Thank you, good morning. The results of the FLAURA study that we will present this evening will define a new standard of care for patients with EGFR mutation positive non-small cell lung cancer. I’ll walk you through the top highlights of the trial. This is a randomised phase III trial that compares osimertinib to standard of care EGFR inhibitors in patients with EGFR mutation positive lung cancer. These are our disclosures.
EGFR mutations are seen in approximately 15-35% of lung adenocarcinomas. The incidence of EGFR mutations are higher in Asian patients. For these patients we now know that EGFR inhibitors are the standard of care; erlotinib, gefitinib and afatinib are the three approved drugs in this space. Regardless of how well patients respond to these drugs, ultimately everybody develops resistance. Half of these patients develop resistance through this new mutation referred to as the T790M mutation.
Osimertinib is a first in class, mutation specific EGFR inhibitor that blocks your common EGFR mutations and also the T790M mutation. So we wanted to see if by shutting down a major escape pathway by giving osimertinib up front whether we would be able to improve patient outcomes. In fact, in preclinical studies we saw this to be the case. In a sixty patient expansion cohort from the phase I study of osimertinib we saw very high response rates in the front line setting and a median PFS of close to 20 months.
So based on all of these lines of evidence we launched the FLAURA phase III clinical trial. This is a double-blind, randomised clinical trial with placebo control where patients with EGFR mutation positive non-small cell lung cancer were randomised to treatment with osimertinib at a dose of 80mg/day or standard of care which could either be gefitinib at its approved dose of 250mg/day or erlotinib at its approved dose of 150mg/day. For patients in the standard of care arm we allowed for crossover to receive osimertinib if they had documented progression and developed the presence of T790M mutation. The primary endpoint for this trial was median progression free survival and secondary endpoints included response rate and survival.
Osimertinib improved median progression free survival in a robust, clinically significant and statistically significant manner. The median PFS for the control group was 10.2 months and for osimertinib it was 18.9 months. The hazard ratio was 0.46. What’s very unique about this curve is that the curves separate very early and stay consistently separated. The p-value for the hazard ratio was less than 0.001.
The overall survival hazard ratio was 0.63 though I would say that the survival data are relatively immature at only about 25%. The p-value here was 0.0068. For this interim analysis at an early point for overall survival we would have required a p-value of 0.0015 to call it statistically significant. So at this point we would call this a strong and promising survival trend.
We also show here that osimertinib has activity against brain metastases. When we look at the 116 patients who came into the trial with a history of brain metastases versus patients who came in without any brain metastases the hazard ratio is nearly identical at 0.46 and 0.47, suggesting that osimertinib exerts activity not only in systemic sites but also in the brain. In fact, when we looked at the number of patients who progressed in the brain while on therapy it was 6% for patients treated with osimertinib compared to 15% for patients treated with standard of care, suggesting that osimertinib protects the brain and the systemic sites.
In conclusion, the FLAURA results demonstrate a 54% reduction in progression free survival with the use of osimertinib when compared to standard of care. The hazard ratio was consistent in patients with and without brain metastases at the time of study entry. What I didn’t show you is that the duration of response was more than two-fold higher at 18.5 for the standard of care versus 17.2 months for osimertinib treated patients. The interim overall survival results show a promising trend with a hazard ratio of 0.63.
The safety profile, which I haven’t gone over because of time, showed clear benefits to patients receiving osimertinib where treatment discontinuation was much less common with osimertinib and grade 3/4 all cause events were almost twelve points lower for patients who received osimertinib therapy.
On the strength of all these observations we conclude that osimertinib is a new standard of care for patients with EGFR mutation positive non-small cell lung cancer. I want to thank you for your attention.
From a mechanistic basis we wouldn’t expect the current wave of PEGFR inhibitors to be effective after patients have been exposed to osimertinib. Clearly we are working on understanding the mechanisms of resistance after patients have been treated with osimertinib and then ongoing work will address how to avoid some of those mechanisms. So this is the next step in terms of where will the field move forward.
