Immunotherapy Update in Oncology

CancerImmunotherapyAn Overview of Current Practice

WelcomeWe’re glad you could join us

Immunology is an exciting new frontier

Each therapeutic agent offers a different mechanism to boost the body’s ability to fight cancer

The purpose of this presentation is to provide an objective overview of the current state of cancer immunology

History of Immunotherapy

History of Immunotherapy In 1796 Dr. Edward Jenner realized cowpox protected

against smallpox Introduced the practice of vaccination

Immunotherapy has attracted new attention Multiple new oncologic agents Immunotherapy may soon be another agent in the standard of

care for treating cancer

History of ImmunotherapyNew cancer immunotherapies include multiple modalities:

Vaccines Growth factors Checkpoint inhibitors Monoclonal antibodies Cytokines Several targeted and nonspecific agents

Tumor Immunotherapy Overview

What is the Immune System?A biological collection of organs, specific cells, molecules,

and other components that protect body against foreign matter1

Immune cells and the substances they make travel through the body to protect it from infectious pathogens and can also help protect against cancer cell proliferation2

1. Abbas et al, 2011; 2. Widmaier et al, 2006

Basis for Antimicrobial Response Immune system can distinguish self from non-self and

vigorously attack non-self and infected self tissues1

Utilizes numerous mechanisms to fight disease Phagocytosis Antimicrobial peptides The complement system Adapt to and recognize specific pathogens

1. Harris et al, 2013

Immune SubsystemsThe human immune system can be classified into two

different subsystems Innate immunity (or non-specific immune system), which

reacts rapidly to any foreign substance Adaptive immunity (or specific immune system), which

provides a somewhat slower reaction to specific foreign substances

Innate ImmunityThe innate immune system includes inherited physical and

biochemical structures present from birth that protect the body from invading substances Innate immune defenses are non-specific Respond to pathogens in a generic way This system does not confer long-lasting immunity against a

pathogen1

The innate immune system is the dominant system of host defense in most organisms2

1. Alberts et al, 2002; 2. Litman et al, 2005

Innate Immunity Innate immunity includes two

layers of protection External (primary) defenses Internal (secondary) defenses

The body’s internal defenses activate the internal system by triggering the body’s inflammatory response

FPO

(Adapted from Nutritional Oncology, 20141)

Inflammatory ResponseThe inflammatory response activates other components of

the innate immune system’s internal defenses Phagocytes Natural killer (NK) cells Antimicrobial proteins Cytokines (e.g., histamine, prostaglandins, etc.) Kinins Chemical reactions initiated by the complement system

Complement SystemThe complement system

A group of 20+ proteins Stimulates other immune

system elements Can also cause lysis of bacteria

and certain other cells Interferons and proteins are

the two main types of non-specific antimicrobial proteins

FPO

(Adapted from Abbas, 20111)

Chaudhary, Dee

should check this reference statement

Adaptive Immunity Also called specific or acquired immunity

Develops upon exposure to a pathogen or foreign substance Creates immunological memory Substances causing this response are antigens

The immune response can destroy anything containing the antigen, whether bacteria or cancer cells

Adaptive immunity is highly specific to its molecular structural characteristics This leads to an enhanced immune response to subsequent

encounters with that same pathogen1

1. Abbas et al, 2011

Adaptive ImmunityThe process of adaptive or acquired immunity is the basis of vaccines

By exposing the immune system to an inactivated form of a pathogen, vaccination protects the person from ever contracting the diseaseFPO

(Adapted from Abbas, 20111)

LymphocytesLymphocytes are involved in adaptive immunity

There are various classes of lymphocytes B lymphocytes recognize soluble antigens and develop into

antibody-secreting cells Helper T lymphocytes recognize antigens on the surfaces of

antigen-presenting cells(APCs) and secrete cytokines Cytokines stimulate different mechanisms of immunity and

inflammation

LymphocytesCytotoxic T lymphocytes

recognize antigens on infected cells and kill these cells

Regulatory T cells suppress and prevent immune response (e.g., to self antigens)

NK cells use receptors with more limited diversity than T or B cell antigen receptors

(Adapted from Cheson et al, 20081)

FPO

Types of Specific Immune ResponseHumoral Immunity

Mediated by proteins, including antibodies, in the blood and other bodily fluids

Produces a cascade of chemicals from the complement system

Antibodies are produced by plasma cells (derived from B cells) Bind to specific antigens,

inactivating them and/or marking them for destruction

Cellular Immunity Also called cell-mediated immunity

Mediated by T cells

May attack target cells directly or indirectly by activating other immune cells Enhances the inflammatory

response

Cellular immunity primarily targets antigenic molecules and microorganisms

Immune System Disorders Includes autoimmune diseases, immunodeficiency inflammatory

diseases and cancer1,2

Immunodeficiency may be due to an immune system that is less active than normal Recurring and life-threatening infections Result of genetic conditions, acquired disease(HIV), or the use of

immunosuppressive medication1

Autoimmunity Results from a hyperactive immune system Attacks body’s innate tissue as a foreign pathogen Common autoimmune diseases include Hashimoto's thyroiditis, rheumatoid

arthritis, diabetes mellitus type 1, and systemic lupus erythematosus

1. Coussens et al, 2001; 2. O’Byrne et al, 2001

Immunotherapy

What is immunotherapy? The NCI defines immunotherapy as “treatment to boost or

restore the ability of the immune system to fight cancer, infections, and other diseases”1

Tumor immunotherapy Aims to augment the weak host immune response (active immunity) Or to administer tumor-specific antibodies or T cells, a form of

passive immunity2

1. National Cancer Institute, 2014; 2. Abbas et al, 2011

How Does it Work? Immunotherapy does not work in one specific mechanism

of action

However, all immunotherapy modalities are intended to augment or restore the body’s own immune function by some means1

May be quite different from the traditional cancer treatments of chemotherapy/targeted therapy, radiation, and surgery, which intend to act directly upon the targeted tumor

1. Mellman et al, 2011

Treatment Approaches In immunotherapy, each modality may encompass several

different treatment approaches—or some combination of: Therapeutic cancer vaccines Cytokines Immunological checkpoint inhibitors Targeted monoclonal antibodies

T-cell Activation and Tumor Suppression Antigen-presenting cells (APCs) take up foreign antigens,

are processed by the APC and then bound to major histocompatibility complex (MHC) molecules on the APC surface

MHC molecules present the processed antigen to T cells

T cells interact with the complex formed by antigen bound to MHC molecule, producing a T-cell activation signal known as signal 11

1. Bowes et al, 2014

T-cell Activation and Tumor SuppressionComplete activation requires a second APC signal, known

as signal 2

Once activated, T cells can directly kill tumor cells that express the antigen for which it has specificity

Activated T cells can release cytokines that kill tumor cells or chemicals that attract other immune cells (e.g., macrophages), to destroy tumor cells1

1. Bowes et al, 2014

Brief History of Immunotherapies in

Cancer

Past Century Stages of cancer immunotherapy development1

1890 – Cancer vaccine developed; demonstrated patient benefit

1960’s – Tumor-specific monoclonal antibodies released 1970’s/1980’s – Clinical benefit of cancer immunotherapy

does not fulfill expectations Late 1990’s – Several cancer immunotherapy drugs spur

renaissance of interest

1. Kirkwood et al, 2012

Immunotherapies

Specific/Targeted ImmunotherapiesTumor-specific monoclonal antibodies

(MABs) act via direct or indirect immune response resulting in cell death

MABs are produced from single B cell clone and consist of multiple identical copies

MABs have several clinical/therapeutic uses Clinical testing/research Immunotherapy against specific cancers

FPO

(Adapted from Halim, 20001)

Specific/Targeted ImmunotherapiesMABs work through various mechanisms of action to elicit cell death1

Blocking signaling pathways necessary for tumor growth Triggers immune-mediated cytotoxic response

Blocking angiogenesis1,2,3

1. Kirkwood et al, 2012; 2. Cheson et al, 2008; 3. Weiner et al, 2010; 4. Halim, 2000

Antigen Non-specific ImmunotherapiesDo not target cancer cells specifically

Stimulate the immune system in a more general way that may lead to a better immune response against cancer cells

Non-specific cancer immunotherapies may be administered as: Monotherapy Adjuvant therapy to boost the immune system and

potentiate other agents, such as vaccines

Antigen Non-specific ImmunotherapiesThese agents include Cytokines

Five classes of cytokines are important in immunity Interleukins Interferons Tumor necrosis factors Colony-stimulating factors Chemokines

CytokinesBinding of a cytokine to a cell can have a variety of

different effects Inducing production of more cytokine molecules Promoting or inhibiting cytokine activity Activating or suppressing target cell activity, proliferation, or

differentiation

Cytokines as Cancer Immunotherapy Recombinant versions of some cytokines are produced

commercially for cancer and other disorders Interleukins, interferons, and colony-stimulating factors

Functions of Cytokines

FPO

(Adapted from Proleukin Training Module 11)

Immuno-stimulatory AgentsPotential mechanisms of these therapies vary

Direct anti-tumor effects Reversal of immune suppression Activation of innate immunity Antigen-non-specific T cell activation1

1. Monjazeb et al, 2012

Immuno-stimulatory Agents CpG oligonucleotides

Potent stimulators of both innate and adaptive immune systems Currently being examined for cancer immunotherapy1

Bacillus Calmette-Guérin (BCG) Nonspecific immune stimulation Activates macrophages and promotes macrophage-mediated killing

of tumor cells Used as adjuvant may stimulate T cell responses BCG is currently used to treat bladder cancer2

1. Bodera et al, 2012; 2. Abbas et al, 2011

Immuno-stimulatory Agents:MABs Antibodies targeted against receptors (MABs)

100+ trials with therapeutic cancer agents1

Used to treat rheumatoid arthritis,2 multiple sclerosis,3 and many forms of cancer Mainstay in treating breast cancer, non-Hodgkin's lymphoma,4

colorectal cancer, leukemia, and head and neck cancers

Demonstrated improved Overall Survival and Progression Free Survival in randomized, Phase 3 clinical trials5,6,

Response rates (RR) 8-10% when used as monotherapy in advanced stage, heavily pretreated, and recurrent disease

RR increased to 30% combined with chemotherapy and/or radiotherapy7

1. Abbas et al, 2011; 2. Feldman et al, 2001; 3. Doggrell, 2003; 4. Vogel et al, 2001; 5. Cheson et al, 2008; 6. Slamon et al, 2001; 7. Robak et al, 2010; 8. Kirkwood et al, 2012

Immuno-stimulatory Agents:MABs Some commercially available MABs

Rituximab (Rituxin®) Ipilimumab (Yervoy®) Tositumomab (Bexxar®) Adalimumab (Humira®) Ibritumomab tiuxetan (Zevalin®)

Immuno-stimulatory Agents Agonistic CD40

CD40 is a tumor necrosis factor receptor expressed on APCs such as: Dendritic cells (DC) B cells Monocytes Many non-immune cells A wide range of tumors

Agents currently in research May be combined with vaccines and chemotherapy in the

future

Immuno-stimulatory Agents Inhibitory CTLA-4 antibodies

CTLA-4 is a protein found on the surface of T cells Normally acts as a type of “off switch” to keep T cells from

attacking body’s other cells CTLA-4 can also stop T cells from attacking tumors Ipilimumab (Yervoy®) is a MAB that attaches to CTLA-4 and

stops T cell inhibition This boosts the immune response

Immuno-stimulatory Agents: Enzyme Inhibitors

Targeted therapies inhibit signaling enzymes, allowing tumor growth

May be called different names based on enzymes they block1FPO

1. Cancer Research UK

(Adapted from Cancer Research UK1)

Immuno-stimulatory Agents: Enzyme Inhibitors

Tyrosine kinase inhibitors (TKIs) include: Axitinib (Inlyta®) Dasatinib (Sprycel®) Erlotinib (Tarceva®) Gefitinib (Iressa®) Imatinib (Glivec®) Pazopanib (Votrient®) Sorafenib (Nexavar®) Sunitinib (Sutent®)

FPO

(Adapted from Cancer Research UK1)

Immuno-stimulatory Agents Proteosome inhibitors

Proteasomes are found in all cells Help degrade excess protein

Proteasome inhibitors cause a build-up of unwanted proteins in the cell Makes cancer cells die Bortezomib (Velcade®) is a proteasome inhibitor used to treat multiple myeloma1

Signal-transduction inhibitors and multi-targeted kinase inhibitors

Current Immunotherapy

ApproachesHow therapies work in the body

CytokinesHeterogeneous group of

secreted proteins produced by multiple cells

Mediates and regulates all aspects of innate and adaptive immunity

FPO


CytokinesHuman genome contains ~180

genes that may encode proteins with structural cytokine characteristics1

Recombinant cytokines produced commercially for use in cancer and other disorders

FPO


Cytokines: Interferons Interferon alpha-2b (Intron-A®), Interferon alpha-2ba

(Roferon-A®) and Pegylated Interferon family of proteins Biologic response modifier1 that activates macrophages and NK

cells Stimulate cellular responses that protect against viruses

Cytokines: InterferonsMechanisms of the antineoplastic effects of

IFN-α probably include: Inhibition of tumor cell proliferation Increased cytotoxic activity of NK cells Increased class I MHC expression on tumor cells

Makes them more susceptible to killing by CTLs Shown to have direct effects on tumor cells1

Anti-proliferative Pro-apoptotic Anti-angiogenic

Cytokines: InterferonsRecombinant IFNα used in treatment of some cancers

Approved for use in1,2: Hairy cell leukemia Malignant melanoma AIDS-related Kaposi's sarcoma Follicular non-Hodgkin's lymphoma

Cytokines: Interleukins Interleukins produced primarily

by T cells and macrophages

Most extensive clinical experience with cytokines is high-dose Interleukin-2 (IL-2 or Proleukin®)2

FPO

(Adapted from Mayer, 20101)

1. Meyer, 2010; 2. Abbas et al, 2011

Cytokines: Interleukins IL-2 plays key role in activation,

maturation, and/or growth of many immune cells Stimulates production by T cells of TNF

and IFN-γ2

CD4 cells (helper T cells) CD8 cells (cytotoxic T cells)

B cells, NK cells, and macrophages

IL-7, IL-12, and IL-21 also being studied as oncological adjuvants and monotherapy

FPO

(Adapted from Mayer, 20101)

1. Meyer, 2010; 2. Abbas et al, 2011

CTLA-4 RegulationEvidence shows that T cell responses to some tumors are

inhibited by involvement of cytotoxic T lymphocyte-associated antigen (CTLA-4)1

CTLA-4 is a negative regulator of T cell activation2

Ipilimumab (Yervoy®)is a fully human anti CTLA-4 agent Binds to CTLA-4 and blocks interaction of CTLA-4 with its ligands,

CD80/CD86 Blockade of CTLA-4 has shown to augment T-cell activation and

proliferation Indicated for the treatment of metastatic or unresectable melanoma The mechanism of action in melanoma is indirect, possibly through T-

cell mediated anti-tumor immune responses2 1. Abbas et al, 2011; 2. Yervoy® PI, 2013

PD-1/PD-L1Evidence shows that T cell response in some tumors is inhibited

by the programmed cell death protein 1 (PD-1/PD-L1) pathway PD-1 keeps immune response in check

Antibody blockade of PD-1 is effective in enhancing T cell killing of tumors in mice and human clinical trials1

Compared to CTLA-4, seems to be found more often in T cells in tumors

Attaches to PD-L1, a protein found on some normal and cancer cells When PD-1 binds to PD-L1, directs T cell to not attack tumor Some cancer cells have large amounts of PD-L1 on cell surface


PD-1/PD-L1Anti-PD-1 antibody MK-3475 (formerly lambrolizumab)

being studied in: Metastatic melanoma Thirteen clinical trials with 30+ tumor types1

BMS-936558 (nivolumab), showed promising Phase II results in: Non-small cell lung cancer Renal carcinoma Colorectal cancer Many patients don't respond, but ones that do seem to show

benefit2

1. Roth, 2014; 2. Topalian et al, 2012

VaccinesGoal of cancer vaccine therapy is to treat disease by

promoting intense, cancer-specific, T cell immune response

Vaccines derived from autologous or allogeneic tissue Autologous vaccines use tumor cells from patient

receiving vaccine Contains all tumor antigens present in tumor, and is

MHC-matched with the patient Allogeneic vaccines prepared with tumor cells from others

Easier to manufacture in quantity, but may lack unique patient antigens

VaccinesOnly cancer treatment vaccine approved by FDA

thus far: Sipuleucel-T (Provenge®)

An autologous vaccine approved for metastatic prostate cancer

Development of virally induced tumors can be blocked by preventive vaccination with viral antigens or attenuated live viruses HPV vaccines promise to reduce the incidence of

HPV-induced tumors1


Other ImmunotherapiesKiller T cell and regulatory T cell

manipulation Lymphokine-activated killer cell (LAK cell) is a white blood cell stimulated to kill tumor cells1

Adoptive therapy with autologous LAK cells and in vivo administration of IL-2 or chemotherapeutic drugs has yielded results in mice, with regression of solid tumors2

FPO

1. NCI, 2014; 2. Abbas et al, 2011

(Adapted from Dendreon website3)

Other ImmunotherapiesVariation of adoptive therapy isolates tumor-infiltrating

lymphocytes (TILs ) from inflammatory infiltrate in and around solid tumors TILs are obtained from surgical resection specimens and

expanded by culture in IL-2 TILs may be enriched for tumor-specific cytotoxic

T lymphocytes (CTLs) and for activated NK cells

TIL therapy for metastatic melanoma being used in various cancer centers1


Other ImmunotherapiesOther drugs boost immune system in a non-specific way, similar

to cytokines

Unlike cytokines, these therapies are not naturally found in the body Used to treat multiple myeloma and some other cancers Known as immunomodulating drugs (IMiDs), and include:

Thalidomide (Thalomid®) Lenalidomide (Revlimid®) Pomalidomide (Pomalyst®)

Thought to work by boosting immune system Not exactly clear how

Issues in Treatment with

Immunotherapy

Therapy Side Effects Interferon-alpha side effects can include:

Flu-like symptoms (chills, fever, headache, fatigue, loss of appetite, nausea, vomiting)

Low white blood cell counts (which increase the risk of infection) Skin rashes Thinning hair

Side effects can be severe and make treatment difficult to tolerate Depression can also be of concern Most side effects do not continue after treatment

discontinuation, but fatigue can last longer Other rare long-term effects include nerve damage1

1. INTRON® A PI, 2014

Therapy Side Effects IL-2

Acute side effects of IL-2 can be severe but predictable: Flu-like symptoms such as chills, fever, fatigue, and

confusion Patients may experience nausea, vomiting, or

diarrhea Many people develop low blood pressure due to

capillary leak syndrome, which must be treated with pressor support

Rare but potentially serious side effects include an abnormal heartbeat, chest pain, and other heart problems, and impaired neutrophil function1

1. PROLEUKIN® PI, 2012

Therapy Side Effects IL-2 (cont’d)

Because of the possible side effects, when IL-2 is given in high doses, it must be done in a hospital by an experienced staff

IL-2 has adverse events noted in the PI and evidenced by its Black Box Warning

Toxicity management and proper patient selection is necessary

Toxicities are rarely chronic According to Atkins et al, “Patients experienced significant

treatment-related morbidity, but long-term sequelae for patients receiving high-dose IL-2 have been extremely rare”1

1. Atkins et al, 2000

Therapy Side EffectsTargeted Therapies

Common skin toxicity of sorafenib (also sunitinib) is hand–foot skin reaction, commonly accompanied by paraesthesias1

Other skin toxicities of TKIs include rash, stomatitis, alopecia, pruritus, and subungual splinter hemorrhages2

In a 106-patient phase II study of sunitinib as second-line therapy of advanced renal cell cancer, the most common adverse events were fatigue(28%), diarrhea(20%), anemia (26%, and neutropenia(42%)3

1. Widakowich et al, 2007; 2. Robert et al, 2005; Motzer et al, 2006

Therapy Side EffectsTargeted Therapies

“It is important to analyze the biologic effects of targeted therapy in cancer cells as well as in normal tissues. Many of the adverse events related to these agents have been described only after more prolonged use, such as the case of cardiac toxicity due to trastuzumab or ILD reported with gefitinib. Some of these effects were unpredictable and not observed during the early phases of drug development.”

(Widakowich et al, 20071)

Therapy Side Effects Ipilibumab

Can allow immune system to attack some normal organs, leading to serious side effects in some patients

Most common side effects include fatigue, diarrhea, skin rash, and itching Less often, can cause more serious GI issues, or problems with nerves, skin, eyes, or other organs

In some people these side effects have been fatal1

1. YERVOY® PI, 2013

Therapy Side EffectsVaccines

PROVENGE® (sipuleucel-T) Side effects are generally mild to moderate and most last

only a day or two In clinical trials, only 1.5% of men discontinued their

treatment because of side effects The most common side effects include chills, fatigue, fever,

and back pain In clinical studies, some men experienced more serious side

effects, such as chest pain, irregular heartbeat, nausea, and vomiting1

1. PROVENGE® PI, 2011

Measuring Response Rates/Interpreting Results

Commonly used criteria include World Health Organization (WHO), Response Evaluation Criteria in Solid Tumors (RECIST), and the revised RECIST 1.1.31

Initial guidelines were primarily designed for patients receiving chemotherapy

More recently, new measures have been developed specifically for patients who are receiving immune-based therapies1

1. Bowes, 2014

Measuring Response Rates/Interpreting ResultsWHO criteria

Complete response (CR) – disappearance of all lesions Partial response (PR) – tumor burden, measured using the SPD

for all baseline lesions, decreased by ≥50% Progressive disease (PD) – an increase in tumor burden by

≥25% from baseline Stable disease – smaller changes in tumor burden that did not

meet the criteria for PD, PR, or CR Earlier immunotherapies, such as interferon and IL-2, used the

more stringent criteria of a decrease of ≥50% to be considered a PR1

1. Bowes, 2014

Measuring Response Rates/Interpreting Results

RECIST criteria were designed to evaluate response to traditional chemotherapies with a cytotoxic MOA and thus do not clearly assess the efficacy of immunotherapy, which works differently1,2

In initial RECIST guidelines (Version 1.0) CR defined as the disappearance of all target lesions PR ≥ 30% decrease in the sum of the longest diameters of target lesions PD was ≥ 20% increase in the sum of the longest diameter of target

lesions, or the appearance of one or more new lesions SD was neither PR or PD3

More recently reviewed immunotherapies were often evaluated for response using the RECIST criteria

1. Sharma et al, 2011; Kirkwood et al, 2012; Nishino et al, 2010

Challenges: Interpreting Response Criteria

The importance of SD in immunotherapy Immune-modifying agents require more time than

chemotherapy to induce an antitumor response Tumor volume may even increase during the early phases of

treatment

Use of immune-related response criteria for cancer patients has been shown to identify a substantial number of patients who are responding to immune-based treatments Would have been considered to have failed treatment using

conventional response criteria1

1. Bowes, 2014

Challenges: Interpreting Response Criteria Immunotherapies present potential challenges to

assessment of treatment using conventional response criteria

Potential limitation of some immune-based treatment May take relatively long period to mount effective immune

response

Patient or the treating physician may conclude treatment is not effective before immune system has enough time to fully respond to therapy1

1. Bowes, 2014

Challenges: Interpreting Response CriteriaWolchock et al proposed alternative

response criteria for immunotherapy1

Criteria referred to as “immune-related response criteria”2

Define response patterns observed in immunotherapy, and identify successful outcomes Originally for metastatic melanoma Recent studies and reviews also proposed

application in: RCC, NSCL, and prostate cancer

1. Bowes, 2014; 2. Chen, 2013

Challenges: Interpreting Response CriteriaEvaluating immunology trials and

response patterns, only 2/4 patterns would be classified as “treatment responses” using RECIST or WHO criteria Other 2 classified as treatment failures even

though patients eventually responded1

Important that radiologists have thorough understanding of immune-modifying strategies shown to improve outcomes in cancer patients

1. Bowes, 2014

Society for Immunotherapy of

Cancer (SITC) Consensus Statement

SITC GuidelinesSociety for Immunotherapy of Cancer (SITC) Consensus

Statement on Tumor Immunotherapy for the Treatment of Cutaneous Melanoma1

Published August 2013

First evidence-based recommendations for when and how to implement melanoma therapies

Provides consensus recommendations from 30 melanoma experts for the use of immunotherapy in the treatment of melanoma

Before the consensus statement, lack of evidence-based guidelines created obstacles and discord in oncology

1. Kaufman et al, 2013

SITC Guidelines: BackgroundScientific literature search identified a 986-item

bibliography1

Data ensured recommendations were evidence-based

From peer-reviewed literature and clinical experience, panel put forth recommendations


SITC Guidelines: BackgroundOutlines role of immunotherapy in

management of Stage IV melanoma1

Interleukin-2 (IL-2, PROLEUKIN®), and ipilimumab (YERVOY®) monotherapy

The above in combination with FDA-approved agents Dacarbazine BRAF inhibitor Vemurafenib (ZELBORAF®)


SITC Treatment RecommendationsSITC reviewed patient selection, toxicities, clinical

end points, and sequencing/combination therapy

The panel recognizes several systemic treatment options for unresectable stage IV melanoma1

High-dose IL-2 Ipilimumab Vemurafenib Dabrafenib Trametinib for patients with BRAF mutated tumors Clinical trials Cytotoxic chemotherapy


SITC Treatment Recommendations In Stage IV melanoma panel recommended

IL-2 1

Considered first line Patients with good PS Meet local institutional guidelines for IL-2 administration Patients who are not candidates for IL-2 therapy should consider

ipilimumab

BRAF inhibitor for patients with BRAF-mutated melanoma2 who: Have poor performance status (PS) Have untreated CNS disease Are not candidates for clinical trial

1. Kaufman et al, 2013; 2. ibid

SITC Treatment RecommendationsImmunotherapy considered for patients

treated with a BRAF inhibitor if: PS improved with treatment CNS disease is controlled IL-2 considered for patients with good PS Ipilimumab considered for patients with poor PS

who respond to a BRAF inhibitor and are not candidates for IL-2 treatment or clinical trials1


Use of Different ImmunotherapiesCytokines1

Data supporting high-dose IL-2, ipilimumab and targeted therapy in the treatment of patients with stage IV melanoma

Interferons SITC guidelines do not recommend interferon-

alpha for stage IV metastatic melanoma


Use of Different ImmunotherapiesCytokines

Interleukin-21

Early clinical trials of high-dose IL-2 Objective response rates of 16–17% 6–7% complete response rate Further follow-up shows 80–90% of complete

responders alive 10–15 years later Durability and consistency of responses led to

FDA approval of IL-2 for metastatic melanoma in 1998



Ipilimumab1

Evaluated in several phase I and II clinical trials Demonstrated an improvement in overall

survival in patients with metastatic melanoma in two large trials

In one study, patients with metastatic melanoma receiving ipilimumab had an improvement in overall survival versus vaccine alone

Ipilimumab+dacarbazine versus dacarbazine alone showed an increase in overall survival



Conventional chemotherapy produces direct cell-killing toxicity that results in decreased tumor size often observed after 2 cycles (6-8 weeks) In one study, patients treated with ipilimumab did not

begin to exhibit significant slowing of disease progression until after 12 weeks1

In some cases, patients first exhibited increase in tumor volume, followed by clearing of tumor several months later

All panelists agree laboratory reports should be obtained before each ipilimumab infusion Panel was divided on long-term follow-up, with some

members recommending repeat laboratory analysis every 3 months for 2 years



BRAF inhibitor vemurafenib1

Evaluated in 675 previously untreated metastatic melanoma patients with the BRAF mutation

Patients received either vemurafenib or dacarbazine

A significant improvement in overall survival and progression-free survival was observed for those receiving vemurafenib


Use of Different ImmunotherapiesNew therapies1

Success of immunotherapy in treatment of melanoma expected to result in approval and development of additional agents over next several years

Programmed death 1 (PD-1) T-cell checkpoint inhibitors for cancer therapy

Both PD-1 and PD-L1 seem promising for cancer immunotherapy


SITC Immunotherapyby Patient Type

FPO

1. Adapted from Kaufman et al, 20131

Immunotherapeutic SequencingPanel recognized1:

Limited to no data on drug sequencing IL-2 should not be used in patients with poor or

declining PS There are no safety data with IL-2 after ipilimumab

or with vemurafenib

Panel recommended IL-2 be given as first-line therapy in suitable patients


Combination TherapyCurrently no prospective data from well

controlled trials on clinical outcomes with concurrent immunotherapy

Several reports of potent abscopal effect when ipilimumab and IL-2 used after localized radiotherapy1

Suggests that this immunotherapy combination and radiation treatment might be a possible therapeutic strategy


SITC Toxicity Recommendations Immunotherapy associated with a range of

toxicities Need to carefully monitor during and after

treatment Autoimmune-like symptoms particularly important

Reported with interferon-α2b, IL-2, and ipilimumab

SITC Toxicity RecommendationsPanel recommends for all patients receiving

immunotherapy1: Routine thyroid function studies Complete blood counts Liver function and metabolic panels Serum LDH tests

Baseline Weekly during induction Monthly if on standard high-dose interferon-α2b

therapy


SITC Toxicity Recommendations Interferon-related depression

Depression and related constitutional symptoms can be major challenge during interferon-α2b therapy

Panel recommends significant history of depression be contraindication to any form of interferon treatment

Selective use of antidepressants in patients who develop depressive symptoms during treatment

SITC Toxicity Recommendations Ipilimumab side effects

Asymptomatic vitiligo Autoimmune thyroiditis Symptomatic skin, gastrointestinal, hepatic and

endocrine immune-related toxic effects

IL-2 May be beneficial to get daily labs during IL-2

treatment

Conclusion

Conclusion Immunotherapy is an established modality for

treating patients with melanoma where some patients achieve durable therapeutic response1

Key points include Evaluation of therapy Differences between response in treating with

chemotherapies vs. immunotherapies Side effect management

ConclusionThere are exciting new horizons with ongoing

research in Drug sequencing New products Combination therapies

With the approval of multiple oncologic agents, immunotherapy will soon join the traditional therapies of chemotherapy, surgery, and radiation therapy as the standard of care in the treatment of cancer

Questions

Health & Medicine

Immunotherapy Update in Oncology