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CNS Activity With Next-Generation ALK Inhibitors

Panelists: Mary Jo Fidler, MD, Rush; Roy S. Herbst, MD, PhD, Yale ; Geoffrey R. Oxnard, MD, Harvard; Naiyer Rizvi, MD, Columbia; Mark A. Socinski, MD,
Published: Thursday, Sep 10, 2015


Transcript: 

Mark A. Socinski, MD: Let’s switch gears a little bit. Roy, I’m going to ask you to briefly talk about ALK-related disease, and we also heard some data at ASCO about another second-generation ALK inhibitor alectinib in this population. Of course, we know we have crizotinib and ceritinib out there now, but what are your thoughts around this new data on alectinib?

Roy S. Herbst, MD, PhD: Well, it’s as we talked about, that the promise of these kinase inhibitors is their responses rates which are high and the challenge, of course, is that most patients become resistant. Of course, we have several drugs in class now, crizotinib and ceritinib for those who are becoming resistant. Certainly, alectinib is another example of a drug with quite impressive activity in the refractory setting. Certainly, it gives us a number of choices.

We’re going to really need to figure out which mutations respond best to which drug. My sense is that it’s still evolving, but certainly the fact is that there are now second generation and soon to be third generation agents. The other thing to look at with all these agents is the toxicity profile. Like with everything else, these agents are given for long periods of time, so one has to look at the most specific, I guess you would say, kinase inhibitor to have the least rash and diarrhea. It’s great that there are data now for multiple agents in this class.

Mark A. Socinski, MD: We’ve used alectinib a fair amount at our center. I must say it’s a well-tolerated drug in this population with a good amount of activity. The other impressive thing and what we do all the time in the ALK population is brain disease, and there were some nice data with regard to response in the brain. That’s a major issue for us in this setting.

Mary Jo Fidler, MD: And the responses in the brain seem to parallel the responses outside of the brain, and also they seem to be nearly as durable.

Mark A. Socinski, MD: Right.

Geoffrey R. Oxnard, MD: I think crizotinib is going to be an easier drug to beat in the first-line with one of these new drugs. Crizotinib isn’t the perfect ALK inhibitor. It has a lot of these brain failures. It was the first-in-class drug, but I think it will be easier to beat crizotinib than it will be to beat erlotinib, gefitinib, afatinib for first-line EGFR drugs.

Alectinib certainly has a toxicity profile that I find my patients have an easier time with than ceritinib, where it can be hard to manage. Again, as you described, over months and months and months of diarrhea and anorexia, ceritinib can be tough on patients.

Mark A. Socinski, MD: Like we mentioned in the EGFR space, I believe the ALEX trial is fairly close to finishing its accrual which compares in the first-line setting crizotinib to alectinib. I tend to agree with you. I think that’s a lower bar to get over relative to the EGFR space in that particular setting.

Geoffrey R. Oxnard, MD: If only you can prevent the brain metastases. That on its own is such a big problem. In my young outpatients, I’m reaching for ceritinib or alectinib second-line instead of whole brain radiation, trying to prevent that morbid intervention and prolong their time.

Mark A. Socinski, MD: How do you follow your patients for brain disease?

Geoffrey R. Oxnard, MD: I do a lot of brain MRIs, but I do it after. I don’t do surveillance brain MRIs without brain metastases being identified. But I have patients who have very little systemic disease and I primarily work with a neuro-oncologist on ceritinib or on alectinib to follow the brain metastases.

Roy S. Herbst, MD, PhD: Do you have a size that makes you concerned? If the brain lesions are more than a certain size, do you then use Gamma Knife or some other procedure?

Geoffrey R. Oxnard, MD: We certainly do — or when do you bite the bullet and go for whole brain radiation? We’re learning about this, and we’re really creating a patient population that we’re learning about as we go that’s been created because of ALK and crizotinib.

Mark A. Socinski, MD: The data at ASCO, I think, with regards to the brain responses in lieu of radiation is very helpful in day to day practice. It’s a prominent issue. Many times since we’re frequently doing MRIs, we find very small lesions that are asymptomatic, don’t have a lot of edema associated with them. Having the option of switching to these second generation agents I think is a real advantage in the ability to delay radiotherapy for some time, maybe not forever, but for some time. I think it’s important in this population.
Transcript Edited for Clarity
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Transcript: 

Mark A. Socinski, MD: Let’s switch gears a little bit. Roy, I’m going to ask you to briefly talk about ALK-related disease, and we also heard some data at ASCO about another second-generation ALK inhibitor alectinib in this population. Of course, we know we have crizotinib and ceritinib out there now, but what are your thoughts around this new data on alectinib?

Roy S. Herbst, MD, PhD: Well, it’s as we talked about, that the promise of these kinase inhibitors is their responses rates which are high and the challenge, of course, is that most patients become resistant. Of course, we have several drugs in class now, crizotinib and ceritinib for those who are becoming resistant. Certainly, alectinib is another example of a drug with quite impressive activity in the refractory setting. Certainly, it gives us a number of choices.

We’re going to really need to figure out which mutations respond best to which drug. My sense is that it’s still evolving, but certainly the fact is that there are now second generation and soon to be third generation agents. The other thing to look at with all these agents is the toxicity profile. Like with everything else, these agents are given for long periods of time, so one has to look at the most specific, I guess you would say, kinase inhibitor to have the least rash and diarrhea. It’s great that there are data now for multiple agents in this class.

Mark A. Socinski, MD: We’ve used alectinib a fair amount at our center. I must say it’s a well-tolerated drug in this population with a good amount of activity. The other impressive thing and what we do all the time in the ALK population is brain disease, and there were some nice data with regard to response in the brain. That’s a major issue for us in this setting.

Mary Jo Fidler, MD: And the responses in the brain seem to parallel the responses outside of the brain, and also they seem to be nearly as durable.

Mark A. Socinski, MD: Right.

Geoffrey R. Oxnard, MD: I think crizotinib is going to be an easier drug to beat in the first-line with one of these new drugs. Crizotinib isn’t the perfect ALK inhibitor. It has a lot of these brain failures. It was the first-in-class drug, but I think it will be easier to beat crizotinib than it will be to beat erlotinib, gefitinib, afatinib for first-line EGFR drugs.

Alectinib certainly has a toxicity profile that I find my patients have an easier time with than ceritinib, where it can be hard to manage. Again, as you described, over months and months and months of diarrhea and anorexia, ceritinib can be tough on patients.

Mark A. Socinski, MD: Like we mentioned in the EGFR space, I believe the ALEX trial is fairly close to finishing its accrual which compares in the first-line setting crizotinib to alectinib. I tend to agree with you. I think that’s a lower bar to get over relative to the EGFR space in that particular setting.

Geoffrey R. Oxnard, MD: If only you can prevent the brain metastases. That on its own is such a big problem. In my young outpatients, I’m reaching for ceritinib or alectinib second-line instead of whole brain radiation, trying to prevent that morbid intervention and prolong their time.

Mark A. Socinski, MD: How do you follow your patients for brain disease?

Geoffrey R. Oxnard, MD: I do a lot of brain MRIs, but I do it after. I don’t do surveillance brain MRIs without brain metastases being identified. But I have patients who have very little systemic disease and I primarily work with a neuro-oncologist on ceritinib or on alectinib to follow the brain metastases.

Roy S. Herbst, MD, PhD: Do you have a size that makes you concerned? If the brain lesions are more than a certain size, do you then use Gamma Knife or some other procedure?

Geoffrey R. Oxnard, MD: We certainly do — or when do you bite the bullet and go for whole brain radiation? We’re learning about this, and we’re really creating a patient population that we’re learning about as we go that’s been created because of ALK and crizotinib.

Mark A. Socinski, MD: The data at ASCO, I think, with regards to the brain responses in lieu of radiation is very helpful in day to day practice. It’s a prominent issue. Many times since we’re frequently doing MRIs, we find very small lesions that are asymptomatic, don’t have a lot of edema associated with them. Having the option of switching to these second generation agents I think is a real advantage in the ability to delay radiotherapy for some time, maybe not forever, but for some time. I think it’s important in this population.
Transcript Edited for Clarity
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