Osimertinib following definitive chemoradiotherapy as the new standard of care for patients with unresectable, stage III, EGFR-mutant NSCLC

Results of the randomised phase III LAURA study, presented during the plenary session at ASCO 2024, establish consolidation therapy with osimertinib as the new standard of care following definitive chemoradiotherapy (CRT) in patients with unresectable stage III, EGFR-mutant non-small cell lung cancer (NSCLC). Compared to placebo, consolidation therapy with osimertinib resulted in a striking 84% reduction in the risk for disease progression or death.

Background

Based on the results of the phase III PACIFIC trial, consolidation therapy with durvalumab has become the standard of care for patients with unresectable stage III NSCLC. However, a post-hoc analysis of this trial indicates that this treatment strategy does not improve outcomes in patients harbouring an EGFR mutation. In contrast, the phase II RECEL study and several real-world studies have suggested a potential benefit of an EGFR TKI in this setting. These findings formed the rationale for the phase III LAURA study in which consolidation therapy with osimertinib was compared to placebo in patients with unresectable stage III, EGFR-mutant NSCLC.

Study design

The LAURA trial is a randomised, placebo-controlled, phase III study in which 216 patients with locally advanced, unresectable, stage III, EGFR-mutant NSCLC who did not have disease progression during or after definitive CRT were randomly assigned (2:1) to receive osimertinib (80 mg once daily), or placebo. Patients in the study were treated until disease progression, toxicity, or other discontinuation criteria. Importantly, cross-over to open-label osimertinib after disease progression was offered to patients in both treatment arms. The primary endpoint of the study consisted of progression-free survival (PFS) by blinded independent central review (BICR), with overall survival (OS), central nervous system (CNS) PFS and safety as key secondary study objectives.

Results

Consolidation therapy with osimertinib in this study resulted in a median PFS of 39.1 months, which is significantly longer than the 5.6 median PFS seen with placebo. This difference translates into a highly significant 84% reduction in the risk for disease progression or death with osimertinib compared to placebo (HR[95%CI]: 0.16[0.10-0.24]; p< 0.001). At the 2-year landmark, 65% of patients in the osimertinib arm were alive and free of progression as compared to 13% in the placebo arm. The benefit in PFS was consistent across all investigated subgroups. Overall, new lesions occurred in 68% of patients in the placebo arm as compared to 22% in the group of patients treated with osimertinib. This difference was mainly driven by a large difference in the incidence of new CNS lesions (8% with osimertinib vs. 29% with placebo) and new lesions in the lung (6% vs. 29%). The OS data of the study are immature, but despite a cross-over rate of 81%, a trend for a better OS was already apparent in favour of consolidation osimertinib.

The safety profile in both treatment arms was consistent with the known safety profiles of osimertinib and CRT, with a higher incidence of radiation pneumonitis (48% vs. 38%), diarrhoea (36% vs. 14%) and rash (24% vs. 14%) in the osimertinib arm. However, the majority of adverse events in the osimertinib arm were non-serious, low-grade and generally did not lead to treatment discontinuation.

Conclusions

Results of the LAURA study demonstrate that consolidation therapy with osimertinib following definitive CRT results in an 84% reduction in the risk for disease progression or death compared to placebo in patients with unresectable, stage III EGFR-mutant NSCLC. The safety profile of osimertinib post-CRT was as expected and manageable. These findings establish osimertinib as the new standard of care in this setting and further underscore the critical importance of EGFR mutation testing in early-stage NSCLC.

Reference

Ramalingam S, et al. Osimertinib (osi) after definitive chemoradiotherapy (CRT) in patients (pts) with unresectable stage (stg) III epidermal growth factor receptor-mutated (EGFRm) NSCLC: Primary results of the phase 3 LAURA study. Presented at ASCO 2024, Abstract LBA4.