New Research in Resistance to Xalkori (crizotinib) for ALK-driven NSCLC
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[Note: This is not a professional opinion, but a report of some very interesting research I read.]
There’s valuable information on resistance to Xalkori (crizotinib) in a newly-published article by Katayama & Shaw (as lead co-authors) and their colleagues in their article titled “Mechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancers” in the research journal Science Translational Medicine: http://www.ncbi.nlm.nih.gov/pubmed/22277784
(Yes, that’s Alice Shaw, MD, PhD again, my oncologist at the Harvard-affiliated MGH in Boston.)
The research looked at just 18 patients with crizotinib-resistant cancer, but that’s enough to gain a lot of insight because of the deep lab analysis work done on those cancers. Although the odds of an individual having the different kinds of resistance won’t be reliable across all crizotinib patients, the value comes from being directionally insightful, not numerically precise.
For starters, only 28% (5/18) had either a resistant ALK mutation or an amplification of the ALK-fusion mutation. These are cases we’d hope would benefit from a 2nd generation ALK inhibitor. We don’t know if this percentage is representative of all crizotinib-resistant patients, but if it were it would imply only a “fair to good chance,” not a “likely chance,” that a 2nd generation ALK inhibitor would be helpful for crizotinib-resistant cancer.
The insights don’t end there, though. For example, the 2nd generation ALK inhibitors were found to vary in their effectiveness against the various resistant ALK mutations and might be less effective on the resistant cancer than crizotinib had been before resistance. And a couple of cases (2/18) developed an additional simultaneous route to bypass ALK inhibition via a gene called KIT.
Hmmm . . . That doesn’t sound so good. Is that all there is? Um, . . .
“There's one more thing” . . . (said in my best understated Steve Jobs / Detective Columbo voice*): . . .
If I’m reading the study correctly, most crizotinib-resistant ALK-driven cancer may have something you didn’t expect, and it might offer hope of being somewhat co-treatable with an additional inhibitor drug: EGFR! Not an EGFR mutation, but an over-active *normal* EGFR gene, pushing the cancer along. And it looks like this was found to some degree in almost every case they could test.
*(BTW, if you don’t understand the Steve Jobs / Detective Columbo reference, see: http://en.wikipedia.org/wiki/Stevenote#.22One_more_thing....22)
=== Resistant ALK Mutation Variants ===
The first form of resistance is the emergence (in survival-of-the-fittest style) of drug-resistant variants of the ALK mutation (4/18 cases) and “amplification” of the ALK fusion mutation (1/18).
The four crizotinib-resistant ALK variant sequences in these patients are named L1196M (an important ‘gateway’ mutation), S1206Y, G1202R, and “1151T insertion”. (These would be in addition to some previously-reported ones named C1156Y and L1152R.) In the lab, S1206Y wasn’t as resistant as the other three, suggesting crizotinib might still slow some weakly resistant variants even if unable to stop them.
The team lab-tested three 2nd generation ALK inhibitor drugs (TAE684, CH5424802, and ASP3026) against some ALK mutations. I might be misinterpreting the data, but against the original ALK these three drugs and crizotinib looked comparably effective. Against the four resistant ALK mutations, their effectiveness varied and the best wasn’t always the same. None were as effective against the resistant mutations as crizotinib had been against the original ALK mutation (and none was very effective against 1151T ins).
At first glance this might suggest shrinkage might be less common when treating resistant mutations with 2nd generation ALK inhibitors, but neither LDK 378 nor Ariad AP26113 were tested or mentioned and only a few mutations were tested. So for now, I’ll remain hopefully optimistic that at least one drug will be found effective enough to do the job for a particular resistant ALK mutation for a while.
(BTW, the marketing material from Ariad on their own early lab work for AP26113 suggested it might work on many ALK variants, including T1151, L1152, C1156, I1171, F1174, V1180, R1181, L1196, L1198, G1202, E1210, E1241, F1245, I1268, G1269, Y1278, and S1206 [that last one requiring a very high dose]. I think most of these were synthetically mutated using lab techniques rather than naturally occurring in patients, but clearly some show up in patients and any of them potentially could.)
=== Amplified ALK Mutation ===
One patient had resistance from amplification of the original “ALK fusion” mutation. (I think this might be what some studies refer to as gene “copy number gain” (CNG).) Basically, it’s the same original ALK mutation, but just more of it, too much for the crizotinib to block it all.
Hypothetically, I’d guess this might mean that a higher dose of crizotinib might help a little more for a while if the patient’s health can tolerate the side-effects and the FDA allowed it, or maybe a 2nd generation ALK inhibitor might help for a while (if one is more potent or more narrowly targeted to the ALK mutation, e.g., maybe the TAE684 column in article’s graph 1E ). Your oncologist should be able to discuss whether something like this could be testable or treatable in an ALK-targeted way.
=== HSP90 Inhibitor ===
With that as context, the research team’s lab work also found that a different kind of inhibitor might sometimes be more effective than the ALK inhibitors they were testing. HSP90 (heat shock protein 90) assists ALK fusion proteins. HSP90 inhibitors are being tested in clinical trials. The research team tested the HSP90 inhibitor 17-AAG (a derivative of natural geldanamycin) and found it was highly effective against the ALK mutations they tested. At the concentration they used, it seemed more potent than all the other drugs they tested, but it also was potent against the normal non-mutated ALK gene, which could mean stronger side effects, too. Other clinical research studies will have to determine the right HSP90 inhibitor and dose level to balance effectiveness vs. tolerable level of side effects.
=== KIT Amplification ===
Two of the 18 ALK resistance cases also had a second simultaneous resistance mechanism: amplification (e.g., copy number gain) of the KIT gene which led to over-expression of both KIT protein and a KIT-assisting ligand called “stem cell factor” (SCF). In engineered cells this combination made the cells resistant to crizotinib, yet sensitive to crizotinib if KIT were inhibited using Gleevec (imatinib).
So apparently there can be multiple simultaneous mechanisms of resistance in crizotinib-resistant cancer cells. For patients whose resistance is known to involve KIT/SCF, it sounds promising that an existing drug might eventually be available to help control the KIT route.
=== EGFR Activation (Phosphorylation) ===
The big surprise was phosphorylated EGFR (pEGFR) mediated resistance, detected in all but one of the cases that could be tested. This is not an EGFR mutation, nor EGFR amplification (e.g., copy number gain), but EGFR activation (phosphorylation, i.e., charged up and working). FWIW, according the article this might possibly be caused by up-regulation of the EGFR receptor itself and two ligands (EGFR ligand amphiregulin and ErbB3 ligand NRG1).
From that data presented, it seems the EGFR activation is usually present even before starting crizotinib and might limit response to crizotinib. In an experiment on a patient’s pre-crizotinib cells which were sensitive to crizotinib but less than normal, treatment with both Xalkori (crizotinib) and Iressa (gefitinib) suppressed cell growth more potently and induced significant apoptosis. In another experiment, it appeared an improved response might be possible by inhibiting both ALK and EGFR, even though the effect wasn’t as potent as crizotinib alone had been on cells that didn’t have EGFR activation. (This suggests there’s more going on here than just these two tyrosine kinases.)
=== It’s So Complicated ===
Yes, it’s complicated. Some ALK inhibitor resistance is due to a resistant ALK mutation, some is due to amplification … amplification … amplification (yes, I’m repeating myself more times than you can handle), some is due to KIT amplification, some is due to EGFR activation, and sometimes inhibiting multiple resistance routes still isn’t enough to lock down the cancer. (We obviously don’t know all the biochemical players in the cancer orchestra yet.)
This sounds like an example of how amazingly adaptable the human body is. You can inhibit or break a gene and you’re your body will try to compensate; you inhibit something more, and it tries to compensate again. That makes it hard to stop cancer, but research like this gives me hope that someday science will learn all the things we’ll need to do to control this beast for many years (most of the time).
=== So What Do We Do? ===
So what should we do when we develop crizotinib resistance?
Ask your oncologist (once they’ve had a chance to read the article). If they have questions, they can contact one of the authors.
For myself, I’d ask my oncologist if it’s possible to have a fresh biopsy of my resistant cancer tested for resistant or amplified ALK mutations, phosphorylated EGFR, and other possible mutations (e.g., KIT), and then treat the resistance accordingly.
Even without testing, I might ask my oncologist if he/she would consider giving ALK+EGFR combo inhibition a try (if the FDA would allow it), especially if my initial response to crizotinib was less than good. If not, I’d hunt for a combo-drug trial of it if one exists. Maybe one of us will find that answer and share it.
Sooner or later, a jump from the ALK inhibitor track to another track will be needed. In this research article, the HSP90 inhibitor experimental trial track seemed promising for crizotinib-resistant ALK-driven lung cancer. Your oncologist may be able to suggest which HSP90’s look most promising. (Other possible tracks: surgery, radiation, chemo, other chemo, immunotherapy, or other experimental things, if time permits.)
This summary and the abstract at http://www.ncbi.nlm.nih.gov/pubmed/22277784 may suffice for most, but your oncologist and some of you will want to buy and read the full article. It’s available by just following the below-the-abstract “LinkOuts” expandable-menu to the publication. (And if you find errors in my summary, please let me know so I can fix it promptly.)
Best hopes
There’s valuable information on resistance to Xalkori (crizotinib) in a newly-published article by Katayama & Shaw (as lead co-authors) and their colleagues in their article titled “Mechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancers” in the research journal Science Translational Medicine: http://www.ncbi.nlm.nih.gov/pubmed/22277784
(Yes, that’s Alice Shaw, MD, PhD again, my oncologist at the Harvard-affiliated MGH in Boston.)
The research looked at just 18 patients with crizotinib-resistant cancer, but that’s enough to gain a lot of insight because of the deep lab analysis work done on those cancers. Although the odds of an individual having the different kinds of resistance won’t be reliable across all crizotinib patients, the value comes from being directionally insightful, not numerically precise.
For starters, only 28% (5/18) had either a resistant ALK mutation or an amplification of the ALK-fusion mutation. These are cases we’d hope would benefit from a 2nd generation ALK inhibitor. We don’t know if this percentage is representative of all crizotinib-resistant patients, but if it were it would imply only a “fair to good chance,” not a “likely chance,” that a 2nd generation ALK inhibitor would be helpful for crizotinib-resistant cancer.
The insights don’t end there, though. For example, the 2nd generation ALK inhibitors were found to vary in their effectiveness against the various resistant ALK mutations and might be less effective on the resistant cancer than crizotinib had been before resistance. And a couple of cases (2/18) developed an additional simultaneous route to bypass ALK inhibition via a gene called KIT.
Hmmm . . . That doesn’t sound so good. Is that all there is? Um, . . .
“There's one more thing” . . . (said in my best understated Steve Jobs / Detective Columbo voice*): . . .
If I’m reading the study correctly, most crizotinib-resistant ALK-driven cancer may have something you didn’t expect, and it might offer hope of being somewhat co-treatable with an additional inhibitor drug: EGFR! Not an EGFR mutation, but an over-active *normal* EGFR gene, pushing the cancer along. And it looks like this was found to some degree in almost every case they could test.
*(BTW, if you don’t understand the Steve Jobs / Detective Columbo reference, see: http://en.wikipedia.org/wiki/Stevenote#.22One_more_thing....22)
=== Resistant ALK Mutation Variants ===
The first form of resistance is the emergence (in survival-of-the-fittest style) of drug-resistant variants of the ALK mutation (4/18 cases) and “amplification” of the ALK fusion mutation (1/18).
The four crizotinib-resistant ALK variant sequences in these patients are named L1196M (an important ‘gateway’ mutation), S1206Y, G1202R, and “1151T insertion”. (These would be in addition to some previously-reported ones named C1156Y and L1152R.) In the lab, S1206Y wasn’t as resistant as the other three, suggesting crizotinib might still slow some weakly resistant variants even if unable to stop them.
The team lab-tested three 2nd generation ALK inhibitor drugs (TAE684, CH5424802, and ASP3026) against some ALK mutations. I might be misinterpreting the data, but against the original ALK these three drugs and crizotinib looked comparably effective. Against the four resistant ALK mutations, their effectiveness varied and the best wasn’t always the same. None were as effective against the resistant mutations as crizotinib had been against the original ALK mutation (and none was very effective against 1151T ins).
At first glance this might suggest shrinkage might be less common when treating resistant mutations with 2nd generation ALK inhibitors, but neither LDK 378 nor Ariad AP26113 were tested or mentioned and only a few mutations were tested. So for now, I’ll remain hopefully optimistic that at least one drug will be found effective enough to do the job for a particular resistant ALK mutation for a while.
(BTW, the marketing material from Ariad on their own early lab work for AP26113 suggested it might work on many ALK variants, including T1151, L1152, C1156, I1171, F1174, V1180, R1181, L1196, L1198, G1202, E1210, E1241, F1245, I1268, G1269, Y1278, and S1206 [that last one requiring a very high dose]. I think most of these were synthetically mutated using lab techniques rather than naturally occurring in patients, but clearly some show up in patients and any of them potentially could.)
=== Amplified ALK Mutation ===
One patient had resistance from amplification of the original “ALK fusion” mutation. (I think this might be what some studies refer to as gene “copy number gain” (CNG).) Basically, it’s the same original ALK mutation, but just more of it, too much for the crizotinib to block it all.
Hypothetically, I’d guess this might mean that a higher dose of crizotinib might help a little more for a while if the patient’s health can tolerate the side-effects and the FDA allowed it, or maybe a 2nd generation ALK inhibitor might help for a while (if one is more potent or more narrowly targeted to the ALK mutation, e.g., maybe the TAE684 column in article’s graph 1E ). Your oncologist should be able to discuss whether something like this could be testable or treatable in an ALK-targeted way.
=== HSP90 Inhibitor ===
With that as context, the research team’s lab work also found that a different kind of inhibitor might sometimes be more effective than the ALK inhibitors they were testing. HSP90 (heat shock protein 90) assists ALK fusion proteins. HSP90 inhibitors are being tested in clinical trials. The research team tested the HSP90 inhibitor 17-AAG (a derivative of natural geldanamycin) and found it was highly effective against the ALK mutations they tested. At the concentration they used, it seemed more potent than all the other drugs they tested, but it also was potent against the normal non-mutated ALK gene, which could mean stronger side effects, too. Other clinical research studies will have to determine the right HSP90 inhibitor and dose level to balance effectiveness vs. tolerable level of side effects.
=== KIT Amplification ===
Two of the 18 ALK resistance cases also had a second simultaneous resistance mechanism: amplification (e.g., copy number gain) of the KIT gene which led to over-expression of both KIT protein and a KIT-assisting ligand called “stem cell factor” (SCF). In engineered cells this combination made the cells resistant to crizotinib, yet sensitive to crizotinib if KIT were inhibited using Gleevec (imatinib).
So apparently there can be multiple simultaneous mechanisms of resistance in crizotinib-resistant cancer cells. For patients whose resistance is known to involve KIT/SCF, it sounds promising that an existing drug might eventually be available to help control the KIT route.
=== EGFR Activation (Phosphorylation) ===
The big surprise was phosphorylated EGFR (pEGFR) mediated resistance, detected in all but one of the cases that could be tested. This is not an EGFR mutation, nor EGFR amplification (e.g., copy number gain), but EGFR activation (phosphorylation, i.e., charged up and working). FWIW, according the article this might possibly be caused by up-regulation of the EGFR receptor itself and two ligands (EGFR ligand amphiregulin and ErbB3 ligand NRG1).
From that data presented, it seems the EGFR activation is usually present even before starting crizotinib and might limit response to crizotinib. In an experiment on a patient’s pre-crizotinib cells which were sensitive to crizotinib but less than normal, treatment with both Xalkori (crizotinib) and Iressa (gefitinib) suppressed cell growth more potently and induced significant apoptosis. In another experiment, it appeared an improved response might be possible by inhibiting both ALK and EGFR, even though the effect wasn’t as potent as crizotinib alone had been on cells that didn’t have EGFR activation. (This suggests there’s more going on here than just these two tyrosine kinases.)
=== It’s So Complicated ===
Yes, it’s complicated. Some ALK inhibitor resistance is due to a resistant ALK mutation, some is due to amplification … amplification … amplification (yes, I’m repeating myself more times than you can handle), some is due to KIT amplification, some is due to EGFR activation, and sometimes inhibiting multiple resistance routes still isn’t enough to lock down the cancer. (We obviously don’t know all the biochemical players in the cancer orchestra yet.)
This sounds like an example of how amazingly adaptable the human body is. You can inhibit or break a gene and you’re your body will try to compensate; you inhibit something more, and it tries to compensate again. That makes it hard to stop cancer, but research like this gives me hope that someday science will learn all the things we’ll need to do to control this beast for many years (most of the time).
=== So What Do We Do? ===
So what should we do when we develop crizotinib resistance?
Ask your oncologist (once they’ve had a chance to read the article). If they have questions, they can contact one of the authors.
For myself, I’d ask my oncologist if it’s possible to have a fresh biopsy of my resistant cancer tested for resistant or amplified ALK mutations, phosphorylated EGFR, and other possible mutations (e.g., KIT), and then treat the resistance accordingly.
Even without testing, I might ask my oncologist if he/she would consider giving ALK+EGFR combo inhibition a try (if the FDA would allow it), especially if my initial response to crizotinib was less than good. If not, I’d hunt for a combo-drug trial of it if one exists. Maybe one of us will find that answer and share it.
Sooner or later, a jump from the ALK inhibitor track to another track will be needed. In this research article, the HSP90 inhibitor experimental trial track seemed promising for crizotinib-resistant ALK-driven lung cancer. Your oncologist may be able to suggest which HSP90’s look most promising. (Other possible tracks: surgery, radiation, chemo, other chemo, immunotherapy, or other experimental things, if time permits.)
This summary and the abstract at http://www.ncbi.nlm.nih.gov/pubmed/22277784 may suffice for most, but your oncologist and some of you will want to buy and read the full article. It’s available by just following the below-the-abstract “LinkOuts” expandable-menu to the publication. (And if you find errors in my summary, please let me know so I can fix it promptly.)
Best hopes
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