In Partnership With Principles and Application of Immunotherapy for Cancer: Advanced Melanoma This program is supported by educational grants from Genentech.

In Partnership With Principles and Application of Immunotherapy for Cancer: Advanced Melanoma This program is supported by educational grants from Genentech and Merck.

About These Slides Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options ( Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

Core Faculty Jeffrey S. Weber, MD, PhD Senior Member and Director Comprehensive Melanoma Research Center H. Lee Moffitt Cancer Center Tampa, Florida Peg Esper, DNP, ANP-BC, AOCN Nurse Practitioner, Medical Oncology Department of Hematology-Oncology Comprehensive Cancer Center University of Michigan Ann Arbor, Michigan This slide lists the faculty who were involved in the production of these slides.

Faculty Disclosures Jeffrey S. Weber, MD, PhD, has disclosed that he has served as a consultant for Bristol-Myers Squibb, Celldex, Genentech, GlaxoSmithKline, and Merck and has ownership interest in Altor, cCAM and Celldex. Peg Esper, DNP, ANP-BC, AOCN, has no real or apparent conflicts of interest to report. This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

Agenda Melanoma and the Immune System
Defining the role of the immune system in cancer Tumor escape from immune surveillance Harnessing the immune system for melanoma treatment Current Immunotherapy for Melanoma Efficacy and safety of currently approved agents Managing potential adverse events associated with immunotherapy Novel Agents and Immunotherapy Combinations

T-Cell Response: First Signal
T-cell receptor Class I MHC Antigen presenting cell CD8+ T cell Tumor antigen Class II MHC T-cell receptor Tumor Tumor antigen CD4+ T cell Snyder A, et al. Curr Opin Genet Dev. 2015;30C:7-16.

T-Cell Response: Accelerate or Brake?
Coactivation Signals Inhibitory Signals TCR CD28 CTLA-4 OX40 PD-1 T cell Use agonistic mAbs to ↑ activation GITR TIM-3 Use blocking mAbs to ↑ activation CD137 BTLA CD27 VISTA HVEM LAG-3 T-Cell Stimulation T-Cell Inhibition Adapted from Mellman I, et al. Nature. 2011;480:

Tumor Immunology: Overview
3 Perforin granzyme Cytokines (IL-2) Resting T cell Activated T cell Tumor 2 Lymph node T-cell clonal expansion Tumor antigen TCR CD28 MHC, major histocompatibility complex; TCR, T cell receptor. Speaker notes: Main concepts include tumor antigen presentation to the immune system via dendritic cells, subsequent activation of T cells, trafficking of activated T cells to tumors and tumor recognition and killing in the tumor microenvironment 1 MHC B7 Dendritic cell

Dampening the Immune System in Cancer
Priming Phase Effector Phase CTLA-4 Dendritic cell Cytotoxic T cell B7 CD28 Tumor B7 PD-L1 PD-1 IDO, indoleamine 2, 3-dioxygenase; MDSC, myeloid-derived suppressor cells; PD-L1, programmed death-ligand 1; T-reg, regulatory T cell. Cytotoxic T cell Exhaustion Negative immune regulators Inhibitory receptors Suppressive cells Suppressive enzymes (IDO, arginase) T T T reg MDSC Ribas A. N Engl J Med. 2012;366: Spranger S, et al. J Immunother Cancer. 2013;1:16.

Immunotherapy for Melanoma

High-Dose IL-2 Therapy: Durable Responses Seen
High-dose IL-2 produces durable responses in 16% of pts with advanced melanoma Few relapses in pts responding for over 2.5 yrs (likely cured) FDA approval in 1998 for melanoma Metastatic Melanoma (N = 270) 1.0 CR (n = 17) PR (n = 26) CR + PR (n = 43) 0.8 0.6 Probability of Continuing Response HD, high-dose; IL-2, interleukin-2; RCC, renal cell carcinoma; FDA, US Food and Drug Administration. Speaker notes: To show and emphasize the potential of immunotherapy with the prolonged responses. Also it was unclear why few patients were responding at the time of these studies. 0.4 0.2 10 20 30 40 50 60 70 80 90 100 110 120 130 Duration of Response (Mos) Atkins MB, et al. J Clin Oncol. 1999;17:

High-Dose IL-2 Therapy in Melanoma
High-dose IL-2 appears to benefit pts, but: Toxic Complex; must be delivered as an inpatient regimen Use remains limited to selected pts treated at experienced centers Efforts to develop more tolerable regimens unsuccessful Efforts to better select pts who might benefit from high- dose IL-2 therapy have produced modest advances Proof of principle that immunotherapy can produce durable benefit in pts with cancer, but newer immunotherapies are needed HD, high-dose; IL-2, interleukin-2; RCC, renal cell carcinoma.

Blocking Immunologic Checkpoints
Priming: T-Cell Activation in the Lymph Node Effector Phase: Peripheral Tissues Dendritic cell CD28 Cytotoxic T cell B7 Tumor CTLA-4 B7 PD-L1 IDO, indoleamine 2, 3-dioxygenase; MDSC, myeloid-derived suppressor cells; PD-L1, programmed death-ligand 1; T-reg, regulatory T cell. Ipilimumab Tremelimumab PD1 MPDL3280A MEDI4736 MSB C Nivolumab Pembrolizumab Pidilizumab Ribas A. N Engl J Med. 2012;366: Spranger S, et al. J Immunother Cancer. 2013;1:16.

Ipilimumab, gp100, or Both: OS in Advanced Melanoma
Median OS, Mos 1.0 HR P < Comparison vs gp100 alone 0.9 Ipilimumab + gp100 (n = 403) Ipilimumab alone (n = 137) gp100 alone (n = 136) 0.8 0.7 1-yr OS: Ipi + gp100 44% Ipi alone: 46% Gp100 alone: 25% 0.6 Proportion Alive 0.5 2-yr OS, % Ipi + gp100 22% Ipi alone: 24% Gp100 alone: 14% 0.4 Ipi, ipilimumab; OS, overall survival. Speaker notes: Survival data from previously treated pts with advanced melanoma that led to the approval of ipilimumab. 0.3 0.2 0.1 1 2 3 4 Yrs Hodi FS, et al. N Engl J Med. 2010;363: 14

Analysis From Phase II and Phase III Trials of Ipilimumab Show OS Plateau at 3 Years
1.0 0.9 0.8 Median OS: 11.4 mos (95% CI: ) 0.7 3-yr OS rate: 22% (95% CI: 20% to 24%) 0.6 Proportion Alive 0.5 0.4 0.3 CI, confidence interval; OS, overall survival. Speaker notes: Key point to highlight is the tail of the curve – prolonged survival in about 20% of patients 0.2 Ipilimumab 0.1 Censored 12 24 36 48 60 72 84 96 108 120 Mos Pts at Risk, n Ipilimumab 1861 839 370 254 192 170 120 26 15 5 Hodi S, et al European Cancer Congress. Abstract LBA 24. Schadendorf D, et al. J Clin Oncol [Epub ahead of print].

Ipilimumab, gp100, or Both in Advanced Melanoma (MDX010-20): irAEs
All Grades (Grade 3/4) Ipi + gp100 (n = 380) Ipi + Placebo (n = 131) gp100 + placebo (n = 132) Any 58 (9.7/0.5) 61 (12.2/2.3) 32 (3.0/0) Dermatologic 40 (2.1/0.3) 44 (1.5/0) 17 (0/0) Gastrointestinal 32 (5.3/0.5) 29 (7.6/0) 14 (0.8/0) Endocrine 4 (1.1/0) 8 (2.3/1.5) 2 (0/0) Hepatic 2 (1.1/0) 4 (0/0) 5 (2.3/0) Ipi, ipilimumab; irAEs, immune-related adverse events. Speaker notes: Immune-related AEs are those that are inflammatory in nature and cannot be attributed to non-immune causes (e.g. infection is ruled out). These are the most common side effects, as has been reported. This automated computer-generated count is based on a pre-specified list of inflammatory-type AEs (“itis”)…..and, as such, may be an OVER-estimate of the number of truly immune-related events that occurred in each arm. Here, the rate of all irAEs (all grades) is 32% in the gp100 arm and about 60% in the ipi arms. Grade 3 events are uncommon: % compared to 3% in the gp100 arm. The most common type of event is skin-based with rare grade 3 events (~2% GI irAEs, most notably diarrhea and colitis, occurs (at any grade) in approximately 30% of subjects. 6-8% are grade 3. Endocrinopathy, most commonly central adrenal insufficiency occurs rarely. Well-defined treatment algorithms have been established for these. The mainstay of treatment is systemic immunosuppressive agents which lead to complete resolution of the events in most cases and do not appear to interfere with the anti-cancer effect of ipilimumab. Endocrinopathy is the exception. While patients feel better quickly with hormone replacement, the ipilimumab effect on the endocrine system appears to be long-lasting and lifelong hormone replacement is likely required. Hodi SF, et al. N Engl J Med. 2010;363: 16

Kinetics of Appearance of irAEs with Ipilimumab
Rash, pruritus Liver toxicity Diarrhea, colitis Hypophysitis Toxicity Grade irAEs, immune-related adverse events. 2 4 6 8 10 12 14 Wks Weber JS, et al. J Clin Oncol. 2012;30:

Ipilimumab: Key to Optimal Patient Management
First Dose: baseline assessment; review medical history, check standard of care lab values including LFTs, TFTs Subsequent doses: before each infusion or as needed, check lab values including AST, ALT, total bilirubin, and thyroid function Conduct thorough assessment of immune-mediated symptoms Educate on importance of detecting and prompt reporting of symptoms Discuss key points about immune-mediated adverse events and importance of prompt medical intervention Confirm patient’s ability to verbalize important symptoms Emphasize that symptoms may be intermittent and can occur wks to mos after treatment is complete A stepwise approach to recommendations for proper and thorough review prior to patients first administration of Ipilimumab. Insuring full standard of care labs profile plus thyroid functions be evaluated. A comprehensive teaching session or follow up to teaching session should be conducted, patient resources such as patient medication hand out and wallet card should be provided. Most importantly, contact information for the office 24/7/365 should be reviewed, what to do during off hours.,Holidays or in the need of seeking emergent care. Patients should be instructed to call at the onset of symptoms and not delay reporting as that may complicate management and interfere with quality of life.

Ipilimumab: Managing Immune-Related Adverse Events
System Symptoms Management GI tract Diarrhea Abdominal pain Dark, bloody stools Moderate enterocolitis: hold ipilimumab, administer antidiarrheal. Persistent diarrhea (> 1 wk): systemic corticosteroids. 7+ stools/day: start methylprednisone, permanently discontinue ipilimumab. Consider infliximab for corticosteroid-refractory pts. Skin Rash (± itching) Blistering/peeling Oral sores Moderate/nonlocalized rash: hold ipilimumab, start topical or systemic corticosteroids. Severe dermatitis: permanently discontinue ipilimumab, start corticosteroids. Liver Jaundice Nausea/vomiting Assess ALT/AST, bilirubin, and thyroid function before each dose and as necessary. Hold ipilimumab if ALT/AST > 2.5 x but ≤ 5 x ULN; permanently discontinue if AST/ALT > 5 x ULN or bilirubin > 3 x ULN. The immunosuppressant mycophenolate can be used for hepatotoxicity in corticosteroid-refractory pts. CNS Weakness in extremities Numbness/tingling Sensory changes Moderate neuropathy: hold ipilimumab. New or worsening neuropathy: permanently discontinue ipilimumab. Consider corticosteroids. Endocrine Headaches Fatigue Behavior/mood changes Menstruation changes Dizziness/light-headedness Moderate endocrinopathy: hold ipilimumab, start corticosteroids. Endocrine abnormalities can be difficult to detect, due to nonspecific symptoms. Consider having an endocrinologist follow the pt. Eyes Vision problems Irritation Monitor for redness suggesting uveitis; treat with topical steroidal eye drops. System Symptoms Management GI tract Diarrhea Abdominal pain Dark, bloody stools Moderate enterocolitis: hold ipilimumab, administer antidiarrheal. Persistent diarrhea (> 1 wk): systemic corticosteroids. 7+ stools/day: start methylprednisone, permanently discontinue ipilimumab. Consider infliximab for corticosteroid-refractory pts Skin Rash (± itching) Blistering/peeling Oral sores Moderate/nonlocalized rash: hold ipilimumab, start topical or systemic corticosteroids. Severe dermatitis: permanently discontinue ipilimumab, start corticosteroids Liver Jaundice Nausea/vomiting Assess ALT/AST, bilirubin, and thyroid function before each dose and as necessary. Hold ipilimumab if ALT/AST > 2.5 x but ≤ 5 x ULN; permanently discontinue if AST/ALT > 5 x ULN or bilirubin > 3 x ULN. The immunosuppressant mycophenolate can be used for hepatotoxicity in corticosteroid-refractory pts CNS Weakness in extremities Numbness/tingling Sensory changes Moderate neuropathy: hold ipilimumab. New or worsening neuropathy: permanently discontinue ipilimumab. Consider corticosteroids Endocrine Headaches Fatigue Behavior/mood changes Menstruation changes Dizziness/light-headedness Moderate endocrinopathy: hold ipilimumab, start corticosteroids. Endocrine abnormalities can be difficult to detect, due to nonspecific symptoms. Consider having an endocrinologist follow the pt Eyes Vision problems Irritation Monitor for redness suggesting uveitis, treat with topical steroidal eye drops GI, gastrointestinal; ALT, alanine transaminase; AST, aspartate transaminase; ULN, upper limit of normal. Ipilimumab adverse reaction management guide. Available at:

Ipilimumab: Managing Immune-Related Adverse Events
System Symptoms Management GI tract Diarrhea Abdominal pain Dark, bloody stools Moderate enterocolitis: hold ipilimumab, administer antidiarrheal. Persistent diarrhea (> 1 wk): systemic corticosteroids. 7+ stools/day: start methylprednisone, permanently discontinue ipilimumab. Consider infliximab for corticosteroid-refractory pts. Skin Rash (± itching) Blistering/peeling Oral sores Moderate/nonlocalized rash: hold ipilimumab, start topical or systemic corticosteroids. Severe dermatitis: permanently discontinue ipilimumab, start corticosteroids. Liver Jaundice Nausea/vomiting Assess ALT/AST, bilirubin, and thyroid function before each dose and as necessary. Hold ipilimumab if ALT/AST > 2.5 x but ≤ 5 x ULN; permanently discontinue if AST/ALT > 5 x ULN or bilirubin > 3 x ULN. The immunosuppressant mycophenolate can be used for hepatotoxicity in corticosteroid-refractory pts. CNS Weakness in extremities Numbness/tingling Sensory changes Moderate neuropathy: hold ipilimumab. New or worsening neuropathy: permanently discontinue ipilimumab. Consider corticosteroids. Endocrine Headaches Fatigue Behavior/mood changes Menstruation changes Dizziness/light-headedness Moderate endocrinopathy: hold ipilimumab, start corticosteroids. Endocrine abnormalities can be difficult to detect, due to nonspecific symptoms. Consider having an endocrinologist follow the pt. Eyes Vision problems Irritation Monitor for redness suggesting uveitis; treat with topical steroidal eye drops. System Symptoms Management GI tract Diarrhea Abdominal pain Dark, bloody stools Moderate enterocolitis: hold ipilimumab, administer antidiarrheal. Persistent diarrhea (> 1 wk): systemic corticosteroids. 7+ stools/day: start methylprednisone, permanently discontinue ipilimumab. Consider infliximab for corticosteroid-refractory pts Skin Rash (± itching) Blistering/peeling Oral sores Moderate/nonlocalized rash: hold ipilimumab, start topical or systemic corticosteroids. Severe dermatitis: permanently discontinue ipilimumab, start corticosteroids Liver Jaundice Nausea/vomiting Assess ALT/AST, bilirubin, and thyroid function before each dose and as necessary. Hold ipilimumab if ALT/AST > 2.5 x but ≤ 5 x ULN; permanently discontinue if AST/ALT > 5 x ULN or bilirubin > 3 x ULN. The immunosuppressant mycophenolate can be used for hepatotoxicity in corticosteroid-refractory pts CNS Weakness in extremities Numbness/tingling Sensory changes Moderate neuropathy: hold ipilimumab. New or worsening neuropathy: permanently discontinue ipilimumab. Consider corticosteroids Endocrine Headaches Fatigue Behavior/mood changes Menstruation changes Dizziness/light-headedness Moderate endocrinopathy: hold ipilimumab, start corticosteroids. Endocrine abnormalities can be difficult to detect, due to nonspecific symptoms. Consider having an endocrinologist follow the pt Eyes Vision problems Irritation Monitor for redness suggesting uveitis, treat with topical steroidal eye drops Principles of Managing irAEs: Hold ipilimumab Initiate steroids therapy (1–2 mg/kg of prednisone or equivalent daily) Consider infliximab (if gastrointestinal toxicity) or mycophenolate (if hepatotoxicity) if steroids do not resolve symptoms Weber JS, et al. J Clin Oncol. 2012;30: GI, gastrointestinal; ALT, alanine transaminase; AST, aspartate transaminase; ULN, upper limit of normal. Ipilimumab adverse reaction management guide. Available at:

Ipilimumab in Melanoma: Current Issues
Dose: 3 mg/kg or 10 mg/kg? Phase III results pending in patients with metastatic melanoma[1] Schedule: maintenance therapy or not? Role in the adjuvant setting? EORTC 18071: ipilimumab 10 mg/kg vs placebo[2] E1609: ipilimumab 3 or 10 mg/kg vs IFN[3] In combinations? Bevacizumab, other immunotherapies (GM-CSF, IFN, IL-2, PD-1 antibodies, and T-Vec), and radiation therapy High toxicity when combined with BRAF inhibitors[4] EORTC, European Organisation for Research and Treatment of Cancer; IPI, ipilimumab; IFN, interferon; GM-CSF, granulocyte macrophase colony-stimulating factor; irAEs, immune-related adverse events; OS, overall survival; PD1, programmed death 1; RFS, recurrence-free survival; IL-2, interleukin-2. 1. ClinicalTrials.gov. NCT Eggermont A, et al. ASCO LBA ClinicalTrials.gov. NCT Ribas A, et al. N Engl J Med. 2013;368:

OS: Ipi + GM-CSF vs Ipi Alone
Phase II trial: pts randomized to receive ipilimumab 10 mg/kg IV on day 1 ± GM-CSF 250 μg SQ on days 1 to 14 of a 21-day cycle 1.0 Stratified 1-sided log-rank P = .014 HR: 0.64 (90% RCI: -- to 0.90) 0.8 0.6 OS Probability 0.4 CI, confidence interval; GM-CSF, granulocyte macrophage colony-stimulating factor; Ipi, ipilimumab; IV, intravenous; NR, not reached; OS, overall survival; RCI, repeated confidence interval; SQ, subcutaneous. 1-yr OS Median OS 0.2 Ipi (n = 122) % mos Ipi + GM-CSF (n = 123) % mos 2 4 6 8 10 12 14 16 18 20 Mos Since Randomization Hodi S, et al. JAMA. 2014;312:

Blocking Immunologic Checkpoints
Priming: T-Cell Activation in the Lymph Node Effector Phase: Peripheral Tissues Tumor Dendritic cell CD28 Cytotoxic T cell B7 Interferons CTLA-4 B7 IDO, indoleamine 2, 3-dioxygenase; MDSC, myeloid-derived suppressor cells; PD-L1, programmed death-ligand 1; T-reg, regulatory T cell. Ipilimumab Tremelimumab PD-L1 PD1 MPDL3280A MEDI4736 MSB C Nivolumab Pembrolizumab Pidilizumab Ribas A. N Engl J Med. 2012;366: Spranger S, et al. J Immunother Cancer. 2013;1:16.

Phase I (KEYNOTE-001): Pembrolizumab Leads to Frequent and Durable Responses
ORR is 37%; 81% with response continue to receive treatment 160 Prior ipilimumab treatment No prior ipilimumab treatment 140 120 100 80 60 Percent Change From Baseline in Longest Diameter of Target Lesion 40 Individual Pts Treated With Pembrolizumab 20 Prior ipilimumab treatment No prior ipilimumab treatment CR PR Still receiving treatment -20 -40 -60 -80 -100 Individual Pts Treated With Pembrolizumab 10 20 30 40 50 60 70 Wks Hamid O, et al. N Engl J Med 2013;369:

Pembrolizumab received FDA approval 9/4/14
Phase I (KEYNOTE-001): Pembrolizumab Leads to Frequent and Durable Responses ORR is 37%; 81% with response continue to receive treatment 160 Prior ipilimumab treatment No prior ipilimumab treatment 140 120 100 Pembrolizumab received FDA approval 9/4/14 80 60 Percent Change From Baseline in Longest Diameter of Target Lesion 40 Individual Pts Treated With Pembrolizumab 20 Prior ipilimumab treatment No prior ipilimumab treatment CR PR Still receiving treatment -20 -40 -60 -80 -100 Individual Pts Treated With Pembrolizumab 10 20 30 40 50 60 70 Wks Hamid O, et al. N Engl J Med 2013;369:

Phase I: Nivolumab Leads to Frequent and Durable Responses
ORR is 31%; 58% with response ongoing at time of analysis 100 Nivolumab 1 mg/kg 80 60 40 20 Change in Target Lesion From Baseline (%) Patients Time to response Ongoing response Response following discontinuation of therapy -20 -40 PD-1, programmed death 1. -60 -80 -100 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 24 48 72 96 120 144 168 Wks Since Treatment Initiations Wks Since Treatment Initiation Topalian SL, et al. J Clin Oncol. 2014;32:

Phase I: Nivolumab Leads to Frequent and Durable Responses
ORR is 31%; 58% with response ongoing at time of analysis 100 Nivolumab 1 mg/kg 80 60 Nivolumab received FDA approval 12/21/14 40 20 Change in Target Lesion From Baseline (%) Patients Time to response Ongoing response Response following discontinuation of therapy -20 -40 PD-1, programmed death 1. -60 -80 -100 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 24 48 72 96 120 144 168 Wks Since Treatment Initiations Wks Since Treatment Initiation Topalian SL, et al. J Clin Oncol. 2014;32:

KEYNOTE-001: Pembrolizumab AE Profile
Grade 3/4 AEs in ≥ 1 Pt, % Pembro 2 mg/kg (n = 89) Pembro 10 mg/kg (n = 84) Fatigue 6 Amylase increase 1 Anemia Autoimmune hepatitis Confusion Diarrhea Dyspnea Encephalopathy Hypophysitis Hypoxia Muscular weakness Muscoloskeletal pain Pancreatitis Peripheral motor neuropathy Pneumonitis Rash Rash maculopapular Robert C, et al. Lancet 2014;384:

Nivolumab AE Profile Grade 3/4 AEs, % Nivolumab (N = 107) Any AE 22.4
Lymphopenia 2.8 Fatigue 1.9 Diarrhea Nausea 0.9 Abdominal pain Dry mouth Vomiting Hyperuricemia Hypophosphatemia Blood thyroid-stimulating hormone increased Hemoglobin decreased Platelet count decreased Hypothyroidism Topalian SL, et al. J Clin Oncol. 2014;32:

Investigator’s choice of chemotherapy* (n = 102)
KEYNOTE-002: Phase II Trial of Pembro vs Chemotherapy in Ipi-Refractory Pts Pembrolizumab 2 mg/kg IV q2w (n = 268) Pts with PD confirmed by independent central review could cross over to pembrolizumab treatment after the first 3-mo assessment Pts with advanced melanoma who progressed on or after ipilimumab (and BRAF, if BRAF V600+) Pembrolizumab 10 mg/kg IV q2w (n = 268) Investigator’s choice of chemotherapy* (n = 102) IPI, ipilimumab; PD-L1, programmed death ligand 1; Q3W, every 3 weeks; AUC, area under the curve; CTLA-4; cytotoxic T-lymphocyte antigen; IV, intravenous; Q2W, every 2 weeks. *Carboplatin + paclitaxel, paclitaxel alone, dacarbazine, or temozolomide. Primary endpoint: PFS, OS Secondary endpoints: ORR, DoR Ribas A, et al. SMR November 16, 2014.

KEYNOTE-002: Pembrolizumab vs Chemotherapy in Ipi-Refractory Melanoma
An international, randomized phase II study in pts with advanced melanoma with PD within 24 wks after ≥ 2 Ipi doses Arm ORR, % Median PFS, Mos (95% CI) Mean PFS, Mos PFS HR (95% CI) PFS P value Pembro 2 mg/kg q3w 21 2.9 ( ) 5.4 0.57 ( ) < .0001 10 mg/kg q3w 25 2.9 ( ) 5.8 0.50 ( ) Chemo 4 2.7 ( ) 3.6 100 90 80 70 60 Pembro vs Chemo Progression-Free Survival, % PFS (%) 50 PFS, progression-free survival; Pembro, pembrolizumab; Q3W, every 3 weeks; CI, confidence interval; HR, hazard ratio. 40 30 20 10 2 4 6 8 10 12 14 16 18 Mos Ribas A, et al. SMR November 16, 2014.

Investigator’s choice of chemotherapy (ICC):
Checkmate-037: Phase III Trial of Nivolumab vs Chemotherapy in IPI-Refractory Pts Stratified by PD-L1 expression (+ vs - or indeterminate)*; BRAF wt vs V600 mutant; best overall response prior to anti–CTLA-4 (clinical benefit vs no clinical benefit) Treat until Progression OR Unacceptable toxicity Pts receiving nivolumab may be treated beyond initial progression if considered by the investigator to be experiencing clinical benefit and tolerating study drug Nivolumab 3 mg/kg IV q2w (n = 268) Pts with advanced melanoma who progressed on or after ipilimumab (and BRAF, if BRAF V600+) Open Label Investigator’s choice of chemotherapy (ICC): Dacarbazine 1000 mg/m2 q3w or Carboplatin AUC 6 IV + Paclitaxel 175 mg/m2 q3w (n = 102) IPI, ipilimumab; PD-L1, programmed death ligand 1; Q3W, every 3 weeks; AUC, area under the curve; CTLA-4; cytotoxic T-lymphocyte antigen; IV, intravenous; Q2W, every 2 weeks. *Positive: ≥ 5% tumor cell surface staining cutoff by immunohistochemistry. Weber JS, et al. Lancet Oncol. 2015;16:

Best Overall Response,* %
Targeting T Cells With Nivolumab Leads to Higher Response Rate vs Chemotherapy Treatment N CR + PR, n ORR,* % (95% CI) Best Overall Response,* % CR PR SD PD UNK Central review† Nivolumab 120 38 (4 CR) 32 (24-41) 3 28 23 35 10 ICC 47 5 (0 CR) 11 (4-23) 11 34 32 *Confirmed response. †Independent radiology review committee based on RECIST 1.1. ICC, investigator’s choice of chemotherapy; CR, complete response; PR, partial response; ORR, overall response rate; SD, stable disease; PD, progressive disease; UNK, unknown; CI, confidence interval; RECIST; Response Evaluation Criteria in Solid Tumors; Pts, patients. Weber JS, et al. Lancet Oncol. 2015;16:

Nivolumab vs Pembrolizumab in Ipilimumab-Refractory Patients
Comparison Nivolumab (Checkmate-037) Pembrolizumab (KEYNOTE-002) Number of patients (IPI-R) 120 (preliminary subset) 180 FDA Approved Schedule 3 mg/kg IV every 2 weeks 2 mg/kg IV every 3 weeks ORR, % (95% CI) 32 (24-41) 21 (15-28) Grades 3-4 drug related toxicities, % 5 8 Weber JS, et al. Lancet Oncol. 2015;16: Ribas A, et al. SMR November 16, 2014.

Phase III CA209-066 First-line Nivolumab vs Chemotherapy Trial: Study Design
Stratified by PD-L1 status,† M-stage Treat until progression* or unacceptable toxicity Primary endpoint: OS Secondary endpoints: PFS ORR PD-L1 correlates Nivolumab 3 mg/kg IV q2w + Placebo IV q3w (n = 210; 206 treated) Unresectable, treatment-naive stage III or IV melanoma; BRAF wild-type; ECOG PS 0-1; 18 yrs of age or older (N = 418) Double-blind Placebo IV q2w + Dacarbazine mg/m2 IV q3w (n = 208; 205 treated) M, metastasis; PD-L1, programmed death ligand 1; Q2W, every 2 weeks; Q3W, every 3 weeks; ECOG; Eastern Cooperative Oncology Group; PS, performance status; OS, overall survival; PFS, progression-free survival; ORR, overall response rate; RECIST, Response Evaluation Criteria in Solid Tumors. †PD-L1 positive: ≥ 5% tumor cell surface staining. *Pts may be treated beyond initial RECIST v1.1–defined progression if considered by the investigator to be experiencing clinical benefit and tolerating study drug. Robert C, et al. N Engl J Med. 2015;372:

OS: First-line Nivolumab vs Chemotherapy
Objective response rate: 40% with nivolumab vs 13.9% with chemo (P <.001) Significantly better OS with nivolumab vs dacarbazine 100 HR 0.42 (99.79% CI: 0.25–0.73; P < .001) Patients Surviving (%) 90 1-yr OS 73% 80 70 Months 60 50 1-yr OS 42% NR, not reached; OS, overall survival; HR, hazard ratio; CI, confidence interval. The final edited version in the manuscript is: “All the patients who underwent randomization were followed up for up to 16.7 months at the time of database lock on August 5, 2014, which was 5.2 months after the first visit of the last patient who had undergone randomization.” History: At one point, we have “minimum follow-up was 5.2 months” in the manuscript abstract. This was subsequently removed for word count reason. The mention of minimum follow-up (from last randomization to data cut, 5 Aug 2014) replaced the median follow-up data (8.9 mo for nivo; 6.8 mo for DTIC; not calculated for overall [N=418] population) due to concern that the imbalance in medians might be misinterpreted as greater loss to follow-up in the DTIC arm while in reality this was due to more death. The final version is the result of multiple rounds of edits, including changes by journal editors. 40 Pts who died, n/N Median OS, mo (95% CI) 30 20 Nivolumab 50/210 NR 10 Dacarbazine 96/208 10.8 ( ) 3 6 9 12 15 18 Robert C, et al. N Engl J Med. 2015;372:

KEYNOTE-006: Analysis of Pembro vs Ipi Trial Design
A multicenter, randomized, controlled phase III study Primary endpoint: PFS, OS Secondary endpoint: ORR, DoR, Safety Stratified by ECOG PS (0 vs 1), line of therapy (first vs second), PD-L1 status (positive vs negative) Pembrolizumab 10 mg IV every 2 weeks for up to 2 yrs Unresectable stage III or IV melanoma; ≤1 prior therapy, excluding checkpoint inhibitors; ECOG PS 0-1; 18 yrs of age or older (estimated N = 645) Pembrolizumab 10 mg IV every 3 weeks for up to 2 yrs DoR, duration of response; ECOG PS; Eastern Cooperative Oncology Group performance status; Ipi, ipilimumabb; ORR, overall response rate; OS, overall survival; Pembro, pembrolizumab; PFS, progression free survival. Ipilimumab 3 mg/kg IV once every 3 weeks for 4 doses Robert C, et al. N Engl J Med. 2015;372:

KEYNOTE-006: Survival Efficacy at First Interim Analysis of Pembro vs Ipi
PFS OS 100 100 90 90 80 80 70 70 60 60 Progression-Free Survival, % 50 Overall Survival, % 50 40 40 30 30 20 20 10 10 2 4 6 8 10 12 14 2 4 6 8 10 12 14 16 18 Time, months Time, months Treatment Arm Median PFS (95% CI), mo Rate at 6 mo, % HR (95% CI) P Pembrolizumab Q2W 5.5 ( ) 47.3 0.58 ( ) <.00001 Pembrolizumab Q3W 4.1 ( ) 46.4 0.58 ( ) Ipilimumab 2.8 ( ) 26.5 — Median OS (95% CI), mo Rate at 12 mo, % HR (95% CI) P NR (NR-NR) 74.1 0.63 ( ) .00052 68.4 0.69 ( ) .0036 NR (12.7-NR) 58.2 — Robert C, et al. N Engl J Med. 2015;372:

Checkmate-067: Nivo + Ipi vs Nivo vs Ipi for First-line Treatment of Melanoma
A randomized, double-blind phase III study Primary endpoint: OS, PFS Secondary endpoint: ORR, OS by PD-L1, Safety Stratified by tumor PD-L1 status (positive vs negative/indeterminate), BRAF mutation status (V600 mutation–positive vs wild-type), and AJCC metastasis stage (M0, M1a, or M1b vs. M1c) Nivolumab 1 mg/kg IV + Ipilimumab 3 mg/kg IV every 3 weeks for 4 doses Nivolumab 3 mg/kg IV every 2 weeks until PD or unacceptable AE Unresectable, treatment-naive stage III or IV melanoma; ECOG PS 0-1; 18 yrs of age or older (N = 945) Placebo + Nivolumab 3 mg/kg IV every 2 weeks for 4 doses Nivolumab 3 mg/kg IV every 2 weeks until PD or unacceptable AE Placebo + Ipilimumab 3 mg/kg IV every 3 weeks for 4 doses Placebo IV every 2 weeks until PD or unacceptable AE All patients receive injections 2 out of every 3 weeks Larkin J, et al. N Engl J Med. 2015;373:23-34.

CheckMate 067: Improved PFS with Nivo + Ipi or Nivo Alone vs Ipi Alone
Median PFS, mos (95% CI) 11.5 ( ) 6.9 ( ) 2.9 ( ) HR (99.5% CI) vs Ipi 0.42 ( )* 0.57 ( )* _ HR (95% CI) vs Nivo 0.74 ( )† 1.0 0.9 0.8 0.7 0.6 Proportion Alive and Progression Free 0.5 0.4 0.3 Ipi, ipilimumab; ITT, intent to treat; Nivo, nivolumab; PFS, progression-free survival. Nivo + Ipi Nivo Ipi 0.2 0.1 3 6 9 12 15 18 21 Mos *Stratified log-rank P < vs Ipi. †Exploratory endpoint. Study not powered to detect a statistical difference between Nivo + Ipi and Nivo. Larkin J, et al. N Engl J Med. 2015;373:23-34.

CheckMate 067: Improved PFS with Nivo + Ipi or Nivo Alone vs Ipi Alone
Median PFS, mos (95% CI) 11.5 ( ) 6.9 ( ) 2.9 ( ) HR (99.5% CI) vs Ipi 0.42 ( )* 0.57 ( )* _ HR (95% CI) vs Nivo 0.74 ( )† 1.0 0.9 Nivolumab was FDA approved in combination with ipilimumab in patients with BRAF V600 wild-type metastatic melananoma based on data from the phase II CheckMate-069 on 9/30/2015 0.8 0.7 0.6 Proportion Alive and Progression Free 0.5 0.4 0.3 Ipi, ipilimumab; ITT, intent to treat; Nivo, nivolumab; PFS, progression-free survival. Nivo + Ipi Nivo Ipi 0.2 0.1 3 6 9 12 15 18 21 Mos *Stratified log-rank P < vs Ipi. †Exploratory endpoint. Study not powered to detect a statistical difference between Nivo + Ipi and Nivo. Larkin J, et al. N Engl J Med. 2015;373:23-34.

CheckMate 067: Nivo + Ipi Provides Most Benefit for PD-L1lo, Similar to Nivo for PD-L1hi
Median PFS HR Median PFS HR 100 Nivo + Ipi Nivo alone Ipi alone 100 Nivo + Ipi Nivo alone Ipi alone 80 80 60 60 PFS, % PFS, % 40 40 20 Ipi, ipilimumab; Nivo, nivolumab; PFS, progression-free survival. 20 3 6 9 12 15 17 3 6 9 12 15 18 21 Mos Mos *Per validated PD-L1 immunohistochemical assay based on PD-L1 staining of tumor cells in a section of at least 100 evaluable tumor cells. Larkin J, et al. N Engl J Med. 2015;373:23-34.

CheckMate 067: Treatment-Related AEs Associated With Nivo and Ipi
Select Treatment-Related AEs, % Nivo + Ipi (n = 313) Nivo (n = 313) Ipi (n = 311) All Grades Grade 3/4 Any select AE 88 40 62 8 74 19 Skin Pruritus Rash Maculopapular rash 59 33 28 12 6 2 3 42 22 4 < 1 54 35 21 Gastrointestinal Diarrhea Colitis 46 44 15 9 20 1 37 Hepatic ALT increase AST increase 30 18 7 Endocrine Hypothyroidism 5 14 11 Pulmonary Pneumonitis AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; IPI, ipilimumab; NIVO, nivolumab. Larkin J, et al. N Engl J Med. 2015;373:23-34.

PD-1/PD-L1 Inhibition: Managing Treatment-Related Adverse Events
Any grade 1 AE Isolated hypothyroidism Grade 2 pneumonitis, nephritis, colitis, hepatitis Symptomatic hypophysitis Any grade 3 AE Initiate steroids or replacement therapy for hypothyroidism Hold PD-1 tx and administer steroids; After improvement to ≤ grade 1, taper steroids over at least 1 mo CST, corticosteroid Continue PD-1 tx and monitor Resume if: AE remains at grade 0/1 after steroid taper Discontinue if: No improvement to ≤ grade 1 within 12 wks Pembrolizumab adverse reaction management guide. Nivolumab adverse reaction management guide.

PD-1/PD-L1 Inhibition: Managing Treatment-Related Adverse Events
Grade 3/4 pneumonitis Grade 3/4 nephritis Grade 3/4 infusion-related reaction Any life-threatening or grade 4 AE Any severe or grade 3 recurrent AE Initiate steroid therapy Hepatitis associated with AST/ALT > 5 x ULN AST/ALT ≥ 50% ↑ from baseline lasting ≥ 1 wk* Total bilirubin > 3 x ULN Permanently discontinue PD-1 tx *In pts with liver metastasis who begin treatment with grade 2 elevation of AST/ALT. Pembrolizumab adverse reaction management guide. Nivolumab adverse reaction management guide.

Patient Education on Novel Therapies
Patient education should include information on: Adverse reaction profiles that differs from standard chemotherapy Early recognition of irAEs essential for effective treatment irAEs are infrequent, treatable and respond well to steroids Who and when to call for adverse reactions Evaluate pt and caregiver for continued educational needs related to the therapy and disease process Reinforce teaching points at every point of contact, office and treatment visits, and phone contact Patient education should start from prior to therapy onset and through out therapy at every contact point the clinician has with the patient. Patients and their care partner(s) should be included to be active participants in the patients care especially if an adverse effect develops. Emphasis on the importance of maintaining a treatment schedule to optimize the best outcomes and conversly to intervene when an adverse effect develops and interferes with quality of life and potential for continuing treatment.

Future Directions

ORR by PD-L1 Expression in Pts With Solid Tumors
Rx Antibody Tumor type N PD-L1 + RR, n/N (%) PD-L1 - RR, Nivolumab[1] Solid tumors 42 9/25 (36) 0/17 (0) Nivolumab[2] 38 7/16 (44) 3/18 (17) MPDL3280A[3] 103 13/36 (36) 9/67 (13) Nivolumab[4] Melanoma 44 8/12 (67) 6/32 (19) 9/23 (39) 5/21 (24) Pembrolizumab[5] 125 41/83 (49) 4/30 (13) Ipi/Nivo[6] 27 4/10 (40) 8/17 (47) Ipi/Nivo[7] 56 8/14 (57) 17/42 (40) IHC, immunohistochemistry; Ipi, ipilimumab; Nivo, nivolumab; ORR, overall response rate; PD-L1, programmed death-ligand 1; RR, response rate; IC, immune cell. Speaker notes: Tumors with PD-L1 expression can often be aggressive and carry a poor prognosis PD-L1 expression is associated with a higher response rate though PD-L1-negative can also respond Preliminary results from combination therapy suggest that response does not correlate with PD-L! expression 1. Topalian SL, et al. N Engl J Med. 2012;366: Grosso J, et al. ASCO Abstract Herbst RS, et al. ASCO Abstract Weber JS, et al. ASCO Abstract Kefford R, et al. ASCO Abstract Callahan. ASCO Abstract Sznol M, et al. ASCO LBA9003.

OS Appears to Favor PD-L1+ Tumors Treated With Pembrolizumab*
1.00 0.75 Survival Probability 0.50 P < .0001 0.25 PD-L1 Status Negative Positive 1-yr OS, % OS, overall survival; PD-L1, programmed death ligand 1; IHC, immunohistochemistry. HR: 0.42; P < .001 0.00 3 6 9 12 15 18 21 24 Time, months *Based on tumor PD-L1 expression by IHC Joseph R, et al. SMR Abstract LBA34.

Nivo Improved OS vs Dacarbazine Regardless of PD-L1 status
100 90 80 Median OS: Not reached 70 Median OS: Not reached 60 Patients Surviving (%) 50 40 Median OS: 12.4 mo 30 Nivolumab, PD-L1 Postive (N = 74) Nivolumab, PD-L1 Negative (N = 128) Dacarbazine PD-L1 Positive (N = 74) Dacarbazine PD-L1 Negative (N = 126) 20 10 Median OS: 10.2 mo 3 6 9 12 15 18 Months Robert C, et al. N Engl J Med. 2015;372:

Issues With PD-L1 as a Biomarker
PD-L1 negativity an unreliable biomarker in certain settings Assays are technically difficult, imperfect; results may differ depending on the antibody/assay (tumor vs immune cells) Expression cut-off, tumor heterogeneity, and inducible gene = sampling error (false negative) Archived tissue different than recent biopsy May be more useful in determining which tumors rather than which pts to treat PD-L1 expression may be less relevant for combination therapies PD-L1 expression may be constitutive (no immune infiltrate) PD-L1, programmed death-ligand 1.

A Roadmap of Immunotherapy-Tumor Interactions
Trafficking of T cells to tumors 4 Priming and activation 3 Anti-CTLA4 Anti-CD137 (agonist) Anti-OX40 (agonist) Anti-CD27 (agonist) IL-2 IL-12 5 Infiltration of T cells into tumors Anti-VEGF Cancer antigen presentation 2 IFN, interferon; GM-CSF, granulocyte macrophage colony-stimulating factor; TLR, toll-like receptor; IL, interleukin; CTLA4, cytotoxic T-lymphocyte-associated protein 4; VEGF, vascular endothelial growth factor; CARs, chimeric antigen receptors; IDO, indoleamine 2,3-dioxygenase. Vaccines IFN-α GM-CSF Anti-CD40 (agonist) TLR agonists 6 Recognition of cancer cells by T cells CARs Release of cancer cell antigens 7 Killing of cancer cells 1 Chemotherapy Radiation therapy Targeted therapy Anti-PD-L1 Anti-PD-1 IDO inhibitors Chen DS, et al. Immunity. 2013;39:1-10.

Conclusions Immunotherapy for melanoma induces responses of long duration and results in prolonged OS Novel patterns of response with checkpoint protein inhibition require new types of response criteria that accommodate progression followed by regression Immune-related adverse events are a unique spectrum of adverse events with checkpoint protein inhibition that require learning new ways to manage toxicity The best is yet to come!

Thank You!

Go Online for More CCO Coverage of Cancer Immunotherapy!
Capsule Summaries of all the key data from recent conferences Additional CME-certified activities on cancer immunotherapy with expert faculty commentary and discussion clinicaloptions.com/oncology

In Partnership With Principles and Application of Immunotherapy for Cancer: Advanced Melanoma This program is supported by educational grants from Genentech.

Similar presentations

Presentation on theme: "In Partnership With Principles and Application of Immunotherapy for Cancer: Advanced Melanoma This program is supported by educational grants from Genentech."— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

In Partnership With Principles and Application of Immunotherapy for Cancer: Advanced Melanoma This program is supported by educational grants from Genentech.

Similar presentations

Presentation on theme: "In Partnership With Principles and Application of Immunotherapy for Cancer: Advanced Melanoma This program is supported by educational grants from Genentech."— Presentation transcript:

Similar presentations

About project

Feedback