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Pemetrexed for Advanced NSCLC

Panelists: Mark A. Socinski, MD, AdventHealth Cancer Institute; Paul K. Paik, MD, Memorial Sloan Kettering Cancer Center; Kristin Higgins, MD, Emory Healthcare; Corey J. Langer, MD, Hospital of the University of Pennsylvania; Heather A. Wakelee, MD, Stanford University Medical Center; Ticiana A. Leal, MD, University of Wisconsin School of Medicine and Public Health
Published: Wednesday, Jul 24, 2019



Transcript: 

Mark A. Socinski, MD: Paul, your thoughts on the IMpower150 trial in the subset of the EGFR population?

Paul K. Paik, MD: It’s certainly a compelling set of data, particularly in the space that we’re navigating now where most patients are in the post-osimertinib space and we don’t have that kind of reliable next thing as we did when patients were in the post-erlotinib first-line setting. It’s compelling. I think for me, the adoption has been less robust, in part because of the clinical trial portfolio that we have in that space for molecular testing at the time of resistance and all of the work that’s going into that. There is a subset of patients for whom I do worry about a couple of things. One of them has to do with the clonal population that’s still being suppressed by osimertinib. The osimertinib, until that first response scan on chemotherapy to prevent that flare from occurring, Memorial Sloan Kettering Cancer Center would be sort of proponents and believers of that. And with the toxicity data behind it, as Heather had mentioned, behind osimertinib and immunotherapy, that’s a big issue and reservation in terms of its adoption. But I do think that it is one of the more compelling things that we’ve seen in that space.

Corey J. Langer, MD: I think the toxicity data are a bit more pertinent for a checkpoint inhibitor followed by the TKI [tyrosine kinase inhibitor], and a little bit less worrisome. Correct me if I’m wrong, but at least 1 trial looked at immune-related toxicities, and I think it included your shop? It was a number of different institutions. The sequence has some bearing on toxicity.

Paul K. Paik, MD: Right, this is in reference to the situation where they were doing osimertinib combined with….

Corey J. Langer, MD: Oh, combined.

Paul K. Paik, MD: Right. You can’t allide osimertinib with atezolizumab, for example, which is an issue, within the context of IMpower150.

Mark A. Socinski, MD: So we’ve talked a lot about KEYNOTE-189. We would all agree it’s practice changing. It’s an impressively positive trial. We don’t talk much about IMpower132, which was essentially the same trial with atezolizumab. And so in my mind, we have 1 positive trial and 1 negative trial. How does the panel feel about that? Do we dismiss IMpower132, or do we say, “Hmm, maybe KEYNOTE-189 is really better than it really is, and maybe IMpower132 may not be as good. Maybe the truth is somewhere in the middle.”

Heather A. Wakelee, MD: I think the question of whether one of these drugs is not like the others is not an easy question to answer. We may never have a head-to-head study. I think we have to be very cautious in trying to make those cross-trial comparisons. That being said, when I’m combining immune therapy with chemotherapy, when it’s carboplatin/pemetrexed, I’m giving pembrolizumab, right? And if I’m giving an IMpower150-type regimen, it’s atezolizumab. And if I’m giving nab-paclitaxel/carboplatin, and the AN agent, it’s pembrolizumab. I’ve done that in a few squamous patients.

Corey J. Langer, MD: But if you had a nonsquamous patient who, for whatever reason, isn’t a candidate for pemetrexed, who perhaps has some degree of renal insufficiency, we do have phase III data with atezolizumab that’s positive.

Heather A. Wakelee, MD: Yes, and then I would do that also.

Mark A. Socinski, MD: IMpower130.

Heather A. Wakelee, MD:  Yes, IMpower130. I will do that in that setting also.

Mark A. Socinski, MD: Corey, what percentage of your patients are not eligible for pemetrexed?

Corey J. Langer, MD: For pemetrexed?

Mark A. Socinski, MD: Yes.

Corey J. Langer, MD: I’d guestimate 15% to 20%. We have to be intellectually honest. Given an older patient who is 75, 80 years of age, and is female, who weighs 100 pounds or 110 pounds and has a normal creatinine at 1.2, 1.3, I can guarantee their creatinine clearance is below 45. If you go back to the package insert for pemetrexed, it’s 45 or higher. Not that you can’t give it. It’s virtually that all of the clinical trials that tested it mandated that minimum glomerular filtration rate, as opposed to EGFR. And the pharmacokinetics are very unpredictable and very variable below 45. If you run into trouble with this drug, it’s in that population. As much as I’d rather not cause hair loss or neuropathy, a taxane, particularly a taxane that’s given weekly, is probably a bit safer. And we have phase III data.


Transcript Edited for Clarity

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Transcript: 

Mark A. Socinski, MD: Paul, your thoughts on the IMpower150 trial in the subset of the EGFR population?

Paul K. Paik, MD: It’s certainly a compelling set of data, particularly in the space that we’re navigating now where most patients are in the post-osimertinib space and we don’t have that kind of reliable next thing as we did when patients were in the post-erlotinib first-line setting. It’s compelling. I think for me, the adoption has been less robust, in part because of the clinical trial portfolio that we have in that space for molecular testing at the time of resistance and all of the work that’s going into that. There is a subset of patients for whom I do worry about a couple of things. One of them has to do with the clonal population that’s still being suppressed by osimertinib. The osimertinib, until that first response scan on chemotherapy to prevent that flare from occurring, Memorial Sloan Kettering Cancer Center would be sort of proponents and believers of that. And with the toxicity data behind it, as Heather had mentioned, behind osimertinib and immunotherapy, that’s a big issue and reservation in terms of its adoption. But I do think that it is one of the more compelling things that we’ve seen in that space.

Corey J. Langer, MD: I think the toxicity data are a bit more pertinent for a checkpoint inhibitor followed by the TKI [tyrosine kinase inhibitor], and a little bit less worrisome. Correct me if I’m wrong, but at least 1 trial looked at immune-related toxicities, and I think it included your shop? It was a number of different institutions. The sequence has some bearing on toxicity.

Paul K. Paik, MD: Right, this is in reference to the situation where they were doing osimertinib combined with….

Corey J. Langer, MD: Oh, combined.

Paul K. Paik, MD: Right. You can’t allide osimertinib with atezolizumab, for example, which is an issue, within the context of IMpower150.

Mark A. Socinski, MD: So we’ve talked a lot about KEYNOTE-189. We would all agree it’s practice changing. It’s an impressively positive trial. We don’t talk much about IMpower132, which was essentially the same trial with atezolizumab. And so in my mind, we have 1 positive trial and 1 negative trial. How does the panel feel about that? Do we dismiss IMpower132, or do we say, “Hmm, maybe KEYNOTE-189 is really better than it really is, and maybe IMpower132 may not be as good. Maybe the truth is somewhere in the middle.”

Heather A. Wakelee, MD: I think the question of whether one of these drugs is not like the others is not an easy question to answer. We may never have a head-to-head study. I think we have to be very cautious in trying to make those cross-trial comparisons. That being said, when I’m combining immune therapy with chemotherapy, when it’s carboplatin/pemetrexed, I’m giving pembrolizumab, right? And if I’m giving an IMpower150-type regimen, it’s atezolizumab. And if I’m giving nab-paclitaxel/carboplatin, and the AN agent, it’s pembrolizumab. I’ve done that in a few squamous patients.

Corey J. Langer, MD: But if you had a nonsquamous patient who, for whatever reason, isn’t a candidate for pemetrexed, who perhaps has some degree of renal insufficiency, we do have phase III data with atezolizumab that’s positive.

Heather A. Wakelee, MD: Yes, and then I would do that also.

Mark A. Socinski, MD: IMpower130.

Heather A. Wakelee, MD:  Yes, IMpower130. I will do that in that setting also.

Mark A. Socinski, MD: Corey, what percentage of your patients are not eligible for pemetrexed?

Corey J. Langer, MD: For pemetrexed?

Mark A. Socinski, MD: Yes.

Corey J. Langer, MD: I’d guestimate 15% to 20%. We have to be intellectually honest. Given an older patient who is 75, 80 years of age, and is female, who weighs 100 pounds or 110 pounds and has a normal creatinine at 1.2, 1.3, I can guarantee their creatinine clearance is below 45. If you go back to the package insert for pemetrexed, it’s 45 or higher. Not that you can’t give it. It’s virtually that all of the clinical trials that tested it mandated that minimum glomerular filtration rate, as opposed to EGFR. And the pharmacokinetics are very unpredictable and very variable below 45. If you run into trouble with this drug, it’s in that population. As much as I’d rather not cause hair loss or neuropathy, a taxane, particularly a taxane that’s given weekly, is probably a bit safer. And we have phase III data.


Transcript Edited for Clarity
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