A phase III, double-blind, placebo-controlled LAURA study met the prespecified criteria for the primary endpoint of progression-free survival (PFS), showing that treatment with osimertinib after definitive chemoradiotherapy in patients with unresectable stage III EGFR-mutated non-small cell lung cancer (NSCLC) amenable to curative-intent treatment, significantly prolonged PFS as compared with placebo.
The hazard ratio (HR) for disease progression or death was 0.16, indicating an 84% reduction in the risk of disease progression or death with osimertinib as compared with placebo. The median PFS was 39.1 months with osimertinib and 5.6 months with placebo. The findings are presented at the Plenary session of the ASCO 2024 Annual Meeting along with simultaneous publication by Dr. Suresh S. Ramalingam of the Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute in Atlanta, GA, US, Dr. Shun Lu of the Department of Medical Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University in Shanghai, China and colleagues on 2 June 2024 in The New England Journal of Medicine.
The authors wrote in the background that approximately 20-30% of patients with NSCLC present with locally advanced stage III disease at the time of diagnosis. Of these patients, 60-90% have unresectable disease. The current standard of care in this setting is concurrent chemoradiotherapy followed by consolidation therapy with durvalumab in patients without progression after chemoradiotherapy.
EGFR mutations are reported in up to one third of patients with unresectable stage III NSCLC who receive chemoradiotherapy. Previous studies have suggested that, as compared with patients without EGFR mutations, patients with unresectable stage III EGFR-mutated NSCLC have shorter or similar PFS and a higher incidence of distant metastases, including in the central nervous system (CNS), after definitive chemoradiotherapy. Data suggest a lower risk of local failure in patients with EGFR-mutated disease. The control of systemic micrometastatic disease is critical to improving long-term outcomes in patients with unresectable stage III EGFR-mutated NSCLC.
Although immune checkpoint inhibitors provide substantial overall survival (OS) benefit to patients with metastatic NSCLC without detectable EGFR mutations, the same benefit has not been shown in patients with EGFR-mutated NSCLC. The benefit of consolidation therapy with durvalumab specifically in patients with unresectable stage III EGFR-mutated NSCLC is uncertain.
Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR TKI), is the preferred first-line treatment for advanced EGFR-mutated NSCLC and is also approved for use in combination with platinum-based chemotherapy in this context. In addition, osimertinib is recommended as adjuvant treatment for resected stage IB–IIIA EGFR-mutated NSCLC. EGFR TKIs have shown preliminary efficacy in unresectable stage III EGFR-mutated NSCLC.
In LAURA, the study investigators randomly assigned patients with unresectable EGFR-mutated stage III NSCLC without progression during or after chemoradiotherapy to receive osimertinib or placebo until disease progression occurred or the regimen was discontinued. The primary endpoint was PFS as assessed by blinded independent central review. A total of 216 patients who had undergone chemoradiotherapy were randomly assigned to receive osimertinib (143 patients) or placebo (73 patients).
Osimertinib resulted in a significant PFS benefit as compared with placebo. The median PFS was 39.1 months with osimertinib versus 5.6 months with placebo, with a HR for disease progression or death of 0.16 (95% confidence interval [CI] 0.10 to 0.24; p < 0.001). The percentage of patients who were alive and progression free at 12 months was 74% (95% CI 65 to 80) with osimertinib and 22% (95% CI 13 to 32) with placebo.
Interim OS data with maturity of 20% showed 36-month OS among 84% of patients treated with osimertinib (95% CI 75 to 89) and 74% with placebo (95% CI 57 to 85), with a HR for death of 0.81 (95% CI 0.42 to 1.56; p = 0.53).
The overall safety profile of osimertinib after chemoradiotherapy was consistent with the established profile of osimertinib and chemoradiotherapy. Although the median duration of total treatment exposure was longer with osimertinib than placebo (24.0 months vs. 8.3 months), the majority of adverse events reported with osimertinib were mild or moderate in severity and did not lead to treatment discontinuation. The incidence of adverse events of grade 3 or higher was 35% in the osimertinib group and 12% in the placebo group; radiation pneumonitis (majority grade 1 to 2) was reported in 48% and 38%, respectively. No new safety concerns emerged.
The authors wrote that additional analyses and follow-up would be of interest, including final OS, CNS PFS, safety, health-related quality-of-life, and exploratory analyses based on circulating tumour DNA. Future research on the efficacy and safety of EGFR TKIs, either as induction treatment before chemoradiotherapy or concomitantly with chemoradiotherapy, in this disease setting will also be of interest.
The study was funded by AstraZeneca.
Reference
Lu S, Kato T, Dong X, et al. for the LAURA Trial Investigators. Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC. NEJM; Published online 2 June 2024. DOI: 10.1056/NEJMoa2402614