Frontline osimertinib improves the overall survival in patients with EGFR-mutation positive metastatic non-small cell lung cancer

The phase III FLAURA trial compares the third generation EGFR-TKI osimertinib with gefitinib or erlotinib as first-line treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). Previous reports of this trial established that osimertinib significantly delays the disease progression compared to the comparator EGFR-TKIs. During ESMO 2019, the final analysis of this trial demonstrated that this progression-free survival (PFS) benefit was translated into a significant overall survival (OS) benefit. At the three-year landmark, this OS benefit translates into a 10% absolute survival benefit in favor of osimertinib (54% vs 44%). After three years, 28% of patients randomized to osimertinib were still on therapy as compared to only 9% in the control arm. As such, the final OS analysis of the FLAURA trial further solidifies osimertinib as the standard of care in the first-line treatment of patients with EGFR mutated advanced NSCLC.

Background

In the phase III FLAURA trial, 556 patients with locally advanced or metastatic NSCLC with a WHO performance status 0/1 who did not receive prior systemic anticancer or EGFR-TKI therapy were randomized (1:1) between osimertinib (80 mg po qd) (N=279) or comparator EGFR-TKI (gefitinib 250mg po qd or erlotinib 150mg po qd) (N=277). Crossover was allowed for patients in the comparator EGFR TKI arm, who could receive open-label osimertinib upon central confirmation of progression and T790M positivity. OS was a key secondary endpoint of this study.

The median age of patients in the study was 64 years, two thirds were Asian and 65% were never smokers. About 20% of patients had central nervous system (CNS) metastases at study entry and 95% had metastatic disease. In the primary analysis of the study, osimertinib was shown to be associated with a significantly better PFS compared to comparator EGFR-TKI, with a 54% reduction in the risk of disease progression or death.

Results

During the 2019 ESMO meeting, the final OS analysis demonstrated a significantly longer OS with osimertinib. In fact, the median OS of patients treated with osimertinib was 38.6 months as compared to 31.8 months with erlotinib or gefitinib (HR[95%CI]: 0.799[0.641-0.997]; p= 0.0462). At three years, this corresponds to an OS rate of 54% with osimertinib and 44% among patients treated with a comparator EGFR TKI. In a prespecified analysis, the OS benefit was consistently seen across all investigated subgroups, irrespective of sex, age, smoking history and the presence of CNS metastases at study entry. Interestingly, an analysis of OS in function of race indicated that the OS benefit of osimertinib was mainly restricted to the subgroup of non-Asian patients. Further research is needed to shed more light on this finding.

At 36 months, 28% of patients randomized to osimertinib were still on therapy as compared to 9% in the control arm. Also with respect to the time to the first subsequent treatment (TFST) osimertinib outperformed gefitinib/erlotinib with a median TFST for osimertinib of 25.5 months, which was almost a year longer than the 13.7 months seen in the control arm. Of note, of the 180 patients in the comparator EGFR-TKI arm who received a first subsequent treatment, 85 patients (47%) crossed over to osimertinib (31% of all patients randomized from the comparator EGFR-TKI arm).

Conclusions

In summary, FLAURA showed a statistically significant and clinically meaningful improvement in OS with osimertinib compared to erlotinib or gefitinib. The median OS for patients in the osimertinib arm was extended by 6.8 months. Osimertinib is the first EGFR-TKI monotherapy to show a statistically significant OS benefit compared to other EGFR-TKIs. As such, these data reinforce osimertinib as the standard of care for first-line treatment of patients with EGFR mutant advanced NSCLC.

Reference

Ramalingam S, Gray J, Ohe Y, et al. Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis. Presented at ESMO 2019; Abstract LBA5_PR.