Optimizing Sequencing of Novel EGFR-Targeted Agents in NSCLC


Closing out his discussion on actionable mutations in NSCLC, Roy Herbst, MD, PhD, discusses optimal sequencing of EGFR-targeted agents.


Roy S. Herbst, MD, PhD: Normally I would start patients with an EGFR mutation with osimertinib, which is usually not debatable. Then if someone shows resistance, I try to not change therapy as long as possible because the resistance can be in some cases mild or just a small proportion of cells, so I keep the oral agent going as long as possible. Off of the protocol, the next step would probably be to add chemotherapy. I like to add chemotherapy, but the data for that are not proven. There are studies now, FLAURA2 and others, that are looking at adding chemotherapy to immunotherapy, but they are not reported yet. Then I will try to find a clinical trial. There is a trial called ORCHARD that we run here, it’s run around the country. It looks at combinations. Why is the patient resistant? Do they have a MET abnormality, do they have some other mutation, RET, or something else that has developed? Sometimes these patients’ disease morphs into small cell lung cancer, so we have to rebiopsy and try to find the best therapy we can based on the tissue.

There is so much exciting work in non–small cell lung cancer. Of course, there are all the targeted agents we have been talking about and finding the right drug for the right patient. With just EGFR, there are several new EGFR inhibitors. There are drugs that target exon 20. There are drugs that target C797S, which is a very common form of resistance to osimertinib. More and more, we are going to have targeting the resistance and understanding resistance, so creating personalized therapy, then personalized therapy at resistance. Of course, all this then moves to the early stage, the ADAURA trial, where we are going to report some updated data in the not too distant future with the time to progression. But at least the disease-free survival early in that trial was extraordinary, and I predict it will stay that way.

That’s an example of how an approved drug like osimertinib can be used in adjuvant therapy and surgery. We are seeing more and more of that. Now we are seeing the immunotherapies being moved up to the earlier stages of the disease as well. We are seeing the advent of neoadjuvant approaches. We have targeted therapy, and immunotherapy, which is a bit behind but certainly making a strong case. All these new therapies are moving to the earlier stages of lung cancer and helping more patients with this disease.

Transcript edited for clarity.

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