A phase II, open-label, single-arm, multicenter, efficacy and safety study of 80 mg osimertinib in patients with leptomeningeal metastases (LM) associated with epidermal growth factor receptor (EGFR) mutation–positive non-small cell lung cancer (NSCLC): BLOSSOM.
Authors: Ahn Myung-Ju , Park Sehhoon , Baldry Richard , Jung Hyun Ae , Sun Jong-Mu , Lee Se-Hoon , Ahn Jin Seok , Kim Yu Jung , Lee Youngjoo , Kim Dong-Wan , Kim Sang-We , Lee Ki Hyeong , Son Nak-Hoon 
Published: June 2024

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Background: Leptomeningeal metastases (LM) present with a high incidence in EGFR-mutated NSCLC following treatment with first- or second-generation EGFR TKIs. Osimertinib has demonstrated significant clinical efficacy in LM at a double dose (160mg), attributed to its superior blood-brain barrier penetration. This study aims to delineate the clinical efficacy, safety, and pharmacokinetic profile of 80mg osimertinib for LM patients exhibiting resistance to earlier-generation EGFR TKIs. Methods: The BLOSSOM trial is a Phase II, multi-center, open-label, single-arm study assessing the efficacy of 80mg osimertinib in EGFR-mutated NSCLC patients with LM developed after prior first- or second- generation EGFR TKI treatment. The primary endpoint was overall survival (OS), with secondary endpoints encompassing RANO-LM assessed objective response rates (ORR), LM-specific duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS) by blind independent review. Pharmacokinetic analysis incorporated plasma and cerebrospinal fluid samples collected on the first day of cycles 3 and 6. Results: Out of 73 patients administered 80mg osimertinib, 64 were evaluated for LM efficacy—T790M negative (n=62) and T790M positive (n=2). Patients were initially diagnosed with either EGFR deletion 19 (n=29) and L858R mutation (n=44), with ECOG PS of 0, 1, 2 in 19.2%, 61.6%, 19.2%. The median OS in total study population was 15.6 months (95% CI: 11.5-20.2). In the LM efficacy evaluable group, the ORR of LM was 51.6%, including 15.6% complete response and 35.9% partial response, and the DCR was 81.3%. The median OS was 15.0 months (95% CI: 11.3-18.7), with survival rates at 6, 12, 18, 24 months being 82%, 60%, 44% and 29%, respectively. Median LM PFS and DOR were 11.2 months (95% CI: 7.7-15.3) and 12.6 months (95% CI: 8-18) including a patient whose response lasted for up to 32.7 months. LM response rates were consistent regardless of prior LM-related treatment exposure. Notably, the geometric mean of cerebrospinal fluid (CSF) to free plasma ratio for osimertinib and its metabolite AZD5104 at C3D1 was 22.2 (range 3.8-64.3) and 10.3 (range 3.3-30.0), at C6D1 was 22.1 (range 4.7-82.3) and 9.3 (range 3.8-29.4) which reflected analogous concentration to the 160mg dosage. Safety profile was mostly grade 1 or 2 which were all manageable with appropriate treatment. Conclusions: This study underscores the notable intracranial efficacy and survival benefit of 80mg osimertinib in predominantly T790M negative NSCLC, with CSF concentrations comparable to the higher 160mg dose. These findings advocate for the consideration of 80mg osimertinib in the treatment regimen for patients with EGFR-mutated LM regardless of T790M mutation status. Clinical trial information: NCT04563871 .