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Next Generation ALK Inhibitors for NSCLC

Insights From: Corey J. Langer, MD, Perelman Center for Advanced Medicine; Hospital of the University of Pennsylvania; Mohammad Jahanzeb, MD, Univerity of Miami Miller School of Medicine; Shirish Gadgeel, MD, Wayne State University School of Medicine; Karmanos Cancer Institute
Published: Monday, Aug 14, 2017


Transcript:

Corey J. Langer, MD: These are third- and fourth-generation TKIs, and it’s really quite amazing to talk about this because 7 years ago, we knew nothing about ALK inhibition. In this era, we now have 3 FDA- approved drugs: crizotinib and second-line drugs ceritinib and alectinib. Brigatinib will most likely be approved in 2017. Perhaps on the immediate horizon is lorlatinib.

Original studies of lorlatinib in phase I and phase II, unlike many of the other TKI trials, allowed multiple prior TKIs. So, lorlatinib is distinguished, at least the early data, in the fact that it was much more inclusive. The trial evaluated this agent in folks who are truly TKI refractory and continued to cite responses. As you’d imagine, heavily pretreated individuals had lower response rates, but we were still seeing responses. There are now ongoing trials looking at lorlatinib specifically in CNS-only disease progression and, again, anecdotal reports of patients with a refractory brain metastasis—for that matter, leptomeningeal disease—that’s actually responding to lorlatinib. So, amongst many of the new agents that are being investigated, I am quite optimistic about this agent. Whether it’s going to actually displace the other agents or be complementary to the first-, second-, and third-generation agents remains to be seen.

Another area of research, of course, is combining TKIs with other small molecules or angiogenesis inhibitors, far less sanguine about checkpoint blockade. But I am reasonably optimistic about the potential for angiogenesis inhibitors, such as bevacizumab or ramucirumab, combined with some of the standard TKIs. And I think in individuals who have multiple mechanisms of resistance—let’s just say, hypothetically, ALK and BRAF, which is conceivable—we will start seeing unusual oral drug combinations that will really address all the major pathways that are driving the growth of the tumor. This is going to require a lot of flexibility and a lot of ingenuity on the part of the thoracic oncologists, so stay tuned. It’s going to be an exciting field.

Just as an example, I have an individual who has an ALK rearrangement and originally responded to crizotinib, but who actually developed CNS progression, slow but clear-cut. We had switched him to ceritinib at that point and he continued to do quite well, though the GI toxicity was a bit of a challenge. We managed to conquer that. More recently, this individual has developed isolated liver progression. We biopsied the liver, and lo and behold, there’s a BRAF mutation—low percentage, but clearly present. ALK translocation was still present. So, how do I manage this individual? I can potentially treat isolated progression with chemoembolization or RFA and continue the original alectinib. I can do that, and at least consider agents that would potentially target BRAF. This may be a one-off—it may be unique—but I foresee the development of unique pathways of resistance that we had not previously identified. And it’s going to require a lot of adaptability in terms of managing these individuals.

Shirish Gadgeel, MD: Lorlatinib and entrectinib are another set of next-generation ALK inhibitors. We have a few more data with lorlatinib, and it appears to have shown activity in patients who have not only progressed after crizotinib, but have also received one of the next-generation ALK inhibitors such as alectinib or ceritinib. The drug does have activity in those patients. In fact, a breakthrough designation has been given by the FDA for this drug.

Entrectinib is another ALK inhibitor. It is also being tested in patients who have previously been treated with crizotinib, but, in addition, it is also being tested in the frontline setting. We have less data of its use in patients who have received crizotinib and then received another next-generation ALK inhibitor. I believe at the present time, in the expected sequence—so, one can talk about the sequence of ALK inhibitors in 2 different time periods—we are still using crizotinib as frontline therapy and then subsequently using one of the next-generation ALK inhibitors. And my suspicion is that, in those patients, we may choose to use lorlatinib as a third ALK inhibitor; whereas, right now, we are moving on to chemotherapy in those patients.

In the very near future, we are going to be moving these next-generation ALK inhibitors forward, one of which, ceritinib, is already approved. I expect that alectinib will also be approved, and I suspect that, in patients who progress on those drugs, we are likely to choose another ALK inhibitor such as lorlatinib, which has already demonstrated some activity. It was a limited data set, only about 45 patients, presented at last year’s ASCO, and there are going to be some more data at this year’s ASCO on lorlatinib’s activity in patients who have progressed after next-generation ALK inhibitors. I think this is where mutation testing might start playing a role, in that patients who progress on next-generation ALK inhibitors may be tested. Their tumors may be molecularly profiled, and patients who have ALK mutations or ALK amplifications are the ones who may be treated with a drug like lorlatinib. But patients who don’t have ALK-dependent mechanisms of resistance may be much more likely to be treated by other drugs, such as cytotoxic chemotherapy.

So, if I had to summarize the expected sequence, I think either ceritinib or alectinib is likely to be approved as frontline therapy. Once lorlatinib gets approved, if it does get approved by the FDA, that will be a preferred choice as the next treatment for patients who have progressed on these drugs, if an ALK-dependent mechanism of resistance is identified in the tumor. If an ALK-dependent mechanism is not identified, those patients may be treated with chemotherapy.

Mohammad Jahanzeb, MD: The question is about the role of entrectinib. It is, again, probably number 6, if you go with the historic sequence of drug development in our list of ALK inhibitors. It is active, it has a role. But the data are more limited than with the other drugs. So, I think it will have a role. What role, and where it fits, will be determined by multiple factors. There’s actually an NCI trial looking at the sequencing of ALK agents, but the design is complicated enough that it’s still not open. I think by the time that it is open and gets approved—because these patients are not very common in our clinical practice—we will probably have found newer ways of treating ALK patients with combinations of these agents, with other agents that are currently in testing. I don’t have high hopes that one day we’ll be crystal clear about what the optimal sequence is. I think it will vary by patients and by availability of drugs. It will vary by what else we have already combined and shown incremental efficacy with. So, the jury will remain out.

Transcript Edited for Clarity
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Transcript:

Corey J. Langer, MD: These are third- and fourth-generation TKIs, and it’s really quite amazing to talk about this because 7 years ago, we knew nothing about ALK inhibition. In this era, we now have 3 FDA- approved drugs: crizotinib and second-line drugs ceritinib and alectinib. Brigatinib will most likely be approved in 2017. Perhaps on the immediate horizon is lorlatinib.

Original studies of lorlatinib in phase I and phase II, unlike many of the other TKI trials, allowed multiple prior TKIs. So, lorlatinib is distinguished, at least the early data, in the fact that it was much more inclusive. The trial evaluated this agent in folks who are truly TKI refractory and continued to cite responses. As you’d imagine, heavily pretreated individuals had lower response rates, but we were still seeing responses. There are now ongoing trials looking at lorlatinib specifically in CNS-only disease progression and, again, anecdotal reports of patients with a refractory brain metastasis—for that matter, leptomeningeal disease—that’s actually responding to lorlatinib. So, amongst many of the new agents that are being investigated, I am quite optimistic about this agent. Whether it’s going to actually displace the other agents or be complementary to the first-, second-, and third-generation agents remains to be seen.

Another area of research, of course, is combining TKIs with other small molecules or angiogenesis inhibitors, far less sanguine about checkpoint blockade. But I am reasonably optimistic about the potential for angiogenesis inhibitors, such as bevacizumab or ramucirumab, combined with some of the standard TKIs. And I think in individuals who have multiple mechanisms of resistance—let’s just say, hypothetically, ALK and BRAF, which is conceivable—we will start seeing unusual oral drug combinations that will really address all the major pathways that are driving the growth of the tumor. This is going to require a lot of flexibility and a lot of ingenuity on the part of the thoracic oncologists, so stay tuned. It’s going to be an exciting field.

Just as an example, I have an individual who has an ALK rearrangement and originally responded to crizotinib, but who actually developed CNS progression, slow but clear-cut. We had switched him to ceritinib at that point and he continued to do quite well, though the GI toxicity was a bit of a challenge. We managed to conquer that. More recently, this individual has developed isolated liver progression. We biopsied the liver, and lo and behold, there’s a BRAF mutation—low percentage, but clearly present. ALK translocation was still present. So, how do I manage this individual? I can potentially treat isolated progression with chemoembolization or RFA and continue the original alectinib. I can do that, and at least consider agents that would potentially target BRAF. This may be a one-off—it may be unique—but I foresee the development of unique pathways of resistance that we had not previously identified. And it’s going to require a lot of adaptability in terms of managing these individuals.

Shirish Gadgeel, MD: Lorlatinib and entrectinib are another set of next-generation ALK inhibitors. We have a few more data with lorlatinib, and it appears to have shown activity in patients who have not only progressed after crizotinib, but have also received one of the next-generation ALK inhibitors such as alectinib or ceritinib. The drug does have activity in those patients. In fact, a breakthrough designation has been given by the FDA for this drug.

Entrectinib is another ALK inhibitor. It is also being tested in patients who have previously been treated with crizotinib, but, in addition, it is also being tested in the frontline setting. We have less data of its use in patients who have received crizotinib and then received another next-generation ALK inhibitor. I believe at the present time, in the expected sequence—so, one can talk about the sequence of ALK inhibitors in 2 different time periods—we are still using crizotinib as frontline therapy and then subsequently using one of the next-generation ALK inhibitors. And my suspicion is that, in those patients, we may choose to use lorlatinib as a third ALK inhibitor; whereas, right now, we are moving on to chemotherapy in those patients.

In the very near future, we are going to be moving these next-generation ALK inhibitors forward, one of which, ceritinib, is already approved. I expect that alectinib will also be approved, and I suspect that, in patients who progress on those drugs, we are likely to choose another ALK inhibitor such as lorlatinib, which has already demonstrated some activity. It was a limited data set, only about 45 patients, presented at last year’s ASCO, and there are going to be some more data at this year’s ASCO on lorlatinib’s activity in patients who have progressed after next-generation ALK inhibitors. I think this is where mutation testing might start playing a role, in that patients who progress on next-generation ALK inhibitors may be tested. Their tumors may be molecularly profiled, and patients who have ALK mutations or ALK amplifications are the ones who may be treated with a drug like lorlatinib. But patients who don’t have ALK-dependent mechanisms of resistance may be much more likely to be treated by other drugs, such as cytotoxic chemotherapy.

So, if I had to summarize the expected sequence, I think either ceritinib or alectinib is likely to be approved as frontline therapy. Once lorlatinib gets approved, if it does get approved by the FDA, that will be a preferred choice as the next treatment for patients who have progressed on these drugs, if an ALK-dependent mechanism of resistance is identified in the tumor. If an ALK-dependent mechanism is not identified, those patients may be treated with chemotherapy.

Mohammad Jahanzeb, MD: The question is about the role of entrectinib. It is, again, probably number 6, if you go with the historic sequence of drug development in our list of ALK inhibitors. It is active, it has a role. But the data are more limited than with the other drugs. So, I think it will have a role. What role, and where it fits, will be determined by multiple factors. There’s actually an NCI trial looking at the sequencing of ALK agents, but the design is complicated enough that it’s still not open. I think by the time that it is open and gets approved—because these patients are not very common in our clinical practice—we will probably have found newer ways of treating ALK patients with combinations of these agents, with other agents that are currently in testing. I don’t have high hopes that one day we’ll be crystal clear about what the optimal sequence is. I think it will vary by patients and by availability of drugs. It will vary by what else we have already combined and shown incremental efficacy with. So, the jury will remain out.

Transcript Edited for Clarity
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