In updated analysis of the final, mature disease-free survival (DFS) data of the ADAURA study, all 682 patients had the opportunity of 3 years of treatment; 66% and 41% patients completed 3 years of planned adjuvant osimertinib and placebo treatment. Adjuvant osimertinib demonstrated a sustained clinically meaningful DFS benefit, consistent with primary reporting, with DFS benefit observed across all subgroups and stages defined. The prolonged DFS benefit over placebo, magnitude of DFS benefit, reduced risk of local and distant recurrence, improved central nervous system (CNS) DFS, and consistent safety profile observed in this updated analysis support adjuvant osimertinib as a highly effective treatment in patients with resected EGFR-mutated stage IB-IIIA non-small cell lung cancer (NSCLC). The findings are reported by Prof. Roy S. Herbst of the Medical Oncology, Yale School of Medicine and Yale Cancer Center in New Haven, CT, US and colleagues on 31 January 2023 in the Journal of Clinical Oncology.
Recently EGFR tyrosine kinase inhibitors (EGFR TKIs) and immune checkpoint inhibitors (ICIs) have demonstrated improvements in DFS in the adjuvant setting among patients with resectable NSCLC. Osimertinib is a third-generation EGFR TKI with demonstrated efficacy in NSCLC, including in the CNS. The primary DFS analysis of the phase III ADAURA study of adjuvant osimertinib was reported 2 years earlier than planned following Independent Data Monitoring Committee recommendation because of an efficacy benefit. Osimertinib demonstrated a significant DFS benefit versus placebo in patients with EGFR-mutated stage IB-IIIA NSCLC after complete tumour resection with or without adjuvant chemotherapy. The DFS hazard ratio (HR) for patients with stage II-IIIA was 0.17 (99.06% confidence interval [CI] 0.11 to 0.26, p < 0.001), DFS HR for stage IB-IIIA was 0.20 (99.12% CI 0.14 to 0.30, p < 0.001, with a median treatment duration of 22.5 months (range, 0-38 months) for the osimertinib group and 18.7 months (range, 0-36 months) for the placebo group.
Whether recurrences are local or distant following surgery can impact post-recurrence survival, the authors explained in the background. CNS metastases are common among patients with NSCLC, and are a poor prognostic factor associated with deterioration in quality-of-life. In the ADAURA primary analysis, patients treated with osimertinib had a lower incidence of metastatic disease and the CNS DFS HR was 0.18 (95% CI 0.10 to 0.33).
In the latest article published in the JCO, the authors report updated DFS data at the protocol-specified maturity of approximately 50% and recurrence patterns after 2 years of further follow-up. They also report a post hoc exploratory analysis of DFS by disease stage according to the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) 8th edition cancer staging manual. Overall, 682 patients with stage IB-IIIA (according to the AJCC/UICC 7th edition) EGFR-mutated (exon 19 deletion/L858R) NSCLC were randomly assigned 1:1 and stratified by stage, mutational status, and race to receive osimertinib 80 mg once-daily or placebo for 3 years.
The primary endpoint was DFS by investigator assessment in stage II-IIIA disease analyzed by stratified log-rank test; following early reporting of statistical significance in DFS, no further formal statistical testing was planned. Secondary endpoints included DFS in stage IB-IIIA, overall survival (OS), and safety. Patterns of recurrence and CNS DFS were prespecified exploratory endpoints.
At data cut-off of 11 April 2022, in stage II-IIIA disease, median follow-up was 44.2 months with osimertinib and 19.6 months with placebo. The DFS HR was 0.23 (95% CI 0.18 to 0.30); 4-year DFS rate was 70% with osimertinib and 29% with placebo. In the overall population, DFS HR was 0.27 (95% CI 0.21 to 0.34); 4-year DFS rate was 73% with osimertinib and 38% with placebo. Fewer patients treated with osimertinib had local/regional and distant recurrence versus placebo. CNS DFS HR in stage II-IIIA was 0.24 (95% CI 0.14 to 0.42).
The long-term safety profile of osimertinib was consistent with the primary analysis. No new safety concerns were reported.
The authors commented that the updated data highlight the importance of routine EGFR testing at diagnosis to ensure that patients have the opportunity for optimal treatment. Future data of interest from ADAURA include long-term safety, subsequent treatment patterns, and OS. Tumour and circulating tumour DNA molecular profiling for analyses of minimal residual disease and acquired resistance may provide important information on persistence and resistance mechanisms to optimise treatment strategies in this setting.
Other ongoing studies will inform the efficacy and safety of osimertinib as adjuvant treatment for resected EGFR-mutated stage IA2-IA3 NSCLC (ADAURA2), as 5-year adjuvant treatment for EGFR-mutated stage II-IIIB (TARGET), as neoadjuvant treatment for EGFR-mutated stage II-IIIB N2 NSCLC (NeoADAURA), and as maintenance therapy in unresectable EGFR-mutated stage III NSCLC (LAURA).
Other EGFR TKIs are being investigated in the adjuvant setting. The adjuvant treatment setting is also expanding beyond EGFR TKIs to include ICIs. However, the benefit of ICI has not been established for patients with EGFR-mutated disease, and patient numbers in prospective studies to date are limited.
The study was previously presented at the ESMO 2022 Congress (9-13 September in Paris, France).
The study was supported by AstraZeneca.
- Herbst RS, Wu Y-L, John T, et al. Adjuvant Osimertinib for Resected EGFR-Mutated Stage IB-IIIA Non–Small-Cell Lung Cancer: Updated Results From the Phase III Randomized ADAURA Trial. JCO; Published online 31 January 2023. DOI: 10.1200/JCO.22.02186