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Targeted TKIs Used for Treatment of ALK-Positive NSCLC

Insights From: Robert C. Doebele, MD, PhD, University of Colorado School of Medicine; Thomas E. Stinchcombe, MD, Duke Cancer Center; David Spigel, MD, Sarah Cannon Research Institute
Published: Friday, Jul 12, 2019



Transcript: 

Robert C. Doebele, MD, PhD: The common variants of ALK gene fusions in lung cancer are most often EML4-ALK. However, there are multiple variants of EML4-ALK where the ALK portion remains the same and there are different lengths of the EML4 gene that have been identified. We can pick those up only if we’re using testing techniques that include next-generation sequencing methods. If we’re using fluorescence in situ hybridization, FISH, or immunohistochemistry [IHC], we can’t tell what type of EML4-ALK variants they are.

There are other variants besides EML4-ALK. For example, KIF5B-ALK. We don’t really understand the true significance of these different variants in terms of patient outcomes or differential treatment, although there are some very interesting emerging data, where different forms of EML4-ALK may predict different types of drug resistance later on. For example, the 2 most common variants are called variant 1 and variant 3, and again, those correspond to different lengths of the EML4 gene, and we’ve seen that there are different resistance patterns.

Variant 1 gene fusions are much less likely to get G1202R mutations than variant 3. Whether that impacts progression-free survival on the drugs or whether that impacts overall survival, we don’t yet know. But I think it’s an interesting area of study, and 1 that can really be ascertained only by doing more modern techniques of testing, including next-generation sequencing.

Our patients with ALK-positive non–small cell lung cancer can look like other patients with non–small cell lung cancer. Although typically we think of these patients as being younger and never smokers, that may not necessarily be true. Probably about 35% to 40% of ALK-positive patients are former or current smokers. They are often older as well. Some more recent studies have suggested that the average age of an ALK-positive non–small cell lung cancer patient may be no different from an unselected non–small cell lung cancer patient.

And the reason that’s important to keep in mind is that we really don’t want to profile our patients and withhold testing based on their characteristics, whether they smoked or not, whether they’re young or old, whether they’re from different ethnic backgrounds, because we know that patients of all types can actually—that their tumors can harbor the ALK gene rearrangement.

We really should be testing all our patients for this because there’s a reasonable chance that even older patients or former smokers may harbor this gene, and we want to offer our patients the best therapy.

Thomas E. Stinchcombe, MD: For those of us who started in the field a while ago, this has been a fascinating journey with ALK-positive patients. First, the target was identified around 2007, and then crizotinib was approved based on a phase I trial expansion cohort. Then it was compared with chemotherapy in the second-line setting and then to chemotherapy in the first-line setting, where it became a targeted first-line therapy.

Those experiences taught us a lot in that if you’re going to develop a drug, it’s very important to have the target identified and enriched for the patient population most likely to respond, and that was crizotinib. The median progression-free survival was going to be about 10 months. And there were some flaws with crizotinib in that it didn’t penetrate the blood-brain barrier very well, and so many patients either had brain metastases at baseline or developed brain metastases, and that was a frequent clinical problem in a site of disease progression. Next came the next-generation ALK inhibitors, and these were very specifically engineered to be more potent and to have a narrower spectrum, which reduces toxicities and penetrates the blood-brain barrier. I think that these have been a tremendous advance in the treatment of ALK-positive patients.

One of the challenges identifying patients is the testing methods and that we continue to struggle with. Initially, we had the ALK FISH probe, and you had to have…positive greater than 15% of patients. There were concerns about the sample quality. This interpretation of the test was very user dependent and challenging. Then we developed the ALK IHC test, and that’s also FDA approved, which made it a little bit simpler. More and more, we’re moving to next-generation sequencing as a method of really testing a broad variety of targets in patients in a single test. And there are sort of 2 varieties of this: the solid-tumor, next-generation sequencing testing as well as the liquid tumor testing. I think this has allowed more patients to be tested, because as a clinician we just never want to miss a patient who has an ALK rearrangement.

The liquid biopsies are revolutionizing the care of patients with a non–small cell lung cancer with nonsquamous disease. Historically, we’ve done tumor biopsies, and then we’ve done a liquid biopsy if there was insufficient tissue or if they had an EGFR TKI at the time of disease progression, hoping to identify the T790M mutation in the case of the EGFR. There are more and more studies showing that there’s a high concordance between the liquid and the solid-tumor biopsy. And the turnaround time is actually shorter with the liquid biopsy, and the panels now get about 70 to 80 genes, which is a broad testing panel, and so I think there’s some increased efficiency for this.

I think 1 of the other interesting things [is] do you do liquid biopsies and then do the tumor biopsy if the liquid biopsy is negative? Because we know there will be some false negatives. Or do you send them both off at the same time, thinking that will be a more comprehensive approach? Because we know that the solid-tumor biopsies miss about 10% because of inadequate samples, maybe tumor heterogeneity, and other factors.

Transcript Edited for Clarity
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Transcript: 

Robert C. Doebele, MD, PhD: The common variants of ALK gene fusions in lung cancer are most often EML4-ALK. However, there are multiple variants of EML4-ALK where the ALK portion remains the same and there are different lengths of the EML4 gene that have been identified. We can pick those up only if we’re using testing techniques that include next-generation sequencing methods. If we’re using fluorescence in situ hybridization, FISH, or immunohistochemistry [IHC], we can’t tell what type of EML4-ALK variants they are.

There are other variants besides EML4-ALK. For example, KIF5B-ALK. We don’t really understand the true significance of these different variants in terms of patient outcomes or differential treatment, although there are some very interesting emerging data, where different forms of EML4-ALK may predict different types of drug resistance later on. For example, the 2 most common variants are called variant 1 and variant 3, and again, those correspond to different lengths of the EML4 gene, and we’ve seen that there are different resistance patterns.

Variant 1 gene fusions are much less likely to get G1202R mutations than variant 3. Whether that impacts progression-free survival on the drugs or whether that impacts overall survival, we don’t yet know. But I think it’s an interesting area of study, and 1 that can really be ascertained only by doing more modern techniques of testing, including next-generation sequencing.

Our patients with ALK-positive non–small cell lung cancer can look like other patients with non–small cell lung cancer. Although typically we think of these patients as being younger and never smokers, that may not necessarily be true. Probably about 35% to 40% of ALK-positive patients are former or current smokers. They are often older as well. Some more recent studies have suggested that the average age of an ALK-positive non–small cell lung cancer patient may be no different from an unselected non–small cell lung cancer patient.

And the reason that’s important to keep in mind is that we really don’t want to profile our patients and withhold testing based on their characteristics, whether they smoked or not, whether they’re young or old, whether they’re from different ethnic backgrounds, because we know that patients of all types can actually—that their tumors can harbor the ALK gene rearrangement.

We really should be testing all our patients for this because there’s a reasonable chance that even older patients or former smokers may harbor this gene, and we want to offer our patients the best therapy.

Thomas E. Stinchcombe, MD: For those of us who started in the field a while ago, this has been a fascinating journey with ALK-positive patients. First, the target was identified around 2007, and then crizotinib was approved based on a phase I trial expansion cohort. Then it was compared with chemotherapy in the second-line setting and then to chemotherapy in the first-line setting, where it became a targeted first-line therapy.

Those experiences taught us a lot in that if you’re going to develop a drug, it’s very important to have the target identified and enriched for the patient population most likely to respond, and that was crizotinib. The median progression-free survival was going to be about 10 months. And there were some flaws with crizotinib in that it didn’t penetrate the blood-brain barrier very well, and so many patients either had brain metastases at baseline or developed brain metastases, and that was a frequent clinical problem in a site of disease progression. Next came the next-generation ALK inhibitors, and these were very specifically engineered to be more potent and to have a narrower spectrum, which reduces toxicities and penetrates the blood-brain barrier. I think that these have been a tremendous advance in the treatment of ALK-positive patients.

One of the challenges identifying patients is the testing methods and that we continue to struggle with. Initially, we had the ALK FISH probe, and you had to have…positive greater than 15% of patients. There were concerns about the sample quality. This interpretation of the test was very user dependent and challenging. Then we developed the ALK IHC test, and that’s also FDA approved, which made it a little bit simpler. More and more, we’re moving to next-generation sequencing as a method of really testing a broad variety of targets in patients in a single test. And there are sort of 2 varieties of this: the solid-tumor, next-generation sequencing testing as well as the liquid tumor testing. I think this has allowed more patients to be tested, because as a clinician we just never want to miss a patient who has an ALK rearrangement.

The liquid biopsies are revolutionizing the care of patients with a non–small cell lung cancer with nonsquamous disease. Historically, we’ve done tumor biopsies, and then we’ve done a liquid biopsy if there was insufficient tissue or if they had an EGFR TKI at the time of disease progression, hoping to identify the T790M mutation in the case of the EGFR. There are more and more studies showing that there’s a high concordance between the liquid and the solid-tumor biopsy. And the turnaround time is actually shorter with the liquid biopsy, and the panels now get about 70 to 80 genes, which is a broad testing panel, and so I think there’s some increased efficiency for this.

I think 1 of the other interesting things [is] do you do liquid biopsies and then do the tumor biopsy if the liquid biopsy is negative? Because we know there will be some false negatives. Or do you send them both off at the same time, thinking that will be a more comprehensive approach? Because we know that the solid-tumor biopsies miss about 10% because of inadequate samples, maybe tumor heterogeneity, and other factors.

Transcript Edited for Clarity
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