In a phase II BLOSSOM study, the investigators demonstrated high efficacy of 80 mg once daily osimertinib in patients with leptomeningeal metastases after treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer (NSCLC). The primary endpoint of overall survival (OS) was 15.6 months for the full analysis set and 15.0 months for the leptomeningeal metastases’ efficacy evaluable set. The objective response rate (ORR) for leptomeningeal metastases reached 51.6%, which included a complete response (CR) rate of 15.6%, while the median progression-free survival (PFS) was 11.2 months based on RANO leptomeningeal metastases evaluations by the blinded independent central review (BICR).
These findings not only highlight a strong radiological response, but also report significant improvements in quality-of-life (QoL) and patient-reported outcomes (PROs). Furthermore, pharmacokinetic analysis showed that the cerebrospinal fluid (CSF)-to-free plasma ratio of osimertinib at an 80 mg dose was comparable with that of the 160 mg dose, supporting previous findings on its effectiveness. The findings are reported at ASCO 2024 Annual Meeting along with a simultaneous publication by Dr. Myung-Ju Ahn of the Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine in Seoul, Republic of Korea, and colleagues on 3 June 2024 in the JCO.
Third-generation EGFR TKI, osimertinib, has been formulated to target intracranial lesions more effectively, demonstrating superior blood-brain barrier penetration and increased CSF drug concentration. Clinically, osimertinib has shown promise in controlling central nervous system progression, as seen in studies with lower rates of intracranial progression in both adjuvant and palliative settings.
The efficacy of osimertinib for leptomeningeal metastases is particularly promising. At a doubled dose of 160 mg once daily, osimertinib has extended PFS and OS up to 8.6 and 13 months in patients, regardless of EGFR T790M mutation status. Standard dose, 80 mg once daily of osimertinib also showed comparable benefit to double dosage osimertinib in patients with leptomeningeal metastases harbouring the EGFR T790M mutation.
In the retrospective analysis, patients with leptomeningeal metastases without EGFR T790M mutation (18.8 months) showed similar OS to patients with EGFR T790M mutation (16.7 months) when treated with 80 mg osimertinib. In another retrospective analysis of studies across the AURA programme (AURA extension, AURA2, AURA17 and AURA3), 80 mg of osimertinib demonstrated by neuroradiological BICR, leptomeningeal metastases ORR of 55% with median PFS and OS reached up to 11.1 and 18.8 months in EGFR T790M-mutated setting.
The authors wrote in the background that even in the absence of this mutation, patients have exhibited similar survival benefits, suggesting a broader potential for osimertinib in leptomeningeal metastases treatment. The critical role of EGFR TKIs in improving outcomes for patients with NSCLC and leptomeningeal metastases, including those who are EGFR T790M mutation–negative, underscores the necessity for further research in this area. However, prospective studies involving many patients with leptomeningeal metastases treated with 80 mg of osimertinib are still limited.
This prospective, phase II, multicentre, open-label, single-arm study was initiated to assess the effectiveness and safety profile of 80 mg osimertinib in patients with EGFR-mutated NSCLC who developed leptomeningeal metastases after first- or second-generation EGFR TKI treatment. In addition, the study team generated comprehensive pharmacokinetic data to further elucidate the CSF penetration and systemic exposure of this dosage, aiming to optimise therapeutic strategies. The primary endpoint was OS, assessed alongside ORR by the BICR and a pharmacokinetic analysis of plasma, and CSF on the first day of cycles 3 and 6.
A total of 73 patients diagnosed with leptomeningeal metastases were treated with osimertinib, including 64 patients evaluable for the leptomeningeal metastases efficacy set of whom 62 with EGFR T790M negative and 2 with EGFR T790M positive tumours. The median OS in the full analysis set was 15.6 months (95% confidence interval [CI] 11.5 to 20.2). The ORR for leptomeningeal metastases was 51.6%, including a 15.6% CR, and the disease control rate was 81.3% by BICR in the leptomeningeal metastases efficacy evaluable set. The median leptomeningeal metastases PFS by BICR was 11.2 months (95% CI 7.7 to 15.3), the duration of response was 12.6 months (95% CI 7.6 to 17.7), and OS was 15.0 months (95% CI 11.3 to 18.7). Pharmacokinetic analysis showed that the CSF-to-free plasma osimertinib ratio was 22%.
This study also employed a comprehensive QoL assessment, revealing significant improvements across various domains, particularly in QLQ-C30 and QLQ-BN20 scores. Patient-reported outcomes, including a 12-question symptom survey from NCI-PRO-CTCAE, indicated notable benefits after osimertinib treatment. Moreover, these QoL enhancements corresponded with positive neurologic and radiologic findings, highlighting osimertinib’s substantial therapeutic value in enhancing daily activities for patients with leptomeningeal metastases.
Osimertinib was well tolerated, with most side effects being mild (grade 1 or 2 skin rash and pruritus) and affecting only about 13% of patients, which is lower compared with a 160 mg dose of osimertinib, where more than 50% of patients experienced rash or diarrhoea. Only 5% of patients required a dose reduction because of side effects.
EGFR T790M mutation status was confirmed by using either blood or tissue samples, which have limitations in accurately capturing the presence of the EGFR T790M mutation in the CSF. To address this issue, the investigators conducted an exploratory analysis using targeted sequencing on CSF samples from 35 patients. The results revealed that all but one patient had EGFR T790M negative status; the exception was a patient whose tumour was also confirmed to be EGFR T790M positive in a tissue sample.
In an accompanied editorial article, Drs. Mark Y. Jeng and Helena A. Yu of the Department of Medicine, Medical Oncology, Memorial Sloan Kettering Cancer Center in New York, NY, US wrote that the BLOSSOM investigators should be commended for conducting a prospective study in this rare patient population which is often excluded from clinical trials. Notably, they enrolled patients who progressed on earlier generation EGFR TKIs, which is less relevant now that osimertinib is considered standard-of-care for all newly diagnosed advanced EGFR-mutated NSCLC. How these results may translate with up-front osimertinib, either as a monotherapy, or in combination with therapies, remains to be determined.
Additionally, the management of patients with leptomeningeal metastases who progress on osimertinib is unclear. Currently, there are ongoing studies assessing the addition of intrathecal pemetrexed and one studying amivantamab plus lazertinib in patients with leptomeningeal metastases who progress with osimertinib.
The study was supported by AstraZeneca by providing osimertinib and funding.
References
- Park S, Baldry R, Ae Jung H, et al. Phase II Efficacy and Safety of 80 mg Osimertinib in Patients With Leptomeningeal Metastases Associated With Epidermal Growth Factor Receptor Mutation–Positive Non–Small Cell Lung Cancer (BLOSSOM). JCO; Published online 3 June 2024. DOI: https://doi.org/10.1200/JCO.24.00708
- Jeng MY, Yu, HA. Leptomeningeal Metastasis in the Era of CNS-Penetrant Tyrosine Kinase Inhibitor Therapy. JCO; published online 28 June 2024. DOI: https://doi.org/10.1200/JCO.24.01061