Sukhmani K. Padda, MD
Osimertinib (Tagrisso) has effectively overcome the T790M resistance mechanism associated with earlier-generation EGFR TKIs, but patients with EGFR
-positive non–small cell lung cancer (NSCLC) are still experiencing disease progression on the third-generation drug, said Sukhmani Padda, MD.
OncLive: What has been the impact of osimertinib on patients with EGFR-mutant NSCLC?
: For third-generation EGFR TKIs, the only one that is FDA-approved right now is osimertinib, which has dramatically changed the landscape. When we are talking about generations of EGFR TKIs, the advantage that third-generation inhibitors have over the older-generation drugs is that they select for activity against T790M, which is one of the most common resistance mechanisms against first- and second-generation EGFR TKIs. In addition, more so than the earlier-generation drugs, third-generation TKIs have less of a EGFR
wild-type on-target effect, which means that they have less skin-related toxicities.
What is the safety profile of osimertinib?
The safety of this drug is based on its mechanisms. The way osimertinib was designed was to have less EGFR
wild-type toxicity. Although it still has some wild-type toxicity—you are not completely absent of having a rash—we are seeing significantly lower rates [versus other TKIs]. There are similar rates of diarrhea that you would see with an earlier-generation TKI. There is also some rare cardiac toxicity that you should be mindful of, in the single-digit [percentage of incidence], such as prolongation of QT interval and decrease in left ventricular ejection fraction.
What are some emerging treatment strategies beyond frontline osimertinib?
Now that osimertinib has moved to the frontline setting, we have to figure out what to do after resistance to it. There were just data presented at the 2018 ESMO Congress by Suresh S. Ramalingam, MD, of Emory University, that started to examine this specific question.
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