Single‐Agent Activity of the Novel KSP Inhibitor ARRY‐520 in Patients with Relapsed or Refractory Multiple Myeloma (RRMM): Results from Subgroup Analyses
Poster Number
P-224
Sagar Lonial1, Jeffrey Zonder2, Adam Cohen3, William Bensinger4, Roger Aitchison5, Brandi Hilder6, Mieke Ptaszynski7, Duncan Walker8, Robert Orlowski9, Jonathan Kaufman1, Jatin Shah9
®
1Department
of Hematology and Medical Oncology Emory Winship Cancer Institute, Atlanta, GA, USA. 2Department of Oncology, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA, 3Fox Chase Cancer Center,
Philadelphia, PA, USA. 4Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, 5Department of Biostatistics, Array BioPharma, Boulder CO, USA, 6Department of Clinical Operations, Array
BioPharma, Boulder CO, USA, Department of Clinical Sciences, Array BioPharma, Boulder CO, USA, 8Department of Translational medicine, Array BioPharma, Boulder CO, USA, 9Department of Lymphoma/Myeloma, The
University of Texas MD Anderson Cancer Center, Houston, TX, USA
Available at www.arraybiopharma.com
Introduction
Study Design and Objectives
 ARRY-520 is a potent, selective inhibitor of the kinesin
5 motor protein
 Kinesin 5 is restricted to proliferating cells
Safety
 ARRY-520 was generally well tolerated, with hematologic toxicity being the most commonly observed adverse
effect
Study Design
 Open label, single arm, multicenter, Phase 2 study to assess
efficacy and safety of single-agent ARRY-520
 Simon 2-stage design:
• Stage 1: 18 evaluable patients accrued; >1 response
triggered Stage 2
• Stage 2: 14 patients accrued for a total of 32 evaluable
patients
 ARRY-520 preferentially targets Mcl-1-addicted cells for
apoptosis
 Primarily hematopoietic cells and tumors
 Some solid tumor subsets
 Safety profile is restricted by target expression and
target biology
 Transient, non-cumulative myelosuppression
 Minimal, infrequent GI and skin toxicity at
recommended dose
 No neuropathy
 Neutropenia and thrombocytopenia have been reversible and not cumulative
 Neutrophil nadir typically occurs within 7 days and recovers to baseline within 14 days of initial dose
Gr 3/4 Hematological Abnormalities
ARRY‐520
Dose
N = 32
 ARRY-520 was administered as a 1h IV infusion at 1.5 mg/m2/day
on D1,2 Q2W
 Prophylactic G-CSF was administered starting D3 or 4 for 5-7
days
Grade
Hematologic Abnormalities* Neutropenia
Thrombocytopenia
Anemia
Febrile Neutropenia
Primary Objective
 ARRY-520 demonstrated clinical activity in a Phase 1
dose-escalation study that warranted further exploration
of activity in a Phase 2 study
 Assess anti-myeloma activity of ARRY-520
Prior Therapies
ARRY‐520
6 (19%)
7 (22%)
10 (31%)
1 (3%)
9 (28%)
8 (25%)
2 (6%)
‐
 ARRY-520 shows a low incidence of non-hematologic Grade 3/4 AEs
 Fatigue, pyrexia, vomiting, pneumonia and confusional state were the only Grade 3/4 treatment-related
AEs reported
 No treatment-related AEs of neuropathy were observed
Patient Demographics ARRY‐520
N = 32
 Confirmed relapsed or refractory multiple myeloma or
plasma cell leukemia
 ≥ 2 prior treatment regimens
 Must have included both bortezomib and an IMiD,
unless patients were not eligible or refused these
treatments
 Measurable disease
 ECOG Performance Status 0-1
 Age ≥ 18 years
 Adequate hematologic, hepatic and renal function
4
*Based on laboratory data, except for febrile neutropenia
Baseline Patient Characteristics and Eligibility
Key Inclusion Criteria
3
Median Prior Regimens
6
(2, 19)
Prior Proteasome Inhibitor
Prior BTZ
BTZ‐refractory
Prior IMiD
Prior Len
Len‐refractory
Prior Corticosteroid
Triple‐Refractory
29 (91%)
29 (91%)
17 (53%)
32 (100%)
31 (97%)
24 (75%)
32 (100%)
13 (41%)
(Len, BTZ, Dex)
Prior Alkylator
Prior Anthracycline
Prior Transplant
32 (100%)
16 (50%)
26 (81%)
N = 32
Gender
Male
Age at Enrollment (yrs)
Median (Range)
ECOG PS
0
1
High Risk Cytogenetics
ISS Stage at Diagnosis
Stage I
Stage II
Stage III
Unknown
Years Since Diagnosis
Median (Range)
18 (56%)
 3/32 patients (9%) came off study due to an AE
65 (51, 82)
Dose Modifications
Gr3/4 Non‐Hematological AEs
7 (22%)
25 (78%)
3 (9%)
ARRY‐520
ARRY‐520
N = 32
9 (28%)
6 (19%)
8 (25%)
9 (28%)
Grade
3
4 (12%)
2 (6%)
1 (3%)
Fatigue
Back Pain
Hypokalemia
3.2 (0.8, 11.4)
4
1 (3%)
‐
1 (3%)
N = 32
3 (9%)
Discontinuation due to AEs
Any AE Leading to Dose Reduction
Febrile Neutropenia
Thrombocytopenia
11 (34%)
‐
3 (9%)
Anti-Myeloma Activity
Single-agent ARRY-520 induced durable responses in heavily pretreated patients with relapsed and
refractory multiple myeloma
• 16% ≥PR. 8.6 month median DOR
AAG levels identify a subgroup of patients with no response to ARRY-520 and short OS
3
MR (n=4)
2.5
ARRY‐520 Response Characteristics
SD or PD (n = 56)
Baseline [AAG] (g/L)
ARRY‐520
N = 32
6
Median Prior Regimens
Overall Best Response (ORR)
PR
MR + PR
SD
PD
Not Evaluable
PR (n=12)
5 (16%)
6 (19%)
14 (44%)
11 (34%)
1 (3%)
2
1.5
1
0.5
Median time to response, (≥PR) Months (Range)
4.4 (2.6, 15.9)
Median duration of response (DOR), (≥PR) Months (Range)
8.6 (1.4, 23.7+)
0
0
 The median overall survival (OS) for ARRY-520 was 19 months (95% CI 7.3, 23.3+ months) in this heavily
pretreated population,
 Patients with ISS Stage III at baseline had notably lower response rate and OS as compared to patients with
Stage I or II disease
 The event free survival (EFS) and OS was similar across patients with disease refractory to lenalidomide or
bortezomib or refractory to last therapy
N
Median EFS
(Months)
10
15
20
25
30
35
40
45
Time on Treatment (months)
 The serum protein a-1 acid glycoprotein (AAG) tightly binds ARRY-520.
 High AAG levels predict reduced exposure to active drug and less distribution of ARRY-520 to target tissues
 Patients with AAG levels above the cutoff have a 0% response rate and shorter OS (4.5 months) as compared to patients
with AAG levels below the cutoff (24%% ORR and 20.2 month median OS)
 Although both ISS stage III and AAG ≥1.1g/dL were associated with poor ORR and short OS, there was no observed
relationship between AAG and ISS score (not shown)
Kaplan Meier plot of Overall Survival by AAG level
ARRY‐520 Subgroup Analysis for ORR and OS
Subgroup
5
Median OS (Months)
All Patients
32
3.7
19.0
AAG ≤1.1 g/L
21
5.3
20.2
AAG > 1.1 g/L
6
2.4
4.5
ISS Stage I at Baseline
10
12.0
20.2
ISS Stage II at Baseline
13
2.3
19.1
ISS Stage III at Baseline
9
1.9
6.2
Bortezomib‐Refractory
17
4.8
19.0
19.1
Lenalidomide Refractory
24
3.7
Dual‐Refractory
13
4.2
9.9
Refractory to Last Therapy
15
3.0
20.2
EFS: Event-Free Survival; OS: Overall Survival
Summary
 ARRY-520 selectively targets the Kinesin5 motor protein - a new mechanism of drug action in MM
 ARRY-520 is not expected to share resistance mechanisms with other drugs: Single-agent activity in MM refractory to IMiDs and proteasome inhibitors
 ARRY-520 was generally well tolerated in heavily pretreated patients
 The most commonly reported adverse events were hematologic
 Neutropenia and thrombocytopenia are typically transient (return to baseline within 2 weeks of dosing) and not cumulative
 Low incidence of non-hematologic adverse events: Minimal GI toxicity and no treatment-related events of neuropathy were reported
 ARRY-520 is active as a single agent in multiple myeloma
 16% ≥PR, 8.6 month median duration of response in heavily pretreated patients
 The median OS for ARRY-520 in this population was 19 months
 The serum protein AAG tightly binds ARRY-520 and impacts pharmacokinetics and exposure to ARRY-520
 ARRY-520 has increased ORR, EFS and OS in the AAG-selected population compared to the overall population
 Patients excluded by AAG have no responses and short OS
Our thanks to the patients and their families for their participation in this study