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Ceritinib and Alectinib in Relapsed ALK+ NSCLC

Insights From: Tony Mok, MD, Chinese University of Hong Kong; David Spigel, MD, Sarah Cannon Research Institute; Alice Shaw, MD, PhD, Harvard Medical School
Published: Tuesday, Mar 21, 2017


Transcript:

David Spigel, MD:
So, as good as crizotinib is, there are many drugs in development. There’s over half a dozen other drugs that are in development to target the same pathway, and we refer to these as second- and even third-generation drugs, although those terms are somewhat made up by the timing of when they were developed.

The 2 biggest examples of agents that have been on the scene in the recent years, and where most of the discussion continues to be around, is a medication called ceritinib and a medication called alectinib. These are considered next-generation agents that are in laboratory models, definitely more potent than crizotinib in inhibiting ALK, and also appeared across the blood brain barrier. So, they appear to have a better ability to get into the brain and hopefully either prevent or treat known metastases. These agents have been proven to be effective, highly effective agents, and what the big question is right now is, are they better than chemotherapy? Are they better than crizotinib? That’s ultimately the big question. Crizotinib was on the scene first, a great drug. You have next-generation drugs, which also are fantastic by themselves in patients who have ALK rearrangements. Are they good enough to replace crizotinib? That’s where we’re at now and what we’ve learned at this World Conference on Lung Cancer meeting in Vienna.

Tony Mok, MD: Generally, crizotinib is quite well tolerated. However, there are a few toxicities that sometimes can prevent the patient from continuation of it. Approximately 4% of the patients may have significant hepatic toxicity, meaning the liver enzymes can go up, and sometimes that can be quite quick and quite severe. So, for this type of patient, we certainly cannot continue with the same medication. And also, there is a very small percentage, less than 1%, of patients who may have something called “interstitial lung disease,” which can present like pneumonitis. And, again, those are the type of patients who become intolerant to crizotinib. But both hepatotoxicity and the pulmonary toxicity are relatively uncommon.

Alice Shaw, MD, PhD: Crizotinib is a multitargeted tyrosine kinase inhibitor. It inhibits a number of different targets, but remarkably, it’s quite well-tolerated. So, the toxicity overall is very mild, and that’s really held up across all the studies of crizotinib from phase I to phase III. The major side effects of crizotinib include visual disturbance and GI side effects. Visual disturbance is seen in up to 80% or so of crizotinib-treated patients. It tends to be mild, typically what we would call grade 1, and it’s pretty characteristic in patients where they describe that this visual disturbance is triggered by moving from dark to light. It triggers some type of adaptation when the light is turned on, and they describe findings to be visual trails or sometimes scattered lights. Typically, it’s quite transient, maybe lasts 30 seconds to a few minutes. And, again, it really is triggered in that particular situation.

The other common side effects are GI, including nausea, vomiting, and diarrhea or constipation. I would say these are generally quite mild and easily managed with antinausea medications or antidiarrheal medicines. There can also be some hepatotoxicity. We see elevated liver function tests in a minority of patients, but these do require monitoring every 2 weeks for the first 8 weeks of crizotinib treatment. And then, finally, the last common side effect we see is peripheral edema. This typically occurs after a few months of treatment, can be cumulative where it worsens over months to years of treatment, and often will require some type of management, including conservative measures like compression stockings and leg elevation, but also sometimes diuretic therapy.

Patients with either ALK- or ROS1-rearranged lung cancer generally do very well on crizotinib. However, almost all patients will relapse on crizotinib. For ALK patients, it’s often within the first year. For ROS1 patients, it’s often within the first couple years. And resistance is due to the cancers often developing secondary mutations and other alterations that now make the cancers no longer respond to crizotinib. This is what we call “acquired resistance.” Over the years, a number of groups have studied mechanisms of crizotinib resistance. I would say, overall, we typically classify them as either alterations or ALK itself, including mutations within the ALK tyrosine kinase domain, amplification of the ALK fusion gene, or the other large class of resistance mechanisms that have to do with what we call “off-target mechanisms.” This means that the cancer cells have activated other pathways besides ALK.

Interestingly, it turns out that in patients who have failed crizotinib, most of them remain very sensitive to more potent ALK inhibition. So, in fact, they’re still ALK dependent. And so, that was somewhat of a surprising finding to us to realize that when a patient fails crizotinib, and this is in the particular setting of ALK-rearranged lung cancer, most of those patients will go on to respond to a more potent second-generation ALK inhibitor like ceritinib or alectinib. Even though we’ve defined these different on-target and off-target mechanisms of resistance, at the end of the day, most patients do respond to more potent ALK inhibitors.

Transcript Edited for Clarity
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Transcript:

David Spigel, MD:
So, as good as crizotinib is, there are many drugs in development. There’s over half a dozen other drugs that are in development to target the same pathway, and we refer to these as second- and even third-generation drugs, although those terms are somewhat made up by the timing of when they were developed.

The 2 biggest examples of agents that have been on the scene in the recent years, and where most of the discussion continues to be around, is a medication called ceritinib and a medication called alectinib. These are considered next-generation agents that are in laboratory models, definitely more potent than crizotinib in inhibiting ALK, and also appeared across the blood brain barrier. So, they appear to have a better ability to get into the brain and hopefully either prevent or treat known metastases. These agents have been proven to be effective, highly effective agents, and what the big question is right now is, are they better than chemotherapy? Are they better than crizotinib? That’s ultimately the big question. Crizotinib was on the scene first, a great drug. You have next-generation drugs, which also are fantastic by themselves in patients who have ALK rearrangements. Are they good enough to replace crizotinib? That’s where we’re at now and what we’ve learned at this World Conference on Lung Cancer meeting in Vienna.

Tony Mok, MD: Generally, crizotinib is quite well tolerated. However, there are a few toxicities that sometimes can prevent the patient from continuation of it. Approximately 4% of the patients may have significant hepatic toxicity, meaning the liver enzymes can go up, and sometimes that can be quite quick and quite severe. So, for this type of patient, we certainly cannot continue with the same medication. And also, there is a very small percentage, less than 1%, of patients who may have something called “interstitial lung disease,” which can present like pneumonitis. And, again, those are the type of patients who become intolerant to crizotinib. But both hepatotoxicity and the pulmonary toxicity are relatively uncommon.

Alice Shaw, MD, PhD: Crizotinib is a multitargeted tyrosine kinase inhibitor. It inhibits a number of different targets, but remarkably, it’s quite well-tolerated. So, the toxicity overall is very mild, and that’s really held up across all the studies of crizotinib from phase I to phase III. The major side effects of crizotinib include visual disturbance and GI side effects. Visual disturbance is seen in up to 80% or so of crizotinib-treated patients. It tends to be mild, typically what we would call grade 1, and it’s pretty characteristic in patients where they describe that this visual disturbance is triggered by moving from dark to light. It triggers some type of adaptation when the light is turned on, and they describe findings to be visual trails or sometimes scattered lights. Typically, it’s quite transient, maybe lasts 30 seconds to a few minutes. And, again, it really is triggered in that particular situation.

The other common side effects are GI, including nausea, vomiting, and diarrhea or constipation. I would say these are generally quite mild and easily managed with antinausea medications or antidiarrheal medicines. There can also be some hepatotoxicity. We see elevated liver function tests in a minority of patients, but these do require monitoring every 2 weeks for the first 8 weeks of crizotinib treatment. And then, finally, the last common side effect we see is peripheral edema. This typically occurs after a few months of treatment, can be cumulative where it worsens over months to years of treatment, and often will require some type of management, including conservative measures like compression stockings and leg elevation, but also sometimes diuretic therapy.

Patients with either ALK- or ROS1-rearranged lung cancer generally do very well on crizotinib. However, almost all patients will relapse on crizotinib. For ALK patients, it’s often within the first year. For ROS1 patients, it’s often within the first couple years. And resistance is due to the cancers often developing secondary mutations and other alterations that now make the cancers no longer respond to crizotinib. This is what we call “acquired resistance.” Over the years, a number of groups have studied mechanisms of crizotinib resistance. I would say, overall, we typically classify them as either alterations or ALK itself, including mutations within the ALK tyrosine kinase domain, amplification of the ALK fusion gene, or the other large class of resistance mechanisms that have to do with what we call “off-target mechanisms.” This means that the cancer cells have activated other pathways besides ALK.

Interestingly, it turns out that in patients who have failed crizotinib, most of them remain very sensitive to more potent ALK inhibition. So, in fact, they’re still ALK dependent. And so, that was somewhat of a surprising finding to us to realize that when a patient fails crizotinib, and this is in the particular setting of ALK-rearranged lung cancer, most of those patients will go on to respond to a more potent second-generation ALK inhibitor like ceritinib or alectinib. Even though we’ve defined these different on-target and off-target mechanisms of resistance, at the end of the day, most patients do respond to more potent ALK inhibitors.

Transcript Edited for Clarity
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