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Clinical Trial Results of Ramucirumab in Squamous NSCLC

Panelists:Edward S. Kim, MD, FACP, Carolinas HealthCare System; Benjamin Levy, MD, Mount Sinai Hospital; Paul K. Paik, MD, Memorial Sloan Kettering Cancer Center
Published: Wednesday, Apr 27, 2016


Transcript:

Benjamin Levy, MD:
Let’s stay on this theme of lack of molecular enrichment strategies and talk about the second monoclonal antibody that’s approved. Ramucirumab was FDA-approved with the use of docetaxel based on the REVEL study, and 25% of those patients were squamous. There were both adenocarcinoma and squamous tumors. So there’s another drug in our therapeutic armamentarium. Ed, you want to talk about this drug, how it works and some of the nuances of the REVEL data?

Edward S. Kim, MD, FACP: Yeah. Ramucirumab is obviously a pan-VEGF inhibitor. It’s a monoclonal antibody. It’s not exactly bevacizumab in that it has a little different function there and you can see that in the clinical data based on what we see as far as side effects and where the efficacy is. Some very important distinctions are that it doesn’t have the same type of bleeding indications and toxicity exists. You can actually use this in squamous cell patients. That’s a big jump for people to think of VEGF in squamous. That’s because we’ve been conditioned so hard that there’s toxicity and people will bleed out and those things. That’s not the case here. And one thing that was interesting also was that prior bevacizumab use was allowed on the study, and so you had patients who were treated after that. It’s in the non-squam, obviously, population, so there was again this sort of benefit that occurred in second-line. It’s important to remember and I’ve laid a wasteland of second-line studies in my career. So to get a significant survival value is an achievement, let me tell you; so it was 10.5 versus 9.1 months. Right away that tells you people are living longer in second-line because that looks almost like the ECOG 1594 first-line trial of overall survival which was about 20 years ago, and improved PFS.

So, again, I think this is what we would expect to see when we look at the necitumumab data, when we look at the ramucirumab data, when we look at any 2 versus 1, 3 versus 2 type study in an unselected population. And you see these one-and-a-half to two-and-a-half month survival benefits, these one-and-a-half to two-and-a-half month PFS benefits. What’s the toxicity, what’s the subset population, what’s the cost? It’s interesting because that’s, again, where the art comes in. And whether you’re deciding by hazard ratios versus median values versus anything, you’ll hear differing opinions.

I think it’s an acceptable regimen. We do have it on our pathways as a preferred regimen for squamous in the second-line subsequent setting. I would certainly use this over docetaxel alone. It doesn’t seem to confer any additional side effects that are significant. There are other options in second-line, so does this become a third-line regimen or what have you. We won’t get into that right now, but it certainly is something again that adds to the equation of better than single agent docetaxel. Certainly this would be something I would use over single agent erlotinib, or vinorelbine, or gemcitabine as well. That’s what I find beneficial as far as our clinical approach to squamous patients.

Benjamin Levy, MD: So you would use this drug and you have used this drug in patients who perhaps aren’t either immunotherapy candidates or in the third-line after immunotherapy.

Edward S. Kim, MD, FACP: Before immunotherapy with second-line and we were starting to use that quite a bit once the PD-1s came. Now this has been pushed aside.

Benjamin Levy, MD: So we participated in the REVEL study. I must admit that I was surprised at the lack of toxicity signal with ramucirumab in addition to docetaxel, so I’m not overly concerned about the toxicity profile. I guess these data and the necitumumab data bring into question what’s clinically meaningful. And ASCO has put forth some metrics as to whether six weeks is clinically meaningful. I agree with you, I think that everything has to be individualized and these patients who you need to elicit a response with, who you can give this drug safely, I would consider it now after immunotherapy or for a patient who is not an immunotherapy candidate. Paul, your thoughts on the drug and your use and experience with it.

Paul K. Paik, MD: Similar to the two of you, it’s become the preferred second-line and beyond chemotherapy regimen supplanting docetaxel. Part of what I like about this today is all the numbers in the overall population at least go in the right direction and are significantly different, including response rate which was not seen with necitumumab. In the subset analyses for squamous lung cancer, in particular, the response rate difference was pretty good, 27% versus 11%. And, again, for a population that’s having a lot of symptoms and where they progress on first-line chemotherapy, a lot of our patients do have symptoms. We really need in, in terms of that benefit, the benefit to them, we need their cancers to shrink. I mean, it’s one thing to have relatively stable disease that lasts a long time, but if someone is really symptomatic, that’s not necessarily going to help them in terms of feeling better. So I do like the regimen. I do think the bar is lower again for second-line setting and beyond in terms of what we’re looking for. Again, the toxicity profile was not that different, which is an important thing. I think we have to give kudos to the study designers because that sort of shadow that we’ve had in squamous lung cancer about angiogenesis inhibitors has been there for a very long time. And while there have been smaller studies showing that it’s going to be safe if we exclude the right number of patients, they included them. And if they had not then we would not be where we are for this subset of patients. It is a relatively big deal from that perspective, at least from my viewpoint as well in terms of the design for this.

Benjamin Levy, MD: Yeah. I think their incorporation of the squamous cell histology historically was thought to perhaps predict an AE with these anti-angiogenic drugs. It didn’t pan out in the study. One last question. In studies that are incorporating docetaxel as the control arm, does docetaxel/ramucirumab instead becoming the control arm?

Paul K. Paik, MD: I think it needs to, but then it gets dirtier because then also if you have regimens where you want to combine it with second-line chemotherapy, then you’re looking at triplet therapy like a targeted therapy plus chemotherapy. Is that going to end up working out? It makes things a little bit more difficult to figure out? But I think in terms of for comparator, docetaxel/ramucirumab is now the de facto standard and that needs to be the comparator, at least against chemotherapy.

Transcript Edited for Clarity
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Transcript:

Benjamin Levy, MD:
Let’s stay on this theme of lack of molecular enrichment strategies and talk about the second monoclonal antibody that’s approved. Ramucirumab was FDA-approved with the use of docetaxel based on the REVEL study, and 25% of those patients were squamous. There were both adenocarcinoma and squamous tumors. So there’s another drug in our therapeutic armamentarium. Ed, you want to talk about this drug, how it works and some of the nuances of the REVEL data?

Edward S. Kim, MD, FACP: Yeah. Ramucirumab is obviously a pan-VEGF inhibitor. It’s a monoclonal antibody. It’s not exactly bevacizumab in that it has a little different function there and you can see that in the clinical data based on what we see as far as side effects and where the efficacy is. Some very important distinctions are that it doesn’t have the same type of bleeding indications and toxicity exists. You can actually use this in squamous cell patients. That’s a big jump for people to think of VEGF in squamous. That’s because we’ve been conditioned so hard that there’s toxicity and people will bleed out and those things. That’s not the case here. And one thing that was interesting also was that prior bevacizumab use was allowed on the study, and so you had patients who were treated after that. It’s in the non-squam, obviously, population, so there was again this sort of benefit that occurred in second-line. It’s important to remember and I’ve laid a wasteland of second-line studies in my career. So to get a significant survival value is an achievement, let me tell you; so it was 10.5 versus 9.1 months. Right away that tells you people are living longer in second-line because that looks almost like the ECOG 1594 first-line trial of overall survival which was about 20 years ago, and improved PFS.

So, again, I think this is what we would expect to see when we look at the necitumumab data, when we look at the ramucirumab data, when we look at any 2 versus 1, 3 versus 2 type study in an unselected population. And you see these one-and-a-half to two-and-a-half month survival benefits, these one-and-a-half to two-and-a-half month PFS benefits. What’s the toxicity, what’s the subset population, what’s the cost? It’s interesting because that’s, again, where the art comes in. And whether you’re deciding by hazard ratios versus median values versus anything, you’ll hear differing opinions.

I think it’s an acceptable regimen. We do have it on our pathways as a preferred regimen for squamous in the second-line subsequent setting. I would certainly use this over docetaxel alone. It doesn’t seem to confer any additional side effects that are significant. There are other options in second-line, so does this become a third-line regimen or what have you. We won’t get into that right now, but it certainly is something again that adds to the equation of better than single agent docetaxel. Certainly this would be something I would use over single agent erlotinib, or vinorelbine, or gemcitabine as well. That’s what I find beneficial as far as our clinical approach to squamous patients.

Benjamin Levy, MD: So you would use this drug and you have used this drug in patients who perhaps aren’t either immunotherapy candidates or in the third-line after immunotherapy.

Edward S. Kim, MD, FACP: Before immunotherapy with second-line and we were starting to use that quite a bit once the PD-1s came. Now this has been pushed aside.

Benjamin Levy, MD: So we participated in the REVEL study. I must admit that I was surprised at the lack of toxicity signal with ramucirumab in addition to docetaxel, so I’m not overly concerned about the toxicity profile. I guess these data and the necitumumab data bring into question what’s clinically meaningful. And ASCO has put forth some metrics as to whether six weeks is clinically meaningful. I agree with you, I think that everything has to be individualized and these patients who you need to elicit a response with, who you can give this drug safely, I would consider it now after immunotherapy or for a patient who is not an immunotherapy candidate. Paul, your thoughts on the drug and your use and experience with it.

Paul K. Paik, MD: Similar to the two of you, it’s become the preferred second-line and beyond chemotherapy regimen supplanting docetaxel. Part of what I like about this today is all the numbers in the overall population at least go in the right direction and are significantly different, including response rate which was not seen with necitumumab. In the subset analyses for squamous lung cancer, in particular, the response rate difference was pretty good, 27% versus 11%. And, again, for a population that’s having a lot of symptoms and where they progress on first-line chemotherapy, a lot of our patients do have symptoms. We really need in, in terms of that benefit, the benefit to them, we need their cancers to shrink. I mean, it’s one thing to have relatively stable disease that lasts a long time, but if someone is really symptomatic, that’s not necessarily going to help them in terms of feeling better. So I do like the regimen. I do think the bar is lower again for second-line setting and beyond in terms of what we’re looking for. Again, the toxicity profile was not that different, which is an important thing. I think we have to give kudos to the study designers because that sort of shadow that we’ve had in squamous lung cancer about angiogenesis inhibitors has been there for a very long time. And while there have been smaller studies showing that it’s going to be safe if we exclude the right number of patients, they included them. And if they had not then we would not be where we are for this subset of patients. It is a relatively big deal from that perspective, at least from my viewpoint as well in terms of the design for this.

Benjamin Levy, MD: Yeah. I think their incorporation of the squamous cell histology historically was thought to perhaps predict an AE with these anti-angiogenic drugs. It didn’t pan out in the study. One last question. In studies that are incorporating docetaxel as the control arm, does docetaxel/ramucirumab instead becoming the control arm?

Paul K. Paik, MD: I think it needs to, but then it gets dirtier because then also if you have regimens where you want to combine it with second-line chemotherapy, then you’re looking at triplet therapy like a targeted therapy plus chemotherapy. Is that going to end up working out? It makes things a little bit more difficult to figure out? But I think in terms of for comparator, docetaxel/ramucirumab is now the de facto standard and that needs to be the comparator, at least against chemotherapy.

Transcript Edited for Clarity
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