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Maintenance Therapy for 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 Online: Sunday, Mar 19, 2017



Transcript:

Mark Socinski, MD:
Whether it’s 4 or 6 cycles, you do maintenance considerations in this setting?

Edward S. Kim, MD: Yes. We try to do maintenance. Right now, there isn’t.

Jared Weiss, MD: In squamous patients?

Edward S. Kim, MD: Right. So, in squamous now, again, necitumumab—although not highly used—is an obvious maintenance situation. Do we proactively use switch maintenance in squamous? No. Some of the data I’ve seen with nab-paclitaxel as a continuation look very nice as well, and speaks to the tolerability.

Mark Socinski, MD: And there is an ongoing phase III trial in squamous looking specifically at maintenance after 4 cycles of continuing the nab-paclitaxel. So, that’ll be a good, and we’ll get to erlotinib as a maintenance a little bit further down the line here. But Ed’s comment there is that the side effect profile of nab-paclitaxel does make it somewhat amenable to more chronic administration. Maybe in an era where we really don’t have a lot of good options for maintenance in the squamous population, this will be an advance in this setting.

Edward S. Kim, MD: And I think to Tracey’s point earlier, we forget about that Fidias study way back when where they used docetaxel. They were able to complete 6 maintenance cycles of docetaxel, which, if any of us tried to do that today, I think we would view that as something very arduous to say the least. Mark Socinski, MD: Yes, but there are some data with gemcitabine. If you happen to have gemcitabine, there is some continuation…

Tracey L. Evans, MD: Well, progression-free survival is better if you go to gemcitabine. There have been some tenths of overall survival benefit, but not consistent.

Mark Socinski, MD: Right, but we would argue that gemcitabine is a drug that could be given for a longer period of time. I want to go back to David Jackman, but Ed brought up the issue of necitumumab. And, obviously, EGFR monoclonal antibodies have had a sordid past in this disease. We had a positive FLEX trial years ago that never gained FDA approval. We won’t discuss why. But we had the son of cetuximab, which is necitumumab, the fully humanized monoclonal antibody. And, in the SQUIRE trial, it showed an overall survival advantage and gained FDA approval. Your thoughts on that trial?

David M. Jackman, MD: I think it’s a wonderful example of thinking how we, as oncologists, need to ask ourselves not just can we, but should we; is this clinically meaningful? Did it improve survival? The answer is yes, it did. It improved overall survival by about a month and a half. It didn’t really improve progression-free survival, or response rate, in any clinically meaningful way. With that, think, what’s our bar for how much of an improvement is worth the additional toxicity? And, in this day and age, the additional cost. And so, for us at our institution, we have not made necitumumab part of our everyday practice.

Mark Socinski, MD: Others? Thoughts?

Edward S. Kim, MD: One of the issues also was it was with cisplatin. So, that’s a tougher sell in the United States to use that combination. And because the efficacy margins were not so robust, one doesn’t feel comfortable just substituting out carboplatin in that situation, at least I don’t.

Mark Socinski, MD: Right. There’s a paucity of data with regard to that. I do think that the link to cisplatin/gemcitabine does create a reaction. But in that patient who’s robust and can take cisplatin/gemcitabine, I would not say it would be an option that I would consider in every squamous patient. Do we have any NCCN members here?

Tracey L. Evans, MD: No.

David M. Jackman, MD: I’m a member, though I’m not on small cell panels specifically.

Mark Socinski, MD: OK. But an interesting NCCN journey where initially it was a category 3 was probably the first example, at least in the lung cancer, where the NCCN made a value judgment, right? And my understanding is that it’s no longer included as part of the NCCN guidelines.

Tracey L. Evans, MD: No. I thought there was a category 3.

Mark Socinski, MD: Yes, there was a category 3.

Tracey L. Evans, MD: Right. They had actually done a cost analysis on that before it was even commercially available. And if it were to maintain a value of a $200,000 per quality-adjusted life year, the price per cycle would have had to be $1,300. Well, they ended up pricing it at $8,000 per cycle.

Jared Weiss, MD: To me, the greatest point of passion in this whole conversation is the cisplatin versus carboplatin. We may all be a little bit bored by it because it’s nothing new, but our patients are not. From a quality of life standpoint, I think there is a very real difference between the agents favoring carboplatin.

Mark Socinski, MD: Have the 4 panel members used necitumumab outside of a clinical trial in an individual patient?

Jared Weiss, MD: No.

Tracey L. Evans, MD: No, but I used to use cetuximab. And I do think there were some people who really benefited, and we do need to try to figure this out. For cetuximab, it looked like the H-score might be the predictive factor, which was a way of scoring immunohistochemistry for EGFR. But then, in the SQUIRE study, that was not actually predictive. When they did another analysis where it was just straight up EGFR immunohistochemistry, which applied to 95% of the patients on the study and did just that, they got the hazard ratio down from 0.84 to 0.79. So, it was able to enhance the benefit a little bit, but still not a great deal.

Mark Socinski, MD: Yes, by excluding 5% of the patients And then, there’s a subsequent analysis looking at—we’re back to Fred Hirsch’s favorite subject—EGFR FISH. And their analysis of the SWOG trial…I forget which number of the SWOG trial.

Edward S. Kim, MD: About 342.

Mark Socinski, MD: Yes, plus or minus cetuximab.; the FISH analysis there as well as the FISH analysis from the SQUIRE trial. I think necitumumab is one of those drugs that needs a biomarker, if you could find the minority of patients, like PD-L1, right? If you find those patients, it’s helpful. We just haven’t been able to refine that. But maybe you could argue we haven’t done the right studies to do that either.

David, I just wanted to get back to your point, because I completely agree. We, as oncologists, have to begin to tackle the value-based issues. My only issue with that is, why are we separating out necitumumab? I would argue ramucirumab and a number of others, maybe bevacizumab. What’s the number where we’re going to say, “This is too expensive. Unless prices come down, it’s not on the pathway”? So, that would be my only comment.

David M. Jackman, MD: Yes, you’re absolutely right. And I think we are just barely scratching the surface of this. Even when we try to make value judgments, oftentimes they’re making it based on drug acquisition costs. And really, we need to take into consideration the entire cost of care. Maybe a drug is a little bit more expensive, but if there are fewer toxicities, fewer hospitalizations, that’s going to factor in. So, we need to start doing this as a community, and we need pharma to take a role in this as well. They need to capture this data when they’re running the trials.

Edward S. Kim, MD: I think we’re going to be told that down the road. We can be proactive about it, which I think we should, but we’re going to be told down the road. And I think that’s difficult, especially in this front-line setting of squamous. As some of the other data comes out, with immunotherapy of single agents, maybe they don’t look as robust as the PD-L1 positive group, but there’s plenty of unselected trials being done. The question would be, would you give a cisplatin/gemcitabine/necitumumab combination versus single-agent unselected PD-1 inhibitor if it ends up getting positive that way and getting approved that way? These are real things that could happen down the road. So, I really think it’s tough, especially based on the data you presented with carboplatin and nab-paclitaxel. It was easy to find a substitute there because the survivals weren’t that far off. Responses were actually better. Again, separate trials, but 41% to 42%, that’s a great response rate.

Mark Socinski, MD: For a doublet, yes.

Jared Weiss, MD: Now these may well become our concern in the future. The payers are pushing, and I think they will ultimately succeed to force practitioners to take on double-sided risk. I think we’re not that far off from this. And it’s going to switch from being a theoretical thought experiment, like we’re doing here, into something that we really have to decide where the value is, whether we like it or not.

Edward S. Kim, MD: Don’t forget all the other stuff—the growth factors, the PET scan versus CT scan. All of that stuff is going to get lumped in, as David was saying about the total cost of care. Whoever invents that app, or maybe it already exists, that’s basically what you’re going to be doing with patients, and they’ll have their own app, too.

Transcript Edited for Clarity

Slider Left
Slider Right


Transcript:

Mark Socinski, MD:
Whether it’s 4 or 6 cycles, you do maintenance considerations in this setting?

Edward S. Kim, MD: Yes. We try to do maintenance. Right now, there isn’t.

Jared Weiss, MD: In squamous patients?

Edward S. Kim, MD: Right. So, in squamous now, again, necitumumab—although not highly used—is an obvious maintenance situation. Do we proactively use switch maintenance in squamous? No. Some of the data I’ve seen with nab-paclitaxel as a continuation look very nice as well, and speaks to the tolerability.

Mark Socinski, MD: And there is an ongoing phase III trial in squamous looking specifically at maintenance after 4 cycles of continuing the nab-paclitaxel. So, that’ll be a good, and we’ll get to erlotinib as a maintenance a little bit further down the line here. But Ed’s comment there is that the side effect profile of nab-paclitaxel does make it somewhat amenable to more chronic administration. Maybe in an era where we really don’t have a lot of good options for maintenance in the squamous population, this will be an advance in this setting.

Edward S. Kim, MD: And I think to Tracey’s point earlier, we forget about that Fidias study way back when where they used docetaxel. They were able to complete 6 maintenance cycles of docetaxel, which, if any of us tried to do that today, I think we would view that as something very arduous to say the least. Mark Socinski, MD: Yes, but there are some data with gemcitabine. If you happen to have gemcitabine, there is some continuation…

Tracey L. Evans, MD: Well, progression-free survival is better if you go to gemcitabine. There have been some tenths of overall survival benefit, but not consistent.

Mark Socinski, MD: Right, but we would argue that gemcitabine is a drug that could be given for a longer period of time. I want to go back to David Jackman, but Ed brought up the issue of necitumumab. And, obviously, EGFR monoclonal antibodies have had a sordid past in this disease. We had a positive FLEX trial years ago that never gained FDA approval. We won’t discuss why. But we had the son of cetuximab, which is necitumumab, the fully humanized monoclonal antibody. And, in the SQUIRE trial, it showed an overall survival advantage and gained FDA approval. Your thoughts on that trial?

David M. Jackman, MD: I think it’s a wonderful example of thinking how we, as oncologists, need to ask ourselves not just can we, but should we; is this clinically meaningful? Did it improve survival? The answer is yes, it did. It improved overall survival by about a month and a half. It didn’t really improve progression-free survival, or response rate, in any clinically meaningful way. With that, think, what’s our bar for how much of an improvement is worth the additional toxicity? And, in this day and age, the additional cost. And so, for us at our institution, we have not made necitumumab part of our everyday practice.

Mark Socinski, MD: Others? Thoughts?

Edward S. Kim, MD: One of the issues also was it was with cisplatin. So, that’s a tougher sell in the United States to use that combination. And because the efficacy margins were not so robust, one doesn’t feel comfortable just substituting out carboplatin in that situation, at least I don’t.

Mark Socinski, MD: Right. There’s a paucity of data with regard to that. I do think that the link to cisplatin/gemcitabine does create a reaction. But in that patient who’s robust and can take cisplatin/gemcitabine, I would not say it would be an option that I would consider in every squamous patient. Do we have any NCCN members here?

Tracey L. Evans, MD: No.

David M. Jackman, MD: I’m a member, though I’m not on small cell panels specifically.

Mark Socinski, MD: OK. But an interesting NCCN journey where initially it was a category 3 was probably the first example, at least in the lung cancer, where the NCCN made a value judgment, right? And my understanding is that it’s no longer included as part of the NCCN guidelines.

Tracey L. Evans, MD: No. I thought there was a category 3.

Mark Socinski, MD: Yes, there was a category 3.

Tracey L. Evans, MD: Right. They had actually done a cost analysis on that before it was even commercially available. And if it were to maintain a value of a $200,000 per quality-adjusted life year, the price per cycle would have had to be $1,300. Well, they ended up pricing it at $8,000 per cycle.

Jared Weiss, MD: To me, the greatest point of passion in this whole conversation is the cisplatin versus carboplatin. We may all be a little bit bored by it because it’s nothing new, but our patients are not. From a quality of life standpoint, I think there is a very real difference between the agents favoring carboplatin.

Mark Socinski, MD: Have the 4 panel members used necitumumab outside of a clinical trial in an individual patient?

Jared Weiss, MD: No.

Tracey L. Evans, MD: No, but I used to use cetuximab. And I do think there were some people who really benefited, and we do need to try to figure this out. For cetuximab, it looked like the H-score might be the predictive factor, which was a way of scoring immunohistochemistry for EGFR. But then, in the SQUIRE study, that was not actually predictive. When they did another analysis where it was just straight up EGFR immunohistochemistry, which applied to 95% of the patients on the study and did just that, they got the hazard ratio down from 0.84 to 0.79. So, it was able to enhance the benefit a little bit, but still not a great deal.

Mark Socinski, MD: Yes, by excluding 5% of the patients And then, there’s a subsequent analysis looking at—we’re back to Fred Hirsch’s favorite subject—EGFR FISH. And their analysis of the SWOG trial…I forget which number of the SWOG trial.

Edward S. Kim, MD: About 342.

Mark Socinski, MD: Yes, plus or minus cetuximab.; the FISH analysis there as well as the FISH analysis from the SQUIRE trial. I think necitumumab is one of those drugs that needs a biomarker, if you could find the minority of patients, like PD-L1, right? If you find those patients, it’s helpful. We just haven’t been able to refine that. But maybe you could argue we haven’t done the right studies to do that either.

David, I just wanted to get back to your point, because I completely agree. We, as oncologists, have to begin to tackle the value-based issues. My only issue with that is, why are we separating out necitumumab? I would argue ramucirumab and a number of others, maybe bevacizumab. What’s the number where we’re going to say, “This is too expensive. Unless prices come down, it’s not on the pathway”? So, that would be my only comment.

David M. Jackman, MD: Yes, you’re absolutely right. And I think we are just barely scratching the surface of this. Even when we try to make value judgments, oftentimes they’re making it based on drug acquisition costs. And really, we need to take into consideration the entire cost of care. Maybe a drug is a little bit more expensive, but if there are fewer toxicities, fewer hospitalizations, that’s going to factor in. So, we need to start doing this as a community, and we need pharma to take a role in this as well. They need to capture this data when they’re running the trials.

Edward S. Kim, MD: I think we’re going to be told that down the road. We can be proactive about it, which I think we should, but we’re going to be told down the road. And I think that’s difficult, especially in this front-line setting of squamous. As some of the other data comes out, with immunotherapy of single agents, maybe they don’t look as robust as the PD-L1 positive group, but there’s plenty of unselected trials being done. The question would be, would you give a cisplatin/gemcitabine/necitumumab combination versus single-agent unselected PD-1 inhibitor if it ends up getting positive that way and getting approved that way? These are real things that could happen down the road. So, I really think it’s tough, especially based on the data you presented with carboplatin and nab-paclitaxel. It was easy to find a substitute there because the survivals weren’t that far off. Responses were actually better. Again, separate trials, but 41% to 42%, that’s a great response rate.

Mark Socinski, MD: For a doublet, yes.

Jared Weiss, MD: Now these may well become our concern in the future. The payers are pushing, and I think they will ultimately succeed to force practitioners to take on double-sided risk. I think we’re not that far off from this. And it’s going to switch from being a theoretical thought experiment, like we’re doing here, into something that we really have to decide where the value is, whether we like it or not.

Edward S. Kim, MD: Don’t forget all the other stuff—the growth factors, the PET scan versus CT scan. All of that stuff is going to get lumped in, as David was saying about the total cost of care. Whoever invents that app, or maybe it already exists, that’s basically what you’re going to be doing with patients, and they’ll have their own app, too.

Transcript Edited for Clarity
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