In an interview with <em>Targeted Oncology</em>, Suresh S. Ramalingam, MD, deputy director of Winship Cancer Institute of Emory University, discussed the updated OS results from the FLAURA trial and evaluated the role of osimertinib in patients with <em>EGFR-</em>mutant NSCLC. He also highlighted some next steps with research for this patient population, such as the potential combination of osimertinib with other agents.
Suresh S. Ramalingam, MD
Although previously reported data from the phase III FLAURA trial demonstrated an improvement in progression-free survival (PFS), the primary endpoint, with frontline osimertinib (Tagrisso) in patients withEGFR-mutant nonsmall cell lung cancer (NSCLC), updated findings presented at the 2019 ESMO Congress also showed a clinically and statistically significant improvement in overall survival (OS) compared with erlotinib (Tarceva) or gefitinib (Iressa).
Osimertinib was previously approved by the FDA in April 2018for the treatment of patients withEGFR-mutant NSCLC in the first-line setting based on the FLAURA trial. Theseupdated data further support the approval of osimertinibin this patient population after meeting the secondary endpoint of the trial, OS.1
In the FLAURA trial, 556 newly diagnosed patients withEGFR-mutant locally advanced or metastatic NSCLC were randomized to receive an oral daily dose of either osimertinib at 80 mg or 1 of 2 standard tyrosine kinase inhibitors (TKIs): erlotinib at 250 mg or gefitinib at 150 mg. Patients with exon 19 or L858R mutations, as well as those with central nervous system (CNS) metastases, were also allowed on the trial.
Median OS was 38.6 months versus 31.8 months in the osimertinib versus control groups, respectively. There was a 20% reduction in the risk of death with osimertinib (HR, 0.799; 95% CI, 0.647-0.997;P= .0462). As of the final OS analysis, 54% of patients remained alive at 36 months with osimertinib versus 44% in the control arm.
Previously reported findings demonstrated a median PFS of 18.9 months with osimertinib versus 10.3 months in the control arm (HR, 0.46; 95% CI, 0.37-0.57;P<.001). The objective response rate was also 80% versus 76%, respectively. Median duration of response with osimertinib was 17.2 months compared with 8.5 months in the control arm.2
The most common adverse events (AEs) included rash or acne, diarrhea, dry skin, paronychia, stomatitis, and decreased appetite. AEs were also less likely to lead to treatment discontinuation with osimertinib, where only 13% of patients discontinued treatment versus 18% in the control arm.
In an interview withTargeted Oncology, Suresh S. Ramalingam, MD, deputy director of Winship Cancer Institute of Emory University, discussed the updated OS results from the FLAURA trial and evaluated the role of osimertinib in patients withEGFR-mutant NSCLC. He also highlighted some next steps with research for this patient population, such as the potential combination of osimertinib with other agents.
TARGETED ONCOLOGY: Going back to the initial development of the trial, what was the rationale for evaluating osimertinib in the frontline for this patient population?
Ramalingam:The FLAURA study was designed to evaluate osimertinib as frontline therapy for [patients with]EGFR-mutated NSCLC. We know that osimertinib inhibits exon 19 and 21EGFRmutations, but it also inhibits the T790M mutation, which is the most common resistance pathway when patients get erlotinib, gefitinib, or afatinib (Gilotrif). We moved osimertinib to the frontline to see if you could prevent the emergence of resistance and thereby improve patient outcomes. That is exactly what the results of the FLAURA study showed in the frontline setting.
TARGETED ONCOLOGY: What makes osimertinib different from other EGFR inhibitors?
Ramalingam:Osimertinib has a few differences from the other EGFR inhibitors. As a third-generation drug, it is very specific for the mutated receptor compared to the other EGFR inhibitors. That means it has a favorable tolerability profile because of fewer effects on the wildtypeEGFR-bearing cells. The second point is osimertinib has better CNS penetration. We know that 40% to 45% ofEGFR-mutated patients will develop brain metastases at some point during the course of their disease, unfortunately. Having a drug that has better CNS penetration is important. The third point is, of course, having T790M inhibition in addition to exon 19 and exon 21 inhibition. Those are some of the things that make osimertinib a unique EGFR TKI.
TARGETED ONCOLOGY: What data has been previously reported to date from this trial?
Ramalingam:Earlier at the 2017 ESMO Congress, we reported the PFS endpoint, which was the primary endpoint for the FLAURA trial. We showed that treatment with osimertinib resulted in improvement in the median PFS from 10.2 months in the control group to 18.9 months with osimertinib. The hazard ratio (HR) was 0.46 and it was highly significant. We also showed that osimertinib had a more favorable tolerability profile, and we saw that osimertinib was associated with responses in the brain for 90% of the patients.
TARGETED ONCOLOGY: What were the updated results presented at the 2019 ESMO Congress?
Ramalingam:At this meeting, we are reporting the OS results of the FLAURA study. OS was a secondary endpoint for the clinical trial. At the time of the original presentation of the data, maturity was low. Now, we have full maturity of the data set, and therefore, we were able to report the final OS results.
What we saw is that osimertinib improved OS by a clinically and statistically significant manner. The median OS was 38.6 months for patients treated with osimertinib compared to 31.8 months in the control group. ThePvalue was significant, and the HR was 0.799. I would also point out that the control group’s OS, which was 31.8 months, is among the highest recorded forEGFR-mutated patients. That reflects crossover of patients in the control group who received osimertinib if they had T790M upon progression.
TARGETED ONCOLOGY: How will these data impact the treatment of patients withEGFR-mutant NSCLC?
Ramalingam:Osimertinib is already an FDA-approved frontline treatment choice in the United States. It’s also approved in many other parts of the world. These data confirm its position as the preferred frontline therapeutic agent with improvement in PFS and OS for exon 19- and exon 21-mutated patients.
TARGETED ONCOLOGY: What are your thoughts on increasing molecular testing to identify more patients that could benefit from osimertinib or other targeted therapies?
Ramalingam:Despite the availability of exciting targeted agents for certain molecular subsets of lung adenocarcinoma, molecular testing [continues] to be done in a suboptimal way. A majority of the patients who are candidates for these treatments are not able to get treatments if they don’t receive molecular testing. We highly encourage physicians to do thorough molecular testing for nonsquamous patients.
TARGETED ONCOLOGY: What are next steps following these data from the FLAURA trial?
Ramalingam:With osimertinib emerging as a frontline treatment inEGFR-mutant patients with lung cancer, the next steps are how do we get to the next higher level. That would come from understanding the resistance mechanisms of osimertinib and developing novel combinations around it. Those efforts are already underway.
TARGETED ONCOLOGY: Are there any specific combinations you are looking forward to in this space?
Ramalingam:The combination of osimertinib with MEK inhibition or with MET inhibition are 2 strategies to prevent resistance emergence by the activation of the MAP kinase pathway. Obviously, combination with chemotherapy is another interesting strategy. We are also looking at osimertinib plus bevacizumab (Avastin) in an ECOG randomized phase III clinical trial. There are a number of exciting approaches that are being tested in the clinic.