ONCAlert | Upfront Therapy for mRCC

Considerations in the Management of ALK+ NSCLC

Targeted Oncology
Published Online:12:50 PM, Wed August 7, 2019

Mark A. Socinksi, MD: As we get toward the end here, let’s talk about what you do in clinical practice. Again, I think we have to reemphasize that comprehensive genomic testing at the time of diagnosis is important, and we talked about the clinical profile of the ALK patient where you should be highly suspicious. And don’t accept a negative FISH [fluorescence in situ hybridization] if you have this suspicion. You should go to either IHC [immunohistochemistry] or next-generation sequencing to diagnose it. We’ve agreed that alectinib is the first-line choice at the current time. Although, obviously, this is a rapidly moving field. A patient may be on alectinib for 3 years. What do you do at the time of progression? We obviously have choices like ceritinib, brigatinib, lorlatinib. And even in selected situations, you would advocate for bringing back crizotinib.

Thomas E. Stinchcombe, MD: What I would do at the time of progression is get a ctDNA [circulating tumor DNA test]. I realize the utility of this is debated, and this is my personal opinion.

Mark A. Socinksi, MD: That’s what I want. I want your personal opinion.

Thomas E. Stinchcombe, MD: Then I think that you want to see that ALK mutation. I think particularly if you see the G1202R, you’re a little bit more inclined to use lorlatinib. And then, if you don’t see any mutations, you might think a little more about chemotherapy. We don’t really have good data, so it’s going to be very patient dependent in this situation. I do try and get tumor biopsies, and I think we touched on this earlier. The other mistake I sometimes think we’re making is we’re so enamored with these new drugs. If patients really have oligoprogression, I try and extend the treatment life of alectinib at this point. We can’t be too enthralled by the newness of these.

Mark A. Socinksi, MD: Right. Do you think blood-based testing is a reasonable way to start?

Thomas E. Stinchcombe, MD: I think it is a reasonable way to start. Just to give you some historical context, we’ve tried the tumor testing with ALK, and the FISH, and IHC, and we’re clearly not getting to the level we need to as a field, in terms of compliance. I think we need to move to, like you do, tumor and ctDNA. We really need to do this. I don’t even think it’s patient or physician education. I think we’ve just hit the practical limits of tumor testing in terms of the adequacy of the biopsy, the techniques that we have. And so, we really need to expand our options for testing.

Mark A. Socinksi, MD: One of the issues that clinicians often face in clinical practice is, within 2 or 3 days, they might have a PD-L1 [programmed death-ligand 1] result. I encourage clinicians to ignore PD-L1 status until you know the genotype of the patient. What are your thoughts about immunotherapy in the ALK-positive population?

Thomas E. Stinchcombe, MD: One of the things we emphasize is genomics trumps PD-L1.

Mark A. Socinksi, MD: Yes, absolutely.

Thomas E. Stinchcombe, MD: Like we talked about, the enthusiasm around immunotherapy is exuberant right now. I think that’s great. It’s been a tremendous advance. But the EGFR and the ALK patients really don’t benefit from single-agent therapy. The response rate is around 5%. You might see 10% in 1 small series here or there. And so, I don’t think single-agent….

Mark A. Socinksi, MD: The durability of those responses is not very long. It’s not like you see response rates of 70%, 80%, and 2 to 3 years durability.

Thomas E. Stinchcombe, MD: I think the real question is, chemotherapy alone, or chemotherapy with immunotherapy? Your trial of the carboplatin/paclitaxel/bevacizumab/atezolizumab allowed patients who had been previously treated with an ALK TKI [tyrosine kinase inhibitor].

Mark A. Socinksi, MD: To date, it’s the only trial other than IMpower130 that did allow those patients on. But to your point, I think the take-home message here is that this is not a population that derives any significant benefit from immunotherapy as monotherapy. I’ve actually had a couple of patients either with ALK or EGFR who had a PD-L1 of 90%, and the outside clinician or the referring physician was about to start immunotherapy. The most recent one I had was an EGFR mutation. The question from the community physician was, “What do I do here?” And I said, “Well, it’s pretty obvious what you should do. You should give them targeted therapy because it is much more effective.” The IMpower150 data did include a small number of ALK patients. It’s hard to really draw conclusions based on small numbers. But I think the important point is, trials like KEYNOTE-189 and others excluded these patients. So you really can’t use that data set to draw conclusions.

Thomas E. Stinchcombe, MD: I think that’s an important point. You really want to have evidence of benefit.

Mark A. Socinksi, MD: We had a nice discussion about the plethora of TKIs in this setting, but again, pemetrexed-based therapy can derive great benefit for these patients.

Thomas E. Stinchcombe, MD: Yes. I think it’s important—the chemotherapy versus the IMpower150, the carboplatin and pemetrexed. It’s the chemotherapy I offer, or I offer the IMpower150 regimen to the patient. Those are my 2 options. I don’t offer the KEYNOTE-189 regimen. I have a feeling I’m in a minority.

Mark A. Socinksi, MD: I think you might be, too, because I’ve heard that this is what people would do. Even though you point out that they were excluded from that trial, it doesn’t seem to matter. To me it matters. So, I agree with you. It’s either [carboplatin/pemetrexed] with or without bevacizumab. But if they’re eligible for bevacizumab, I would favor the IMpower150 approach and do that.

Thomas E. Stinchcombe, MD: We talked a lot about testing. I think the other challenge that we sometimes face is the false positive, and I think this is something where, maybe if a patient doesn’t fit the typical profile, secondary testing is really critical. Then you may initiate a therapy that’s inactive and do this patient a disservice.

Mark A. Socinksi, MD: Right. I think most of the false positives occur with FISH testing, right?

Thomas E. Stinchcombe, MD: Yes.

Mark A. Socinksi, MD: Yeah, I think that’s a great point, particularly if you find what’s called ALK-positive on FISH, and there may be another driver that’s there. I had a case several years ago where the patient had a KRAS mutation but was also called ALK-positive. When I spoke to Dr Sanja Dacic at UPMC, she said, “Yes, I had to call it. I don’t believe it. I believe KRAS, but I would ignore that ALK thing.” So I think you do see some false positives.

Thomas E. Stinchcombe, MD: Yes.

Mark A. Socinksi, MD: This has been a great discussion. Is there anything emerging or new that you’re excited about?

Thomas E. Stinchcombe, MD: Well, I think there are 2 other phase III trials in the frontline setting: ensartinib versus crizotinib, and lorlatinib versus crizotinib. I think that this leads us with a potential to have 5 or 6 next-generation ALK TKIs as first-line therapies. That’s where we look at the toxicity profile, and we’re going to have to do the dreaded cross-trial comparison to really think about it. But it’s great to have a wealth of options for patients these days, compared to 2011.

Mark A. Socinksi, MD: Well, this has been a great discussion. I want to thank you, Dr Stinchcombe, for your insightful discussion. And thank you, to our audience, for watching this Targeted Oncology presentation on ALK-positive non–small cell lung cancer.

Transcript edited for clarity.

Mark A. Socinksi, MD: As we get toward the end here, let’s talk about what you do in clinical practice. Again, I think we have to reemphasize that comprehensive genomic testing at the time of diagnosis is important, and we talked about the clinical profile of the ALK patient where you should be highly suspicious. And don’t accept a negative FISH [fluorescence in situ hybridization] if you have this suspicion. You should go to either IHC [immunohistochemistry] or next-generation sequencing to diagnose it. We’ve agreed that alectinib is the first-line choice at the current time. Although, obviously, this is a rapidly moving field. A patient may be on alectinib for 3 years. What do you do at the time of progression? We obviously have choices like ceritinib, brigatinib, lorlatinib. And even in selected situations, you would advocate for bringing back crizotinib.

Thomas E. Stinchcombe, MD: What I would do at the time of progression is get a ctDNA [circulating tumor DNA test]. I realize the utility of this is debated, and this is my personal opinion.

Mark A. Socinksi, MD: That’s what I want. I want your personal opinion.

Thomas E. Stinchcombe, MD: Then I think that you want to see that ALK mutation. I think particularly if you see the G1202R, you’re a little bit more inclined to use lorlatinib. And then, if you don’t see any mutations, you might think a little more about chemotherapy. We don’t really have good data, so it’s going to be very patient dependent in this situation. I do try and get tumor biopsies, and I think we touched on this earlier. The other mistake I sometimes think we’re making is we’re so enamored with these new drugs. If patients really have oligoprogression, I try and extend the treatment life of alectinib at this point. We can’t be too enthralled by the newness of these.

Mark A. Socinksi, MD: Right. Do you think blood-based testing is a reasonable way to start?

Thomas E. Stinchcombe, MD: I think it is a reasonable way to start. Just to give you some historical context, we’ve tried the tumor testing with ALK, and the FISH, and IHC, and we’re clearly not getting to the level we need to as a field, in terms of compliance. I think we need to move to, like you do, tumor and ctDNA. We really need to do this. I don’t even think it’s patient or physician education. I think we’ve just hit the practical limits of tumor testing in terms of the adequacy of the biopsy, the techniques that we have. And so, we really need to expand our options for testing.

Mark A. Socinksi, MD: One of the issues that clinicians often face in clinical practice is, within 2 or 3 days, they might have a PD-L1 [programmed death-ligand 1] result. I encourage clinicians to ignore PD-L1 status until you know the genotype of the patient. What are your thoughts about immunotherapy in the ALK-positive population?

Thomas E. Stinchcombe, MD: One of the things we emphasize is genomics trumps PD-L1.

Mark A. Socinksi, MD: Yes, absolutely.

Thomas E. Stinchcombe, MD: Like we talked about, the enthusiasm around immunotherapy is exuberant right now. I think that’s great. It’s been a tremendous advance. But the EGFR and the ALK patients really don’t benefit from single-agent therapy. The response rate is around 5%. You might see 10% in 1 small series here or there. And so, I don’t think single-agent….

Mark A. Socinksi, MD: The durability of those responses is not very long. It’s not like you see response rates of 70%, 80%, and 2 to 3 years durability.

Thomas E. Stinchcombe, MD: I think the real question is, chemotherapy alone, or chemotherapy with immunotherapy? Your trial of the carboplatin/paclitaxel/bevacizumab/atezolizumab allowed patients who had been previously treated with an ALK TKI [tyrosine kinase inhibitor].

Mark A. Socinksi, MD: To date, it’s the only trial other than IMpower130 that did allow those patients on. But to your point, I think the take-home message here is that this is not a population that derives any significant benefit from immunotherapy as monotherapy. I’ve actually had a couple of patients either with ALK or EGFR who had a PD-L1 of 90%, and the outside clinician or the referring physician was about to start immunotherapy. The most recent one I had was an EGFR mutation. The question from the community physician was, “What do I do here?” And I said, “Well, it’s pretty obvious what you should do. You should give them targeted therapy because it is much more effective.” The IMpower150 data did include a small number of ALK patients. It’s hard to really draw conclusions based on small numbers. But I think the important point is, trials like KEYNOTE-189 and others excluded these patients. So you really can’t use that data set to draw conclusions.

Thomas E. Stinchcombe, MD: I think that’s an important point. You really want to have evidence of benefit.

Mark A. Socinksi, MD: We had a nice discussion about the plethora of TKIs in this setting, but again, pemetrexed-based therapy can derive great benefit for these patients.

Thomas E. Stinchcombe, MD: Yes. I think it’s important—the chemotherapy versus the IMpower150, the carboplatin and pemetrexed. It’s the chemotherapy I offer, or I offer the IMpower150 regimen to the patient. Those are my 2 options. I don’t offer the KEYNOTE-189 regimen. I have a feeling I’m in a minority.

Mark A. Socinksi, MD: I think you might be, too, because I’ve heard that this is what people would do. Even though you point out that they were excluded from that trial, it doesn’t seem to matter. To me it matters. So, I agree with you. It’s either [carboplatin/pemetrexed] with or without bevacizumab. But if they’re eligible for bevacizumab, I would favor the IMpower150 approach and do that.

Thomas E. Stinchcombe, MD: We talked a lot about testing. I think the other challenge that we sometimes face is the false positive, and I think this is something where, maybe if a patient doesn’t fit the typical profile, secondary testing is really critical. Then you may initiate a therapy that’s inactive and do this patient a disservice.

Mark A. Socinksi, MD: Right. I think most of the false positives occur with FISH testing, right?

Thomas E. Stinchcombe, MD: Yes.

Mark A. Socinksi, MD: Yeah, I think that’s a great point, particularly if you find what’s called ALK-positive on FISH, and there may be another driver that’s there. I had a case several years ago where the patient had a KRAS mutation but was also called ALK-positive. When I spoke to Dr Sanja Dacic at UPMC, she said, “Yes, I had to call it. I don’t believe it. I believe KRAS, but I would ignore that ALK thing.” So I think you do see some false positives.

Thomas E. Stinchcombe, MD: Yes.

Mark A. Socinksi, MD: This has been a great discussion. Is there anything emerging or new that you’re excited about?

Thomas E. Stinchcombe, MD: Well, I think there are 2 other phase III trials in the frontline setting: ensartinib versus crizotinib, and lorlatinib versus crizotinib. I think that this leads us with a potential to have 5 or 6 next-generation ALK TKIs as first-line therapies. That’s where we look at the toxicity profile, and we’re going to have to do the dreaded cross-trial comparison to really think about it. But it’s great to have a wealth of options for patients these days, compared to 2011.

Mark A. Socinksi, MD: Well, this has been a great discussion. I want to thank you, Dr Stinchcombe, for your insightful discussion. And thank you, to our audience, for watching this Targeted Oncology presentation on ALK-positive non–small cell lung cancer.

Transcript edited for clarity.
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