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Ongoing Research in EGFR+ NSCLC

Panelists: Benjamin P. Levy, MD, Johns Hopkins Sidney Kimmel Cancer Center; Hossein Borghaei, DO, MS, Fox Chase Cancer Center; Roy S. Herbst, MD, PhD, Yale Cancer Center; Suresh S. Ramalingam, MD, Emory University School of Medicine; Naiyer A. Rizvi, MD, Columbia University Medical Center; Thomas E. Stinchcombe, MD, Duke Cancer Institute
Published: Wednesday, Feb 28, 2018



Transcript: 

Benjamin P. Levy, MD: Let me ask one practical consideration that has come up in our tumor board at Hopkins several times recently. There’s a patient who’s on a first- or second-generation TKI, and has been before the osimertinib data came out, who is progressing, and then the T790M is negative. And there has been some of us who have said, “Well, let’s go ahead and just give osimertinib because it’s a frontline approval anyway and it’s a good drug.” The response rate in T790M-negative patients, to my knowledge, of osimertinib is around 25%. Do people feel compelled to use osimertinib in that setting in a T790-negative patient given it’s going to have a first-line approval, or is this a disappointment for a clinical trial or chemotherapy?

Suresh S. Ramalingam, MD: This is a setting where you would give chemotherapy and then perhaps come back to osimertinib. You take advantage of not only giving a more potent EGFR inhibitor but also the de-synthesizing effect after they’ve been off an EGFR TKI for a while. So, I would say going to chemotherapy in that situation makes sense. Now, if the patient is progressing in the brain, then that might be a situation where you may bring in osimertinib.

Roy S. Herbst, MD, PhD: Yes, we nurse these patients through progression. I would tolerate a good amount of progression in someone before I pull the switch for something else. So, I like that idea. It’s growing a little bit in the brain, the systemic disease is growing just a little bit as well. Switch to osimertinib, see what happens, but then you’re looking for incredible…

Benjamin P. Levy, MD: Even if they’re T790M-negative?

Roy S. Herbst, MD, PhD: Even if they’re T790M-negative.

Hossein Borghaei, DO, MS: Yes, I remember in the old days when we only had erlotinib. There were a bunch of patients on erlotinib; you would either radiate them when they were progressing or you drop the erlotinib, do chemotherapy, and go back to erlotinib. But you used to do this intercalating of chemotherapy with targeted therapy and it worked for a while, but not until we had better options.

Benjamin P. Levy, MD: So, we have another drug that has been looked at recently, dacomitinib. This was presented last year at ASCO. This drug has been around for a while. We participated in the phase I effort many years ago, but there is another phase III trial in an EGFR-mutant patient population comparing dacomitinib with a first-generation TKI. Tom, do you want to talk about that data and the clinical relevance of it?

Thomas E. Stinchcombe, MD: Sure. This was in EGFR mutation-selective patients and compared dacomitinib to gefitinib. And the trial, very similar to some other trials, showed a similar response rate. The progression-free survival was statistically significantly longer with dacomitinib. I think the challenge was that there were more EGFR-related toxicities with the irreversible EGFR binding, particularly rash and diarrhea. About two-thirds of patients needed dose reduction on the dacomitinib. So, I think this confirms our concept that maybe more potent EGFR inhibition is a way to improve efficacy. But I think in this specific case, the problem is the EGFR receptors on the normal tissues, this is where osimertinib was such a big advance and it spares those at this point.

Benjamin P. Levy, MD: Yes. And if you look at the PFS curves and how they diverge in the dacomitinib trial, they diverge around 6 months, whereas in the osimertinib trial they diverged very early on. So, I think there are some differences here in these drugs. Do we think this will get approval for first-line therapy, this drug?

Hossein Borghaei, DO, MS: I’m not a good person to predict that. I think the osimertinib data are a lot stronger.

Naiyer A. Rizvi, MD: It may get approved. It doesn’t mean that it’s going to get used.

Benjamin P. Levy, MD: Right.

Thomas E. Stinchcombe, MD: I think if both were approved, I would choose osimertinib.

Hossein Borghaei, DO, MS: Absolutely.

Roy S. Herbst, MD, PhD: I think the data-positive trial should be considered for approval. But, again, will we use it when we have something that looks equally effective or more effective and less toxic?

Benjamin P. Levy, MD: So, let’s move on to the last part of this section, which is, we clearly defined the use of EGFR TKIs in advanced-stage setting. We’re looking at them in earlier-stages disease, however. We’ve had some data presented last year, I think they’ve been published now, looking at adjuvant TKI for resected EGFR-mutant lung cancer. Roy, can you talk to us a little bit about this data, this Chinese study, looking at the role of this approach?

Roy S. Herbst, MD, PhD: Right. The Zhong study from Lancet. Well, it makes sense that if someone’s EGFR-mutated after doing your best with local therapy, combined modality therapy, to move on and give them an EGFR inhibitor. There were a number of trials over the years. There was the RADIANT trial to look at erlotinib versus placebo. That did not show any major benefit.

This trial is quite interesting from China. Of course, there are many more patients there who have an EGFR mutation. They took patients with stage 3 disease and they randomized them to either chemotherapy or to an EGFR inhibitor. And the EGFR inhibitor did have an improvement in PFS, hazard ratio of 0.6. There were a couple of issues with this trial. Where’s the radiation? Normally in many of these patients, we would have given chemoradiation, too; if you were to use the EGFR inhibitor, you probably would have wanted to use a chemotherapy first. So, it’s not a really fair comparison.

With that said, I think that it does show that there is activity in this type of population. But what was notable in that trial was that the activity was lost after the drug was stopped. So, it was only for the period the drug was on, and there was no survival benefit. That said, I think with the newer generation drugs…

Suresh S. Ramalingam, MD: Immature survival benefit at this point.

Roy S. Herbst, MD, PhD: Right. Immature at this point. There is the ALCHEMIST trial that’s looking at erlotinib versus placebo, massive effort of the Cooperator Groups that we all support. I think that trial, hopefully, will better answer the question of an EGFR inhibitor versus placebo in the patients who’ve had the maximum adjuvant therapy for early-stage disease. Then there’s the ADAURA trial. And the thing about the ADAURA trial, which makes it relevant, we weren’t accruing to the ADAURA trial…

Benjamin P. Levy, MD: It’s adjuvant osimertinib.

Roy S. Herbst, MD, PhD: Yes, it’s adjuvant osimertinib, and of course, we were focusing on the ALCHEMIST trial. But with osimertinib with these data, I think it is important to ask this question—this trial will probably accrue mostly in Asia, but this trial will answer the question—Does the new generation EGFR inhibitor, perhaps less toxic, more effective, have a benefit? So, we do need to figure out how to get these EGFR inhibitors into earlier disease, but as of now, there is no standard of practice.

Benjamin P. Levy, MD: Is there anyone on the panel where you’ve used these drugs in the adjuvant setting, off of a trial, or had to convince patients to temper the enthusiasm that they don’t need it? I’ve had this when I was in New York, patients coming in saying, “I have an EGFR mutation, I want the target of therapy.” Is part of our role to push back a little bit and at least put them on trial, not do this off of a trial?

Roy S. Herbst, MD, PhD: I’ve always tried to do it on trial, especially if you’ve got the trial running, because they’d be offering the therapy off trial. It’s not really...

Hossein Borghaei, DO, MS: Sorry. There’s one other point we should discuss. Most of these studies have given the drug, the TKI, for a limited time. And invariably, when you look at the data, once the TKI stopped, the progression matches the control. So, the question of duration of therapy becomes important. Are we looking at the analogous case, which would be like the breast cancer patients who had hormone-positive tumors? First it was 5 years, now it’s 10 years, and now there might be additional studies saying maybe even longer. So, I think those kinds of studies we haven’t even started looking at whether we should continue the TKI indefinitely in some of these patients. I think we do have a lot of work to do in this area.

Benjamin P. Levy, MD: Yes, a lot of unanswered questions.

Thomas E. Stinchcombe, MD: I think the most common question I get from patients is, “I’ve got an EGFR mutation, can I skip chemotherapy in the adjuvant setting?”

Benjamin P. Levy, MD: Right.

Thomas E. Stinchcombe, MD: And I’ve been fairly firm that they need the adjuvant chemotherapy, that’s the thing that’s improving the survival benefit. But that’s a relatively common question.

Naiyer A. Rizvi, MD: Also, it’s hard to give these drugs adjuvantly. In the advanced-stage setting where you see tumors shrinking and it’s working, it’s keeping things in check, and patients are willing to tolerate the toxicities more, to give it after their resection, for them to take erlotinib at 150 mg a day continuously for 2 years, is pretty tough.

Roy S. Herbst, MD, PhD: They’re going to have some rash and diarrhea in many cases.

Naiyer A. Rizvi, MD: Fatigue, hair loss.

Benjamin P. Levy, MD: Some financial toxicity potentially as well.

Thomas E. Stinchcombe, MD: Like Naiyer said, you don’t get the symptom improvement that you do in the metastatic setting just to inspire the patient.

Transcript Edited for Clarity 

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Transcript: 

Benjamin P. Levy, MD: Let me ask one practical consideration that has come up in our tumor board at Hopkins several times recently. There’s a patient who’s on a first- or second-generation TKI, and has been before the osimertinib data came out, who is progressing, and then the T790M is negative. And there has been some of us who have said, “Well, let’s go ahead and just give osimertinib because it’s a frontline approval anyway and it’s a good drug.” The response rate in T790M-negative patients, to my knowledge, of osimertinib is around 25%. Do people feel compelled to use osimertinib in that setting in a T790-negative patient given it’s going to have a first-line approval, or is this a disappointment for a clinical trial or chemotherapy?

Suresh S. Ramalingam, MD: This is a setting where you would give chemotherapy and then perhaps come back to osimertinib. You take advantage of not only giving a more potent EGFR inhibitor but also the de-synthesizing effect after they’ve been off an EGFR TKI for a while. So, I would say going to chemotherapy in that situation makes sense. Now, if the patient is progressing in the brain, then that might be a situation where you may bring in osimertinib.

Roy S. Herbst, MD, PhD: Yes, we nurse these patients through progression. I would tolerate a good amount of progression in someone before I pull the switch for something else. So, I like that idea. It’s growing a little bit in the brain, the systemic disease is growing just a little bit as well. Switch to osimertinib, see what happens, but then you’re looking for incredible…

Benjamin P. Levy, MD: Even if they’re T790M-negative?

Roy S. Herbst, MD, PhD: Even if they’re T790M-negative.

Hossein Borghaei, DO, MS: Yes, I remember in the old days when we only had erlotinib. There were a bunch of patients on erlotinib; you would either radiate them when they were progressing or you drop the erlotinib, do chemotherapy, and go back to erlotinib. But you used to do this intercalating of chemotherapy with targeted therapy and it worked for a while, but not until we had better options.

Benjamin P. Levy, MD: So, we have another drug that has been looked at recently, dacomitinib. This was presented last year at ASCO. This drug has been around for a while. We participated in the phase I effort many years ago, but there is another phase III trial in an EGFR-mutant patient population comparing dacomitinib with a first-generation TKI. Tom, do you want to talk about that data and the clinical relevance of it?

Thomas E. Stinchcombe, MD: Sure. This was in EGFR mutation-selective patients and compared dacomitinib to gefitinib. And the trial, very similar to some other trials, showed a similar response rate. The progression-free survival was statistically significantly longer with dacomitinib. I think the challenge was that there were more EGFR-related toxicities with the irreversible EGFR binding, particularly rash and diarrhea. About two-thirds of patients needed dose reduction on the dacomitinib. So, I think this confirms our concept that maybe more potent EGFR inhibition is a way to improve efficacy. But I think in this specific case, the problem is the EGFR receptors on the normal tissues, this is where osimertinib was such a big advance and it spares those at this point.

Benjamin P. Levy, MD: Yes. And if you look at the PFS curves and how they diverge in the dacomitinib trial, they diverge around 6 months, whereas in the osimertinib trial they diverged very early on. So, I think there are some differences here in these drugs. Do we think this will get approval for first-line therapy, this drug?

Hossein Borghaei, DO, MS: I’m not a good person to predict that. I think the osimertinib data are a lot stronger.

Naiyer A. Rizvi, MD: It may get approved. It doesn’t mean that it’s going to get used.

Benjamin P. Levy, MD: Right.

Thomas E. Stinchcombe, MD: I think if both were approved, I would choose osimertinib.

Hossein Borghaei, DO, MS: Absolutely.

Roy S. Herbst, MD, PhD: I think the data-positive trial should be considered for approval. But, again, will we use it when we have something that looks equally effective or more effective and less toxic?

Benjamin P. Levy, MD: So, let’s move on to the last part of this section, which is, we clearly defined the use of EGFR TKIs in advanced-stage setting. We’re looking at them in earlier-stages disease, however. We’ve had some data presented last year, I think they’ve been published now, looking at adjuvant TKI for resected EGFR-mutant lung cancer. Roy, can you talk to us a little bit about this data, this Chinese study, looking at the role of this approach?

Roy S. Herbst, MD, PhD: Right. The Zhong study from Lancet. Well, it makes sense that if someone’s EGFR-mutated after doing your best with local therapy, combined modality therapy, to move on and give them an EGFR inhibitor. There were a number of trials over the years. There was the RADIANT trial to look at erlotinib versus placebo. That did not show any major benefit.

This trial is quite interesting from China. Of course, there are many more patients there who have an EGFR mutation. They took patients with stage 3 disease and they randomized them to either chemotherapy or to an EGFR inhibitor. And the EGFR inhibitor did have an improvement in PFS, hazard ratio of 0.6. There were a couple of issues with this trial. Where’s the radiation? Normally in many of these patients, we would have given chemoradiation, too; if you were to use the EGFR inhibitor, you probably would have wanted to use a chemotherapy first. So, it’s not a really fair comparison.

With that said, I think that it does show that there is activity in this type of population. But what was notable in that trial was that the activity was lost after the drug was stopped. So, it was only for the period the drug was on, and there was no survival benefit. That said, I think with the newer generation drugs…

Suresh S. Ramalingam, MD: Immature survival benefit at this point.

Roy S. Herbst, MD, PhD: Right. Immature at this point. There is the ALCHEMIST trial that’s looking at erlotinib versus placebo, massive effort of the Cooperator Groups that we all support. I think that trial, hopefully, will better answer the question of an EGFR inhibitor versus placebo in the patients who’ve had the maximum adjuvant therapy for early-stage disease. Then there’s the ADAURA trial. And the thing about the ADAURA trial, which makes it relevant, we weren’t accruing to the ADAURA trial…

Benjamin P. Levy, MD: It’s adjuvant osimertinib.

Roy S. Herbst, MD, PhD: Yes, it’s adjuvant osimertinib, and of course, we were focusing on the ALCHEMIST trial. But with osimertinib with these data, I think it is important to ask this question—this trial will probably accrue mostly in Asia, but this trial will answer the question—Does the new generation EGFR inhibitor, perhaps less toxic, more effective, have a benefit? So, we do need to figure out how to get these EGFR inhibitors into earlier disease, but as of now, there is no standard of practice.

Benjamin P. Levy, MD: Is there anyone on the panel where you’ve used these drugs in the adjuvant setting, off of a trial, or had to convince patients to temper the enthusiasm that they don’t need it? I’ve had this when I was in New York, patients coming in saying, “I have an EGFR mutation, I want the target of therapy.” Is part of our role to push back a little bit and at least put them on trial, not do this off of a trial?

Roy S. Herbst, MD, PhD: I’ve always tried to do it on trial, especially if you’ve got the trial running, because they’d be offering the therapy off trial. It’s not really...

Hossein Borghaei, DO, MS: Sorry. There’s one other point we should discuss. Most of these studies have given the drug, the TKI, for a limited time. And invariably, when you look at the data, once the TKI stopped, the progression matches the control. So, the question of duration of therapy becomes important. Are we looking at the analogous case, which would be like the breast cancer patients who had hormone-positive tumors? First it was 5 years, now it’s 10 years, and now there might be additional studies saying maybe even longer. So, I think those kinds of studies we haven’t even started looking at whether we should continue the TKI indefinitely in some of these patients. I think we do have a lot of work to do in this area.

Benjamin P. Levy, MD: Yes, a lot of unanswered questions.

Thomas E. Stinchcombe, MD: I think the most common question I get from patients is, “I’ve got an EGFR mutation, can I skip chemotherapy in the adjuvant setting?”

Benjamin P. Levy, MD: Right.

Thomas E. Stinchcombe, MD: And I’ve been fairly firm that they need the adjuvant chemotherapy, that’s the thing that’s improving the survival benefit. But that’s a relatively common question.

Naiyer A. Rizvi, MD: Also, it’s hard to give these drugs adjuvantly. In the advanced-stage setting where you see tumors shrinking and it’s working, it’s keeping things in check, and patients are willing to tolerate the toxicities more, to give it after their resection, for them to take erlotinib at 150 mg a day continuously for 2 years, is pretty tough.

Roy S. Herbst, MD, PhD: They’re going to have some rash and diarrhea in many cases.

Naiyer A. Rizvi, MD: Fatigue, hair loss.

Benjamin P. Levy, MD: Some financial toxicity potentially as well.

Thomas E. Stinchcombe, MD: Like Naiyer said, you don’t get the symptom improvement that you do in the metastatic setting just to inspire the patient.

Transcript Edited for Clarity 
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