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Managing Resistance to EGFR TKIs in NSCLC

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: Tuesday, Aug 14, 2018



Transcript: 

Benjamin P. Levy, MD: Are we in the business of doing routine biopsies in these patients post osimertinib? Is this something that we need to do to gain more information or is it just for moving to chemotherapy? What’s the message here?

Jonathan W. Riess, MD, MS: I think the standard now, in terms of standard treatment post progression on osimertinib, is chemotherapy. As mentioned, the IMpower150 study looks particularly promising in the subset analysis with carboplatin, Taxol (paclitaxel), bevacizumab, and the addition of atezolizumab. We’re learning more that single-agent immunotherapy doesn’t seem to be as effective in EGFR-mutant non–small lung cancer. If you look at meta-analyses of many of the single-arm PD-1 and PD-L1 studies, they didn’t really show much benefit compared to, for example, docetaxel alone. My standard has been platinum-based chemotherapy. I do try to enumerate mechanisms of resistance with a minimum of a plasma biopsy, which is much less invasive than a tissue biopsy. Sometimes, there are a number of clinical trials. We have some at UC Davis Comprehensive Cancer Center, and there are others available at other institutions as well, looking to overcome resistance with other targeted therapy combinations. I would encourage providers who are treating these patients who progress on osimertinib to take a look around and try to refer them for some of these clinical trials.

And then, the other thing I sometimes do for oligoprogressive disease—looking at local ablative therapy, focused radiation, and so forth, if there are 1 or 2 major sites of progression—I’ve considered continuing the TKI. Now that osimertinib is a first-line option, and because we don’t have an approved targeted therapy after that for EGFR-mutant patients, that’s something I’ve started to use more as well.

Benjamin P. Levy, MD: Are you more inclined to do that? Trying to get that practice of addressing oligometastatic progression and continuing the TKI, that’s something we’ve learned from the first- and second-generation TKIs. Given the lack of second-line options when deciding what to actually do post osimertinib, are you more inclined to be more aggressive in that approach by attacking the oligometastatic disease with radiation?

Jonathan W. Riess, MD, MS: With frontline osimertinib, I’ve become more aware of clear cases of oligoprogression, where there has been growth in several sites, or in patients who are more symptomatic, and it is not generally eliminated with chemotherapy after trying to enumerate the mechanisms of resistance for potential trials. This is something that, before we had osimertinib, I did a good amount of. Then we had osimertinib as second-line therapy, so I was more apt to switch to that. But since we don’t have anything targeted that’s approved now after osimertinib, I’ve done that a bit more.

Zofia Piotrowska, MD: Osimertinib resistance is rare but we do sometimes see, with the first- and second-generation drugs, that small-cell transformation—patients who had prior adenocarcinomas where you actually see a histologic transformation to a small-cell phenotype. Clinically, those patients behave more like small-cell patients with more aggressive disease. When you’re treating someone with osimertinib, if you see that kind of rapid progression, I think it is important to get a biopsy in that context. This informs for subsequent therapies and the choice of chemotherapy, in particular.

Alexander Drilon, MD: That’s a great point. Osimertinib was just recently approved in the first line. The median progression-free survival was about 19 months. People who are progressing are probably more likely to be early progressors. We need to take a look, to try to find out why, whether it is because of a mechanism of resistance, or a mutation, or whether it be small-cell transformation, which can grow much faster. I think this is warranted to rule out small-cell in many of those cases who, as of right now, will probably be the early progressors.

Zofia Piotrowska, MD: And that’s often something that we can pick up in the plasma right? I often use plasma as a first pass. For patients in which small-cell is a possibility, tissue becomes more important.

Alexander Drilon, MD: The tipoff could be with a TP53 mutation in the plasma. If something’s growing fast and there’s acquisition of those mutations there, they are generally universally found in small-cell lung cancer. That may be a tipoff that there could be a small-cell histology or a high-grade or endocrine tumor that’s developed.

Benjamin P. Levy, MD: Lyudmila, you’ve been very patient.

Lyudmila A. Bazhenova, MD: I feel very strongly that we need to biopsy those patients. Without doing a biopsy, we will never learn what happens to them. Sometimes you find stuff. I can show you guys a case and see what you’ve done. I have a patient with EGFR deletion 19. He had a long progression-free survival on erlotinib and then progressed through the T790M mechanism. At that time, he was put on ruxolitinib. He responded and then progressed. He was put on osimertinib, and he responded with a durable response. Then he progressed. They biopsied his adrenal mass. It’s RET fusion with CCDC6. He was not exposed to platinum-based doublet therapy. What would you guys do? Would you give him a platinum-based doublet or would you pull in your off-label RET inhibitors that are available in the market?

Alexander Drilon, MD: So, this was a RET fusion that was emergent after osimertinib?

Lyudmila A. Bazhenova, MD: It wasn’t in the beginning.

Alexander Drilon, MD: When?

Lyudmila A. Bazhenova, MD: This is at the third biopsy. So, first biopsy: post progression of erlotinib, no RET. At post progression of osimertinib, RET.

Alexander Drilon, MD: I think this is something new that we’re seeing. There are funky mechanisms of resistance that are emerging. Especially after these next-generation agents, we’ve seen other fusions emerge in patients who develop acquired resistance. From a scientific perspective, we might be tempted to do something like combination therapy. Certainly, if there’s a trial, I would do that. But short of that, we would resort to standard-of-care chemotherapy.

Benjamin P. Levy, MD: Fortunately, we’ll be talking about RET at the very end and all of the emerging data that’re coming out. That’s a very interesting case.

Lyudmila A. Bazhenova, MD: I put him on a RET inhibitor, on the trial, and he responded.

Benjamin P. Levy, MD: Wonderful. A happy ending.

Lyudmila A. Bazhenova, MD: Single-agent RET inhibitor.

Transcript Edited for Clarity 

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Transcript: 

Benjamin P. Levy, MD: Are we in the business of doing routine biopsies in these patients post osimertinib? Is this something that we need to do to gain more information or is it just for moving to chemotherapy? What’s the message here?

Jonathan W. Riess, MD, MS: I think the standard now, in terms of standard treatment post progression on osimertinib, is chemotherapy. As mentioned, the IMpower150 study looks particularly promising in the subset analysis with carboplatin, Taxol (paclitaxel), bevacizumab, and the addition of atezolizumab. We’re learning more that single-agent immunotherapy doesn’t seem to be as effective in EGFR-mutant non–small lung cancer. If you look at meta-analyses of many of the single-arm PD-1 and PD-L1 studies, they didn’t really show much benefit compared to, for example, docetaxel alone. My standard has been platinum-based chemotherapy. I do try to enumerate mechanisms of resistance with a minimum of a plasma biopsy, which is much less invasive than a tissue biopsy. Sometimes, there are a number of clinical trials. We have some at UC Davis Comprehensive Cancer Center, and there are others available at other institutions as well, looking to overcome resistance with other targeted therapy combinations. I would encourage providers who are treating these patients who progress on osimertinib to take a look around and try to refer them for some of these clinical trials.

And then, the other thing I sometimes do for oligoprogressive disease—looking at local ablative therapy, focused radiation, and so forth, if there are 1 or 2 major sites of progression—I’ve considered continuing the TKI. Now that osimertinib is a first-line option, and because we don’t have an approved targeted therapy after that for EGFR-mutant patients, that’s something I’ve started to use more as well.

Benjamin P. Levy, MD: Are you more inclined to do that? Trying to get that practice of addressing oligometastatic progression and continuing the TKI, that’s something we’ve learned from the first- and second-generation TKIs. Given the lack of second-line options when deciding what to actually do post osimertinib, are you more inclined to be more aggressive in that approach by attacking the oligometastatic disease with radiation?

Jonathan W. Riess, MD, MS: With frontline osimertinib, I’ve become more aware of clear cases of oligoprogression, where there has been growth in several sites, or in patients who are more symptomatic, and it is not generally eliminated with chemotherapy after trying to enumerate the mechanisms of resistance for potential trials. This is something that, before we had osimertinib, I did a good amount of. Then we had osimertinib as second-line therapy, so I was more apt to switch to that. But since we don’t have anything targeted that’s approved now after osimertinib, I’ve done that a bit more.

Zofia Piotrowska, MD: Osimertinib resistance is rare but we do sometimes see, with the first- and second-generation drugs, that small-cell transformation—patients who had prior adenocarcinomas where you actually see a histologic transformation to a small-cell phenotype. Clinically, those patients behave more like small-cell patients with more aggressive disease. When you’re treating someone with osimertinib, if you see that kind of rapid progression, I think it is important to get a biopsy in that context. This informs for subsequent therapies and the choice of chemotherapy, in particular.

Alexander Drilon, MD: That’s a great point. Osimertinib was just recently approved in the first line. The median progression-free survival was about 19 months. People who are progressing are probably more likely to be early progressors. We need to take a look, to try to find out why, whether it is because of a mechanism of resistance, or a mutation, or whether it be small-cell transformation, which can grow much faster. I think this is warranted to rule out small-cell in many of those cases who, as of right now, will probably be the early progressors.

Zofia Piotrowska, MD: And that’s often something that we can pick up in the plasma right? I often use plasma as a first pass. For patients in which small-cell is a possibility, tissue becomes more important.

Alexander Drilon, MD: The tipoff could be with a TP53 mutation in the plasma. If something’s growing fast and there’s acquisition of those mutations there, they are generally universally found in small-cell lung cancer. That may be a tipoff that there could be a small-cell histology or a high-grade or endocrine tumor that’s developed.

Benjamin P. Levy, MD: Lyudmila, you’ve been very patient.

Lyudmila A. Bazhenova, MD: I feel very strongly that we need to biopsy those patients. Without doing a biopsy, we will never learn what happens to them. Sometimes you find stuff. I can show you guys a case and see what you’ve done. I have a patient with EGFR deletion 19. He had a long progression-free survival on erlotinib and then progressed through the T790M mechanism. At that time, he was put on ruxolitinib. He responded and then progressed. He was put on osimertinib, and he responded with a durable response. Then he progressed. They biopsied his adrenal mass. It’s RET fusion with CCDC6. He was not exposed to platinum-based doublet therapy. What would you guys do? Would you give him a platinum-based doublet or would you pull in your off-label RET inhibitors that are available in the market?

Alexander Drilon, MD: So, this was a RET fusion that was emergent after osimertinib?

Lyudmila A. Bazhenova, MD: It wasn’t in the beginning.

Alexander Drilon, MD: When?

Lyudmila A. Bazhenova, MD: This is at the third biopsy. So, first biopsy: post progression of erlotinib, no RET. At post progression of osimertinib, RET.

Alexander Drilon, MD: I think this is something new that we’re seeing. There are funky mechanisms of resistance that are emerging. Especially after these next-generation agents, we’ve seen other fusions emerge in patients who develop acquired resistance. From a scientific perspective, we might be tempted to do something like combination therapy. Certainly, if there’s a trial, I would do that. But short of that, we would resort to standard-of-care chemotherapy.

Benjamin P. Levy, MD: Fortunately, we’ll be talking about RET at the very end and all of the emerging data that’re coming out. That’s a very interesting case.

Lyudmila A. Bazhenova, MD: I put him on a RET inhibitor, on the trial, and he responded.

Benjamin P. Levy, MD: Wonderful. A happy ending.

Lyudmila A. Bazhenova, MD: Single-agent RET inhibitor.

Transcript Edited for Clarity 
View Conference Coverage
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