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Treating With Osimertinib in EGFR-Mutated NSCLC

Insights From: Sai-Hong Ignatius Ou, MD, PhD, University of California, Irvine School of Medicine
Published: Tuesday, Jun 04, 2019



Transcript: 

Sai-Hong Ignatius Ou, MD, PhD: The overall efficacy and survival data for the AURA1 and the AURA2 study with longer follow-up is consistent with what has been reported for osimertinib. We look forward to the final overall survival data from the FLAURA study. The study is important to see if osimertinib can demonstrate overall survival benefit over a first-generation EGFR TKI [tyrosine kinase inhibitor]. I think that’s important and based on a phase III study. So, we look forward to the data hopefully very soon.

I suspect that the higher dose of osimertinib, 160 mg, had more adverse effects than the 80 mg of osimertinib, with slightly more diarrhea, stomatitis, paronychia, and more patients had to get a dose reduction from the 160 mg cohort.

The optimal use of osimertinib in EGFR-mutant lung cancer is the first-line upfront use. I believe that because of the superior progression-free survival, the much better tolerability compared to first-generation EGFR TKI, and the superior CNS [central nervous system] activity, those are the 3 major reasons that I will use osimertinib up front in EGFR-mutant non–small cell lung cancer. I would not wait to sequence. The resistance to osimertinib is heterogeneous. We will have to get a repeat biopsy to understand the resistance mechanism and tailor the treatment toward separate resistance mutations. Chemotherapy is always an option post-osimertinib.

Additionally, you can combine osimertinib with chemotherapy, but it is not recommended. I don’t recommend it, but I know that clinicians do use that. It’s easily combinable with carboplatin and pemetrexed. I hear some clinicians are reluctant to use osimertinib up front because they worry about what happens after osimertinib failure. But, given the heterogeneous resistance mechanism, we need to test this out. If you have a C797S mutation with resistance, you can use chemotherapy. There are other antibodies that can target the EGFR that can be used. If you develop a MET amplification, osimertinib has been successfully combined with a MET inhibitor, both in clinical trials and case report settings.

So you can use the combination, and if you have other bypass pathways that are not amenable to targeted therapy, you can use chemotherapy. If you have developed ALK fusions or a RET fusion, we, with other investigators, have published a combination of ALK TKI with osimertinib or RET TKI with osimertinib and have been able to successfully treat the patients.

I actually have 1 patient who is still on a RET inhibitor with osimertinib. It’s part of the study by Lecia V. Sequist, MD, at the Cancer Discovery paper. She is still doing well with the combination. So there are lots of ways to overcome resistance, and I would not hesitate to use osimertinib up front. I would recommend using osimertinib up front when you have patients with EGFR-mutated lung cancer.

Transcript Edited for Clarity
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Transcript: 

Sai-Hong Ignatius Ou, MD, PhD: The overall efficacy and survival data for the AURA1 and the AURA2 study with longer follow-up is consistent with what has been reported for osimertinib. We look forward to the final overall survival data from the FLAURA study. The study is important to see if osimertinib can demonstrate overall survival benefit over a first-generation EGFR TKI [tyrosine kinase inhibitor]. I think that’s important and based on a phase III study. So, we look forward to the data hopefully very soon.

I suspect that the higher dose of osimertinib, 160 mg, had more adverse effects than the 80 mg of osimertinib, with slightly more diarrhea, stomatitis, paronychia, and more patients had to get a dose reduction from the 160 mg cohort.

The optimal use of osimertinib in EGFR-mutant lung cancer is the first-line upfront use. I believe that because of the superior progression-free survival, the much better tolerability compared to first-generation EGFR TKI, and the superior CNS [central nervous system] activity, those are the 3 major reasons that I will use osimertinib up front in EGFR-mutant non–small cell lung cancer. I would not wait to sequence. The resistance to osimertinib is heterogeneous. We will have to get a repeat biopsy to understand the resistance mechanism and tailor the treatment toward separate resistance mutations. Chemotherapy is always an option post-osimertinib.

Additionally, you can combine osimertinib with chemotherapy, but it is not recommended. I don’t recommend it, but I know that clinicians do use that. It’s easily combinable with carboplatin and pemetrexed. I hear some clinicians are reluctant to use osimertinib up front because they worry about what happens after osimertinib failure. But, given the heterogeneous resistance mechanism, we need to test this out. If you have a C797S mutation with resistance, you can use chemotherapy. There are other antibodies that can target the EGFR that can be used. If you develop a MET amplification, osimertinib has been successfully combined with a MET inhibitor, both in clinical trials and case report settings.

So you can use the combination, and if you have other bypass pathways that are not amenable to targeted therapy, you can use chemotherapy. If you have developed ALK fusions or a RET fusion, we, with other investigators, have published a combination of ALK TKI with osimertinib or RET TKI with osimertinib and have been able to successfully treat the patients.

I actually have 1 patient who is still on a RET inhibitor with osimertinib. It’s part of the study by Lecia V. Sequist, MD, at the Cancer Discovery paper. She is still doing well with the combination. So there are lots of ways to overcome resistance, and I would not hesitate to use osimertinib up front. I would recommend using osimertinib up front when you have patients with EGFR-mutated lung cancer.

Transcript Edited for Clarity
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: Working Group for Changing Standards in EGFR-Mutated Lung Cancers: Real-World Applications of the Evidence for NursesJun 29, 20191.5
Oncology Briefings™: Current Perspectives on Preventing and Managing Tumor Lysis SyndromeJun 30, 20191.0
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