IPILIMUMAB UPDATE

Current Status

• GLOBAL STUDY

– 17 COUNTRIES : NORTH AMERICA, EU, AUSTRALIA– Canada 6 sites

• PATIENTS ENROLLED (as of May 19, 2009 9:20 am EST)

Global Canada– 91 Enrolled 1 Enrolled– 23 Screen Failures 1 Screen Failure– 57 Randomized 0 Randomized

Immune Modulation Via Anti-CTLA-4

Antigen-releaseFrom Cancer Cells

APC

CD28TCR

B7-1,2Peptide/MHC

Tumor

CTLA-4

Attenuated or TerminatedProliferation

APC

IL-2

UnrestrainedProliferation

Courtesy of Jim Allison

ipilimuamb

T cellT cell

Benefit : Risk Study CA184-022

CA184022 (N=217)

10 mg/kg(N=72)

3 mg/kg

(N=72)

0.3 mg/kg

(N=73)

BORR a

(95% CI)

11.1%

(4.9, 20.7)

4.2%

(0.9, 11.7)

0

Overall Survival, median months

11.0

(6.9, NR)

8.7

(6.9, 12.1)

8.6

(7.4, 13.0)

Overall irAE rate 70% 65% 26%

Grade3/4 irAE rate 25% 7% 0

Drug-related Deaths (<70 days) 0 0 0

aTrend test: statistically significant trend (P = 0.0015) indicating a dose effect in favor of 10 mg/kg,

which was influenced by the large difference between 10 mg/kg and 0.3 mg/kg.

Integrated Response Data Independent Radiologist Assessment (n=227)

• 21 patients (9.3%) had PR after PD diagnosis at Week 12

Studies CA184-008 and CA184-022

10 mg/kg only(N=227)

Best overall response rate 7.5 %

Disease control rate, 27.8 %

Best overall response, n (%) Complete response

Partial response

Stable disease

Progressive disease

Unknown

2 (0.9)

15 (6.6)

46 (20.3)

123 (54.2)

41 (18.1)

CA184007 (10mg/kg+placebo)

CA184008 (10mg/kg)

CA184022 (10mg/kg)

HISTORICAL

1-year overall survival rate with 95% CI

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Ipilimumab and Comprehensive Historical Data:Survival at 1 Year

Historical (42 Phase 2 Trials, N=2100): Korn EL, et al. J. Clin. Oncol. 2008;26:527-534.

*CA184-007: pretreated population 10mg/kg + placebo (N=25): Median OS 14.8 mo. (6.6 - 20.5), 1-y survival 50.8% (30.0 - 69.2)

SAFETY

irAE = any adverse event associated with drug exposure and consistent with an immune mechanism after disease progression, infections etc are ruled out or deemed unlikely as contributing to the event

• Immune in nature and presumably a consequence of the intrinsic biological activity of ipilimumab.

• Supportive data, (autoimmune serology tests, biopsies): helpful but not necessary to deem an event an irAE

What is an immune related AE?

Most frequent immune related AE

•4 main categories of irAEs at the program wide level– Skin events: Rash/pruritis– GI events: Diarrhea– Hepatotoxicity– Endocrinopathy

•Algorithms for patient management are available for PIs and site personal

Safety and Tolerability of 10mg/kg (N=325)

• Drug-related adverse events (AEs) in 84.6% of patients

– 32.6% were Grade 3/4/5

• Immune-related AEs (irAEs) in 72.3% of patients

– 25.2% were Grade 3/4 and occurred in 4 main types

• Gastrointestinal (12.3%); Liver (6.8%); Skin (2.8 %); Endocrine (2.5%)

• Complications: ~1%

• 5 deaths were considered at least possibly related to treatment

– 4 immune-related:

• multi-organ failure, hypovolemic shock, abnormal hepatic function, and acute glomerulonephritis

– 1 not immune-related:

• acute myeloid leukemia

Summary - safety

• Patient education is very important

• Most drug-related AEs were consistent with immune-mediated events and likely related to the drug

• irAEs were manageable and generally reversible within 2–6 weeks

• Complications were rare

• Management algorithms are effective in controlling adverse events and avoiding complications (e.g. perforation)

Time to onset of irAEs

Median time to onset, weeks

(n , 95% CI)

Type Grade 2-5 Grade 3-5

Skin

3.6

(61, 3.1–4.1)

4.4

(9, 3.1–4.4)

GI

6.6

(76, 5.1–8.0)

6.9

(40, 5.7–8.9)

Liver

6.7

(23, 6.1–9.3)

6.7

(23, 6.1–9.7)

Endocrine 9.2

(16, 6.7–11.1)

10.1

(8, 7.0–11.4)

Lebbé, C et al. Perspectives in Melanoma XII 2008; Abstract O-015.

Time to ResolutionGrade 2-4 irAEs – 10 mg/kg

Monotherapy 10mg/kg treated subjects

Censored

Monotherapy 10mg/kg treated subjects

Censored

Median: 2.29 weeks Median: 4.00 weeks

Median: 20.1 weeks

GI Liver

Endocrine

Median: 6.14 weeks

Skin

Pro

po

rtio

n n

ot

reso

lved

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Subjects at riskno Tx 10mg/kg 76 49 28 2116 10 8 6 5 5 5 4 4 4 4

Monotherapy 10mg/kg treated subjects

Censored

Week30 32 34 36 38 40 42 44 46 48 50 52 54

4 2 2 2 2 2 2 2 2 1 1 1 0 22 17 11 8 7 6 5 3 1 1 1 1 0

Monotherapy 10mg/kg treated subjects

Censored

Pro

po

rtio

n n

ot

reso

lved

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Subjects at riskno Tx 10mg/kg 16 14 13 11 9 9 8 8 7 6 6 5 4 4 3

Week

30 32 34 36 38 40 42 44 46 48 50 52 54

3 3 1 1 1 1 1 1 1 1 1 1 0

Pro

po

rtio

n n

ot

reso

lved

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 2 4 6 8 10 12 14 16 18 20 22 24 26 28

615439 31251716 151211 9 9 7 7 6

Week

30 32 34 36 38 40 42 44 46 48 50 52 54 56

4 3 2 2 1 1 1 1 1 1 1 1 1 0

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Week0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54

Lebbé, C et al. Perspectives in Melanoma XII 2008; Abstract O-015.

Safety surveillance

•Review safety lab data before treatment •Continue irAEs monitoring

At the patient level

•Stringent treatment discontinuation guidelines

•Patient education on irAEs is a must

•Early diagnosis and prompt treatment is the key to control irAEs•Treatment of an irAE per algorithm is highly recommended

•irAE low grade•vigilance •In some cases low dose steroids

•irAE high grade•Vigilance, some cases hospitalization •Most cases require high dose steroids

•Seeking specialist consult is highly recommended

Ipilimumab in the Adjuvant Setting

PROTOCOL : CA184-029

• Primary: Recurrence*-free survival

• Secondary:

– Overall survival

– Distant metastases-free survival

– Adverse event profile

– Quality of life

– Quality-of-life-adjusted-survival

* Recurrence: Appearance of one or more new melanoma lesions: local, regional or distant

Key Safety and Efficacy Variables

• ≥ 18 years with complete and adequate resection of Stage III melanoma

– Histological confirmed cutaneous melanoma, metastatic to lymph node

– Stage IIIA (if N1a, at least 1 metastasis > 1mm); any Stage IIIB or IIIC

– No in-transit metastases/Satellite metastases

– No mucosal/ocular or melanoma of unknown origin

– Documented disease-free (operating report or pathology report)

– Full lymphadenectomy must be performed within 12 weeks prior to randomization. ** Specifications for the management of lymph nodes are in Appendix J of the

protocol.

– No prior therapy for melanoma except surgery

– No non-oncology vaccines can be used 4 weeks prior or after any dose of study drug

– No autoimmune disease. *Patients with vitiligo are eligible

Patient Selection Criteria

Trial design (before treatment)

Max 7 days

C O N S E N T

Max 13 weeks

S U R G E R Y

T R E A T M E N T

R A N D O M I Z A T I O N

D1

Max 12 weeks

Screening phase Referral time

RANDOMIZATION

WE

E

K

12

END

OF

TREA TMENT

INDUCTION PHASE

•1 administration every 21 days

•D1, D22, D43, D64

MAINTENANCE PHASE

•1 administration every 12 wks

• up to 3 years

•or until disease progression, unacceptable toxicity or withdrawal

Trial design (treatment)

...

END

OF

TREA TMENT

FOLLOW UP

•Every 12 wks

• up to 3 yrs or distant progression

• then every 24 wks

Trial design (follow up)

...

Treatment Withdrawal:

Patients will discontinue treatment and move to Follow-up Phase in the event of:

– Recurrence (local, regional or distant metastases)

– A major protocol violation (impact patient safety)

– Unacceptable toxicity or an Adverse Event that is possibly, probably, or certainly related to treatment and meets one of the criteria that is listed in the protocol, sections 5.6.3, 5.6.4 or 5.8.1

– When in the Investigators opinion it is in the best interest of the subject

– Treatment refusal or pregnancy

– Unblinding

1. Institutional standard of care2. Is the placebo arm justified?3. Satellite Mets4. melanoma of unknown primary5. Prior radiotherapy6. Safety profile7. Others?

1 Lens M, J of Clin Onc, 2002

MOST FREQUENTLY ASKED QUESTIONS “group discussion”

Satellite Mets

THANK YOU