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Second Generation ALK Inhibitors in NSCLC

Panelists: Benjamin P. Levy, MD, Sibley Memorial Hospital; Shirish M. Gadgeel, MD, University of Michigan; Lyudmila A. Bazhenova, MD, UCSD Morris Cancer Center; Anne S. Tsao, MD, MD Anderson Cancer Center; Mohammad Jahanzeb, MD, FACP, University of Miami, Miller School of Medicine
Published: Friday, Oct 26, 2018



Transcript:

Benjamin P. Levy, MD:
So, that’s a nice segue into the whole sequencing question off the trial. I agree, the mechanisms of resistance for ALK TKIs [tyrosine kinase inhibitors] is not the same as the first- and second-generation TKIs and EGFR. It’s a little more durable; we have ALK-dependent, independent mechanisms, point mutations, amplifications, bypass, signaling pathways. What in routine clinical practice are you doing post alectinib (Alecensa)? If alectinib is your drug of choice, is it the similar story as osimertinib [Tagrisso]? Or do these patients need to be biopsied? Do we need to do plasma interrogation? Does it inform treatment decisions? Is G1202R a mutation that brigatinib has activity with or that lorlatinib [PF-6463922] may have activity with? So how do we do this in routine clinical practice?

Shirish M. Gadgeel, MD: At the present time, I am actually enrolling them on an experimental protocol for lorlatinib. Lorlatinib has shown efficacy in patients who progressed on specifically alectinib and ceritinib, with a response rate somewhere in the range of about 35% in a median progression-free survival, in the range of about 6 months. So, it’s a viable option. There’s data to suggest from the lorlatinib study that patients who have ALK-dependent resistance mechanisms may have a better probability of benefit from lorlatinib. Whereas if it is an ALK-independent, not that lorlatinib would not work, but it is less. And so, it is possible that in the future, as we gather more and more of this data, that, yes, we will be trying to repeat biopsies or maybe a liquid biopsy, and define the molecule mechanism of resistance in patients who develop progression of disease on these next-generation ALK inhibitors.

I’ll just mention one other thing. I think what Anne suggested, that one can use brigatinib after alectinib, that’s a worthwhile approach. But one has to emphasize we don’t have an FDA approval for that, as of yet. And, that we don’t have good clinical data, but I think that based on the preclinical data it’s a worthwhile option. But we may land up in practical situations, at the present time at least, where many of these patients may end up needing cytotoxic chemotherapy.

Shirish M. Gadgeel, MD: Pemetrexed [Alimta], again in this group of patients, can have sustained and substantial benefit, so one can be reluctant. And again, to emphasize what MJ [Mohammad Jahanzeb, MD, FACP]said, in these patients single agent immunotherapy would be something that would be considered after cytotoxic chemotherapy.

Anne S. Tsao, MD: I would rather circulate them back out through ALK TKIs than to go to an immunotherapy.

Mohammad Jahanzeb, MD, FACP: So I agree with all of the excellent points that have been made. Just a couple of things on chemotherapy. Chemotherapy still works, and sometimes it takes time to get preauthorization approval, and the drug shipped. And I want to emphasize that some of these patients crash and burn very quickly, or they progress very rapidly. So, during that time, if you’re uncertain as to when the next TKI will arrive, it’s okay to give chemotherapy.

And the other thing I didn’t get to give my opinion on, what I do, is still alectinib in the first-line. But I think if the data bear out, there’s a huge advantage to 1 pill a day, versus 4 pills twice daily. So I think aspect alone will make this a superior choice. And we may or may not have mentioned that the brain activity doesn’t look like any less than alectinib. Seventy-eight percent response rate, as we saw.

Lyudmila A. Bazhenova, MD: And I think at this point we really don’t know how to sequence second generation ALK inhibitors. I think the first generation ALK inhibitors are already at this point, not going to be used as much in first-line. The only comprehensive dataset we have is lorlatinib, post–second- generation response rate is about 30%. For the rest of the drugs we have anecdotes. I have patients who responded to brigatinib after alectinib, and I also have patients otherwise who responded to alectinib after brigatinib. I have patients who responded to brigatinib after ensartinib [X-396]. So, I think it’s an open field.

I do believe in post-progression biopsies for those patients, mostly because small cell transformation has been described in ALK progression, and the chemotherapy choice would be different in those patients. But, again, in emerging data on ALK-dependent versus ALK-independent mechanism, I think it will sway me towards trying a third ALK TKI versus trying chemotherapy, depending on what I see.

Anne S. Tsao, MD: And the ALK master protocol will hopefully give more information about this so.

Benjamin P. Levy, MD: It speaks the need to these clinical trials. We have to have these questions answered, and hopefully trials like the ALK master protocol will try to get to this sequencing issue and define it a little better than we have now. Briefly let’s mention; speaking of lorlatinib; we talked about its activity potentially in a highly pretreated group of ALK-rearranged patients. We’ve seen some data at [IASLC 19th]World [Conference on] Lung [Cancer] with ROS1-rearrangements. ROS1-rearrangements, roughly 1[%] to 2% of advanced non–small cell lung cancer. The only approved drug right now is crizotinib. But we have some data coming out with entrectinib [RXDX-101] that was presented last year at World Lung. We’ll see some data as well here, but also with lorlatinib. Shirish, do you want to briefly just talk about this?

Shirish M. Gadgeel, MD: Yes. So, many of these ALK inhibitors—because there is some homology between ALK and ROS1 enzymes—do have activity against ROS, it is important to note. Alectinib is one exception—it has activity against ALK but does not have activity in ROS1 patients.

So, the data that is going to be presented by Dr [Sai-Hong Ignatius] Ou[, MD, PhD,] at this year’s World Lung is going to look at a cohort of patients with ROS1-positive non–small cell lung cancer that was treated with lorlatinib; a standard dose of 100 mg a day. There were a total 47 patients, 13 of them were crizotinib-naïve, and 34 patients had been previously treated with crizotinib. The response rate in patients who were crizotinib-naïve, or ROS1 TKI-naïve, was 61%. And it was 26% in patients who had previously received crizotinib.

Whereas what I think was impressive, was that the drug did have activity in the CNS [central nervous system], where the response rates were in the range of about 50[%] to 60%. And so, one of the potential advantages of this drug is that this dataset shows that, even though overall activity may not be necessarily superior to what has been observed with other ROS1 inhibitors such as entrectinib, crizotinib, but its activity in the CNS may lead to this drug being used. We don’t know that it necessarily delays time to CNS metastases in patients who don’t have baseline CNS disease. But that could be potentially an advantage with this drug.

Benjamin P. Levy, MD: So many drugs to keep up with.

Shirish M. Gadgeel, MD: And then different toxicities.

Benjamin P. Levy, MD: That’s right.

Shirish M. Gadgeel, MD: Toxicity of hyperglycemia, hypercholesterolemia.

Benjamin P. Levy, MD: And multiple targets it may hit.


Transcript Edited for Clarity
 

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Transcript:

Benjamin P. Levy, MD:
So, that’s a nice segue into the whole sequencing question off the trial. I agree, the mechanisms of resistance for ALK TKIs [tyrosine kinase inhibitors] is not the same as the first- and second-generation TKIs and EGFR. It’s a little more durable; we have ALK-dependent, independent mechanisms, point mutations, amplifications, bypass, signaling pathways. What in routine clinical practice are you doing post alectinib (Alecensa)? If alectinib is your drug of choice, is it the similar story as osimertinib [Tagrisso]? Or do these patients need to be biopsied? Do we need to do plasma interrogation? Does it inform treatment decisions? Is G1202R a mutation that brigatinib has activity with or that lorlatinib [PF-6463922] may have activity with? So how do we do this in routine clinical practice?

Shirish M. Gadgeel, MD: At the present time, I am actually enrolling them on an experimental protocol for lorlatinib. Lorlatinib has shown efficacy in patients who progressed on specifically alectinib and ceritinib, with a response rate somewhere in the range of about 35% in a median progression-free survival, in the range of about 6 months. So, it’s a viable option. There’s data to suggest from the lorlatinib study that patients who have ALK-dependent resistance mechanisms may have a better probability of benefit from lorlatinib. Whereas if it is an ALK-independent, not that lorlatinib would not work, but it is less. And so, it is possible that in the future, as we gather more and more of this data, that, yes, we will be trying to repeat biopsies or maybe a liquid biopsy, and define the molecule mechanism of resistance in patients who develop progression of disease on these next-generation ALK inhibitors.

I’ll just mention one other thing. I think what Anne suggested, that one can use brigatinib after alectinib, that’s a worthwhile approach. But one has to emphasize we don’t have an FDA approval for that, as of yet. And, that we don’t have good clinical data, but I think that based on the preclinical data it’s a worthwhile option. But we may land up in practical situations, at the present time at least, where many of these patients may end up needing cytotoxic chemotherapy.

Shirish M. Gadgeel, MD: Pemetrexed [Alimta], again in this group of patients, can have sustained and substantial benefit, so one can be reluctant. And again, to emphasize what MJ [Mohammad Jahanzeb, MD, FACP]said, in these patients single agent immunotherapy would be something that would be considered after cytotoxic chemotherapy.

Anne S. Tsao, MD: I would rather circulate them back out through ALK TKIs than to go to an immunotherapy.

Mohammad Jahanzeb, MD, FACP: So I agree with all of the excellent points that have been made. Just a couple of things on chemotherapy. Chemotherapy still works, and sometimes it takes time to get preauthorization approval, and the drug shipped. And I want to emphasize that some of these patients crash and burn very quickly, or they progress very rapidly. So, during that time, if you’re uncertain as to when the next TKI will arrive, it’s okay to give chemotherapy.

And the other thing I didn’t get to give my opinion on, what I do, is still alectinib in the first-line. But I think if the data bear out, there’s a huge advantage to 1 pill a day, versus 4 pills twice daily. So I think aspect alone will make this a superior choice. And we may or may not have mentioned that the brain activity doesn’t look like any less than alectinib. Seventy-eight percent response rate, as we saw.

Lyudmila A. Bazhenova, MD: And I think at this point we really don’t know how to sequence second generation ALK inhibitors. I think the first generation ALK inhibitors are already at this point, not going to be used as much in first-line. The only comprehensive dataset we have is lorlatinib, post–second- generation response rate is about 30%. For the rest of the drugs we have anecdotes. I have patients who responded to brigatinib after alectinib, and I also have patients otherwise who responded to alectinib after brigatinib. I have patients who responded to brigatinib after ensartinib [X-396]. So, I think it’s an open field.

I do believe in post-progression biopsies for those patients, mostly because small cell transformation has been described in ALK progression, and the chemotherapy choice would be different in those patients. But, again, in emerging data on ALK-dependent versus ALK-independent mechanism, I think it will sway me towards trying a third ALK TKI versus trying chemotherapy, depending on what I see.

Anne S. Tsao, MD: And the ALK master protocol will hopefully give more information about this so.

Benjamin P. Levy, MD: It speaks the need to these clinical trials. We have to have these questions answered, and hopefully trials like the ALK master protocol will try to get to this sequencing issue and define it a little better than we have now. Briefly let’s mention; speaking of lorlatinib; we talked about its activity potentially in a highly pretreated group of ALK-rearranged patients. We’ve seen some data at [IASLC 19th]World [Conference on] Lung [Cancer] with ROS1-rearrangements. ROS1-rearrangements, roughly 1[%] to 2% of advanced non–small cell lung cancer. The only approved drug right now is crizotinib. But we have some data coming out with entrectinib [RXDX-101] that was presented last year at World Lung. We’ll see some data as well here, but also with lorlatinib. Shirish, do you want to briefly just talk about this?

Shirish M. Gadgeel, MD: Yes. So, many of these ALK inhibitors—because there is some homology between ALK and ROS1 enzymes—do have activity against ROS, it is important to note. Alectinib is one exception—it has activity against ALK but does not have activity in ROS1 patients.

So, the data that is going to be presented by Dr [Sai-Hong Ignatius] Ou[, MD, PhD,] at this year’s World Lung is going to look at a cohort of patients with ROS1-positive non–small cell lung cancer that was treated with lorlatinib; a standard dose of 100 mg a day. There were a total 47 patients, 13 of them were crizotinib-naïve, and 34 patients had been previously treated with crizotinib. The response rate in patients who were crizotinib-naïve, or ROS1 TKI-naïve, was 61%. And it was 26% in patients who had previously received crizotinib.

Whereas what I think was impressive, was that the drug did have activity in the CNS [central nervous system], where the response rates were in the range of about 50[%] to 60%. And so, one of the potential advantages of this drug is that this dataset shows that, even though overall activity may not be necessarily superior to what has been observed with other ROS1 inhibitors such as entrectinib, crizotinib, but its activity in the CNS may lead to this drug being used. We don’t know that it necessarily delays time to CNS metastases in patients who don’t have baseline CNS disease. But that could be potentially an advantage with this drug.

Benjamin P. Levy, MD: So many drugs to keep up with.

Shirish M. Gadgeel, MD: And then different toxicities.

Benjamin P. Levy, MD: That’s right.

Shirish M. Gadgeel, MD: Toxicity of hyperglycemia, hypercholesterolemia.

Benjamin P. Levy, MD: And multiple targets it may hit.


Transcript Edited for Clarity
 
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