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No OS Benefit in EGFR T790M Advanced NSCLC Treated with Osimertinib vs Chemotherapy

Final overall survival data from the AURA3 study possibly impacted by a high percentage of treatment crossover
02 Sep 2020
Anticancer agents & Biologic therapy;  Lung and other thoracic tumours;  Personalised medicine

In patients with epidermal growth factor receptor (EGFR) T790M advanced non-small cell lung cancer (NSCLC), no statistically significant benefit in overall survival (OS) was observed with osimertinib comparing to platinum-pemetrexed treatment, which possibly reflects the high crossover rate of patients from the therapy with platinum-pemetrexed to osimertinib. The final results from the AURA3 study were reported on 27 August 2020 in the Annals of Oncology by Prof. Yi-Long Wu of the Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences in Guangzhou, China and colleagues. The hazard ratio (HR) for median OS was 0.87, while analysis of OS adjusted for crossover showed the HR of 0.54. High percentage (73%) of patients treated with platinum-pemetrexed chemotherapy were subsequently treated with osimertinib in this study.

Osimertinib is a third-generation, irreversible, oral EGFR tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR TKI sensitising and T790M resistance mutations and has demonstrated efficacy in NSCLC, including central nervous system metastases.

The authors wrote in the study background that in the AURA3 (NCT02151981), osimertinib significantly prolonged progression-free survival (PFS) and improved response in patients with EGFR T790M advanced NSCLC and progression on prior EGFR TKI treatment. In their article published on 27 August 2020 in the Annals of Oncology, the AURA3 investigators reported the final OS analysis in this study.

In the AURA3, adult patients were randomised 2:1 to osimertinib given orally 80 mg once daily or pemetrexed plus carboplatin/cisplatin given intravenously, every 3 weeks, up to 6 cycles. Patients could crossover to osimertinib on progression confirmed by blinded independent central review. The OS and safety were study secondary endpoints.

In total, 279 patients were randomised to osimertinib; 140 patients were randomised to platinum-pemetrexed from whom 136 received the treatment. At data cut-off of 15 March 2019, 188 patients (67%) receiving osimertinib and 93 patients (66%) receiving platinum-pemetrexed had died.

The HR for OS was 0.87 (95% confidence interval [CI] 0.67–1.12; p = 0.277) with the median OS 26.8 months (95% CI 23.5–31.5) versus 22.5 months (95% CI 20.2–28.8), respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively.

After crossover adjustment, the HR was 0.54 (95% CI 0.18–1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage towards osimertinib, HR 0.21 (95% CI 0.16–0.28; p < 0.001). At data cut-off, 99 of 136 patients (73%) in the platinum-pemetrexed arm had crossed over to osimertinib, 66 of 99 (67%) of whom had died. Among patients receiving subsequent anticancer therapy, platinum chemotherapy was most common after osimertinib (65%)

The most common adverse events possibly related to study treatment were diarrhoea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3, <1%) in the osimertinib arm versus nausea (47%; grade ≥3, 3%) in the platinum-pemetrexed arm. Grade ≥3 possibly treatment-related adverse events have been observed less frequently with osimertinib (9%) than with platinum-pemetrexed (34%).

The authors concluded that no statistically significant benefit in OS was observed for osimertinib versus platinum-pemetrexed in the AURA3, possibly reflecting the high crossover rate of patients from the platinum-pemetrexed arm to receive the treatment with osimertinib. The continued tolerable safety profile reported 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 EGFR T790M advanced NSCLC and disease progression on a prior EGFR TKI treatment.

The study was funded by AstraZeneca. 

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. Annals of Oncology; Published online 27 August 2020. DOI: https://doi.org/10.1016/j.annonc.2020.08.2100

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