ONCAlert | Upfront Therapy for mRCC

Treating With ALK Inhibitors in NSCLC

Targeted Oncology
Published Online:7:18 PM, Mon August 19, 2019

Mark A. Socinksi, MD: Going back to alectinib now being the standard of care, what do you tell patients in terms of their expectations when you start someone on alectinib? How long do you say they’re likely to have disease control, but it gets back to the PFS [progression-free survival] data and that sort of thing?

Thomas E. Stinchcombe, MD: I generally tell patients that there’s about an 80%, 90% chance of response, and that they should feel symptomatically better in the first couple of weeks. I generally don’t use the term progression-free survival when I’m talking to a patient. I generally say, “This is going to control your cancer, generally, for about 2 or 3 years.” That is the term I’ve used because I think we want to emphasize that this is going to be a long-term therapy, and it’s actually really beneficial. I think this is important when we talk to patients, too, about those who need a rebiopsy. This is not an academic exercise. This is a real clinical benefit to you.

Mark A. Socinksi, MD: Let’s talk a little bit about progression. What do you typically see? Let me ask you about 1 example. You have a patient let’s say on alectinib who has good control of their systemic disease, and then they develop oligometastatic disease in the brain. How do you handle that patient?

Thomas E. Stinchcombe, MD: I think brain metastases is challenging because you have a number of options. One is, how many of them are there? Are they amenable to stereotactic radiosurgery? Generally, I would probably favor doing stereotactic radiosurgery if they’re asymptomatic and small, and then continue alectinib with closer surveillance.

Mark A. Socinksi, MD: As long as the systemic disease is controlled?

Thomas E. Stinchcombe, MD: Yes. Lorlatinib is now available, and that has some CNS [central nervous system] activity in patients who progress on next-generation ALK TKIs [tyrosine kinase inhibitors]. So maybe that’s an option. If our choices are between whole brain radiation therapy and a systemic therapy, I much prefer the systemic therapy because of the potential long-term neurocognitive effects associated with whole brain radiation.

Mark A. Socinksi, MD: That’s a good point. I was mainly focusing on the use of locoregional therapy in a limited number of brain metastases. But to your point, if you have diffuse brain metastases or leptomeningeal disease, it obviously might cause you to rethink the systemic strategy even though the systemic disease is controlled at the current time.

Thomas E. Stinchcombe, MD: Yes.

Mark A. Socinksi, MD: You alluded to the issue of rebiopsy at the time of progression. If you think back to where this came into vogue, it was really the EGFR-mutated patients on first-generation drugs, and we were looking specifically for T790M. That was a great story while it lasted. But in ALK, it’s always been kind of questionable, regarding the value or how informative a rebiopsy is. Of course, this is an evolving science. I guess the question is, do you routinely rebiopsy? And if you do, how often is that informative in terms of what you do next?

Thomas E. Stinchcombe, MD: I think this is, like you said, an evolving field. I think the purpose of the rebiopsy is based on some preliminary evidence that the presence or absence of a mutation may be associated with benefit of other ALK tyrosine kinase inhibition. These patients who remain ALK-dependent may benefit from additional ALK therapy. For the ones who are ALK-independent, mechanisms of resistance through bypass tracks and other things may not benefit from further ALK therapy but may need chemotherapy or some other clinical trial. I often will try and do the liquid biopsy because I consider that a low-risk, efficient procedure. Sometimes I will do a rebiopsy, and I think the 1 mutation that really stands out is the G1202R deletion because that tends to be a more potent resistance mutation. I think there is some preliminary evidence that lorlatinib has activity against that from the second-line trials.

Mark A. Socinksi, MD: I think we got a little discouraged early on because many of the studies looking at resistance mechanisms after crizotinib suggested that non-ALK resistance mechanisms were dominant versus ALK. And now with the second-generation drugs, it appears to be that more of the secondary mutations are in play.

Thomas E. Stinchcombe, MD: Yes. I think that’s a fascinating look into the biology. The more potent the ALK inhibition, the more likely you are to get an ALK tyrosine kinase mutation. And maybe crizotinib was not hitting these with the sufficient potency needed to induce the resistance mutation? I think that now the prevalence may be up to 50%, 60%. That may be an underestimate because sometimes these patients are hard to biopsy. The testing can be challenging. But I think that’s going to be the next step in the field, to segregate patients into specific ALK inhibitors based on the mutations with prospective data.

Mark A. Socinksi, MD: What’s your sense, and I realize that this may be a complete guess, after a drug like alectinib, if you retest at the time of progression, how often do you think you find something that may alter what you do next?

Thomas E. Stinchcombe, MD: I would assume I would find....

Mark A. Socinksi, MD: It’s a hard question.

Thomas E. Stinchcombe, MD: Yes, it’s a hard question.

Mark A. Socinksi, MD: That’s why I asked.

Thomas E. Stinchcombe, MD: It’s nice to be in that chair. I think we’d find ALK or resistance mutations 50%, 60% of the time. And then, the G1202R may be about 25% or 30% of all patients or so, about half the mutations. I think that’s a unique one. We might have preferentially used lorlatinib in that group of patients. I think it’s also going to be critical, as we try and develop new drugs in a clinical trial setting, to have that to help us understand. Really, these can transform to small cell lung cancer, but I think that’s reported less so than with the EGFR population. That’s another reason why if the disease is suddenly taking a more virulent turn, I think it’s definitely worth rebiopsying just to make sure that something has not changed. I think the other issue that no one likes to talk about is, we talk about the 50%, 60% of patients with ALK tyrosine kinase mutations. We don’t really know what’s going on with the other 30% or 40%, and I think that’s a huge area that the field needs to address at this point.

Mark A. Socinksi, MD: If you found a non-ALK resistance, what would you do in that situation? Would you empirically try another ALK inhibitor, or would you, getting back to our chemotherapy discussion, remember that chemotherapy can be helpful in these patients?

Thomas E. Stinchcombe, MD: I think chemotherapy would be the standard answer. I think I have seen 1 patient who had MET amplification and I got to crizotinib. There’s some interest that crizotinib may have some activity in those MET-amplified patients. And then there’s L1998, and there’s a case report that those may resensitize to crizotinib. I think the challenge is that these are all case reports and small things….

Mark A. Socinksi, MD: Anecdotal.

Thomas E. Stinchcombe, MD: Anecdotal.

Mark A. Socinksi, MD: They’re fascinating. There are several that showed that based on rebiopsies, you went from drug A to drug B, and you had a response. And it was all predicted based upon the secondary mutation. But these are all individual cases. Again, fascinating biology, but in clinical practice, realizing that the average community oncologist may see 1 or 2 of these patients a year, right?

Thomas E. Stinchcombe, MD: I think that brings up a good point. When I see second opinions of patients, if the patient hasn’t undergone a biopsy, I’m not critical of that physician or anything at this point because right now I think it’s a promising preliminary result, but it’s not enough to mandate that every patient undergo a biopsy. Because the question really is, how are you going to apply that to improve the patient’s life? I think that’s the next series of prospective trials.

Transcript edited for clarity.

Mark A. Socinksi, MD: Going back to alectinib now being the standard of care, what do you tell patients in terms of their expectations when you start someone on alectinib? How long do you say they’re likely to have disease control, but it gets back to the PFS [progression-free survival] data and that sort of thing?

Thomas E. Stinchcombe, MD: I generally tell patients that there’s about an 80%, 90% chance of response, and that they should feel symptomatically better in the first couple of weeks. I generally don’t use the term progression-free survival when I’m talking to a patient. I generally say, “This is going to control your cancer, generally, for about 2 or 3 years.” That is the term I’ve used because I think we want to emphasize that this is going to be a long-term therapy, and it’s actually really beneficial. I think this is important when we talk to patients, too, about those who need a rebiopsy. This is not an academic exercise. This is a real clinical benefit to you.

Mark A. Socinksi, MD: Let’s talk a little bit about progression. What do you typically see? Let me ask you about 1 example. You have a patient let’s say on alectinib who has good control of their systemic disease, and then they develop oligometastatic disease in the brain. How do you handle that patient?

Thomas E. Stinchcombe, MD: I think brain metastases is challenging because you have a number of options. One is, how many of them are there? Are they amenable to stereotactic radiosurgery? Generally, I would probably favor doing stereotactic radiosurgery if they’re asymptomatic and small, and then continue alectinib with closer surveillance.

Mark A. Socinksi, MD: As long as the systemic disease is controlled?

Thomas E. Stinchcombe, MD: Yes. Lorlatinib is now available, and that has some CNS [central nervous system] activity in patients who progress on next-generation ALK TKIs [tyrosine kinase inhibitors]. So maybe that’s an option. If our choices are between whole brain radiation therapy and a systemic therapy, I much prefer the systemic therapy because of the potential long-term neurocognitive effects associated with whole brain radiation.

Mark A. Socinksi, MD: That’s a good point. I was mainly focusing on the use of locoregional therapy in a limited number of brain metastases. But to your point, if you have diffuse brain metastases or leptomeningeal disease, it obviously might cause you to rethink the systemic strategy even though the systemic disease is controlled at the current time.

Thomas E. Stinchcombe, MD: Yes.

Mark A. Socinksi, MD: You alluded to the issue of rebiopsy at the time of progression. If you think back to where this came into vogue, it was really the EGFR-mutated patients on first-generation drugs, and we were looking specifically for T790M. That was a great story while it lasted. But in ALK, it’s always been kind of questionable, regarding the value or how informative a rebiopsy is. Of course, this is an evolving science. I guess the question is, do you routinely rebiopsy? And if you do, how often is that informative in terms of what you do next?

Thomas E. Stinchcombe, MD: I think this is, like you said, an evolving field. I think the purpose of the rebiopsy is based on some preliminary evidence that the presence or absence of a mutation may be associated with benefit of other ALK tyrosine kinase inhibition. These patients who remain ALK-dependent may benefit from additional ALK therapy. For the ones who are ALK-independent, mechanisms of resistance through bypass tracks and other things may not benefit from further ALK therapy but may need chemotherapy or some other clinical trial. I often will try and do the liquid biopsy because I consider that a low-risk, efficient procedure. Sometimes I will do a rebiopsy, and I think the 1 mutation that really stands out is the G1202R deletion because that tends to be a more potent resistance mutation. I think there is some preliminary evidence that lorlatinib has activity against that from the second-line trials.

Mark A. Socinksi, MD: I think we got a little discouraged early on because many of the studies looking at resistance mechanisms after crizotinib suggested that non-ALK resistance mechanisms were dominant versus ALK. And now with the second-generation drugs, it appears to be that more of the secondary mutations are in play.

Thomas E. Stinchcombe, MD: Yes. I think that’s a fascinating look into the biology. The more potent the ALK inhibition, the more likely you are to get an ALK tyrosine kinase mutation. And maybe crizotinib was not hitting these with the sufficient potency needed to induce the resistance mutation? I think that now the prevalence may be up to 50%, 60%. That may be an underestimate because sometimes these patients are hard to biopsy. The testing can be challenging. But I think that’s going to be the next step in the field, to segregate patients into specific ALK inhibitors based on the mutations with prospective data.

Mark A. Socinksi, MD: What’s your sense, and I realize that this may be a complete guess, after a drug like alectinib, if you retest at the time of progression, how often do you think you find something that may alter what you do next?

Thomas E. Stinchcombe, MD: I would assume I would find....

Mark A. Socinksi, MD: It’s a hard question.

Thomas E. Stinchcombe, MD: Yes, it’s a hard question.

Mark A. Socinksi, MD: That’s why I asked.

Thomas E. Stinchcombe, MD: It’s nice to be in that chair. I think we’d find ALK or resistance mutations 50%, 60% of the time. And then, the G1202R may be about 25% or 30% of all patients or so, about half the mutations. I think that’s a unique one. We might have preferentially used lorlatinib in that group of patients. I think it’s also going to be critical, as we try and develop new drugs in a clinical trial setting, to have that to help us understand. Really, these can transform to small cell lung cancer, but I think that’s reported less so than with the EGFR population. That’s another reason why if the disease is suddenly taking a more virulent turn, I think it’s definitely worth rebiopsying just to make sure that something has not changed. I think the other issue that no one likes to talk about is, we talk about the 50%, 60% of patients with ALK tyrosine kinase mutations. We don’t really know what’s going on with the other 30% or 40%, and I think that’s a huge area that the field needs to address at this point.

Mark A. Socinksi, MD: If you found a non-ALK resistance, what would you do in that situation? Would you empirically try another ALK inhibitor, or would you, getting back to our chemotherapy discussion, remember that chemotherapy can be helpful in these patients?

Thomas E. Stinchcombe, MD: I think chemotherapy would be the standard answer. I think I have seen 1 patient who had MET amplification and I got to crizotinib. There’s some interest that crizotinib may have some activity in those MET-amplified patients. And then there’s L1998, and there’s a case report that those may resensitize to crizotinib. I think the challenge is that these are all case reports and small things….

Mark A. Socinksi, MD: Anecdotal.

Thomas E. Stinchcombe, MD: Anecdotal.

Mark A. Socinksi, MD: They’re fascinating. There are several that showed that based on rebiopsies, you went from drug A to drug B, and you had a response. And it was all predicted based upon the secondary mutation. But these are all individual cases. Again, fascinating biology, but in clinical practice, realizing that the average community oncologist may see 1 or 2 of these patients a year, right?

Thomas E. Stinchcombe, MD: I think that brings up a good point. When I see second opinions of patients, if the patient hasn’t undergone a biopsy, I’m not critical of that physician or anything at this point because right now I think it’s a promising preliminary result, but it’s not enough to mandate that every patient undergo a biopsy. Because the question really is, how are you going to apply that to improve the patient’s life? I think that’s the next series of prospective trials.

Transcript edited for clarity.
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