VISIT US IN CHICAGO JUNE 2-4 AT BOOTH 2073!

Browse by Series:

Development of ALK-Targeted Therapy for NSCLC

Mark A. Socinski, MD
Published: Friday, Jun 16, 2017



Transcript:

Mark A. Socinski, MD:
The introduction of targeted agents in the ALK-positive, as well as the ROS1 non–small cell lung cancer patients, has really revolutionized and changed the standard of care. 2007 was the year that ALK was first described in adenocarcinoma of the lung. Shortly thereafter, it was discovered that crizotinib had activity in this disease, even though crizotinib was entered in clinical trials thinking it was, and actually it is, a MET inhibitor. However, it does have ALK activity. It was developed in that space and approved in that space in a relatively short period of time, coming to market in 2011.

In the course of that, we had 2 profile trials that compared crizotinib to the standard-of-care chemotherapy in the ALK-positive patients. The first one was in the second-line setting, and crizotinib was superior in response in progression-free survival compared to either docetaxel or pemetrexed, which were second-line cytotoxic standards. And then there was a second profile trial that looked at crizotinib versus a platinum/pemetrexed combination in the first-line setting. Once again, the response rate to crizotinib, as well as the progression-free survival, was superior to the orally administered crizotinib relative to platinum-based chemotherapy. So, in a relatively short period of time, we really had, in that population, a change in how we managed our patients.

Now ALK and ROS have a lot of homology in terms of the translocation protein. Crizotinib does have substantial activity in ROS1-positive patients. We saw a response rate of 70% or so in a progression-free survival rate of 19 months, which is quite remarkable. We don’t have any randomized data relative to chemotherapy in the ROS1 space, but I think that response rate in that progression-free survival time is so outstanding that I don’t think that chemotherapy would even come close to that in that population. So, I would advocate that we don’t necessarily need a randomized trial in the ROS1-positive space because of the great activity of crizotinib.

Although crizotinib is an effective treatment, it is not a curable treatment. So, patients will progress. On average, it’s in the 9- to 10-month range. And when you’re treating with crizotinib, there are a number of different mechanisms of resistance. We divide them into ALK-mediated resistance, and from crizotinib, that either means amplification of the ALK gene or secondary mutations in the protein that make it resistant to crizotinib. There are a number of other non–ALK mediated mechanisms—such as the bypass track activation, KRAS, EGFR, and others—that have been described in this space. So, those are the major mechanisms of resistance to crizotinib, which, again, typically occur about 9- to 10-months into treatment.

We now have 3 ALK-specific agents. We refer to them as the second-generation ALK agents. The first was ceritinib, the second was alectinib, and the third now is brigatinib. These are more potent ALK inhibitors, and all of them were at least initially tested in patients who have failed crizotinib.

We know that after failing crizotinib, in the activity of these true ALK inhibitors, or second-generation drugs, the response rates are 50% or above. Again, the progression-free survival times range roughly from 9 to 12 months. The toxicity patterns are very favorable for patients. And so, the introduction of these agents into this space really has increased the number of options that we have for patients who initially fail crizotinib.

I think the real key is, what’s the role of rebiopsy, or retesting, once an ALK patient has progressed? To draw an analogy of that, we know in the EGFR-positive patients that there’s a dominance of a secondary mutation called T790M and it occurs in about 60% of patients. So, in the EGFR-mutant space, we do retest either with plasma or with tissue to look for T790M because we have a very good T790M drug.

In the ALK space, after a crizotinib failure, I mentioned the non-ALK– versus ALK-mediated mechanisms of resistance. In the ALK-mediated mechanisms of resistance, secondary mutations do occur. But following crizotinib, only about 25% to 30% of patients have a secondary mutation as a reason for their pattern of resistance, and there’s no 1 dominant mutation. There has actually been maybe 15 or so described in that space, but not a dominant one like we see in the EGFR space with T790M.

So, from a practice or from a clinical point of view, we haven’t necessarily embraced the concept of rebiopsy and retesting in the ALK space because it was uncertain how to use that data. I think with the advent of the second-generation drugs that we’ve mentioned—ceritinib, alectinib, brigatinib—we know that all of these are active after crizotinib and that they have a different pattern of activity against different mutations that are seen in this setting. When you have a number of choices, and certainly we want to get the best drug to the patient, I think retesting takes on a different level of importance in this setting because there are specific secondary mutations that may be best treated with, say, brigatinib versus alectinib. I think it’s going to become increasingly important over time.

Transcript Edited for Clarity
Slider Left
Slider Right


Transcript:

Mark A. Socinski, MD:
The introduction of targeted agents in the ALK-positive, as well as the ROS1 non–small cell lung cancer patients, has really revolutionized and changed the standard of care. 2007 was the year that ALK was first described in adenocarcinoma of the lung. Shortly thereafter, it was discovered that crizotinib had activity in this disease, even though crizotinib was entered in clinical trials thinking it was, and actually it is, a MET inhibitor. However, it does have ALK activity. It was developed in that space and approved in that space in a relatively short period of time, coming to market in 2011.

In the course of that, we had 2 profile trials that compared crizotinib to the standard-of-care chemotherapy in the ALK-positive patients. The first one was in the second-line setting, and crizotinib was superior in response in progression-free survival compared to either docetaxel or pemetrexed, which were second-line cytotoxic standards. And then there was a second profile trial that looked at crizotinib versus a platinum/pemetrexed combination in the first-line setting. Once again, the response rate to crizotinib, as well as the progression-free survival, was superior to the orally administered crizotinib relative to platinum-based chemotherapy. So, in a relatively short period of time, we really had, in that population, a change in how we managed our patients.

Now ALK and ROS have a lot of homology in terms of the translocation protein. Crizotinib does have substantial activity in ROS1-positive patients. We saw a response rate of 70% or so in a progression-free survival rate of 19 months, which is quite remarkable. We don’t have any randomized data relative to chemotherapy in the ROS1 space, but I think that response rate in that progression-free survival time is so outstanding that I don’t think that chemotherapy would even come close to that in that population. So, I would advocate that we don’t necessarily need a randomized trial in the ROS1-positive space because of the great activity of crizotinib.

Although crizotinib is an effective treatment, it is not a curable treatment. So, patients will progress. On average, it’s in the 9- to 10-month range. And when you’re treating with crizotinib, there are a number of different mechanisms of resistance. We divide them into ALK-mediated resistance, and from crizotinib, that either means amplification of the ALK gene or secondary mutations in the protein that make it resistant to crizotinib. There are a number of other non–ALK mediated mechanisms—such as the bypass track activation, KRAS, EGFR, and others—that have been described in this space. So, those are the major mechanisms of resistance to crizotinib, which, again, typically occur about 9- to 10-months into treatment.

We now have 3 ALK-specific agents. We refer to them as the second-generation ALK agents. The first was ceritinib, the second was alectinib, and the third now is brigatinib. These are more potent ALK inhibitors, and all of them were at least initially tested in patients who have failed crizotinib.

We know that after failing crizotinib, in the activity of these true ALK inhibitors, or second-generation drugs, the response rates are 50% or above. Again, the progression-free survival times range roughly from 9 to 12 months. The toxicity patterns are very favorable for patients. And so, the introduction of these agents into this space really has increased the number of options that we have for patients who initially fail crizotinib.

I think the real key is, what’s the role of rebiopsy, or retesting, once an ALK patient has progressed? To draw an analogy of that, we know in the EGFR-positive patients that there’s a dominance of a secondary mutation called T790M and it occurs in about 60% of patients. So, in the EGFR-mutant space, we do retest either with plasma or with tissue to look for T790M because we have a very good T790M drug.

In the ALK space, after a crizotinib failure, I mentioned the non-ALK– versus ALK-mediated mechanisms of resistance. In the ALK-mediated mechanisms of resistance, secondary mutations do occur. But following crizotinib, only about 25% to 30% of patients have a secondary mutation as a reason for their pattern of resistance, and there’s no 1 dominant mutation. There has actually been maybe 15 or so described in that space, but not a dominant one like we see in the EGFR space with T790M.

So, from a practice or from a clinical point of view, we haven’t necessarily embraced the concept of rebiopsy and retesting in the ALK space because it was uncertain how to use that data. I think with the advent of the second-generation drugs that we’ve mentioned—ceritinib, alectinib, brigatinib—we know that all of these are active after crizotinib and that they have a different pattern of activity against different mutations that are seen in this setting. When you have a number of choices, and certainly we want to get the best drug to the patient, I think retesting takes on a different level of importance in this setting because there are specific secondary mutations that may be best treated with, say, brigatinib versus alectinib. I think it’s going to become increasingly important over time.

Transcript Edited for Clarity
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Oncology Briefings™: Updates in Novel Therapeutic Options for Lung Neuroendocrine TumorsMay 31, 20181.0
Community Practice Connections™: Working Group to Optimize Outcomes in EGFR-mutated Lung Cancers: Evolving Concepts for Nurses to Facilitate and Improve Patient CareJun 30, 20181.5
Publication Bottom Border
Border Publication
x