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IMPower150: Implications for the Treatment of NSCLC

Panelists: Jack West, MD, Swedish Cancer Institute; Gregory J. Riely, MD, PhD, Memorial Sloan Kettering Cancer Center; Jared Weiss, MD, UNC School of Medicine; Charu Aggarwal, MD, MPH, University of Pennsylvania Hospital
Published: Monday, Jul 23, 2018



Transcript: 

Jack West, MD: Let’s turn to, if we can, another trial, and we have a bunch of ones to introduce. And one we’ve heard about now for about 6 months is IMpower150. It has been shown in different iterations, and we’ve seen more mature data over time, including overall survival. Charu, can you outline the trial in terms of its design and what it basically means for us?

Charu Aggarwal, MD, MPH: So, IMpower150 was one of several trials that was interesting at ASCO this year because of the overall survival results that were presented. IMpower150 randomized metastatic nonsquamous lung cancer patients with any PD-L1 expression to receive chemotherapy in combination with immunotherapy using atezolizumab, chemotherapy in combination with antiangiogenesis with bevacizumab, or chemotherapy in combination with both. So, in essence, they were comparing quadruplet therapy to 2 triplet arms, and what the authors reported was that the use of quadruplet therapy, namely carboplatin/Taxol/atezolizumab/bevacizumab, was superior in terms of overall survival, when compared to chemotherapy and atezolizumab. So, looking at this data, it’s interesting to see that there is an overall survival advantage for a subset of patients. However, what have really come out of this data are the patients who have EGFR mutations as well as ALK translocation.

Jack West, MD: So, in all these other trials we’ve talked about, the patients with an EGFR mutation or ALK rearrangements have been excluded from these first-line trials because we have a therapy that is generally well tolerated, oral, and has a response rate of 70% to 80%, and there have been some signals that our immunotherapy agents are not as strong for this group. But these patients were allowed, although they had to have received a prior targeted therapy and progressed on that before going on this chemotherapy-naïve, if not first-line, trial.

Jared Weiss, MD: I would say, as background though, that while we have a lot of data that these EGFR and ALK patients don’t have quite the same response rate—probably less than half the response rates of patients without these changes—we do have data from other trials, particularly with atezolizumab, showing that response rate is not zero.

Jack West, MD: Right, true.

Charu Aggarwal, MD, MPH: And I would say that the patients with EGFR mutations and ALK rearrangements formed a small subgroup of this trial.

Jack West, MD: About 13%, I think.

Charu Aggarwal, MD, MPH: Yes, out of 1200 patients, there was a small subset. And the authors concluded that perhaps this could be a reasonable combination therapy. However, I will say that the survival numbers, or the advantage that we are seeing, does not really compare to what we can get with targeted therapy with much less side effects, with much better ease of use for the patient, and much better quality of life. So, while these data are intriguing, I don’t think they are practice changing for those 2 subsets of otherwise well and easy-to-treat lung cancer patients.

Jack West, MD: Well, I would say that I think you can only take them as far as they were tested, which is after initial targeted therapies, and saying that in patients who have received an EGFR inhibitor, ALK inhibitor, or more and then are progressing and candidates for chemotherapy-based treatment, it could be a good way to integrate immunotherapy into that in a setting where historically we’ve seen very disappointing results for immunotherapy as monotherapy in the later-line setting. Greg?

Gregory J. Riely, MD, PhD: Yes, and I think this trial looked at that question of first-line chemotherapy and included people who had had TKIs beforehand. And this addresses the question we face in clinic of that patient who got 2 years on osimertinib and then they’ve progressed. What do we do with that patient? And this trial enrolled that patient, which is not particularly with osimertinib but with prior TKI use. And so, I’m glad they enrolled that patient. I’m glad that we have them in this. I have to say I’m not convinced by the data I’ve seen that this is somehow magically better for that group of patients. It’s not clear that this quadruplet is somehow particularly effective for the EGFR-mutant patient or for an ALK-positive patient. We haven’t seen those curves broken out specifically to look at just EGFR-mutant patients, and we haven’t seen even a table showing characteristics of these patients. Was there an imbalance in EGFR exon 19 deletions? We don’t know.

Jack West, MD: Much more to learn. And, in fact, in the New England Journal of Medicine publication, that was really not even covered.

Gregory J. Riely, MD, PhD: Right.

Jack West, MD: What is notable, Dr. Socinski presented a bit on this amidst a lot of other data at ASCO. And it was interesting that the 4-drug combination with bevacizumab was superior to chemotherapy/bevacizumab, but chemotherapy with atezolizumab without the bevacizumab was not that beneficial. And it raises the question of how much the bevacizumab is contributing. It raises the question of whether this might be a specific regimen that is uniquely beneficial for these patients but still leaves plenty of questions. Another issue was the liver metastases that were called out, and I think a lot of us are suspicious that that is not that specific to this regimen but it was a highlighted subset.

Jared Weiss, MD: To dovetail on your point about regimen choice, if I can talk about something other than immunotherapy for just a moment, I don’t like to give frontline patients paclitaxel. If you look at the EGFR and ALK subgroups, this is a population expected to live a lot longer, and so I prefer to avoid the use of a taxane as part of their first-line regimen because I don’t want them to live with neuropathy for the rest of their lives. Pemetrexed is a very well tolerated agent. I think it’s become beloved in the thoracic community, far in excess of what the toxicity tables represent because of what we’re hearing from patients about how they feel. And it may be a little bit mundane, but I’m pretty attached to using a nontaxane frontline regimen for these nonsquamous patients. And that’s also a limitation…

Jack West, MD: Well, I think that with what is emerging as a range of options of chemotherapy backbones and immunotherapy agents in various combinations, just like we’ve had various doublet combinations available for decades before this, it is fair to just say these will all work reasonably comparably well, while you’ve got to choose one. My view is, at least in the groups that are not EGFR or ALK, you don’t get anything from the IMpower150 regimen except for hair loss and neuropathy compared with KEYNOTE-189 for essentially a very overlapping population.

Transcript Edited for Clarity 
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Transcript: 

Jack West, MD: Let’s turn to, if we can, another trial, and we have a bunch of ones to introduce. And one we’ve heard about now for about 6 months is IMpower150. It has been shown in different iterations, and we’ve seen more mature data over time, including overall survival. Charu, can you outline the trial in terms of its design and what it basically means for us?

Charu Aggarwal, MD, MPH: So, IMpower150 was one of several trials that was interesting at ASCO this year because of the overall survival results that were presented. IMpower150 randomized metastatic nonsquamous lung cancer patients with any PD-L1 expression to receive chemotherapy in combination with immunotherapy using atezolizumab, chemotherapy in combination with antiangiogenesis with bevacizumab, or chemotherapy in combination with both. So, in essence, they were comparing quadruplet therapy to 2 triplet arms, and what the authors reported was that the use of quadruplet therapy, namely carboplatin/Taxol/atezolizumab/bevacizumab, was superior in terms of overall survival, when compared to chemotherapy and atezolizumab. So, looking at this data, it’s interesting to see that there is an overall survival advantage for a subset of patients. However, what have really come out of this data are the patients who have EGFR mutations as well as ALK translocation.

Jack West, MD: So, in all these other trials we’ve talked about, the patients with an EGFR mutation or ALK rearrangements have been excluded from these first-line trials because we have a therapy that is generally well tolerated, oral, and has a response rate of 70% to 80%, and there have been some signals that our immunotherapy agents are not as strong for this group. But these patients were allowed, although they had to have received a prior targeted therapy and progressed on that before going on this chemotherapy-naïve, if not first-line, trial.

Jared Weiss, MD: I would say, as background though, that while we have a lot of data that these EGFR and ALK patients don’t have quite the same response rate—probably less than half the response rates of patients without these changes—we do have data from other trials, particularly with atezolizumab, showing that response rate is not zero.

Jack West, MD: Right, true.

Charu Aggarwal, MD, MPH: And I would say that the patients with EGFR mutations and ALK rearrangements formed a small subgroup of this trial.

Jack West, MD: About 13%, I think.

Charu Aggarwal, MD, MPH: Yes, out of 1200 patients, there was a small subset. And the authors concluded that perhaps this could be a reasonable combination therapy. However, I will say that the survival numbers, or the advantage that we are seeing, does not really compare to what we can get with targeted therapy with much less side effects, with much better ease of use for the patient, and much better quality of life. So, while these data are intriguing, I don’t think they are practice changing for those 2 subsets of otherwise well and easy-to-treat lung cancer patients.

Jack West, MD: Well, I would say that I think you can only take them as far as they were tested, which is after initial targeted therapies, and saying that in patients who have received an EGFR inhibitor, ALK inhibitor, or more and then are progressing and candidates for chemotherapy-based treatment, it could be a good way to integrate immunotherapy into that in a setting where historically we’ve seen very disappointing results for immunotherapy as monotherapy in the later-line setting. Greg?

Gregory J. Riely, MD, PhD: Yes, and I think this trial looked at that question of first-line chemotherapy and included people who had had TKIs beforehand. And this addresses the question we face in clinic of that patient who got 2 years on osimertinib and then they’ve progressed. What do we do with that patient? And this trial enrolled that patient, which is not particularly with osimertinib but with prior TKI use. And so, I’m glad they enrolled that patient. I’m glad that we have them in this. I have to say I’m not convinced by the data I’ve seen that this is somehow magically better for that group of patients. It’s not clear that this quadruplet is somehow particularly effective for the EGFR-mutant patient or for an ALK-positive patient. We haven’t seen those curves broken out specifically to look at just EGFR-mutant patients, and we haven’t seen even a table showing characteristics of these patients. Was there an imbalance in EGFR exon 19 deletions? We don’t know.

Jack West, MD: Much more to learn. And, in fact, in the New England Journal of Medicine publication, that was really not even covered.

Gregory J. Riely, MD, PhD: Right.

Jack West, MD: What is notable, Dr. Socinski presented a bit on this amidst a lot of other data at ASCO. And it was interesting that the 4-drug combination with bevacizumab was superior to chemotherapy/bevacizumab, but chemotherapy with atezolizumab without the bevacizumab was not that beneficial. And it raises the question of how much the bevacizumab is contributing. It raises the question of whether this might be a specific regimen that is uniquely beneficial for these patients but still leaves plenty of questions. Another issue was the liver metastases that were called out, and I think a lot of us are suspicious that that is not that specific to this regimen but it was a highlighted subset.

Jared Weiss, MD: To dovetail on your point about regimen choice, if I can talk about something other than immunotherapy for just a moment, I don’t like to give frontline patients paclitaxel. If you look at the EGFR and ALK subgroups, this is a population expected to live a lot longer, and so I prefer to avoid the use of a taxane as part of their first-line regimen because I don’t want them to live with neuropathy for the rest of their lives. Pemetrexed is a very well tolerated agent. I think it’s become beloved in the thoracic community, far in excess of what the toxicity tables represent because of what we’re hearing from patients about how they feel. And it may be a little bit mundane, but I’m pretty attached to using a nontaxane frontline regimen for these nonsquamous patients. And that’s also a limitation…

Jack West, MD: Well, I think that with what is emerging as a range of options of chemotherapy backbones and immunotherapy agents in various combinations, just like we’ve had various doublet combinations available for decades before this, it is fair to just say these will all work reasonably comparably well, while you’ve got to choose one. My view is, at least in the groups that are not EGFR or ALK, you don’t get anything from the IMpower150 regimen except for hair loss and neuropathy compared with KEYNOTE-189 for essentially a very overlapping population.

Transcript Edited for Clarity 
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