Positive Findings From ADAURA Trial Reported, But Questions Remain

The early unblinding of results from the phase 3 ADAURA clinical trial (NCT02511106) evaluating osimertinib (Tagrisso), a third-generation EGFR tyrosine kinase inhibitor (TKI), was met with much fanfare in the oncology community as details of the interim results spread.¹ Investigators reported that in patients with stage IB to IIIA EGFR mutation–positive non–small cell lung cancer (NSCLC), disease-free survival (DFS) was significantly improved for patients who received adjuvant osimertinib compared with those patients who received placebo.

Specifically, the interim analysis showed an 83% reduction in the risk of disease recurrence or death (HR, 0.17; 99.06% CI, 0.11-0.26), with the greatest benefit observed in patients with more advanced stages of disease. Among patients with stage IIIA disease, the HR was 0.12 (95% CI, 0.07-0.20); among those with stage II disease, it was 0.17 (95% CI, 0.08-0.31); and among those with stage IB disease, it was 0.39 (95% CI, 0.18-0.76). The prognosis in patients who received placebo was poor, with a DFS probability of 28% at 3 years among patients with stage II to IIIA disease.

ADAURA randomized 682 patients to receive either adjuvant osimertinib or placebo. Oral osimertinib tablets were administered at 80 mg once daily for 3 years or until disease recurrence. More than 200 sites in the United States, Europe, South America, Asia, and the Middle East conducted the study.

In an editorial published in the New England Journal of Medicine, David Planchard, MD, PhD, analyzed historical data that led to the initiation of the ADAURA trial. He noted that advances in the treatment for localized resectable NSCLC have been sparse.² In this population, the survival benefit in patients with stage II to IIIA disease who have been treated with platinum-based chemotherapy is about 5% at 5 years, with an 11% reduction in the risk of death.³

Results from the trial were an important development because previous studies involving first-generation EGFR TKIs in similar settings, such as the phase 3 RADIANT study (NCT00373425), had negative outcomes in stage IB to IIIA NSCLC.⁴ In the RADIANT trial, patients (n=973) were assigned 2:1 to erlotinib (Tarceva) 150 mg once per day or placebo for 2 years.

The primary end point was DFS. There was no statistically significant difference in median DFS (50.5 months for erlotinib vs 48.2 months for placebo; HR, 0.90; 95% CI, 0.74-1.10; P = .324). Among the 161 patients (16.5%) in the EGFR– positive subgroup, median DFS favored erlotinib (46.4 vs 28.5 months; HR, 0.61; 95% CI, 0.38-0.98; P = .039), but this was not statistically significant.

Conversely, 2 trials that demonstrated a benefit with first-generation EGFR TKIs and chemotherapy were the phase 2 EVAN trial (NCT01683175) with erlotinib and the phase 3 ADJUVANT trial (NCT01405079) with gefitinib (Iressa).^5,6

In the EVAN trial, patients treated with adjuvant erlotinib had a 2-year DFS rate of 81.4% versus 44.6% in patients who received chemotherapy (relative risk, 1.823; 95% CI, 1.19-2.78; P = .0054). Investigators in the ADJUVANT trial reported that patients who received adjuvant gefitinib had a significantly longer DFS rate than patients who received chemotherapy in the intention-to-treat population. Specifically, those who received gefitinib had a DFS of 30.8 months compared with 19.8 months for patients in the chemotherapy arm (HR, 0.56; 95% CI 0.40-0.79; P = .001). Further, the DFS was higher at 3 years (39.6% vs 32.5%), although this benefit did not translate to an overall survival advantage (HR, 0.92; P = .67).

Recurrence Rates in ADAURA Investigators for ADAURA noted reductions in locoregional recurrence (7%) and distant recurrence (4%) for patients who received osimertinib compared with patients who received placebo (18% and 28%, respectively). In particular, recurrence of central nervous system (CNS) disease was 2% in the osimertinib arm compared with 11% in the placebo arm. At 24 months, 98% of patients (95% CI, 95%-99%) in the osimertinib arm and 85% of the patients (95% CI, 80%-89%) in the placebo arm were alive without CNS-related disease (HR for CNS disease, 0.18; 95% CI, 0.10-0.33).

This is a clear differentiation between osimertinib and first-generation TKIs and chemotherapy. Gefitinib has been associated with a distant recurrence rate of 27%; similarly, chemotherapy has been associated with a recurrence rate of 24%.

Despite the benefit observed for osimertinib, the ADAURA trial did not answer whether patients should undergo treatment with standard-of-care chemotherapy.² Data from in vitro and clinical trials evaluating EGFR TKIs in combination with chemotherapy suggest a synergistic relationship that may result in limited acquired resistance.⁷

Findings from ADAURA suggest a benefit of testing for EGFR mutations in patients with earlier stage disease.

This combination is undergoing further study as neoadjuvant therapy in patients with EGFR mutation–positive stage II to IIIB disease in the phase 3 NeoADAURA trial (NCT04351555) and as first-line therapy in patients with EGFR mutation–positive metastatic disease in the phase 3 FLAURA2 trial (NCT04035486).

Other combinations include the SAVANNAH (NCT03778229) and ORCHARD (NCT03944772) studies. The SAVANNAH trial is combining osimertinib with savolitinib, and the ORCHARD study is investigating osimertinib in combination with either savolitinib, gefitinib, necitumumab (Portrazza), or platinum-based chemotherapy.

_References:

_{1. Wu YL, Tsuboi M, He J, et al; ADAURA Investigators. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071}

_{2. Planchard D. Adjuvant osimertinib in EGFR-mutated non-small-cell lung cancer.N Engl J Med. 2020;383(18):1780-1782. doi:10.1056/NEJMe2029532}

_{3. Pignon JP, Tribodet H, Scagliotti GV, et al; LACE Collaborative Group. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26(21):3552-3559. doi:10.1200/ JCO.2007.13.9030}

_{4. Kelly K, Altorki NK, Eberhardt WEE, et al. Adjuvant erlotinib versus placebo in patients with stage IB-IIIA non-small-cell lung cancer (RADIANT): a randomized, double-blind, phase III trial. J Clin Oncol. 2015;33(34):4007- 4014. doi:10.1200/JCO.2015.61.8918}

_{5. Yue D, Xu S, Wang Q, et al. Erlotinib versus vinorelbine plus cisplatin as adjuvant therapy in Chinese patients with stage IIIA EGFR mutationpositive non-small-cell lung cancer (EVAN): a randomised, open-label, phase 2 trial. Lancet Respir Med. 2018;6(11):863-873. doi:10.1016/ S2213-2600(18)30277-7}

_{6. Wu YL, Zhong W, Wang Q, et al. CTONG1104: adjuvant gefitinib versus chemotherapy for resected N1-N2 NSCLC with EGFR mutation— final overall survival analysis of the randomized phase III trial 1 analysis of the randomized phase III trial. J Clin Oncol. 2020;38(suppl 15):9005. doi:10.1200/JCO.2020.38.15_suppl.9005}