1. BLOOM: Osimertinib Shows Promising Activity in Patients With EGFRm+ Advanced NSCLC and Leptomeningeal Metastases
CCO Independent Conference Coverage* of the 2016 ASCO Annual Meeting, June 3-7, 2016
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
m, mutant; NSCLC, non-small-cell lung cancer.
This activity is supported by educational grants from Amgen, Ariad, Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech, Incyte, Merck, and Taiho Pharmaceuticals.

2. Leptomeningeal Metastases
LMs occur in 3-5% of pts with NSCLC[1,2] and in 9% of pts with EGFR-mutant NSCLC[3]
Median OS after diagnosis mos in pts with LM[1,4]
Cause of death: systemic progression in 41%, LM and systemic progression in 31%, and LM progression in 28%[2]
First and second generation EGFR-TKIs have limited penetration of blood–brain barrier[5-7]
LM, leptomeningeal metastases; NHP, non-human primate; NSCLC, non-small-cell lung cancer; PK, pharmacokinetics; TKIs, tyrosine kinase inhibitors.
1. Liao, et al. J Thorac Oncol. 2015;10: Chamberlain, et al. Arch Neurol. 1998;55: Kuiper et al. Lung Cancer ;89: Umemura, et al. Lung Cancer. 2012;77: CHMP assessment report for Giotrif. EMA De Vries, et al. Invest New Drugs. 2012;30: Zhao, et al. Clin Lung Cancer ;14:
Slide credit: clinicaloptions.com

3. Phase I BLOOM Study: Background
Osimertinib: third-generation EGFR TKI with systemic activity in pts with EGFR-mutant NSCLC and brain metastases[1,2]
Marked brain exposure in rodent and NHP models as compared with gefitinib and rociletinib[3]
Approved for second-line tx of EGFR T790 NSCLC
BLOOM: phase I study evaluating safety, tolerability, PK, and anti-tumor activity of osimertinib in EGFR-TKI pretreated pts with NSCLC
Current analysis and update of cohort with LM[4]
LM, leptomeningeal metastases; NHP, non-human primate; NSCLC, non-small-cell lung cancer; PK, pharmacokinetics; TKI, tyrosine kinase inhibitor.
1. Goss, et al. Eur J Cancer. 2015;51:S Ahn, et al. Eur J Cancer ;51:S625-S Ballard, et al. J Thorac Oncol. 2015;10(9, Suppl 2):S Yang JC-H, et al. ASCO Abstract 9002.
Slide credit: clinicaloptions.com

4. BLOOM: Study Design—LM cohort 1
Advanced or metastatic NSCLC with confirmed LM, EGFR L858R or exon 19 deletion in primary tumor, prior EGFR-TKI treatment, ECOG PS 0-2, stable extracranial disease, ≥ 1 LM lesion by MRI
(N = 21)
Assessments
AEs*
Efficacy
PK in CSF
Quantification of EGFRm DNA in CSF
Osimertinib
160 mg PO QD
Efficacy assessments: OS, brain MRI and extracranial MRI or CT scan*†, CSF cytology, neurological exam*, CNS symptoms*
CT/MRI, CSF cytology and neurological exam every 6 wks
1 cycle = 21 days of continuous dosing
AE, adverse event; CSF, cerebrospinal fluid; CNS, central nervous system; DNA, deoxyribonucleic acid; ECOG, Eastern Cooperative Oncology Group; LM, leptomeningeal metastases; m, mutant; NSCLC, non-small-cell lung cancer; PK, pharmacokinetics; PS, performance status; RECIST, Response Evaluation Criteria In Solid Tumors; TKI, tyrosine kinase inhibitor.
*As assessed by study investigator. †RECIST for CNS disease; RECIST 1.1 for extracranial disease.
Slide credit: clinicaloptions.com
Yang JC-H, et al. ASCO Abstract 9002.

5. BLOOM: Baseline Characteristics
All pts Asian with adenocarcinoma histology
Characteristic
N = 21
Male, n 6
Median age, yrs (range)
59.0 (44-75)
Smoking status, n
Current/former/never
1/5/15
ECOG PS, n
0/1/2
1/11/9
Normal neurological assessment, n 11
Prior lines of systemic therapy, median (range)
3.0 (1-8)
Prior whole brain radiotherapy, n
Prior EGFR-TKIs*, n
Gefitinib
Erlotinib
Dacomitinib
HM61713 (BI ) 16 3 1
Prior systemic response to EGFR-TKI, n PR SD PD 14
Tumor Tissue EGFR Mutation Status (Local Test) N
Ex19Del 9
L858R 13
Ex19Del/L858R 1
T790M in CSF 2
T790M in plasma 6
LM, leptomeningeal metastases; NSCLC, non-small cell lung cancer; PD, progressive disease; PS, performance status; SD, stable disease; TKI, tyrosine kinase inhibitor.
*1 pt received 2 lines of therapy: gefitinib and HM61713
Slide credit: clinicaloptions.com
Yang JC-H, et al. ASCO Abstract 9002.

6. BLOOM: Safety Drug-related grade ≥ 3 AEs: 3
Drug-Related AEs >10%, n
CTCAE Grade
Total
N = 21 1 2
≥ 3
Missing
Diarrhea 7 3 12
Nausea 9 10
Rash (grouped terms) 6
Dry skin 5
Paronychia 4
Dermatitis acneiform
Increased ALT
Fatigue
Drug-related grade ≥ 3 AEs: 3
AEs leading to dose interruption and dose reduction in 2 pts
Skin pruritus (n = 1), neutropenia (n = 1)
No discontinuations due to drug-related AEs
1 death from aspiration pneumonia not related to drug
AE, adverse event; ALT, alanine aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events.
Slide credit: clinicaloptions.com
Yang JC-H, et al. ASCO Abstract 9002.

7. BLOOM: Efficacy Response, n N = 21 Confirmed* Unconfirmed
Best MRI imaging intracranial response
Responding 7 1
Stable disease 9 2
CSF cytology clearance
Responding in 2 consecutive samples
Improved neurological function 5
Best Confirmed Neurological Status† 21
Improved No change Worsened Early withdrawal Unconfirmed 18 15 12 10
Number of Pts 9 6 5 3 3 1 1 1
CSF, cerebrospinal fluid.
Normal (n = 11)
Abnormal (n = 10)
Neurological Status at Baseline
* Responses confirmed ≥ 4 wks after initial response
†Response assessed by neurologic exam
Slide credit: clinicaloptions.com
Yang JC-H, et al. ASCO Abstract 9002.

8. BLOOM: CSF Clearance of Tumor Cells
EGFR mutation DNA copy number detected by droplet digital PCR
Data available for 9 pts who had ≥ 12 wks of assessments and CSF samples available
6 pts had decrease of > 50% in EGFR mutation DNA copies up to C9D1; decrease sustained in 5/6 pts
Improved neurological function: 4
LM-MRI response: 4
LM-MRI stable disease: 2
CSF clearance: 2
EGFRm in CSF: Change in DNA Copy Number (Mutant DNA copies/mL)
Pt 1† Pt 2 Pt 3‡ Pt 4 Pt 5 Pt 6 Pt 7† Pt 8 Pt 9
100 80 60 40 20
EGFRm change From Baseline (%)
–20
–40
–60
–80
–100
CSF, cerebrospinal fluid; LM, leptomeningeal metastases; m, mutant; PCR, polymerase chain reaction.
Screen
C2D1
C3D1
C5D1
C7D1
C9D1
C11D1
C13D1
C15D1
C17D1
†Pts with T790M mutations detected in screening CSF ‡No sample available on C11D1
Slide credit: clinicaloptions.com
Yang JC-H, et al. ASCO Abstract 9002.

9. BLOOM: Time on Treatment
15 pts with treatment ongoing at time of data cutoff (March 10, 2016)
Pts with a confirmed intracranial LM response (n = 7)
Pts
160 mg QD
80 mg QD (dose reduction)
T790M positive in the CSF
Dose interrupted
Confirmed CSF clearance
Discontinued
CSF, cerebrospinal fluid; LM, leptomeningeal metastases. * 1 2 3 4 5 6 7 8 9 10 11 12 13
Time Since Treatment Initiation, mos
*Pt death due to aspiration pneumonia.
Arrows represent observations at time of data cutoff
Yang JC-H, et al. ASCO Abstract 9002.
Slide credit: clinicaloptions.com

10. BLOOM: Conclusions
Osimertinib shows promising activity and safety in pretreated pts with EGFR-mutated advanced NSCLC and LM
Toxicity manageable
7 pts with confirmed LM response ongoing > 9 mos
Investigators suggest further investigation of osimertinib warranted in this setting
BLOOM study ongoing [NCT ]
Open cohort of pts with T790M-positive NSCLC and LM, with T790M status determined by testing of plasma or extracranial tumor
CSF, cerebrospinal fluid; LM, leptomeningeal metastases; NSCLC, non-small-cell lung cancer.
Slide credit: clinicaloptions.com
Yang JC-H, et al. ASCO Abstract 9002.

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