DR FUCHS: Ramucirumab is a monoclonal antibody targeting angiogenesis, the VEGF pathway, but in contrast to aflibercept or bevacizumab targets the receptor, so the VEGF receptor as opposed to the circulating ligand, which bevacizumab and aflibercept target.
And we think that that not only inactivates the receptor but obviously also blocks the ligands from binding. And it seems to have activity in animal models in gastric cancer. In Phase I, there were a few patients with gastric cancer who seemed to benefit, with response and stable disease. So this trial was conducted, 355 patients who had progressed on front-line, randomized in a 2-to-1 fashion to ramucirumab single agent or a placebo, double blind, so you couldn’t know for sure.
And what the study shows is that there is a statistically significant improvement in both progression-free and overall survival for patients who got ramucirumab. And although you have to be careful about cross-study comparisons, but if you do that and you compare that trial to the trials that compared chemotherapy to placebo in second line, the results seem almost identical. In fact, the survival on ramucirumab and trials of either irinotecan or docetaxel are almost identical in the placebo arms, like almost the same. So at least the suggestion cross study is that this single agent seems to have a benefit that you would otherwise achieve with single-agent chemotherapy but what appears to be much better tolerability.
DR LOVE: I was really curious that you attempted or that this trial attempted using the agent by itself. We’ve seen chemotherapy being combined with anti-angiogenics. I guess I can think of a couple of situations, ovary, maybe GBM, where you see responses to bev by itself, but usually it’s with chemo. What was the thinking?
DR FUCHS: I think 2 reasons, Neil. One is that, as Randy mentioned, in 2008 when we wrote the study, there weren’t studies showing a survival benefit for second-line therapy. And more importantly, the FDA and the EMA and all the agencies, there is no approved second-line therapy for gastric cancer in this country and most other countries. And as a result, we really thought that it was reasonable and ethical to consider this study.
A lot of people in 2008 said to me, “You’ll never get this study going. You’ll never get it enrolled. In fact, it enrolled faster than expected.
DR LOVE: And what about anti-angiogenic effects we’re used to seeing, I guess, off target in terms of hypertension/proteinuria?
DR FUCHS: So there definitely was a higher rate of hypertension in the study, but, in fact, it was really in the teens. So nothing that couldn’t be managed with antihypertensive therapy. That’s, in fact, really the only toxicity that was higher in the ramucirumab arm compared to placebo. A number of toxicities are higher in the placebo arm but likely reflect the state of patients with second-line gastric cancer.
DR LOVE: Now, is this an agent that oncologists should be aware that maybe they’re going to wake up in the morning soon and check their phone and see that it’s approved, or do you think a lot more data is going to be needed?
DR FUCHS: The trial in and of itself is potentially subject to review by the FDA. And my understanding is that that is under consideration — that is, to consider approval for the agent by itself in second line. But there’s another study completed, the RAINBOW study, in which same population, failed front line, randomized to paclitaxel with or without ramucirumab. So asking the question, does it add to second-line chemotherapy? And the results from that study will probably be out soon. So in contrast to picking up their iPhone® and seeing whether the drug is approved, they’ll probably sooner see, in the next few weeks, whether that study is positive or not.
DR LOVE: Interesting. Rich, any comment about prior studies in gastric and gastroesophageal, bevacizumab and other anti-angiogenics?
DR GOLDBERG: As you know, the bevacizumab study was negative.
DR LOVE: That was the AVAGAST study?
DR GOLDBERG: Right. And so that was a disappointment for all of us. I think as we’ve used bevacizumab more, perhaps we could say that the initial blush of incredible efficacy that we thought we were going to see with the Hurwitz trial has not turned out to be the case. And it’s negative in pancreatic. It’s negative in gastric. Doesn’t really have another role.
DR LOVE: So I’m kind of curious. We were talking about second-line therapy, Randy. Based on the data that you’ve seen so far — and, again, hopefully we’ll get some more data — but just coming out of this one study, is this a drug that you would use or would like to use?
DR HECHT: Yes. I would definitely consider using this. The toxicity profile is superb, especially compared to — even though I think properly dosed a taxane and irinotecan can be given in this population, it’s hard to beat, basically, virtually no toxicity. So I hope that it goes to the FDA. I hope that it’s in our armamentarium, what to use.