Managing Resistance to Third-Generation TKIs in NSCLC

Lyudmila Bazhenova, MD, University of California San Diego, talks about understanding, preventing, and delaying EGFR-resistance in the era of osimertinib therapy at the 2019 Annual Perspectives in Thoracic Oncology meeting.


Dr. Lyudmila Bazhenova:  I'm Dr. Lyudmila Bazhenova, Professor of Medicine and thoracic oncologist from University of California, San Diego. At this conference, I'm going to be discussing two topics.

One of them is management of immune‑related adverse events in your patients who are receiving chemotherapy. The second topic is managing resistance to third‑generation EGFR tyrosine kinase inhibitors.

The current management for patients with stage 4 EGFR‑mutant non‑small‑cell lung cancer includes osimertinib as a first‑line therapy based on improvement in progression free survival, as well as overall survival in FLAURA study. In that study, osimertinib was compared to gefitinib or erlotinib.

Unfortunately, despite the fact that osimertinib is very effective, it is still not a cure, and eventually, all the patients will progress. Currently, we do not have any prospective clinical trials explaining to us what is the best strategy for patients who progressed on osimertinib. We are still learning about resistance mechanism.

As a standard of care for my patients who are progressing on osimertinib, I would recommend chemotherapy. However, I would also recommend doing a post‑progression biopsy and see if there are any additional molecular abnormalities that can be targeted.

Based on a liquid biopsy analysis of the FLAURA study after progression from osimertinib we know that additional molecular abnormalities can happen. We've seen MET amplifications. We've seen a C797S mutation. We've seen a HER2 mutation, BRAF mutations. We have seen CDK amplifications.

We are still generating the data, if it is appropriate to treat those patients based on their acquired new molecular abnormalities. I would definitely consider it in my practice.

If you have access to a clinical trial such as ORCHARD trial which will answer those questions prospectively, I strongly recommend you refer the patient to the center that has an ORCHARD trial open.

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