patients with concurrent cancer and autoimmune disease...

Patients with concurrent cancer and autoimmune disease:

Immu-NO-therapy?

Anndee S. Gritte, PharmD PGY2 Oncology Resident

South Texas Veterans Health Care System The University of Texas at Austin College of Pharmacy

UT Health San Antonio

August 16, 2019

Learning Objectives

1. Describe immunotherapy and its place in oncology2. Identify challenges with immunotherapy in patients with autoimmune disease3. Evaluate the literature for the use of immunotherapy in autoimmune disease4. Formulate an evidence-based recommendation regarding the use to immunotherapy in patients with pre-

existing autoimmune diseases

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The Immune System and Cancer

1. Cancer1,2 a. Cancer is a group of more than 100 different diseases and is the second leading cause of death in

Americans i. Estimated new cases of cancer in 2019: 1,762,450

ii. Estimated deaths from cancer in 2019: 606,880 b. The mechanisms by which normal cells become cancer cells is incompletely understood

i. Believed that a physical, chemical or biological agent damages a normal cell leading to genetic alterations and modifications of mechanisms that control cell growth and proliferation

ii. Propagation of these alterations during cell division lead to unlimited growth, invasion and metastases

2. The Immune System and Cancer a. Overview of the immune system 3,4

i. The immune system defends the body using barriers, organs, cellular elements and molecules that interact with invading pathogens

1. Systems of Immunity: a. Innate (native) immunity

i. Nonspecific to antigens and responds quickly after antigen exposure ii. Includes physical components such as skin and mucous membranes as

well as cellular components such as natural killer (NK) cells, dendritic cells, and macrophages (see figure 1)

b. Adaptive (acquired) immunity: Further divided into humoral and cellular immunity

i. Involves the formation of an immune response specific to the antigen ii. Takes much longer to respond

iii. Includes CD8+ T cells, CD4+ T cells, and B cells (see figure 1)

Figure 1. Innate and Adaptive Immune responses3

b. Cancer Immunoediting: Elimination, Equilibrium, Escape2,5,6

i. Elimination 1. The Cancer-Immunity Cycle

a. The immune system has a protective role in tumor development b. Adaptive and innate immunity destroy a developing tumor before the cancer

becomes clinically apparent i. Seven steps are associated with an anticancer immune response leading

to effective killing of cancer cells (figure 2)

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Figure 2. Interactions between tumor cells and the immune system6

ii. Equilibrium

1. If the cancer cell is not destroyed in the elimination phase, the equilibrium phase begins 2. Adaptive immunity maintains cancer cells in a state of dormancy

a. Activated CD4+ and CD8+ T-cells and pro-inflammatory cytokines b. Original variants of the cancer cell are destroyed c. New variants of the cancer cell are produced providing resistance to immune

attack iii. Escape

1. Surviving tumor variants induce immunosuppressive effects within the tumor microenvironment and evade immune recognition

2. The cancer cells expand in an uncontrolled manner leading to observable malignant disease

3. History of Cancer Immunotherapy

a. Cancer Immunotherapy 7,8,9 i. A form of cancer treatment that uses the power of the body’s own immune system to prevent,

control and eliminate cancer 1. Four types of immunotherapy:

a. Non-specific immunotherapy: interleukin-2 (IL-2), interferon (IFN), and anti-tumor vaccines

b. Oncolytic viruses c. Adoptive cell therapy: utilizes gene editing to modify a patient’s own immune

cells d. Immune checkpoint inhibitors (ICI): monoclonal antibodies that enhance the

function of anti-tumor T cells via the programmed cell death protein 1 (PD-1) pathway and the cytotoxic T lymphocyte associated protein 4 (CTLA-4) pathway

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ii. Cancer Immunotherapy Development Timeline

Figure 3. Key developments in cancer immunotherapy and ICI history 7,8,10

4. Cancer Immunotherapy in Melanoma4-9

a. Melanoma11-14 i. Cancer that arises from melanocytes, or pigment producing cells, within the skin, the most

serious type of skin cancer

Figure 4. Stages of melanoma development12

ii. Localized disease

1. 84% of cases 2. Treat with surgery for cure (5-year survival: 98.7%)

iii. Metastatic disease 1. 12% of cases 2. Limited treatment options (5-year survival: 24.8%)

b. Treatment History of Metastatic Melanoma15-22

i. Dacarbazine 1. Alkylating agent that was identified in the 1970s as a treatment option for melanoma

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2. Adverse events: myelosuppression, hepatotoxicity, and nausea and vomiting 3. FDA approved based on disease response rate, never showed survival benefit

a. Median overall survival 6-9 months b. 5-year overall survival was 6%

ii. High dose IL-2 1. Human recombinant IL-2 promotes immune cell activation and response, works on the

equilibrium component of immunoediting 2. Adverse effects: hypotension, tachycardia, respiratory distress, altered mental status

a. Requires ICU admission for administration due to likelihood of requiring pressor support

b. Restricted to patients with excellent performance status 3. FDA approved based on improved overall survival

a. Median survival of 11.4 months, with 20 patients still alive at 62 months and 15 alive past 4 years

b. Unfortunately, only tolerated in a small number of patients iii. Immune checkpoint inhibitors

1. Ipilimumab a. Monoclonal antibody binding to CTLA-4, one mechanism tumors were using to

induce immunosuppressive effects, the escape component of immunoediting b. Approved for use in 2011 c. Hodi, et al (2010)21

i. Evaluated ipilimumab versus glycopeptide vaccine in 676 patients with unresectable stage III or IV melanoma, previously received dacarbazine, temozolomide, fotemustine, carboplatin, or IL-2

ii. Median overall survival of 10.1 months with ipilimumab versus 6.4 months with other therapy

iii. Excluded patient with pre-existing autoimmune disorders 2. Nivolumab

a. Monoclonal antibody binding to PD-1, one mechanism tumors use to induce

immunosuppressive effects, the escape component of immunoediting

b. CheckMate 066 (2015)22 i. Evaluated nivolumab versus dacarbazine in 418 patients with

unresectable, previously untreated stage III or IV melanoma ii. Overall survival of 72.9% with nivolumab compared with 42.1% with

dacarbazine iii. Excluded patients with autoimmune disorders

c. CheckMate 067 (2015)18,19 i. Evaluated nivolumab versus nivolumab plus ipilimumab versus

ipilimumab in 945 previously untreated patients with unresectable stage III or stage IV melanoma

ii. 3-year overall survival evaluated in a subsequent analysis and was 58% with nivolumab-ipilimumab, 52% with nivolumab alone, and 34% with ipilimumab alone

iii. Excluded patients with autoimmune disorders

c. National Comprehensive Cancer Network Cutaneous Melanoma Guidelines23 i. Metastatic or unresectable disease first line treatment regimens:

1. Anti-PD-1 monotherapy: nivolumab or pembrolizumab 2. Combination targeted therapy with BRAF V600-activating mutation 3. Nivolumab + ipilimumab in certain patient populations

ii. Dacarbazine and IL-2 no longer considered first line, preferred regimens

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Immune Checkpoint Inhibitors (ICI)

1. CTLA-4 24,25

Figure 5. CTLA-4 inhibition of T cells25

d. How does CTLA-4 function normally in the immune system?

ii. CTLA-4 is expressed constitutively on regulatory T cells and plays a role in T cell activation in the lymph nodes (see figure 2a)

iii. CTLA-4 binds to B7 on antigen presenting cells, leading to decreased T cell activation and proliferation → decreased immune response (see figure 2b)

iv. Blocking the action of CTLA-4 leads to a more robust immune activation (see figure 2c) e. Because CTLA-4 functions further upstream than PD-1 does, blocking the CTLA-4 pathway has more

collateral effects than PD-1 inhibition

2. PD-1 and PD-L15,10,26

Figure 6. PD-1/PD-L1 interactions in the immune system and with tumor cells26

c. How does PD-1 function in the immune system normally?

i. PD-1 functions as an inhibitory signal within in the immune system to prevent overactivation (see figure 3)

ii. PD-1 expression is induced in a variety of activated immune cells and conditions, including: 1. T cells that are constantly exposed to antigen 2. Exhausted CD8 T cells 3. Activated macrophages

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4. Tumor microenvironment regulated by VEGF-A iii. PD-1 has two ligands, PD-L1 and PD-L2 that both serve to inhibit T cell function

1. When PD-1 binds to PD-L1 T cells are inhibited

2. Inversely, blocking either PD-1 or PD-L1, will prevent this inhibition 3. See table 1 for cellular sites of PD-L1 and PD-L2 expression

d. Tumors express PD-L1 as a mechanism of inducing immunosuppression

Table 1. Expression of PD-L1 and PD-L210

PD-L1 Expression PD-L2 Expression

• Immune cells such as macrophages, B cells and dendritic cells and non-professional APCs

• Vascular endothelial cells

• Tumor/malignant cells and virus‐infected cells

• Immune cells such as macrophages, dendritic cells

• Epithelial tissues such as respiratory tract epithelial cells

• Hematologic cancer cells

3. ICIs approved for use in oncologic conditions

Table 2. Currently approved uses for ICIs27-32

Ipilimumab Nivolumab Pembrolizumab

Atezolizumab Durvalumab Avelumab

Mechanism CTLA-4 inhibition PD-1 inhibition PD-L1 inhibition

FDA Approved Indications

• Melanoma*

• Renal cell carcinoma**

• Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer

Typically given in combination with PD-1 inhibitor

• Bladder cancer

• Cervical cancer

• MSI-H or dMMR colorectal cancer

• Gastric cancer

• Head and neck cancer**

• Hepatocellular carcinoma

• Hodgkin lymphoma

• Melanoma**

• Merkel Cell Carcinoma

• Non-Hodgkin Lymphoma

• Non-small cell lung cancer

• Renal cell carcinoma**

• Small cell lung cancer

• Urothelial carcinoma

• Other MSI-H or dMMR cancers

• Breast cancer with PD-L1 expression >1%

• Non-small cell lung cancer**

• Renal cell carcinoma

• Small cell lung cancer**

• Urothelial carcinoma

*Can be given as single agent **Recommended first line treatment

4. ICI Adverse Effects33-36

a. Primary toxicity is related to over activation of the immune system against self, or immune related adverse events (irAE)

ii. See table 3 for the most common manifestations of these irAEs iii. See figure 5 for a sample timeline of irAEs onset

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Table 3. Common irAEs with ICI33,35,26

Pneumonitis Colitis/Diarrhea Hepatitis Dermatologic Endocrine

Description Focal or diffuse inflammation of the lung parenchyma

Inflammation of the colon including, abdominal pain, diarrhea and bloody stools

Elevation of AST/ALT, bilirubin. Rarely vomiting, jaundice

Rash, pruritis, vitiligo, erythematous macules, papules, and plaques

Thyroid dysfunction, adrenal insufficiency, hypophysitis

Agents More common with PD-1, PD-L1

More common with CTLA-4

All All All

Incidence Serious <1% Overall ~4%

Serious up to 10% with CTLA-4

Overall 7-10% Overall 14-17% Serious <2%

Overall 1-2%

Timeline Median onset 2.8 months (range 9 days to 19.2 months)

6-8 weeks after initiation of ipilimumab less predictable with PD-1/PD-L1

8-12 weeks after initiation of ipilimumab less predictable with PD-1/PD-L1

Within one month but can occasionally arise later in therapy

8-12 weeks after initiation

Diagnosis Cough, dyspnea, CT chest

Clinical Rule out other causes

Lab values Rule out other causes

Clinical Rule out other causes

Lab values (TSH, hormone levels, etc.)

Management (See appendix A for grading)

Grade 1: Consider holding ICI Grade 2: Hold ICI, consider, prednisone 1-2mg/kg/day Grade 3-4: Discontinue ICI, prednisone 1-2mg/kg; can add infliximab or mycophenolate

Grade 1: Consider holding ICI, loperamide Grade 2: Hold ICI, prednisone 1mg/kg/day Grade 3-4: Discontinue ICI, IV methylprednisolone 2mg/kg/day; can add infliximab or vedolizumab

Grade 1: Continue ICI Grade 2: Hold ICI, consider prednisone 0.5-1mg/kg/day Grade 3-4: Discontinue ICI, prednisone 1-2mg/kg/day; can, add mycophenolate

Grade 1: Continue ICI; topical steroids and emollients or oral antihistamines Grade 2: Consider holding ICI, same treatment as grade 1 OR consider prednisone 0.5-1mg/kg/day Grade 3 or 4: Hold ICI, topical steroids and prednisone 1-2mg/kg/day

Elevated TSH: -Continue ICI, levothyroxine Hypophysitis: -Hold ICI until symptoms resolve, if symptomatic treat with prednisone 1-2mg/kg/day

Figure 7. Onset of irAEs with Ipilumumab37

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b. Several studies have shown a correlation between the development of irAEs and ICI response iv. Grangeon, et al (2019)34

1. Evaluated 270 patients with NSCLC treated with nivolumab 2. Median progression free survival 5.2 months in patients with irAEs of any grade and

1.97 months in patients without irAEs 3. Median overall survival 8.21 months in patients without irAEs and was not reached at

study conclusion in patients with irAEs

c. Management 33,35,36 i. Depends on manifestation and severity of the side effect

ii. Most severe adverse effects are treated with systemic or topical corticosteroids to suppress the

overactive immune response

1. See table 3 for management of individual manifestations of irAEs

2. See appendix A for toxicity grading

iii. Corticosteroids (prednisone doses ≥ 10 mg or equivalent) should be avoided with

immunotherapy as they directly antagonize the immune system

1. Arbour, et al. (2018)38 evaluated patients receiving PD-1 inhibitors and compared those

receiving corticosteroids of ≥10mg of prednisone equivalent at baseline to those who

did not

2. Patients receiving baseline corticosteroids had poorer outcomes than those who were

not, including significantly shorter progression free survival and overall survival

Cancer and Autoimmune Disorders

1. Autoimmune disease background39-41 a. Autoimmune disorders affect 3-5% of the population b. There are at least 100 distinct autoimmune disorders that have been described, some are organ specific

and others are known to affect many different organ systems i. Significantly lower survival in patients with pre-existing autoimmune disorders

ii. See figure 2 for autoimmune disorders by organ system c. The development of all autoimmune disorders is not necessarily the same, but all are considered an

intolerance to self by the immune system

Figure 8. Autoimmune disorders can affect a wide variety of organ systems39

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2. Link between autoimmune disorders and cancer39,41,42 a. Many autoimmune disorders, including systemic lupus erythematous (SLE), rheumatoid arthritis (RA),

and inflammatory bowel disease (IBD), are associated with an increased risk of developing cancers

b. Constant immune stimulation and chronic inflammation seen with autoimmune disorders is thought to put patients with autoimmune disorders at higher risk of developing cancer

3. Autoimmunity and the PD-1 pathway42,43 a. Recent evidence has shown dysregulation in the PD-1/PD-L1 pathway among several autoimmune

disorders

b. Other autoimmune disorders have some evidence for PD-1 involvement including autoimmune

hepatitis, Behcet’s disease, myasthenia gravis, autoimmune uveitis, Sjogren’s syndrome, systemic lupus erythematosus (SLE), Ankylosing spondylitis, and myocarditis

Clinical Question

Can immune checkpoint inhibitors be used in patients with pre-existing autoimmune disease?

Table 4. Menzies AM, Johnson DB, Ramanujam S, et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Annals of Oncology. 2017;28:368-376.44

Design and Methods

Retrospective chart review across 13 melanoma centers in the US, Australia, and Europe to explore the safety and efficacy of anti-PD-1 antibodies in patients preexisting autoimmune disorders

Population Inclusion Criteria Exclusion Criteria

• Advanced melanoma

• Pre-existing autoimmune disorders and/or major immune related adverse effects with prior ipilimumab

• Treated with anti-PD-1 antibodies

Any patients not meeting inclusion criteria

Factors evaluated • Patient characteristics (e.g. age, sex, prognostic factors, pathologic staging)

• Activity or inactivity of autoimmune disorder defined by clinician on clinical grounds

• Immunosuppressive therapy for autoimmune disorder at time of anti-PD-1 initiation

• Adverse effects classified by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grading

Outcomes • Safety of anti-PD-1 antibodies, defined by worsening of the autoimmune disorder or recurrent of prior irAE with ipilimumab necessitating therapeutic intervention with systemic immune-modifying agents

• Incidence of irAEs

• Treatment response: o Response evaluation criteria in solid tumors (RECIST) 1.1 o Progression-free survival (PFS) o Duration of response o Overall survival (OS)

Type 1 Diabetes

• Animal models have shown increased prevalence and faster onset of type 1 diabetes in animal models

Multiple Sclerosis

•Cells within the central nervous system (CNS) express PD-1 and its ligands constitutively and under inflammatory conditions

•Blocking PD-L1 or PD-L2 increases lymphocyte infiltration in the CNS and accelerates onset and disease progression

Inflammatory Bowel Disease (IBD)

•Patients with IBD express a greater amount of PD-L1 within their intestinal mucosa than healthy subjects do

Rheumatoid Arthritis

•The PD-1/PD-L1 pathway has demonstrated dysregulation in the synovial fluid

•These patients also demonstrate increased cytokine production, demonstrating that there is likely a T cell component

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Statistical Analysis

• Categorical and continuous variables were summarized using percentages and medians, no formal hypothesis testing performed

• PFS and OS estimated using Kaplan-Meier method

Results

Baseline characteristics

N=119, 109 receiving pembrolizumab and 10 receiving nivolumab Preexisting autoimmune disorder (N=52), significant ipilimumab toxicity (N=67)

Characteristics Number (%)

Age, median (range) 71 (23-88)

Autoimmune disorder

Rheumatologic 27 (52%)

Dermatologic 8 (15%)

Gastrointestinal 6 (12%)

Neurologic 5 (10%)

Endocrine 4 (8%)

Respiratory 2 (4%)

Hematologic 2 (4%)

Active autoimmune disorder at PD-1 start 15 (29%)

Treatment of autoimmune disorder at PD-1 Start

None 32 (62%)

Corticosteroids 9 (17%)

Steroid-sparing agents 5 (10%)

Both steroids and steroid-sparing agents 5 (10%)

Outcomes • 20 patients (38%) experienced a flare of their underlying autoimmune o 14/27 (52%) of patients with rheumatologic disorders o 3/8 (37.5%) with psoriasis o No flares occurred in patients with gastrointestinal, neurologic, or respiratory disorders

• Flare severity o Most flares (85%) were mild, grade 1-2 o 8 patients interrupted therapy and 2 permanently discontinued

• Flares occurred at a median 38 days after therapy initiation

• More flares in those with active symptoms at therapy initiation than with inactive (9/15 vs 11/37, P=0.039)

• Conventional adverse events occurred in 15 patients, 5 of which were grade 3-4

• Treatment response observed in 17/52 (33%) of patients

• Response rates were similar in those with and without flares of autoimmune disorders

• Median progression free survival (PFS)- 6.2 months

• 14 patients died during study period

Author’s conclusions

Anti-PD-1 antibodies induce relatively frequent immune toxicities in patients with baseline autoimmunity, but these immune toxicities are often mild and easily managed, and the patients achieve high rates of clinical response

Reviewer’s Critique

Strength’s Limitations

• Wide inclusion criteria • Retrospective

• Limited statistical analysis performed

• Small patient population, particularly small representation of certain autoimmune disorders

• Baseline autoimmune therapy not provided

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Overall Conclusions

• Overall rates of immune-related adverse effects were low and most were not serious

• Largest autoimmune populations were rheumatological, dermatological, and gastrointestinal

• Overall patient populations in this study were too small to make broad conclusions about the

use of immunotherapy in this patient population, but in general, a co-occurring autoimmune

disorder should not solely eliminate immunotherapy as a therapeutic option

Table 5. Danlos FX, Voisin AL, Dyevre V, et al. Safety and efficacy of anti-programmed death 1 antibodies in patients with cancer and pre-existing autoimmune or inflammatory disease. European journal of cancer. 2018; 91:21-29.45

Design and Methods

Prospective, observational cohort study to describe and analyze the safety and effectiveness of anti-PD-1 antibodies in patients with pre-existing autoimmune disorder

Population Inclusion criteria: Exclusion criteria:

• Patients included in the prospective Registry of Severe Adverse Events of Immunomodulating Monoclonal Antibodies in Oncology (REISAMIC) registry

• Registry includes all patients treated with anti-PD-1 antibodies following marketing authorization as part of patient access programs for unlicensed medication or during compassionate use

• Malignant hematologic disease

• A second advanced cancer

• Chronic viral infection

• Autoimmune disorders not included: atopic diseases, metabolic inflammatory diseases, and autoimmunity caused by infectious diseases or drugs

Factors evaluated

• Patient characteristics (e.g age, sex, pathologic staging)

• Pre-existing autoimmune disorder and treatment of autoimmune disorder

• Patients cancer status

• Previous cancer treatments

Outcomes • Overall survival

• Overall response rate

• Toxicity including immune related adverse events

• Discontinuation or maintenance of therapy


• Categorical variables described as number and percentage

• Continuous variables were described as the number, mean with standard deviation, and median interquartile range

• IrAE-free survival and OS in the two groups were estimated using the Kaplan Meier method and compared using a log-rank test

• A univariate logistic regression was used for intergroup comparisons of the ORR

Results


N=45 patients enrolled in REISAMIC compared with 352 autoimmune disorder-free patients over the same period

Characteristic Pre-existing autoimmune disorder (n=45)

Autoimmune-Free (n=352)

Age in years, median (IQR), years

62.3 (23-88) 62.4 (20-92)

Pre-existing autoimmune disorder, n (%)

Dermatologic 33 --

Endocrine 9 --

Rheumatological 7 --

Symptomatic autoimmune disorder, n (%)

25 (55.6%) --

Cancer type, n (%)

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Melanoma 36 (80%) 215 (61.1%)

NSCLC 6 (13.3%) 133 (37.8%)

Other 3 (6.7%) 4 (1.1%)

Cancer Stage, n (%)

III 3 (6.7%) 46 (13.1%)

IV 42 (93.3%) 304 (86.4%)

Immunotherapy received, n (%)

Anti-PD-1 agents 44 (97.8%) 352 (100%)

Anti-PD-L1 agent 1 (2.2%) 0

Outcomes Immune related adverse events (irAEs) in patients with autoimmune disorders:

• 20/45 patients experienced irAEs (44.4%) (grade 2- 14, grade 3- 5, no grade 4 or 5 events) o 11/20 events were considered a flare o 10 patients developed symptoms that were not associated with pre-existing

autoimmunity (thyroiditis, colitis, gastritis, etc.)

• 15/20 patients continued therapy despite AEs

• 12/20 patients required a specific treatment for irAE (6 being systemic corticosteroids)

• 4 patients required definitively discontinuation of therapy due to colitis, acute tubulointerstitial nephritis (ATN), and a flare of myasthenia gravis

Outcome Pre-existing autoimmune disorder (n=45)

Autoimmune-free (n=352)

P-Value

irAE 20/45 (44.4%) 102/352 (29%) --

irAE-free survival time, median 5.4 months 13 months 0.0002

Overall survival at last follow-up 26 (57.8%) Not provided 0.38

Overall response rate 38% 28% 0.098


Patients with pre-existing autoimmune disorders had an increased risk of irAEs and experiencing flares when treated with anti-PD-1 antibodies. However, these agents seem to be just as safe and effective in patients with autoimmune disorders


Strengths Limitations

• Prospective • Small overall autoimmune disorder patient population

• Observational

Overall Conclusions

• Patients with pre-existing autoimmune disorders experienced more irAEs but these tended to

be non-severe and did not generally affect the patient’s ability to stay on the therapy

• Overall response rates and overall survival in the autoimmune disorder population were

comparable to autoimmune-free patients

• Largest autoimmune populations included were dermatologic, endocrine, and rheumatologic

Table 6. Abdel-Wahab N, Shah M, Lopez-Olivo MA, Suarez-Almazor ME. Use of immune checkpoint inhibitors in the treatment of patients with cancer and pre-existing autoimmune disease: A systematic review. Ann Intern Med. 2018;168:121-130.46

Design and Methods

Systematic review to describe the use of checkpoint inhibitors in patients with cancer and pre-existing autoimmune disease

Population Inclusion Criteria Exclusion criteria

• Case reports, case series, and observational • Diagnosis of an autoimmune disorder after immunotherapy

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• Patients of any age with cancer and an established diagnosis of an autoimmune disease before

• Received a checkpoint inhibitor

• Provided a detailed clinical description of each case

• Developed an adverse event and demonstrated autoimmune-specific autoantibodies after the receipt of immunotherapy

Factors evaluated

• Patient demographic and baseline characteristics

• Status of pre-existing autoimmune disease – active versus inactive and presence of immunosuppressive therapy

• ICI agent patient is receiving

• Treatment related adverse events, time to development of event, and management of event

• Clinical outcomes including adverse event outcomes

• Tumor response

Outcomes • Adverse events both new irAEs and exacerbations of autoimmune disorder

• Results were stratified by immunotherapy used, pre-existing autoimmune disorder, activity of pre-existing autoimmune disorder, and autoimmune disorder actively being treated


• Descriptive statistics with medians and ranges for continuous variables and frequencies and percentages for dichotomous variables

Results


49 publications included: 39 case reports, 4 case series, and 5 retrospective observational studies N=123 patients

Characteristic Patients

Median age (range) 61.4 (26-87)

Cancer, n (%)

Melanoma 103 (83.7)

Lung 16 (13)

Other 4 (3.2)

Autoimmune disorder, n (%)

Psoriasis or psoriatic arthritis 28 (22.8)

Rheumatoid Arthritis 20 (16.3)

Autoimmune thyroid disease 11 (8.9)

Ulcerative colitis or Crohn’s Disease 13 (10.6)

Other 51 (41.4)

Active autoimmune disorder, % 46.2%

Currently receiving therapy for autoimmune disorder at initiation of immunotherapy, %

43.6%

Immunotherapy received, n (%)

Anti-PD-1 Agent 64 (52.0)

Ipilimumab 55 (44.7)

Anti-PD-L1 Agent 1 (0.8)

Outcomes Outcome Psoriasis/Psoriatic Arthritis (n=28)

Rheumatoid Arthritis (n=20)

Autoimmune thyroid disease (n=11)

Inflammatory Bowel Disease (n=13)

Adverse events, n (%)

25 (89) 15 (75) 5 (45) 8 (62)

Recurring or worsening

18 (64) 7 (35) 2 (17) 5 (39)

New irAEs 3 (11) 5 (25) 3 (27) 2 (15)

Both new and recurring

4 (14) 3 (15) -- 1 (8)

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• No differences observed between patients with active autoimmune disorders versus inactive

• Patients receiving therapy for autoimmune disorders at initiation of immunotherapy had fewer adverse events compared with those not receiving therapy (59% vs 83%)

• More disease flares with anti-PD-1/anti-PD-L1 agents (62% vs 36%)

• More new-onset irAEs with ipilimumab (42% vs 26%)

• Adverse events improved in 90% of patients

• 25 (50%) of patients with adverse events had a partial or complete response with their cancer compared with 5 patients (35.7%) who did not have adverse events

• 5 patients died, 2 of which were due to a serious adverse event

Immunotherapy discontinuation, n

6 7 2 3

Overall patient population outcomes Patients, n (%)

Adverse events 92 (75)

Autoimmune disorder flares 50 (41)

New irAEs 31 (25)

Both new irAEs and flares 11 (9)

Therapy discontinuation 21 (17.1)


Flares and irAEs are not uncommon in patients with autoimmune disorders and they may be successfully managed without discontinuation of therapy. However, they may occasionally result in severe, fatal disease and clinicians should be aware that patients should be monitored closely. The severity of the patients underlying autoimmunity, cancer prognosis, and alternative therapeutic options should all be weighed as risks and benefits



• Provided outcomes broken down by autoimmune disorder, autoimmune therapy and autoimmune control

• Lack of consistent definitions and pertinent data of included studies

• No statistical analyses performed

• Most data from case reports, will tend to be more unique/unusual and less representative of the population

Overall Conclusions

• The nature of studies included in this systematic review makes it difficult to draw specific conclusions about the use of immunotherapy in patients with pre-existing autoimmune disorders

• This study provides some evidence by specific autoimmune disorder types across several different cancers

• Largest autoimmune populations included were dermatologic, rheumatologic, and thyroid

Table 7. Cortellini A, Buti S, Santini D, et al. Clinical outcomes of patients with advanced cancer and pre-existing autoimmune diseases treated with anti-programmed death-1 immunotherapy: a real-world transverse study. The Oncologist. 2019;24:1-11.47

Design and Methods

Retrospective, multicenter observational study of patients with pre-existing autoimmune disorders and advanced cancer treated with anti-PD-1 agents at 15 Italian centers from September 2013 through May 2018, for safety and efficacy

Population Inclusion Criteria Exclusion criteria

• Patients with stage IV cancers

• Treated with single agent anti-PD-1 agents, regardless of treatment line

• None

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Factors evaluated

• Patient characteristics (e.g age, sex, ECOG score, disease burden, treatment line)

• Disease responses as evaluated by RECIST criteria

• Pre-existing autoimmune disorder categorized by organ system

• Activity of autoimmune disorder at initiation of immunotherapy and concomitant autoimmune therapy

• Immune related adverse events

Outcomes • Incidence of autoimmune disorders among patients with cancer undergoing immunotherapy with anti-PD-1

• Incidence of irAEs between patients with and without pre-existing autoimmune disorders and inactive versus active autoimmune disorders

• Evaluate the correlation between pre-existing autoimmune disorders and clinical outcomes: o Objective response rate (ORR) o Median progression free survival (PFS) o Median overall survival (OS)


• χ2 and Fisher’s exact test were used to evaluate ORRs, the incidence of irAEs and the discontinuation rates due to adverse events among subgroups, according to the sample size

• Odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to estimate the association between the incidence of irAEs and covariates

• In the multivariate analysis, logistic regression was used to evaluate the parameters that were significant at the univariate safety analysis (primary tumor was included in multivariate analysis regardless of its significance at univariate analysis)

• Median PFS, median OS, median time to irAEs, and median follow-up were evaluated using the Kaplan-Meier method

• Cox proportional hazards model was used to evaluate predictor variables in univariate and multivariate analysis for median PFS and median OS

Results


N=751 patients, 85 of which has preexisting autoimmune disorders

Characteristic N (%)

Overall population

Median Age, years 69

Cancer type

NSCLC 492 (65.5)

Melanoma 159 (21.2)

RCC 94 (12.5)

Other 6 (0.8)

Pre-existing autoimmune disorders

Active Disease 15 (17.6)

Type of Disease

Thyroid disorders 51 (60)

Dermatologic 14 (16.4)

Rheumatologic 10 (11.8)

Other or multiple sites 11 (12.9)

On autoimmune treatment 15 (17.6)

Outcomes Outcome No autoimmune disorder (n=666)

Inactive autoimmune disorders (n=70)

Active autoimmune disorders (n=15)

irAE, any grade, n (%) 266 (39.9, 95% CI: 35.2-45.0)

45 (64.3, 95% CI: 46.8-86.0)

11 (73.3, 95% CI: 44.9-92.2)

irAE, grade 3 or 4, n (%) 59 (8.8, 95% CI: 6.7-11.4)

6 (8.6, 95% CI: 3.1-18.6)

2 (13.3, 95% CI: 1.6-48.1)

17

• Incidence of overall irAEs was significantly higher in patients with pre-existing autoimmune disorders, as compared with patients without (65.9% vs 39.9%, p<0.0001)

• No significant differences in the rates of serious (grade 3-4) irAEs (9.4% vs 8.8%, p=0.8663)

• At multivariate analysis, pre-existing autoimmune disorders (both inactive and active), female sex, and ECOG-PS 0-1 were all significantly related to greater incidence of irAEs of any grade

• No significant differences in patients discontinuing treatment

• Most common overall adverse events were dermatologic, endocrine, and gastrointestinal

• Most common grade 3-4 adverse events were gastrointestinal, skin, and pneumological

• Primary tumor (melanoma), first line treatment, low burden of disease, and ECOG 0-1 were found to be independent predictors of increased PFS

Autoimmune flare, any grade, n (%)

-- 33 (47.1, 95% CI: 32.4- 66.2)

7 (46.7, 95% CI: 18.7-96.1)

Discontinuation of therapy 48 (7.2) 4 (5.7) 2 (13.3)

ORR, % (95% CI) 36.3 (30.7-40.2) 38.1 (24.4-56.6) 50 (23.0-76.9)

Median PFS, months (95% CI) 8.0 (6.6-9.1) 14.4 (5.3-17.1) 6.8 (5.1-9.4)

OS, months (95% CI) 16.5 (14.1-20.9) 15.7 (10.3-24.3) 9.8 (5.8-24.6)


Patients with pre-existing autoimmune disorders who underwent treatment with anti-PD-1 agents have a statistically significant increase in the risk of irAEs as well as risk of worsening of their underlying autoimmune disorder. However, this does not mean that these patients should not be treated with these agents; these agents should be evaluated for each individual patient



• Data stratified by presence of autoimmunity and activity of autoimmune disorder

• Retrospective

• Baseline characteristics not stratified by autoimmunity

• Small autoimmune disorder sample sizes

• Baseline steroid doses not provided

Overall Conclusions

• Patients with pre-existing autoimmune disorders have an increased risk of overall irAEs and flares of their underlying autoimmune disorder, but not severe irAEs

• Patients with autoimmune disorders demonstrated benefit with ICI therapy with treatment response and overall survival

• Largest autoimmune populations included were thyroid, dermatologic, and rheumatologic

Conclusions and Recommendations

1. Immunotherapy, immune checkpoint inhibitors specifically, have represented a landmark improvement in

cancer treatment and play a key role in many different cancers

2. Patient’s with autoimmune disorders were excluded from these landmark studies

3. Immune related adverse effects are the most common side effects with immunotherapy and patients with pre-

existing autoimmune disorders are at increased risk for developing irAEs

4. Rates of serious adverse events in this population remain similar to those seen in patients without autoimmune

disorders

5. Patient’s with pre-existing autoimmune disorders may still benefit from immunotherapy and should be

considered for immunotherapy even with an increased risk of irAEs.

6. Considerations for any patient with concurrent autoimmunity and cancer

a. Standard of care for cancer type and the number of first-line treatment options:

i. NSCLC: Multiple first line treatment options with and without immunotherapy

ii. Metastatic melanoma: Immunotherapy is standard of care

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b. Type of autoimmune disorder:

i. Dermatologic, rheumatologic, and thyroid autoimmune disorders have the most data with ICIs

ii. Autoimmune disorders that can be easily monitored and adjusted and/or is not typically a

progressive condition: thyroid disorders and type 1 diabetes mellitus

iii. Neurologic conditions, including multiple sclerosis and myasthenia gravis, and

severe/uncontrolled gastrointestinal disorders do not have enough data to make firm

recommendations with ICI use

c. Current autoimmune disorder therapy:

i. Data does not specify which autoimmune treatment patients were receiving while on

concurrent ICIs

ii. Patients receiving no treatment, topical therapies, thyroid replacement and low dose

corticosteroids (≤ prednisone 10mg daily or equivalent) should not have interaction between

autoimmune disorder treatment and ICI therapy

iii. Patients receiving systemic corticosteroids (>10mg prednisone daily or equivalent), other

systemic immunosuppressive therapies and newer biologic agents may have interaction

between autoimmune treatment and ICI therapy

d. Current autoimmune disorder control:

i. Data eludes that patients with pre-existing autoimmune disorders have an increased risk of

overall irAEs and flares of their underlying autoimmune disorders whether well controlled or not

well controlled

ii. Patients with dermatologic, rheumatologic and thyroid disorders receiving concurrent ICIs had

flares or irAEs that were not severe regardless of autoimmune disorder control prior to ICI

initiation

e. Final recommendations

i. For patients with cancers in which immunotherapy is the standard of care and a concurrent

dermatologic, rheumatologic or thyroid autoimmune disorder, we have sufficient evidence for

the safety of ICI use in this population

ii. To limit interactions between autoimmune disorder therapy and ICI, it is preferred that patients

are receiving no treatment, topical therapies, thyroid replacement and low dose corticosteroids

(≤ prednisone 10mg daily or equivalent) for their dermatologic, rheumatologic or thyroid

disorder when being initiated on an ICI

iii. For patients who do not meet these criteria, consideration for treatment with immunotherapy

should be reviewed on a case by case basis

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Appendices

Appendix A. irAE Grading by System 35,36

Pneumonitis Colitis/Diarrhea Hepatitis* Dermatologic Endocrine

Grade 1 Asymptomatic; confined to one lobe of the lung or <25% of lung parenchyma; clinic or diagnosis observations only

Fewer than 4 bowel movements above baseline per day and no colitis symptoms

Alanine transaminase (ALT) or aspartate transaminase (AST) <3x ULN

Macules/papules covering <10% body surface area (BSA) with or without symptoms -OR- mild/localized pruritis

Not graded Subclinical hypothyroidism: elevated TSH, normal free T4 Clinical hypothyroidism: elevated TSH, low free T4, symptoms present Thyrotoxicosis: suppressed TSH, with normal or high free T4 Hypophysitis: inflammation of the pituitary gland, may be associated with low ACTH, low AM cortisol, and other lab abnormalities

Grade 2 Presence of new/worsening symptoms including: shortness of breath, cough, chest pain, fever, and increased oxygen requirement

4-6 bowel movements above baseline per day, colitis symptoms, not interfering with ADLs

AST, ALT 3-5x ULN

Macules/papules covering 10-30% BSA, with or without symptoms, limiting instrumental activities of daily living (iADLs) -OR- intense or widespread intermittent pruritis

Grade 3 Severe symptoms involving all lung lobes or >50% of lung parenchyma, limiting self-care ADLs

More than 6 bowel movements above baseline per day, colitis symptoms, interfering with ADLs, hemodynamic instability, hospitalization, other serious complications

AST, ALT >5-20 x ULN

Macules/papules covering >30% BSA with or without symptoms, limiting self-care activities of daily living (ADLs) -OR- intense, widespread, constant pruritis

Grade 4 Life threatening respiratory compromise

AST, ALT >20x ULN

*For Grade >1 transaminitis with bilirubin >1.5x ULN (unless Gilbert’s syndrome), rule out viral etiology, disease related

hepatic dysfunction, other drug-induced transaminase elevations, consider GI evaluation and limit/discontinue

hepatotoxic medications.

patients with concurrent cancer and autoimmune disease...

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