November 2019

By Tom Newsom-Davis, BTOG Vice-Chair

1st Line Osimertinib Overall Survival Results: FLAURA

The overall survival (OS) date from the FLAURA study was presented at the Presidential Session of ESMO 2019, following publication of the Progression Free Survival (PFS) in 2018.

The Study
FLAURA is a phase 3 trial of over 550 previously untreated patients with advanced stage EGFRmut NSCLC, randomised to receive either a 1st generation EGFR tyrosine kinase inhibitor, TKI (gefitinib or erlotinib) or the 3rd generation EGFR TKI, osimertinib. The primary end-point was PFS, and OS was one of the secondary end-points.

Patients with exon 19 deletion or exon 21 (L858R) mutations were eligible for the study, and this, as well as Asian vs. non-Asian heritage were the stratification factors. Patients in the control arm (gefitinib or erlotinib) were allowed to cross-over to osimertinib in event of disease progression and confirmation of the presence of an EGFR T790M mutation. As expected in EGFRmut NSCLC, most patients were female (63%), of Asian heritage (62%) and non-smokers (64%)

The Results
The osimertinib arm showing an improvement in median OS from 18.6 months to 31.8 months (hazard ratio 0.799, p-value = 0.0462). Several landmark survival points were presented, for example 24-month OS increased from 59% to 74%. With respect to subgroups, most of these benefitted from osimertinib however there was some variation. In particular, patients of Asian origin and patients with an L858R exon 21 mutation seemed to benefit less from osimertinib (hazard ratio 0.995 and 0.996 respectively).

As was shown in previous data, osimertinib was well tolerated with less rash and liver abnormalities that the control arm, and similar rates of other side effects.

FLAURA confirms the superiority of osimertinib. It is the only study which has shown a statistically significant improvement in overall survival over another EGFR TKI and reinforces osimertinib’s position as the standard of care for 1st line treatment of EGFRmut lung cancer. However although we now know that osimertinib is better than 1st generation TKIs, FLAURA did not involve the 2nd generation EGFR TKIs, Afatinib or Dacomitinib. In addition, it did not include rarer EGFR mutations (such as G719X, S768I, L861Q) and so we do not know if the benefits of osimertinib extend to these patients too.

The overall survival benefit seen in FLAURA confirms that using osimertinib first is better than using a different EGFR TKI, and then switching to osimertinib in event of progression and the presence of the T790M resistance mutation. This is backed up by data on 2nd line therapies: In both arms, 30% of patient never received any treatment after their first line EGFR TKI. In the control arm, 47% of patients received osimertinib as a 2nd line treatment.

Osimertinib is licensed in the 1st and 2nd line treatment of EGFRmut lung cancer. It is available on the NHS as a 2nd line treatment after progression on an EGFR TKI and in the presence of the T790M resistance mutation. The 1st line use of Osimertinib is currently undergoing re-review by NICE.