4-Year Results of the Ponatinib Phase 2 PACE Trial in Heavily

4-Year Results of the Ponatinib Phase 2 PACE Trial in Heavily

Abstract P228
4-Year Results of the Ponatinib Phase 2 PACE Trial in Heavily Pretreated Leukemia Patients
Jorge E. Cortes,1 Javier Pinilla-Ibarz,2 Philipp D. Le Coutre,3 Ronald Paquette,4 Charles Chuah,5 Franck E. Nicolini,6 Jane Apperley,7 Hanna Jean Khoury,8 Moshe Talpaz,9 Michele Baccarani,10
Stephanie Lustgarten,11 Frank G. Haluska,12 François Guilhot,13 Michael W. Deininger,14 Andreas Hochhaus,15 Timothy P. Hughes,16 Neil P. Shah,17 Hagop M. Kantarjian1
1The
University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA; 3Charité Universitätsmedizin Berlin, Berlin, Germany; 4Ronald Reagan UCLA Medical Center, University of California, Los Angeles, CA, USA;
5Singapore General Hospital and Duke-NUS Medical School, Singapore, Singapore; 6Centre Hospitalier Lyon Sud, Pierre Bénite, France; 7Centre for Haematology, Imperial College, London, UK; 8Winship Cancer Institute of Emory University, Atlanta, GA, USA; 9Comprehensive Cancer Center,
University of Michigan, Ann Arbor, MI, USA; 10S. Orsola-Malpighi University Hospital, Bologna, Italy; 11ARIAD Pharmaceuticals, Inc., Cambridge, MA, USA; 12BioCancell Ltd., Jerusalem, Israel (previously employed by ARIAD); 13Inserm CIC 1402, CHU de Poitiers, Poitiers, France;
14Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; 15Jena University Hospital, Jena, Germany; 16University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, Australia; 17University of California San Francisco, San Francisco, CA, USA
INTRODUCTION
•
•
Ponatinib is approved for adult patients with refractory
chronic myeloid leukemia (CML) or Philadelphia
chromosome–positive acute lymphoblastic leukemia
(Ph+ ALL); it is the only TKI approved for patients with
the T315I mutation2,3
The ongoing pivotal phase 2 PACE trial
(NCT01207440) evaluated ponatinib (starting dose
45 mg/d) in patients with CML or Ph+ ALL refractory to
dasatinib or nilotinib, or with the T315I mutation4
Ponatinib was found to be associated with arterial
occlusive events (AOEs) in the PACE trial.5 While dose
reduction recommendations were part of the protocol
to manage adverse events (AEs), dose reductions
were instructed in Oct 2013 to mitigate AOEs6
Median age, years
(range)
Sex, male, n (%)
Median time from
diagnosis to first dose,
years (range)
To evaluate the efficacy and safety of ponatinib with
4 years median follow-up in the ongoing phase 2 PACE
trial (NCT01207440), with a focus on patients with
chronic phase (CP)–CML
METHODS
The design of the ongoing PACE trial has been previously
described4
•
•
Primary endpoints were major cytogenic response
(MCyR) by 12 months for CP-CML and major
hematologic response (MaHR) by 6 months for
accelerated phase (AP)–CML, blast phase (BP)–CML,
and Ph+ ALL patients
Secondary endpoints for all patients included major
molecular response (MMR), duration of response,
progression-free survival (PFS), overall survival (OS),
and safety
All
n=449
60 (18–94)
59 (18–94)
144 (53)
238 (53)
7 (0.5–27)
6 (0.3–28)
Prior TKI therapy,a n (%)
1 TKI
18 (7)
2 TKIs
90 (33)
≥3 TKIs
162 (60)
100
60
Resistant/intolerant (n=203)
72
59
55
54
T315I (n=64)
MCyR
Patients in
MCyR as of
Oct 2013
n
58
39
44
34
Totalb
36
29
24
20
23
19
45 or 30 to
15 mg/d
263 (59)
15 mg/d
CCyR
CP-CML, n=270
Maintained
Response as
of Aug 2015
n (%)
Patients in
MMR as of
Oct 2013
n
MMR
MR4
MR4
MR4.5
MR4.5
66 (96)
51
46 (90)
59
56 (95)
45
40 (89)
215 (80)
375 (84)
Intolerant only
39 (14)
49 (11)
52 (19)
Best response of MMR or
better to most recent
dasatinib or nilotinib,
n (%)
8 (3)
No mutation detected,
n (%)
138 (51)
T315I mutation, n (%)
64 (24)
81 (18)
16 (4)
MR4, 4-log molecular response (≤0.01% BCR-ABLIS); MR4.5, 4.5-log molecular response (≤0.0032% BCR-ABLIS)
Response at any time in advanced phase leukemia:
• AP-CML (n=83): MaHR was achieved in 61% of patients and MMR in 22%
• BP-CML (n=62): MaHR was achieved in 31%
• Ph+ ALL (n=32): MaHR was achieved in 41%
198 (44)
Estimated Duration of MCyRa for Patients
With CP-CML at 4 Years
128 (29)
Any Grade
Grade 3/4
Abdominal pain
124 (46)
27 (10)
191 (43)
41 (9)
Rash
126 (47)
10 (4)
187 (42)
18 (4)
Constipation
111 (41)
7 (3)
168 (37)
10 (2)
Headache
115 (43)
9 (3)
167 (37)
11 (2)
Dry skin
112 (42)
9 (3)
163 (36)
11 (2)
Fatigue
80 (30)
6 (2)
136 (30)
Hypertension
92 (34)
34 (13)
Pyrexia
69 (26)
Ponatinib
dose post
Oct 2013
Long-term
outcomes
assessed at
4 years
Data analysis
cut-off
Patients in this
analysis
Median
follow-up
Unless benefit-risk analysis justified
treatment with a higher dose, the
following dose reductions were
instructed in PACE:
• 15 mg once daily for CP-CML
patients with MCyR
• 30 mg once daily for CP-CML
patients without MCyR
• 30 mg once daily for AP-CML or
BP-CML patients
• PFS, OS
• Maintenance of MCyR,
maintenance of MMR
• Treatment-emergent AEs,
cumulative and exposure-adjusted
incidence rates of new AOEs and
venous thromboembolic events
(VTEs)
• Kaplan-Meier method
• Exposure-adjusted incidence rates
of new AOEs are reported as the
no. of events/100 patient-years
• August 3, 2015
• Total, N=449
• CP-CML, n=270; AP-CML, n=85;
BP-CML, n=62
• Ph+ ALL, n=32
• 48.2 months (range, 0.1–58.5) for
patients with CP-CML
135 (30)
51 (11)
Other reduction
0
19
3 (1)
133 (30)
11 (2)
No dose reduction as of Oct 2013
Total
10
52
15 mg/d
7
29
Other
3
23
25 (100)
17
17 (100)
Nausea
75 (28)
2 (1)
129 (29)
3 (1)
Diarrhea
53 (20)
2 (1)
97 (22)
7 (2)
Increased lipase
72 (27)
33 (12)
97 (22)
54 (12)
Vomiting
49 (18)
4 (2)
96 (21)
5 (1)
Myalgia
65 (24)
3 (1)
95 (21)
3 (1)
Pain in extremity
63 (23)
9 (3)
91 (20)
9 (2)
Back pain
56 (21)
3 (1)
84 (19)
6 (1)
Thrombocytopenia
122 (45)
95 (35)
197 (44)
160 (36)
Neutropenia
53 (20)
45 (17)
113 (25)
100 (22)
Anemia
51 (19)
26 (10)
110 (25)
70 (16)
a Excludes
patients who lost response prior to Oct 2013
reduction = 45 to 30 mg/d or any other reduction not specified: 10/10 (100%) maintained MCyR and 6/6 (100%) MMR
c Other = 45 or 30 mg/d: 8/10 (80%) maintained MCyR and 2/3 (67%) MMR
• Regardless of dose reduction or no dose reduction in Oct 2013,
maintenance of response was high (over 90% of responding patients)
• 81 out of 84 patients who were dose reduced to 15 mg maintained
response at 4 years median follow-up
Estimated Duration of MMR for Patients
With CP-CML at 4 Years
• The most common treatment-emergent AEs included skin-related AEs
(including rash, dry skin), constitutional symptoms (including abdominal
pain, constipation, headache, fatigue, pyrexia, nausea, diarrhea,
vomiting), vascular (hypertension), pancreatic (increased lipase),
and myelosuppression (thrombocytopenia, neutropenia, anemia)
• The most common grade 3/4 treatment-emergent AEs (observed in
≥10% of patients) were thrombocytopenia, neutropenia, anemia,
increased lipase, and hypertension
• AOEs included a collection of preferred terms where no individual
term occurred in >10% of patients; incidence of AOEs is summarized
in the table below
141
121
158
Cumulative and Exposure-Adjusted Incidences of
AOEs and VTEsa
162
CP-CML
n=270
a
MCyR by 12 months
Estimated PFS for Patients With CP-CML at 4 Years
Estimated OS for Patients With CP-CML at 4 Years
All
Grades
SAEs
77 (29)b
63 (23)c
104 (23)d
83 (19)e
Cardiovascular
39 (14)
30 (11)
56 (13)
41 (9)
Cerebrovascular
33 (12)
26 (10)
39 (9)
31 (7)
Peripheral vascular
31 (11)
25 (9)
40 (9)
31 (7)
Exposure-adjusted AOEs,
no. of patients with events
per 100 patient-years
14.2
10.9
14.1
10.7
13 (5)
12 (4)
25 (6)
22 (5)
2.0
1.8
2.9
2.5
Exposure-adjusted VTEs,
no. of patients with events
per 100 patient-years
110 (41)
133 (30)
Discontinued
treatment, n (%)
160 (59)
316 (70)
Disease
progression
28 (10)
AEs
50 (19)
72 (16)
Deatha
8 (3)
25 (6)
Otherb
74 (27)
118 (26)
101 (22)
7 deaths were assessed by investigators as possibly or probably related to
ponatinib (CP-CML: pneumonia, acute myocardial infarction; AP-CML: fungal
pneumonia, gastrointestinal hemorrhage; BP-CML/Ph+ ALL: cardiac arrest, gastric
hemorrhage, mesenteric arterial occlusion)
b Includes withdrawal by patient (including for transplant) (CP-CML, n=30; all, n=40),
lack of efficacy (CP-CML, n=15; all, n=26), investigator decision (CP-CML, n=11; all,
n=17), lost to follow-up (CP-CML, n=0; all, n=3), noncompliance (CP-CML, n=3; all,
n=3), protocol violation (CP-CML, n=1; all, n=1), and other reasons (CP-CML, n=14;
all, n=28)
a
a
b
At 4 years median follow-up:
• The majority (75%) of ongoing CP-CML
patients were receiving the 15 mg/d dose of
ponatinib (22% 30 mg/d and 4% 45 mg/d)
16
45
15.7
15.5
40
14
12
10
8
35
32.7
mg/d
10.4
31.4
mg/d
25.5
mg/d
6
4
9.6
19.7
mg/d
2
0
30
25
20
15
10
5
0 to <1 year
1 to <2 years
2 to <3 years
3 to <4 years
0
Intervalb
Progression was defined as death, development of AP- or BP-CML, loss of complete hematologic response (CHR) in the absence of
cytogenetic response, loss of MCyR, or increasing white blood cell count without CHR. Patients who do not demonstrate
progression or loss of response are censored at the last response assessment date
• 41% of CP-CML patients remained on study
18
In the safety population
Later intervals exclude patients with prior events; ongoing patients may have a different risk than those at study start
• Exposure-adjusted incidence of new AOEs did not increase over time
In advanced phase leukemia:
In advanced phase leukemia:
• 38% of patients who had an AOE (n=104) remain on study
• AP-CML (n=83): estimated 4-year PFS was 22%
• AP-CML (n=83): estimated 4-year OS was 51%
• BP-CML/Ph+ ALL (n=94): median PFS was 3.0 months (95% CI, 2.0–4.2)
• BP-CML/Ph+ ALL (n=94): median OS was 6.9 months (95% CI, 5.0–9.2)
• Patients with ≥2 risk factors including history of ischemic disease had
a relative risk (95% CI) of serious AOEs of 2.6 (1.5–4.3)
Presented at the 21st Annual Meeting of the European Hematology Association (EHA), June 9–12, 2016, Copenhagen, Denmark
– 59% MCyR and 54% CCyR
– 39% MMR, including 29% MR4 and 23% MR4.5
• Ponatinib treatment continues to result in deep and
lasting cytogenetic and molecular responses
– Kaplan-Meier estimates of 4-year MCyR and
MMR were 82% and 61%, respectively
– The probability of PFS and OS was 56% and
77%, respectively
• Owing to the association of ponatinib with AOEs,
prospective dose reductions were introduced in
Oct 2013
• OPTIC (Optimizing Ponatinib Treatment In CML) – a
prospective trial evaluating a range of ponatinib doses
(45, 30, and 15 mg/d) is ongoing (NCT02467270)
ACKNOWLEDGMENTS
The authors would like to thank the patients, their families, and their caregivers; the PACE
investigators and their team members at each study site; and colleagues from ARIAD
Pharmaceuticals, Inc., MolecularMD, and the CML community. Professional medical writing
assistance was provided by Diane Davies, PhD, CMPP, of Evidence Scientific Solutions,
Philadelphia, PA, USA, and funded by ARIAD Pharmaceuticals, Inc.
1. O’Hare T, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently
inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16:401–12.
2. Iclusig [package insert]. Cambridge, MA: ARIAD Pharmaceuticals, Inc; 2014. 3. Iclusig [summary
of product characteristics]. Leatherhead, UK: ARIAD Pharma Ltd; 2015. 4. Cortes JE, et al.
A phase 2 trial of ponatinib in Philadelphia chromosome–positive leukemias. N Engl J Med.
2013;369:1783–96. 5. Iclusig® (ponatinib) tablets for oral use: highlights of prescribing information.
Cambridge, MA: ARIAD Pharmaceuticals, Inc; 2014. http://www.accessdata.fda.gov/
drugsatfda_docs/label/ 2015/203469s020lbl.pdf. Revised Dec 2015. 6. ARIAD announces changes
in the clinical development program of Iclusig [press release]. Cambridge, MA: ARIAD
Pharmaceuticals, Inc; Oct 9, 2013. 7. Cortes JE, et al. Ponatinib efficacy and safety in heavily
pretreated leukemia patients: 3-year results of the PACE trial (abstract P234). Poster presented at:
20th Congress of the European Hematology Association; 11–14 June 2015; Vienna, Austria.
Summary of Exposure-Adjusted Incidence Rates for
Newly Occurring AOEsa in All Patients
Primary reasons for
discontinuation,
n (%)
• After 4 years median follow-up in this heavily pretreated
CP-CML population, ponatinib responses were:
REFERENCES
Categorization of AOEs and VTEs is based on a broad collection of >400 MedDRA preferred terms related to vascular
ischemia or thrombosis
b 41 patients had >1 AOE; c 25 patients had >1 serious AOE; d 51 patients had >1 AOE; e 32 patients had >1 serious AOE
SAEs, serious adverse events
a
Remained on study at
4 years, n (%)
Other reduction = 45 to 30 mg/d or any other reduction not specified; Other = 45 or 30 mg/d
– Maintenance of response was high, in particular,
for patients at 15 mg/d
All
n=449
SAEs
VTEs
Total
– Exposure-adjusted incidence of AOEs has not
increased over time
All
Grades
AOEs, n (%):
Dose reductions as of Oct 2013
SUMMARY
Hematologic, n (%)
Patient Disposition
37.3
(0.1–58.5)
21
25
Smoking and family history were not collected as part of the trial. Patients were excluded
from the trial with significant or active cardiovascular disease, including myocardial
infarction, unstable angina or CHF (in prior 3 months), or history of clinically significant
atrial or ventricular arrhythmia
b Aspirin was included in the antiplatelet agents as well as separately
48.2
(0.1–58.5)
4
10 (2)
– Antihypertensives 19%, aspirinb 9%,
antiplatelet agentsb 8%, antidiabetes
agents 5%, lipid-modifying agents 5%,
anticoagulants 3%
Median follow-up,
months (range)
30 to 15 mg/d
131 (29)
– Ischemic heart disease 22%, nonischemic
heart disease 43%
32.3
(3–52)
13 (3)
8 (3)
• Baseline history of cardiovascular disease:
29.4
(3–45)
29
87 (32)
– Diabetes 16%, hypertension 53%,
hypercholesterolemia 51%, obesity 24%
Median dose intensity,
mg/d (range)
2
Arthralgia
• Baseline cardiovascular risk factors for all
patients7,a:
All
n=449
45 to 15 mg/d
19 (95)
Includes approved and investigational TKIs
CP-CML
n=270
69
Dose Intensity (mg/d)
Statistics
• Starting dose: 45 mg once daily
• Dose reductions to 30 mg once
daily or 15 mg once daily were
permitted to manage AEs
6
20
a
Ponatinib
dose
No AOE
After Oct 2013
33 (94)
• Baseline concomitant medications:
Patients With No AOEs Prior to
Oct 2013
AOE
After Oct 2013
35
b Other
Resistant
Grade 3/4
Occurrence of New AOEs Following Prospective Dose
Reductions in All Ongoing Patients
Nonhematologic, n (%)
Maintained
Response as
of Aug 2015
n (%)
69
All, n=449
Any Grade
MMR
No dose reduction as of Oct 2013
Totalc
MCyR
Treatment-Emergent AEs Reported in ≥20% of Patients
Dose reductions as of Oct 2013
48
31 (7)
155 (35)
Maintenance of Response Following Prospective Dose
Reductions in CP-CML Patients Who Achieved MCyR or MMRa
70
40
0
Both resistant and
intolerant
a
Total (n=267)
80
Resistant/intolerant to
dasatinib or nilotinib,
n (%)
OBJECTIVE
•
CP-CML
n=270
Response to Ponatinib in Patients With CP-CML:
Response at Any Time
No. of Patients With Events per
100 Patient-Years
•
Patient Characteristics
Ponatinib is a potent oral tyrosine kinase inhibitor (TKI)
with activity against native and resistant BCR-ABL,
including T315I1
Patients (%)
•
RESULTS
DISCLOSURES
This study was sponsored by ARIAD Pharmaceuticals, Inc. JEC: consulting or advisory role
(ARIAD, BMS, Novartis, Pfizer), research funding (ARIAD, BMS, Novartis, Pfizer, Teva);
JP-I: honoraria (ARIAD, BMS, Pfizer), consulting or advisory role (ARIAD), speakers’ bureau
(BMS, Pfizer); PDLC: honoraria (ARIAD, BMS, Novartis, Pfizer), research funding (Novartis);
RP: speakers’ bureau (ARIAD, BMS); CC: honoraria (Avillion, BMS, Novartis), travel,
accommodations, expenses (BMS); FEN: honoraria (ARIAD, BMS, Novartis), consulting or
advisory role (BMS, Novartis), speakers’ bureau (ARIAD, BMS,
Novartis), research funding (Novartis); JA: consulting or advisory
role (ARIAD, BMS, Novartis, Pfizer), research funding (ARIAD,
BMS, Novartis), travel, accommodations, expenses (Novartis);
HJK: honoraria (BMS, Novartis, Pfizer), consulting or advisory
role (BMS, Novartis, Pfizer); MT: consulting or advisory role
(Pfizer), research funding (ARIAD, Pfizer), travel, accommodation,
expenses (ARIAD, Pfizer); MB: honoraria (ARIAD, BMS,
Novartis, Pfizer), consulting or advisory role (ARIAD),
speakers’ bureau (ARIAD, BMS, Novartis, Pfizer), travel,
accommodations, expenses (ARIAD, Novartis);
SL, FGH: employment (ARIAD), stock and other ownership
interests (ARIAD); FG: honoraria (ARIAD); MWD: consulting or
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