Disclosures Consulting fees from: Bristol Myers Squibb, Genentech, - PDF document

Winship Cancer Institute of Emory University Immune ‐ Based Therapeutic Approaches in Genitourinary Malignancies Michael B. Atkins, MD Professor of Medicine Deputy Director Georgetown ‐ Lombardi Comprehensive Cancer Center Disclosures • Consulting fees from: Bristol Myers ‐ Squibb, Genentech, GlaxoSmithKline, Merck, Novartis, and Pfizer Page 1

Immunotherapy for GU Cancer RCC ● High Dose IL-2: – Contemporary clinical experience – Patient Selection opportunities ● Vaccine Approaches ● Checkpoint inhibitors – Anti-CTLA4 – PD1 pathway blockade Bladder Cancer RCC: Eight Years of Impressive Progress Setting Phase III Alternative Sunitinib Good or Pazopanib intermediate HD IL-2 1st-Line risk* Bevacizumab + IFN  Therapy Poor risk* Temsirolimus Sunitinib Sunitinib or Prior cytokine Sorafenib bevacizumab Everolimus Prior VEGFR 2nd-Line Clinical Trials Therapy inhibitor Axitinib Prior mTOR Clinical Trials inhibitor Does Immunotherapy have any role? Page 2

High-Dose IL-2 Therapy: RCC Response Durations-255 RR 15% (37/255); 7% CR Durable Responses in almost 50% of responding patients Median Response Duration –54 months Median Survival 16 mos CWG Phase III RCC: PFS Proportion alive and free from progression 1.0 HD IL-2 Median PFS IL-2 and IFN IL-2/IFN 3.1 mos 0.8 HD IL-2 3.1 mos 0.6 0.4 0.2 0.0 72 0 12 24 36 36 48 48 60 60 72 Time from randomization (months) Page 3

Combined UCLA/DFHCC Model + CA-9 Staining Pathology Low High Risk Group Good Intermed Intermed Good Poor Poor Atkins, et al Clin Can Res, 2005 Activity of IL-2 is greater than package Insert Response* % Historical rate 14 IL-2 Select Trial (all pts n=120)* 28 p=0.0016 95% CI=20.5-37.3% Likely explanations for improved RR include: 1) Enhanced “ pre-screening ” - smaller non-clear cell population 2) Impact of alternative therapies on IL-2 referral patterns 3) Application of debulking nephrectomy - fewer patients treated with primary in place *Using WHO Criteria McDermott et al ASCO 2010 Page 4

Response by Tumor Features Tumor risk group RR (95% CI) P-value * 27% (6%-61%) 0.89 Good (n=11) 24% (15%-35%) Intermediate (n= 83) 28% (12%-49%) Poor (n=25) CA-9 Score 22% (13%-33%) 0.19 High (>85% n=77) 33% (19%-50%) Low (<85% n=39) Combined Score Good (n=74) 23% (14%-34%) 0.39 Poor (n=42) 30% (17%-46%) IL-2 Select Trial: Commentary • Potential explanations for this result: – Tumor factors are important but markers other than CA-9 will be more predictive – Samples analyzed are not “representative” given the lack of standards for tumor processing at community centers – Host factors (e.g. patient immune response, tumor microenvironment) may play are larger role in determining response Page 5

Response to IL-2 may be associated with tumor expression of PD-L1/B7H3 RR p-value* PD-L1 Tumor Negative (n=95) 19% 0.012 Positive (n=18) 50% B7H3 Tumor Negative (n=28) 10.7% 0.075 Positive (n=85) 29.4% IHC performed at Mayo Clinic by Kwon, Leibovich, et al. Vaccines for RCC IMA-901 phase 2 study N  68 Cyclophosphamide  Advanced RCC (300 mg/m 2 single infusion) +  HLA-A*02 + IMA-901 + GM-CSF  Prior cytokine or 1:1 TKI therapy  Measurable lesion(s) IMA-901 + GM-CSF  Documented progression IMA-901 delivered via 17 intradermal vaccinations over 9 months. Primary endpoint: Disease control rate Secondary endpoints: ORR, DoR, TTP, PFS, OS, safety Page 6

Vaccines for RCC IMA-901 phase 2 study • PFS was comparable in the 2 arms • Trend for prolonged OS in +Cy arm OS: 23.5 mo for +Cy vs 14.8 mo for − Cy; 100 HR = 0.57; P = .090 100 Progression-free Survival Percentage Survival 80 80 Percentage 60 60 40 40 20 20 +Cy +Cy -Cy -Cy 0 0 0 2 4 6 8 10 0 10 20 30 40 Time, mo Time, mo Cy, cyclophosphamide. Walter S, et al. Nat Med . 2012;18:1254-1261. Myeloid Derived Suppressor Cells in RCC Pts on Sunitinib 8.00 CD15+CD14 ‐ CD33+HLADR ‐ 7.00 a p = < .05 (compared to normal) b p = < .001 (compared to normal) 6.00 b Positive by FACS (%) b 5.00 c p = < .05 (compared to pre-treatment) d p = < .001 (compared to pre-treatment) 4.00 c c 3.00 2.00 d d d 1.00 a 0.00 Normals MTSS Pre ‐ MTSS C1D28 MTSS C2D28 MTSS C4D28 Treatment N = 30 N = 23 N = 20 N = 10 N = 34 Ko et al, 2009. Page 7

Vaccines for RCC IMA-901 phase 3 study N  330 Cyclophosphamide (300 mg/m 2 single infusion) + Sunitinib Sunitinib + (1 cycle) 3:2 IMA-901 + GM-CSF Stratification Risk group (low vs intermediate) Sunitinib Region (WEE vs CEE vs US) Nephrectomy (yes vs no) IMA-901 delivered with GM-CSF via 10 intradermal vaccinations over 4 months Primary endpoint: OS Secondary endpoints: OS in patients with defined biomarker signature, PFS, best tumor response, safety, immune cell populations Initial OS and immune response results expected soon, final data in 2015 Rini BI, et al. ASCO 2011. Abstract TPS183. Vaccines for RCC AGS-003 Phase I/II AGS-003 Monotherapy Phase II AGS-003 + Sunitinib (n = 20) 1 (n = 21) 2 Median PFS: 5.6 months (95% CI, 5.0–10.8) Median PFS 11.9 months >2.5 months, poor MSKCC risk 6.0 months, poor MSKCC risk >5.1 months, intermediate MSKCC risk 14.9 months, intermediate MSKCC risk Median OS: 18.5 months (95% CI, 9.3–NR) Median OS: Not reached 7.9 months, poor MSKCC risk No grade 3/4 AEs were observed No grade 3/4 AEs were observed Logan T, et al. ASCO GU 2010. Abstract 379. Figlin RA, et al. ASCO GU 2012. Abstract 348. Page 8

Phase II Trial of AGS-003 + Sunitinib: Overall Survival Results: 21 pts (Figlin et al) • Estimated median OS = 29.3 months per Kaplan Meier method • Encouraging OS compared to expected sunitinib OS in similar risk mRCC subjects Vaccines for RCC AGS-003 phase 3 study Pretreatment Induction (48 weeks) Booster AGS-003 (8 doses) + AGS-003 quarterly + Diagnosis, ≥ SD standard treatment standard treatment nephrectomy, n = 300 until PD screening ↓ Registration, leukapheresis Standard treatment ≥ SD Standard treatment (AGS-003 arm only) n = 150 until PD Stratification based upon number of Heng risk factors (1, 2, 3, or 4). Page 9

Co-stimulation 2014: Immune Checkpoints + -  Co-stimulation regulates naive and activated T cells  There are positive and negative co-stimulatory signals  Many of the negative checkpoint pathways promote tolerance and turn off T-cells (e.g. CTLA-4, PD-1/PD-L1) CTLA-4 Blockade in mRCC ● Ipilimumab Phase II trial – Single institution (NCI) * – Major response rate = 9% – Max dose tested 3 mg/kg • (dose response in melanoma) ● Survival effect in melanoma despite low response rate ● Additional studies warranted – CTLA-4 Blockade + Bev (Hodi et al, DFHCC Melanoma Phase I, 2014, in press) *Yang, JIT 2007 Page 10

Role of PD-1 in Suppressing Antitumor Immunity Differences between blocking CTLA4/B7 and blocking PD-1/PD-L1 RCC Cell Activation (cytokines, lysis, proliferation, migration) T cell T cell T cell MHC TCR TCR TCR TCR MHC MHC MHC Dendritic RCC cell Dendritic T cell cell cell CD28 CD28 B7 PD-L1 PD-1 B7 CTLA4 (B7-H1) CTLA4 Clinical Development of Inhibitors of PD-1 Immune Checkpoint Target Antibody Molecule Company Development stage PD-1 Nivolumab- Fully human Bristol-Myers Phase III Squibb multiple tumors BMS-936558 IgG4 Pidilizumab Humanized IgG1 CureTech Phase II multiple tumors CT-011 Pembrolizumab Humanized IgG4 Merck Phase I-II MK-3475 PD-L1 BMS-936559 Fully human Bristol-Myers Phase I Squibb IgG4 MedI-4736 Engineered MedImmune Phase I human IgG1 MPDL-3280A Engineered Genentech Phase I-II human IgG1 MSB0010718C EMD Serono Phase I Page 11

Nivolumab in mRCC- Phase 1 Trial  RR of 29% observed; PFS 7.3 months  Several responses persisted well beyond the duration of therapy 23 Drake CG, et al. ASCO 2013. Abstract 4514. Partial Regression of Metastatic RCC in a Patient Treated with 1 mg/kg BMS-936558 Pretreatment 6 months  57-year-old patient had developed progressive disease after receiving sunitinib, temsirolimus, sorafenib, and pazopanib  Currently in cycle 6 with ongoing PR Courtesy of C. Drake, Johns Hopkins Univ Page 12

Nivolumab in mRCC: Phase I Trial  44% of patients had ≥ 3 prior therapies  Median OS not yet reached 25 Drake CG, et al. ASCO 2013. Abstract 4514. Select adverse events ( ≥ 1%) occurring in patients with mRCC treated with nivolumab (n=34) Category Any Grade Grade 3-4 n (%) n (%) Any treatment-related AE 29 (85.3) 6 (17.6) Skin 12 (35) 1 (3) Endocrinopathies 6 (18) 0 Gastrointestinal 6 (18) 0 Hepatic 4 (12) 1 (3) Infusion reaction 2 (6) 0 Pulmonary 2 (6) 1 (3) Drake, McDermott… Atkins, ASCO 2013 Page 13

Correlation of PD-L1 Expression in Pretreatment Tumor Biopsies with Clinical Outcomes PD-L1 expression by IHC in 61 pretreatment tumor biopsies across tumor types from 42 pts Proportion of Patients CR/PR Non-responders RCC * PD-L1 (+) PD-L1 (-) * 2 pts still under evaluation P=0.006** ** Results based on a post-hoc analysis Patient samples: 18 MEL,10 NSCLC, 7 CRC, 5 RCC, 2 CRPC Topalian et al NEJM, 2012 Nivolumab Phase 3 Trial Nivolumab N  822 3 mg/kg IV every 2 wks  mRCC  ≤ 2 prior anti-angiogenic therapies  ≤ 3 total prior systemic Everolimus regimens 10 mg PO daily Primary endpoint: OS Secondary endpoints: PFS, ORR, OR duration, Safety Accrual completed early 2014 28 Motzer R, et al. ASCO 2013. Abstract TPS4592. Page 14