AURA3 Fails To Demonstrate OS Benefit For Osimertinib

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Use of osimertinib does not significantly improve overall survival (OS) compared with conventional chemotherapy for patients with previously treated advanced non-small-cell lung cancer (NSCLC) positive for an EGFR T790M mutation, say the AURA3 investigators. 

The final OS analysis follows the initial results from the phase III trial showing a significant improvement in progression-free survival (PFS), as well as subgroup findings suggesting that patients with central nervous system metastases had a better objective response rate (ORR) and PFS with osimertinib. 

Median OS was numerically longer among the 279 patients randomly assigned to receive osimertinib 80 mg/day than the 136 patients instead given up to six cycles of pemetrexed plus carboplatin or cisplatin, at 26.8 versus 22.5 months.  

But the hazard ratio (HR) for death of 0.87 was not statistically significant, report Yi-Long Wu, from Guangdong Lung Cancer Institute in Guangzhou, China, and co-authors in the Annals of Oncology. 

The investigators note that 73% of patients given chemotherapy had crossed over to osimertinib therapy by time of data cutoff and received a median 11.0 months of osimertinib therapy, compared with a median 13.8 months among those who were randomly assigned to receive the EGFR–tyrosine kinase inhibitor (TKI). 

After adjusting for the impact of crossover to osimertinib, the median OS in the platinum–pemetrexed arm fell to 15.9 months with a HR of 0.54, say the researchers who believe the high crossover rate may therefore explain “[t]he lack of a significant survival benefit” among the osimertinib-treated patients. 

Yi-Long Wu et al say there were “no new safety signals” for osimertinib and that the EGFR–TKI was associated with a lower rate of grade 3 or more severe adverse events (AEs) than chemotherapy, affecting 9% versus 34% of patients. In addition, 9% of patients who crossed over to osimertinib experienced AEs of this severity. 

Treatment was discontinued because of AEs by 5% of osimertinib-treated patients, and 1% of crossover patients, versus 9% of those given chemotherapy. Two fatal cases of pneumonitis were considered to be possibly related to osimertinib, as was a third death from respiratory failure in a crossover patient and two deaths in patients receiving platinum–pemetrexed. 

“The continued tolerable safety profile reported here for osimertinib, together with superior PFS, improved patient quality of life and longer time to symptom deterioration versus platinum-pemetrexed, reinforces osimertinib as standard-of-care second-line treatment for patients with T790M advanced NSLSC and disease progression on a prior EGFR-TKI”, the investigators conclude. 

However, when considering the AURA3 results in light of the positive FLAURA trial findings for first-line osimertinib versus comparator EGFR–TKIs, the researchers observe that “there is no way to confidently predict which patients who start first- or second-generation EGFR-TKIs will progress with T790M disease.” 

They therefore advise: “In view of this, and the clinical benefit reported from FLAURA, using osimertinib as first-line treatment provides more patients the opportunity to receive the associated OS benefit of osimertinib versus comparator first-line EGFR-TKI.” 

Reference 

Papadimitrakopoulou VA, Mok TS, Han J-Y, et al. Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis. Ann Oncol; Advance online publication 27 August 2020. https://doi.org/10.1016/j.annonc.2020.08.2100