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Nab-Paclitaxel plus Carboplatin 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: Tuesday, Mar 29, 2016


Transcript:

Edward S. Kim, MD, FACP:
And so, when you come to nab-paclitaxel and how they’ve most recently done with Mark Socinski’s study, the phase III study, the first thing people said was, ‘Well, it’s still Taxol. You’re just changing the delivery, whether it’s albumin-bound versus chromophore-bound. Why should there be any difference?’ True. So that’s why the FDA said, ‘Well, you can use response rate as an endpoint because overall survival (OS) should be the same?’ I mean, it should be. After 1000 patients—not a small study—a lot of people said that was not resources utilized well, 41%. Remember, carboplatin/Taxol/Avastin was 35% in a more favorable response population.

Benjamin Levy, MD: Right.

Edward S. Kim, MD, FACP: And the subset of squamous was over 400 patients in this 1000-patient study, so astounding to me. Again, based on what we see as far as the presentation of patients and even when choosing drugs right now when we look at even some of the immunotherapies, will response drive our choice in the light of no survival? And I think that’s something that people have not adopted as much as I thought would happen. That’s been surprising to me. The other aspect is that we touched on this over-70 population. You can look at subsets—we always do—and gosh, if any one of us keep looking at these Forest plots, we start getting dizzy. But the survival in the over-70 population that had over 150 patients, more than 10% in this study was almost 20 months versus 10, doubling 20. We’re not talking about 15 versus 10, 12 versus 10, 20. I mean, if I were sitting there as a CEO of a company, I’d be forced to have to test that. Because later if I didn’t, I’d be looked upon as stupid.

Benjamin Levy, MD: Keep in mind, the average age of a lung cancer patient is 71.

Edward S. Kim, MD, FACP: So that’s how I organize those things in my mind. Do I think they’re all good regimens? Yes. Do we have preferences in our system that we’ve listed? Yes. We do list carboplatin and nab-paclitaxel as one of our preferred regimens for squamous patients.

Benjamin Levy, MD: I think that you touched upon an issue with the response rate being 41%, which is so important, especially in a group of patients who can be very symptomatic from their disease. And so we have adopted this, as well, based on a response rate. I don’t know if I can explain biologically the over-70 population and why there’s almost a doubling in overall survival (OS). But other things, the need not to pre-medicate with steroids with this drug and the AE profile, for us has been very helpful. Paul, your thoughts on this drug and using it, gemcitabine-based regimens versus solvent-based paclitaxel.

Paul K. Paik, MD: Right. So outside of the limited scope of the regimens that have been tested head-to-head, I think as Ed was saying, and what you’ve mentioned, we have regimens that are all reasonably effective. If you put them side-by-side and look at the response rate, progression-free survival (PFS), OS data, they’re all very similar except for some outliers like the subset analysis in Mark Socinski’s trial for Abraxane and carboplatin. That’s formally being tested in a more rigorous fashion within this specific population.

The hazard ratio for survival in the over-age-70 population, as Ed had said, it was very large. And while you could argue it’s a subset analysis—the hazard ratio was 0.58, I think—–there may very well be something that’s there. For me, selection, absent the ability to provide a lot of or absent the head-to-head data, comes down to questions of sequence in terms of the overall care for the patient, which I think we’ll get into in a little habit, and also the side-effect profile for these agents. Carboplatin/Abraxane, the data certainly are that its rate of neuropathy in particular are better. But the rates of anemia and thrombocytopenia are substantially higher. They are almost three-fold higher into the 20% range for grade 3/4 anemia and thrombocytopenia. And for my patient population, the patients I see, the anemia can be a bit challenging. In addition, I think the back-to-back, at least the way that it was studied, the sort of nonstop chemo for carboplatin/Abraxane, very few, I’ve not encountered one patient who can tolerate that at any sustained level.

Benjamin Levy, MD: Given the anemia, the myelosuppression factor—and we’ve had the same issue here, the studies and even the maintenance study will talk about what we’re participating in is a weekly regimen all the way through the induction regimen—are you doing a day-1-and-8 schedule with these patients? Are you doing a weekly or days 1, 8, 15 on a 28-day schedule? How are you using it?

Paul K. Paik, MD: Yeah, so usually we settle on a 2-on-1-off schedule; for patients who might be able to tolerate it, 3 on, 1 off. But there’s that break that needs to be there. And one can argue that if you were to not give the four weeks nonstop per cycle, that there might be some decrement in efficacy. But 46% of the patients on the trial required a dose reduction for Abraxane. You get a sense from the data that yes, not everyone is able to tolerate it and yet we still saw this difference. So I still think there’s something there that is going to be fleshed out more. As you had mentioned, in a patient who’s very symptomatic, where you need to maximize the chance of some substantial degree of shrinkage, I think you’re left with the data—which is the response rate that you’ve got to go with, I think.

Benjamin Levy, MD: Right. You talked a little bit about the lack of head-to-head comparison between some of these regimens. We had some data presented at ASCO last year comparing carboplatin/Abraxane versus a gemcitabine-based regimen, carboplatin/gemcitabine, specifically in the squamous cell population. Can you just talk a little bit about that? And does that change things at all for you?

Paul K. Paik, MD: That’s right. So Yang and colleagues from China had compared carboplatin/Abraxane head-to-head in a randomized phase II with carboplatin and gemcitabine. About 127 patients enrolled in total, so a little north of 50 per arm. And while there was a trend toward improvement in terms of response rate, PFS, OS, this was not significant. The important thing to note is that the way that the regimen was given was also different. It was not carboplatin/Abraxane given in the fashion that was reported in the larger head-to-head trial for carboplatin/Taxol; it was Abraxane given at 135 mg/m2—I think it was day 1, day 8—and then it was carboplatin given at AUC 5. Again, the dose density is different, the dosages were different, so comparing this to what we’re used to in terms of carboplatin/Abraxane and schedule is very difficult to do. So a trend toward improved outcomes, but not significant. That answer against platinum/gemcitabine still has not been addressed as a result.

Benjamin Levy, MD: Yeah. I think that the study, certainly we can glean some insight that there may be a little bit [of] preferential activity with the carboplatin/Abraxane in terms of response rate and PFS. But [it] didn’t seem to approach statistical significance, again showing a response rate though north of 40 in the carboplatin/Abraxane arm. And to me, that again is so important, especially for a patient that we encounter with advanced squamous cell who tends to be very symptomatic.

Paul K. Paik, MD: That’s right.

Benjamin Levy, MD: Ed, any other thoughts?

Edward S. Kim, MD, FACP: I think one of our challenges in doing a head-to-head is we don’t know what the dose or schedule of the control arm is.

Benjamin Levy, MD: That’s right.

Edward S. Kim, MD, FACP: And I have folks who ask me, ‘Well, how do you dose carboplatin and Abraxane because it’s very strict?’ And I say, ‘Well, yeah, I think you can drop a dose.’ And we do a 2-on-1-week off schedule and drop the doses. And they’re like, ‘Oh, well, you shouldn’t do that.’ I’m like, ‘Okay, so what would you propose to use otherwise?’ ‘Well, I use carboplatin and gemcitabine.’ ‘Well, what dose of gemcitabine and schedule do you use of gemcitabine?’ ‘Well, okay, I want to use carboplatin/Taxol.’ ‘What dose and schedule do you use?’ You know, Taxol is dosed at two or three dose levels below what its original intended dose was, and the same with gemcitabine. It’s all art of oncology, art of medicine stuff, and it’s just interesting to hear the rigid adherence to some when there’s this very generalized acceptance to others just because we’re used to it. It’s like that old sweater. You don’t think it looks ratty but everyone else does when you wear it out, but you like it because it’s comfortable. Sometimes it’s time to change.

Paul K. Paik, MD: I think that’s an important point that individualized medicine where medicine is both an art and a science and having that in the balance and walking that tightrope when you’re seeing patients. We talk about individualized or personalized approaches for targeted therapies, but we have to have individualized approaches for chemotherapy regimens and schedules when we see these patients. So I think it’s an excellent point.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Edward S. Kim, MD, FACP:
And so, when you come to nab-paclitaxel and how they’ve most recently done with Mark Socinski’s study, the phase III study, the first thing people said was, ‘Well, it’s still Taxol. You’re just changing the delivery, whether it’s albumin-bound versus chromophore-bound. Why should there be any difference?’ True. So that’s why the FDA said, ‘Well, you can use response rate as an endpoint because overall survival (OS) should be the same?’ I mean, it should be. After 1000 patients—not a small study—a lot of people said that was not resources utilized well, 41%. Remember, carboplatin/Taxol/Avastin was 35% in a more favorable response population.

Benjamin Levy, MD: Right.

Edward S. Kim, MD, FACP: And the subset of squamous was over 400 patients in this 1000-patient study, so astounding to me. Again, based on what we see as far as the presentation of patients and even when choosing drugs right now when we look at even some of the immunotherapies, will response drive our choice in the light of no survival? And I think that’s something that people have not adopted as much as I thought would happen. That’s been surprising to me. The other aspect is that we touched on this over-70 population. You can look at subsets—we always do—and gosh, if any one of us keep looking at these Forest plots, we start getting dizzy. But the survival in the over-70 population that had over 150 patients, more than 10% in this study was almost 20 months versus 10, doubling 20. We’re not talking about 15 versus 10, 12 versus 10, 20. I mean, if I were sitting there as a CEO of a company, I’d be forced to have to test that. Because later if I didn’t, I’d be looked upon as stupid.

Benjamin Levy, MD: Keep in mind, the average age of a lung cancer patient is 71.

Edward S. Kim, MD, FACP: So that’s how I organize those things in my mind. Do I think they’re all good regimens? Yes. Do we have preferences in our system that we’ve listed? Yes. We do list carboplatin and nab-paclitaxel as one of our preferred regimens for squamous patients.

Benjamin Levy, MD: I think that you touched upon an issue with the response rate being 41%, which is so important, especially in a group of patients who can be very symptomatic from their disease. And so we have adopted this, as well, based on a response rate. I don’t know if I can explain biologically the over-70 population and why there’s almost a doubling in overall survival (OS). But other things, the need not to pre-medicate with steroids with this drug and the AE profile, for us has been very helpful. Paul, your thoughts on this drug and using it, gemcitabine-based regimens versus solvent-based paclitaxel.

Paul K. Paik, MD: Right. So outside of the limited scope of the regimens that have been tested head-to-head, I think as Ed was saying, and what you’ve mentioned, we have regimens that are all reasonably effective. If you put them side-by-side and look at the response rate, progression-free survival (PFS), OS data, they’re all very similar except for some outliers like the subset analysis in Mark Socinski’s trial for Abraxane and carboplatin. That’s formally being tested in a more rigorous fashion within this specific population.

The hazard ratio for survival in the over-age-70 population, as Ed had said, it was very large. And while you could argue it’s a subset analysis—the hazard ratio was 0.58, I think—–there may very well be something that’s there. For me, selection, absent the ability to provide a lot of or absent the head-to-head data, comes down to questions of sequence in terms of the overall care for the patient, which I think we’ll get into in a little habit, and also the side-effect profile for these agents. Carboplatin/Abraxane, the data certainly are that its rate of neuropathy in particular are better. But the rates of anemia and thrombocytopenia are substantially higher. They are almost three-fold higher into the 20% range for grade 3/4 anemia and thrombocytopenia. And for my patient population, the patients I see, the anemia can be a bit challenging. In addition, I think the back-to-back, at least the way that it was studied, the sort of nonstop chemo for carboplatin/Abraxane, very few, I’ve not encountered one patient who can tolerate that at any sustained level.

Benjamin Levy, MD: Given the anemia, the myelosuppression factor—and we’ve had the same issue here, the studies and even the maintenance study will talk about what we’re participating in is a weekly regimen all the way through the induction regimen—are you doing a day-1-and-8 schedule with these patients? Are you doing a weekly or days 1, 8, 15 on a 28-day schedule? How are you using it?

Paul K. Paik, MD: Yeah, so usually we settle on a 2-on-1-off schedule; for patients who might be able to tolerate it, 3 on, 1 off. But there’s that break that needs to be there. And one can argue that if you were to not give the four weeks nonstop per cycle, that there might be some decrement in efficacy. But 46% of the patients on the trial required a dose reduction for Abraxane. You get a sense from the data that yes, not everyone is able to tolerate it and yet we still saw this difference. So I still think there’s something there that is going to be fleshed out more. As you had mentioned, in a patient who’s very symptomatic, where you need to maximize the chance of some substantial degree of shrinkage, I think you’re left with the data—which is the response rate that you’ve got to go with, I think.

Benjamin Levy, MD: Right. You talked a little bit about the lack of head-to-head comparison between some of these regimens. We had some data presented at ASCO last year comparing carboplatin/Abraxane versus a gemcitabine-based regimen, carboplatin/gemcitabine, specifically in the squamous cell population. Can you just talk a little bit about that? And does that change things at all for you?

Paul K. Paik, MD: That’s right. So Yang and colleagues from China had compared carboplatin/Abraxane head-to-head in a randomized phase II with carboplatin and gemcitabine. About 127 patients enrolled in total, so a little north of 50 per arm. And while there was a trend toward improvement in terms of response rate, PFS, OS, this was not significant. The important thing to note is that the way that the regimen was given was also different. It was not carboplatin/Abraxane given in the fashion that was reported in the larger head-to-head trial for carboplatin/Taxol; it was Abraxane given at 135 mg/m2—I think it was day 1, day 8—and then it was carboplatin given at AUC 5. Again, the dose density is different, the dosages were different, so comparing this to what we’re used to in terms of carboplatin/Abraxane and schedule is very difficult to do. So a trend toward improved outcomes, but not significant. That answer against platinum/gemcitabine still has not been addressed as a result.

Benjamin Levy, MD: Yeah. I think that the study, certainly we can glean some insight that there may be a little bit [of] preferential activity with the carboplatin/Abraxane in terms of response rate and PFS. But [it] didn’t seem to approach statistical significance, again showing a response rate though north of 40 in the carboplatin/Abraxane arm. And to me, that again is so important, especially for a patient that we encounter with advanced squamous cell who tends to be very symptomatic.

Paul K. Paik, MD: That’s right.

Benjamin Levy, MD: Ed, any other thoughts?

Edward S. Kim, MD, FACP: I think one of our challenges in doing a head-to-head is we don’t know what the dose or schedule of the control arm is.

Benjamin Levy, MD: That’s right.

Edward S. Kim, MD, FACP: And I have folks who ask me, ‘Well, how do you dose carboplatin and Abraxane because it’s very strict?’ And I say, ‘Well, yeah, I think you can drop a dose.’ And we do a 2-on-1-week off schedule and drop the doses. And they’re like, ‘Oh, well, you shouldn’t do that.’ I’m like, ‘Okay, so what would you propose to use otherwise?’ ‘Well, I use carboplatin and gemcitabine.’ ‘Well, what dose of gemcitabine and schedule do you use of gemcitabine?’ ‘Well, okay, I want to use carboplatin/Taxol.’ ‘What dose and schedule do you use?’ You know, Taxol is dosed at two or three dose levels below what its original intended dose was, and the same with gemcitabine. It’s all art of oncology, art of medicine stuff, and it’s just interesting to hear the rigid adherence to some when there’s this very generalized acceptance to others just because we’re used to it. It’s like that old sweater. You don’t think it looks ratty but everyone else does when you wear it out, but you like it because it’s comfortable. Sometimes it’s time to change.

Paul K. Paik, MD: I think that’s an important point that individualized medicine where medicine is both an art and a science and having that in the balance and walking that tightrope when you’re seeing patients. We talk about individualized or personalized approaches for targeted therapies, but we have to have individualized approaches for chemotherapy regimens and schedules when we see these patients. So I think it’s an excellent point.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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