Molecular Testing and EGFR-Mutant Non-Small Cell Lung Cancer - Episode 10

Osimertinib in T790M-Mutant Lung Cancer


Luis E. Raez, MD: Osimertinib is approved for patients with non—small cell lung cancer who also have the EGFR mutation in either exon 19 or 21, have already been treated with a tyrosine kinase inhibitor, and have developed the resistant mutation, T790M. Osimertinib is an oral agent. It’s a tyrosine kinase inhibitor like the other ones, but it’s able to overcome the T790M-resistant mutation. We give it once a day. The dosage is 80 mg. We prefer that you don’t take it with any food and don’t mix it with any other pills or medications.

When the patients are on TKI therapy and that fails, there’s an opportunity to give them osimertinib. In general, it’s true that osimertinib is less toxic. That’s amazing for the patients because they just failed 1 of the 3 tyrosine kinase inhibitors, and the other 2 cannot overcome the failure of the 1 that they are having, so they are going to have to move on to osimertinib. The patients expect that— because it sounds like a stronger drug—they are going to get more side effects, but they’re willing to endure anything because they don’t want to go to chemotherapy. It’s amazing that the amount of rash and diarrhea seems to be less than with the other TKIs, so that’s why I think osimertinib has been very good for second-line treatment.

Benjamin P. Levy, MD: The phase III AURA3 trial compared osimertinib (Tagrisso) with chemotherapy for patients who were T790M-positive. These were patients who had all received a first-generation TKI, developed progression, and had the T790M mutation. They were then randomized to osimertinib or chemotherapy. The benefit was huge. The response rate advantage was with osimertinib. The progression-free survival was longer, and the hazard ratio was in the 0.356 range, which we’ve never seen before.

We don’t have data on overall survival yet, but based on that—and I think we knew this from the AURA trials before; keep in mind osimertinib got approved in November 2015—this phase III AURA3 trial is confirmation that osimertinib is superior to chemotherapy. There were impressive results with a drug that show not only improvements in outcomes but also that it’s so well tolerated compared with chemotherapy that it’s a huge victory for science but a better win for our patients.

My experience with osimertinib has mirrored the data. In around 70% of the patients I see, this drug elicits a response rate with improvement of their symptoms as well. I have used this drug a lot; I have a high number of patients with EGFR-mutant lung cancer. We look for T790M aggressively in the plasma when we are ready for a therapeutic switch. If they’re T790M-positive, then of course they get this drug. But not only have I been impressed with the drug’s effect, I’ve also been just as impressed with the drug’s tolerability.

I have seen very few side effects with this drug. For many of my patients who’ve struggled with the rash and diarrhea from their first-generation TKI, we don’t see those signals with osimertinib; we don’t see those toxicity signals. For now, it’s the only drug approved for T790M-mutant lung cancer, and it’s a good one. Once you put that first patient on this drug and you see how well they do in the context of chemotherapy, you’ll be reminded to test for T790M again. The drug’s efficacy and tolerability are a nice reminder to look for the T790M mutation carefully.

Luis E. Raez, MD: We are very pleased with osimertinib. Before osimertinib, the only option we had for our patients was to start palliative chemotherapy as soon as they failed the tyrosine kinase inhibitor. When osimertinib became available with clinical trials, we could give the patient this benefit, and usually, the patients who have failed tyrosine kinase inhibitors or developed the T790M mutation resistance have had a higher chance of response to osimertinib—even higher than palliative chemotherapy. That’s why we have had a very good experience with osimertinib. We have more than a dozen patients already treated. The toxicity is surprisingly very manageable. It seems that the toxicity from the rash and diarrhea is less prevalent than the toxicity with the other TKIs—something that the patients take very gladly because they have failed the frontline therapy and are expecting that because they want to be rescued by this osimertinib, they are ready to endure any side effect. And surprisingly, there are no side effects, or the side effects are less prevalent. That makes the quality of life very good for them.

Transcript Edited for Clarity