Osimertinib Combo Significantly Reduces CNS Progression in EGFRm NSCLC

Holographic concept of lung cancer display, lung disease: © catalin - stock.adobe.com

The combination of osimertinib with platinum-pemetrexed led to improved central nervous system (CNS) efficacy vs osimertinib alone among patients with EGFR-mutated non–small cell lung cancer (NSCLC), according to findings from the phase 3 FLAURA2 study (NCT04035486).¹

The phase 3 trial included 118 of 279 patients in the combination arm and 104 of 278 in the monotherapy arm in the CNS full analysis set (cFAS). Among these patients, 40 of 118 and 38 of 104 had ≥1 measurable target CNS lesion and were included in the post hoc CNS evaluable-for-response set (cEFR).

In the cFAS, patients with existing CNS metastases had a hazard ratio (HR) for CNS progression or death of 0.58 (95% CI, 0.33-1.01) in the combination therapy group vs the monotherapy group, showing that the patients receiving the combination therapy were 42% less likely to experience CNS progression or death than those receiving monotherapy. Among patients without baseline CNS metastases, the HR was 0.67 (95% CI, 0.43-1.04) in the combination therapy group compared with the monotherapy group, indicating a 33% reduction in the risk of CNS progression or death in the combination therapy group.

The phase 3, international, open-label, randomized FLAURA2 trial randomly assigned patients with EGFR-mutated NSCLC to receive either osimertinib plus platinum-pemetrexed (combination) or osimertinib monotherapy until disease progression or discontinuation. Patients were stratified by race, performance status, and EGFR mutation tissue testing method.

All patients had brain scans performed at baseline and progression and at scheduled assessments until progression for patients with baseline CNS metastases. These scans were assessed by neuroradiologist CNS blinded independent central review.

Exploratory end points evaluated in the preplanned analysis were CNS progression-free survival , CNS objective response rate (ORR), CNS duration of response (DOR), CNS disease control rate, and CNS tumor shrinkage in patients with baseline CNS metastases. Investigators also evaluated CNS efficacy of osimertinib with and without platinum-pemetrexed among patients without baseline CNS metastases.

A total of 557 patients were randomly assigned to treatment, and all had baseline brain scans, including 470 (84%) by magnetic resonance imaging and 87 (16%) by computed tomography. In the cFAS, patients were well balanced between treatment arms. A total of 65 patients (55%) treated with the combination and 59 patients (57%) given the monotherapy arm had >1 CNS lesion at baseline. This included 34 (29%) patients and 27 (26%) patients with 4 CNS lesions, respectively. Additionally, 16 patients (14%) and 18 (17%) patients in the combination and monotherapy arms received prior brain radiotherapy.

The study also looked at the ORRs and complete response (CR) rates in the CNS. In the cFAS, the ORR was 73% for the combination therapy arm and 69% for the monotherapy arm. The CR rates were 59% and 43%, respectively. In the cEFR group, the ORR was 88% with the combination therapy and 87% with the monotherapy. The CR rate was 48% and 16%, respectively.

The median time to response in the cFAS was 11.8 weeks (interquartile range [IQR], 6.3-24.3 weeks) among those given the combination vs 8.4 weeks (IQR, 6.1-23.9 weeks) given osimertinib alone. In the combination arm, the median CNS DOR was not reached vs 26.2 months in the monotherapy arm.

Among 222 patients with baseline CNS metastases, fewer patients had CNS progression with the combination therapy (9%) vs osimertinib monotherapy (19%). Among patients with baseline leptomeningeal metastases, 8 of 13 in the combination arm remained alive and CNS progression-free vs none in the monotherapy arm. When considering other contributing factors like non-CNS progression or death, the risk of developing CNS progression remained significantly lower with the combination therapy vs monotherapy. At 24 months, only 9% of patients receiving the combination developed CNS progression vs 23% in the monotherapy group.

Overall, this study suggests that combination therapy with osimertinib and chemotherapy is more effective than monotherapy in preventing CNS progression or death in patients with EGFR-mutated advanced NSCLC, both in those with and without baseline CNS metastases.

REFERENCE:

Jänne PA, Planchard D, Kobayashi K, et al. CNS efficacy of osimertinib with or without chemotherapy in epidermal growth factor receptor-mutated advanced non-small-cell lung cancer. J Clin Oncol. Published online December 2, 2023. doi:10.1200/JCO.23.02219