Adjuvant osimertinib (Tagrisso) continued to confer an overall survival (OS) benefit vs placebo at 8 years in patients with completely resected, EGFR-mutated stage IB to IIIA
At a data cutoff of May 4, 2026, the 8-year OS rate in the primary stage II to IIIA population was 74% (95% CI, 67 - 80) with osimertinib (n = 233) vs 58% (95% CI, 50 - 65) with placebo (n = 237; HR, 0.53; 95% CI, 0.38 - 0.75), at median follow-ups of 92.0 and 68.5 months, respectively.
In the overall stage IB to IIIA population, the 8-year OS rate was 79% (95% CI, 74%-83%) with osimertinib (n = 339) vs 64% (95% CI, 58%-70%) with placebo (n = 343; HR, 0.52; 95% CI, 0.39-0.71), at median follow-ups of 93.3 and 79.6 months. Data maturity was 26% overall (osimertinib, 20%; placebo, 31%), and investigators characterized the analysis as the longest OS follow-up from any global phase 3 adjuvant trial in EGFR-mutated early-stage NSCLC.1
"These additional long-term findings further characterize the established survival benefit of adjuvant osimertinib for patients with resected EGFR-mutated stage IB-IIIA NSCLC, with or without adjuvant chemotherapy," presenting author Roy S. Herbst, MD, PhD, of Dartmouth Cancer Center, said in a news release issued by the IASLC.3 "This is the first study to establish the new paradigm that bringing the best targeted drugs to patients with earlier-stage disease can delay progression and improve survival."
ADAURA was the first global phase 3 adjuvant trial to demonstrate both a disease-free survival (DFS) and OS benefit with targeted therapy in resected EGFR-mutated NSCLC. Earlier EGFR TKIs had shown initial DFS benefits in this setting without improving OS. In the primary DFS analysis, adjuvant osimertinib reduced the risk of disease recurrence or death by 80% in the overall population (HR, 0.20; 99.12% CI, 0.14-0.30; P < .0001), and the updated analysis at a data cutoff of April 11, 2022, showed a median DFS of 65.8 months vs 28.1 months with placebo (HR, 0.27; 95% CI, 0.21-0.34).1
The final planned OS analysis, at a data cutoff of January 27, 2023, and 18% maturity, showed 5-year OS rates of 88% vs 78% in the overall population (HR, 0.49; 95.03% CI, 0.34-0.70; P < .0001) and 85% vs 73% in the stage II to IIIA population (HR, 0.49; 95.03% CI, 0.33-0.73; P = .0004). The FDA approved adjuvant osimertinib for this indication in December 2020, and 3 years of adjuvant osimertinib is recommended as standard of care by NCCN, ESMO, and ASCO guidelines.
Adherence to the full 3-year course remains a practical concern:
ADAURA randomly assigned 682 patients with completely resected stage IB to IIIA EGFR-mutated NSCLC, with or without adjuvant chemotherapy, 1:1 to osimertinib at 80 mg once daily or placebo for a planned 3 years; randomization was stratified by stage, EGFR mutation type (exon 19 deletion vs L858R), and race. The primary end point was investigator-assessed DFS in the stage II to IIIA population, and OS was the key secondary end point. All patients had the opportunity to complete 3 years of study treatment before the current analysis.1
Following a protocol amendment in August 2023, patients alive at the final planned OS analysis were asked to consent to yearly survival follow-up. Of the 558 patients alive at that analysis, 431 (77%) had additional survival data through the May 4, 2026, cutoff or from accessible records, comprising 237 of 297 (80%) in the osimertinib arm and 194 of 261 (74%) in the placebo arm. The remaining 127 patients (23%) remained censored at their last known alive date from the January 2023 cutoff. Disease progression data were not collected after April 2022.1
Investigators noted an asymmetric imbalance in prognostic factors among patients with vs without additional survival data. In the placebo arm, patients with additional data were more likely to have been disease free at the April 2022 cutoff (56% vs 27%) and to have stage IB disease (37% vs 27%); these differences were less pronounced in the osimertinib arm (81% vs 77% disease free; 32% vs 38% stage IB). Because any resulting overestimation of 8-year landmark OS was likely greater in the placebo arm, investigators concluded that the observed between-arm difference is probably a conservative estimate.1
The 8-year OS benefit was observed across all 3 disease stages per AJCC/UICC 7th edition: 91% (95% CI, 82 - 95) vs 77% (95% CI, 68 - 85) in stage IB (HR, 0.50; 95% CI, 0.23 - 1.01), 78% (95% CI, 68 - 85) vs 63% (95% CI, 52 - 71) in stage II (HR, 0.60; 95% CI, 0.36 - 0.97), and 70% (95% CI, 59 - 78) vs 52% (95% CI, 41 - 63) in stage IIIA (HR, 0.49; 95% CI, 0.31-0.77).1
In the overall population, OS favored osimertinib in all predefined subgroups, including patients who received adjuvant chemotherapy (HR, 0.54; 95% CI, 0.36-0.80) and those who did not (HR, 0.58; 95% CI, 0.36 - 0.94), patients with exon 19 deletions (HR, 0.45; 95% CI, 0.29 - 0.68) and L858R mutations (HR, 0.72; 95% CI, 0.46 - 1.11), and Asian (HR, 0.64; 95% CI, 0.43 - 0.93) and non-Asian (HR, 0.45; 95% CI, 0.27 - 0.74) patients. The HR in male patients was 0.74 (95% CI, 0.44 - 1.22) vs 0.47 (95% CI, 0.32 - 0.69) in female patients.1
Genomic analyses of tissue (n = 7) and plasma (n = 17) samples collected at progression offered preliminary insight into resistance. Only 1 patient with tissue-based results progressed during osimertinib treatment, with MET amplification; most other patients progressed after treatment discontinuation, with no obvious drivers of resistance and a genomic landscape similar to that of the placebo arm. Investigators said additional research is warranted to characterize acquired resistance during adjuvant therapy and its implications for subsequent treatment.1
Ongoing osimertinib studies in early-stage disease include the phase 2 TARGET trial (NCT05526755) of 5 years of adjuvant osimertinib in resected stage II to IIIB disease, the phase 3 ADAURA2 trial (NCT05120349) in resected stage IA disease, and the phase 3 NeoADAURA trial (NCT04351555) of neoadjuvant osimertinib with or without chemotherapy in resectable stage II to IIIB N2 disease.1
References
