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

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Results of the Phase 3, placebo-controlled trial
(SUCCEED) evaluating the mTOR inhibitor
ridaforolimus as maintenance therapyin advanced
sarcoma patientsfollowing clinical benefit
fromprior 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
• Ridaforolimus a rapamycin analog and potent mTOR
  inhibitor
• Clinical activity in sarcomas in Phase 1 and 2
  studies

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Ridaforolimus antitumor activity in sarcoma
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Ridaforolimus previous activity demonstrated in
sarcomas
Clinical benefit rate CRPRSD gt4 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
PD
Ineligible
IRC
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
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PFS per independent radiology review
Independent Radiology Review (HR0.72, p0.0001)
PFS rate Median PFS 3 mon
6 mon Ridaforolimus 17.7 weeks 70
34 Placebo 14.6 weeks 54
23
Weeks
(Data cut-off date 10-25-2010)
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PFS per investigator assessment
Investigator Assessment (HR0.69, plt0.0001)
PFS rate Median PFS 3 mon
6 mon Ridaforolimus 22.4 weeks 72
37 Placebo 14.7 weeks 55
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Weeks
(Data cut-off date 10-25-2010)
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Consistent progression free survival improvement
across multiple subgroup analyses
favor placebo
favor rida
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SUCCEED trend in Overall Survival (OS)
HR 0.88, p0.2256 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
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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 (gt90) 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 (plt0.0001)
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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

HR0.94 (95 CI 0.76, 1.18, p0.6152)
Ridaforolimus Placebo
Weeks
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Adverse events noted during SUCCEED trial
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Adverse events reported with the class of mTOR
inhibitors
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, p0.0001)
• Trend toward OS benefit (HR 0.88, p0.2256)
• 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
(HR0.72, p0.0001)
Ridaforolimus Placebo
Investigator Assessment (HR0.69, plt0.0001)
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