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Results of the Phase 3, placebo-controlled trial Results of the Phase 3, placebo-controlled trial (SUCCEED) evaluating the mTOR inhibitor (SUCCEED) evaluating the mTOR inhibitor

ridaforolimus as maintenance therapyridaforolimus as maintenance therapyin advanced sarcoma patientsin advanced sarcoma patientsfollowing clinical benefit fromfollowing clinical benefit from

prior standard cytotoxic chemotherapy 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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• mTOR signaling dysregulated in multiple sarcomas

• Ridaforolimus: a rapamycin analog and potent mTOR inhibitor

• Clinical activity in sarcomas in Phase 1 and 2 studies

The PI3K-AKT-mTOR pathway regulates cell growth, The PI3K-AKT-mTOR pathway regulates cell growth, proliferation and metabolism in sarcomaproliferation and metabolism in sarcoma

PI3K

4E-BP1

TSC

Ridaforolimus

mTOR

FKBP

PTEN

PI3K

AKT

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Ridaforolimus: antitumor activity in sarcomaRidaforolimus: antitumor activity in sarcoma

CT

PET

Baseline Day 5(53% )

Day 54(85% )

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Ridaforolimus: previous activity demonstrated Ridaforolimus: previous activity demonstrated in sarcomasin sarcomas

Route of ridaforolimus

Number and diagnosis

Clinical benefit rate

Rate ofPFS @

6 months

Phase 1/2 oral 147 all tumors(85 sarcomas)

27% 23%

Phase 2 IV 212 sarcomas 29% 23%

EORTC historical review of sarcoma database for “active” agents (Glabbeke, European Journal of Cancer 38 (2002) 543–549

14%

Clinical benefit rate: CR+PR+SD >4 months

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PD

Metastatic sarcoma after 1-3 lines CT, per

SOC Ineligible

Ridaforolimus Placebo (40 mg QD x 5 per week)

SOC watchful waiting

IRCCR, PR, SD

randomization

Sarcoma standard care and the SUCCEED pivotal Sarcoma standard care and the SUCCEED pivotal Phase III trial design Phase III trial design

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SUCCEED study endpointsSUCCEED 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 Pivotal Phase III trial design statistics and key featuresstatistics 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 Patient characteristics were balanced at study entryat study entry

Placebo (N=364)

Ridaforolimus (N=347) P-Value

Age mean (SD)

50.6 (15.0)

52.0 (16.0)

0.2360

Gender Male/Female (%)

43/57

45/55

0.4969

ECOG 0/1 (%)

50/50 50/50 1.0000

Histology soft tissue/bone (%) 91/9 89/11 0.4476

Prior chemo 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

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PFS per independent radiology reviewPFS per independent radiology review

Independent Radiology Review (HR=0.72, p=0.0001)

Weeks

(Data cut-off date 10-25-2010)

PFS rate Median PFS 3 mon 6 mon

Ridaforolimus 17.7 weeks 70% 34%Placebo 14.6 weeks 54% 23%

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PFS per investigator assessmentPFS per investigator assessment

Weeks

Investigator Assessment (HR=0.69, p<0.0001)

(Data cut-off date 10-25-2010)

PFS rate Median PFS 3 mon 6 mon

Ridaforolimus 22.4 weeks 72% 37%Placebo 14.7 weeks 55% 23%

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Consistent progression free survival Consistent progression free survival improvement across multiple subgroup analysesimprovement across multiple subgroup analyses

favor rida favor placebo

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SUCCEED: trend in SUCCEED: trend in Overall Survival (OS)Overall Survival (OS)

386 death events based on data cut-off date 4-30-2011 (6 months after PFS data cut-off date)

HR 0.88, p=0.2256Median OS

ridaforolimus: 21.4 monthsPlacebo: 19.2 months

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Tumor response: Tumor response: Clinical Benefit Rate (CBR) ≥ 4 monthsClinical 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 Exploratory analysis of cancer-related symptomssymptoms

• 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 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 Survival following disease progression was similar for the ridaforolimus and placebo groupssimilar for the ridaforolimus and placebo groups

Post-progression survival = duration from disease Post-progression survival = duration from disease progression to deathprogression to death

HR=0.94 (95% CI [0.76, 1.18], HR=0.94 (95% CI [0.76, 1.18], p=0.6152) p=0.6152) Ridaforolimus

Placebo

Weeks

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Adverse events noted during SUCCEED trialAdverse events noted during SUCCEED trial

MedDRA System Organ Class Preferred Term

Placebo (N=359) Ridaforolimus (N=343)All Grades

(%)Grade ≥ 3

(%)All Grades

(%)Grade ≥ 3

(%) PERCENT of Patients

with ≥ 1 Adverse Event94 26 100 64

Stomatitis

18 <1 61 9

Infections (all sites included)

26 3 52 6

Fatigue

22 2 36 3

Thrombocytopenia

4 1 34 10

Diarrhea

18 0 32 3

Cough

16 <1 31 <1

Rash

6 0 28 <1

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Adverse events reported with the class of Adverse events reported with the class of mTOR inhibitors mTOR inhibitors

MedDRA System Organ Class Preferred Term

Placebo (N=359) Ridaforolimus (N=343)All Grades

(%)Grade ≥ 3

(%)All Grades

(%)Grade ≥ 3

(%) Anemia

10 3 28 7

Hypertriglyceridemia

9 <1 27 2

Hypercholesterolemia

5 0 21 <1

Hyperglycemia

3 <1 14 7

Renal and other urinary disorders

7 <1 16 3

Pneumonitis <1 <1 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 Summary: Ridaforolimus improves disease control to maintain benefit of prior therapycontrol 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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AcknowledgementsAcknowledgements• 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 slidesBackup slides

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Comparison of Independent radiology review and Comparison of Independent radiology review and investigator assessment (concordance rate 80%)investigator assessment (concordance rate 80%)

Weeks

Investigator Assessment (HR=0.69, p<0.0001)

Ridaforolimus Placebo

Independent Radiology Review (HR=0.72, p=0.0001)

Ridaforolimus Placebo

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Efficacy result of pediatric populationsEfficacy result of pediatric populationsRidaforolimus 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