Osimertinib Activity in Patients With Leptomeningeal Disease From Non-Small Cell Lung Cancer: Updated Results From the BLOOM Study Abstract 9002 Yang JC, Kim DW, Kim SW, Cho BC, Lee JS, Ye X, Yin X, Yang Z, Jiang H, Ahn MJ
Leptomeningeal Metastases INCIDENCE In patients with NSCLC 1,2 : 3% to 5% In patients with EGFRm NSCLC 3 : 9% PROGNOSIS Median OS from diagnosis 1,4 : 4.5 months to 11.0 months Cause of death 2 : 28% LM progression 31% LM + systemic progression 41% systemic progression First and second-generation EGFR-TKIs have limited BBB penetration 5,6,7 Osimertinib has demonstrated systemic activity in patients with EGFRm NSCLC and brain metastases 8,9 BBB, blood brain barrier; CNS, central nervous system; EGFRm, epidermal growth factor receptor mutation positive; EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; LM, leptomeningeal metastasis; NSCLC, non-small cell lung cancer; OS, overall survival 1. Liao BC, et al. J Thorac Oncol. 2015;10(12):1754-1761. 2. Chamberlain MC, et al. Arch Neurol. 1998;55(4):506-512. 3. Kuiper JL, et al. Lung Cancer. 2015;89(3):255-261. 4. Umemura S, et al. Lung Cancer. 2012;77(1):134-139. 5. Committee for Medicinal Products for Human Use (CHMP) assessment report for afatinib, EMA 2013. Available at: www.ema.europa.eu/docs/en_gb/document_library/epar_-_public_assessment_report/human/002280/wc500152394.pdf. Accessed on June 8, 2016. 6. de Vries NA, et al. Invest New Drugs. 2012;30(2):443-449. 7. Zhao J, et al. Clin Lung Cancer. 2013;14(2):188-193. 8. Goss GD, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 3113. 9. Ahn MJ, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 3083.
CNS Exposure of Osimertinib: Preclinical Rationale Osimertinib induced sustained tumor regression in an EGFRm PC9 mouse brain metastasis model Human PK and mouse PKPD model suggests doses of 80 mg and 160 mg could be active in human CNS disease PET imaging showed marked exposure of osimertinib in NHP and mouse model, in contrast to rociletinib and gefitinib Brain exposure in NHP *corrected for radioactivity in cerebral blood. Brain to blood ratio AUC 0-90 min * [ 11 C]osimertinib (n = 3) 2.6 ± 1.4 [ 11 C]rociletinib (n = 2) 0.025 [ 11 C]gefitinib (n = 2) 0.28 Summation images acquired between 5 minutes and up to 2 hours after intravenous microdose <3 µg Summation images acquired 0 min up to 2 hours after intravenous microdose <3 µg AUC, area under curve; CNS, central nervous system; PD, pharmacodynamics; PET, positive emission tomography; PK, pharmacokinetics; NHP, non-human primate Ballard P, et al. J Thorac Oncol. 2015;10(9 Suppl 2): Abstract Mini10.12. Ballard P, et al. Clin Cancer Res. 2016; Submitted.
BLOOM Study Design Overview Phase I study to assess the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of AZD3759 or osimertinib in patients with EGFRm advanced NSCLC AZD3759 Cohort 1 50 mg bid Cohort 2 100 mg bid Dose Escalation Cohort 3 200 mg bid Cohort 4 300 mg bid Cohort 5 500 mg bid 200 mg or 300 mg bid* Dose Expansion Cohorts Leptomeningeal metastasis EGFR-TKI naïve or pre-treated Brain metastasis EGFR-TKI naïve Osimertinib 160 mg qd Cohort 1: EGFRm NSCLC and LM Stable extracranial disease, N = 21 (current report) EGFR-TKI pre-treated patients with NSCLC and LM *Both AZD3759 200 mg and 300 mg bid were explored to evaluate long-term tolerability and efficacy; Requires stable extracranial disease if EGFR TKI pre-treated; T790M status is based on testing of an extracranial tumor or plasma sample. National Institutes of Health. Available at: https://clinicaltrials.gov/ct2/show/nct02228369. Accessed on June 8, 2016. Cohort 2: T790M positive NSCLC and LM No restriction on stable extracranial disease, N = 20 (accrual ongoing)
BLOOM Study Design: Osimertinib LM Cohort 1 Study objectives, cohort 1 EGFRm NSCLC and LM: To assess the safety and tolerability of osimertinib in patients with LM Osimertinib LM cohort 1 Advanced or metastatic EGFRm NSCLC and confirmed diagnosis of LM by positive CSF cytology Key inclusion criteria: Primary tumor with EGFR L858R or exon 19 deletion Prior EGFR-TKI treatment ECOG PS 0 2 First patient dosed: April 14, 2015 Data cut-off: March 10, 2016 Stable extracranial disease At least one LM lesion by MRI scan Osimertinib 160 mg qd Adverse events * Efficacy assessment: OS Assessments Brain MRI and extracranial MRI or CT scan* CSF cytology Neurological exam * CNS symptoms * PK in CSF Quantification of EGFRm DNA in CSF *As assessed by study investigator; modified RECIST for CNS disease; RECIST 1.1 for extracranial disease; CT/MRI, CSF cytology and neurological exam frequency every 6 weeks; 1 cycle = 21 days of continuous dosing. CSF, cerebrospinal fluid; CT, computed tomography; ECOG, Eastern Cooperative Oncology Group Performance Status; MRI, magnetic resonance imaging; RECIST, Response Evaluation Criteria In Solid Tumors National Institutes of Health. Available at: https://clinicaltrials.gov/ct2/show/nct02228369. Accessed on June 8, 2016.
Patient Demographics: Osimertinib LM Cohort 1 All 21 patients were Asian with adenocarcinoma histology Two patients had T790M detected in CSF at study entry; 6 patients had T790M detected in plasma Duration of treatment: 1 to 49 weeks ongoing Twenty-one patients dosed; 15 patients are ongoing treatment Safety analysis: n = 21 Efficacy analysis n = 21* *Efficacy analysis set included all dosed patients; One patient received two lines of therapy: gefitinib and HM61713; One patient had both Ex19Del and L858R detected at baseline. Ex19del, exon 19 deletion Characteristic, n N = 21 Gender: Male / female 6 / 15 Age: Median (range), years 59.0 (44-75) Smoking status: Current / former / never 1 / 5 / 15 ECOG PS: 0 / 1 / 2 1 / 11 / 9 Neurological assessment at baseline: Normal / abnormal 11 / 10 Prior lines of systemic therapy: Median (range) 3.0 (1-8) Prior whole brain radiotherapy 11 Prior EGFR-TKIs : Gefitinib / erlotinib / dacomitinib / HM61713 (BI 1482694) 16 / 3 / 1 / 1 Prior systemic response to EGFR-TKI: Partial response / stable disease / progressive disease 14 / 6 / 1 Tumor tissue EGFRm mutation status (local test) : Ex19Del / L858R 9 / 13
Twenty patients experienced 1 AE Grade 3 AEs were observed in 9 (43%) patients Drug-related grade 3 AEs were observed in 3 (14%) patients Serious AEs occurred in 3 (14%) patients, none of which were drug-related AEs leading to dose interruption and dose reduction were observed in 2 (10%) patients due to skin pruritus and neutropenia, respectively No drug-related AEs led to dose discontinuation One patient died due to aspiration pneumonia not related to drug Summary of Adverse Events Population: safety analysis, n = 21. As assessed by the study investigator. Patients could experience multiple events with different grades; table shows the highest grade AE experienced by each patient. Drug-related AEs by preferred term, n (%) CTCAE grade 1 2 3 Missing Total * N = 21, 160 mg Diarrhea 7 (33) 3 (14) 1 (5) 1 (5) 12 (58) Nausea 9 (43) 0 (0) 0 (0) 1 (5) 10 (48) Rash (grouped terms) 6 (29) 3 (14) 0 (0) 0 (0) 9 (43) Dry skin 5 (24) 1 (5) 0 (0) 0 (0) 6 (29) Paronychia 4 (19) 2 (10) 0 (0) 0 (0) 6 (29) Dermatitis acneiform 6 (29) 0 (0) 0 (0) 0 (0) 6 (29) Increased ALT 4 (19) 1 (5) 0 (0) 0 (0) 5 (24) Fatigue 1(5) 0 (0) 1 (5) 0 (0) 2 (10) * Only AEs with frequency >10% were listed; One drug-related Grade 3 neutropenia not listed. AE, adverse event; ALT, alanine aminotransferase; CTCAE, common terminology criteria for adverse events
Osimertinib Activity Across LM Assessments Efficacy assessments were conducted on 21 patients Best Confirmed Neurological Status Seven patients had confirmed * radiological improvement Two patients had confirmed * CSF cytology clearance; no tumor cells were detected in two consecutive CSF samples Five patients had confirmed * improved neurological function Best MRI Imaging Intracranial Response, n (%) Confirmed * N = 21 Unconfirmed Responding 7 (33) 1 (5) Stable disease 9 (43) 2 (10) Number of Patients 21 18 15 12 9 6 3 0 10 1 1 1 NORMAL (N=11) 5 Improved No change Worsened Early withdrawal Unconfirmed 3 ABNORMAL (N=10) Early withdrawal 2 (10) Neurological Status at Baseline Population: efficacy, n = 21.*Response confirmation was done at least 4 weeks after the initial response; Response assessed by neurological examination
Changes in EGFRm DNA Copy Number in CSF With Osimertinib Treatment Droplet digital PCR was used to detect EGFRm DNA copy number; data were available for 9 patients* All patients had EGFR-TKI sensitizing mutations detected in screening CSF; 2 patients had T790M Among them, 6 patients had a >50% decrease in EGFRm DNA copies up to C9D1; 5 had sustained decrease 4 out of 6 improved neurological function 4 out of 6 LM-MRI responded; 2 out of 6 LM-MRI stable disease 2 out of 6 CSF clearance EGFRm Change From Baseline, % 100 80 60 40 20 0 20 40 60 80 100 EGFRm in CSF: Change in DNA Copy Number (Mutant DNA Copies / ml) Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9 Population: efficacy analysis, n = 21. *Note: Patients with at least 12 weeks of assessment are included 9 out of 21 patients reached 12 week assessment and had CSF samples available for EGFRm DNA detection. Patients with T790M mutations detected in screening CSF; No sample was available from this patient on C11D1. C, Cycle = 21 days of continuous dosing; D, Day; PCR, polymerase chain reaction
Time on Treatment Patients with a confirmed intracranial LM response (n = 7) Patients * 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Dose Duration, Months *Patient died due to aspiration pneumonia. Arrows represent observations at the time of data cut-off. Two patients experienced AEs leading to dose reduction: one patient had skin pruritus and one patient had neutropenia 160 mg qd 80 mg qd (dose reduction) T790M positive in the CSF Dose interrupted Confirmed CSF clearance Discontinued Fifteen patients were ongoing treatment at time of data cut-off (March 10, 2016), seven of whom had been on treatment for >9 months
Case Study: 63 Year Old Korean Male Patient Diagnosed with advanced NSCLC (L858R) in June, 2013 with most recent disease progression in March, 2015 Prior therapy included: Gefitinib (March, 2013 to May, 2015) WBRT (April, 2013 to May, 2013) Osimertinib 160 mg qd started May 20, 2015 LM response ongoing from week 6 Stable extracranial disease since week 6; partial response since week 12 Normal neurological function since baseline Continuous response for >9 months by data cut-off Brain MRI: Baseline Brain MRI: Week 6 WBRT; whole brain radiotherapy
Conclusions Preclinical data indicate that osimertinib crosses the BBB Osimertinib shows encouraging preliminary safety, tolerability, and activity in pretreated patients with EGFRm advanced NSCLC and LM The AE profile is as expected and manageable Neurological function improved from baseline in 5 patients Radiological improvements in LM were seen in 7 patients Clearance of tumor cells from the CSF occurred in 2 patients at 2 consecutive visits Time on treatment suggests durable clinical benefit with 15 patients remaining on treatment, 7 of whom have been on treatment for >9 months Further evaluation of osimertinib in this setting is warranted The BLOOM study is ongoing and a cohort enrolling patients with T790M positive NSCLC and LM is open; T790M status is based on testing of an extracranial tumor or plasma sample