IPILIMUMAB UPDATE

Current Status GLOBAL STUDY –17 COUNTRIES : NORTH AMERICA, EU, AUSTRALIA –Canada 6 sites PATIENTS ENROLLED (as of May 19, :20 am EST) GlobalCanada –91 Enrolled1 Enrolled –23 Screen Failures1 Screen Failure –57 Randomized0 Randomized

Immune Modulation Via Anti-CTLA-4 Antigen-release From Cancer Cells APC CD28 TCR B7-1,2 Peptide/MHC Tumor CTLA-4 Attenuated or Terminated Proliferation APC IL-2 Unrestrained Proliferation Courtesy of Jim Allison ipilimuamb T cell

Benefit : Risk Study CA CA (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 rate70%65%26% Grade3/4 irAE rate25%7%0 Drug-related Deaths (<70 days)000 a Trend test: statistically significant trend (P = ) 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 CA and CA mg/kg only (N=227) Best overall response rate7.5 % 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)

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: *CA : pretreated population 10mg/kg + placebo (N=25): Median OS 14.8 mo. ( ), 1-y survival 50.8% ( )

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) TypeGrade 2-5Grade 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) Endocrine9.2 (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 Resolution Grade 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 GILiver Endocrine Median: 6.14 weeks Skin Proportion not resolved Subjects at risk no Tx 10mg/kg Monotherapy 10mg/kg treated subjects Censored Week Monotherapy 10mg/kg treated subjects Censored Proportion not resolved Subjects at risk no Tx 10mg/kg Week Proportion not resolved Week Week 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 : CA

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

Stratification factors: Stage Region ( Region (North America, Europe, Australia)

≥ 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)

RANDOMIZATIONRANDOMIZATION W E E K 12 ENDOFTREATMENT ENDOFTREATMENT 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)...

ENDOFTREATMENT ENDOFTREATMENT 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, or –When in the Investigators opinion it is in the best interest of the subject –Treatment refusal or pregnancy –Unblinding

1.Institutional standard of care 2.Is the placebo arm justified? 3.Satellite Mets 4.melanoma of unknown primary 5.Prior radiotherapy 6.Safety profile 7.Others? 1 Lens M, J of Clin Onc, 2002 MOST FREQUENTLY ASKED QUESTIONS “group discussion”

Satellite Mets

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