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Crizotinib Resistance in ALK+ NSCLC

Insights From: Tony Mok, MD, Chinese University of Hong Kong; David Spigel, MD, Sarah Cannon Research Institute
Published: Friday, Feb 10, 2017


Transcript:

Tony Mok, MD:
Patients who go on crizotinib did respond nicely, but after median duration of about 10 to 12 months, almost every patient would develop resistance. Now, there were diverse mechanisms or resistance that had been reported. We classify them as ALK-related and non-ALK-related. For the ALK-related, there are possibly 2 mechanisms. There is actually the CNS-centered, meaning that the brain metastases may progress due to the fact that the drug may not penetrate the brain as good as they’d like to be.

The other possibility is the fact that this is what we call a “gatekeeper mutation.” There can be multiple areas along the receptor area that they may have a single point mutation that changes the topology of the receptor in the binding pocket, such that the crizotinib can no longer bind to this ATP (adenosine triphosphate)-binding pocket. As a result, we have lost efficacy of control of the cancer. Now there are also non-ALK related mechanisms, such as transformation into other cell types phenotypically—or they actually may even have been reported of EGFR mutations or KRAS mutations that occur after the usage of the crizotinib in this patient, but they are relatively uncommon. So, the major part is what we call, in the CNS, the brain metastases as well as the “gatekeeper mutations.”

David Spigel, MD: We know that patients who are on effective drugs like crizotinib, at some point they will relapse. Their disease will progress through that therapy, and it is variable. We know some patients—unfortunately, even very early on—can have either no responses or very short-lived responses. Fortunately, that’s a minority of our patients. Most patients are going to get several months of disease control, even beyond 1 year, as I mentioned earlier. There are even patients who can have several years of disease control. I, and many physicians, care for patients with many years of disease control with never receiving chemotherapy.

But, we know at some point, patients will become resistant. And when that happens, it can be a challenging time for not only the patients but the providers as well because patients can go downhill, so to speak, rather quickly where they’re doing well on a therapy for a while, really no symptoms of their cancer, and then all of a sudden they have symptoms of cancer. So, there’s a bit of rush to make an assessment of why that’s occurring and what your next plan of care is going to be. Is it going to be moving on to another tyrosine kinase inhibitor targeting ALK mutations, or is it going to be moving on to chemotherapy? And that period can be difficult for patients and providers in making the best decision for that patient in a timely manner.

It’s interesting that, like all patients with lung cancer, there can be progressive disease in different parts of the body. But, with ALK-rearranged lung cancer, we pay particular attention to the CNS, or the brain specifically, as we recognize that at least half the patients can have brain metastases at some point in their care, often at baseline. When you’re just diagnosing a patient, we do routine imaging of the brain anyway for advanced lung cancer at baseline, regardless of ALK status.

But, in our patients with ALK rearrangements, it’s important not only to look at baseline but at points beyond that—so, in a serial fashion. We’re not used to doing that. We’re not used to routinely looking in the brain when patients are not having symptoms, but is it highly recommended. It’s the way I practice, too—periodically look in the brain, with MRI imaging at least, or some form of imaging. Even if it was CT, it’s going to be important to identify asymptomatic metastases. Or, in some cases, patients having symptoms or widespread metastases in the brain is a real problem, as it’s their first sign of progression. We do look out for lung, bone, and hepatic progression as well, but it’s the CNS that sometimes can slip by physicians and family members even, and that’s where patients can get in trouble by doctors not recognizing that early enough.

Transcript Edited for Clarity
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Transcript:

Tony Mok, MD:
Patients who go on crizotinib did respond nicely, but after median duration of about 10 to 12 months, almost every patient would develop resistance. Now, there were diverse mechanisms or resistance that had been reported. We classify them as ALK-related and non-ALK-related. For the ALK-related, there are possibly 2 mechanisms. There is actually the CNS-centered, meaning that the brain metastases may progress due to the fact that the drug may not penetrate the brain as good as they’d like to be.

The other possibility is the fact that this is what we call a “gatekeeper mutation.” There can be multiple areas along the receptor area that they may have a single point mutation that changes the topology of the receptor in the binding pocket, such that the crizotinib can no longer bind to this ATP (adenosine triphosphate)-binding pocket. As a result, we have lost efficacy of control of the cancer. Now there are also non-ALK related mechanisms, such as transformation into other cell types phenotypically—or they actually may even have been reported of EGFR mutations or KRAS mutations that occur after the usage of the crizotinib in this patient, but they are relatively uncommon. So, the major part is what we call, in the CNS, the brain metastases as well as the “gatekeeper mutations.”

David Spigel, MD: We know that patients who are on effective drugs like crizotinib, at some point they will relapse. Their disease will progress through that therapy, and it is variable. We know some patients—unfortunately, even very early on—can have either no responses or very short-lived responses. Fortunately, that’s a minority of our patients. Most patients are going to get several months of disease control, even beyond 1 year, as I mentioned earlier. There are even patients who can have several years of disease control. I, and many physicians, care for patients with many years of disease control with never receiving chemotherapy.

But, we know at some point, patients will become resistant. And when that happens, it can be a challenging time for not only the patients but the providers as well because patients can go downhill, so to speak, rather quickly where they’re doing well on a therapy for a while, really no symptoms of their cancer, and then all of a sudden they have symptoms of cancer. So, there’s a bit of rush to make an assessment of why that’s occurring and what your next plan of care is going to be. Is it going to be moving on to another tyrosine kinase inhibitor targeting ALK mutations, or is it going to be moving on to chemotherapy? And that period can be difficult for patients and providers in making the best decision for that patient in a timely manner.

It’s interesting that, like all patients with lung cancer, there can be progressive disease in different parts of the body. But, with ALK-rearranged lung cancer, we pay particular attention to the CNS, or the brain specifically, as we recognize that at least half the patients can have brain metastases at some point in their care, often at baseline. When you’re just diagnosing a patient, we do routine imaging of the brain anyway for advanced lung cancer at baseline, regardless of ALK status.

But, in our patients with ALK rearrangements, it’s important not only to look at baseline but at points beyond that—so, in a serial fashion. We’re not used to doing that. We’re not used to routinely looking in the brain when patients are not having symptoms, but is it highly recommended. It’s the way I practice, too—periodically look in the brain, with MRI imaging at least, or some form of imaging. Even if it was CT, it’s going to be important to identify asymptomatic metastases. Or, in some cases, patients having symptoms or widespread metastases in the brain is a real problem, as it’s their first sign of progression. We do look out for lung, bone, and hepatic progression as well, but it’s the CNS that sometimes can slip by physicians and family members even, and that’s where patients can get in trouble by doctors not recognizing that early enough.

Transcript Edited for Clarity
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