Mary Jo Fidler, MD, discusses targeting the EGFR-gene activating mutations, first- and second-generation inhibitors, and the potential of osimertinib.
Osimertinib (Tagrisso) has impressed researchers in the field of EGFR-mutant non—small cell lung cancer (NSCLC), most recently with results from the phase III FLAURA trial solidifying its benefit.
In FLAURA, treatment with frontline osimertinib led to a median progression-free survival (PFS) of 18.9 months (95% CI, 15.2-21.4). This represented a 54% risk reduction in progression or death compared with a standard EGFR tyrosine kinase inhibitor (TKI) for patients with locally advanced or metastatic EGFR-mutant NSCLC.
Additionally, in results from the phase III AURA3 trial presented at the 2017 ASCO Annual Meeting, osimertinib improved responses in patients with T790M-positive NSCLC who progressed after first-line EGFR-TKI therapy and harbored central nervous system (CNS) metastases.
In the subset analysis of patients with CNS metastases in AURA3, the overall response rate was 70% with osimertinib, compared with 31% for patients treated with platinum-based doublet chemotherapy (odds ratio, 5.13; 95% CI, 1.44-20.64; P = .015).
“It has been quite an exciting year,” said Mary Jo Fidler, MD. “We have great therapies for EGFR-activated NSCLC.”
During her presentation at the 2017 OncLive® State of the Science SummitTM on Advanced Non—Small Cell Lung Cancer, Fidler, associate professor, medical oncology, hematology, internal medicine, Rush University Medical Center, shared her insight on strategies with driver mutations in NSCLC, including targeting the EGFR-gene activating mutations, first- and second-generation inhibitors, and the potential of osimertinib.
In an interview during the meeting, Fidler discussed the promise of novel therapies in these subpopulations.Fidler: We saw a nice phase III trial comparing osimertinib with standard frontline platinum-based doublet chemotherapy in patients who had progressed on a first-generation TKI with T790M as a secondary mutation. That trial clearly showed a benefit of osimertinib over platinum doublet chemotherapy.
At the 2017 ASCO Annual Meeting, we saw some nice data showing the CNS penetration of osimertinib; we can see CNS responses that parallel that in the systemic response.
I also spoke about osimertinib in the frontline setting, as we now have data from the FLAURA trial. This trial compared osimertinib with erlotinib (Tarceva) or gefitinib (Iressa) as a frontline agent, and the PFS data are really impressive. The overall survival data are not yet mature, but [osimertinib] seems to be better tolerated and is a real winner in that trial.Unfortunately, all patients will still progress. The PFS data with osimertinib in the frontline setting goes out to the median of 18 months, which is great, but all patients will progress. The challenge we have now is, how do we keep people on targeted agents? There is some preliminary work looking at mechanisms of resistance for osimertinib. We have some information on first- and second-generation EGFR TKIs, but finding the right combination of protein therapy to counteract resistance is important.
Also, [it is important to educate]. It is also important to have patients’ tissue rebiopsied, or use serum if tissue is not easily available. There are some cases where the EGFR will transform into a different histology and behave more like a small cell lung cancer.The big takeaway is that we have to find the mutations—so [we need to] test the adenocarcinomas upfront, patients with small biopsies or histologies that might be questionable, and light smokers. The other thing is that we should be testing patients upon progression to see if there is any actionable resistance mutation. Even if we don't find T790M, or if osimertinib gets frontline approval, there are resistance mechanisms that we do have targeted agents for in existence, and hopefully some that will be in development soon.The CNS data with osimertinib is important to keep in mind because these patients with driver mutations, such as ALK and EGFR, probably do have a higher tendency to have brain metastases, so those are patients who I do consider screening for brain metastases periodically because treating them early when they are less symptomatic is better for outcomes.