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Treating ALK-Mutated NSCLC With Disease Progression

Panelists: Benjamin P. Levy, MD, Johns Hopkins Sidney Kimmel Cancer Center; Lyudmila A. Bazhenova, MD, University of California San Diego; Alexander Drilon, MD, Memorial Sloan Kettering Cancer Center; Zofia Piotrowska, MD, Massachusetts General Hospital Cancer Center; Jonathan W. Riess, MD, MS, UC Davis Comprehensive Cancer Center
Published: Friday, Aug 31, 2018



Transcript: 

Benjamin P. Levy, MD: Now we have the first-line data, and I think it’s firmly cemented. I think we can all agree that it’s firmly cemented, alectinib as the preferred first-line drug for ALK-positive stage 4 patients. But we have a lot of data that’s emerged with brigatinib, ceritinib, and alectinib that started out in the second-line setting. Lyudmila, do you want to go through the data and highlight the brigatinib data that we have so far?

Lyudmila A. Bazhenova, MD: Sure. We all agree that alectinib is currently our de facto, preferred first-line agent. However, we still have patients who are currently receiving crizotinib. And remember, alectinib is not yet approved in Canada or Europe as a first-line option. There is only access to alectinib as a first-line option in the United States.
There are a lot of patients who may still be doing well on crizotinib. When they progress, you basically have 3 options. You have ceritinib, which has been tested in a post crizotinib setting. The response rates are approximately 60% to 70%, with a progression-free survival rate that is around 7 months. Then you have alectinib. In 2 studies, in the crizotinib-failure setting, the response rates were about 60% to 70%, and the progression-free survival was around 9 months.

And then you have brigatinib. I want to spend a little bit more time talking about brigatinib, because the data is a little bit more recent. Brigatinib has been studied in a trial called ALTA. The ALTA study looked at patients who were failing with crizotinib, who were not exposed to other second-generation ALK tyrosine kinase inhibitors. They did not use ceritinib or alectinib. They were allowed to have prior chemotherapy. Patients were randomly assigned to 2 groups: 90 mg continuous versus vs 90 mg for 7 days, leading to an increase to 180 mg. Those arms were not designed to be statistically compared. The reason why 2 arms were done was so that we could choose which of those dose combinations to move forward with for approval. There is actually a rationale for using a higher dose of brigatinib, because it has a higher CNS response rate. It has a higher CNS progression-free survival. It has a higher systemic progression-free survival. That’s why the ALTA study was necessary to confirm that finding. ALTA did show that the progression-free survival of brigatinib in the crizotinib-failure setting was 15.6 months.

Benjamin P. Levy, MD: One of the highest progression-free survivals that we’ve seen in the second-line setting.

Lyudmila A. Bazhenova, MD: And this is not the only study. A phase I study was just updated at the last ASCO Annual Meeting. In the phase I brigatinib study, in the crizotinib-naive population, the progression-free survival was 16 months. If you compare those drugs side by side, brigatinib does have the longest reported progression-free survival with all of the caveats of cross-trial comparisons. But we have to do it, because we don’t have any other studies. In the preclinical data, there is actually a rationale for why brigatinib might give you a higher progression-free survival. If you look at IC50s for inhibition of different ALK-resistant mutations, brigatinib seems to cover all of them except ceritinib and alectinib. There are certain pockets of resistant mutations that ceritinib and alectinib may be resistant to.

The drug is relatively well tolerated. There is about a 30% chance for mild nausea, a 30% chance for mild diarrhea, and 17% of patients will get hypertension. There is a very rare side effect that I think we need to talk about: early onset pulmonary events. The incidence of early onset pulmonary events is about 12% in all grades. The incidence of grade 3 early onset pulmonary events is about 3%, so it’s rare. It’s not a pneumonitis, because the timing of the event is different. It usually happens around day number 2. Patients may develop dyspnea. They may develop hypoxia. You can stop the drug and everything usually goes away within 3, 4, or 5 days. And then you can rechallenge. The symptoms might not recur upon the rechallenge.

If you’re thinking about prescribing brigatinib, just be aware that you have to pay attention to shortness of breath for about 2, 3 days after the first dose. That was the rationale for doing 90 mg followed by 180 mg. When brigatinib was studied in a phase I trial, the early onset pulmonary events were dose related.

Benjamin P. Levy, MD: That’s a very nice summary of brigatinib, and it puts it in context of the other drugs. Where does this drug go? Compared with the other second-line data, it looks very convincing. We’re going to have a frontline study—where it’s compared with crizotinib—report out very soon. If we see similar results to what we saw in the ALEX study, or even better, and we see second-line results that are a little bit better than alectinib, does this drug potentially enter the market in the first-line setting, after this frontline ALTA data?

Lyudmila A. Bazhenova, MD: I think it could. We do have a little preview of what the first-line efficacy of brigatinib is. In the phase I study, there were 8 patients enrolled who were crizotinib naive. The response rate was 100%, and there was a progression-free survival of 32 months. So, it is possible that this drug, after ALTA-1L, which is expected to be released by the end of this year or the beginning of next year, might add one more drug to our first-line setting. The question is going to be, what are we going to do after your patient has failed with alectinib or has failed with brigatinib in the first-line setting?

Benjamin P. Levy, MD: Sequencing strategies is always a challenge. It’s somewhat of an embarrassment of riches to have all of these drugs. Who would have thought we would have been struggling with what to sequence and how, given how few targeted therapies we had 5 to 10 years ago. Speaking of more drugs in the ALK space, we have lorlatinib, a next-generation ALK inhibitor. We have seen some data with lorlatinib, an update to what we’ve seen before. Zofia, can you walk us through the data with lorlatinib?

Zofia Piotrowska, MD: I think you’re right. It’s really humbling to have so many different drugs. Lorlatinib, a third-generation ALK and ROS-1 inhibitor, was designed not only to be a very potent ALK and ROS-1 inhibitor, but also to have very good brain penetration. The data that’s been shown so far, and was updated at the 2018 ASCO Annual Meeting, has been very promising. They’ve looked at lorlatinib in patients who were pretreated only with prior crizotinib, and then, really strikingly, in patients who were pretreated with 1 or 2 prior lines of second-generation ALK inhibitors, or even patients who had 3 or more prior ALK inhibitors. It’s really striking that we are in a situation where this is even a population to consider.

We saw really impressive results across the board. That’s really the bottom line with lorlatinib. In the lorlatinib study, they looked at systemic response rate and intracranial response rate. We really see that lorlatinib is highly effective, whether other patients have been treated previously with crizotinib or any number of prior first- or second-generation ALK inhibitors. In patients who were treated with prior second-generation ALK inhibitors, we’re seeing overall systemic response rates in the 40% range and intracranial response rates in the 40% range as well. And the duration of response in the intracranial setting can be 15 months or so. So, I think lorlatinib is really a very promising drug. We’re very excited to see more data with lorlatinib, and I’m really hoping to see it move into widespread use.

Benjamin P. Levy, MD: I’ll ask you the same question that I asked Lyudmila. Where does this drug fit in? Is it going to be in the refractory setting, post alectinib? Do we move it into the frontline setting?

Zofia Piotrowska, MD: I think the theme of targeted therapies in 2018 is that when a drug works in later lines of therapy, we ultimately want to see what it does in the frontline setting. Soon, it is hopefully going to be here for later lines of therapy for patients who have been previously treated with alectinib, brigatinib, ceritinib, or other second-generation drugs. But ultimately, I look forward to seeing the first-line data, because I think it could be very promising there as well.

Transcript Edited for Clarity 

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Transcript: 

Benjamin P. Levy, MD: Now we have the first-line data, and I think it’s firmly cemented. I think we can all agree that it’s firmly cemented, alectinib as the preferred first-line drug for ALK-positive stage 4 patients. But we have a lot of data that’s emerged with brigatinib, ceritinib, and alectinib that started out in the second-line setting. Lyudmila, do you want to go through the data and highlight the brigatinib data that we have so far?

Lyudmila A. Bazhenova, MD: Sure. We all agree that alectinib is currently our de facto, preferred first-line agent. However, we still have patients who are currently receiving crizotinib. And remember, alectinib is not yet approved in Canada or Europe as a first-line option. There is only access to alectinib as a first-line option in the United States.
There are a lot of patients who may still be doing well on crizotinib. When they progress, you basically have 3 options. You have ceritinib, which has been tested in a post crizotinib setting. The response rates are approximately 60% to 70%, with a progression-free survival rate that is around 7 months. Then you have alectinib. In 2 studies, in the crizotinib-failure setting, the response rates were about 60% to 70%, and the progression-free survival was around 9 months.

And then you have brigatinib. I want to spend a little bit more time talking about brigatinib, because the data is a little bit more recent. Brigatinib has been studied in a trial called ALTA. The ALTA study looked at patients who were failing with crizotinib, who were not exposed to other second-generation ALK tyrosine kinase inhibitors. They did not use ceritinib or alectinib. They were allowed to have prior chemotherapy. Patients were randomly assigned to 2 groups: 90 mg continuous versus vs 90 mg for 7 days, leading to an increase to 180 mg. Those arms were not designed to be statistically compared. The reason why 2 arms were done was so that we could choose which of those dose combinations to move forward with for approval. There is actually a rationale for using a higher dose of brigatinib, because it has a higher CNS response rate. It has a higher CNS progression-free survival. It has a higher systemic progression-free survival. That’s why the ALTA study was necessary to confirm that finding. ALTA did show that the progression-free survival of brigatinib in the crizotinib-failure setting was 15.6 months.

Benjamin P. Levy, MD: One of the highest progression-free survivals that we’ve seen in the second-line setting.

Lyudmila A. Bazhenova, MD: And this is not the only study. A phase I study was just updated at the last ASCO Annual Meeting. In the phase I brigatinib study, in the crizotinib-naive population, the progression-free survival was 16 months. If you compare those drugs side by side, brigatinib does have the longest reported progression-free survival with all of the caveats of cross-trial comparisons. But we have to do it, because we don’t have any other studies. In the preclinical data, there is actually a rationale for why brigatinib might give you a higher progression-free survival. If you look at IC50s for inhibition of different ALK-resistant mutations, brigatinib seems to cover all of them except ceritinib and alectinib. There are certain pockets of resistant mutations that ceritinib and alectinib may be resistant to.

The drug is relatively well tolerated. There is about a 30% chance for mild nausea, a 30% chance for mild diarrhea, and 17% of patients will get hypertension. There is a very rare side effect that I think we need to talk about: early onset pulmonary events. The incidence of early onset pulmonary events is about 12% in all grades. The incidence of grade 3 early onset pulmonary events is about 3%, so it’s rare. It’s not a pneumonitis, because the timing of the event is different. It usually happens around day number 2. Patients may develop dyspnea. They may develop hypoxia. You can stop the drug and everything usually goes away within 3, 4, or 5 days. And then you can rechallenge. The symptoms might not recur upon the rechallenge.

If you’re thinking about prescribing brigatinib, just be aware that you have to pay attention to shortness of breath for about 2, 3 days after the first dose. That was the rationale for doing 90 mg followed by 180 mg. When brigatinib was studied in a phase I trial, the early onset pulmonary events were dose related.

Benjamin P. Levy, MD: That’s a very nice summary of brigatinib, and it puts it in context of the other drugs. Where does this drug go? Compared with the other second-line data, it looks very convincing. We’re going to have a frontline study—where it’s compared with crizotinib—report out very soon. If we see similar results to what we saw in the ALEX study, or even better, and we see second-line results that are a little bit better than alectinib, does this drug potentially enter the market in the first-line setting, after this frontline ALTA data?

Lyudmila A. Bazhenova, MD: I think it could. We do have a little preview of what the first-line efficacy of brigatinib is. In the phase I study, there were 8 patients enrolled who were crizotinib naive. The response rate was 100%, and there was a progression-free survival of 32 months. So, it is possible that this drug, after ALTA-1L, which is expected to be released by the end of this year or the beginning of next year, might add one more drug to our first-line setting. The question is going to be, what are we going to do after your patient has failed with alectinib or has failed with brigatinib in the first-line setting?

Benjamin P. Levy, MD: Sequencing strategies is always a challenge. It’s somewhat of an embarrassment of riches to have all of these drugs. Who would have thought we would have been struggling with what to sequence and how, given how few targeted therapies we had 5 to 10 years ago. Speaking of more drugs in the ALK space, we have lorlatinib, a next-generation ALK inhibitor. We have seen some data with lorlatinib, an update to what we’ve seen before. Zofia, can you walk us through the data with lorlatinib?

Zofia Piotrowska, MD: I think you’re right. It’s really humbling to have so many different drugs. Lorlatinib, a third-generation ALK and ROS-1 inhibitor, was designed not only to be a very potent ALK and ROS-1 inhibitor, but also to have very good brain penetration. The data that’s been shown so far, and was updated at the 2018 ASCO Annual Meeting, has been very promising. They’ve looked at lorlatinib in patients who were pretreated only with prior crizotinib, and then, really strikingly, in patients who were pretreated with 1 or 2 prior lines of second-generation ALK inhibitors, or even patients who had 3 or more prior ALK inhibitors. It’s really striking that we are in a situation where this is even a population to consider.

We saw really impressive results across the board. That’s really the bottom line with lorlatinib. In the lorlatinib study, they looked at systemic response rate and intracranial response rate. We really see that lorlatinib is highly effective, whether other patients have been treated previously with crizotinib or any number of prior first- or second-generation ALK inhibitors. In patients who were treated with prior second-generation ALK inhibitors, we’re seeing overall systemic response rates in the 40% range and intracranial response rates in the 40% range as well. And the duration of response in the intracranial setting can be 15 months or so. So, I think lorlatinib is really a very promising drug. We’re very excited to see more data with lorlatinib, and I’m really hoping to see it move into widespread use.

Benjamin P. Levy, MD: I’ll ask you the same question that I asked Lyudmila. Where does this drug fit in? Is it going to be in the refractory setting, post alectinib? Do we move it into the frontline setting?

Zofia Piotrowska, MD: I think the theme of targeted therapies in 2018 is that when a drug works in later lines of therapy, we ultimately want to see what it does in the frontline setting. Soon, it is hopefully going to be here for later lines of therapy for patients who have been previously treated with alectinib, brigatinib, ceritinib, or other second-generation drugs. But ultimately, I look forward to seeing the first-line data, because I think it could be very promising there as well.

Transcript Edited for Clarity 
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