Cancer Immunotherapy in the Modern Era. David R. Spigel, MD Sarah Cannon Research Institute Nashville, Tennessee

Size: px

Start display at page:

Download "Cancer Immunotherapy in the Modern Era. David R. Spigel, MD Sarah Cannon Research Institute Nashville, Tennessee"

Maximilian Tate
5 years ago
Views:

1 Cancer Immunotherapy in the Modern Era David R. Spigel, MD Sarah Cannon Research Institute Nashville, Tennessee

2 Key Events in the History of Cancer Immunotherapy 1890 First cancer vaccine developed (Coley) 1960s Adjuvants (eg, BCG) shown to eradicate some tumors 1986 IFN-α approved as cancer immunotherapy 1991 First tumor-associated antigen cloned (MAGE-1) Dendritic Cell Vaccines 1953 Coley s work first published 1985 Adoptive immunotherapy for patients with cancer 1992 IL-2 approved as cancer immunotherapy Immune Checkpoint Inhibitors

Selected Cells of the Human Immune System Dendritic cell (DC) A variety of cells can capture and process antigens and present antigens to T cells in context of self-mhc (dendritic cells, macrophages,

4 Selected Cells of the Human Immune System Dendritic cell (DC) A variety of cells can capture and process antigens and present antigens to T cells in context of self-mhc (dendritic cells, macrophages, B cells) Dendritic cells are primary or professional antigen presenting cells Helper T cell Recognizes antigens and produces cytokines that activate a T-cell or B-cell response (adaptive response) Cytotoxic and regulatory T lymphocytes (CTL and Tregs) Following sensitization, attacks and lyses cells bearing target antigen (adaptive response); suppression of immune response MHC, major histocompatibility complex. Armstrong AC, et al. BMJ. 2001;323(7324):

processing CTL DC Step 3: Lymphocyte activation T-cell receptor

5 Fundamentals of the Cellular Anticancer Immune Response Tumor Step 4: Lymphocytes kill tumor cells Tumor cells Step 1: Antigen processing CTL DC Step 3: Lymphocyte activation T-cell receptor Antigen- MHC DC Step 2: Antigen presentation T cell Lymph nodes and spleen

6 A Roadmap of Immunotherapy-Tumor Interactions 4 Trafficking of T cells to tumors Priming and activation Anti-CTLA4 Anti-CD137 (agonist) Anti-OX40 (agonist) Anti-CD27 (agonist) IL-2 IL Infiltration of T cells into tumors Anti-VEGF Cancer antigen presentation Vaccines IFN-α GM-CSF Anti-CD40 (agonist) TLR agonists 2 6 Recognition of cancer cells by T cells CARs Release of cancer cell antigens Chemotherapy Radiation therapy Targeted therapy 1 7 Killing of cancer cells Anti-PD-L1 Anti-PD-1 IDO inhibitors Chen DS, et al. Immunity. 2013;39(1):1-10.

7 Immunotherapy Approaches Immunotherapy Specific: Requires defined antigen source Specific: T-cell targeted Non-specific: Host must define antigen Adoptive: response generated ex vivo Active: requires host immunocompetence PD-1/PD-L1 CTLA-4 Cytokines Other ACT Vaccines IFN IL-2 Bavituximab Toll-like receptor agonists Talactoferrin

8 Cancer Vaccines: Proposed Mechanism of Action Intradermal Vaccine: Protein or Peptide + Adjuvant Adjuvant Activates DC Target Peptides Class II MHC Specific CD4 T cell TCR Class I MHC Antigen Uptake by Immature DC TCR CD8 T cell Drake CG, et al. Nat Rev Clin Oncol. 2014;11(1): ACTIVATED CD8 T cell

9 Phase III IMPACT Study: Sipuleucel-T in mcrpc Sipuleucel-T: cellular immunotherapy produced by exposing a patient s leukapheresed cells to recombinant fusion protein consisting of prostatic acid phosphatase antigen and GM-CSF Patients with asymptomatic or minimally symptomatic mcrpc (N = 512) Randomized 2:1* Primary endpoint: OS Sipuleucel-T q2w x 3 (n = 341) Placebo q2w x 3 (n = 171) Kantoff P, et al. New Engl J Med. 2010;363(5): Treat at physician discretion Treat at physician discretion and/or salvage protocol *Stratified by primary Gleason score, number of bone metastases, and bisphosphonate use P R O G R E S S I O N

10 Sipuleucel-T Immunotherapy in mcrpc: IMPACT Probability of Survival, % Placebo (n = 171) Median Survival: 21.7 Mos. Kantoff P, et al. New Engl J Med. 2010;363(5): Median OS benefit: 4.1 months HR : 0.78 (95% CI: ; P =.03) Sipuleucel-T (n = 341) Median Survival: 25.8 Mos Months Since Randomization

11 Selected Vaccine Trials in Patients With NSCLC Vaccine N TNM Stage Whole-Cell Vaccines Belagenpumatucel-L 1 75 II-IV Antigen-Specific Vaccines CIMAvax-EGF* 2 83 IIIB-IV MAGE-A IB-II L-BLP IIIB-IV TG III/IV Efficacy Outcomes Improved survival in patients treated with higher doses; 15% RR in advanced stages 5 mos improvement in survival in patients with seroconversion (8.4 mos vs 3.5 mos) Trend toward improvement of disease-free interval in MAGE-A3 treated group Stage IIIB patients: median OS NR vs 13.3 mos (2-yr survival rate: 60.0% vs 36.7%) Patients with activated NK phenotype had higher median OS when treated with vaccine plus chemotherapy vs chemotherapy alone (18 mos vs 11.3 mos) *Pooled analysis from 3 trials 1. Nemunaitis J, et al. J Clin Oncol. 2006;24(29): Gonzalez G, et al. Hum Vaccin. 2007;3(1): Vansteenkiste J, et al. J Clin Oncol. 2007;25(18S):Abstract Butts C, et al. J Clin Oncol. 2005;23(27): Acres B, et al. J Clin Oncol. 2009;27(15S): Abstract 3027.

12 Cancer Vaccines: Issues Induce immune reaction against vaccine, but not the tumor Immune system mainly recognizes neo-antigens from passenger mutations rather than shared antigens Antigens different for each tumor Vaccine must involve autologous tumor cells Most immune-responsive tumors autovaccinate, but immune regulation prevents an effective response Even if vaccine enhances antitumor immunity, cells likely to be suppressed in the tumor microenvironment Conclusion: Vaccines are unlikely to have a major effect in the absence of immune checkpoint control

13 Ipilimumab: Mechanism of Action T-cell activation T-cell inhibition T-cell potentiation T-cell CTLA-4 T-cell T-cell TCR CD28 TCR CD28 CTLA-4 TCR CTLA-4 APC MHC B7 APC MHC B7 APC MHC B7 IPILIMUMAB blocks CTLA-4 Hodi FS, et al. N Engl J Med. 2010;363(8):

14 Ipilimumab in Metastatic Melanoma Previously Treated Patients Previously Untreated Patients OS, % Median OS, Mos Ipi + gp Ipi 10.1 gp HR P Value < Months Patients Survival, % Ipi + D Placebo + D Median OS, Mos Est 1, 2, 3-Yr Survival, % 47.3, 28.5, , 17.9, 12.2 HR 0.72 P Value <.001 Ipilimumab + dacarbazine Placebo + dacarbazine Months Ipilimumab + gp100 vs gp100 1 Ipilimumab vs Placebo 2 1. Hodi FS, et al. N Engl J Med. 2010;363(8): Robert C, et al. N Engl J Med. 2011;364(26):

15 Response Criteria for Immunotherapy RECIST CR PR SD PD Disappearance of all target lesions, reduction in shortaxis diameter of pathology LN to <10 mm 30% decrease in sum of longest diameters of target lesions Neither PR nor PD Immune-Related Response Criteria 2 20% increase ( 5 mm absolute increase) in sum of longest diameters, in comparison with smallest sum of longest diameters recorded during treatment ircr irpr irsd irpd Disappearance of all lesions on 2 consecutive observations 4 weeks apart 50% decrease in tumor burden compared with baseline in 2 observations 4 weeks apart 50% decrease in tumor burden compared with baseline not established, nor 25% increase vs nadir 25% increase in tumor burden compared with nadir (at any single timepoint) in 2 consecutive observations 4 weeks apart 1. Eisenhauer EA, et al. Eur J Cancer. 2009;45(2): Wolchok JD, et al. Clin Cancer Res. 2009;15(23):

16 Association of Response With Survival Proportion Alive CR/PR/SD (by WHO criteria) irpr/irsd (by the irrc) PD and unknown response Months Wolchok JD, et al. Clin Cancer Res. 2009;15(23):

17 Adverse Events Associated With Ipilimumab Are Immune-Related irae (All Grades) 1. Robert C, et al. N Engl J Med. 2011;364(26): Hodi FS, et al. N Engl J Med. 2010;363(8): IPI + DTIC 1 N = 247 IPI + PBO 2 N = 251 Total, % Dermatologic, % Pruritus Rash Gastrointestinal, % Diarrhea Colitis Hepatic, % Increase in alanine aminotransferase Increase in aspartate aminotransferase Hepatitis Rate of grade 3/4 toxicity, % irae, immune-related adverse event

18 Identification of Immune-Related AEs iraes associated with ipilimumab are well known Patients receiving ipilimumab therapy should be monitored for early identification of these iraes Organ System Gastrointestinal Signs/Symptoms Any change in normal bowel habits or change from baseline Liver Skin Neurologic Endocrine Elevation in liver function tests AST >2.5 x ULN ALT >2.5 x ULN Total bilirubin >1.5 x ULN Pruritus, rash Motor and sensory neuropathy Unilateral and bilateral weakness Sensory alterations Paresthesia Fatigue, headache, changes in mental status, abdominal pain, unusual bowel habits, hypotension, abnormal thyroid function tests and/or serum chemistry values Ipilimumab Immune-Mediated Adverse Reaction Management Guide. Available at: Accessed October 16, 2014.

19 General Principles of Immune-Related Toxicity Management Generally based on severity of symptoms Grade 1: supportive care; +/- withhold drug Grade 2: withhold drug, consider redose if toxicity resolves to grade 1. Low-dose corticosteroids (prednisone 0.5 mg/kg/day or equivalent) if symptoms do not resolve within a week Grade 3-4: discontinue drug; high-dose corticosteroids (prednisone 1-2 mg/kg/day or equivalent) tapered over 1 month once toxicity resolves to grade 1 Presence of iraes may be a biomarker for response

20 Less Common Immune-Related Adverse Events Hematologic (hemolytic anemia, thrombocytopenia) Cardiovascular (myocarditis, pericarditis, vasculitis) Ocular (blepharitis, conjunctivitis, iritis, scleritis, uveitis) Renal (nephritis)

21 Selection of Patients Predictive biomarkers Clinical features associated with response or resistance Tumor burden and rate of disease progression Kinetics of tumor response for immune therapy versus alternate therapies Clinical contraindications (autoimmunity, drug interactions) Potential for durable response with immune therapy versus alternate therapies (requirement for ongoing treatment) Availability and toxicity/effectiveness of alternate therapies

22 The Next Generation of Cancer Immunotherapy David R. Spigel, MD Sarah Cannon Research Institute Nashville, Tennessee

23 Programmed Death Receptor (PD-1) PD-1 is expressed on T, B, and NK cells Ligands are PD-L1 and -L2, expressed on APCs and tumor cells Ligation inhibits T-cell activation and proliferation causing cell-cycle arrest without apoptosis More subtle immune checkpoint than CTLA-4 mabs against PD-1 and PDL-1 results in tumor regression Clonal exhaustion in infectious diseases; these clones express high levels of PD-1

24 CTLA-4 vs PD-1: Distinct Immune Checkpoints B7.1/2 CD28 APC Signal 1 CTLA-4 to cell surface APC Signal 1 Naïve/resting T cell CTLA-4 Costim. ligand Costim. receptor Experienced T cell APC Traffic to Tissue Signal 1 periphery Signal 1 T-cell priming Topalian SL, et al. Curr Opin Immunol. 2012;24(2): Inflammation PD-L1 PD-1

25 Potential Differences in PD-1 vs PD-L1 Blockade B7.1 APC/target cell? apoptotic signal in tumor cells B7-H1 PD-1 T cell (-) Signal B7-DC Anti PD-1 APC/target cell? apoptotic signal in tumor cells Anti B7-H1 B7-H1 B7.1 PD-1 T cell (-) Signal B7-DC Topalian SL, et al. Curr Opin Immunol. 2012;24(2):

26 PD-1/PD-L1 Inhibitors Currently in Clinical Development Target Agent Class K D Nivolumab IgG4 fully human Ab 3 nm (MDX1106, BMS936558) PD-1 Pembrolizumab (MK-3475) IgG4 engineered humanized Ab 29 pm Pidilizumab (CT-011) IgG1 humanized Ab - AMP-224 Fc-PD-L2 fusion protein - BMS (MDX-1105) IgG4 fully human Ab - PD-L1 MPDL3280A MEDI4736 IgG1 engineered fully human Ab IgG1 engineered fully human Ab - - MSB C NA -

1 with confirmation by ICR) 81% of pts with response still on treatment at time of analysis (median followup: 11

27 Activity of Anti-PD-1 Agents in Solid Tumors Nivolumab Activity (ORR) 1 Melanoma: 28% NSCLC: 18% RCC: 27% Patient with metastatic melanoma Pembrolizumab Activity (ORR) 2 Melanoma: 38% Highest dose: 52% (assessed by RECIST 1.1 with confirmation by ICR) 81% of pts with response still on treatment at time of analysis (median followup: 11 mos) 1. Topalian SL, et al. N Engl J Med. 2012;366(26): Hamid O, et al. N Engl J Med. 2013;369(2):

28 Agent Nivolumab 1 (Anti-PD1) Activity of Anti-PD-1 and Anti-PD-L1 in Metastatic Melanoma Dose and schedule mg/kg q2w N ORR % Median response duration, months Median PFS/ 24-week PFS rate % months Median survival 16.8 months 1 yr/2 yr survival 62%/43% Pembrolizumab 2 (Anti-PD1) 2-10 mg/kg q2-3w 411 (168 IPI-N) 34% (40% IPI-N) NR 5.5 months NR 69%/ND MPDL3280 (Anti- PD-L1) BMS (Anti- PD-L1) mg/kg q3w mg/kg q2w 44 29% ND 43% ND ND 52 17% ND 42% ND ND 1. Topalian SL, et al. J Clin Oncol. 2014;32(10): Ribas A et al. J Clin Oncol. 2014;32(5S): LBA Herbst RS, et al. J Clin Oncol. 2013;31(Suppl): Abstract Brahmer JR, et al. N Engl J Med. 2012;366(26):

29 Outcomes With Nivolumab in Patients With Metastatic RCC Dose, mg/kg Objective Response Rate, % (n/n) Median DoR, Wks (Range) All doses 29.4 (10/34) 56.1 ( ) (5/18) 56.1 ( ) (5/16) 56.1 ( ) 24 Wks SD Rate, % (n/n) 48 Wks 26.5 (9/34) 5.9 (2/34) 22.2 (4/18) 5.6 (1/18) 31.3 (5/16) 6.3 (1/16) Drake CG, et al. J Clin Oncol. 2013;31(Suppl): Abstract 4514.

30 OS: Nivolumab in Patients With Advanced NSCLC Overall Survival OS Rate % (95% CI) [patients at risk] Group Died/Treated Median OS (95% CI) 1-Year 2-Year Censored 1 mg/kg 26/ (5.3, 11.1) 32 (16, 49) [8] 12 (3, 27) [2] 3 mg/kg 20/ (7.3, --) 56 (38, 71) [17] 45 (27, 61) [9] 10 mg/kg 48/ (5.2, 12.4) 40 (27, 52) [23] 19 (10, 31) [9] 1-year OS Rate 56% (17 patients at risk) 2-year OS Rate 45% (9 patients at risk) Months Since Treatment Initiation Patients at Risk Nivolumab 1 mg/kg Nivolumab 3 mg/kg Nivolumab 10 mg/kg Brahmer JR, et al. J Clin Oncol. 2014;32(5s): Abstract 8112.

31 Efficacy of Nivolumab in Untreated Patients With NSCLC Tumor Responses Squamous n = 9 Nonsquamous n = 11 Total n = 20 ORR, n (%) 2 (22) 4 (36) 6 (30) Ongoing responders, n (%) 1 (50) 3 (75) 4 (67) Best overall response, n (%) Complete response 1 (11) 1 (9) 2 (10) Partial response 1 (11) 3 (27) 4 (20) Stable disease 3 (33) 4 (36) 7 (35) Survival Outcomes PFS/OS PFS rate at 24 weeks, % Median PFS, weeks year OS rate, % Gettinger S, et al. J Clin Oncol. 2014;32(5s): Abstract 8024.

32 Nivolumab in Squamous Cell NSCLC Checkmate-063 Trial ORR (~11 months minimum follow up) Nivolumab 3 mg/kg 15% Estimated one-year survival rate 41% Median OS 8.2 months Stable disease 26% Disease control rate 41% Ramalingam SS, et al. Presented at: 2014 Chicago Multidisciplinary Symposium on Thoracic Oncology; October 30-November 1, 2014: Chicago, Illinois. Abstract LB2.

33 Efficacy of Pembrolizumab in Untreated Patients With NSCLC RECIST v1.1, Central Review a irrc, Investigator Review ORR b DCR b ORR b DCR b Pembro Dose n n (%) [95% CI] n (%) [95% CI] n n (%) [95% CI] n (%) [95% CI] 2 mg/kg Q3W 6 2 (33%) [4%-78%] 3 (50%) [12%-88%] 6 4 (67%) [22%-96%] 5 (83%) [36%-100%] 10 mg/kg Q3W 20 4 (20%) [6%-44%] 14 (70%) [46%-88%] (46%) [24%-68%] 18 (82%) [60%-95%] 10 mg/kg Q2W 16 5 (31%) [11%-59%] 10 (63%) [35%-85%] 17 7 (41%) [18%-67%] 12 (71%) [44%-90%] Total (26%) [14%-42%] 27 (64%) [48% 78%] (47%) [32%-62%] 35 (78%) [63%-89%] Interim median PFS c : 27.0 weeks (95% CI, ) by RECIST v1.1 per central review 37.0 weeks (95% CI, 27.0-NR) by irrc per investigator review Analysis cut-off date: March 3, DCR, disease-control rate (complete response + partial response + stable disease) a 3 patients did not have measurable disease by RECIST v1.1 per independent central review at baseline and were not evaluated for response by RECIST v1.1. b Includes confirmed and unconfirmed responses. c From product-limit (Kaplan-Meier) method for censored data. PDL-1 positive at 1% Rizvi NA, et al. J Clin Oncol. 2014;32(5s): Abstract 8007.

MEDI4736 (Anti-PD-1) in Patients With NSCLC All patients with 1 follow-up scan (n = 84) Majority of patients have limited follow-up and have not reached week 12 tumor assessment RECIST Response

34 MEDI4736 (Anti-PD-1) in Patients With NSCLC All patients with 1 follow-up scan (n = 84) Majority of patients have limited follow-up and have not reached week 12 tumor assessment RECIST Response Response evaluable MEDI mg/kg q2w MEDI4736 All doses 13% (6/47) 16% (9/58) PD-L1+ 39% (5/13) 25% (5/20) PD-L1-5% (1/19) 3% (1/29) Disease Control Rate Response Evaluable MEDI mg/kg q2w MEDI4736 All doses 30% (14/17) 35% (20/58) PD-L1+ 54% (7/13) 45% (9/20) PD-L1-32% (6/19) 24% (7/29) Brahmer JR, et al. J Clin Oncol. 2014;32(5s): Abstract 8021.

MPDL3280A Phase IA: Efficacy Summary 26 of 29 responders continued to respond at last assessment Time on study in responders: 3 to 15+ months Additional delayed responses not reflected in above ORR

35 MPDL3280A Phase IA: Efficacy Summary 26 of 29 responders continued to respond at last assessment Time on study in responders: 3 to 15+ months Additional delayed responses not reflected in above ORR Other tumor types (14) include CRC (PR in 1/4) and gastric cancer (PR in 1/1) Population, % Overall population (N = 140) NSCLC (n = 41) Melanoma (n = 38) RCC (n = 47) RECIST 1.1 Response Rate (ORR*) SD of 24 Weeks or Longer 24- Week PFS *ORR includes unconfirmed PR/CR and confirmed PR/CR. Generally well tolerated Grade 3/4 related AE 13%; 2% immune related Herbst RS, et al. J Clin Oncol. 2013;31(Suppl): Abstract 3000.

36 iraes in NSCLC Anti-PD-1 nivolumab (129 NSCLC patients) 53% related AEs, 5% grade 3/4 AEs Pneumonitis 6%, grade 3/4 in 3 patients, 2 deaths Anti-PD-1 pembrolizumab (221 NSCLC patients) 48% related AEs (fatigue), 6% grade 3/4 AEs Pneumonitis grade 3/4 in 3 patients Anti-PD-L1 MPDL3280A (85 NSCLC patients) 66% related AEs, 11% grade 3/4 (fatigue) No grade 3-5 pneumonitis Anti-PD-L1 BMS (207 patients) 61% related AEs, 9% grade 3/4 AEs No pneumonitis Anti-PD-L1 MEDI4736 (26 patients, 13 NSCLC) 34% related AEs, no grade 3/4 AEs, no pneumonitis, no colitis

37 Pneumonitis Grade Grade 1 Radiographic changes only Grade 2 Mild to moderate new symptoms Grade 3-4 Severe new symptoms; new/worsening hypoxia; lifethreatening Management Consider delay of I-O therapy Monitor for symptoms every 2-3 days Consider pulmonary and ID consults Delay I-O therapy Pulmonary and ID consults Monitor symptoms daily, consider hospitalization 1mg/kg/day of prednisolone IV or oral equivalent Consider bronchoscopy, lung biopsy Discontinue I-O therapy Hospitalize Pulmonary and ID consults 2-4 mg/kg/day methylprednisolone IV or IV equivalent Prophylactic antibiotics for opportunistic infections Consider bronchoscopy, lung biopsy Lipson EJ, et al. Presented at the 2014 American Society of Clinical Oncology Annual Meeting - Optimizing the Use of New Targeted Therapies in the Face of Toxicity; May 30-June 3, 2014; Chicago, Illinois.

38 PD-L1 As a Biomarker in NSCLC Nivolumab Pembrolizumab MPDL3280A MEDI4736 Assay C3 SP263 Cells scored Tumor cell membrane Tumor cell (and stroma) Tumor and immune cells Tissue Archival Recent Arch./Recent Arch./Rece nt Setting 1 st line 2L ++ 1 st line 2L ++ 2L ++ 2L ++ Cut-point 5% 1% 5% 1% 1% 50% 1% 5% 10% ORR in PD-L1 + 50% N =10 13% N = 38 15% N = % N = % N = % N = 41 31% N = 26 46% N = 13 83% N = 6 39% N = 13 ORR in PD-L1-0% N = 7 17% N = 30 14% N = 35??? 9-13% N = 40 11% N = 88 20% N =20 18% N = 33 18% N = 40 5% N =19 Topalian SL, et al. N Engl J Med. 2012;366(26): ; Grosso J, et al. J Clin Oncol. 2013;31(Suppl): Abstract 3016; Brahmer JR, et al. J Clin Oncol. 2014;32(5S): Abstract 8112; Gettinger SN, et al. J Clin Oncol. 2014;32(5S): Abstract 8024; Daud AI, et al. Cancer Res. 2014;74(19 Suppl): Abstract CT104; Gandhi L, et al. Cancer Res. 2014;74(19 Suppl): Abstract CT105; Rizvi NA, et al. J Clin Oncol. 2014;32(5S): Abstract 8022; Garon EB, et al. J Clin Oncol. 2014;32(5S): Abstract 8020; Hamid O, et al. J Clin Oncol. 2013;31(Suppl): Abstract 9010; Herbst RS, et al. J Clin Oncol. 2013;31(Suppl): Abstract 3000; Powderly JD, et al. J Clin Oncol. 2013;31(Suppl): Abstract 3001; Spigel DR, et al. J Clin Oncol. 2013;31(Suppl): Abstract 8008; Segal NH, et al. J Clin Oncol. 2014;32(5S): Abstract 3002; BrahmerJR, et al. J Clin Oncol. 2014;32(5S): Abstract 8021.

39 Possible Limitations to PD-L1 PD-L1 expression is dynamic PD-L1 is heterogeneous within tissue Unclear what level of expression is important Importance of co-localization with TILs Scalability and reliability of assays Archived material Variability in tissue collection timing, cell sampling, mab used for staining, IHC criteria

40 PD-1/PD-L1 Therapy: Select Pivotal Trials Tumor Type Melanoma RCC NSCLC Phase III (unless otherwise indicated) Pembro (2 doses) vs ipi [NCT ] Nivo vs ipi vs ipi/nivo [NCT ] Nivo vs chemo (ipi progression) [NCT ,NCT ] Pembro vs chemo (ipi progression; phase II) [NCT ] Nivo vs everolimus (TKI progression) [NCT ] Nivo/ipi vs sunitinib MPDL + bev vs MPDL vs sunitinib (phase II) [NCT ] Pembro (2 doses) vs doc [NCT ] Nivo vs doc (squamous or nonsquamous) [NCT , NCT ] Nivo vs chemo choice [NCT ] HNSCC Nivo vs investigator s choice [NCT ] Patients with known or suspected autoimmune disease are generally excluded from these trials.

41 Many Potential Immunotherapy Combinations Immune-checkpoint blockade is still early in development Future is likely in combinations Multiple checkpoints (eg, PD-1 + LAG3) Small molecule inhibitors (eg, VEGFi or inos modulation + PD-L1) Radiation (eg, CTLA-4 or OX40 + RT) Chemotherapy (eg, cyclophosphamide to deplete T reg prior to checkpoint blockade) Adoptive cell therapy Grosso JF, et al. Cancer Immun. 2013;13:5.

42 Ipilimumab + Nivolumab for Melanoma Change in Target Lesions From Baseline, % First occurrence of new lesion Cohort 2: 1 mg/kg nivolumab + 3 mg/kg ipilimumab Weeks Since Treatment Initiation Change in Target Lesions From Baseline All Patients in Concurrent Cohorts Patients Therapy, % ORR 80% Tumor Reduction Ipilimumab 7 <3 Nivolumab 28 <2 Combination (cohort 2) Wolchok JD, et al. N Engl J Med. 2013;356(2): Wolchok JD, et al. J Clin Oncol. 2013;31(Suppl): Abstract 9012.

43 Phase I Study of Nivolumab + Ipilimumab in mrcc Change in Baseline, % Change in Baseline Target Lesions, % Weeks Since First Dose Hammers HJ, et al. J Clin Oncol. 2014;32(5S): Abstract Weeks Since First Dose N3 + I1 (n = 20) N1 + I3 (n = 22) 1st Occurrence of New Lesion

44 What About Other Combinations? Combinations of immunotherapies with other classes of therapy Targeted therapies Vaccines Metabolites Radiation Chemotherapy

45 Combining Immunotherapy and Targeted Therapy OS (%) Improved Survival With Ipilimumab Immunotherapy Ipi + gp100 Ipi gp Targeted Therapy Combination??? Percent Alive Percent Alive Percent Alive Mos 44 OS (%) Improved Survival With Vemurafenib Vemurafenib (n = 336) 6 mos OS: 84% Dacarbazine (n = 336) 20 6 mo OS: 64% Mos Yrs Yrs Yrs 1. Hodi FS, et al. N Engl J Med. 2010;363(8): Chapman PB, et al. N Eng J Med. 2011; 364(26):

46 Combination Therapy May Result in Increased Toxicity Patient Number Cohort 1* Doses of Ipilimumab Before ALT-AST Elevation, n Time to Onset of ALT-AST Elevation After First Dose Ipilimumab, Days Treatment GCS; Vem discontinued for 5 days then restarted with dose reduction; Ipi permanently discontinued GCS; Vem discontinued for 4 days then restarted with dose reduction; Ipi continued (2 doses) GCS; Vem discontinued for 5 days then restarted with dose reduction; Ipi continued (1 dose) GCS; Vem discontinued for 4 days then restarted with dose reduction; Ipi continued (1 dose) Time to Resolution of ALT-AST Elevation, Days Toxicity Relapse With Repeated Ipilimumab 4 NA 6 No 6 No 12 Yes Cohort GCS; Vem discontinued for 7 days then restarted with dose reduction; Ipi permanently discontinued (1 dose) 10 NA Vem and Ipi permanently discontinued 20 NA *Cohort 1: 1-month run-in of single-agent vemurafenib 960 mg BID followed by 4 infusions of ipilimumab 3 mg/kg every 3 weeks plus vemurafenib. Patient also had grade 2 increase in total bilirubin. Cohort 2: vemurafenib 760 mg BID plus ipilimumab 3 mg/kg every 3 wks. Patient also had grade 3 increase in total bilirubin. Ribas A, et al. N Engl J Med. 2013;368(14):

T-VEC: An HSV-1-Derived Oncolytic Immunotherapy Designed to Produce Local and Systemic Effects Local Effect: Virally-Induced Tumor Cell Lysis Selective viral replication in tumor tissue Tumor cells

47 T-VEC: An HSV-1-Derived Oncolytic Immunotherapy Designed to Produce Local and Systemic Effects Local Effect: Virally-Induced Tumor Cell Lysis Selective viral replication in tumor tissue Tumor cells rupture for an oncolytic effect Systemic Effect: Tumor-Specific Immune Response Systemic tumorspecific immune response Death of distant cancer cells Kaufman HL, et al. J Clin Oncol. 2014;32(5S): Abstract 9008a.

48 T-VEC Responses in Injected And Uninjected Lesions Cycle 1 Cycle 13 Kaufman HL, et al. J Clin Oncol. 2014;32(5S): Abstract 9008a.

49 Primary Overall Survival 100% Events / N (%) Median (95% CI) in Months T-VEC 189 / 295 (64) 23.3 (19.5, 29.6) 80% GM-CSF 101 / 141 (72) 18.9 (16.0, 23.7) Kaplan-Meier Percent 60% 40% 20% Survival T-VEC GM-CSF Difference % (95% CI) 12 mo 73.7% 69.1% 4.6 (-4.7, 13.8) HR = 0.79 (95% CI: 0.62, 1.00) Unadjusted Log-rank P = mo 49.8% 40.3% 9.5 (-0.5, 19.6) 0% 36 mo 38.6% 30.1% 8.5 (-1.2, 18.1) 48 mo 32.6% 21.3% 11.3 (1.0, 21.5) Patients at risk: T-VEC GM-CSF Kaufman HL, et al. J Clin Oncol. 2014;32(5S): Abstract 9008a.

50 Percentage Change From Baseline Combination Ipilimumab and T-VEC in Melanoma * Only patients who received both T-Vec and ipilimumab. CR, CRu, and PD included. One patient with PD not shown in the plot because tumor burden could not be accurately calculated (missing post-baseline data) Percentage change from baseline: 538 Percentage change from baseline: 265 Stage IIIb (n = 1) Patients (N = 17) Stage IIIc (n = 3) Puzanov I, et al. J Clin Oncol. 2014;32(5s): Abstract Investigator-Assessed Responses, n (%) N = 18 * Overall response 10 (56) (95% CI: 31-79) Complete response 6 (33) Partial response 4 (22) Stable disease 3 (17) Progressive disease 5 (28) Stage IV M1a (n = 4) Stage IV M1b (n = 5) Stage IV M1c (n = 4)

Future Targets for Immunotherapy TIM-3 (T-cell immunoglobulin and mucin-domaincontaining molecule-3) Expressed by activated and exhausted T cells; natural ligand expressed on tumor cells Blockade of

51 Future Targets for Immunotherapy TIM-3 (T-cell immunoglobulin and mucin-domaincontaining molecule-3) Expressed by activated and exhausted T cells; natural ligand expressed on tumor cells Blockade of TIM-3 results in better immune function LAG-3: (lymphocyte activation gene-3) Expressed by activated T cells and Treg cells Blockade results in inhibition of Treg activity GITR (glucocorticoid-induced TNF-R related gene) Costimulatory molecule expressed on subsets of T cells Agonistic anti-gitr antibodies are in early clinical development

52 Other Immunomodulating Drugs in Development Anti-Ox40 Anti-CD27 Anti-CD40 Anti-CD137 (4-1BB)

53 Remaining Questions How do we select patients who will respond? How do we fit immunotherapy into the current treatment algorithm? Combination immunotherapy Sequencing with standard therapies How do we combine therapies to optimize the number of responding patients?

The Immunotherapy of Oncology

The Immunotherapy of Oncology The 30-year Overnight Success Story M Avery, BIOtech Now 2014 Disclosures: Geoffrey R. Weiss, M.D. None The History A. Chekov: It has long been noted that the growth of malignant