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IMpower131 & KEYNOTE-407/189 Squamous NSCLC Treatments

Panelists: Mark A. Socinski, MD, Florida Hospital Cancer Institute; Maximilian Hochmair, MD, Otto Wagner Spital; Suresh Senan, MRCP, FRCR, PhD, VU University Medical Center; Leora Horn, MD, MSc, FRCPC, Vanderbilt University Medical Center; Thomas E. Stinchcombe, MD, Duke University Health System
Published: Wednesday, Nov 21, 2018



Transcript: 

Mark A. Socinski, MD:
We have a couple squamous trials: the KEYNOTE-407 and IMpower131 trials. Could you summarize that data for us?

Maximilian Hochmair, MD: KEYNOTE-407 was traditional chemotherapy/carboplatin/paclitaxel in combination with plus/minus pembrolizumab [Keytruda]. We saw in all patients an independent PD-L1 [programmed death-ligand 1] staining and a better PFS [progression-free survival] and OS [overall survival] That means, for me, that this is the new standard of care, which Dr. Luis Paz-Ares will present. The data showed us that this is the new standard of care in terms of OS, PFS, and remission rate. There will also be a discussion on what we can do for the patients with a PD-L1 staining greater than 50%. From my point of view, the OS is 0.63 in KEYNOTE-024, where there are mono- and combination therapies. Patients who have a higher PD-L1 staining, I will administer monotherapy.

Mark A. Socinski, MD: I agree. In the IMpower131 trial, we saw that there were the coprimary endpoints of PFS and OS. PFS was positive, and the OS was not.

Maximilian Hochmair, MD: I prefer the KEYNOTE-407 in this situation, but we have to wait for the OS update from the IMpower131 study, after which we can make better decisions.

Mark A. Socinski, MD: It’s interesting to me that the control arms, if you look at the 2 studies, were both squamous. If you look at the KEYNOTE-407, the median survival [MS] of the control arm was 11 months. If you look at IMpower131, the median survival of the control arm was 14 months; it’s a 3-month difference in those, and so you start to wonder about patient selection. Although this is surprising to me, I wouldn’t have expected that much of a difference in the control arm. In the KEYNOTE-407 study, 60% of the patients received carboplatin/nab-paclitaxel; I don’t think it’s really that different, to be honest with you. Still, the better your control arm does, the more difficult it is for the investigational arm to show a difference.

Thomas E. Stinchcombe, MD: The KEYNOTE-407 sets the standard, and I’ve sort of adopted this. For the United States, it’s in the NCCN [National Comprehensive Cancer Network] Guidelines, so it’s an option for us to use. Until the IMpower131 trial matures and provides survival benefit data, this is the preferred regimen.

Mark A. Socinski, MD: Are both included in the ESMO [European Society of Medical Oncology] Guidelines?

Maximilian Hochmair, MD: Yes.

Mark A. Socinski, MD: From both trials.

Maximilian Hochmair, MD: But I want to point out that squamous patients have more comorbidities compared to the nonsquamous. I won’t use much in the KEYNOTE-189; this is a regiment we will use in most patients. Patients with squamous are more ill, and we have to decide which patient can fit into the real trial.

Mark A. Socinski, MD: That’s a good point. The squamous population tends to be older and possess more comorbidities. There are often more performance status issues with these patients. Remember, everything we’ve talked about thus far has been ECOG [Eastern Cooperative Oncology Group] performance status 0 or 1. I do think, too, that the monotherapy in the high expressers is very attractive in patients with squamous.

But getting back to the question we had regarding nonsquamous, and getting back to the KEYNOTE-042, is there a temptation in patients with squamous, where you might have a sicker population, to use monotherapy in the less-than-50% patients? Is it really a 3-drug approach?

Leora Horn, MD, MSc, FRCPC: If they can tolerate the 3-drug approach, that is my preferred regiment. I find that the squamous regiment is easier than the KEYNOTE-189 regiment because it’s 4 cycles of chemotherapy and then just maintenance pembrolizumab. It’s hard to treat with maintenance pemetrexed and pembrolizumab for 2 years: Patients get tired, so half the time you end up dropping a drug, whereas even if you could get 2 cycles of the platinum doublet with the pembrolizumab, they can’t get 3 or 4 drugs. It’s a reasonable approach.

Mark A. Socinski, MD: In the maintenance part of KEYNOTE-189, do you have a preferred drug to drop in the maintenance setting?

Leora Horn, MD, MSc, FRCPC: In men, maybe pemetrexed, but for your female patients, I don’t like dropping it. They don’t do as well on the I-O [immunotherapy] drugs. If you can encourage them to continue, that is ideal.

Maximilian Hochmair, MD: In the KEYNOTE-189, in the beginning, I was scared from the combination of both drugs—that chemotherapy and immunotherapy create toxicities—but then we learned how to handle the situation. It is safe. My problem was when you have a creatinine elevation. We didn’t know if it was from nephritis or as a side effect of pemetrexed. This was something we had to become accustomed to. We also have to puncture the kidney sometimes.

Mark A. Socinski, MD: I’ll summarize the discussion here. We have a consensus that the PD-L1 staining is a standard of care, that every patient with stage IV NSCLC should have PD-L1 determined at the time of initial diagnosis and that if you are a high-expresser, it’s defined by the KEYNOTE-024 benchmark of greater than 50%. We all agree that monotherapy with pembrolizumab is the standard of care, although there are certain patients for whom you would use triplet therapy in the population. Less than 50% negative, we’re all committed to 3-drug regimens. There is a little bit of enthusiasm for adding bevacizumab based on the IMpower150, but probably only a minority of patients would be receiving that. We’ll come back to that when we talk about the EGFR-mutant population.


Transcript Edited for Clarity
 

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Transcript: 

Mark A. Socinski, MD:
We have a couple squamous trials: the KEYNOTE-407 and IMpower131 trials. Could you summarize that data for us?

Maximilian Hochmair, MD: KEYNOTE-407 was traditional chemotherapy/carboplatin/paclitaxel in combination with plus/minus pembrolizumab [Keytruda]. We saw in all patients an independent PD-L1 [programmed death-ligand 1] staining and a better PFS [progression-free survival] and OS [overall survival] That means, for me, that this is the new standard of care, which Dr. Luis Paz-Ares will present. The data showed us that this is the new standard of care in terms of OS, PFS, and remission rate. There will also be a discussion on what we can do for the patients with a PD-L1 staining greater than 50%. From my point of view, the OS is 0.63 in KEYNOTE-024, where there are mono- and combination therapies. Patients who have a higher PD-L1 staining, I will administer monotherapy.

Mark A. Socinski, MD: I agree. In the IMpower131 trial, we saw that there were the coprimary endpoints of PFS and OS. PFS was positive, and the OS was not.

Maximilian Hochmair, MD: I prefer the KEYNOTE-407 in this situation, but we have to wait for the OS update from the IMpower131 study, after which we can make better decisions.

Mark A. Socinski, MD: It’s interesting to me that the control arms, if you look at the 2 studies, were both squamous. If you look at the KEYNOTE-407, the median survival [MS] of the control arm was 11 months. If you look at IMpower131, the median survival of the control arm was 14 months; it’s a 3-month difference in those, and so you start to wonder about patient selection. Although this is surprising to me, I wouldn’t have expected that much of a difference in the control arm. In the KEYNOTE-407 study, 60% of the patients received carboplatin/nab-paclitaxel; I don’t think it’s really that different, to be honest with you. Still, the better your control arm does, the more difficult it is for the investigational arm to show a difference.

Thomas E. Stinchcombe, MD: The KEYNOTE-407 sets the standard, and I’ve sort of adopted this. For the United States, it’s in the NCCN [National Comprehensive Cancer Network] Guidelines, so it’s an option for us to use. Until the IMpower131 trial matures and provides survival benefit data, this is the preferred regimen.

Mark A. Socinski, MD: Are both included in the ESMO [European Society of Medical Oncology] Guidelines?

Maximilian Hochmair, MD: Yes.

Mark A. Socinski, MD: From both trials.

Maximilian Hochmair, MD: But I want to point out that squamous patients have more comorbidities compared to the nonsquamous. I won’t use much in the KEYNOTE-189; this is a regiment we will use in most patients. Patients with squamous are more ill, and we have to decide which patient can fit into the real trial.

Mark A. Socinski, MD: That’s a good point. The squamous population tends to be older and possess more comorbidities. There are often more performance status issues with these patients. Remember, everything we’ve talked about thus far has been ECOG [Eastern Cooperative Oncology Group] performance status 0 or 1. I do think, too, that the monotherapy in the high expressers is very attractive in patients with squamous.

But getting back to the question we had regarding nonsquamous, and getting back to the KEYNOTE-042, is there a temptation in patients with squamous, where you might have a sicker population, to use monotherapy in the less-than-50% patients? Is it really a 3-drug approach?

Leora Horn, MD, MSc, FRCPC: If they can tolerate the 3-drug approach, that is my preferred regiment. I find that the squamous regiment is easier than the KEYNOTE-189 regiment because it’s 4 cycles of chemotherapy and then just maintenance pembrolizumab. It’s hard to treat with maintenance pemetrexed and pembrolizumab for 2 years: Patients get tired, so half the time you end up dropping a drug, whereas even if you could get 2 cycles of the platinum doublet with the pembrolizumab, they can’t get 3 or 4 drugs. It’s a reasonable approach.

Mark A. Socinski, MD: In the maintenance part of KEYNOTE-189, do you have a preferred drug to drop in the maintenance setting?

Leora Horn, MD, MSc, FRCPC: In men, maybe pemetrexed, but for your female patients, I don’t like dropping it. They don’t do as well on the I-O [immunotherapy] drugs. If you can encourage them to continue, that is ideal.

Maximilian Hochmair, MD: In the KEYNOTE-189, in the beginning, I was scared from the combination of both drugs—that chemotherapy and immunotherapy create toxicities—but then we learned how to handle the situation. It is safe. My problem was when you have a creatinine elevation. We didn’t know if it was from nephritis or as a side effect of pemetrexed. This was something we had to become accustomed to. We also have to puncture the kidney sometimes.

Mark A. Socinski, MD: I’ll summarize the discussion here. We have a consensus that the PD-L1 staining is a standard of care, that every patient with stage IV NSCLC should have PD-L1 determined at the time of initial diagnosis and that if you are a high-expresser, it’s defined by the KEYNOTE-024 benchmark of greater than 50%. We all agree that monotherapy with pembrolizumab is the standard of care, although there are certain patients for whom you would use triplet therapy in the population. Less than 50% negative, we’re all committed to 3-drug regimens. There is a little bit of enthusiasm for adding bevacizumab based on the IMpower150, but probably only a minority of patients would be receiving that. We’ll come back to that when we talk about the EGFR-mutant population.


Transcript Edited for Clarity
 
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