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A Game-Changing Year for NSCLC

Panelists: Mark A. Socinski, MD, Advent Health Cancer Institute; John V. Heymach, MD, PhD, MD Anderson Cancer Center; Leora Horn, MD, MSc, FRCPC, Vanderbilt University Medical Center; Mohammad Jahanzeb, MD, University of Miami Health System; Heather A. Wakelee, MD, Stanford University Medical Center; Jarushka Naidoo, MBBCh, Sidney Kimmel Cancer Center
Published: Tuesday, Apr 09, 2019



Transcript: 

Mark A. Socinski, MD: Well this has been great. This has been extremely informative. Before we end this discussion, I’d like to get some closing thoughts from each of our panelists. I’m going to give MJ the toughest job, so I’m going to start over with Heather here, and we’ll just go down the line and give us some closing thoughts for the audience.

Heather A. Wakelee, MD: Right. It’s just amazing the rapidity of advances that we’re seeing right now. And I think that I’m going to come back to something you brought up a couple of times. But as we meet a new patient who’s just been diagnosed, you don’t want to make that treatment recommendation until you really have the full story. And so you don’t act just on the PD-L1, you also need to get the driver mutation information. Again, that’s going to vary. If you have a patient who has a heavy smoking history, the likelihood of that driver mutation while not zero, is low enough. If they’re symptomatic you’re not going to wait. But normally we want to wait.

And then if it turns out that they have a driver mutation, we’ve got a great third-generation EGFR TKI [tyrosine kinase inhibitor] with osimertinib, usually starting there. A great ALK drug with alectinib and several others as well, but that’s usually, those are the 2 I’m agreeing that that’s what I would start.

And where there’s a lot of research happening is what do we do when those drugs stop working? Because as great as they are, they stop working. And that’s a really important cutting-edge area. And then for everybody else, and for these folks as well, maybe at some point, we still have chemotherapy, and chemotherapy plus immune therapy was the lesson of 2018, and that if there’s not a, unless there’s a reason not to do it, that’s what I’m starting most of my patients on. And the reasons not to do it would be driver mutation or if they have high PD-L1, I usually will start with single-agent pembrolizumab.

Mark A. Socinski, MD: John?

John V. Heymach, MD, PhD: Yeah. So for me the most important development over this past year is the relative importance of getting broad Next Generation sequencing for potential rare drivers. And you know for a long time we were able to just profile EGFR and ALK. But if you look now in addition to the approvals for ROS1 with crizotinib and for BRAF with dabrafenib, dabrafenib and trametinib, you know now we’ve got NTRK fusions and really spectacular data with larotrectinib. We’ve got highly active drugs for EGFR exon20, for HER2 exon20. Strong data for RET fusions with LOXO-292 in the BLU-667. So my big take-home point is it’s time for really everybody to be shifting to make sure they’re not missing these rare mutations. That’s a game changer for those patients if we find them.

Mark A. Socinski, MD: Yeah, I completely agree. I mean I, you know, I say we probably all lay in bed tonight, “Did I miss an oncogenic driver in my practice population?” We don’t want to miss that one.

Mark A. Socinski, MD: Jarushka?

Jarushka Naidoo, MBBCh: So I think the main game changed for me is the PACIFIC trial I/O [immuno-oncology] for cure that immunotherapy, which had been shown in these various iterations, a combination of chemo [chemotherapy] or a learn to be beneficial in metastatic disease, but now for the first time has the promise of helping an early-stage lung cancer patient from achieving true disease-free status with a practice-changing phase III study showing both progression-free and overall survival benefit. So to me that would be the No 1 study to take home.

Mark A. Socinski, MD: Yeah, and it creates a lot of enthusiasm for the adjuvant trials, right?

Heather A. Wakelee, MD: Yes, and neoadjuvant.

Jarushka Naidoo, MBBCh: And neoadjuvant.

Mark A. Socinski, MD: And the neoadjuvant trials, yeah. Leora?

Leora Horn, MD, MSc, FRCPC: It’s hard to follow what they said, but I think the one thing I’ll add.

Mark A. Socinski, MD: Think how MJ feels.

Leora Horn, MD, MSc, FRCPC: I know. The one thing I think I’ll add is just building on what Heather said, because we see this. Sometimes our patients come in and they had their blood test that was negative and they were started on something because blood takes, the blood took quicker than the tissue to come back. And if you have tissue, you should test the tissue. And if you have a negative test in blood, that is not good enough to say a patient doesn’t have a driving mutation. That patient needs to have a tissue biopsy. And so I think there’s, we have a multitude of riches, and we have good options for our patients, and it’s just, make sure you do the right tests on the patient so you can get them that right drug.

Mark A. Socinski, MD: Yeah, and we didn’t have chance to talk much about plasma-based testing but I think the take-home message is that the only time blood is helpful is it’s positive with something.

Leora Horn, MD, MSc, FRCPC: Correct.

Mark A. Socinski, MD: If it’s negative, you can trust it, you have to do tissue.

Leora Horn, MD, MSc, FRCPC: Yes.

Mark A. Socinski, MD: And MJ?

Mohammad Jahanzeb, MD: I agree with everything that has been said and I would, again, amplify that not doing broad genomic profiling which would include both next generation sequencing and liquid biopsies is providing inferior care to lung cancer patients, non–small cell lung cancer patients today. So that should be emphasized. There’s been, of course, tremendous progress. I finished training when there was zero FDA-approved drugs in lung cancer, if you can believe it. The first approval of cisplatin came with Navelbine in 1994, and now to be able to have 12 pills, 5 in the EGFR space and 5 in the ALK space, and a pair of drugs for BRAF. So a dozen pills. And 7 or 8 antibodies. And all the other chemo [chemotherapy] drugs that we all know about.

It’s amazing. It’s almost dizzying and the pace of progress is clearly quickening. We are becoming more nuanced and in immunotherapy space, we all have talked about the data, but what doesn’t come out is what I was talking about earlier today. The longer breaks that I’ve noticed we have been able to give our patients. We have never been able to give breaks this long with chemotherapy, but we have a subset of patients whose immune system remembers who the enemy is, even without the drugs circulating in their blood. So that’s I think an important phenomenon. And other than that I think future studies should be focused on selecting the right patient for I/O.

The last AACR [American Association for Cancer Research], the year before there was a presentation on the immune genomic markers that predict for response. For example, STK11 down regulates all the immune markers. So today if I have a patient whose next-gen [next-generation] sequencing report has a low mutation burden, STK11 alteration, and PDL-1-0, I may tell the patient that it may be a waste of time to do immunotherapy. So that’s just the beginning of selection process, and I’m sure more and more such markers will come to fore.

Mark A. Socinski, MD: Yeah, when you think about it, I’m celebrating my 30th year anniversary from completion of my fellowship at the Dana-Farber. And I agree with you, it’s amazing progress that we’ve made. We have much more work to do, but it really is gratifying to have all of this happen and create options and to have you know the follow-up of KEYNOTE-024 where we have a 30-month median survival, again in a selected population. And we see the same thing in the driver population so it’s great.

So I want to thank you all for your contributions to this discussion. It’s been wonderful. On behalf of our panel, we thank you for joining us, and we hope you found this Peer Exchange® discussion to be useful and informative.

Transcript Edited for Clarity

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Transcript: 

Mark A. Socinski, MD: Well this has been great. This has been extremely informative. Before we end this discussion, I’d like to get some closing thoughts from each of our panelists. I’m going to give MJ the toughest job, so I’m going to start over with Heather here, and we’ll just go down the line and give us some closing thoughts for the audience.

Heather A. Wakelee, MD: Right. It’s just amazing the rapidity of advances that we’re seeing right now. And I think that I’m going to come back to something you brought up a couple of times. But as we meet a new patient who’s just been diagnosed, you don’t want to make that treatment recommendation until you really have the full story. And so you don’t act just on the PD-L1, you also need to get the driver mutation information. Again, that’s going to vary. If you have a patient who has a heavy smoking history, the likelihood of that driver mutation while not zero, is low enough. If they’re symptomatic you’re not going to wait. But normally we want to wait.

And then if it turns out that they have a driver mutation, we’ve got a great third-generation EGFR TKI [tyrosine kinase inhibitor] with osimertinib, usually starting there. A great ALK drug with alectinib and several others as well, but that’s usually, those are the 2 I’m agreeing that that’s what I would start.

And where there’s a lot of research happening is what do we do when those drugs stop working? Because as great as they are, they stop working. And that’s a really important cutting-edge area. And then for everybody else, and for these folks as well, maybe at some point, we still have chemotherapy, and chemotherapy plus immune therapy was the lesson of 2018, and that if there’s not a, unless there’s a reason not to do it, that’s what I’m starting most of my patients on. And the reasons not to do it would be driver mutation or if they have high PD-L1, I usually will start with single-agent pembrolizumab.

Mark A. Socinski, MD: John?

John V. Heymach, MD, PhD: Yeah. So for me the most important development over this past year is the relative importance of getting broad Next Generation sequencing for potential rare drivers. And you know for a long time we were able to just profile EGFR and ALK. But if you look now in addition to the approvals for ROS1 with crizotinib and for BRAF with dabrafenib, dabrafenib and trametinib, you know now we’ve got NTRK fusions and really spectacular data with larotrectinib. We’ve got highly active drugs for EGFR exon20, for HER2 exon20. Strong data for RET fusions with LOXO-292 in the BLU-667. So my big take-home point is it’s time for really everybody to be shifting to make sure they’re not missing these rare mutations. That’s a game changer for those patients if we find them.

Mark A. Socinski, MD: Yeah, I completely agree. I mean I, you know, I say we probably all lay in bed tonight, “Did I miss an oncogenic driver in my practice population?” We don’t want to miss that one.

Mark A. Socinski, MD: Jarushka?

Jarushka Naidoo, MBBCh: So I think the main game changed for me is the PACIFIC trial I/O [immuno-oncology] for cure that immunotherapy, which had been shown in these various iterations, a combination of chemo [chemotherapy] or a learn to be beneficial in metastatic disease, but now for the first time has the promise of helping an early-stage lung cancer patient from achieving true disease-free status with a practice-changing phase III study showing both progression-free and overall survival benefit. So to me that would be the No 1 study to take home.

Mark A. Socinski, MD: Yeah, and it creates a lot of enthusiasm for the adjuvant trials, right?

Heather A. Wakelee, MD: Yes, and neoadjuvant.

Jarushka Naidoo, MBBCh: And neoadjuvant.

Mark A. Socinski, MD: And the neoadjuvant trials, yeah. Leora?

Leora Horn, MD, MSc, FRCPC: It’s hard to follow what they said, but I think the one thing I’ll add.

Mark A. Socinski, MD: Think how MJ feels.

Leora Horn, MD, MSc, FRCPC: I know. The one thing I think I’ll add is just building on what Heather said, because we see this. Sometimes our patients come in and they had their blood test that was negative and they were started on something because blood takes, the blood took quicker than the tissue to come back. And if you have tissue, you should test the tissue. And if you have a negative test in blood, that is not good enough to say a patient doesn’t have a driving mutation. That patient needs to have a tissue biopsy. And so I think there’s, we have a multitude of riches, and we have good options for our patients, and it’s just, make sure you do the right tests on the patient so you can get them that right drug.

Mark A. Socinski, MD: Yeah, and we didn’t have chance to talk much about plasma-based testing but I think the take-home message is that the only time blood is helpful is it’s positive with something.

Leora Horn, MD, MSc, FRCPC: Correct.

Mark A. Socinski, MD: If it’s negative, you can trust it, you have to do tissue.

Leora Horn, MD, MSc, FRCPC: Yes.

Mark A. Socinski, MD: And MJ?

Mohammad Jahanzeb, MD: I agree with everything that has been said and I would, again, amplify that not doing broad genomic profiling which would include both next generation sequencing and liquid biopsies is providing inferior care to lung cancer patients, non–small cell lung cancer patients today. So that should be emphasized. There’s been, of course, tremendous progress. I finished training when there was zero FDA-approved drugs in lung cancer, if you can believe it. The first approval of cisplatin came with Navelbine in 1994, and now to be able to have 12 pills, 5 in the EGFR space and 5 in the ALK space, and a pair of drugs for BRAF. So a dozen pills. And 7 or 8 antibodies. And all the other chemo [chemotherapy] drugs that we all know about.

It’s amazing. It’s almost dizzying and the pace of progress is clearly quickening. We are becoming more nuanced and in immunotherapy space, we all have talked about the data, but what doesn’t come out is what I was talking about earlier today. The longer breaks that I’ve noticed we have been able to give our patients. We have never been able to give breaks this long with chemotherapy, but we have a subset of patients whose immune system remembers who the enemy is, even without the drugs circulating in their blood. So that’s I think an important phenomenon. And other than that I think future studies should be focused on selecting the right patient for I/O.

The last AACR [American Association for Cancer Research], the year before there was a presentation on the immune genomic markers that predict for response. For example, STK11 down regulates all the immune markers. So today if I have a patient whose next-gen [next-generation] sequencing report has a low mutation burden, STK11 alteration, and PDL-1-0, I may tell the patient that it may be a waste of time to do immunotherapy. So that’s just the beginning of selection process, and I’m sure more and more such markers will come to fore.

Mark A. Socinski, MD: Yeah, when you think about it, I’m celebrating my 30th year anniversary from completion of my fellowship at the Dana-Farber. And I agree with you, it’s amazing progress that we’ve made. We have much more work to do, but it really is gratifying to have all of this happen and create options and to have you know the follow-up of KEYNOTE-024 where we have a 30-month median survival, again in a selected population. And we see the same thing in the driver population so it’s great.

So I want to thank you all for your contributions to this discussion. It’s been wonderful. On behalf of our panel, we thank you for joining us, and we hope you found this Peer Exchange® discussion to be useful and informative.

Transcript Edited for Clarity
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