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

Yang, James Chih‐Hsin; Kim, Sang We; Kim, Dong Wan; Lee, Jong Seok; Cho, Byoung Chul; Ahn, Jin Seok; Lee, Dae H.; Kim, Tae Min; Goldman, Jonathan W.; Natale, Ronald B.; Brown, Andrew P.; Collins, Barbara; Chmielecki, Juliann; Vishwanathan, Karthick; Mendoza-Naranjo, Ariadna; Ahn, Myung Ju

doi:10.1200/jco.19.00457

Cited by 282 publications

(236 citation statements)

References 40 publications

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“…In the BLOOM study, LM ORR was 62%, and the median systemic PFS and OS were 8.6 and 11.0 months, respectively. 23 In this study, there was no apparent correlation between LM response and previous WBRT, consistent with that reported in the BLOOM study. 23 The AURA studies only allowed the inclusion of patients with WHO performance status 0 or 1 and asymptomatic CNS metastases (including LMs).…”

Section: Discussionsupporting

confidence: 90%

“…The relationship between changes from the baseline in non-CNS tumor size and LM responses at each visit was explored graphically. Data from patients included in the AURA LM analysis (treated with osimertinib [80 mg qd]) and the BLOOM study (treated with osimertinib [160 mg qd]) 23 were used in this comparative analysis. Only patients who provided a percentage change from baseline measurement and postbaseline LM response were included in the comparison.…”

Section: Graphical Comparison Of Lm Response and Longitudinal Non-cnsmentioning

confidence: 99%

“…[17][18][19][20][21][22] In the BLOOM trial (NCT02228369), osimertinib exhibited systemic and CNS activities in patients with EGFRm NSCLC and LMs at 160 mg once daily (qd). 23 In a positron emission tomography study in healthy volunteers, microdoses of 11 C-labeled osimertinib were found to cross an intact blood-brain barrier and exhibit widespread exposure in the brain. 24 The AURA program assessed the efficacy and safety of the recommended dose of osimertinib used in clinical practice (80 mg qd) in patients with EGFR T790M-positive advanced NSCLC.…”

Section: Introductionmentioning

confidence: 99%

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Osimertinib for Patients With Leptomeningeal Metastases Associated With EGFR T790M-Positive Advanced NSCLC: The AURA Leptomeningeal Metastases Analysis

Ahn

Chiu

Cheng

et al. 2020

Journal of Thoracic Oncology

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112

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Introduction: Osimertinib has shown promising activity in patients with leptomeningeal metastases (LMs) of EGFRpositive NSCLC at 160 mg once daily (qd) (BLOOM; NCT02228369). We report LM activity with osimertinib (80 mg qd) in a retrospective analysis of studies across the AURA program (AURA extension, AURA2, AURA17, and AURA3). Methods: Patients with EGFR T790M-positive advanced NSCLC and progression after previous EGFR-tyrosine kinase inhibitor therapy received osimertinib (80 mg qd). Patients with central nervous system (CNS) metastases (including LMs) were eligible if the lesions were neurologically asymptomatic and stable. Patients with evidence of LMs at the study entry were retrospectively included for the analysis; brain scans were assessed for radiologic LM response by neuroradiologically blinded, independent central review per the modified Response Assessment in Neuro-Oncology LM criteria. LM objective response rate, duration of response, progression-free survival, and overall survival were assessed. A longitudinal analysis was performed to investigate the relationship between changes from the baseline in non-CNS tumor sizes and LM responses at each visit of patients in AURA LM and BLOOM studies. Results: For the 22 patients included in the analysis, LM objective response rate was 55% (95% confidence interval [CI]: 32-76). Median LM duration of response was not reached (95% CI: 2.8-not calculable [NC]). Median LM progression-free survival and overall survival were 11.1 months (95% CI: 4.6-NC) and 18.8 months (95% CI: 6.3-NC), respectively. The longitudinal analysis revealed similar non-CNS and LM responses between the patients in AURA LM and BLOOM programs. Conclusions: Patients with EGFR T790M-positive NSCLC and radiologically detected LM obtained clinical benefit from osimertinib (80 mg qd).

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Section: Discussionsupporting

confidence: 90%

Section: Graphical Comparison Of Lm Response and Longitudinal Non-cnsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Osimertinib for Patients With Leptomeningeal Metastases Associated With EGFR T790M-Positive Advanced NSCLC: The AURA Leptomeningeal Metastases Analysis

Ahn

Chiu

Cheng

et al. 2020

Journal of Thoracic Oncology

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112

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“…1 Patients with poor performance status and diffuse LMD might be better served by supportive care alone rather than an intervention, and providing these patients with a reasonable estimate of their prognosisd which depends on accurate characterization of the nature of their LMDdwould be essential for them to make an informed decision on care. Conversely, identification of nLMD would suggest consideration of focal SRS to these lesions, 6,7 perhaps along with novel systemic treatments, [9][10][11] though the optimal treatment is far from established. Developing and implementing more efficacious and less morbid approaches to the treatment of both diffuse and discrete LMD will require well-designed and thoughtfully analyzed clinical trials.…”

mentioning

confidence: 99%

Classifying Leptomeningeal Disease: An Essential Element in Managing Advanced Metastatic Disease in the Central Nervous System

Kirkpatrick

2020

International Journal of Radiation Oncology*Biology*Physics

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“…Yang et al (2020) reported an ORR of 62% with a median DoR of 15.2 months. 135 Osimertinib further led to an improvement of neurological symptoms and CSF clearance in 57% and 28% of the patients, respectively. 135 Notably, the median OS of 11.0 months slightly surpassed historical reported results.…”

Section: Efficacy Of Egfr-tkis In Brain Metastases and Leptomeningealmentioning

confidence: 96%

Critical Review of EGFR-Mutated NSCLC: What We Do and Do Not Know

Meisel

Prof

2020

healthbook TIMES Onco Hema

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Over the past decade numerous large-scale sequencing approaches have identified increasingly more oncogenic driver mutations in non-small cell lung cancer (NSCLC) (Figure 1A) 1 , which have facilitated the rational development of targeted therapies and led to marked survival benefits compared to classical treatment approaches with chemotherapy (Figure 1B). 2 Mutations in the epidermal growth factor receptor (EGFR) gene are amongst the most frequently observed 1,3,4 , but significant differences in mutation frequency exist depending on histology, gender, smoking status and ancestry. The highest rate of EGFR mutations (≥50%) has been found in Asian female non-smokers with adenocarcinoma histology and a bronchioalveolar subtype. 5-7 The EGFR family, also referred to as HER or ErbB receptors, comprises four receptor tyrosine kinases: EGFR (HER1), ERBB2 (HER2), ERBB3 (HER3) and ERBB4 (HER4). 5 Ligand binding to the extracellular region of EGFR leads to autophosphorylation, activation and EGFR dimerization, which in turn initiates intracellular signalling cascades. 5 Signal transduction subsequently leads to cell proliferation and survival via activation of RAS/ RAF/MEK and PI3K/AKT pathways, among others. 5 EGFR became a prime therapeutic target in NSCLC in 2004, following the discovery that somatic mutations in the EGFR gene enhance tyrosine kinase activity in lung cancer patients. 5 These somatic EGFR mutations activate the kinase receptor in the absence of ligand binding, and can trigger oncogenesis by inducing a constitutively active state that leads to sustained downstream signalling. 8 Subsequently, targeted therapy with tyrosine kinase inhibitors (TKIs) has emerged as the mainstay treatment for advanced NSCLC patients with activating mutations (Figure 1C). 9 Three generations of EGFR-TKIs are currently approved but they are not all equal in terms of EGFR binding, metabolism, anti-tumor activity (Table 1A) and safety. 10 First-generation EGFR-TKIs (e.g., gefitinib and erlotinib) reversibly bind to EGFR and inhibit the binding of adenosine triphosphate (ATP) to the tyrosine kinase domain (Figure 2A-B). Although gefitinib and erlotinib have shown efficacy in first-, second-, and third-line treatment of NSCLC, the benefit seen is usually transient because NSCLC with EGFR-activating mutations treated with first-generation EGFR-TKIs inevitably develop resistance. 11 Up to half of patients treated with first-generation EGFR-TKIs develop acquired resistance through a T790M EGFR substitution mutation. 12 Second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) form irreversible, covalent attachments to the EGFR kinase domain and have demonstrated improvements in progressionfree survival (PFS) relative to those treated with first-generation EGFR-TKIs. 13, 14 Moreover, the third-generation EGFR-TKI, osimertinib, is highly active in NSCLC patients with the EGFR T790M mutation who had disease progression with first-and second-generation EGFR-TKIs. 15 Although the treatment landscape of advanced NSCLC has dramatically ch...

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

Cited by 282 publications

References 40 publications

Osimertinib for Patients With Leptomeningeal Metastases Associated With EGFR T790M-Positive Advanced NSCLC: The AURA Leptomeningeal Metastases Analysis

Osimertinib for Patients With Leptomeningeal Metastases Associated With EGFR T790M-Positive Advanced NSCLC: The AURA Leptomeningeal Metastases Analysis

Classifying Leptomeningeal Disease: An Essential Element in Managing Advanced Metastatic Disease in the Central Nervous System

Critical Review of EGFR-Mutated NSCLC: What We Do and Do Not Know

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