Osimertinib reduces risk of metastasis, CNS progression in stage III EGFRm NSCLC

Treatment with osimertinib following chemoradiotherapy (CRT) helps lower the risk of distant metastases and central nervous system (CNS) disease progression in patients with unresectable stage III epidermal growth factor receptor-mutated (EGFRm) nonsmall cell lung cancer (NSCLC), results of the phase III LAURA study have shown.

“Osimertinib demonstrated clinically meaningful improvements in CNS progression-free survival (PFS) and time to death or distant metastases (TTDM) versus placebo, supporting osimertinib post-CRT as the standard of care in unresectable stage III EGFRm NSCLC,” the investigators said.

In this study, 216 patients without progression during or after definitive platinum-based CRT were randomly allocated in a 2:1 ratio to receive either osimertinib 80 mg daily (n=143) or placebo (n=73) until progression (by blinded independent central review [BICR]) or discontinuation.

The median CNS PFS by neuroradiologist BICR was not reached with osimertinib (95 percent confidence interval [CI], not calculable [NC]–NC) compared with 14.9 months with placebo (95 percent CI, 7.4–NC; hazard ratio [HR] for CNS PFS, 0.17, 95 percent CI, 0.09–0.32). [Ann Oncol 2024;35:1116-1125]

Analysis of CNS PFS by investigator assessment was consistent with that by BICR assessment. At 12 months, the cumulative incidence of CNS progression was 9 percent (95 percent CI, 5–14) and 36 percent (95 percent CI, 24–47) with osimertinib and placebo, respectively.

Patients in the osimertinib group also showed clinically meaningful improvements in TTDM compared with those in the placebo group (HR, 0.21, 95 percent CI, 0.11–0.38). At 12 months, the cumulative incidence of distant metastases was 11 percent (95 percent CI, 6–17) and 37 percent (95 percent CI, 26–48) with osimertinib and placebo, respectively.

“This protective effect of osimertinib against CNS progression and the prolongation of TTDM, together with the primary PFS benefit, supports osimertinib as the new standard of care for unresectable stage III EGFRm NSCLC following CRT,” the investigators said. [N Engl J Med 2024;391:585-597]

CNS efficacy

Osimertinib has also demonstrated its CNS efficacy in other preclinical and clinical settings. Preclinical studies have shown osimertinib penetration of the blood–brain barrier and exposure throughout the brain. [Clin Cancer Res 2016;22:5130-5140; Clin Cancer Res 2021;27:189-201; Clin Transl Sci 2023;16:955-965; J Cereb Blood Flow Metab 2020;40:799-807] 

In clinical trials of EGFRm NSCLC, osimertinib has demonstrated CNS efficacy in both advanced and early-stage adjuvant settings. Treatment with this agent has resulted in durable CNS response and a lower risk of CNS progression or recurrence. [J Clin Oncol 2023;41:1830-1840; J Clin Oncol 2018;36:3290-3297; J Clin Oncol 2018;36:2702-2709; J Thorac Oncol 2020;15:637-648]

"Our findings from LAURA confirm the protective effect of osimertinib against CNS progression and distant metastases in patients with unresectable stage III EGFRm NSCLC after CRT, which addresses an important unmet need in this patient population,” the investigators said.

Osimertinib, a third-generation, irreversible, oral EGFR-TKI, inhibits both EGFR-TKI sensitizing and EGFR T790M resistance mutations. Other phase III studies have exhibited its efficacy in both advanced and resectable EGFRm NSCLC based on improvements in PFS and overall survival. [Cancer Discov 2014;4:1046-1061; N Engl J Med 2020;382:41-50; N Engl J Med 2018;378:113-125]