Transcript ASCO 2011 slides - Sarcoma Oncology

Results of the Phase 3, placebo-controlled trial
(SUCCEED) evaluating the mTOR inhibitor
ridaforolimus as maintenance therapy
in advanced sarcoma patients
following clinical benefit from
prior standard cytotoxic chemotherapy
S. P. Chawla, J. Y. Blay, I. Ray-Coquard, A. Le Cesne,
A. P. Staddon, M. M. Milhem, N. Penel, R. F. Riedel,
B. Bui Nguyen, L. D. Cranmer, P. Reichardt, E. Bompas,
Y. Song, R. M. Lee, J. E. Eid, J. Loewy, F. G. Haluska,
P. F. Dodion, G. D. Demetri,
on behalf of all SUCCEED investigators
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The PI3K-AKT-mTOR pathway regulates cell growth,
proliferation and metabolism in sarcoma
• mTOR signaling
dysregulated in multiple
sarcomas
PI3K
PI3K
AKT
• Ridaforolimus: a
PTEN
TSC
mTOR
rapamycin analog and
potent mTOR inhibitor
Ridaforolimus
4E-BP1
FKBP
• Clinical activity in
sarcomas in Phase 1 and
2 studies
2
Ridaforolimus: antitumor activity in sarcoma
CT
PET
Baseline
Day 5
(53% )
Day 54
(85% )
3
Ridaforolimus: previous activity demonstrated
in sarcomas
Phase 1/2
Phase 2
Route of
ridaforolimus
Number and
diagnosis
Clinical
benefit rate
Rate of
PFS @
6 months
oral
147 all tumors
(85 sarcomas)
27%
23%
IV
212 sarcomas
29%
23%
EORTC historical review of sarcoma database for
“active” agents
14%
(Glabbeke, European Journal of Cancer 38 (2002) 543–549
Clinical benefit rate: CR+PR+SD >4 months
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Sarcoma standard care and the SUCCEED pivotal
Phase III trial design
Metastatic
sarcoma after 1-3
lines CT, per SOC
IRC
PD
Ineligible
CR, PR, SD
SOC watchful waiting
randomization
Ridaforolimus
Placebo
(40 mg QD x 5 per week)
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SUCCEED study endpoints
• Primary endpoint
– Improvement in PFS by independent radiology review
• Secondary endpoints
–
–
–
–
Overall survival
Best target lesion response
Cancer-related symptoms
Safety and tolerability
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Pivotal Phase III trial design
statistics and key features
• Statistical design: 650 patients with 90% power to
detect 33% improvement in PFS (516 PFS events,
=0.025, one-sided)
• Stratified for line of therapy, histology, and geography
• Two interim analyses
• 711 patients enrolled between Oct ‘07 and Jan ‘10;
702 patients received either ridaforolimus or placebo
• Largest randomized study ever in the soft tissue and
bone sarcoma population
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Patient characteristics were balanced
at study entry
Placebo
(N=364)
Ridaforolimus
(N=347)
P-Value
50.6 (15.0)
52.0 (16.0)
0.2360
Male/Female (%)
43/57
45/55
0.4969
0/1 (%)
50/50
50/50
1.0000
soft tissue/bone (%)
91/9
89/11
0.4476
1st/2nd or 3rd (%)
62/38
61/39
0.9386
Sarcoma grade
high/low (%)
73/6
74/4
0.7152
Metastatic sites
lung/liver (%)
64/19
67/14
0.5296
Age
mean (SD)
Gender
ECOG
Histology
Prior chemo
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PFS per independent radiology review
Independent Radiology Review (HR=0.72, p=0.0001)
PFS rate
Ridaforolimus
Placebo
Median PFS
17.7 weeks
14.6 weeks
3 mon 6 mon
70%
34%
54%
23%
Weeks
(Data cut-off date 10-25-2010)
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PFS per investigator assessment
Investigator Assessment (HR=0.69, p<0.0001)
PFS rate
Ridaforolimus
Placebo
Median PFS
22.4 weeks
14.7 weeks
3 mon 6 mon
72%
37%
55%
23%
Weeks
(Data cut-off date 10-25-2010)
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Consistent progression free survival
improvement across multiple subgroup analyses
favor rida
favor placebo
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SUCCEED: trend in Overall Survival (OS)
HR 0.88, p=0.2256
Median OS
ridaforolimus:
21.4 months
Placebo:
19.2 months
386 death events based on data cut-off date 4-30-2011
(6 months after PFS data cut-off date)
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Tumor response:
Clinical Benefit Rate (CBR) ≥ 4 months
CBR (CR+PR+SD)
Ridaforolimus
40.6%
Placebo
28.6%
p-Value
0.0009
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Exploratory analysis of cancer-related symptoms
• Questionnaires completed by the patients periodically in 3
categories: pain, cough and shortness of breath
• Vast majority (>90%) of patients who stayed on therapy
were free of severe symptoms in both treatment groups
– Small numerical imbalances favoring placebo at some time
points
• Large amount of missing information mainly due to
treatment discontinuation
– Greater in placebo patients over time
• Analysis is inconclusive due to large amount of missing
information
– Following disease progression, no information about
cancer-related progression was collected
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SUCCEED: ridaforolimus inhibited tumor growth
Waterfall plots
Best target lesion response
(mean)
Ridaforolimus -1.3%
Placebo
+10.3%
(p<0.0001)
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Survival following disease progression was
similar for the ridaforolimus and placebo groups
Post-progression survival = duration from disease
progression to death
HR=0.94 (95% CI [0.76, 1.18], p=0.6152)
Ridaforolimus
Placebo
Weeks
16
Adverse events noted during SUCCEED trial
MedDRA System Organ Class
Preferred Term
PERCENT of Patients
with ≥ 1 Adverse Event
Stomatitis
Infections (all sites included)
Fatigue
Thrombocytopenia
Diarrhea
Cough
Rash
Placebo (N=359)
All Grades Grade ≥ 3
(%)
(%)
94
26
18
26
22
4
18
16
6
<1
3
2
1
0
<1
0
Ridaforolimus (N=343)
All Grades Grade ≥ 3
(%)
(%)
100
64
61
52
36
34
32
31
28
9
6
3
10
3
<1
<1
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Adverse events reported with the class of
mTOR inhibitors
MedDRA System Organ Class
Preferred Term
Anemia
Hypertriglyceridemia
Hypercholesterolemia
Hyperglycemia
Renal and other urinary disorders
Pneumonitis
Placebo (N=359)
All Grades Grade ≥ 3
(%)
(%)
10
3
9
<1
5
0
3
<1
7
<1
<1
<1
Ridaforolimus (N=343)
All Grades Grade ≥ 3
(%)
(%)
28
7
27
2
21
<1
14
7
16
3
10
3
6 deaths due to “pulmonary disorders” with ridaforolimus vs. none in placebo.
1 drug-related pneumonitis, 2 pleural effusion , 1 pulmonary embolism,
2 respiratory distress
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Summary: Ridaforolimus improves disease
control to maintain benefit of prior therapy
• Study met the primary endpoint in PFS improvement
(HR 0.72, p=0.0001)
• Trend toward OS benefit (HR 0.88, p=0.2256)
• Better tumor growth control
• No adverse impact on survival following disease
progression
• No major unexpected AEs, and toxicities similar to
other mTOR inhibitors
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Acknowledgements
• All of the sarcoma patients and their families who
made this trial SUCCEED
• All of the worldwide investigators and study team
members
• The study sponsors, Merck and Ariad Pharmaceuticals
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Backup slides
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Comparison of Independent radiology review and
investigator assessment (concordance rate 80%)
Independent Radiology Review
(HR=0.72, p=0.0001)
Ridaforolimus
Placebo
Investigator Assessment
(HR=0.69, p<0.0001)
Ridaforolimus
Placebo
Weeks
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Efficacy result of pediatric populations
Ridaforolimus group
• 7 patients enrolled
• 64% tumor size reduction in
one osteosarcoma patient
• 1 PR, 4 SD, 2 PD
• CBR ≥ 4mos: 5/7 = 71%
• PFS durations: 59, 48, 23, 20,
19, 16, and 8 weeks
Placebo group
• 5 patients enrolled
• No Responder
• 1 SD, 4 PD
• CBR ≥ 4mos: 1/5 = 20%
• PFS durations: 20, 8, 4, 4,
and 4 weeks
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