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Osimertinib As Frontline Therapy in EGFR-Positive 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: Wednesday, Jul 25, 2018



Transcript: 

Benjamin P. Levy, MD: Hello, and thank you for joining this OncLive® Peer Exchange® titled, “Precision Medicine in Advanced Non–Small Cell Lung Cancer.” Metastatic lung adenocarcinoma remains the model for translational medicine in oncology, as the elucidation of new molecular targets and the rapid development of novel targeted therapies continue to transform the landscape of therapy. In this OncLive® Peer Exchange®, I’m joined by a group of my colleagues, all leaders in the field of thoracic oncology clinical research. We’re going to talk about the targeted therapies that we have available today and data from the 2018 ASCO Annual Meeting and will discuss how the latest research will advance the clinical management of non–small cell lung cancer.

I’m Dr. Benjamin Levy. I’m an assistant professor of oncology and clinical director of medical oncology at the Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital in Washington, DC. Participating today on our distinguished panel are: Dr. Lyudmila Bazhenova, medical oncologist and professor of medicine at UC San Diego Health; Dr. Alex Drilon, medical oncologist and clinical director of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York, New York; Dr. Zofia Piotrowska, instructor of medicine in the department of Hematology/Oncology at Massachusetts General Hospital Cancer Center in Boston, Massachusetts; and Dr. Jonathan Riess, assistant professor of medicine in the Division of Hematology/Oncology at UC Davis Comprehensive Cancer Center. Thank you so much for joining us. Let’s begin.

I think we’ve learned a lot about precision medicine in other tumor types. In my mind, lung cancer has been the poster child for personalized medicine, and I think that story really begins with EGFR. This is a mutation that’s relevant and is identified in up to 15% to 20% of all non–small cell lung cancer adenocarcinoma. We now have important phase III trials comparing TKIs—either erlotinib, gefitinib, or afatinib—that outperform chemotherapy in terms of response rate, progression-free survival, and, importantly, quality of life. It’s really altered the way that we think about treating these patients. But now we’ve got more practice-changing data with a next-generation TKI, osimertinib. Zofia, do you want to walk us through the story of osimertinib, landing initially in the T790M space, but then, more importantly, changing things for us based on the FLAURA data that have recently published?

Zofia Piotrowska, MD: Yes, it has been a very exciting time. Osimertinib was formerly known as AZD9291. It first came onto the scene about 5 years ago as a drug that was developed to overcome T790M-mediated resistance to first- and second-generation EGFR inhibitors. T790M is a resistance mutation in EGFR that we know is seen in about 50% to 60% of patients who progress on erlotinib, gefitinib, and afatinib. With that knowledge in mind, osimertinib was developed for that indication and was quickly shown to be quite effective in that space.

There were phase I data, phase II data, and, ultimately, a phase III study that showed that osimertinib was superior to chemotherapy in patients who are T790M positive after first- or second-generation therapy. Most recently, osimertinib was moved to the first-line setting based on the results of the FLAURA trial. FLAURA was a randomized phase III study that compared osimertinib to a standard of care, erlotinib or gefitinib, and demonstrated a really meaningful improvement in progression-free survival for patients treated with first-line osimertinib. We saw a median progression-free survival of about 19 months compared to the standard of care arm that performed as expected: around 10 months. This data has really transformed practice. It has led to the FDA approval of osimertinib as first-line treatment for EGFR-mutant lung cancer.

Benjamin P. Levy, MD: I think we initially thought of osimertinib as this great T790M drug, but it really hits the sensitizing mutations quite nicely, which was the rationale for moving it up front. In terms of toxicity differences, also kind of as a highlight of the FLAURA trial, can you comment on the discrepancy and toxicities of osimertinib and first- and second-generation TKIs?

Zofia Piotrowska, MD: One of the really nice distinguishing features of osimertinib has been its nice therapeutic window. It’s very effective and potent against mutant EGFR, activating mutations in T790M, but is relatively sparing of wild-type EGFR. And that has translated to a very nice safety profile with decreased rates of the typical EGFR toxicities that we expect to see: rash and diarrhea. It has not only been a very effective therapy but is also really well tolerated by our patients.

Benjamin P. Levy, MD: Yes. I think we all know it’s efficacy, and we’re learning about it in clinical practice. But certainly, FLAURA cemented this with a progression-free survival of close to 2 years—19 months. Let’s comment on the tolerability of this drug in everyday practice. Are people looking for toxicities or is it well tolerated across the board?

Jonathan W. Riess, MD, MS: Overall, I found it to be fairly well tolerated, particularly compared to the previous-generation EGFR TKIs, with respect to rash and diarrhea. It’s still kind of occurring. It could still be substantial enough, where you need to take a potential dose reduction into account. But I found it to be a good amount less, and it is very manageable. Another thing that I’ve noted is that there is a small risk for pneumonitis. And typically, with the first- and second- generation EGFR TKIs, we’ve predominately seen that more in the Asian population. I found that there’s been some data shown that this can also happen with osimertinib and more in a Caucasian population as well. So, it’s something not to discount. It is uncommon, but we do see it and should keep an eye out for it—including occasional kind-of patchy infiltrates that may come and go without any clinical significance. Sometimes, however, that could also be more substantial. The take-away message, in terms of toxicity, is that it’s something that’s uncommon, but I do keep a careful eye out for it.

Alexander Drilon, MD: The last take-away message I wanted to throw in is the fact that we’re really getting better at designing these drugs that not only have activity against resistance mechanisms, but also have excellent CNS coverage. Osimertinib is certainly one of these drugs. It has been shown to work in patients with brain metastases. But beyond that, in the BLOOM study, we also saw that it can work in patients with leptomeningeal disease. This is a big win for patients.

Benjamin P. Levy, MD: I would agree. The progression-free survival curves held up in those patients with brain metastases who were enrolled in the study. This was not a small amount of patients.

Transcript Edited for Clarity 

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Transcript: 

Benjamin P. Levy, MD: Hello, and thank you for joining this OncLive® Peer Exchange® titled, “Precision Medicine in Advanced Non–Small Cell Lung Cancer.” Metastatic lung adenocarcinoma remains the model for translational medicine in oncology, as the elucidation of new molecular targets and the rapid development of novel targeted therapies continue to transform the landscape of therapy. In this OncLive® Peer Exchange®, I’m joined by a group of my colleagues, all leaders in the field of thoracic oncology clinical research. We’re going to talk about the targeted therapies that we have available today and data from the 2018 ASCO Annual Meeting and will discuss how the latest research will advance the clinical management of non–small cell lung cancer.

I’m Dr. Benjamin Levy. I’m an assistant professor of oncology and clinical director of medical oncology at the Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital in Washington, DC. Participating today on our distinguished panel are: Dr. Lyudmila Bazhenova, medical oncologist and professor of medicine at UC San Diego Health; Dr. Alex Drilon, medical oncologist and clinical director of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York, New York; Dr. Zofia Piotrowska, instructor of medicine in the department of Hematology/Oncology at Massachusetts General Hospital Cancer Center in Boston, Massachusetts; and Dr. Jonathan Riess, assistant professor of medicine in the Division of Hematology/Oncology at UC Davis Comprehensive Cancer Center. Thank you so much for joining us. Let’s begin.

I think we’ve learned a lot about precision medicine in other tumor types. In my mind, lung cancer has been the poster child for personalized medicine, and I think that story really begins with EGFR. This is a mutation that’s relevant and is identified in up to 15% to 20% of all non–small cell lung cancer adenocarcinoma. We now have important phase III trials comparing TKIs—either erlotinib, gefitinib, or afatinib—that outperform chemotherapy in terms of response rate, progression-free survival, and, importantly, quality of life. It’s really altered the way that we think about treating these patients. But now we’ve got more practice-changing data with a next-generation TKI, osimertinib. Zofia, do you want to walk us through the story of osimertinib, landing initially in the T790M space, but then, more importantly, changing things for us based on the FLAURA data that have recently published?

Zofia Piotrowska, MD: Yes, it has been a very exciting time. Osimertinib was formerly known as AZD9291. It first came onto the scene about 5 years ago as a drug that was developed to overcome T790M-mediated resistance to first- and second-generation EGFR inhibitors. T790M is a resistance mutation in EGFR that we know is seen in about 50% to 60% of patients who progress on erlotinib, gefitinib, and afatinib. With that knowledge in mind, osimertinib was developed for that indication and was quickly shown to be quite effective in that space.

There were phase I data, phase II data, and, ultimately, a phase III study that showed that osimertinib was superior to chemotherapy in patients who are T790M positive after first- or second-generation therapy. Most recently, osimertinib was moved to the first-line setting based on the results of the FLAURA trial. FLAURA was a randomized phase III study that compared osimertinib to a standard of care, erlotinib or gefitinib, and demonstrated a really meaningful improvement in progression-free survival for patients treated with first-line osimertinib. We saw a median progression-free survival of about 19 months compared to the standard of care arm that performed as expected: around 10 months. This data has really transformed practice. It has led to the FDA approval of osimertinib as first-line treatment for EGFR-mutant lung cancer.

Benjamin P. Levy, MD: I think we initially thought of osimertinib as this great T790M drug, but it really hits the sensitizing mutations quite nicely, which was the rationale for moving it up front. In terms of toxicity differences, also kind of as a highlight of the FLAURA trial, can you comment on the discrepancy and toxicities of osimertinib and first- and second-generation TKIs?

Zofia Piotrowska, MD: One of the really nice distinguishing features of osimertinib has been its nice therapeutic window. It’s very effective and potent against mutant EGFR, activating mutations in T790M, but is relatively sparing of wild-type EGFR. And that has translated to a very nice safety profile with decreased rates of the typical EGFR toxicities that we expect to see: rash and diarrhea. It has not only been a very effective therapy but is also really well tolerated by our patients.

Benjamin P. Levy, MD: Yes. I think we all know it’s efficacy, and we’re learning about it in clinical practice. But certainly, FLAURA cemented this with a progression-free survival of close to 2 years—19 months. Let’s comment on the tolerability of this drug in everyday practice. Are people looking for toxicities or is it well tolerated across the board?

Jonathan W. Riess, MD, MS: Overall, I found it to be fairly well tolerated, particularly compared to the previous-generation EGFR TKIs, with respect to rash and diarrhea. It’s still kind of occurring. It could still be substantial enough, where you need to take a potential dose reduction into account. But I found it to be a good amount less, and it is very manageable. Another thing that I’ve noted is that there is a small risk for pneumonitis. And typically, with the first- and second- generation EGFR TKIs, we’ve predominately seen that more in the Asian population. I found that there’s been some data shown that this can also happen with osimertinib and more in a Caucasian population as well. So, it’s something not to discount. It is uncommon, but we do see it and should keep an eye out for it—including occasional kind-of patchy infiltrates that may come and go without any clinical significance. Sometimes, however, that could also be more substantial. The take-away message, in terms of toxicity, is that it’s something that’s uncommon, but I do keep a careful eye out for it.

Alexander Drilon, MD: The last take-away message I wanted to throw in is the fact that we’re really getting better at designing these drugs that not only have activity against resistance mechanisms, but also have excellent CNS coverage. Osimertinib is certainly one of these drugs. It has been shown to work in patients with brain metastases. But beyond that, in the BLOOM study, we also saw that it can work in patients with leptomeningeal disease. This is a big win for patients.

Benjamin P. Levy, MD: I would agree. The progression-free survival curves held up in those patients with brain metastases who were enrolled in the study. This was not a small amount of patients.

Transcript Edited for Clarity 
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