Suresh S. Ramalingam, MD
The much-anticipated progression-free survival (PFS) findings from the phase III FLAURA trial did not disappoint the lung cancer community, as the third-generation EGFR inhibitor osimertinib (Tagrisso) demonstrated a significant improvement in PFS over current first-line therapies for patients with EGFR
-mutant non–small cell lung cancer (NSCLC).
Results showed that frontline osimertinib was associated with a 54% reduction in the risk of progression or death versus standard therapy, which included erlotinib (Tarceva) or gefitinib (Iressa). In the double-blind study, the median PFS was 10.2 months (95% CI, 9.6-11.1) for standard therapy and 18.9 months (95% CI, 12.5-21.4) with osimertinib (HR, 0.46; 95% CI, 0.37-0.57; P
Though overall survival (OS) data remain immature, there is an encouraging trend that favors osimertinib. Additionally, the trial’s findings highlighted a benefit with osimertinib in patients who also had brain metastases.
“We showed activity in the brain, a robust PFS benefit, almost a two-fold improvement in duration of response, and a promising survival trend, which is why we are excited about the results of the FLAURA study,” explained Suresh A. Ramalingam, MD.
In an interview with OncLive
during the 2017 ESMO Congress, Ramalingam, deputy director of Winship Cancer Institute of Emory University, discussed the practice-changing FLAURA findings and his thoughts on sequencing should the FDA approve osimertinib in the frontline setting.
OncLive: Please share your insight on the FLAURA findings?
The FLAURA study was a phase III clinical trial that compared, head to head, osimertinib—a new, third-generation EGFR inhibitor—to standard of care, which are presently used drugs such as erlotinib and gefitinib. Osimertinib is approved in the United States by the FDA for the second-line treatment of EFGR
-mutated patients in those who have developed a T790M mutation as a resistance mechanism to the first-generation drug.
What we tried to do with the FLAURA study is move osimertinib to the first-line setting and compare it head to head. The hypothesis is that it shuts off the resistance pathway. Therefore, we compared osimertinib in a cohort of 556 patients with a double-blind, placebo-controlled, randomized, phase III trial. It was a 1:1 randomization between osimertinib versus either erlotinib or gefitinib. The primary endpoint of the trial was PFS as assessed by the investigator. What we found was that there was a clear superiority for osimertinib over standard of care.
Here are the numbers: the median PFS with standard of care was 10.2 months; the median PFS with osimertinib was 18.9 months. The hazard ratio was 0.46, and the P value was highly significant. Therefore, this means a 54% reduction in the risk of death or progression with osimertinib.
The second efficacy point to make is that the duration of response was more than two-fold higher for patients treated with osimertinib. For standard of care, it was 8.5 months; for osimertinib, it was 17.2 months. The third point is OS. We found that even though the data are very immature at this point—at only 25%—the hazard ratio for OS is 0.63, with a P value of .0068.
Though not statistically significant at this time, it is a very promising trend. That is important because we allowed crossover from the control arm for patients who develop progression in T790M.
We also found activity in the brain. Patients with brain metastases that came into the study had a very similar hazard ratio, at .47, as the overall population.
What is the safety profile of osimertinib?
Osimertinib is a mutation-specific EGFR inhibitor. What that tells you is that it has a more profound effect on the mutant receptor than the wild-type receptor, which means the toxicities tend to be lower. We have seen this in trials done already with osimertinib, where the skin toxicities and overall toxicity burden is much lighter on the patients.
In FLAURA, we saw a similar picture. If you look at grade 3/4 adverse events, it was considerably lower with osimertinib compared with standard of care. When you look at skin toxicity, it was almost half as common with osimertinib as it was with standard of care.