Heme Onc Today New York Melanoma Meeting March 22-23, 2013 PD-1 antibodies

Heme Onc Today New York Melanoma Meeting March 22-23, 2013 PD-1 antibodies Jeffrey Weber Moffitt Cancer Center Tampa, FL

Disclosures I have consulted for BMS, Merck, Genentech and GSK for Ad Boards and DSMBs I have received less than $10,000 per year from any of the above I have served in the past on a Speaker s Bureau for Genentech My institution has received research funding from BMS, Merck, Genentech and GSK

PD-1: Role in T Cell Activation What is PD-1? Member of CD28 family involved in T cell regulation Expressed by activated T cells, memory T cells, and regulatory T cells Downregulates T cell activity upon binding to PD-L1/L2 Tumor PD-L1 expression may correlate with negative prognosis potential mechanism of tumor self-defense PD-1 = programmed death-1. Curran MA et al. PNAS. 2010;107:4275-4280.

PD-1 is Important for Immune Tolerance PD-1 is an activation antigen expressed on T and B lymphocytes PD-1 interacts with its ligands (PD-L1 and PD-L2) to inhibit activation of T lymphocytes & anti-tumor immune response Human cancers can hijack the PD-1 pathway PD-1 blockade may reactivate antitumor immunity Hamid, O et al SMR 2012

Study Design: Phase 1/2 Multi-Dose Regimen 8-week treatment cycle Rapid PD or clinical deterioration Off study Day 1 15 29 43 57 SCANS * * * * *Dose administered IV q2wk Unacceptable toxicity CR/PR/SD or PD but clinically stable Eligibility: Advanced MEL, RCC, NSCLC, CRC, or CRPC with PD after 1 to 5 systemic therapies Follow-up every 8 weeks x 6 (48 weeks) Treat to confirmed CR, worsening PD, unacceptable toxicity, or 12 cycles (96 weeks) MEL = malignant melanoma. Hodi FS et al. ASCO 2012 Annual Meeting. Abstract 8507.

BMS-936558: Treatment-Related Adverse Events Drug-Related Adverse Event Total Population* All Grades Grades 3-4 MEL Total Population No. (%) of Patients, All Doses MEL Any adverse event 207 (70) 82 (79) 41 (14) 21 (20) Fatigue 72 (24) 30 (29) 5 (2) 2 (2) Rash 36 (12) 21 (20) Diarrhea 33 (11) 18 (17) 3 (1) 2 (2) Pruritus 28 (9) 15 (14) 1 (0.3) Nausea 24 (8) 9 (9) 1 (0.3) 1 (1) Appetite decreased 24 (8) 7 (7) Hemoglobin decreased 19 (6) 7 (7) 1 (0.3) 1 (1) Pyrexia 16 (5) 5 (5) *AEs occurring in 5% of the total population. Common grade 3-4 AEs also included lymphopenia (3 patients) and abdominal pain and lipase increased (2 each). An additional 27 grade 3-4-related AEs were observed and one or more occurred in a single patient. Hodi FS et al. ASCO 2012 Annual Meeting. Abstract 8507; Topalian S et al NEJM 2012

Pneumonitis in pt on PD-1 ab over time Dec 1, 2011 Oct 11, 2011 Jun 30, 2011

Clinical Activity of BMS-936558 in Melanoma Patients Pop Dose (mg/kg) Patients n ORR n (%) Duration of Response (mo) SD 24 weeks n (%) PFSR at 24 weeks (%) All MEL 0.1-10 94 28 (31) 1.9+ to 24.9+ 6 (6) 41 0.1 14 4 (29) 5.6 to 7.5+ 1 (7) 40 0.3 16 3 (19) 1.9+ to 3.8+ 1 (6) 31 MEL 1 27 8 (30) 5.3+ to 24.9+ 3 (11) 45 3 17 7 (41) 9.2+ to 22.4+ 1 (6) 55 10 20 4 (20) 17.0 to 24.6+ 0 30 ORR was assessed using modified RECIST v1.0. Three melanoma patients had a persistent reduction in baseline target lesions in the presence of new lesions but were not classified as responders for the ORR calculation. Hodi FS et al. ASCO 2012 Annual Meeting. Abstract 8507; Topalian S et al NEJM 2012

Changes in Target Lesions Over Time in Melanoma Patients after BMS 936558 Hodi, S. et al ASCO 2012

PD-L1 Expression in Melanoma PD-L1-positive metastatic lesions correlated with improved survival in 56 patients with stage III-IV melanoma 1 In patients with MEL, NSCLC, CRC, RCC, or CRPC treated with BMS-936558 (n = 42), PD-L1 expression in pretreatment tumor biopsies was associated with clinical outcomes, 17 IHC-negative biopsies with zero responses and 25 IHC-positive biopsies with 9 responses (36%) 2,3 Further studies in melanoma patients are planned to define the role of PD- L1 as a potential molecular marker of response to BMS-936558 Melanoma Immunohistochemical staining with anti-pd-l1 monoclonal antibody 5H1 of melanoma lymph node metastasis 4 1. Taube JM et al. Sci Transl Med. 2012;4:127ra37; 2. Topalian SL et al. ASCO 2012 Annual Meeting. Abstract 2509; 3. Hodi FS et al. ASCO 2012 Annual Meeting. Abstract 8507; 4. Topalian SL et al. N Engl J Med. 2012 Jun 2 [Epub ahead of print].

Phase I Trial Of PD-1 Antibody BMS 936558 With Vaccine Patients were all HLA A*0201 positive and failed at least one prior regimen, but had not received ipilimumab 34 patients were treated at 1, 3 and 10 mg/kg PD-1 antibody every 2 weeks for 12 weeks with a multi-peptide vaccine Up to two cycles given for 24 weeks, then patients that were stable or better were boosted every 12 weeks for up to 2 years Peptides included gp100 209-217 (210M), gp100 280-288 (288V), NY ESO-1 157-165 (165V), and MART-1 26-35 (27L) all emulsiified in Montanide ISA 51VG Leukapheresis done at week 0, 12 and 24 for T cell assays New cohorts include those who are HLA A2 positive and had either no, or dose limiting prior ipi toxicity, or are A2 negative and had no ipi dose limiting iraes From Kudchadkar, R et al ASCO 2012

Demographics of patients receiving PD-1 antibody with a peptide vaccine Characteristic Sex Male Female Ethnicity Not Hispanic or Latino Hispanic or Latino Age Median (range), years <65 years 65 years BRAF mutational status Non-mutated Mutated Unknown Metastatic (M) classification at diagnosis M1a M1b M1c Serum LDH No data Normal (<250 U/L) Elevated Origin of melanoma Cutaneous Ocular Unknown Primary N 18 16 34 0 59 (16-87) 22 12 19 8 7 1 1 32 1 1 32 25 5 4 From Kudchadkar, R et al ASCO 2012

Toxicities of PD-1 antibody with vaccine Adverse event Number of Patients, n (%) 1 mg/kg (n = 10) 3 mg/kg (n = 13) 10 mg/kg (n = 11) Grade 1 Grade 2 Grade 3 Grade 4 Grade 1 Grade 2 Grade 3 Grade 4 Grade 1 Grade 2 Grade 3 Grade 4 Fatique 7 (70%) 0 0 0 5 (42%) 2 (17%) 0 0 8 (67%) 0 0 0 Injection site reaction 4 (40%) 1 (10%) 0 0 6 (50%) 2 (17%) 0 0 5 (42%) 1 (8%) 0 0 Fever 3 (30%) 0 0 0 1 (8%) 1 (8%) 0 0 1 (8%) 0 0 0 Chills 1 (10%) 0 0 0 1 (8%) 0 0 0 2 (17%) 0 0 0 Infusion reaction 0 0 0 0 0 0 0 0 1 (8%) 0 0 0 Rash 3 (30%) 0 0 0 1 (8%) 1 (8%) 0 0 4 (33%) 0 0 0 Pruritis 2 (20%) 0 0 0 0 0 0 0 0 0 0 0 Diarrhea 5 (50%) 0 0 0 3 (25%) 1 (8%) 0 0 2 (17%) 0 0 0 Nausea 4 (40%) 0 0 0 4 (33%) 1 (8%) 0 0 1 (8%) 0 0 0 Dyspnea 1 (10%) 0 0 0 1 (8%) 1 (8%) 0 0 1 (8%) 0 0 0 Pneumonitis 0 0 0 0 1 (8%) 0 1 (8%) 0 0 0 0 0 Arthralgia 0 1 (10%) 0 0 1 (8%) 0 0 0 0 0 0 0 Thyroiditis 0 0 0 0 1 (8%) 0 0 0 1 (8%) 0 0 0 Eye pain 1 (10%) 0 0 0 0 0 1 (8%) 0 0 0 0 0 From Kudchadkar, R et al ASCO 2012

From Kudchadkar, R et al ASCO 2012 Clinical efficacy of PD-1 antibody with a peptide vaccine 1 CR and 8 PR of 34 patients evaluated for response 3 patients were stable for 24 weeks ORR = 28% with DCR (CR+PR+SD) = 35% The drug was well tolerated for up to 84 weeks, with no MTD reached; one episode of grade three optic neuritis and one grade three pulmonary toxicity observed, one DLT at 3 mg/kg Thyroiditis, hypophysitis, fatigue, pulmonary toxicity, rash and fevers observed

PR CR SD PD 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 Days on study From Kudchadkar, R et al ASCO 2012

Box Plot: Pre-treatment NY-ESO-1(157-165V) tetramer positive CD8 T cells Percentage (%) 3 P=0.0008 2 NY-ESO-1 1 0 Responders Non-Responders From Kudchadkar, R et al ASCO 2012

Changes in T reg and CTLA-4 expressing cells are associated with response with BMS 936558 Decreased T regs and response p=0.001 Decreased CTLA-4/CD8 T cells and response p=0.01 From Kudchadkar R et al ASCO 2012

Regression With Ipilimumab After Failing Anti-PD-1 Ab Pretreatment 5-18-11 Postcycle 1 ipilimumab 8-16-11 From Kudchadkar R et al ASCO 2012

%-PD-1 on CD4+ T cells %-PD-1 on CD4+ T cells Changes in PD-1 on CD4 T cells induced by ipilimumab at 3 and 6 months PD-1 induction by ipilimumab treatment on CD4+ T cells 40 P=0.0029 20 P<0.0001 30 15 20 10 10 5 0 pre 3-mon 0 pre N=22 N=33 6-mon Weber, J et al unpublished data 2013

CT scans pre- and 12 weeks post PD-1 ab after failing TIL and ipilimumab Pre-treatment Post-treatment week 12

Re-induction therapy with anti-pd-1 antibody: similar kinetics to ipilimumab? Lipson, E et al CCR 2012

Future Plans: BMS 936558 Phase II trial of simultaneous PD-1 ab and ipilimumab Phase II trial of sequential reciprocal PD-1 ab and ipilimumab Phase III 2:1 randomized second line trial of PD-1 ab at 3 mg/kg versus investigator s choice chemotherapy Pivotal phase III randomized first line trial of PD-1 ab at 3 mg/kg versus dacarbazine (ex-us) Pivotal phase III randomized first line trial of PD-1 ab at 3 mg/kg versus ipilimumab versus the combination

MK-3475 is a High-Affinity Humanized IgG4 PD-1 Blocking Antibody Mouse variable (CDR) sequences grafted onto human framework Parental Antibody Mouse IgG1 K D : ~28 pm IC50: ~800 pm EC50: ~118 pm MK-3475 Human IgG4 K D : ~29 pm IC50: ~600 pm EC50: ~70 pm Similar reactivity to human and cynomolgus PD-1, no reactivity to mouse or rat PD-1 Humanized IgG4 - no cytotoxic (ADCC/CDC) activity Contains stabilizing S228P sequence alteration Hamid, O et al SMR 2012

Phase I PD-1 Antibody MK-3475 Cohorts of 3-6 patients were enrolled (3+3 design) at escalating IV doses of 1, 3, and 10 mg/kg IgG4 human MoAb Nine patients, 3 at each dose level, completed the dose-limiting toxicity (DLT) period (28 d). Patients had non small cell lung cancer (NSCLC, n=3), rectal cancer (n=2), melanoma (MEL, n=2), sarcoma (n=1), or carcinoid (n=1). Drug-related adverse events (AEs) included Grade 1 fatigue (n=3), nausea (n=2), diarrhea (n=1), dysgeusia (n=1), breast pain (n=1), and pruritus (n=1). One drug-related Grade 2 AE of pruritus was reported. No drug-related AEs Grade 3 seen Updated melanoma data show 10 pts treated, one ucr, 3 uprs, 2 SD, an excellent record At 10 mg/kg, half life of the antibody was 13.6 days Patnaik, J et al ASCO 2012

Patient Characteristics Part B Total Enrollment: Dec, 2011 through July, 2012 Median Age Male Female ECOG PS 0 PS 1 Unknown 10.0 mg/kg every 2 week (FPI: Dec, 2011) 10.0 mg/kg every 3 week (FPI: Jan, 2012) 2.0 mg/kg every 3 week (FPI: May, 2012) B-raf mutation status Yes No Unknown Prior therapy with IPI Prior therapy with B-raf or/and MEK inhibitors N= 132 N=57 (43.2%) N=54 (40.9%) N=21 (15.9%) 63.0 yrs-old N=77 (58.3%) N=55 (41.6%) N=93 (70.4%) N=36 (27.3%) N=3 (2.3%) N=26 (19.7%) N=88 (66.7%) N=18 (13.6%) N=48 (36.3%) N=4 (3.0%) Hamid, O et al SMR 2012 FPI = First Patient In (dosed)

Immune-Related Adverse Events per Investigator Assessment; Overall Incidence 2 Patients Part B: All Melanoma Patients: N=132 Adverse Events All Grades Grades 3-5 All AEs All AEs N (%) N (%) Any Immune Adverse Event 21 (15.9) 7 (5.3%) Rash 6 (4.5%) 0 Influenza 4 (3.0%) 0 Pruritus 3 (2.2%) 0 Eczema 3 (2.2%) 0 Vitiligo 3 (2.2%) 0 Hypothyroidism 3 (2.2%) 1 (0.7%) Pyrexia 2 (1.5%) 0 Arthralgia 2 (1.5%) 0 Myositis 2 (1.5%) 0 Cough 2 (1.5%) 0 Hamid, O et al SMR 2012 Patients who started treatment with MK-3475 before July 31, 2012 and have entered data by Sept 28, 2012

Best Overall Response of MK-3475 (Unconfirmed + Confirmed Responses) in Advanced MEL Patients (Part B; based on immune related Response Criteria*) Complete Response (N, 95% CI) Objective Response (N, 95% CI) Disease Control Rate (N, 95% CI) All MEL N=85 9% (8; 4% -18%) 51% (43; 39 % -61%) 59% (50; 48% -69%) IPI Naïve N=58 14% (8; 6% -25%) 55% (32; 41% -68%) 64% (37; 50% -76%) IPI Treated N=27 0% (0) 41% (11; 22% -61%) 48% (13; 29% -68%) All patients were dosed at 10 mg/kg Includes all patients who received first dose as of April 25, 2012. Investigator reported response information as of October 19, 2012. Objective response= confirmed and unconfirmed complete and partial response Disease control rate= Objective response + stable disease *irrc: Wolchok, JD, Hoos, A, O Day S, et al., Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune- Related Response Criteria. Clinical Cancer Research, 2009 Dec 1;15(23):7412-20. Epub 2009 Nov 24) Hamid, O et al SMR 2012

% Change from Baseline (sum of longest diameters) Maximum Percent Change from Baseline in Tumor Burden by irrc (Central Review Part B) 560 500 * Hamid, O et al SMR 2012 Individual Patient ** *0 % change in tumor burden **Skin only disease (n=1) with complete regression All patients are dosed at 10mg/kg

Characteristics of Responses: Time to Respond & Duration for 43 Patients with Objective Response Hamid, O et al SMR 2012 IPI naive IPI treated Complete Response Partial Response On Study Median duration of treatment, 7.6 months (3.3-11) one patients discontinued due to PD and four patients discontinued due to AEs 0 4 8 12 16 20 24 28 32 36 40 44 48 52 On Treatment Duration in Weeks

Future plans: Randomized phase II Study of MK-3475 versus Chemotherapy in Patients with Advanced Melanoma (P08719/MK-3475-002) R A N D O M I Z A T I O N 1:1:1 MK-3475 at 2 mg/kg MK-3475 at 10 mg/kg Chemotherapy treatment of Investigator choice PD Crossover Eligibility MK-3475 Main objective To evaluate clinical efficacy (ORR, PFS, and OS) in patients with previously treated advanced melanoma receiving either MK-3475 or chemotherapy Hamid, O et al SMR 2012

Conclusions BMS 936558 with vaccine at 1, 3 or 10 mg/kg has a 28% RECIST ORR in previously treated, ipilimumab naïve melanoma, and 31% ORR at 0.3 to 10 mg/kg; 3 mg/kg had the best efficacy Only one DLT of 34 patients observed in the 12 week DLT period in the Moffitt trial: optic neuritis, two other patients had grade 3 pneumonitis between 12 and 24 weeks MK-3475 has a 30-50% ORR by irrc in ipi naïve or experienced patients Both are generally well tolerated, with excellent duration of response Increased CD4/CD8+ CTLA-4+ T cells and increased T regulatory cells found in non-responders to BMS 936558 with vaccine These biomarker data support sequencing trials of PD-1 antibodies and ipilimumab and suggest predictive markers to be evaluated

Acknowledgements MacLean Hall Jay Martinez Bin Yu Wenshi Wang Amod Sarnaik Donna Gallenstein Patricia Urbas Ragini Kudchadkar Geoffrey Gibney Nursing staff Clinic 5 Tissue Core Acquisition Jodi Kroeger Kate Shapland Shari Pilon-Thomas James Mulé Vernon Sondak Jonathan Zager Ricardo Gonzalez National Cancer Institute Donald A. Adam Comprehensive Melanoma Research Center grant