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.
Based on positive data from the phase III FLAURA study, osimertinib has become the frontline standard of care for this patient population. Results showed that osimertinib significantly improved median progression-free survival at 18.9 months versus 10.2 months with the earlier TKIs erlotinib (Gilotrif) and gefitinib (Iressa; HR, 0.46; 95% CI, 0.37-0.57; P
<.001). While objective response rates were similar at 80% with osimertinib versus 76% on standard TKIs, the median duration of response was 17.2 months versus 8.5 months in favor of osimertinib (95% CI, 7.3-9.8).1
Padda, an assistant professor of medicine at Stanford Cancer Institute, said that despite the clear survival benefit, patients are now developing resistance mechanisms that are unique to osimertinib.
In a study presented at the 2018 ESMO Congress, researchers suggested that MET
amplification and EGFR
C797S mutations were key alterations associated with resistance to frontline osimertinib. In this analysis of the FLAURA trial, plasma samples were analyzed through next-generation sequencing at baseline and the time of progression. Findings showed that MET
amplification was the most common acquired resistance mechanism in patients who progressed on osimertinib (15%), followed by C797S (7%), and PI3KCA
To overcome this challenge, ongoing studies are looking at the use of combination approaches, such as pairing osimertinib with other antibodies.
In an interview with OncLive
, Padda discussed the practice-changing impact of osimertinib and addressed the challenges that still remain in EGFR
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.
There are basically 2 dominant [resistance] mechanisms that emerge. One is acquired EGFR
mutations, the most common one being C797S, which prevents the binding of osimertinib to its target. Then you have gene amplification, of which MET
is the most dominant.
The issue, however, is with the mechanisms of resistance to frontline osimertinib; they are much more heterogeneous than what we saw with progression on first- and second-generation EGFR TKIs. On these earlier drugs, 60% of patients had a T790M mutation develop. We no longer see that kind of dominant resistance mechanism, which complicates things. In addition, these resistance mechanisms that we do see are often happening concurrently. The paradigm then becomes very complex.