6/7/16. Melanoma. Updates on immune checkpoint therapies. Molecularly targeted therapies. FDA approval for talimogene laherparepvec (T- VEC)

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1 Melanoma John A Thompson MD July 17, 2016 Featuring: Updates on immune checkpoint therapies Molecularly targeted therapies FDA approval for talimogene laherparepvec (T- VEC) 1

(ipilimumab) PD-1 Blockade (nivolumab) Ipilimumab: Mechanism of Action T-cell activation T-cell inhibition T-cell potentiation CTLA4 T cell

2 Mechanism of ac-on of Ipilimumab and Nivolumab Tumor Microenvironment Activation (cytokines, lysis, proliferation, migration to tumor) Dendritic cell +++ CD28 CTLA-4 anti-ctla T cell T cell PD-1 PD-L1 Tumor cell anti-pd-1 PD-1 PD-L2 anti-pd-1 CTLA-4 Blockade (ipilimumab) PD-1 Blockade (nivolumab) Ipilimumab: Mechanism of Action T-cell activation T-cell inhibition T-cell potentiation CTLA4 T cell CD28 APC T cell T cell CD28 APC CTLA4 CTLA4 APC IPILIMUMAB blocks CTLA-4 5 Ipilimumab Patterns of Response Hoos A, et al. J Natl Cancer Inst 2010;102:

Immune-related Adverse Events (iraes) Associated with Ipilimumab Skin: Pruritus Rash Endocrine Fatigue Headache Mental status changes Hypotension

Liver AST/ALT, Bilirubin Neurological Uni- or bilateral weakness Sensory alterations Paresthesias http://dailymed.nlm.nih.

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

3 Immune-related Adverse Events (iraes) Associated with Ipilimumab Skin: Pruritus Rash Endocrine Fatigue Headache Mental status changes Hypotension Abnormal thyroid function tests/ serum chemistries Gastrointestinal Diarrhea Abdominal Pain Blood in stool Bowel perforation Peritoneal signs Liver AST/ALT, Bilirubin Neurological Uni- or bilateral weakness Sensory alterations Paresthesias ALT, alanine aminotransferase; AST, aspartate aminotransferase. Mechanism of ac-on of Ipilimumab and Nivolumab Tumor Microenvironment Activation (cytokines, lysis, proliferation, migration to tumor) Dendritic cell +++ CD28 CTLA-4 anti-ctla T cell +++ T cell PD-1 PD-L1 Tumor cell anti-pd-1 PD-1 PD-L2 anti-pd-1 CTLA-4 Blockade (ipilimumab) PD-1 Blockade (nivolumab) 3

$Activity of Anti Programmed Death 1 (PD-1) Antibody in Patients with Refractory Melanoma Complete/partial Response (CR/PR): 33/107 (31%) Stable Disease (SD):. 7/107 (7%) Topalian SL, et al.$

4 Activity of Anti Programmed Death 1 (PD-1) Antibody in Patients with Refractory Melanoma Complete/partial Response (CR/PR): 33/107 (31%) Stable Disease (SD):. 7/107 (7%) Topalian SL, et al. N Engl J Med 2012;366: Topalian SL, et al. J Clin Oncol 2014;32: CA Study Design Randomized, double-blind, phase III study to compare NIVO + IPI or NIVO alone to IPI alone N=314 NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses then NIVO 3 mg/kg Q2W Unresectable or Metatastic Melanoma Previously untreated 945 patients Randomize 1:1:1 Stratify by: PD-L1 expression* BRAF status AJCC M stage N=316 NIVO 3 mg/kg Q2W + IPI-matched placebo Treat until progression** or unacceptable toxicity N=315 *Verified PD-L1 assay with 5% expression level was used for the stratification of patients; validated PD-L1 assay was used for efficacy analyses. IPI 3 mg/kg Q3W for 4 doses + NIVO-matched placebo **Patients could have been treated beyond progression under protocol-defined circumstances. Larkin J, et al. N Engl J Med 2015;373: CA Co-primary Endpoint: Progression-Free Survival (Intent-to-Treat) NIVO + IPI (N=314) NIVO (N=316) IPI (N=315) Median PFS, months (95% CI) 11.5 ( ) 6.9 ( ) 2.9 ( ) 1.0 HR (95% CI) vs. IPI 0.42 ( )* 0.57 ( )* -- Proportion alive and progression-free NIVO + IPI NIVO IPI HR (95% CI) vs. NIVO ( )** *Stratified log-rank P< vs. IPI **Exploratory endpoint No. at Risk Months NIVO + IPI NIVO IPI Larkin J, et al. N Engl J Med 2015;373:

5 CA Response to Treatment NIVO + IPI (n=314) NIVO (n=316) IPI (n=315) ORR, % (95% CI)* 58 (52 63) 44 (38 49) 19 (14 24) Two-sided P value vs IPI <0.001 < Best response (%) Complete response Partial response Stable disease Larkin J, et al. N Engl J Med 2015;373:23-34 CA Safety Summary PaAents ReporAng Event, % Treatment-related adverse event (AE) Treatment-related AE leading to disconanuaaon NIVO + IPI (N=313) NIVO (N=313) IPI (N=311) Any 3 4 Any 3 4 Any Treatment-related death* *One reported in the NIVO group (neutropenia) and one in the IPI group (cardiac arrest) 67.5% of patients (81/120) who discontinued the NIVO + IPI combination due to treatmentrelated AEs developed a response Tumor Staining for PD-L1: Correlation with Response to Therapy with Anti-PD-1 or Anti-PD-L1 Overall Response Rate PD-L1 Positive PD-L1 Negative Topalian (NEJM 2012) 13/31 0/18 Grosso (ASCO 2013) 7/17 3/21 Herbst (ASCO 2013) 13/36 9/67 Robert (NEJM 2015) 53% 33% Topalian SL, et al. N Engl J Med 2012;366: Grosso J, et al. ASCO Meeting Abstracts 2013;31:3016. Herbst RS, et al. ASCO Meeting Abstracts 2013;31:3000. Robert C, et al. N Engl J Med 2015;372:

Genomic and transcriptomic features of response to anti-pd-1

from J Naidoo British Journal of Cancer Advance Online

Intra-tumoral delivery of IL-12 plasmid DNA via in vivo

6 Genomic and transcriptomic features of response to anti-pd-1 therapy of melanoma Hugo et al Cell 165:35, 2016 Figure 1 from J Naidoo British Journal of Cancer Advance Online Publication 11 September 2014 doi: /bjc Cancer Research UK. Intra-tumoral delivery of IL-12 plasmid DNA via in vivo electroporation (IT-pIL12-EP or ImmunoPulse TM IL-12) 18 6

The virus invades both tumor cells and normal healthy cells The virus is an attenuated virus that does not replicate in healthy cells Healthy cells remain

antigens Normal healthy cells Tumor cells Mature dendritic cells The virus invades both tumor cells and normal healthy cells The virus selectively replicates

sites Dendritic cells process and present TSAs to mediate a tumor specific immune response Adaptive immune response identifies and destroys tumor cells

7 The virus invades both tumor cells and normal healthy cells The virus is an attenuated virus that does not replicate in healthy cells Healthy cells remain undamaged Replicated viruses repeat cell lysis cycle in nearby tumor cells Virus GM-CSF Granulocyte-macrophage colony-stimulating factor TSAs Tumor specific antigens Normal healthy cells Tumor cells Mature dendritic cells The virus invades both tumor cells and normal healthy cells The virus selectively replicates and generates GM-CSF in tumor cells Tumor cells rupture to release replicated viruses and GM-CSF; TSAs are exposed GM-CSF recruits dendritic cells to tumor sites Dendritic cells process and present TSAs to mediate a tumor specific immune response Adaptive immune response identifies and destroys tumor cells systemically Phase 2 results with OncoVEX GMCSF [Senzer NN. JCO 2009] signaling pathways in melanoma. Kinase Signaling Pathways in Melanoma Davies MA, et al. Oncogene 2010;29:

8 Age at Diagnosis of Metastatic Melanoma and Prevalence of BRAF Mutation (N = 308) Menzies AM, et al. Clin Cancer Res 2012;18: PET Scans at Baseline and Day 15 After Vemurafenib #69 MDA #63 MSKCC Chapman PB et al. Presented at ECCO 15/ESMO 34. Sept 20-24, Berlin, Germany. Abstract 6 BA. Kinase oncogene dependence and principles of drug resistance. Nikhil Wagle et al. JCO 2011;29: by American Society of Clinical Oncology 8

9 Well-differentiated Squamous Cell Carcinomas Macdonald JB, et al. J Am Acad Dermatol 2015;72: Long GV, et al. Lancet 2015;386:

10 Effects of Immunotherapy and Targeted Therapy on Melanoma Survival Curves Ribas A et al. Clin Cancer Res 2012;18: NCCN Recommendations for Metastatic or Unresectable Melanoma: First-line Systemic Therapy BRAF Mutated= BRAF Wild-type Preferred if need early response All other cases BRAF/MEK inhibitor combination (preferred): Dabrafenib/trametinib Vemurafenib/cobimetinib BRAF inhibitor monotherapy (vemurafenib or dabrafenib) Anti-PD-1 monotherapy (nivolumab or pembrolizumab) Ipilimumab/nivolumab combination Clinical trial Anti-PD-1 monotherapy (nivolumab or pembrolizumab) Ipilimumab/nivolumab combination Clinical trial Unanswered questions: Optimal duration of therapy? Biomarkers to predict response? Combination vs sequential therapy? Role of T-cell therapies? 10

Melanoma: From Chemotherapy to Targeted Therapy and Immunotherapy. What every patient needs to know. James Larkin

Melanoma: From Chemotherapy to Targeted Therapy and Immunotherapy What every patient needs to know James Larkin Melanoma Therapy 1846-2017 Surgery 1846 Cytotoxic Chemotherapy 1946 Checkpoint Inhibitors