Osimertinib (Tagrisso), at 160 mg daily, demonstrated efficacy in the central nervous system (CNS) and a manageable safety profile in patients with EGFR
-mutant advanced non–small cell lung cancer (NSCLC) who have leptomeningeal metastases (LMs), according to results of the phase I BLOOM trial.
Results showed that the third-generation EGFR TKI led to an LM objective response rate (ORR) of 62% (95% CI, 45%-78%) and a median duration of response (DOR) of 15.2 months (95% CI, 7.5-17.5) by neuroradiologic blinded independent central review (BICR) in this patient population. By investigator assessment, the ORR was 41% (95% CI, 26%-58%) and the median DOR was 8.3 months (95% CI, 5.6-16.5).
Moreover, with 75% maturity, the median investigator-assessed progression-free survival (PFS) was 8.6 months (95% CI, 5.4-13.7) and the median overall survival (OS), with 68% maturity, was 11.0 months (95% CI, 8.0-18.0) with osimertinib. The 12-month investigator-assessed PFS rate was 42% (95% CI, 27%-57%).
“Osimertinib, at 160 mg once daily, showed meaningful therapeutic efficacy in terms of radiologic response, neurologic improvement, [cerebrospinal fluid] clearance, and a manageable safety profile in patients with LM from EGFR
-mutant advanced NSCLC whose disease had progressed on EGFR-TKI therapy,” the authors wrote in the study, which was published in the Journal of Clinical Oncology
“Given the lack of standardized treatment as well as the current treatment limitations and/or invasive nature of the available experimental therapies, osimertinib has the potential to become a treatment option for patients with EGFR
-mutant NSCLC and LM previously treated with an EGFR TKI.”
Forty-one patients with LMs from EGFR
-mutant advanced NSCLC whose disease had progressed on prior EGFR-TKI therapy were enrolled on the 2-part, multicenter, open-label phase I BLOOM study. Between April 2015 and October 2017, patients were treated with osimertinib at 160 mg daily.
Patients were enrolled sequentially onto 2 cohorts: unselected and EGFR
T790M-positive disease. To be eligible for enrollment, patients must have been ≥18 years old and have a histologically or cytologically confirmed diagnosis of NSCLC, as well as exon 19 deletions or L858R mutations. Patients also must have had a confirmed LM diagnosis, ≥1 LM site that could be repeatedly assessed, had progressed on a prior EGFR TKI, and had an ECOG performance status of 0 to 2.
All patients were Asian; 71% were female, 71% had coexisting brain metastases, and 49% had prior radiotherapy to the brain. At the data cutoff of October 15, 2017, 78% of patients had progressed or died; 7 patients were still being treated with osimertinib. The median treatment duration was 8.6 months (range, 0.1-29.7).
Twelve patients had an LM complete response (CR) and 11 had an LM partial response (PR) by BICR; by investigator assessment, 1 patient had an LM CR and 10 patients had an LM PR. The median LM duration of response by investigator assessment was 18.9 months (95% CI, 7.6—not calculable).
The CNS ORR was 58% (95% CI, 28%-85%) and the confirmed overall ORR was 41% (95% CI, 26%-58%). Tumor shrinkage in the CNS was found in 73% of patients; in the non-CNS, this was 84%. The LM and overall disease control rates were 78% and 73%, respectively. Moreover, cerebrospinal fluid tumor cell clearance was confirmed in 11 patients (28%).
Additional results showed that, of the 23 LM responders, the site of first progression was non-CNS (22%), CNS (9%), and LM (9%). Moreover, nonresponders experienced a progression in non-CNS regions (43%), and CNS (21%) and LM (21%). Sixty-five percent of LM responders and 43% of LM non-responders did not experience disease progression.
Neurologic function was improved in 12 of 21 (57%) patients, with an abnormal assessment at baseline.
Regarding safety, all patients experienced ≥1 adverse event (AEs); 66% of patients had a grade ≥3 AE; 24% had AEs were possibly related to osimertinib. One grade 4 AE of pneumonitis was possibly causally related to treatment Twenty-two percent of patients discontinued treatment and 12% had dose reductions, both due to AEs. Seven AEs (17%) were fatal.
In April 2018, the FDA approved osimertinib as a first-line treatment for patients with NSCLC whose tumors harbor EGFR
mutations (exon 19 deletions or exon 21 L858R substitution mutations).
Yang JCH, Kim SW, Kim DW, et al. Osimertinib in patients with epidermal growth factor receptor mutation–positive non–small-cell lung cancer and leptomeningeal metastases: the BLOOM study. J Clin Oncol. 2019;38(6):538-548, doi: 10.1200/JCO.19.00457.