Targeting NSCLC with Uncommon EGFR Mutations - Episode 9

Novel Agents Targeting EGFR Mutations in Non–Small Cell Lung Cancer

Considerations for use of novel EGFR-targeted agents osimertinib, amivantamab, and poziotinib in NSCLC, in the context of respective clinical trial data.


Roy S. Herbst, MD, PhD: I would use osimertinib in any patient with newly diagnosed EGFR-mutated lung cancer. Again, it’s usually exon 19 or 21. If it was exon 20, I would go to the computer and see what the activity has been, if it was an uncommon mutation that I wasn’t that familiar with. But osimertinib is the best drug right now. It is EGFR-mutation specific, meaning it doesn’t work on the cells that don’t have an EGFR mutation, so it won’t work on the normal cells. The EGFR mutation is in the tumor cells, somatic, so that’s very nice because that allows us to spare normal cells. There is a little bit of no drug is perfect, so if you use it in high enough doses you will see the EGFR-related toxicities like skin rash and diarrhea. But it is quite effective, it has median profession-free survival close to 20 months, so that’s quite good. It also has a very high penetration of the brain. Targeting the brain is a very important factor in all this because the brain is a site where it’s hard to get good levels of EGFR inhibitors, and tumors will grow in the brain. I think that all those favor this drug. The first-generation drugs were reversible inhibitors, this is an irreversible inhibitor. So osimertinib, in the United States at least, and in most of the world is standard of care in the front line for EGFR-mutated lung cancer.

Amivantamab is a dual antibody against EGFR and c-MET. Amivantamab is approved for exon 20, the patients who may not respond to the typical osimertinib drug. It’s also being used in combination with lazertinib, which is an EGFR TKI [tyrosine kinase inhibitor], a similar drug to osimertinib. We have used a bit of it here for patients who have the exon 20. We have seen some response. It also has an issue with an infusion reaction, which is something that one has to keep in mind. But we’re beginning to use that newly approved drug.

I have known about poziotinib for a long time. It’s an agent that targets exon 20. It has shown some moderate activity. The response rates are not what you see with osimertinib in exons 19 and 21. It’s not 80% and 70%; it’s 30%, 40%, 50%, with a little more toxicity. But poziotinib has been studied in exon 20, and amivantamab, lazertinib, and there are several other targeted agents from different groups that are being looked at in this setting. It’s interesting. These are even rarer than the exon 19 and 21 mutations. But given the large number of people with lung cancer in the world, 2 million a year, and 10% of those may be having EGFR-mutated lung cancer in the United States, and there are maybe 30% to 40% in Asia, there is large funnel of patients that are coming in for some of these therapies.

In these patients, I would probably manage toxicities with topical antibiotics for the skin. We use lotions and creams. For the GI [gastrointestinal] tract, we use antidiarrheal medicines. Again, you don’t see them as much with the EGFR mutation selective drugs like osimertinib, but these certainly are issues to consider.

Transcript edited for clarity.