Frontline Therapy for EGFR Plus NSCLC: Osimertinib's Impact

Justin Gainor, MD:The approach to treatment of patients with advancedEGFR-mutant lung cancer has certainly changed over the past several years. Historically, patients would be treated with either a first- or second-generation EGFR inhibitor. We know that the median progression-free survival with that approach was about a year for first-generation EGFR inhibitors. And at the time of development of resistance, about 50% to 60% of patients would have developed a single gatekeeper resistance mutation,EGFRT790M. Among those patients who developed T790M, we’ve recently developed data showing that use of a mutant-selective T790M-specific inhibitor, such as osimertinib, could induce responses in the vast majority of patients after progression on a first- or second-generation inhibitor.

Over the past year or so, though, that paradigm of starting with a first- or second-generation inhibitor and then using a third-generation inhibitor among those who developed T790M has changed, and it has changed in response to the FLAURA data. So, FLAURA was a randomized phase III study that compared using a first-generation inhibitor, gefitinib or erlotinib, versus osimertinib in newly diagnosedEGFR-mutant patients. In FLAURA, osimertinib led to significant improvements in progression-free survival compared with the first-generation inhibitors. And the median PFS in FLAURA was approximately 19 months for patients receiving osimertinib. Importantly, patients who received osimertinib also had improved control of central nervous system [CNS] metastases. In my clinical experience, I’ve also found that osimertinib tends to be quite well tolerated, with a favorable adverse effect profile. And as a result, I believe that osimertinib should be the standard of care for newly diagnosed first-lineEGFR-mutant patients.

Alexander Drilon, MD:The FLAURA trial is a landmark trial that randomizedEGFR-mutant lung cancer patients to osimertinib, which is a third-generation EGFR TKI [tyrosine kinase inhibitor], versus first-generation agents erlotinib or gefitinib, recognizing that osimertinib has several advantages. It’s able to target the most common mechanism of resistance with the first-generation agents, vis-à-vis a gatekeeper T790M mutation. In addition to that, it also has excellent CNS coverage, especially for patients who have brain metastases. And we know that patients who don’t have brain metastases, given that they have lung cancer, also have a proclivity or a tendency to develop brain metastases in certain situations.

It’s not a surprise the results of the FLAURA trial were positive for an improved benefit in terms of survival with osimertinib versus erlotinib and gefitinib, and that’s with progression-free survival. It really changed the standard of care. And now there’s FDA approval for osimertinib as the first-line therapy of choice forEGFR-mutant lung cancer cases. And I think this really underscores the paradigm of using your best drug first, knowing that osimertinib was previously approved for patients who have progression on a first-generation or second-generation TKI that then develop a T790M mutation. Now we’re moving that to the frontline setting and using it for everybody.

Justin Gainor, MD:An alternative approach that has been put forward after FLAURA has been that clinicians should still continue using a first- or a second-generation inhibitor first followed by a third-generation inhibitor such as osimertinib. In my mind, that approach is flawed, and the reason that that’s the case is that among patients who receive first- or second-generation inhibitors, just 50% to 60% will actually develop T790M and thus be candidates for receiving osimertinib in the second-line setting. Furthermore, we also know that from various clinical trials that not every single patient makes it to the next therapy. Even when patients are eligible for crossover in clinical trials, the numbers of crossover don’t reach 100%. And so, I feel that we should use our very best therapy first in order to try to maximize efficacy while also maintaining a favorable safety profile.

Transcript edited for clarity.