1. health and fitness
2. disease
3. cancer

LBA4
Evaluation of Anaplastic Lymphoma Kinase (ALK) Inhibitor Brigatinib (AP26113)
in Patients With ALK+ Non–Small Cell Lung Cancer (NSCLC) and Brain Metastases
David Kerstein,1 Scott N Gettinger,2 Kathryn Gold,3 Corey J Langer,4 Alice T Shaw,5 Lyudmila A Bazhenova,6 Ravi Salgia,7 David J Dorer,1 Maureen G Conlan,1 D Ross Camidge8
1
ARIAD Pharmaceuticals, Inc., Cambridge, MA, USA; 2Yale Cancer Center, New Haven, CT, USA; 3The University of T
exas MD Anderson Cancer Center, Houston, TX, USA; 4University of Pennsylvania Abramson Cancer Center, Philadelphia, PA, USA;
5
Massachusetts General Hospital, Boston, MA, USA; 6University of California San Diego Moores Cancer Center, La Jolla, CA, USA; 7The University of Chicago Medicine, Chicago, IL, USA; 8University of Colorado Cancer Center, Aurora, CO, USA
INTRODUCTION
Figure 1. Patient Stratification
Figure 2. Time on Treatment
Discontinued
100
90
80
79
ALK+ NSCLC patients
a
Patients (%)
–– About half of patients have first disease progression in the
central nervous system (CNS), suggesting inadequate
CNS exposure5
Response Summary
• Brigatinib demonstrated intracranial CNS antitumor activity
with durable responses in ALK+ NSCLC patients with
intracranial CNS metastases at baseline
–– ORR in patients with
§§ Measurable lesions: 53%
§§ Nonmeasurable lesions: 30%
–– Median duration of intracranial response: 18.9 months
–– Median intracranial PFS: 22.3 months
Figure 5. Duration of Intracranial Response
Remain on study
137
total patients enrolled in
the phase 1/2 trial
• Crizotinib is active in ALK–rearranged (ALK+) NSCLC; however,
most patients eventually develop disease progression3–5
SUMMARY
Patients (n=49)
• Anaplastic lymphoma kinase (ALK) gene rearrangements have
been identified as driver mutations in non–small cell lung cancer
(NSCLC) and other cancers1–2
RESULTS
70
60
50
40
30
20
–– Among patients with known brain metastases, the CNS was
a site of development of new lesions or progression of
nontarget lesions in 70% of crizotinib-treated patients with
disease progression6
10
49 patients with intracranial CNS metastases identified
on baseline MRI by central review
• Brigatinib (AP26113) is an investigational oral tyrosine kinase
inhibitor that has preclinical activity against rearranged ALK and
clinically identified crizotinib-resistant mutants7
16 patients with measurable
intracranial CNS metastases
• A phase 1/2 study evaluated brigatinib in patients with advanced
malignancies, including ALK+ NSCLC
0
25
50
75
100
125
150
0
175
0
6
12
24
30
Time (Months)
Time on Treatment (Weeks)
• Median time on study for ALK+ NSCLC patients with intracranial
CNS metastases at baseline: 56.1 (0.1–150) weeks
33 patients with only
nonmeasurable intracranial
CNS metastases
18
Figure 3. Response in Brain
• For patients with a response and a follow-up scan (n=16), median
(Kaplan-Meier estimate) duration of intracranial response =
18.9 months
Future Directions
• A prospective evaluation of brigatinib in ALK+ NSCLC
patients with intracranial CNS metastases is under way
as part of a separate, pivotal, randomized, phase 2 trial in
patients with ALK+ NSCLC resistant to crizotinib (ALTA:
ALK in Lung Cancer Trial of AP26113)
Figure 6. Intracranial PFS
100
OBJECTIVE
METHODS
Overall Trial
• In this phase 1/2, single-arm, multicenter study (N=137;
NCT01449461), patients with advanced malignancies received
brigatinib at total daily doses of 30–300 mg
• The primary efficacy endpoint of the phase 2 portion of the trial
was objective response rate (ORR) by RECIST v1.18
• Secondary endpoints included safety, tolerability, best target
lesion response, progression-free survival (PFS), and time
to progression
• Clinical data presented are as of 19 Jan 2015
Specific Methods for This Analysis
• Contrast-enhanced brain magnetic resonance imaging (MRI)
scans from ALK+ NSCLC patients with intracranial CNS
metastases at baseline were analyzed by neuroradiologists in
an independent central review. The reviewers were blinded to
investigator assessment and systemic response
• In this post hoc analysis, up to 5 measurable intracranial CNS
metastases could be chosen as target lesions by the independent
reviewers. Intracranial response (including PFS and duration of
response) was defined using criteria based on RECIST8
–– Response in patients with at least 1 measurable intracranial
CNS metastasis (≥10 mm) was defined as ≥30% decrease
in sum of longest diameters of target lesions and
nonprogression in nontarget lesions
b
72/79 patients had baseline MRI scans available for central review at the time of this analysis
Evaluable patients had at least 1 postbaseline MRI available for central review at the time of this analysis
Baseline
Table 1. Baseline Characteristics
Characteristic
Median age, y (range)
• MRI scan dataset contains scans through 19 Jan 2015
ALK+ NSCLC
With Intracranial CNS
Metastases
n=49
Total ALK+ NSCLC
n=79
53 (30–73)
54 (29–83)
Sex, n (%)
Female
25 (51)
39 (49)
Race, n (%)
White
42 (86)
65 (82)
Asian
5 (10)
10 (13)
Other
2 (4)
4 (5)
0
20 (41)
30 (38)
1
28 (57)
48 (61)
2
1 (2)
1 (1)
ECOG, n (%)
a
Prior crizotinib, n (%)
Number of prior
chemotherapy
regimens, n (%)
a
45 (92)
11 (22)
20 (25)
2 regimens
16 (33)
23 (29)
≥3 regimens
11 (22)
14 (18)
48 Weeks
Figure 4. Activity in ALK+ NSCLC Patients With
Measurable Intracranial CNS Metastases (n=15)
Progressive disease
Partial response
Stable disease
Complete response
40
rotocol amendment as of 30 November 2012 restricted enrollment to Eastern Cooperative Oncology Group (ECOG) performance
P
status 0 or 1
20
0
–40
50
40
ACKNOWLEDGMENTS
30
20
0
0
ALK+ NSCLC
With Intracranial CNS
Metastases
n=49
Total ALK+ NSCLC
n=79
Remain on study, n (%)
32 (65)
47 (59)
Discontinued treatment, n (%)
17 (35)
32 (41)
Documented progressive disease
8 (16)
16 (20)
Adverse event
1 (2)
6 (8)
Characteristic
a
Death
2 (4)
3 (4)
Clinical progressive disease
2 (4)
2 (3)
–60
2 (4)
2 (3)
Withdrawal by subject
1 (2)
2 (3)
Protocol violation
1 (2)
1 (1)
Causes of death: 1 patient (180 mg qd) died from hypoxia considered possibly related to the study drug by the investigator
(last dose, day 1) and 1 patient (240 mg qd) died from dyspnea considered not related by the investigator (last dose, day 397)
b
Causes of death: 2 patients listed in footnote a; 1 additional patient (90 mg qd) died from an unknown cause considered possibly
related by the investigator (last dose, day 568)
a
18
24
30
36
Systemic Efficacy
• Brigatinib treatment achieved objective responses in 36/48 (75%
[95% CI, 60%–86%]) patients with ALK+ NSCLC and intracranial
CNS metastases
–– Median duration of response = 11.2 months
–– Median PFS = 12.9 months
a
One patient was not evaluable for response due to lack of follow-up scan
ALK+ NSCLC Patients With
Intracranial CNS Metastases
n=49
–80
All Patients in Study
N=137
5. Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease
prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non–small-cell
lung cancer. J Thorac Oncol. 2012;7:1807-1814.
6. Costa DB, Shaw AT, Ou SHI, et al. Clinical experience with crizotinib in patients with
advanced ALK-rearranged non–small-cell lung cancer and brain metastases. J Clin Oncol.
2015 Jan 26. Epub ahead of print.
7. Squillace RM, Anjum R, Miller D, et al. AP26113 possesses pan-inhibitory activity versus
crizotinib-resistant ALK mutants and oncogenic ROS1 fusions. Cancer Res. 2013;
73(8 suppl):5655.
8. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.
29 (59)
0
70 (51)
2 (1)
DISCLOSURES
Diarrhea
28 (57)
0
56 (41)
2 (1)
Fatigue
24 (49)
2 (4)
55 (40)
5 (4)
Cough
16 (33)
1 (2)
44 (32)
1 (<1)
Headache
16 (33)
0
45 (33)
1 (<1)
Increased lipase
15 (31)
7 (14)
24 (18)
12 (9)
This study was sponsored by ARIAD Pharmaceuticals, Inc. DK: employment (ARIAD); SNG:
nothing to disclose; KG: honoraria (Bristol-Myers Squibb), consulting or advisory role (Pfizer),
research funding (Puma, ARIAD, Roche/Genentech, AstraZeneca, Bristol-Myers Squibb); CJL:
research funding (ARIAD); ATS: honoraria (Pfizer, Novartis, Roche), consulting or advisory role
(Pfizer, Novartis, Genentech, Roche, Ignyta), research funding (Pfizer, Novartis, Genentech,
ARIAD); LAB: stock (Epic Sciences), honoraria (Novartis), consulting or advisory role (Clovis
Pharmaceuticals, Boehringer Ingelheim, Seattle Genetics), speakers bureau (Genentech, Pfizer),
research funding (ARIAD, Heat Bio, Mirati Pharmaceuticals, AstraZeneca, Boehringer Ingelheim,
Roche, Merck, Astex Pharmaceuticals, Chugai Pharmaceuticals, Eisai, Eli Lilly, Johnson &
Johnson, MedImmune, Novartis, NanoCarrier, Astellas); RS: nothing to disclose; DJD, MGC:
employment (ARIAD); DRC: honoraria (ARIAD), research funding (ARIAD)
Increased amylase
13 (27)
3 (6)
30 (22)
5 (4)
CR, n (%)
1 (7)
9 (30)
Increased AST
10 (20)
1 (2)
24 (18)
1 (<1)
PR, n (%)
7 (47)
NA
SD or non-CR/
non-PD,b n (%)
Back pain
10 (20)
1 (2)
22 (16)
2 (1)
5 (33)
17 (57)
Constipation
10 (20)
0
27 (20)
0
PD, n (%)
2 (13)
4 (13)
Dyspnea
10 (20)
3 (6)
31 (23)
9 (7)
Hypertension
10 (20)
5 (10)
20 (15)
7 (5)
Pyrexia
10 (20)
0
18 (13)
1 (<1)
Presented at the 5th European Lung Cancer Conference, 15–18 April 2015, Geneva, Switzerland
4. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in
ALK-rearranged lung cancers. Sci Transl Med. 2012;4:120ra17.
Nausea
9 (30)
• Patients received 90 mg qd (n=9), 120 mg qd (n=1), 90 mg qd for
7 days followed by escalation to 180 mg qd (90Ò180 mg qd; n=17),
180 mg qd (n=14), 90 mg bid (n=1), and 240 mg qd (n=3)
• Responses were observed at 90, 120, 90Ò180, 180, and 240 mg qd
3. Xalkori (crizotinib) prescribing information. New York, NY: Pfizer Inc; 2014.
Grade ≥3
n (%)
8 (53)
D for measurable brain metastases
S
Non-CR/non-PD for nonmeasurable brain metastases
CR = complete response, NA = not applicable, PD = progressive disease, PR = partial response, SD = stable disease
2. Hallberg B, Palmer RH. Mechanistic insight into ALK receptor tyrosine kinase in human
cancer biology. Nat Rev Cancer. 2013;13:685-700.
Any Grade
n (%)
ORR, n (%)
b
1. Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol.
2011;12:175-180.
Grade ≥3
n (%)
Patients With Only Nonmeasurable
Intracranial CNS Metastases
n=30
a
REFERENCES
Any Grade
n (%)
Patients With Measurable
Intracranial CNS Metastases
n=15
a
Physician decision
12
Table 4. Treatment-Emergent Adverse Events, ≥20% in
ALK+ NSCLC Patients With Intracranial CNS Metastases
*
Table 3. Intracranial Response in ALK+ NSCLC Patients
With Intracranial CNS Metastases
b
6
• For patients with a follow-up scan (n=45), median (Kaplan-Meier
estimate) intracranial PFS = 22.3 months
* Crizotinib-naive
Dotted line at –30% indicates threshold for partial response
Table 2. Patient Disposition and T
reatment Exposure
The authors would like to thank the patients, their families, and their caregivers; the phase
1/2 investigators and their team members at each study site; and colleagues from ARIAD
Pharmaceuticals, Inc. Professional medical writing assistance was provided by Lela Creutz,
PhD, of Peloton Advantage, LLC, Parsippany, New Jersey, USA, and funded by ARIAD
Pharmaceuticals, Inc.
Time (Months)
a
–20
*
60
10
• Patient with ALK+ NSCLC was previously treated with crizotinib
and received brigatinib 180 mg qd
• Partial response is ongoing as of 19 Jan 2015
71 (90)
1 regimen
8 Weeks
Images courtesy of D R Camidge
70
–100
–– Response in patients with only nonmeasurable intracranial
CNS metastases was defined as disappearance of all lesions
• Limited data regarding local radiotherapy to the brain were
collected and these data were not considered in this review
80
Best Change From Baseline in
Target Brain Lesions (%)
• To evaluate intracranial efficacy and safety of brigatinib in ALK+
NSCLC patients with intracranial CNS metastases at baseline in a
phase 1/2 study
a
90
30 patients evaluable
for efficacyb
Patients (%)
15 patients evaluable
for efficacyb
Safety Summary
• The most common adverse events (nausea, diarrhea,
fatigue, and cough) in patients with intracranial CNS
metastases at baseline occurred at a similar incidence in
the broader study population
AST = aspartate aminotransferase
• Treatment-emergent serious adverse events, ≥4%, for patients
with intracranial CNS metastases included dyspnea (4 [8%]),
hypoxia (3 [6%]), and pyrexia (2 [4%])
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