Approximately 30% of patients with NSCLC present with early-stage disease (stage I – IIIA) and up to 20% of these patients are EGFR-mutation positive (over 50% in Asia). The treatment recommendation for patients with stage II and III NSCLC, and for selected patients with stage IB disease, is surgical tumor resection and adjuvant cisplatin-based chemotherapy. However, with high recurrence rates, there is a clear unmet need for novel therapies to improve outcomes in early-stage NSCLC. Osimertinib is a potent, irreversible, third generation EGFR tyrosine kinase inhibitor (TKI) that selectively inhibits both EGFR sensitizing mutations and EGFR T790M resistance mutations, and has also shown activity in brain metastases. Based on results from the FLAURA and AURA3 trials, it is currently approved as first-line treatment of EGFR-mutated (EGFRm)advanced NSCLC and as second-line treatment of EGFR T790M mutation-positive advanced NSCLC.

The international, double blind, randomized phase III ADAURA trial was designed to investigate osimertinib’s efficacy and safety in early-stage EGFRm NSCLC. Due to evidence of impressive efficacy, the trial was unblinded early following a recommendation from the Independent Data Monitoring Committee. The first results from the unplanned interim analysis were presented at the ASCO 2020 virtual plenary session by Roy Herbst, MD, PhD (Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut, USA). The trial enrolled 682 patients with completely resected stage IB, II, or IIIA non-squamous NSCLC, with or without prior adjuvant chemotherapy. Patients were stratified by stage of disease, EGFR mutation status (exon 19 deletion versus L858R) and race (Asian versus non-Asian) and randomized to receive either osimertinib (80mg once daily) or placebo as adjuvant therapy for up to 3 years after complete tumor resection. In this analysis, patients had been followed-up for at least 1 year. The primary endpoint is disease free survival (DFS) by investigator assessment in stage II/IIIA patients, and the secondary endpoints include DFS in the overall population (stage IB/II/IIIA), overall survival (OS) and safety.

Adjuvant osimertinib demonstrated a clinically meaningful and statistically significant improvement in median DFS compared with placebo in patients with stage II/IIIA NSCLC (not reached [NR] versus 20.4 months; hazard ratio [HR] 0.17, P < 0.0001); the 2-year DFS rate was 90% versus 44%, respectively. Similarly, in the overall population, DFS was prolonged with osimertinib compared with placebo (NR versus 28.1 months; HR 0.21, P < 0.0001); the 2-year DFS rate was 89% versus 53%, respectively. A consistent benefit was shown across all subgroups, regardless of stage of disease, EGFR mutation or race, and also regardless of whether patients had received prior adjuvant chemotherapy. The 2-year DFS rates broken down by stage were consistently high with osimertinib across stages IB, II and IIIA, at 87%, 91% and 88% respectively, in contrast to placebo at 73%, 56% and 32%. The safety profile of osimertinib was consistent with previous studies, with mild EGFR-TKI class effects and no treatment-related deaths. The median duration of exposure to osimertinib was 22 months. At the time of the interim analysis, OS data were not yet mature.

Dr Herbst concluded that “adjuvant osimertinib will provide a highly effective, practice-changing treatment in patients with stage IB, II or IIIA EGFR mutation-positive non-small cell lung cancer after a complete tumor resection”. A discussant for the ADAURA trial, David Spigel, MD, FASCO (Sarah Cannon Research Institute, Tennessee Oncology, Nashville, Tennessee, USA) commented that “adjuvant osimertinib substantially improved DFS in early stage EGFRm NSCLC and should be the new standard of care”. He stressed the need to test all patients with NSCLC for a sensitizing EGFR mutation, and added that chemotherapy is still a standard part of adjuvant therapy in stage II and IIIA EGFR mutated NSCLC.

Reference

Herbst RS, et al. J Clin Oncol. 2020;38 (suppl; abstract LBA5)