Dr. Padda on Overcoming Resistance to Osimertinib in EGFR+ NSCLC

Sukhmani Padda, MD
Published: Thursday, Jan 31, 2019



Sukhmani Padda, MD, assistant professor of medicine, Stanford University Medical Center, member, Stanford Cancer Institute, discusses the need for approaches to treatment for patients with EGFR-positive non–small cell lung cancer (NSCLC) who have developed resistance to frontline osimertinib (Tagrisso).

The third-generation EGFR TKI osimertinib has emerged as the standard frontline therapy for this patient population, based on encouraging data from the FLAURA study. Thoracic oncologists are also impressed by the unprecedented central nervous system penetration seen with osimertinib. However, the next challenge for research is deciding what to do when patients progress on this targeted therapy.

There were data recently presented at the 2018 ESMO Congress, Padda says, which showed that there are 2 acquired mechanisms of resistance that patients develop. C797S, the most common, prevents the binding of osimertinib to the disease, and MET amplification is also seen. The biggest hurdle with these mechanisms, she explains, is that they are very heterogeneous and tend to happen concurrently. With progression on first- and second-generation TKIs, patients would usually develop a dominant resistant mechanism that could be treated as a second driver mutation.

Currently, when a patient progresses on frontline osimertinib, physicians have to rely on platinum doublet chemotherapy. However, there are several ongoing studies looking at more effective combinatory approaches.
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Sukhmani Padda, MD, assistant professor of medicine, Stanford University Medical Center, member, Stanford Cancer Institute, discusses the need for approaches to treatment for patients with EGFR-positive non–small cell lung cancer (NSCLC) who have developed resistance to frontline osimertinib (Tagrisso).

The third-generation EGFR TKI osimertinib has emerged as the standard frontline therapy for this patient population, based on encouraging data from the FLAURA study. Thoracic oncologists are also impressed by the unprecedented central nervous system penetration seen with osimertinib. However, the next challenge for research is deciding what to do when patients progress on this targeted therapy.

There were data recently presented at the 2018 ESMO Congress, Padda says, which showed that there are 2 acquired mechanisms of resistance that patients develop. C797S, the most common, prevents the binding of osimertinib to the disease, and MET amplification is also seen. The biggest hurdle with these mechanisms, she explains, is that they are very heterogeneous and tend to happen concurrently. With progression on first- and second-generation TKIs, patients would usually develop a dominant resistant mechanism that could be treated as a second driver mutation.

Currently, when a patient progresses on frontline osimertinib, physicians have to rely on platinum doublet chemotherapy. However, there are several ongoing studies looking at more effective combinatory approaches.

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Archived Version of a Live Webcast: Virtual Current Trends™: European Perspectives on the Advancing Role of CAR T-Cell Therapy in Hematologic MalignanciesJun 29, 20192.0
Community Practice Connections™: Practical Application of Sequencing for EGFR-Mutant Lung Cancers: A Focus on Recent Evidence and Key Next Steps in TrialsJun 29, 20192.5
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