Cancer Immunotherapyd2qrtshcpf0x30.cloudfront.net/nodes/187/IO Grand Rounds.pdf · 2017-05-18 · Cancer Immunotherapy Early Recognition and Effective Management of Immune-Related

Cancer ImmunotherapyEarly Recognition and Effective Management of Immune-Related Adverse Events

Disclaimer

• This slide deck in its original and unaltered format is foreducational purposes and is current as of November2016. The content and views presented in thiseducational activity are those of the authors and do notnecessarily reflect those of Creative EducationalConcepts or the supporter.

• These materials may discuss therapeutic products thathave not been approved by the US Food and DrugAdministration and off-label uses of approved products.A qualified healthcare professional should be consultedbefore using any therapeutic product discussed.Readers should verify all information and data beforetreating patients or employing any therapies describedin this educational activity.

Usage Rights

• This slide deck is provided for educational purposesand slides may be used for personal, non-commercial presentations only as long as contentand references remain the same.

• No part of this slide deck may be published ordistributed in print or electronic format withoutprior written permission from Creative EducationalConcepts.

• Physicians: 1.0 AMA PRA Category 1 Credit(s)™• Pharmacists: 1.0 ACPE contact hours (.10 CEUs) • Nurses: 1.0 contact hour

Faculty Information:

You can find your faculty member’s full bio and disclosure in your handout or online at www.ceconcepts.com/ONCGR

Special Thanks!

Supported through an independent educational grant from AstraZeneca.

Accreditation

Presented by Creative Educational Concepts, Inc. (CEC)

1) Outline dynamic interaction between cancer and the immune system and rationale for use of cancer immunotherapy.

2) Compare and contrast mechanism of action, efficacy, and safety of current and emerging immune checkpoint inhibitors.

Learning Objectives

3) Anticipate common warning signs and symptoms of immune-related adverse events (irAEs) associated with CTLA-4 and PD-1/PD-L1 immune checkpoint blockade.

4) Evaluate strategies members of the healthcare team can employ to monitor and effectively manage irAEs associated with CTLA-4 and PD-1/PD-L1 immune checkpoint blockade to improve patient safety and outcomes.

Learning Objectives (cont.)

Reproduced from Immunity, Vol. 39, Daniel S. Chen and Ira Mellman, Oncology Meets Immunology: The Cancer Immunity Cycle, Page 2, Copyright 2013, with permission from Elsevier via Copyright Clearance Center.

Immune System and CancerDynamic Interaction

Pre-malignant lesion

Advanced oncogenesis

Tumor growth

Immunosurveillance

Immunoselection

ImmunosubversionEscape

Equilibrium

Cancer ImmunoeditingImmunosurveillance → Immunosubversion

Adapted from Zitvogel L, et al. Nat Rev Immunol. 2006.

Elimination

• To overcome the mechanisms by which tumors suppress and evade the immune response

− Restore efficient immunosurveillance and tumor elimination, and shift the balance from immune evasion to immune protection

Cancer Immunotherapy Rationale for Use

Disis ML. Semin Oncol. 2014.

Cancer Immunotherapy Types

Galluzzi L, et al. Oncotarget. 2014.

Reproduced from N Engl J Med, Antoni Ribas, MD, PhD, Tumor Immunotherapy Directed at PD-1, Vol. 366, Page 2518. Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society via Copyright Clearance Center.

Immune Checkpoint Blockade CTLA-4 and PD-1/PD-L1 Inhibitors

CTLA-4 and PD-1/PD-L1 Inhibitors

Current FDA Status and Indications

• Approved

− Treatment of unresectable or metastatic melanoma

− Adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy

CTLA-4 Inhibitors Ipilimumab (Human IgG1 mAb)

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125377s073lbl.pdf.

• Orphan drug designation − Malignant mesothelioma

CTLA-4 Inhibitors (cont.) Tremelimumab (Human IgG2 mAb)

http://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD_Results_2.cfm.

PD-1 InhibitorsNivolumab (Human IgG4 mAb)


• Approved

− BRAF V600 wt unresectable or metastatic melanoma, as a single agent

− Metastatic NSCLC and progression on or after platinum-based chemotherapy; patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab

− Advanced RCC in patients who have received prior antiangiogenic therapy

PD-1 InhibitorsNivolumab (cont.)


• Accelerated approval − BRAF V600 mutation-positive unresectable or

metastatic melanoma, as a single agent

− Unresectable or metastatic melanoma, in combination with ipilimumab

• Approved − Unresectable or metastatic melanoma

PD-1 InhibitorsPembrolizumab (Humanized IgG4 mAb)

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125514s004s006lbl.pdf.

• Accelerated approval

− In patients with metastatic NSCLC whose tumors express PD-L1 as determined by an FDA-approved test and who have disease progression on or after platinum-containing chemotherapy; patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab

PD-1 InhibitorsPembrolizumab (cont.)

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125514s004s006lbl.pdf.

PD-1/PD-L1 BlockadeSelected Emerging Agents

Agent Class On-going Phase III StudiesAtezolizumab(MPDL3280A)

Anti-PD-L1 NSCLCBladder cancerHNSCCRCCTriple negative breast cancer

Durvalumab(MEDI4736)

Anti-PD-L1 NSCLCBladder cancerHNSCC

Avelumab(MSB0010718C)

Anti-PD-L1 Merkel cell carcinomaGastric cancerNSCLCBladder cancerOvarian cancer

Tumor Response Kinetics

• Immune-mediated response patterns may differ from those associated with conventional therapies, which has prompted the development of immune-related response criteria (irRC)a

Immune-Related Adverse Events (irAEs)

• By enhancing immune system function, immune checkpoint blockade can lead to autoinflammatory side effects called irAEsb

Immune Checkpoint BlockadeUnique Clinical Features

aWolchok JD, et al. Clin Cancer Res. 2009; bWeber JS, et al. J Clin Oncol. 2015.

CTLA-4 Blockade Kinetics of Response to Ipilimumab

Saenger YM, Wolchok JD. Cancer Immun. 2008.

Week 20: Regression Week 36: Still Regressing

Screening Week 12: Progression

Metastatic Melanoma

Wolchok J, et al. ASCO. 2015.

PD-1 Blockade Kinetics of Response to Pembrolizumab

Metastatic Melanoma

NSCLC

Factor RECIST irRC

Measurement of tumor burden

• Unidimensional • Bidimensional

CR • Disappearance of all target and non-target lesions

• Lymph nodes must regress to <10mm short axis

• No new lesions• Requires confirmation

• Same as RECIST

PR • ≥30% decrease in tumor burden compared to baseline

• Requires confirmation

• ≥50% decrease in tumor burden compared to baseline


PD • ≥20% plus 5mm absolute increase in tumor burden compared with nadir

• Progression of non-target lesions and/or appearance of new lesions (at any single time point)

• ≥25% increase in tumor burden compared to most recent prior evaluation

• New lesions added to tumor burden


SD • Any response pattern that does not meet criteria for CR, PR, or PD

• Same as RECIST

Immune Checkpoint BlockadeRECIST vs irRC

Agarwala SS. Semin Oncol. 2015.

Immune Checkpoint BlockadeKey Points About Evaluating Activity

• Antitumor activity may appear to be delayed compared to response times associated with cytotoxic therapies

• Patients may experience response after the appearance of progressive disease

• Development of progressive disease should be confirmed prior to discontinuation of therapy

• Development of small lesions in the presence of other responsive lesions may be clinically insignificant

• Durable stable disease may be indicative of response

Agarwala SS. Semin Oncol. 2015.

Reproduced from the European Journal of Cancer, Vol. 54, JM Michot, et. al., Immune- related adverse events with immune checkpoint blockade: a comprehensive review, Page 144, Copyright 2015, with permission from Elsevier via Copyright Clearance Center.

irAEsClinical Spectrum

Immune Checkpoint BlockadeirAEs and Outcomes

• Preclinical melanoma tumor models using CTLA-4 knock-outs have demonstrated enhanced immune-mediated tumor rejection AND immune related depigmentation, but not irAEs as seen in patientsa

• Although still somewhat controversial, irAEs does not seem to correlate with responseb,c

‒ There does, however, appear to be a weak association with CTLA-4 blockade and stronger one with PD-1 blockaded,e

aWeber JS, et al. J Clin Oncol. 2012; bSpain L, et al. Cancer Treat Rev. 2016; cHorvat TZ, et al. J Clin Oncol. 2015; dDowney SG, et. Clin Cancer Res. 2007; eFreeman-Keller M, et al. Clin Cancer Res. 2016.

irAEsGeneral Issues

• Infections and other etiologies should be ruled out or deemed unlikely as contributing to the irAEs

• Most irAEs occur during the first 3-4 months− Late irAEs, however, also can occur (eg, one episode

has been seen at month 47 during maintenance phase of therapy)

− Each irAE has different kinetics of onset and some can wax and wane, particularly colitis

• Steroids can be used to manage almost all irAEs− Prolonged steroid tapers are required

Weber JS, et al. J Clin Oncol. 2012; Weber JS, et al. ASCO. 2015; Weber JS, et al. J Clin Oncol. 2015.

Weber JS, et al. J Clin Oncol. 2012.

CTLA-4 Blockade With Ipilimumab Kinetics of irAEs in Melanoma

Toxi

city

Gra

de

Time (weeks)

Weber JS, et al. ASCO. 2015.

PD-1 Blockade With Nivolumab Kinetics of irAEs in Melanoma

Skin

0

5

10

15

20

25

30

35

0 10 20 30 40

Ap

pro

xim

ate

pro

po

rtio

n o

f p

atie

nts

(%

)

Time (weeks)

Gastrointestinal

Endocrine

Hepatic

Pulmonary

Renal

Reproduced from the European Journal of Cancer, Vol. 54, JM Michot, et. al., Immune-related adverse events with immune checkpoint blockade: a comprehensive review, Page 142, Copyright 2016, with permission from Elsevier via Copyright Clearance Center.

CTLA-4 and PD-1/PD-L1 BlockadeDistribution of Grade 1-2 irAEs

CTLA-4

PD-1

PD-L1

% p

atie

nts

40

30

20

10

0

57

CTLA-4 and PD-1/PD-L1 BlockadeDistribution of Grade 3-5 irAEs

CTLA-4

PD-1

PD-L1

1815

10

5

0

% p

atie

nts

Reproduced from the European Journal of Cancer, Vol. 54, JM Michot, et. al., Immune-related adverse events with immune checkpoint blockade: a comprehensive review, Page 142, Copyright 2016, with permission from Elsevier via Copyright Clearance Center.

Ipilimumab vs Nivolumab vs ComboirAEs Reported in ≥10% of Patients

Wolchok J, et al. ASCO. 2015. LBA1.

Patients Reporting Event, %

NIVO + IPI (N=313)

NIVO (N=313) IPI (N=311)

Any Grade

Grade 3–4

Any Grade

Grade 3–4

Any Grade

Grade 3–4

Skin 59.1 5.8 41.9 1.6 54.0 2.9

Pruritus 33.2 1.9 18.8 0 35.4 0.3

Rash 28.4 2.9 21.7 0.3 20.9 1.6

Rash maculopapular 11.8 1.9 4.2 0.3 11.9 0.3

Gastrointestinal 46.3 14.7 19.5 2.2 36.7 11.6

Diarrhea 44.1 9.3 19.2 2.2 33.1 6.1

Colitis 11.8 7.7 1.3 0.6 11.6 8.7

Hepatic 30.0 18.8 6.4 2.6 7.1 1.6

↑alanine aminotransferase 17.6 8.3 3.8 1.3 3.9 1.6

↑aspartate aminotransferase 15.3 6.1 3.8 1.0 3.5 0.6

Endocrine 30.0 4.8 14.4 0.6 10.9 2.3

Hypothyroidism 15.0 0.3 8.6 0 4.2 0

• Responsibility of all health care providers

• Early reporting by patients with close monitoring, and early intervention by health care providers

• Provide thorough and continuous patient education about the signs and symptoms of irAEs

• Assess for signs and symptoms of irAEs before each cycle of immunotherapy

• Know management algorithm specific to each irAE− Safety profiles of immunosuppressants

• Monitor and manage toxicities of immunosuppressants− Hyperglycemia and diabetes

− Opportunistic infection

Management of irAEs General Principles

Management of irAEs Based on CTCAE Severity Grade

Severity CTCAE Grade

Type of Patient Care

SteroidsOther

Immunosuppressive Drugs

Immunotherapyand Subsequent

Approach

1 Ambulatory Not recommended Not recommended Continue

2 AmbulatoryTopical steroids or

systemic steroids oral 0.5-1 mg/kg/d

Not recommendedSuspend** temporarily

3 Hospitalization

Systemic steroids oral or IV 1-2 mg/kg/d for 3

d then reduce to 1 mg/kg/d

To be considered for patients with

unresolved symptoms after 3-5 days of steroid

courseOrgan specialist advised

Suspend and discuss resumption

based on risk/benefit ratio

with patient

4

Hospitalization consider the

intensive care unit

Systemic steroids IV methylprednisolone 1-2

mg/kg/d for 3 d and then reduce to 1

mg/kg/d

To be considered for patients with

unresolved symptoms after 3-5 days of steroid

courseOrgan specialist advised

Discontinue permanently

**Outside skin or endocrine disorders, where immunotherapy can be maintained.

Michot JM, et al. Eur J Cancer. 2016.

• Low grade rashes common− Reticular erythema− Papules to plaques

• Other dermatologic symptoms− Pruritus− Vitiligo

• Rare toxic epidermal necrosis

• Recent retrospective analysis suggests that skin side effects with PD-1 blockade may be associated with response and survival

irAEsDermatitis

Postow MA. Am Soc Clin Oncol Educ Book. 2015; Freeman-Keller M, et al. Clin Cancer Res. 2016.

Ipilimumab-Associated DermatitisPresentation and Findings

Right upper arm:

Vacuolar changes(magnification x20)

Back:

Confluent red rash

Back:

Papular lesions(Close up)

Anti-CD8 staining:

Extensive epidermalexocytosis(magnification x20)

A B

C D

Jaber SH, et al. Arch Dermatol. 2006.

• Encourage the preventative use of moisturizers

• Photograph, document, and follow

• Dermatology biopsy

• Mild (grade 1)− Topical therapies including emollient skin creams, topical anti-

histamines, topical steroid creams

• Moderate (grade 2)− Hold immunotherapy, consider more potent topical steroid,

systemic anti-histamines, systemic corticosteroids

• Severe (grade 3+)− Hold/discontinue immunotherapy, aggressive topical

therapies, high dose systemic corticosteroids

DermatitisManagement

Postow MA. Am Soc Clin Oncol Educ Book. 2015; Fecher LA, et al. Oncologist. 2013.

• Diarrhea is a common irAE (37% all grade and 12% grades 3/4) with ipilimumab; less common with PD-1 blockade

• Colonoscopy or sigmoidoscopy shows diffusely erythematous, friable, and occasionally ulcerated mucosa

• Colon biopsy usually demonstrates inflammatory colitis with CD4>CD8 infiltrate in interstitium

• Most cases respond to symptomatic treatment or high-dose steroids with a long taper (over a month)

• Infliximab is used in steroid-refractory cases

• Can rarely lead to gastrointestinal perforation (1%), profound ileus or megacolon requiring surgery

irAEsColitis and Enteritis

Postow MA. Am Soc Clin Oncol Educ Book. 2015; Weber JS, et al. J Clin Oncol. 2015.

Colitis and EnteritisColonoscopy and Histopathology Findings

• Colonoscopy− Multifocal circumscribed

erythematous lesions

• Histopathology − Predominantly chronic

inflammation

− Eosinophils and focal active cryptitis

• Differentiate diarrhea from colitis

• Typical presentation is quick escalation of uncontrollable diarrhea that is not responsive to typical anti-diarrheal therapies

• Quick intervention with corticosteroids is essential to prevent escalation and bowel perforation

• Endoscopic evaluation

• Supportive care

− Dietary modifications, fluid repletion, electrolyte repletion, anti-motility agents

irAEsColitis vs Diarrhea


• Rule out other causes

• Treat symptomatically

• No Steroids

• Follow closely for resolution

Colitis and EnteritisManagement − Grade 1,2


• Assess duration and magnitude to determine need for hospitalization

• Endoscopy is often useful, even for prolonged grade 2 diarrhea

• High dose steroids

− 120 mg methylprednisolone IV daily

− Slow taper, over 1 month

• If persists (eg, 72 hours), consider infliximab 5mg/kg (TNF-blocking antibody)

Colitis and EnteritisManagement − Grade 3,4


• Liver function tests (LFT) elevations in patients may be associated with symptoms of hepatotoxicity (jaundice, right upper quadrant pain, vomiting) or may be completely asymptomatic; many patients have other non-specific symptoms (fever, malaise)

• LFT must be assessed prior to administration of each dose of ipilimumab or PD-1/PD-L1 inhibitors

• All subjects must meet LFT criteria before each dose of ipilimumab

− With no liver metastases < 2.5X ULN for AST, ALT

− With liver metastases; < 5X ULN for AST, ALT, < 2.5X ULN for total bilirubin

irAEsHepatitis


• 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, particularly viral; other metabolic disorders; imaging; consider biopsy if LFTs persist and the etiology is unclear

• Consider corticosteroid therapy

HepatitisManagement


• LFTs >8x or total bilirubin >5x

− Intensified monitoring; labs every 1-3 days until begin to resolve

− High dose steroids, eg, methylprednisolone 1-2 mg/kg/day; if LFTs decrease convert to oral steroids

− If after 3 days, no improvement or rebound, add mycophenolate 1 g BID PO

− If no improvement in 5-7 days, add tacrolimus 0.1 to 0.15 mg/kg/day IV (trough level 5-20 ng/ml)

− If no improvement in 5-7 days, add infliximab 5 mg/kg once, although it too can cause hepatotoxicity

Hepatitis (cont.)Management


• Include pan-hypopituitarism, hypothyroidism, hyperthyroidism, pancreatitis, and adrenal insufficiency

• Up to 10% (all grades) with ipilimumab or anti-PD-1/PD-L1

• Management of primary hypo- or hyperthyroidism

− Hyperthyroidism: most cases resolve spontaneously, with subsequent development of hypothyroidism; if symptomatic, use beta-blocker as initial management

− Hypothyroidism thyroid hormone replacement

− Typically, do not require corticosteroid therapy or suspension of checkpoint inhibitors

− Symptoms resolve with treatment

irAEsEndocrinopathies

Weber JS, et al. J Clin Oncol. 2012; Postow, Am Soc Clin Oncol Educ Book. 2015; Villadolid J, et al. Transl Lung Cancer Res. 2015; Naidoo J, et al. Ann Oncol. 2015.

• Can present with severe headache, fatigue, weakness, memory loss, impotence, personality changes, and visual impairment

• Pituitary dysfunction can cause downstream effects on all hormone levels

• Differential includes CNS metastases

• Monitor TSH before each dose

• Diagnostic MRI with pituitary cuts as well as laboratory evaluation of hormone levels

EndocrinopathiesHypophysitis

Blansfield JA, et al. J Immunother 2005; Attia P, et al. J Clin Oncol 2005; Phan GQ, et al. Proc Natl Acad Sci USA. 2003.

• Discontinue checkpoint inhibitors

• High-dose corticosteroid administration with a taper over 4 weeks

• Obtain endocrine consult

• Replace deficient hormones

• Symptoms will resolve with treatment

• Slow return of some endocrine function

• Most patients require life-long hydrocortisone supplement

• Use stress dose hydrocortisone in perioperative period and critical illness

HypophysitisManagement


• Relatively infrequent (<1% all grades) with IPI or PD-1

• Symptoms: − Numbness, tingling, foot drop and localized muscle weakness, or

generalized ascending motor and diaphragmatic weakness

• Observed so far:− Myasthenia gravis (MG)-like syndrome

− Peripheral neuropathy

• Management: get a neurologic consult!− For grade 2 or more, discontinue antibodies, work-up including labs

and brain MRI, high dose corticosteroid administration with a prolonged taper, neurology consultation, EMG if appropriate

− Hospitalize if MG-like syndrome

− Consider rapidly moving to IVIG and infliximab if grades 3-4 and without resolution of symptoms within 24-48 hours

irAEsNeurological Toxicities


• Relatively rare: 0.5 to 1.5% of patients at grades 2-3

• Very uncommon with PD-L1 antibodies

• Check pulse oximetry in all patients

• Get a chest X-ray in anyone with SOB, chronic cough, increased sputum, and have a low threshold for obtaining a CT of the chest

• CT findings may lag behind the patient’s symptoms

• High dose steroids with at least 45-60 day tapers with starting doses of at least 1-2 mg/kg are required

• Steroids may need to be re-escalated if symptoms return

• Use infliximab at 5 mg/kg if without relief in one week

irAEsPneumonitis


Organizing PneumonitisIpilimumab-Related

Barjaktarevic IZ, et al. Chest. 2013.

A B

C D

• Pancreatitis− Amylase/lipase elevation, abdominal pain low, and out of

proportion to elevation of lab tests

• Uveitis− Redness, change in vision; ophthalmology evaluation− Topical corticosteroid eye drops

• Nephritis (rare)− CT scans show stranding = inflammation− Consider steroids if Cr > 2.0

• Arthritis− Late manifestation with chronic PD-1/PD-L1− Often exacerbation of pre-existing arthritis

Immune Checkpoint BlockadeOther irAEs


• No difference in incidence of toxicity or grade of toxicity for the use of IPI or PD-1 under or over 65

• The overall survival for those treated with ipilimumab does not vary significantly by age

• It appears that ipilimumab and PD-1/PDL1 antibodies can be safely given to those at any age

• Caution should be used in using IPI or IPI/NIVO in those functionally over 80 with co-morbidities, who will not tolerate the colitis or prolonged steroid taper very well

Immune Checkpoint BlockadeirAEs in Elderly Patients

Management of irAEsPatient and Caregiver Education

• Describe signs and symptoms, including complications if not treated promptly

• Emphasize early recognition and prompt reporting

• Discuss preventative measures, if applicable

• Instruct patient to present agent-specific wallet card to all healthcare providers

• Stress compliance with corticosteroid therapy

• Provide supportive care instructions

• Enforce early reporting of worsening condition

Fecher LA, et al. Oncologist. 2013.

Patient and CaregiverEvaluate Education Needs

• Assess both patient and caregiver

− Knowledge of therapy and the disease process

− Educational level and preferred learning methods

• Develop a plan

• Implement teaching, use a variety of materials and methods

• Evaluate patient and caregiver for continued educational needs related to the therapy and disease process


Patient and Caregiver EducationProvide Contact Information

• Whom to call

• Why to call

• When to call

• Where to call (MUST HAVE 24/7 clinician availability)


Patient and Caregiver EducationChallenges

• General

− Effect of treatment is on the immune system, not directly targeting the tumor

− Extensive side effect profile, when to notify clinician

− Variability in when irAEs may occur

− Variability in response to treatment

Benefits of therapy outweigh potential risks, particularly when irAEs are recognized early and

treated quickly

Management of irAEsFAQs by Oncologists

• How often severe or dose-limiting irAEs occur?

• What are the most common irAEs?

• What are the resources available for dealing with the severe irAEs?

• How best to monitor the patients for irAEs, and how often to monitor after they occur?

• When to call the subspecialist?

Management of irAEsWhen To Call The Sub-Specialist?

Skin

Grades 1-2 No, manage the symptoms

Grades 3-4 Yes, consider a biopsy

GI

Grades 1-2 Only if scoping changes the management

Grades 3-4 Only if therapy-refractory, or grade 4

Hepatic

Grades 1-2 No

Grades 3-4 Only if therapy-refractory, or grade 4

Endocrine

Grades 1-2 Yes, if symptomatic

Grades 3-4 Yes, always

Management of irAEsWhen To Call The Sub-Specialist?

Pancreatic

Grades 1-2 No

Grades 3-4 Only if grade 4 or symptomatic

Pulmonary

Grades 1-2 Generally no, but consider

Grades 3-4 Almost always

Neurologic

Grades 1-2 Generally yes, if grade 2

Grades 3-4 Almost always

Renal

Grades 1-2 No

Grades 3-4 Only if therapy-refractory

Management of irAEs

Case Studies

Case 1Recurrent Melanoma

• A 69-year old man with recurrent melanoma is currently receiving pembrolizumab

• Between Cycles 2 & 3, patient has complaint of mild nausea with occasional emesis, mild diarrhea

• Labs reveal elevated LFTs: AST [164] and ALT [202]; the patient has had continued fatigue, but weight is stable

Case 1How Would You Manage This Patient?

1) Continue 3rd cycle with weekly labs

2) Stop pembrolizumab and switch to a taxane-based regimen

3) Administer steroids and hold therapy

4) Delay treatment until next cycle

5) Unsure

• Treatment held− Methylprednisolone dose pack initiated (What do you think

of this approach? What would be alternative?)

− Return visit in one week scheduled with labs

• At return visit in one week, labs have returned to Grade 1 and Cycle 3 initiated

• No further elevation of LFTs beyond Grade 1 to date

• Following Cycle 4, radiographic and clinical evaluation both show disease regression

• Continues on treatment at present

Case 1Patient Case Resolution

Case 2Unresectable Metastatic Melanoma

• A 40-year old woman presents with unresectable metastatic melanoma and lung metastases

• PMH: Not contributory – otherwise healthy

• Restaging after 4 cycles of ipilimumab (partial response)

• Three days later, presents to ED with profuse diarrhea, “too many times to count”

• What caused the diarrhea?

Case 2Workup and Treatment

• Differential diagnosis:− Infectious colitis

− Ipilimumab-induced diarrhea

• Work up: − Stool sample: O&P, Culture, C. Difficile toxin, WBC

− Colonoscopy:

“Focal erosion in terminal ileum with chronic inflammation. Marked cryptitis throughout the colon”

Interpreted as Chronic active colitis

• Treatment:− Hospital admission, IV hydration

− High-dose steroid with very slow taper

Case 2New Presentation

• A month later, presented to ED with high fever, photophobia, confusion, delirium. Also had severe headache a few days prior.

• What caused this clinical condition?

Case 2Differential Diagnosis and Treatment

• Differential diagnosis:

− Brain metastasis, infection, ipilimumab-induced

− Ipilimumab-induced hypophysitis:

− AMS, visual disturbances, severe frontal headache, fever, weakness, anorexia

− Pan Hormone deficiency: Suppressed TSH, ACTH, FSH, LH, FT4, cortisol, testosterone, prolactin

− MRI brain with pituitary cut: enlarged pituitary gland

− Treatment: high-dose steroid (methylprednisolone 1-2 mg/kg/day IV with slow taper), endocrine consult and hormone supplement

ACTH=adrenocorticotropic hormone; AMS=atypical mole syndrome; ED=emergency department; FSH=follicle-stimulating hormone; FT4=free thyroxine; LH=luteinizing hormone; MRI=magnetic resonance imaging; THS=thyroid-stimulating hormone.

Key Take Home Points

• Cancer immunotherapy (eg, immune checkpoint blockade) associated with unique clinical features

− Immune-mediated response patterns (irRC developed)

− irAEs (autoinflammatory in nature)

• Early recognition and effective management of irAEs crucial to optimal use of cancer immunotherapy

− Responsibility of all healthcare providers, and facilitated by well-coordinated interprofessional team

− Thorough and continuous patient and caregiver education essential

Documents

Cancer Immunotherapyd2qrtshcpf0x30.cloudfront.net/nodes/187/IO Grand Rounds.pdf · 2017-05-18 · Cancer Immunotherapy Early Recognition and Effective Management of Immune-Related