DISCLAIMERDISCLAIMERThis slide deck in its original and unaltered format is for educational purposes and is

current as of May 2012. All materials contained herein reflect the views of thefaculty, and not those of IMER, the CME provider, or the commercial supporter. Thesematerials may discuss therapeutic products that have not been approved by the US

Food and Drug Administration and off-label uses of approved products. Readersshould not rely on this information as a substitute for professional medical advice,

diagnosis, or treatment. The use of any information provided is solely at your own risk,and readers should verify the prescribing information and all data before treating

patients or employing any therapeutic products described in this educational activity.

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DISCLAIMERDISCLAIMERParticipants have an implied responsibility to use the newly acquired information

to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for

patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by

clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s

product information, and comparison with recommendations of other authorities.

DISCLOSURE OF UNLABELED USEDISCLOSURE OF UNLABELED USEThis activity may contain discussion of published and/or investigational uses of

agents that are not indicated by the FDA. IMER does not recommend the use of any agent outside of the labeled indications. 

The opinions expressed in the activity are those of the faculty and do not necessarily represent the views of IMER. Please refer to the official prescribing information for

each product for discussion of approved indications, contraindications, and warnings.

Disclosure of Conflicts of InterestDisclosure of Conflicts of Interest

Peg Esper, MSN, MSA, RN, APRN-BC, AOCN®, reported a financial interest/relationship or affiliation in the form of: Speakers' Bureau, Novartis Pharmaceuticals Corporation, Pfizer, Inc., Prometheus.

Evan M. Hersh, MD, reported a financial interest/relationship or affiliation in the form of: Speakers' Bureau, Bristol-Myers Squibb Company, Pfizer and Glaxo Smith Kline and consultant to Genentech and Pfizer.

Krista M. Rubin, MS, RN, FNP-BC, reported a financial interest/relationship or affiliation in the form of: Consultant, Bristol-Myers Squibb Company, Genentech, Inc., Merck & Co., Inc.

Learning ObjectivesLearning ObjectivesUpon completion of this activity, participants Upon completion of this activity, participants

should be better able to:should be better able to:

Identify the emerging role of novel therapies in the treatment of advanced melanoma

Implement strategies for the safe administration of novel therapies

Apply evidence-based or best practice supportive care to manage side effects and optimize therapeutic outcomes of patients with melanoma receiving novel therapies

Provide accurate and health-literate responses to melanoma patients’ questions regarding their disease, treatment guidelines, and side effects

Activity OverviewActivity Overview

Peg Esper, MSN, MSA, RN, ANP-BC, AOCN®

University of Michigan ComprehensiveCancer Center

Introduction to Faculty PanelIntroduction to Faculty Panel Peg Esper, MSN, MSA, RN, ANP-BC, AOCN® (Chairperson)

– Nurse Practitioner, Medical Oncology

– University of Michigan Comprehensive Cancer Center

Evan M. Hersh, MD – Professor of Medicine, Microbiology and Immunology

– Arizona Cancer Center, University of Arizona

Krista M. Rubin, MS, RN, FNP-BC– Nurse Practitioner, Center for Melanoma

– Massachusetts General Hospital

Activity AgendaActivity Agenda

6:30 – 6:35 AM Welcome and Activity Overview

6:35 – 6:50 AM Clinical Update: What’s New in Melanoma Therapy?

6:50 – 7:10 AM The Workshop: Nursing Management Strategies for Patients With Advanced Melanoma

7:10 – 7:55 AM Putting the Workshop Into Practice: Roundtable Discussions on Metastatic Melanoma Case

Studies

7:55 – 8:00 AM Audience Questions and Answers

Treatment Update in Treatment Update in Advanced MelanomaAdvanced Melanoma

Evan M. Hersh, MDArizona Cancer CenterUniversity of Arizona

2012 Overview of Melanoma2012 Overview of Melanoma

Fastest rising incidence of any cancer over the last 3 decades

– 76,250 cases in 2012

Median age at diagnosis: 60 yrs

Early metastatic potential

Early and common CNS seeding

Historic lack of effective systemic therapies until recently

– Mortality 9,180 cases in 2012

CNS = central nervous system.Weber, 2008; ACS, 2011.

Melanoma: Incidence, Mortality, Melanoma: Incidence, Mortality, and Survival by Stage and Survival by Stage

Incidence Survival Curves by AJCC Stage

20-yr survival curves for patients with melanoma by stage. The differences between the curves are highly significant (p < .0001). Age adjusted incidence rates of all ages,

all races, both male and female, 1975–2008

AJCC = American Joint Committee on Cancer.Howlader et al, 2010; Edge et al, 2010.

Stage I (n = 18,370)

Stage II (n = 9,269)

Stage III (n = 3,307)

Stage IV (n = 7,972)

0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

Survival, Years

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Systemic Therapy for Metastatic Systemic Therapy for Metastatic Melanoma: Prior HistoryMelanoma: Prior History

Surgery (metastasectomy)

Dacarbazinea (DTIC)1

High-dose bolus IL-22

Biochemotherapy with IL-2

Carboplatin/paclitaxel

Temozolomide (US)

Fotemustine (Europe)

aFDA approved: 11970s, 21998.OS = overall survival; IL-2 = interleukin-2.Middleton et al, 2000; Agarwala, 2009; Serrone et al, 2000; Gonzalez-Larriba et al, 2010; Flaherty et al, 2010; Seront et al, 2010.

Ipilimumab Is a Member of a Novel Class Ipilimumab Is a Member of a Novel Class of Immunotherapeutic Antibodiesof Immunotherapeutic Antibodies

1) Co-stimulation via CD28 ligation transduces T-cell

activating signals

3) Blocking CTLA-4 ligation enhances T-cell responses

2) CTLA-4 ligation on activated T cells down-

regulates T-cell responses

MHC

TCR

T cell CTLA-4

APC

MHC

TCR

Ipilimumab

T cell

CTLA-4

APC

T-cell activation

MHC

TCR

T cell

APC

CD28

CTLA-4

T-cell inactivation

B7 B7B7

T-cell activation

CD28 CD28

CTLA-4 = cytotoxic T-lymphocyte antigen-4; MHC = major histocompatibility complex; TCR = T-cell receptor; APC = antigen presenting cell. Fong et al, 2008.

Ipilimumab Registration TrialsIpilimumab Registration Trials

Second-line MDX010-20 trial HLA-A2 positive (N = 650)

– 3 arms 3:1:1 (ipilimumab/gp100 vaccine, ipilimumab alone, gp100 alone)

– First study in metastatic melanoma to demonstrate OS benefit in large randomized placebo-controlled trial

First-line CA184-024 trial, randomized placebo control (N = 500)

– Ipilimumab/DTIC vs. placebo/DTIC

– Reported as having positive OS (ipilimumab/DTIC combination vs. DTIC)

HLA-A2 = human leukocyte antigen-alpha 2.

Hodi et al, 2010; Wolchok et al, 2011.

RANDOMIZE

Pre-treatedmetastaticmelanoma(N = 676)

(n = 137)

(n = 136)

(n = 403)

gp100 + placebo

Ipilimumab + placebo

Ipilimumab + gp100

Hodi et al, 2010.

MDX010-20: Study DesignMDX010-20: Study Design

Ipilimumab + gp100 (A)

Ipilimumab alone (B)

gp100 alone (C)

1 2 3 4

Time (yrs)

Comparison HR p Value 

Arms A vs. C 0.68 .0004

Arms B vs. C 0.66 .0026

HR = hazard ratio.Hodi et al, 2010.

Kaplan-Meier Analysis of SurvivalKaplan-Meier Analysis of Survival

Baseline Tumor Assessment

First Scheduled Tumor Assessment

Screening

Ipilimumab 10 mg/kgq12wks

Ipilimumab 10 mg/kgq3wks x 4

Wk 12 Wk 24Wk 1

Induction

Maintenancea

DTIC 850 mg/m2

q3wks x 8

PreviouslyUntreatedMetastaticMelanoma(N = 502)

Placeboq3wks x 4

Placeboq12wks

R

R = blindedrandomization

(1:1)

DTIC 850 mg/m2

q3wks x 8

aIn absence of progression.Wolchok et al, 2011.

Ipilimumab Plus DTIC Vs. DTIC Alone Ipilimumab Plus DTIC Vs. DTIC Alone (Study 024): Design(Study 024): Design

Ipilimumab Plus DTIC Vs. DTIC: OSIpilimumab Plus DTIC Vs. DTIC: OS

CI = confidence interval.Wolchok et al, 2011.

Study 024: Select AEsStudy 024: Select AEs

Select AEs are shown, regardless of attribution

GI = gastrointestinal; AEs = adverse events.Wolchok et al, 2011.

Study 024: Select AEs (cont.)Study 024: Select AEs (cont.)

Select AEs are shown, regardless of attribution

a1 (0.4%) hypophysitis in a patient on maintenance was reported on Day 364.ALT = alanine aminotransferase; AST = aspartate aminotransferase.Wolchok et al, 2011.

Ipilimumab Patterns of ResponseIpilimumab Patterns of Response

Hoos et al, 2010; Images courtesy of K. Harmankaya, MD.

Baseline (Day 0) Week 12 (Day 84)

Week 16 (Day 112) Week 72 (Day 503)

Targeted MAPK Pathway: BRAFTargeted MAPK Pathway: BRAF

cKIT mutations: 3% of all melanomas – almost exclusively acral letiginous, mucosal, or chronic sun damaged skin

BRAF mutations: 50% cutaneous melanomas – intermittent sun exposed skin

MAPK = mitogen activated protein kinase; BRAF = serine/threonine protein kinase. Curtin et al, 2006; Presented with permission, Copyright 2011 by C Lovly, L Horn, & W Pao, 2012.

Phase III First-Line BRIM3 Phase III First-Line BRIM3 Study DesignStudy Design

BRAFV600E mutation

Stratification• Stage• ECOG PS (0 vs. 1)• LDH level (↑ vs. nL)• Geographic region

Screening960 mg po bid

(n = 337)

1,000 mg/m2 IV q3wks (n = 338)

Dacarbazine

Vemurafenib

RandomizationN = 675

ECOG PS = Eastern Cooperative Oncology Group performance status; LDH = lactate dehydrogenase level; IV = intravenous; po = oral; bid = twice daily. Chapman et al, 2011.

ECOG PS = Eastern Cooperative Oncology Group performance status; LDH = lactate dehydrogenase level; IV = intravenous; po = oral; bid = twice daily. Chapman et al, 2011.

Best Tumor Response by Individual PatientBest Tumor Response by Individual Patient

Vemurafenib: 48.4% response

Dacarbazine: 5.5% response

Chapman et al, 2011.

100

90

80

70

60

50

40

30

20

10

0

PF

S (

%)

No. Patients in Follow-Up

Dacarbazine

Vemurafenib

0 1 2 3 4 5 6 7 8 9 10 11 12

HR 0.26 (95% CI; 0.20–0.33)

Log-rank p < .001

Time (mos)

274

275

213

268

85

211

48

122

28

105

16

50

10

35

6

16

3

4

0

3

Dacarbazine (N = 274)

Vemurafenib (N = 275)

Progression-Free SurvivalProgression-Free Survival(12/30/10 cutoff)(12/30/10 cutoff)

Median 1.6 mos

Median 5.3 mos

Chapman et al, 2011.

PET Scans at Baseline PET Scans at Baseline and Day 15 After Vemurafeniband Day 15 After Vemurafenib

#63 MSKCC#69 MDACC

PET = positron emission tomography; MDACC = The University of Texas M. D. Anderson Cancer Center; MSKCC = Memorial Sloan-Kettering Cancer Center.Chapman, 2009.

Survival in BRAF V600-Mutant Advanced Survival in BRAF V600-Mutant Advanced Melanoma Treated With Vemurafenib Melanoma Treated With Vemurafenib

Phase II study in 132 previously-treated patients

Response Rate: 53%

– 6% CR, 47% PR

DOR: 6.7 mos

PFS: 6.8 mos (CI 5.6-8.1)

OS: 15.9 mos (CI 11.6–18.3 mos)

Comparison

– DTIC OS 6–8 mos

– Phase II chemotherapy survival: 6.3 mos

CR = complete response; PR = partial response; DOR = duration of response; PFS = progression-free survival.Sosman et al, 2012.

Phase III of HD IL-2 +/- VaccinePhase III of HD IL-2 +/- Vaccine

Study population (eligible for HD IL-2)

– Stage IV or unresectable stage III melanoma

– HLA-A0201 positive

– No brain metastases

– No previous HD IL-2

1:1 randomization

– 1) HD IL-2 q8hrs x 12 doses q3wks

– 2) IL-2 + gp100 vaccine

179 evaluable patients accrued (93 IL-2/86 Vac)

– 21 centers, 2000–2007

HD = high-dose.Schwartzentruber et al, 2011.

Phase III of HD IL-2 +/- Vaccine (cont.)Phase III of HD IL-2 +/- Vaccine (cont.)

Outcome IL-2, No. (%) IL-2 + Vaccine, No. (%) p Value

No. patients 93 85

CR (investigator) 2 (2) 9 (11) .02

CR + PR (investigator) 9 (10) 17 (20) .05

CR + PRa

(central, primary end point)6 (6) 14 (16) .03

PFS (median) 1.6 m 2.2 m .008

OS (median) 11.1 m 17.8 m .06

aMost of RR difference due to responses in M1b/lung met.RR = response rate.Schwartzentruber et al, 2011.

HFS = hand-foot syndrome; M/F= masculine/feminine.Boasberg et al, 2011.

Patient Characteristics

M/F 32 / 18

Stage # (%)

IIIC 2 (4)

IV:M1a 4 (8)

IV:M1b 11 (22)

IV:M1c 34 (66)

LDH

Normal 30 (60)

Elevated 20 (40)

Toxicity #

26 grade 3 events related to study drug

Neutropenia 10

Neuropathy 7

Mucositis 4

Fatigue 3

Proteinuria 1

HFS 1

No study drug-related grade 4 toxicity

nabnab-Paclitaxel Plus Bevacizumab -Paclitaxel Plus Bevacizumab in Melanomain Melanoma

RECIST = Response Evaluation Criteria In Solid Tumors; SD = stable disease; PD = progressive disease. Boasberg et al, 2011.

RR (RECIST) # (%)

CR 2 (4)

PR 16 (32)

SD 22 (44)

PD 10 (20)

Clinical benefit (CR + PR + SD) 40 (80)

PFS

PFS at 4 mos 73%

Median PFS 7.63 mos

Median duration of follow-up 41.6 mos

OS

1-yr survival 62%

2-yr survival 30%

Median survival 16.8 mos

nabnab-Paclitaxel Plus Bevacizumab -Paclitaxel Plus Bevacizumab in Melanoma (cont.)in Melanoma (cont.)

New Treatment Algorithm for New Treatment Algorithm for Stage IV MelanomaStage IV Melanoma

Clinical trial

Treatment naïve

– HD IL-2 if eligible

– High priority protocol if eligible

– Vemurafenib (V600) or imatinib (c-kit) if tumor mutated

– Ipilimumab alone or with other drugs if not mutated

Previously treated

– High priority protocol if eligible

– HD IL-2, ipilimumab, vemurafenib, or imatinib if appropriate

– nab-Paclitaxel plus bevacizumab off label therapy

– Standard therapy, or phase I or II protocol

Low tumor burden: ImmunoRx; High burden: BRAF inhibitor

Chemotherapy options include

– Dacarbazine, temozolomide, dacarbazine- or temozolomide-based combination chemotherapy/biochemotherapy, paclitaxel, paclitaxel/cisplatin, paclitaxel/carboplatin

Rx = prescription.NCCN, 2012a.

Evolution of Response Criteria:Evolution of Response Criteria:mWHO to irRCmWHO to irRC

WHO = World Health Organization; irRC = immune-related response criteria; SPD = sum of perpendicular diameters.Wolchok et al, 2009.

Monitoring Disease Response in Monitoring Disease Response in Patients Receiving IpilimumabPatients Receiving Ipilimumab

Analysis of 5 clinical trials (N = 269)

– CR 10–106 wks after treatment initiation

– PR 5–62 wks after treatment initiation

– Therapeutic responses peak between 12–24 wks, slow responses up to and beyond 12 mos

– DOR 6–187+ wks

Clinical trial monitoring (Hodi et al, 2010)

– Baseline

– 12 wks

– 16, 20, 24 wks if no early PD and SD or better at Wk 12

– q3mos thereafter

Callahan et al, 2010; Hamid et al, 2007; Boasberg et al, 2010; Hodi et al, 2010.

Key Takeaways:Key Takeaways:Treatment of Advanced MelanomaTreatment of Advanced Melanoma

Melanoma is increasing dramatically in incidence

2 new therapies have been approved recently

– Ipilimumab

– Vemurafenib

2 other therapies are promising

– HD IL-2 + peptide vaccine (vaccine experimental)

– nab-Paclitaxel plus bevacizumab (off label)

A new treatment paradigm for melanoma is at hand

The Workshop: Nursing The Workshop: Nursing Management Strategies for Management Strategies for

Patients With Advanced Melanoma Patients With Advanced Melanoma

Peg Esper, MSN, MSA, RN, ANP-BC, AOCN®

University of Michigan Comprehensive Cancer Center

Nursing Management: Nursing Management: Ipilimumab AdministrationIpilimumab Administration

Ipilimumab (FDA approved 3/25/11)

– 3 mg/kg IV over 90 mins q3wks for a total of 4 doses

– Available as

• 50 mg / 10 mL

• 200 mg / 40 mL

– Store the diluted solution for no more than 24 hrs under refrigeration (2–8°C, 36–46°F) or at room temperature (20–25°C, 68–77°F)

– Compatible with 0.9% NaCl or D5W

– Discard partially used vials or empty vials of ipilimumab

NaCl = sodium chloride; D5W = 5% dextrose injection.Yervoy™ prescribing information, 2012.

Nursing Management: Nursing Management: Vemurafenib AdministrationVemurafenib Administration

Vemurafenib (240 mg tablets; approved 8/17/11)

– Recommended dose: 960 mg (four 240-mg tablets) bid

– The first dose should be taken in the morning and the second dose approximately 12 hrs later

– Swallow whole with a glass of water, either with or without a meal

– Should not be crushed or chewed

– If a dose is missed, it can be taken up to 4 hrs prior to the next dose; both doses should not be taken at the same time

Zelboraf® prescribing information, 2012.

Additional RegimensAdditional Regimens HD IL-2

– 600,000 IU/kg administered as IV bolus over 15 mins q8hrs up to 14 doses

– 1-wk break period and then repeat

Chemotherapy regimens include

– DTIC 1,000 mg/m2 IV q3wks

– Carboplatin and paclitaxel q3wks

– Temozolomide 200 mg/m2 daily x 5 days (q3wks); 75 mg/m2 x 42 days on 14 days off

Proleukin® prescribing information, 2012; Temodar® prescribing information, 2012; Sosman, 2011.

IL-2 ToxicitiesIL-2 Toxicities Significant immune-mediated toxicity profile Dose related and schedule dependent Toxicities, while acute, reverse after completion of therapy

Common toxicities related to IL-2 therapy include– Fever and rigors – Hypotension

– N/V/D – Mental status changes

– Oliguria, ↑ creatinine – Respiratory dysfunction

– Hematologic toxicity – Dry skin, desquamation

– Infections – Skin rashes/pruritis

– Weight gain during treatment

Most severe toxicities (grade 3/4) observed with IL-2 therapy are associated with CLS

Rare – Cardiac related deaths

N/V/D = nausea, vomiting, diarrhea; CLS = capillary leak syndrome.Proleukin® prescribing information, 2012; Schwartz et al, 2002.

IL-2 Side-Effect Monitoring and Treatment IL-2 Side-Effect Monitoring and Treatment

TLC = triple lumen catheter; PRN = as needed; NSAIDs = non-steroidal anti-inflammatory drugs.Proleukin® prescribing information, 2012; Schwartz et al, 2002.

Ipilimumab: The Ipilimumab: The ““ITIS SyndromesITIS Syndromes”” The most frequent target organ effects of ipilimumab include

– Skin (dermatitis)– GI tract (enterocolitis)– Hepatic system (hepatitis)– Neurologic system (neuritis)– Endocrine system (hypophysitis, thyroiditis)– Additionally: Nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and vasculitis (smaller percent)

Most commonly observed adverse reactions (≥ 5%, any grade)– Diarrhea– Rash– Fatigue– Pruritis– Colitis

Yervoy™ prescribing information, 2012.

Yervoy™ prescribing information, 2012.

Ipilimumab Boxed WarningIpilimumab Boxed Warning Severe and fatal immune-mediated adverse reactions due to T-cell

activation and proliferation can occur and may involve any organ system

The most common adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy

Most adverse reactions are initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of ipilimumab

Permanently discontinue and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose

New Agent Side-Effect Profile:New Agent Side-Effect Profile:VemurafenibVemurafenib

Arthralgia

Rash

Nausea

Photosensitivity

Fatigue

Pruritus

HFSR / palmar-plantar dysesthesia

Development of SCC, keratoacanthoma type

HFSR = hand foot skin reaction; SCC = squamous cell carcinoma.Puzanov et al, 2010; Lacouture et al, 2010.

Managing Toxicities of TreatmentManaging Toxicities of Treatment

GRADE OF TOXICITY

GRADE 1 Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated

GRADE 2 Minimal, local, or noninvasive intervention indicated; limiting age-appropriate instrumental ADLs

GRADE 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADLs

GRADE 4 Life-threatening consequences; urgent intervention indicated

GRADE 5 Death

ADLs = activities of daily living. NCI-(CTC-AE) v4.0, 2010.

Managing New Agent ToxicitiesManaging New Agent Toxicities

Dermatologic

– Rash

– Vitiligo

– Pruritis

– HFSR

– Photosensitivity

Puzanov et al, 2010; Photos courtesy of Peg Esper, MSN, MSA, RN, ANP-BC, AOCN®.

• Use of emollient creams

• Antipruritic agents• Steroid creams if

indicated• Avoid hot showers• Loose clothing• Avoid changing

detergents, softeners, etc.

• Limit sun exposure and use sunscreen

IPILIMUMAB

• Immune-mediated IRAE

• Corticosteroid use more common

• Can progress to Stevens-Johnson syndrome in rare cases

• Hold or discontinue PRN

VEMURAFENIB

• Use of minocycline for papular/pustular rashes

• Frequent skin evaluations to check for SCC

• Dermatologist referral PRN

• Hold or discontinue PRN

RashRash

Lemech et al, 2012; Lacouture, 2011.

NCI-CTCAE v4.03: Grading of RashNCI-CTCAE v4.03: Grading of Rash

Definition: A disorder characterized by the presence of macules (flat) and papules (elevated). Also known as morbilliform rash, it is one of the most common cutaneous adverse events, frequently affecting the upper trunk, spreading centripetally and associated with pruritus..

Grading is based on percent of BSA covered by macules/papules

BSA = body surface area.NCI-CTCAE v4.03, 2010.

HFSR (Palmar-Plantar Dysesthesia): VemurafenibHFSR (Palmar-Plantar Dysesthesia): Vemurafenib

Thickened skin with patchy hyperkeratodermia seen primarily over high pressure areas

Believed to be related to affects of agents on keratinocyte differentiation

Discomfort can be severe and prevent ambulation

Use of gel inserts for shoes

Podiatrist evaluation pre-Tx

Urea based creams

Foot soaks

Choi et al, 2011; Photos courtesy of Peg Esper, MSN, MSA, RN, ANP-BC, AOCN®.

GI Adverse Effects (AEs)GI Adverse Effects (AEs) Diarrhea – Primarily ipilimumab, but may be seen with vemurafenib

Can rapidly progress to colitis if not treated

– Grade 1 (2 or < episodes in 24 hrs)

• Antidiarrheals with close follow-up

• Consider need for stool evaluation (clostridium)

– Grade 2 (3–6 episodes in 24 hrs)

• Oral budesonide (9 mg/d) along with antidiarrheals

• Urgent sigmoidoscopy

– Grade 3 (7+ episodes in 24 hrs)

• Oral corticosteroids

– Prednisone, methylprednisolone, dexamethasone

Symptomatic treatment of diarrhea/colitis has been required up to 2 yrs in some reports

Thumar et al, 2011; Hodi, 2010.

Progression to Colitis: Ipilimumab Progression to Colitis: Ipilimumab 7+ stools/day over baseline, fever, ileus, peritoneal signs Dehydration or bleeding (colitis on sigmoidoscopy)

– Inpatient admission– IV corticosteroids– Possible infliximab, 5 mg/kg for corticosteroid-resistant or

refractory cases– Bowel rest – Possible TPN for prolonged diarrhea

Severe unrelenting cases– Tacrolimus or sirolimus may be added– Diverting ileostomy or partial/total colectomy may be considered

Discontinuation of therapy recommended for patients with severe enterocolitis

TPN = total parenteral nutrition.Thumar et al, 2011; Weber, 2009; Ledezma, 2009; Greenstein, 2008, Lemech et al, 2012.

More Immune-Related More Immune-Related Adverse Events (IRAEs)Adverse Events (IRAEs)

Ipilimumab

Autoimmune HepatitisAutoimmune Hepatitis

Transaminitis reported in up to 20% of patients treated with anti-CTLA-4 antibodies

Severe autoimmune hepatitis reported 2%

Liver biopsies have revealed diffuse lymphocytic infiltrates

Discontinue treatment for grade 3 or higher elevations

Oral corticosteroids for 30 days+ may be needed

Elevations of grade 4 level require hospitalization and IV corticosteroids

LFTs/bilirubin must be checked prior to every dose

Observe for symptoms of increased fatigue, N/V, or mental status changes

LFTs = liver function tests.Thumar et al, 2011; Lemech et al, 2012.

EndocrinopathiesEndocrinopathies

Seen in 15% of phase III study participants

Hypothyroidism

– Elevated TSH

– Symptoms of fatigue, hair thinning, constipation, weight gain

– Replacement thyroid hormone is indicated

– Ongoing monitoring of thyroid hormone levels (baseline, prior to each cycle and as clinically indicated)

– Some patients may ultimately be able to taper off thyroid supplement therapy

Hyperthyroidism was also seen

TSH = thyroid stimulating hormone.Weber, 2009; Lemech et al, 2012.

HypophysitisHypophysitis

Inflammation of the pituitary gland

Symptoms include: Fatigue, headache, loss of libido, pressure behind eyes, nausea, diminished visual fields

Laboratory data

– Decreased cortisol

– Decreased testosterone

– Decreased ACTH

Radiographic studies

– MRI scan of brain with attention to the sella region with diffuse enlargement of the pituitary gland

ACTH = adrenocorticotrophic hormone; MRI = magnetic resonance imaging.Weber, 2009; Kaehler et al, 2010; Thumar et al, 2011.

Hypophysitis (cont.)Hypophysitis (cont.) Management includes

– Replacement of deficient hormones

• Cortisol (hydrocortisone, initial dexamethasone/prednisone)

• Thyroid replacement therapy

• Testosterone

– Consider endocrinology consult

– Patients may ultimately be able to taper off replacement therapy

Thumar et al, 2011; Weber, 2009; Image adapted from Kaehler et al, 2010.

Additional AEsAdditional AEs Ocular (seen with both ipilimumab and vemurafenib)

– Uveitis (decreased visual acuity, photophobia, tearing)

– Conjunctivitis

Neurologic (ipilimumab)– Myopathies (weakness, altered sensory function, paresthesias)

– 1 case of fatal Guillian-Barre and 1 case of grade 3 peripheral motor neuropathy seen in investigational studies

General (ipilimumab and vemurafenib)– Fatigue

– Anorexia

– Cough

– Anemia

– Headache

Thumar et al, 2011; Yervoy® prescribing information, 2012; Zelboraf® prescribing information, 2012; Lemech et al, 2012.

Baseline labs to

include CBC, LFTs,

Lytes

IPILIMUMAB

• Labs to be rechecked prior to each cycle of treatment

• Monitor thyroid function and chemistry panel prior to each cycle of treatment

VEMURAFENIB

• Molecular testing to confirm BRAF mutation

• LFTs to be checked at least monthly and as clinically indicated

• EKG 15 days into Tx, then monthly x 3, then q3mos

Labs and EvaluationsLabs and Evaluations

CBC = complete blood count; Lytes = electrolytes; EKG = electrocardiogram.Yervoy® prescribing information, 2012; Zelboraf® prescribing information, 2012.

Drug-Drug InteractionsDrug-Drug Interactions

Ipilimumab

– No known drug-drug interactions

Vemurafenib

– CYP substrates: Concomitant use of vemurafenib with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP1A2, or CYP2D6 is not recommended. If co-administration cannot be avoided, exercise caution and consider a dose reduction of the concomitant CYP1A2 or CYP2D6 substrate drug.

– May increase exposure to concomitantly administered warfarin. Exercise caution and consider additional INR monitoring when used concomitantly with warfarin.

INR = international normalized ratio; CYP = cytochrome P450.Yervoy® prescribing information, 2012; Zelboraf® prescribing information, 2012.

When to Discontinue IpilimumabWhen to Discontinue IpilimumabPermanently discontinue ipilimumab for any of the following:

Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day

Failure to complete full treatment course within 16 wks from administration of first dose

Severe or life-threatening adverse reactions, including any of the following:

– Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (7 or more over baseline)

– Stool incontinence

– Need for IV hydration for > 24 hrs

– Gl hemorrhage and Gl perforation

AST or ALT > 5 times ULN or total bilirubin > 3 times ULN

Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations

Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis

Severe immune-mediated reactions involving any organ system (eg, nephritis, pneumonitis, pancreatitis, non-infectious myocarditis)

Immune-mediated ocular disease that is unresponsive to topical immunosuppressive therapy

ULN = upper limit of normal.Yervoy® prescribing information, 2012.

Dose Modification Information:Dose Modification Information:VemurafenibVemurafenib

*The intensity of clinical AEs graded by the CTC-AE. Zelboraf® prescribing information, 2012.

Grade (CTC-AE)* Recommended Vemurafenib Dose Modification

Grade 1 or Grade 2 (tolerable) Maintain vemurafenib at dose of 960 mg bid

Grade 2 (intolerable) or Grade 3

1st Appearance Interrupt treatment until Grade 0–1 Resume dosing at 720 mg bid

2nd Appearance Interrupt treatment until Grade 0–1Resume dosing at 480 mg bid

3rd Appearance Discontinue permanently

Grade 4

1st Appearance Discontinue permanently or interrupt vemurafenib treatment until Grade 0–1Resume dosing at 480 mg bid

2nd Appearance Discontinue permanently

Patient Education: GeneralPatient Education: General Assess for both patient and family (or significant other)

– Knowledge of therapy and disease process

– Educational level

– Preferred learning methods

Develop a plan

Implement teaching, using a wide variety of materials and methods

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

Contact

– Who to call

– Why to call

– When to call

– Where to call (must have 24/7 clinician availability)

Patient Education: ChallengesPatient Education: Challenges

Ipilimumab

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

– Vast side-effect profile, when to notify clinician

– Variability in response to treatment

– Four treatments in the FDA approved therapy

Ledezma, 2009.

Patient Education: Challenges (cont.)Patient Education: Challenges (cont.)

Vemurafenib

– What is BRAF?

– Do I have genetic mutations?

– Yes, it is 4 pills bid!

– You treat 1 skin cancer, but develop another type of skin cancer?

– Does this cure my cancer?

Putting the Workshop Into Putting the Workshop Into Practice: Roundtable Practice: Roundtable

Discussions on Metastatic Discussions on Metastatic Melanoma Case Studies Melanoma Case Studies

Krista M. Rubin, MS, RN, FNP-BCMassachusetts General Hospital

Putting the Workshop Into Putting the Workshop Into PracticePractice

Please assign a moderator for your table

You have 10 minutes to discuss the case

Moderators:

– Please record all group responses on the “Moderator Handout”

– Leave this handout on your table; this will be collected at the end of the presentation by IMER staff

Case Study 1Case Study 1

Case Study 1: HistoryCase Study 1: History

30-yr-old man with a history of a 2.3 mm, non-ulcerated nodular, melanoma of (R) forearm s/p wide excision and negative sentinel node biopsy [T3aN0MX: Stage IIA]. No adjuvant Rx recommended. Followed accordingly.

2 yrs later, develops SOB playing basketball. Presents to ER: CXR showed large (L) pleural effusion.

– Rx: Thoracentesis (therapeutic and diagnostic) for ~ 1 L bloody fluid

– Cytology → IHC: MART–1, HMB45, S100 all (+) c/w metastatic melanoma

– Imaging studies: Large subcarinal LN and multiple (L) pleural masses. Brain MRI(-). Pleurodesis with symptomatic improvements in dyspnea.

SOB = shortnes of breath; ER = emergency room; CXR = chest X-ray; IHC = immunohistochemistry; MART-1, HMB45, and S100 = IHC markers of melanocytic tumors; LN = lymph node; PMH = patient medical history.

Case Study 1: History (cont.)Case Study 1: History (cont.)

Repeat imaging 1 wk later revealed an increase in size of known tumor and new bilateral pleural masses, diffuse LAN in the prevascular and anterior mediastinum.

PMH notable controlled asthma

Meds: Fluticasone 110 mcg INH, 2 puffs bid (albuterol inhaler prn)

Allergies: NKA

FH: Negative for melanoma

SH: Married, 2-yr old twins, works in investment banking. Non-smoker and social drinker.

FH = family history; SH = social history.

Case Study 1: QuestionsCase Study 1: Questions

What treatment options would be discussed with this patient?

What would be recommended and why?

Case Study 1: Treatment Options Case Study 1: Treatment Options

Clinical trials− None available for first-line therapy at the time of diagnosis

Immunotherapy− Ipilimumab

− HD IL-2

Targeted therapy− BRAF inhibitor if BRAF mutation identified

Chemotherapy − DTIC

− Temozolomide (off-label)

− Carbo/paclitaxel (off-label) Best Supportive Care (BSC)

NCCN, 2012a.

Case Study 1: Treatment Options (cont.)Case Study 1: Treatment Options (cont.)

Given rapid progression of disease, obtaining tissue for BRAF analysis felt to be crucial to treatment recommendations

Biopsy of plural met obtained – no mutation identified (BRAF WT)

Recommendation for ipilimumab

− Given his otherwise good health

− BRAF WT

− Concern for asthma exacerbation off inhaled corticosteroids and pulmonary toxicity from IL-2

− Best chance of durable response

Began Rx 1 wk later after insurance approvals obtained

WT = wild-type.NCCN, 2012a.

Case Study 1: Monitoring and ResponseCase Study 1: Monitoring and Response

Tolerated first infusion well: No issues

F/U labs notable for increased LFTs: Grade 1

Second infusion

– Pre-Rx labs unremarkable

– Increasing dyspnea: O2 sats 92%–93%, mild intermittent pruritus

– Labs stable

– Fatigue worsening

Third infusion

– Grade 1 elevation of amylase/lipase, LFTs normal

– No abdominal complaints

– Dyspnea stable to slightly improved

– Pruritus improved with moisturizers

– Fatigue stable

F/U = follow-up.

Case Study 1: Monitoring and Case Study 1: Monitoring and Response (cont.) Response (cont.)

Fourth infusion

– Labs all normal

– Dyspnea improved: Sats increased at 96%

– Erythematous papules on chest and abdomen- (+) pruritus

– Fatigue much improved

CT scans (full body) obtained 4 wks from the time of the last dose showed minor regression of adenopathy, no new lesions

Repeat scans 6 wks later showed further response: No new lesions – patient continues to have slow, but clear clinical response with improved symptoms, now 5 mos from his last dose

CT = computed tomography.

Case Study 2Case Study 2

Case Study 2: HistoryCase Study 2: History

PL is a 50-yr-old man

PMH: HTN, anxiety

SH: Married, 2 adult children, respiratory therapist. Non-smoker and social drinker.

FH: Negative for melanoma or pancreatic cancer

Medications: Venlafaxine 75 mg po qd, olmesartan medoxomil/HCTZ 20/12.5 mg po qd

ALL: ASA → active systemic anaphylaxis

HTN = hypertension; HCTZ = hydrochlorothiazide.

Case Study 2 (cont.) Case Study 2 (cont.) Presents to local dermatologist with a bleeding and

changing mole. Biopsy demonstrated a 2.0 mm, ulcerated, SSM of the (L) lateral trunk, 8 mitoses/mm2.

He underwent wide excision and sentinel node evaluation: Drained to both (L) groin and (L) axilla. Final path – 0 nodes involved. No residual melanoma.

T2bN0Mx – Stage IIA disease

SSM = superficial spreading melanoma.NCCN, 2012a.

Case Study 2: QuestionsCase Study 2: Questions

What treatment options would be discussed with this patient?

What would be recommended and why?

Case Study 2: Treatment Options Case Study 2: Treatment Options

Treatment options for stage IIA melanoma

– Observation

– Clinical trial

NCCN, 2012a.

Case Study 2: Treatment Course Case Study 2: Treatment Course

Patient chose participation in E1697: An intergroup trial of 1 month of IFN vs. observation for patients with lower risk for recurrence

He was randomized to IFN arm

– Wk 2: Experienced Grade 3 nausea prompting holding 2 doses, nausea improved, restarted with 33% DR as per protocol

– Completed the full course of induction receiving all 20 doses

– Followed q3mos with H&P and CXR

IFN = interferon; DR = dose reduction; H&P = history and physical examination.ClinicalTrials.gov

Case Study 2: MonitoringCase Study 2: Monitoring 2 yrs later, patient noted a non-tender lump in (L) axilla

– Upon examination – 2 cm rubbery mobile node, no other palpable nodes. Location was concerning, but texture not.

– Plan: Re-evaluate in 1 month

1 month later is 3 cm

– FNA obtained same day- (+) for metastatic melanoma

PET-CT and brain MRI: NED other than FDG avid, enlarged (L) axillary node

Axillary node dissection was performed

Path → met melanoma in 1/15 nodes, with the metastasis measured at 4.0 cm and ECE noted

Since he had already received IFN, post-operative XRT was recommended to (L) axilla

FNA = fine needle aspiration; NED = no evidence of disease; FDG = fluorodeoxiglucose avidity; XRT = radiotherapy; ECE = extracapsular extension.NCCN, 2012a.

Case Study 3Case Study 3

Case Study 3: HistoryCase Study 3: History

30-yr-old man with a history of a 2.3 mm, non-ulcerated nodular, melanoma of (R) forearm [T3aN0MX: Stage IIA]

2 yrs later: Presents to ER and CXR showed large (L) pleural effusion

Due to rapid progression of disease, tissue was obtained for BRAF analysis: No mutation identified (BRAF WT)

Ipilimumab recommended

– Given his otherwise good health

– BRAF WT

– Concern for asthma exacerbation off inhaled corticosteroids and pulmonary toxicity from IL-2

– Best chance of durable response

Therapy started 1 wk later after insurance approvals were obtained

Case Study 3: Monitoring and Case Study 3: Monitoring and ResponseResponse

Tolerated first infusion well (no issues)

F/U labs notable for increased LFTs (Grade 1)

Second infusion: Increasing dyspnea, labs stable, fatigue worsening

Third infusion: Dyspnea stable to slightly improved, pruritus improved with moisturizers, fatigue stable

Fourth infusion: Dyspnea improved, erythematous papules on chest and abdomen- (+) pruritus, fatigue much improved

CT scans (full body) obtained 4 wks from the time of the last dose showed minor regression of adenopathy, no new lesions

Case Study 3 (cont.)Case Study 3 (cont.)

Tolerated 4 doses (induction) ipilimumab no issues

Repeat scans 6 wks later showed further response

– No new lesions: Patient continues to have slow, but clear clinical response with improved symptoms, now 5 mos from his last dose

Repeat imaging 8 wks later demonstrated small, but clear progression of pleura based nodules, and brain MRI demonstrated a 4 mm cerebellar metastasis

There was no edema, patient remained asymptomatic from a neurologic standpoint. Slight increase in cough, but overall, respiratory status was stable from last evaluation.

Case Study 3: Clinical QuestionCase Study 3: Clinical Question

What treatment options are recommended?

– Recall

• Patient is BRAF WT

• Now has a new brain metastasis

• He is young

• No other comorbidities

Case Study 3: Treatment CourseCase Study 3: Treatment Course

CNS: Decision made to proceed with stereotactic radiosurgery (SRS)

Systemic disease

– Given his initial response to ipilimumab before progression, data supports re-induction with another 4 cycles

SRS was administered in a single session: Given the small size of the met, there was little risk of seizure or edema, thus neither anti-seizure medications nor steroids were recommended. A 6-wk F/U brain MRI was scheduled.

NCCN, 2012b.

Case Study 3: Treatment Course Case Study 3: Treatment Course (cont.)(cont.)

1 wk after SRS, he received his first dose of re-induction which he tolerated without adverse event, but his fatigue was moderate to severe (Grade 2–3)

Second dose of ipilimumab was held for Grade 3 amylase/lipase, but without pancreatitis. Labs were repeated bwkly and did resolve to Grade 1 prior to the third infusion.

6-wk F/U MRI showed response to SRS and no new lesions

He received his fourth dose of induction without further toxicity. Fatigue stable, cough worse.

Given worsening cough, CTs obtained 1 wk later, demonstrated stable disease, no new lesions

NCCN, 2012b.

Case Study 3: Clinical QuestionCase Study 3: Clinical Question

What are the treatment recommendations for this patient at your facility?

– Chemotherapy

• CVD + IL-2/IFN (biochemotherapy)

• Carbo/paclitaxel (combination)

• DTIC or temozolomide (single-agent)

– Observation (repeat scans again in some designated time period: 6, 8, 10, or 12 wks)

– Hospice

NCCN, 2012a.

Case Study 4Case Study 4

Case Study 4: HistoryCase Study 4: History

PL is a 50-yr-old man

PMH: HTN, anxiety

SH: Married, supportive wife, 2 children, respiratory therapist. Non-smoker and social drinker.

FH: Negative for melanoma or pancreatic cancer

Medications: Venlafaxine 75 mg po qd, olmesartan medoxomil/HCTZ 20/12.5 mg po qd

ALL: ASA → active systemic anaphylaxis

T2bN0Mx – Stage IIA melanoma, patient chose a clinical trial: E1697: Randomized to IFN for 1 month

Case Study 4: Follow-UpCase Study 4: Follow-Up

2 yrs later, patient noted a nontender lump in (L) axilla. Exam: 2-cm rubbery mobile node, no other palpable nodes. Location was concerning, but texture not. Plan: Re-evaluate in 1 month.

1 month later, the node is 3 cm. FNA obtained same day- (+) for metastatic melanoma.

PET-CT and brain MRI: NED other than FDG avid, enlarged (L) axillary node

Axillary node dissection was performed Path → met melanoma in 1/15 nodes, with the metastasis

measured at 4.0 cm and ECE noted Since he received IFN, post-operative XRT was

recommended to (L) axilla

NCCN, 2012a.

Case Study 4: Follow-Up (cont.) Case Study 4: Follow-Up (cont.) 1 month after XRT completed, patient called to report low back pain “pulled a

muscle”; endorsed severe pain making it difficult to walk– MRI L-spine: Diffuse bony metastatic disease with destruction of the L4 vertebral

body with pathological fracture and extensive surrounding edema and enhancement.

– CT: Splenic lesion, 2 small liver lesions – possibly perfusion anomalies vs. mets. New multiple bilateral pulmonary nodules, the largest in the RLL, ~ 1.3 cm.

– Brain MRI: NED Palliative XRT to (L) spine planned, and at the same time, BRAF status was to

be obtained BRAF mutation status returned V600E mutant: Difficulty obtaining drug d/t

insurance issues Patient did again require admission for intractable pain and nausea Started vemurafenib while in-house Ultimately required kyphoplasty X2 to stabilize fractures and subsequently had

placement of intrathecal infusion pump Remained on vemurafenib for ~ 3 mos. An interval scan showed stable

disease, but repeat imaging demonstrated progression with new brain mets. Brain MRI: Multiple new small brain mets – largest being 6 mm

RLL = right lower lobe.NCCN, 2012a.

Case Study 4: Clinical QuestionCase Study 4: Clinical Question

What would be the next step at your institution?

What other services may be offered?

Case Study 4: Treatment Options Case Study 4: Treatment Options

CNS options: WB-XRT vs. SRS

Systemic options: Chemotherapy, immunoRx, BSC

After much discussion, a treatment plan was established to pursue ipilimumab for the following reasons

– CNS disease was small, patient was asymptomatic

– Given multiple sites, WB-XRT would be recommended vs.multiple SRS

– Data supporting CNS effect with ipilimumab

WB-XRT = whole brain radiotherapy.NCCN, 2012b; Margolin et al, 2012.

Case Study 4 (cont.)Case Study 4 (cont.)

Patient received his first dose of ipilimumab at the time of this writing

Remains on 4 mg po dexamethasone for nausea

– Discussion points:

• Dexamethasone and ipilimumab

• Plans for CNS progression

• Plans for systemic progression