Understanding Side Effects Of Immune Therapy in Cancer

MORGANNA FREEMAN, DO, FACP ASSISTANT CLINICAL PROFESSOR OF CUTANEOUS ONCOLOGY

Disclosures

Consultant for Bristol Myers Squibb, Merck, Sanofi-Aventis, Novartis, and Academy of Oncology Nurse & Patient Navigators

Speakers’ Bureau for Bristol Myers Squibb, Merck, Sanofi-Aventis, and Novartis

Thomas of Celano, First Life of St. Francis, 1230 El Greco, St Francis in Prayer, 1580

“When [St. Francis] the blessed servant of God saw these things he was filled with wonder, but he did not know what the vision meant.

Thus Francis rose, one might say, sad and happy, joy and grief alternating in him.

He wondered anxiously what this vision could mean, and his soul was uneasy as it searched for understanding.”

Learning Objectives

I. Appreciate impact of immune therapy in cancer

II. Understand MOA vs standard chemotherapy

III. Review immune-mediated toxicities by organ system IV. Explain treatment & monitoring parameters

V. Apply knowledge to improve care of cancer patients

Learning Objectives

I. Appreciate impact of immune therapy in cancer

II. Understand MOA vs standard chemotherapy

III. Review immune-mediated toxicities by organ system IV. Explain treatment & monitoring parameters

V. Apply knowledge to improve care of cancer patients

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Stage IV Melanoma: 3 Year OS

Callahan, Margaret K., et al. "Nivolumab plus ipilimumab in patients with advanced melanoma: updated survival, response, and safety data in a phase I dose-escalation study." Journal of Clinical Oncology (2017): JCO-2017.

Brahmer J, Horn L, Jackman D, et al: Five-year follow-up from the CA209-003 study of nivolumab in previously treated advanced non-small cell lung cancer: Clinical characteristics of long-term survivors. 2017 AACR Annual Meeting. Abstract CT077. Presented April 3, 2017.

Stage IV Lung Cancer: 5 Year OS

Hodi SF, Kluger HM, Sznol M, et al. Durable, Long-term Survival in Previously Treated Patients With Advanced Melanoma Who Received Nivolumab Monotherapy in a Phase I Trial. Presented at the 2016 AACR Annual Meeting; April 16-20, New Orleans, Louisiana. Abstract CT001

Stage IV Melanoma: 5 Year OS

Stage IV Melanoma: 10 Year OS

Schadendorf, Dirk, et al. "Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma." Journal of clinical oncology 33.17 (2015): 1889.

A Perplexing Resurrection

Extraordinary advances far beyond that seen with traditional chemotherapy, AND

16 million cancer survivors today -> 30 million by 2040 -> growing number of Stage IV patients, BUT

Varied toxicity profile & reported deaths from unrecognized side effects have tempered enthusiasm for these drugs

Learning Objectives

I. Appreciate impact of immune therapy in cancer

II. Understand MOA vs standard chemotherapy

III. Review immune-mediated toxicities by organ system IV. Explain treatment & monitoring parameters

V. Apply knowledge to improve care of cancer patients

Mechanism of Action

CD8+ T cell

Tumor

Immune Priming

Checkpoint Inhibition

CD8+ T cell

CD4+ T cell

Brahmer JR. J Clin Oncol. 2013; 31:1021-28.

Ipilimumab

Pembrolizumab

Nivolumab

Mechanism of Action

Atezolizumab

Durvalumab Tremelimumab

Currently Approved Therapies

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NSCLC: • Nivolumab • Pembrolizumab • Pembrolizumab +

Carbo + Pem • Atezolizumab

Bladder: • Nivolumab • Pembrolizumab • Atezolizumab • Durvalumab • Avelumab

Renal: • Nivolumab • Ipi + Nivo

MSI-high (any tumor): • Pembrolizumab

Melanoma: • Pembrolizumab • Nivolumab • Ipilimumab • Ipi + Nivo

Merkel Cell: • Avelumab • Pembrolizumab

SqCC of H&N: • Nivolumab • Pembrolizumab

HCC: • Nivolumab (after

PD on Sorafenib)

Gastric/GEJ: • Pembrolizumab for

PDL1 expressing tumors

CRC: • Nivolumab for MSI-

high/dMMR after progression on FOLFOX/FOLFIRI

• Pembrolizumab (same indication)

Soft tissue sarcoma: • Olaratumab

Learning Objectives

I. Appreciate impact of immune therapy in cancer

II. Understand MOA vs standard chemotherapy

III. Review immune-mediated toxicities by organ system IV. Explain treatment & monitoring parameters

V. Apply knowledge to improve care of cancer patients

Toxicities Seen With Checkpoint Inhibition

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Hepatic: • Transaminitis • DILI • Acute hepatic

failure

Cutaneous: • Rash • Steven-Johnson

syndrome • Bullous

pemphigoid • Vitiligo • Alopecia • Pruritis

Renal: • Nephritis

General: • Fatigue • Infusion reactions

GI: • Enterocolits • Colits • Colonic perforation

Musculoskeletal: • Myalgias • Arthralgias • Rhabdomyolysis

Pulmonary • Pneumonitis • Pleural effusion

Neuro: • Mono- and poly-

neuropathy • Sensory / motor

• Cognitive dysfunction

Cardiac: • Heart block • Cardiomyopathy • Myocarditis • ACS

HEENT: • Uveitis • SICCA syndrome

Immune-Related Adverse Events

Skin Toxicities

How Frequent?

50% of pts treated with ipi 35% of pts treated with pembro, nivo

◦ Onset: 3 wks (immediate) to 6 mos (delayed) to 3 years (late)

New & unusual toxicities with investigational agents

◦ Timing of onset can vary

Where, Why & How

Types of Rash

Targetoid / Centrally Necrotic

Acneiform / Maculopapular

Erythematous / “Sunburn”-Like Desquamating / Bullous

Focal Findings

Vitiligo “Halo” Sign Albinism

Erythema Nodosum Dermatomyositis Radiation Recall

…and the Scary Stuff

Oral Ulcerations Desquamation Toxic Epidermal Necrolysis

Mild Moderate Severe

Grade I-II Maculopapular

+/- itching, burning, tightness 10-30% of BSA

Does not limit ADLs

Topical Steroids Low potency: Hydrocortisone

Medium potency: Triamcinolone

Anti-Itch Therapy PO Atarax, Benadryl, H2 blockers

Drug Therapy Ok to continue

Grade II-III Maculopapular

+ itching, burning, tightness >50% of BSA

Does not limit ADLs

Topical Steroids High potency: Betamethasone

Anti-Itch Therapy

PO Atarax, Benadryl, H2 blockers

Drug Therapy Hold if >50% BSA

PO steroids if not better after 1 week

Grade III-IV Blistering

+/- Mouth/Genital/Eye Involvement >50% of BSA

Significantly limits ADLs

Skin Biopsy +/- Dermatology consult

Hospitalization Indicated

IV Steroids, IV fluids, consider Abx IVIG in severe cases (SJS, TEN)

Drug Therapy May need permanent discontinuation

What to Do, and When

QOL Issue

Skindex-16: score 0 (best QoL) to 96 (worst QoL)

3 domains: symptoms, emotional effects, & effects on functioning

Higher grade of rash = poorer QOL

Witherspoon, J. N., et al. "Correlation of patient characteristics and NCI-Common Terminology Criteria for Adverse Events (CTCAE) v 3.0 grading with dermatology-related quality of life (QoL) in patients with EGFR inhibitor-induced rash." Journal of Clinical Oncology 26.90150 (2008): 9559-9559.

Pulmonary Toxicities

Pneumonitis Symptoms: SOB, dry cough, fever, chest pain More frequent with PD-1/PD-L1 therapy than with CTLA4 blockade

◦ Higher incidence with combination therapy (chemotherapies and targeted agents with known risk of pneumonitis)

Monotherapy CTLA4 blockade results more often in sarcoid-like granulomas and/or BOOP ◦ Murine models of ALI show CTLA-4 contributes to inflammation, increased

PD-L1 expression seen in sarcoidosis

More common in patients with lung cancer

CSGA Nat Genet 1997; Munthe-Kaas JACI 2004; Zhu ERS 2009; Liu Human Imm 2010; Nakajima J Immunol 2010; Braun Am J Respir Crit Care 2014

What to Do, and When Routinely check POx in all PD-1/PD-1/IPI patients

CXR in anyone with SOB, cough (low threshold CT Chest)

Pred 1-2mg/kg, taper over 45-60 days Limited data on Infliximab

Cardiac Toxicities

Cardiotoxicities

Rare but serious and potentially fatal

One retrospective study (n = 752) reported ipilimumab-induced myocardial fibrosis, pericarditis, takotsubo-like syndrome, acute CHF, complete heart block, and myocarditis

Heinzerling, Lucie, et al. "Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy." Journal for immunotherapy of cancer 4.1 (2016): 50.

Where, Why and How

Preclinical study in 2 mouse models of myocarditis showed increased inflammation in mice with PD1−/− CD8+ T cells compared to mice with PD1+/+ CD8+ T cells

PD-1 deficiency led to spontaneous myocarditis & dilated CM in mice caused by antibodies to cardiac troponin

CTLA-4 deficient mice are known to rapidly develop multi-organ lymphocytic infiltration with severe myocarditis

Cardiotoxic effects induced by checkpoint inhibitors could be explained by lowering the threshold for activation of T cells specific for self-antigens in the heart

What to Do, and When Fatigue and weakness = alarm symptoms

EKG, Echo, troponins, CK in any patient with new SOB, cough, chest pain, fatigue

Pred 1-2mg/kg, taper over 45-60 days ◦ Trend troponins & follow serial Echo in patients with established Dx

High mortality (30%) even in treated patients

GI Toxicities

Enterocolitis: How Frequent?

Where, Why and How

Diarrhea = increased stool frequency

Colitis = abdominal pain + increased stool frequency ◦ Descending colon is the most

common site ◦ CT imaging if severe abdominal pain

and/or peritoneal signs ◦ Persistent symptoms raise risk for

perforation

What to Do, and When

Initiate steroids for Grade 2 or higher Often will require at least 2 weeks of steroids at 1mg/kg ◦ Consider Infliximab for refractory cases

lasting > 7-10 days

Some patients will relapse after 1st course of Infliximab and may require additional dosing ◦ Little benefit to pre-medication with

Infliximab at this time

Transaminitis: How Frequent?

Where, Why and How Mostly asymptomatic especially if only transaminitis (autoimmune hepatitis)

DILI = AST/ALT plus bilirubin increase

More frequent with CTLA4 blockade (10%), less with PD-1/PD-L1 blockade (5%)

Anti PD1/PD-L1 therapy of HCC results in increased hepatitis (20%) ◦ Nivolumab + pazopanib or + sunitinib resulted in Gr 3/4 irAE of 9, 20 %

Pathology: panlobular hepatitis, perivenular infiltrates, or lymphocytic infiltrates

What to Do, and When

Elevation LFTs > 3 fold baseline (>2.5 X ULN; Grade 2) requires close attention

Intensified monitoring; labs every 3 days

Consider disease burden, medications, infections; imaging; consider biopsy if LFTs >8x and/or T. Bili >5x

Intensified monitoring: Labs every 1-3 days

High dose steroids: Methylprednisolone 120 mg IV daily ◦ If after 3 days no improvement or rebound: Mycophenylate 1 g BID ◦ If no improvement 5-7 days: 0.10 to 0.15 mg/kg/day tacrolimus (trough level 5-20 ng/ml)

If no improvement in 5-7 days: consider Infliximab 5 mg/kg once

Neuro & Endocrine Toxicities

Neuro irAEs

Acute Bell’s palsy, GBS, sensory/motor neuropathies ◦ Melanocytes & Schwann cells both derived from neural crest; share similar antigens ◦ Gangliosides expressed on melanocytes are highly immunogenic, may be responsible

for initiating peripheral motor sensory neuropathies, GBS

Ipi-induced encephalitis: N-methyl-D-aspartate receptor (NMDAR) also expressed on melanocytes

Others: Myasthenia Gravis-like syndrome, PRES, aseptic meningitis ◦ MRI spine, NCVs, LP for workup ◦ Plasmapheresis, IVIG, pyridostigmine in the case of Myasthenia Gravis

Endocrine irAEs Hypophysitis, hypothyroidism, hyperthyroidism, thyroiditis, primary adrenal insufficiency, DM ◦ Thyroid toxicities more frequent with PD-1/PD-L1

(10%) therapy than with CTLA4 (5%) ◦ Hypophysitis more often seen with Ipilimumab

Complete recovery of gonadal axis has been reported in 57% of men and recovery of the thyroid axis in 37-50% of cases

Where, Why and How

Case reports of Type I DM & DKA secondary to anti-PD-1 antibodies + primary adrenal insufficiency due to Ipilimumab have been described

Growing body of literature implicates T-cell dysregulation as critical to the pathogenesis of CAD and Type II DM

Gangliosides expressed on melanocytes are highly immunogenic, may be responsible for neuropathies, GBS

Strissel KJ, Denis GV, Nikolajczyk BS. Immune regulators of inflammation in obesity-associated type 2 diabetes and coronary artery disease. Curr Opin Endocrinol Diabetes Obes. 2014;21:330–8. [PMC free article] [PubMed] Kolbus D, Ljungcrantz I, Andersson L, Hedblad B, Fredrikson GN, Bjorkbacka H, et al. Association between CD8+ T-cell subsets and cardiovascular disease. J Intern Med. 2013;274:41–51. [PubMed] CSGA Nat Genet 1997; Munthe-Kaas JACI 2004; Zhu ERS 2009; Liu Human Imm 2010; Nakajima J Immunol 2010; Braun Am J Respir Crit Care 2014

Learning Objectives

I. Appreciate impact of immune therapy in cancer

II. Understand MOA vs standard chemotherapy

III. Review immune-mediated toxicities by organ system IV. Explain treatment & monitoring parameters

V. Apply knowledge to improve care of cancer patients

Applied Teaching Points

Early recognition = effective treatment = continuation of tx

Pts & caregivers must be taught about irAEs before starting therapy ◦ Unlike chemo, tend to be delayed (onset wks-mos after starting tx) ◦ Combination therapy can intensify severity and spectrum

Some may develop after completion of tx (arthralgia, myalgia) ◦ Any organ system is vulnerable (i.e. any “-itis” can happen)

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Toxicity Impacts Adherence

More Grade 3 or 4 AEs (69% vs 44%) Six times as many Grade 3 or 4 AEs leading to treatment discontinuation (30% vs 5%)

Larkin et al, N Engl J Med 2015;373:23

Delayed Toxicity in Melanoma Patients

One developed severe diarrhea >2 years after completing treatment

Two patients experienced delayed skin conditions ◦ Ulcerative lesions on the upper extremities 3 years later ◦ Scaly, pruritic plaque-like lesions c/w eczema 7 years later

One developed neuropathic pain requiring chronic narcotic therapy 3 years post-tx

One treated with XRT + Ipi (multiple brain mets) had significant functional decline ◦ Progressive weakness, memory loss, and seizures; died suddenly of unknown cause

5 years post therapy

Johsnon DB et al. Survivorship in Immune Therapy: Assessing Chronic Immune Toxicities, Health Outcomes, and Functional Status among Long-term Ipilimumab Survivors at a Single Referral Center. Cancer Immunol Res. 2015 May;3(5):464-9. doi: 10.1158/2326-6066.CIR-14-0217. Epub 2015 Feb 3.

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Smartphones & Online Tools

Nursing Resources

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Patient Resources

Distinct Needs

Treatment guidelines ◦ Evidence-based,

comprehensive ◦ Early recognition =

effective treatment ◦ Pts & caregivers must be

taught about irAEs before starting therapy

Treatment guidance ◦ Some may develop after

completion of therapy ◦ Any organ system is

vulnerable (any “-itis” can happen)

◦ “Prepare for being unprepared”

Thank You! mofreeman@coh.org @docwithacalling