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Further Sequencing in Squamous NSCLC

Panelists: Mark A. Socinski, MD, Florida Hospital Cancer Institute; Tracey L. Evans, MD, University of Pennsylvania; David M. Jackman, MD, Dana-Farber Cancer Institute; Edward S. Kim, MD, Levine Cancer Institute; Jared Weiss, MD, UNC Lineberger Comprehensive Cancer Center
Published: Thursday, Mar 23, 2017



Transcript:

Mark Socinski, MD:
In the squamous patient—for that small percentage that are going to get pembrolizumab and are high expressors once they’ve progressed on pembrolizumab—are you back to your usual paradigm in that population of patients?

Tracey L. Evans, MD: I am. As far as line of therapy, I don’t think that that’s a very useful concept right now, especially when we’re changing modalities. I think it probably doesn’t make as much sense to follow up with second-line immunotherapy if you use first-line immunotherapy. But in terms of if I use first-line immunotherapy and they progress, then I’ll just start over with cytotoxic chemotherapy and use a platinum-based doublet, and that’s not a problem.

Jared Weiss, MD: We’re starting to see some clinical trial designs of later-line, early-stage immunotherapy that require PD-1 or PD-L1 refractories. I think these are stacking up a little more in squamous, actually. So, where trials are available, the PD-1 or PD-L1 progressor may have options other than chemotherapy, if they’re considered.

Tracey L. Evans, MD: Right, but those are clinical trials, and my expectation would be that they are a little bit behind with their likelihood of having a response to the additional same concept therapy. Chemotherapy, for them, is a clean slate.

Jared Weiss, MD: It’s totally new. To an extent, not all, but most of the agents that hit our top 10 list of things being studied are T cell stimulatory agents, with 1 or 2 exceptions.

Tracey L. Evans, MD: But I don’t know if we’re going to see the same trial. In cytotoxic chemotherapy, you clearly see a drop off in efficacy. It doesn’t matter what you give first line, the efficacy is roughly similar. And it doesn’t matter what you give second line, the efficacy is roughly just as bad. And I would expect that would happen with immunotherapy, but I could be wrong. We have RADVAX studies going on in our institution where you’re trying to potentiate the immunotherapy that they already had by radiating a piece of their tumor, and seeing if you can cause an antigen release to increase the immune response. Hopefully, it’ll work.

Mark Socinski, MD: I know this is going to be hard for all of you, but I want you to go back before the immuno-oncology (I-O) tsunami occurred, to get back to the drug that Ed brought up and that’s ramucirumab. Antiangiogenic antibodies were a no-no in squamous disease because of the risk of bleeding—that experience with bevacizumab that we had that was not the experience with ramucirumab. In the REVEL trial, which we’ve talked about but I’m going to have you discuss it so I can get your opinion, there was the addition of ramucirumab to docetaxel. I think what happened before ramucirumab could have any traction in the community—that was approved in December of 2014—nivolumab came around with that very positive trial, which occurred 3 months later. It kind of got swallowed up in that and never had time for traction. If the immunotherapy tsunami never happened, where do you think ramucirumab would be? We know you’re not a fan of docetaxel, but let’s face it, for a long time, docetaxel was the only choice we had in the second-line setting, right, as an approved choice?

Jared Weiss, MD: I think if you were to go back, let’s say, at least a decade, if that trial had come out, I think it would have been received very favorably. We wouldn’t be speaking in the way we’re speaking of it. Because as was pointed out earlier, for a while squamous was the desert where we were not empowered to really help these patients the way we are today.

Mark Socinski, MD: And specifically, antiangiogenic therapy was a no-no.

Jared Weiss, MD: It was a big no-no. In phase II, I think it was about a one-third rate of fatal hemoptysis.

Mark Socinski, MD: It was 4 of 13.

Jared Weiss, MD: Well, that’s about one-third.

Mark Socinski, MD: Life threatening or fatal.

Jared Weiss, MD: And I witnessed one of these. In training, I witnessed the patient who, on repeat pathologic review, was found to have a mixed squamous adenocarcinoma, but who was read out, initially, as purely adenocarcinoma. He did get bevacizumab, and he and I were playing chess when his entire blood volume experienced hemoptysis. For those who lived through this early experience, it’s something you never forget. I think there was a culture against these agents in that class in squamous, but that’s not what we’ve seen with ramucirumab. This agent does appear to be safe in squamous patients.

The randomized trial was well conducted. It was conducted ethically. The data, as best we know, were conducted well. It has all the right stopgaps, and I think the question for practitioners is, are you using docetaxel to additive? If you are, it does add something, albeit small. And then, the value question that we were just discussing is whether it reaches that threshold to be worth using. But it is a legitimate agent.

Mark Socinski, MD: Yes, and it reminds me that we talked about necitumumab before, and the magnitude of that benefit. These were very similar clinical trial outcomes. Ramucirumab did have the triple threat—response rate, PFS, and OS. So, it had that advantage to it. But the overall survival was very similar to necitumumab. So, that would be an issue. Is it your go-to treatment if, let’s say, the patient has a significant autoimmune history? Is that your second-line choice if you can’t give immunotherapy?

Edward S. Kim, MD: We had that combination, and we still do, on our pathways, prior to the I-O tsunami, as you describe it. And we were using it quite frequently as our second-line default in patients with squamous cell disease. Not only was the side effect profile very favorable compared to bevacizumab, but in the non–squamous side they even showed responses post previous bevacizumab. There were a lot of differences between that drug and bevacizumab, and you didn’t take pause in writing for it. To me, if I could get 2 or 3 cycles of the combination and then continue someone on maintenance—this way I didn’t have to give them 4, 5, or 6 cycles of docetaxel—that was a win. And so, we used it quite a bit until nivolumab was approved. That changed everything.

Jared Weiss, MD: When you used it, were you giving your docetaxel at 75 mg/m2, the standard dose?

Edward S. Kim, MD: Yes. You dose reduced if you needed to, but it was very well tolerated and you really didn’t feel like you were adding much at all. You didn’t watch for blood pressure, for renal insufficiency, or all these things. It was very well tolerated.

Tracey L. Evans, MD: I was always nervous about it because in the eligibility for the actual study, it says that they excluded central tumors that involve the central airway and the vasculature. I’m not always sure. I look at my own scans, but I’m not always sure what that means. I am still nervous about using a drug like that in squamous disease.

Mark Socinski, MD: If you actually read the publication by Ed Garon, and you read the patient selection in there, there’s a long list of things that people were kicked out for. And I’m reading this going, “If they stuck to this, there were a lot of exclusions.”

Tracey L. Evans, MD: Correct. It doesn’t seem like your typical squamous-cell case. And the one guy I gave it to had terrible asthenia and terrible stomatitis, which does increase with the combination.

Mark Socinski, MD: Yes, it does.

Tracey L. Evans, MD: And then, there was nivolumab.

Transcript Edited for Clarity

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Transcript:

Mark Socinski, MD:
In the squamous patient—for that small percentage that are going to get pembrolizumab and are high expressors once they’ve progressed on pembrolizumab—are you back to your usual paradigm in that population of patients?

Tracey L. Evans, MD: I am. As far as line of therapy, I don’t think that that’s a very useful concept right now, especially when we’re changing modalities. I think it probably doesn’t make as much sense to follow up with second-line immunotherapy if you use first-line immunotherapy. But in terms of if I use first-line immunotherapy and they progress, then I’ll just start over with cytotoxic chemotherapy and use a platinum-based doublet, and that’s not a problem.

Jared Weiss, MD: We’re starting to see some clinical trial designs of later-line, early-stage immunotherapy that require PD-1 or PD-L1 refractories. I think these are stacking up a little more in squamous, actually. So, where trials are available, the PD-1 or PD-L1 progressor may have options other than chemotherapy, if they’re considered.

Tracey L. Evans, MD: Right, but those are clinical trials, and my expectation would be that they are a little bit behind with their likelihood of having a response to the additional same concept therapy. Chemotherapy, for them, is a clean slate.

Jared Weiss, MD: It’s totally new. To an extent, not all, but most of the agents that hit our top 10 list of things being studied are T cell stimulatory agents, with 1 or 2 exceptions.

Tracey L. Evans, MD: But I don’t know if we’re going to see the same trial. In cytotoxic chemotherapy, you clearly see a drop off in efficacy. It doesn’t matter what you give first line, the efficacy is roughly similar. And it doesn’t matter what you give second line, the efficacy is roughly just as bad. And I would expect that would happen with immunotherapy, but I could be wrong. We have RADVAX studies going on in our institution where you’re trying to potentiate the immunotherapy that they already had by radiating a piece of their tumor, and seeing if you can cause an antigen release to increase the immune response. Hopefully, it’ll work.

Mark Socinski, MD: I know this is going to be hard for all of you, but I want you to go back before the immuno-oncology (I-O) tsunami occurred, to get back to the drug that Ed brought up and that’s ramucirumab. Antiangiogenic antibodies were a no-no in squamous disease because of the risk of bleeding—that experience with bevacizumab that we had that was not the experience with ramucirumab. In the REVEL trial, which we’ve talked about but I’m going to have you discuss it so I can get your opinion, there was the addition of ramucirumab to docetaxel. I think what happened before ramucirumab could have any traction in the community—that was approved in December of 2014—nivolumab came around with that very positive trial, which occurred 3 months later. It kind of got swallowed up in that and never had time for traction. If the immunotherapy tsunami never happened, where do you think ramucirumab would be? We know you’re not a fan of docetaxel, but let’s face it, for a long time, docetaxel was the only choice we had in the second-line setting, right, as an approved choice?

Jared Weiss, MD: I think if you were to go back, let’s say, at least a decade, if that trial had come out, I think it would have been received very favorably. We wouldn’t be speaking in the way we’re speaking of it. Because as was pointed out earlier, for a while squamous was the desert where we were not empowered to really help these patients the way we are today.

Mark Socinski, MD: And specifically, antiangiogenic therapy was a no-no.

Jared Weiss, MD: It was a big no-no. In phase II, I think it was about a one-third rate of fatal hemoptysis.

Mark Socinski, MD: It was 4 of 13.

Jared Weiss, MD: Well, that’s about one-third.

Mark Socinski, MD: Life threatening or fatal.

Jared Weiss, MD: And I witnessed one of these. In training, I witnessed the patient who, on repeat pathologic review, was found to have a mixed squamous adenocarcinoma, but who was read out, initially, as purely adenocarcinoma. He did get bevacizumab, and he and I were playing chess when his entire blood volume experienced hemoptysis. For those who lived through this early experience, it’s something you never forget. I think there was a culture against these agents in that class in squamous, but that’s not what we’ve seen with ramucirumab. This agent does appear to be safe in squamous patients.

The randomized trial was well conducted. It was conducted ethically. The data, as best we know, were conducted well. It has all the right stopgaps, and I think the question for practitioners is, are you using docetaxel to additive? If you are, it does add something, albeit small. And then, the value question that we were just discussing is whether it reaches that threshold to be worth using. But it is a legitimate agent.

Mark Socinski, MD: Yes, and it reminds me that we talked about necitumumab before, and the magnitude of that benefit. These were very similar clinical trial outcomes. Ramucirumab did have the triple threat—response rate, PFS, and OS. So, it had that advantage to it. But the overall survival was very similar to necitumumab. So, that would be an issue. Is it your go-to treatment if, let’s say, the patient has a significant autoimmune history? Is that your second-line choice if you can’t give immunotherapy?

Edward S. Kim, MD: We had that combination, and we still do, on our pathways, prior to the I-O tsunami, as you describe it. And we were using it quite frequently as our second-line default in patients with squamous cell disease. Not only was the side effect profile very favorable compared to bevacizumab, but in the non–squamous side they even showed responses post previous bevacizumab. There were a lot of differences between that drug and bevacizumab, and you didn’t take pause in writing for it. To me, if I could get 2 or 3 cycles of the combination and then continue someone on maintenance—this way I didn’t have to give them 4, 5, or 6 cycles of docetaxel—that was a win. And so, we used it quite a bit until nivolumab was approved. That changed everything.

Jared Weiss, MD: When you used it, were you giving your docetaxel at 75 mg/m2, the standard dose?

Edward S. Kim, MD: Yes. You dose reduced if you needed to, but it was very well tolerated and you really didn’t feel like you were adding much at all. You didn’t watch for blood pressure, for renal insufficiency, or all these things. It was very well tolerated.

Tracey L. Evans, MD: I was always nervous about it because in the eligibility for the actual study, it says that they excluded central tumors that involve the central airway and the vasculature. I’m not always sure. I look at my own scans, but I’m not always sure what that means. I am still nervous about using a drug like that in squamous disease.

Mark Socinski, MD: If you actually read the publication by Ed Garon, and you read the patient selection in there, there’s a long list of things that people were kicked out for. And I’m reading this going, “If they stuck to this, there were a lot of exclusions.”

Tracey L. Evans, MD: Correct. It doesn’t seem like your typical squamous-cell case. And the one guy I gave it to had terrible asthenia and terrible stomatitis, which does increase with the combination.

Mark Socinski, MD: Yes, it does.

Tracey L. Evans, MD: And then, there was nivolumab.

Transcript Edited for Clarity
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