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Progression of ALK+ NSCLC

Panelists: Mark A. Socinski, MD, Florida Hospital Cancer Institute; Tracey L. Evans, MD, University of Pennsylvania; Alexander Drilon, MD, Memorial Sloan Kettering Cancer Center; Vali A. Papadimitrakopoulou, MD, The University of Texas MD Anderson Cancer Center; Jared Weiss, MD, UNC Lineberger Comprehensive Cancer Center
Published: Thursday, Mar 16, 2017


Transcript:

Mark Socinski, MD:
I want to switch gears a little bit and go to the next topic. Everyone remembers in 2007, we had ALK described in adenocarcinoma of the lung by some Japanese investigators. The initial observation was that crizotinib—although not really a defined ALK inhibitor per se, more of a good MET inhibitor—was maybe not the best ALK inhibitor, but it had activity. It got approved based upon phase I/phase II data, and now we have phase III data against standard chemotherapy in the first- and second-line. So it’s now our standard of care. However, like EGFR mutations, we understand that resistance develops typically 9 to 10 months into treatment with crizotinib. And Alex, what do we know about crizotinib resistance in this setting of ALK disease?

Alexander Drilon, MD: There are 2 major groups of mechanisms of resistance to crizotinib. There are the ALK dominant mechanisms, where the tumor might manifest with acquired ALK amplification or an ALK mutation. However, the profile of these mutations is different from what you’re seeing with EGFR, where you have 60% emergence of the gatekeeper, T790M. The gatekeeper, L1196M, occurs in a fraction of ALK, but you see a smattering of other different mutations. And then, the second group is the patients whose tumors develop non-ALK–dependent mechanisms, where they might acquire some dependence on EGFR or on KRAS. However, it seems like the majority of that doesn’t matter so much if you come in with a second-generation drug because most patients who receive either alectinib or ceritinib are poised to respond after acquired resistance to crizotinib. So, there’s much more to learn about acquired resistance, but it seems like the majority of patients continue to manifest a dependence on ALK after crizotinib.

Mark Socinski, MD: So, there’s not really a T790M story here in this particular subset of patients?

Alexander Drilon, MD: Well, we can talk a little bit about the mechanism of resistance of the second-generation drugs, where you’re seeing much more of an emergence of the solvent-front mutation, G1202R, which is a little nastier to treat. Fortunately, there are newer drugs we can talk about later that are poised to aggregate that mechanism of resistance.

Mark Socinski, MD: We have 2 drugs currently approved, based on their activity in crizotinib-refractory resistant patients: ceritinib and alectinib. Jared, why don’t you tell us your perspective of how these drugs fit in to current practice?

Jared Weiss, MD: We have efficacy data for both agents following resistance to crizotinib. The PFS on each of these agents is roughly comparable. While there are differences in mechanisms of resistance that are covered by each of these agents, as I think Alex expressed, they’re relatively minor. Most patients will respond to both agents, so I’m not doing a repeat biopsy to decide between them. In my practice, toxicity has been the major driver of my personal choice. And while I consider ceritinib a very reasonable agent in this context, I’ve been using alectinib preferentially just for toxicity reasons. Mark Socinski, MD: What are your views on ceritinib in terms of toxicity and those sorts of issues? You mentioned, when we were talking about the first-generation EGFR inhibitors, what I would call a “biologically effective dose.” Many drugs get developed at the maximum tolerated dose; that’s historically what we’ve done. But, in many of these driver situations, you may not need MTD (maximum tolerated dose) dosing. Is there room for a lower dose for, for instance, ceritinib? Is the toxicity ameliorated when you lower the dose? What are your thoughts on that?

Jared Weiss, MD: Well, in the absence of a competitor agent, that’s probably what I would be doing in my practice. You can probably go even to half-dosing and do just fine. I don’t have a lot of clinical experience with that. I’ll defer to the rest of the panel if anyone does because availability of alectinib had just reset.

Vali Papadimitrakopoulou, MD: So, there are emerging data that the lower dose, 450 mg, given with a low-fat meal for afatinib, is equivalent pharmacokinetically to the 750-mg dose and is associated with less toxicity.

Mark Socinski, MD: You said afatinib, but you meant ceritinib.

Vali Papadimitrakopoulou, MD: Ceritinib, yes. That’s what I meant, yes. We’re still discussing ALK. So, there are some data, but how much adoption of ceritinib in this setting with the lower dose? We will see. I think it is a matter of time because they are new data, so many people have been adopting the dose reductions if they didn’t have any other choices.

Transcript Edited for Clarity
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Transcript:

Mark Socinski, MD:
I want to switch gears a little bit and go to the next topic. Everyone remembers in 2007, we had ALK described in adenocarcinoma of the lung by some Japanese investigators. The initial observation was that crizotinib—although not really a defined ALK inhibitor per se, more of a good MET inhibitor—was maybe not the best ALK inhibitor, but it had activity. It got approved based upon phase I/phase II data, and now we have phase III data against standard chemotherapy in the first- and second-line. So it’s now our standard of care. However, like EGFR mutations, we understand that resistance develops typically 9 to 10 months into treatment with crizotinib. And Alex, what do we know about crizotinib resistance in this setting of ALK disease?

Alexander Drilon, MD: There are 2 major groups of mechanisms of resistance to crizotinib. There are the ALK dominant mechanisms, where the tumor might manifest with acquired ALK amplification or an ALK mutation. However, the profile of these mutations is different from what you’re seeing with EGFR, where you have 60% emergence of the gatekeeper, T790M. The gatekeeper, L1196M, occurs in a fraction of ALK, but you see a smattering of other different mutations. And then, the second group is the patients whose tumors develop non-ALK–dependent mechanisms, where they might acquire some dependence on EGFR or on KRAS. However, it seems like the majority of that doesn’t matter so much if you come in with a second-generation drug because most patients who receive either alectinib or ceritinib are poised to respond after acquired resistance to crizotinib. So, there’s much more to learn about acquired resistance, but it seems like the majority of patients continue to manifest a dependence on ALK after crizotinib.

Mark Socinski, MD: So, there’s not really a T790M story here in this particular subset of patients?

Alexander Drilon, MD: Well, we can talk a little bit about the mechanism of resistance of the second-generation drugs, where you’re seeing much more of an emergence of the solvent-front mutation, G1202R, which is a little nastier to treat. Fortunately, there are newer drugs we can talk about later that are poised to aggregate that mechanism of resistance.

Mark Socinski, MD: We have 2 drugs currently approved, based on their activity in crizotinib-refractory resistant patients: ceritinib and alectinib. Jared, why don’t you tell us your perspective of how these drugs fit in to current practice?

Jared Weiss, MD: We have efficacy data for both agents following resistance to crizotinib. The PFS on each of these agents is roughly comparable. While there are differences in mechanisms of resistance that are covered by each of these agents, as I think Alex expressed, they’re relatively minor. Most patients will respond to both agents, so I’m not doing a repeat biopsy to decide between them. In my practice, toxicity has been the major driver of my personal choice. And while I consider ceritinib a very reasonable agent in this context, I’ve been using alectinib preferentially just for toxicity reasons. Mark Socinski, MD: What are your views on ceritinib in terms of toxicity and those sorts of issues? You mentioned, when we were talking about the first-generation EGFR inhibitors, what I would call a “biologically effective dose.” Many drugs get developed at the maximum tolerated dose; that’s historically what we’ve done. But, in many of these driver situations, you may not need MTD (maximum tolerated dose) dosing. Is there room for a lower dose for, for instance, ceritinib? Is the toxicity ameliorated when you lower the dose? What are your thoughts on that?

Jared Weiss, MD: Well, in the absence of a competitor agent, that’s probably what I would be doing in my practice. You can probably go even to half-dosing and do just fine. I don’t have a lot of clinical experience with that. I’ll defer to the rest of the panel if anyone does because availability of alectinib had just reset.

Vali Papadimitrakopoulou, MD: So, there are emerging data that the lower dose, 450 mg, given with a low-fat meal for afatinib, is equivalent pharmacokinetically to the 750-mg dose and is associated with less toxicity.

Mark Socinski, MD: You said afatinib, but you meant ceritinib.

Vali Papadimitrakopoulou, MD: Ceritinib, yes. That’s what I meant, yes. We’re still discussing ALK. So, there are some data, but how much adoption of ceritinib in this setting with the lower dose? We will see. I think it is a matter of time because they are new data, so many people have been adopting the dose reductions if they didn’t have any other choices.

Transcript Edited for Clarity
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