, nintedanib did show a survival benefit. And, in Europe, there’s approval along with docetaxel in that setting, whereas that approval is not the case in the United States, and it isn’t really an available option.

Mark A. Socinski, MD: But the drug is approved for a pulmonary hypertension.

Edward Garon, MD: That is correct. It’s approved, just not for that indication.

Roy S. Herbst, MD, PhD: That’s what I was going to say. That’s another interesting aspect of this, again, having effects as we would expect on vasculature. I think we need more creative trials, different endpoints. I think, Yelena, you said it earlier, we’re getting more sophisticated in what we can study and how we can measure it. So, stay tuned.

Yelena Y. Janjigian, MD: That’s right. And nintedanib is very well-tolerated. We have a phase II trial in gastric they’re almost done with, and I can tell you it’s an easy drug to use. So, I think it has length.

Roy S. Herbst, MD, PhD: I can say one thing. You know, we’re constantly looking for new drugs. One project that’s been on my mind the last 2 years is this thing called Lung Map, which is the Lung Master Protocol—and Mark, of course, you’re involved with it very closely, too. And in squamous lung cancer we’re looking in the refractory setting for drugs that might have activity, and the premise is to have a biomarker, but we realize many patients won’t have a biomarker so we have non-matched arms, too. I can tell you that we have to be creative now. Trying to find drug or drug combinations is not easy. So, I think the drugs we’re talking about today all have possibilities—at least in lung, and it sounds like in the other tumor types as well—to look at combinations. We just need trial designs where we don’t have to study 300 patients before we do make a decision. You have to figure out how to do it in the first 20 or 30 using more novel imaging techniques, surrogate biomarkers still to be defined.

Transcript Edited for Clarity
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