New Biological Insights and Recent Therapeutic Advances in the Management of Lung Cancer: A Clinical Investigator Think Tank
Benefits of second-line ramucirumab/docetaxel observed in the REVEL study
8:05 minutes.
TRANSCRIPTION:
DR LANGER: So this is the second angiogenesis inhibitor to be approved in advanced non-small cell. It does not target the ligand but rather the receptor. This was a second-line trial, all comers. So it included not just adenocarcinoma but squamous cell, which were not enrolled in the original ECOG-4599 trial, which had led to bev’s approval. And here, well over 1,000 patients — I think it was over 1,250 — were randomized to standard second-line treatment, docetaxel either alone or in combination with ramucirumab. And there was a credible, modest, statistically significant, I’d argue still clinically meaningful improvement in response rate, progression-free survival and, most importantly, in overall survival. In fact, the overall survival observed was not too far off from that observed with bev in the original Phase III. So I think with the tincture of time, it’s been 12 to 13 years since bev’s approval, we’ve seen generally better patients getting onto these second-line trials. It was a huge trial. I think cynics would argue, “There’s a one and a half-month improvement. Really all that meaningful, particularly for the cost of the drug?” But if you look at progress in non-small cell, it’s been rampant incrementalism for the last 25 years, with a few exceptions mostly in the era of molecular targets. So for those who are giving pem/carbo up front without bevacizumab, this would not be an illogical combination in the second line, giving ramucirumab with docetaxel. DR LOVE: Not an illogical combination. Does that mean — are you going to use it? Are you using it? DR LANGER: I usually give bev up front. And the number of patients who were bev exposed in this trial was very small. So I’m not sure I have a good feel for how well this is going to work in that group. DR LOVE: Dave, what are your thoughts about this? DR SPIGEL: I think that’s an easy way out of that question, because we know that those patients were included. I agree with everything Corey said. I mean, it’s a positive study. It led to its FDA approval. It met its primary and secondary endpoints: PFS, response rate and OS. So it’s funny. I have not thought about giving it until yesterday. I had a patient who was not eligible for a trial. And we don’t even have the regimen built yet. So I think outside of a study, I think it will get used. I’m not sure if the experience will be more in patients who have not received bev in the first-line setting for some of the theoretical concerns that Corey is probably thinking of. But really, the study allowed those patients on the trial, and it allowed patients with squamous cancers who don’t get bev. So, technically, this is a new second-line option for patients. I’m not sure how popular it will be initially. DR LOVE: What was the situation with your patient you saw yesterday? DR SPIGEL: A patient who has comorbid issues that prevent them from going onto a clinical trial. DR LOVE: But the patient got what, carbo/pem up front? DR SPIGEL: Yes, has gotten carbo/pem up front. DR LOVE: And then what? Relapsed on pem maintenance? DR SPIGEL: That’s correct. DR LOVE: And what are you thinking about? How old is the patient, incidentally? DR SPIGEL: This patient is in their sixties. DR LOVE: And what are you thinking? DR SPIGEL: So again, this is a patient who’s not a candidate for any of our clinical trials. So off study, I would normally give something like docetaxel alone. And so this came to mind: Could I do more than docetaxel? DR LOVE: So is that what you think you’re going to do? DR SPIGEL: Yes, that’s what we’re working on. In fact, I had an email last night saying the regimen’s been built. DR LOVE: Wow! Interesting. Mark, what do you think about that? DR KRIS: I gave it for the first time a couple of days ago. We’ve built out our regimen already. But it actually was extremely easy, because in most institutions it’s already approved for gastric. DR SPIGEL: That’s right. DR KRIS: So it’s just building out — so the dose and schedule is a little different. It is what it is. It’s another drug. It will have some utility. It has the rare triad of improvements in response, PFS and survival that’s pretty unusual. You don’t see many trials doing that. So all the reasons that we gave bev in the first place, we can give this. I think it fills a need now in people who haven’t had bev up front, because it’s an FDA-approved second-line anti-angiogenesis agent. And that’s kind of one reason I went for it. I didn’t want to have to fight with an insurance company. DR LOVE: What about squamous? Would you consider it, Corey? DR LANGER: I would consider it in squamous. They were included in the study. Dave is correct in that it did include bev-pretreated patients, but it was a small minority of those actually accrued, about 170. I do have a population of folks who get just pem/carbo up front who I would consider it in. I have not yet given it. It is, as Mark has pointed out, really the first time in the second-line setting, where we’ve seen that triad of improvement in response, PFS and overall survival for a second agent added to standard chemo. You could argue in the nintedanib arm in the Phase III, at least in the adeno group did the same, but it was not the entire trial. The overall trial did not show a survival advantage. And this comes after dozens of efforts in this realm, in this therapeutic venue, none of which have shown any further survival advantage. So it’s a standout trial in that regard. Granted the benefits are modest, but not too much different from what we observed with bevacizumab originally. DR OXNARD: I’m just noticing that the bleeding events didn’t appear — there’s not any increase in pulmonary hemorrhage or hemoptysis. People have hemoptysis on docetaxel, too, sometimes. Right? Or GI hemorrhage. So, despite the inclusion of the squams, there’s not a major difference in safety signal. There was more hypertension. It’s the expected side effects. And it’s not been built yet for us, but I think we’re going to have to talk about it with patients, and I suspect some patients will want it. DR LOVE: And again, would you be more likely to use it in somebody who hasn’t had bev? DR OXNARD: Yes. DR LOVE: And what about squamous? DR OXNARD: I’m comfortable using it in squamous based on this data. DR LOVE: I mean, what we’ve heard from the GI people, it seems like it’s pretty similar to bev in terms of hypertension, proteinuria, not any kind of major difference. Anne, have you used this approach? DR TSAO: So we are. We’re having it on our formulary. We’ve built our template as well. But I just want to make a comment about previous use of bev. I actually would be very comfortable giving this in patients who’ve previously received bev. I am one of those who tends to be a believer in anti-angiogenesis. And I think that there are some patients who get great responses with the bevacizumab. And I think that that should probably extend further, hopefully, with the second-line treatment with another anti-angiogenic. DR LOVE: Interesting. Dave, is this a regimen you’ve used or you think you’re ready to use? And in what situations? DR CARBONE: I have not yet used it, though I do think that the data are interesting and important. And in an era where we’re used to tripling the PFS and outcomes with targeted agents, it’s received a little bit less attention in that space. But I think there’s still a huge need for the mutation-negative patients to improve their outcomes with manageable toxicity. And in the nintedanib trial, for example, the previous bev, actually, there was a subset, even though it was small. But there was no signal that there was any difference. In fact, those patients actually did a little better with the nintedanib than nonbev-treated patients. So I’m not entirely sure that a different agent targeting a similar pathway is cross resistant. |