Osimertinib in Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study

Abstract

Purpose: In this phase I study (BLOOM), osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was evaluated in patients with leptomeningeal metastases (LMs) from EGFR-mutated (EGFRm) advanced non-small-cell lung cancer (NSCLC) whose disease had progressed on previous EGFR-TKI therapy.

Patients and methods: Patients with cytologically confirmed LM received osimertinib 160 mg once daily. Objectives were to assess confirmed objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), pharmacokinetics (PK), and safety. Additional efficacy evaluations included changes from baseline in CSF cytology and neurologic examination. Measurable lesions were assessed by investigator according to RECIST version 1.1. LMs were assessed by neuroradiologic blinded central independent review (BICR) according to Response Assessment in Neuro-Oncology LM radiologic criteria and by investigator.

Results: Forty-one patients were enrolled. LM ORR and DoR by neuroradiologic BICR were 62% (95% CI, 45% to 78%) and 15.2 months (95% CI, 7.5 to 17.5 months), respectively. Overall, ORR by investigator was 41% (95% CI, 26% to 58%), and median DoR was 8.3 months (95% CI, 5.6 to 16.5 months). Median investigator-assessed PFS was 8.6 months (95% CI, 5.4 to 13.7 months) with 78% maturity; median OS was 11.0 months (95% CI, 8.0 to 18.0 months) with 68% maturity. CSF tumor cell clearance was confirmed in 11 (28%; 95% CI, 15% to 44%) of 40 patients. Neurologic function was improved in 12 (57%) of 21 patients with an abnormal assessment at baseline. The adverse event and PK profiles were consistent with previous reports for osimertinib.

Conclusion: Osimertinib showed meaningful therapeutic efficacy in the CNS and a manageable safety profile at 160 mg once daily in patients with EGFRm NSCLC and LM.

Trial registration: ClinicalTrials.gov NCT02228369.

Figures

FIG 1.

Patient disposition. (*)Reasons for screening failure included T790M status negative or not assessed (n = 30), negative CSF cytology (n = 1), screening failure as a result of other inclusion/exclusion criteria (n = 10), consent withdrawn (n = 1), and death (n = 2).

FIG 2.

Neurologic assessment. The best neurologic assessment relative to baseline in the safety analysis set is shown. All patients had baseline assessments; 5 (12%) of 41 patients had no postbaseline neurologic assessments. (*) Baseline is defined as the last result obtained before the start of study treatment. (†) Best overall neurologic assessment is the maximum improvement from baseline or the minimum worsening from baseline in the absence of an improvement recorded at 2 consecutive visits where better or equal values were recorded.

FIG 3.

Investigator-assessed (A) progression-free survival (PFS) and (B) overall survival (OS). Evaluable for response set. Censored data are indicated by tick marks, and 95% CIs are shown. For the PFS analysis, patients who had not progressed or died at the time of analysis were censored at the time of their last evaluable RECIST assessment. For the OS analysis, any patients not known to have died at the time of analysis were censored at the last recorded date the patient was known to be alive.