Patient Selection for Antiangiogenic Therapy

Transcript:Mark A. Socinski, MD: One of the issues that’s pertinent to the lung cancer population is the issue of age, both in terms of efficacy of antiangiogenic agents, as well as safety. I’ll start with you, Eddy. Your perspective on that elderly patient?

Edward Garon, MD: So, that has been part of the analysis for the datasets that have led to approvals of both bevacizumab in the frontline setting and ramucirumab in the previously treated setting. There was a subset analysis from the E4599 study that indicated that the benefit of bevacizumab was in patients who were younger. The age cutoff, I believe, was 70 there. Different cutoffs have been either 65 or 70. With ramucirumab, it was also evaluated in terms of age, again looking back after the study and seeing what the differences were. And some of the results were consistent with the E4599 study when one looks at survival.

In general, I agree with what everyone has said that the tolerability has been quite good. There, of course, are concerns about coronary artery disease and other things that do tend to be more common as patients age. But I think that some of those things are still exploratory. Certainly, now across two registration trials, we’ve seen the greatest benefit being in patients who are younger. However, these are based off of subset analyses, and the confidence intervals are large for the older patients.

Mark A. Socinski, MD: Yes, small numbers. Roy, your thoughts on age.

Roy S. Herbst, MD, PhD: I’m going to agree again. With age, it’s not really how old the car is, but how many miles are on it. Although that’s not entirely true in cancer—you got to be a little bit careful. Again, do you have a compelling reason to use it? I think that’s the question. This is a good regimen. It’s been used for a long time, but in the absence of a biomarker, I think what I’ve seen is a trend, at least in the practices in our area, in that the added benefit is rather small with the potential for side effects being rather high. So, I have seen people move away from that, and in the non-squamous population, we tend to use more of the carboplatin/pemetrexed. Then in squamous, of course, where we haven’t really used that, we’re looking for new things.

Mark A. Socinski, MD: Dr. Langer, a good friend of ours, did a combined analysis of ECOG 4599 in PointBreak, and looked at the cut-point of 754. And it was really above the age of 75 where there were, again, small numbers, subset analysis. There was not clearly an efficacy benefit. There were real concerns about toxicity in the older patient.

Roy S. Herbst, MD, PhD: The hypertension you have to deal with.

Mark A. Socinski, MD: Yes, all these sorts of things. Is this a concern to the colon cancer population?

Johanna Bendell, MD: Certainly almost the opposite for colon is what we’ve seen.

Mark A. Socinski, MD: Oh, really?

Johanna Bendell, MD: So, in our subset analysis, the elderly...

Mark A. Socinski, MD: Do better?

Johanna Bendell, MD: Older patients still do better with the addition of antiangiogenesis. And, in fact, there was a study called the AVEX—it’s British—where they looked at patients who were over 70 and not candidates for doublet chemotherapy. And they randomized them to capecitabine plus bevacizumab or capecitabine alone. What was very interesting about the study is that the patients all got benefit from bevacizumab. There was a significant progression-free survival benefit, and there was also a response rate benefit. So, certainly for colon cancer, maybe it’s a little bit different. We also have seen there were a lot of studies looking at the arterial thrombotic events. And the patients who were at higher risk were patients who were 80 and above and also had a risk of coronary artery disease, so tying in all of the potential toxicities.

Mark A. Socinski, MD: Comorbidities are important, yes.

Johanna Bendell, MD: And with comorbidities, it’s a different story. But for colon, we do see that benefit even in an older population.

Manish A. Shah, MD: I’d like to add in terms of when not to do it. So, there are two large studies in colon cancer in the adjuvant setting where the addition of antiangiogenic therapy was proven not to be beneficial. Just for all of our viewers, it’s important to know that these aren’t completely benign drugs. There are side effects—hypertension, and risk of blood clots, and things like that. And, in the adjuvant setting, it’s one area where it hasn’t been proven. In lung cancer, is that true?

Mark A. Socinski, MD: Well, yes, same exact thing in lung cancer. We had the ECOG 1505 trial that Dr. Wakelee presented in Denver at the IASLC (International Association for the Study of Lung Cancer) meeting. And I think there were two curves there, although they were completely superimposed in terms of overall survival.

Roy S. Herbst, MD, PhD: It took a long time.

Mark A. Socinski, MD: Yes, but there was absolutely no benefit in the adjuvant setting, and this was a year of use, so it is similar to the colon story.

Roy S. Herbst, MD, PhD: I think in lung it’s probably not quite as good of a drug, so the therapeutic index is a little smaller. Again, what we really need in lung is some sort of biomarker. There’s no doubt the drug has effect, and that’s been the elusive search for 15 years.

Mark A. Socinski, MD: And in gastric cancer?

Yelena Y. Janjigian, MD: Well, in gastric cancer, bevacizumab came close, but not close enough. The phase II data looked very promising, and our own Manish Shah generated some of it. So, when it was explored in a phase III study, in a large AVAGAST study, what that study really showed was a significant trend toward improvement in all outcomes, such as response rate and PFS. But the primary endpoint was not met, and there’s a lot of data out there. Again, this is another validation of that observation, that gastric cancer is an extremely heterogeneous disease. And the gastric cancer in the Western population is a completely different disease. Maybe if we’re trying to draw a parallel between EGFR-mutant adenocarcinoma of the lung versus KRAS-mutant, it’s just the Western population gastric cancer, it’s more proximal tumors, G-junction tumors. They’re more aggressive, and they’re probably more VEGF-driven.

And so, if you looked at the subgroup analysis of patients from the AVAGAST study for our patients, Western patients in the United States and Europe, there was a very robust benefit. And, interestingly, our experimental arm—the bevacizumab arm—did worse or not much better than their comparison arm, the Asian placebo arm, because, again, gastric cancer in the United States and Western world is a more aggressive illness. And perhaps these biologic agents, particularly a VEGF inhibitor, have more of a role in our disease because they’re more proximal tumors. The gastric genome atlas shows that they’re morphologically and molecularly unique. And learning from these sort of observations, the ramucirumab trial really limited—and a lot of future trials in gastric—they put a lid on what percent of population in each trial can be approved in Asia. Because Asia, it’s a large market. And so they can quickly accrue trials, but the benefit may be diluted.

Edward Garon, MD: One plug I’ll make then, for when we’re talking about differences in data from Asia for a trial that I’m involved with, is that there are some data now about the world of angiogenesis inhibition in EGFR mutant non—small cell lung cancer, which, of course, is a considerably more common disease. And this is something that has been evaluated over a long period of time. But there’s recently been data out of Japan looking at bevacizumab data, with both bevacizumab and ramucirumab being evaluated, as well, in combination with erlotinib or other EGFR inhibitors in EGFR mutant non–small cell lung cancer.

Roy S. Herbst, MD, PhD: We saw that many years ago in the BeTa trial, which actually took bevacizumab, erlotinib. The results, the hazard ratio was in the .6-range for time to progression. It just wasn’t a survival benefit. The question is, was it a crossover? Why did that occur? But I would agree with you, that’s something worth studying.

Mark A. Socinski, MD: Yes, that Japanese trial, there was an incredibly impressive difference in PFS with that. But I’ve not seen any survival data from that.

Roy S. Herbst, MD, PhD: I guess there was a US trial that’s trying to do that.

Mark A. Socinski, MD: Yes, that’s accruing. It’s getting there, and I believe there’s a European trial, too. I can’t remember of the name of it, but I think the plan, at least with the US and the Japanese trials was to combine that data at some point, too.

Roy S. Herbst, MD, PhD: And with EGFR resistance, there’s still 50% or more of patients that become resistant with EGFR-mutant lung tumors for which we don’t have a good plan.

Transcript Edited for Clarity