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Page 1: 010 Burch - ACCP
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Continuing on the Road and Continuing on the Road and Taking Detours: How to Stay Taking Detours: How to Stay

on Track and What to Do When on Track and What to Do When Unexpected Events OccurUnexpected Events OccurUnexpected Events OccurUnexpected Events Occur

Holly Phillips, Pharm.D.PGY1 Program Director

University of Colorado Hospital

Introduction

• Review when and how to follow-up after the interview process

• Discuss the contents of a thank you letter

• Explain the National Matching Service (NMS) scramble process

Tips for Interview Follow-Up

• Always contact the Residency Program Director (RPD) to confirm they have received your application materials.

• Keep a list of the people you meet during• Keep a list of the people you meet during your interview. Send thank you notes to those people with which you spent significant time.

• Vary the contents of each thank you letter.

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Thank You Letters• Letters versus e-mails• Timeliness• Contents:

– Comment on the aspects of the program you feel willComment on the aspects of the program you feel will be a good match for you

– Thank interviewers for their time– Add a personal touch / reference to your time

together that will help the interviewer differentiate you as a candidate

– Sign it legibly!

Thank You Letters

• What NOT to include:– References to the social aspects of the city /

location– References to other programs / rankingReferences to other programs / ranking

preferences– Any negative or “constructive” feedback

regarding the interview process– Blatant “name dropping”

The Scramble• National Matching Service (NMS) “scramble”

process • Cannot participate if you have matched with

another program or accepted another offer• Programs with unmatched positions can makePrograms with unmatched positions can make

verbal or written offers to unmatched candidates OR candidates who did not participate in the match.

• Resources:– www.ASHP.org– www.natmatch.com/ashprmp

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Navigating the Roadmap from Navigating the Roadmap from Student to Pharmacy ProfessionalStudent to Pharmacy Professional

Navigating the Roadmap from Navigating the Roadmap from Student to Pharmacy ProfessionalStudent to Pharmacy Professional

ACCP 2007 Annual MeetingDenver, ColoradoOctober 13, 2007

ObjectivesObjectivesObjectivesObjectives• Describe the core elements of a curriculum vitae

(CV), letter of intent, and communication skills needed to be successful when applying for post-graduate training or professional careers.

• Review the steps involved in successfully pursuing postgraduate training.

• Identify appropriate interview techniques when pursuing post-graduate training or job opportunities.

• Discuss potential career options for pharmacists.

Introduction: Meet Clark KentIntroduction: Meet Clark KentIntroduction: Meet Clark KentIntroduction: Meet Clark KentClark Kent is a P3 student who is trying to decide if he wants to pursue residency training or go into a job after graduation. Faculty members have been encouraging him to pursue residency training, but

the pharmacists he works with at his internship (grocery chain) do not believe he needs a residency(grocery chain) do not believe he needs a residency

to have a clinical position. He does not yet know what area of pharmacy he wants to pursue, but he would like to participate in patient care activities in

the future. Additionally, Clark is concerned about his financial situation: over $60,000 in loans. He knows

that annual salaries for residency are $30,000-40,000 while $80,000+ for a pharmacist position.

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More about Clark Kent…More about Clark Kent…More about Clark Kent…More about Clark Kent…Clark received his Bachelor of Science degree in

Biology and has a GPA of 3.1 in his pharmacy program. He belongs to the student chapters of

American Society of Health-System Pharmacists, American Pharmacists Association, and American

College of Clinical Pharmacy. Through these organizations, he has participated in a few

volunteer activities, such as Operation Immunization and two health fairs. The 2007

ACCP Annual Meeting is his first national professional meeting.

Clark’s Initial QuestionsClark’s Initial QuestionsClark’s Initial QuestionsClark’s Initial Questions• What do I have to have in my CV?• How do I write a letter of intent?• What could I say during an interview that

would inspire someone to choose me for a pjob or residency?

• Should I do a residency?• What about my financial situation?

• WHAT AM I GOING TO DO?

Starting the Journey: Preparing Starting the Journey: Preparing Your CV and Letter of Intent and Your CV and Letter of Intent and

Navigating Potential PostNavigating Potential Post--Graduate Graduate Programs or Career OptionsPrograms or Career Options

Starting the Journey: Preparing Starting the Journey: Preparing Your CV and Letter of Intent and Your CV and Letter of Intent and

Navigating Potential PostNavigating Potential Post--Graduate Graduate Programs or Career OptionsPrograms or Career Options

Kelly R. Ragucci, PharmD, FCCP, BCPS, CDEAssociate Professor, Clinical Pharmacy and Outcome Sciences

South Carolina College of PharmacyMUSC Campus

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What is a Curriculum Vitae (CV)?What is a Curriculum Vitae (CV)?What is a Curriculum Vitae (CV)?What is a Curriculum Vitae (CV)?

• Organized summary of one’s education, professional accomplishments credentialsprofessional accomplishments, credentials, and other related experiences

• Mostly used for specialized health professional and academic positions, fellowships and residencies

What should I include on my CV?What should I include on my CV?What should I include on my CV?What should I include on my CV?

• Personal Information– Name– AddressAddress– Telephone number(s)– E-mail address

• Professional Information– Licensure– Certifications, certificates

What should I include on my CV?What should I include on my CV?What should I include on my CV?What should I include on my CV?

• Education and Training– Degree(s): currently pursuing and previousg ( ) y p g p– Distinction(s)– School(s) – Location(s)– Graduation date(s)

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What should I include on my CV?What should I include on my CV?What should I include on my CV?What should I include on my CV?

• Advanced Professional Practice Experiences– Type of rotation– Name of practice site/location– Name and credentials of preceptor– Dates of rotation (month/year)– Brief description of your responsibilities

• Can include rotations yet to be completed

What should I include on my CV?What should I include on my CV?What should I include on my CV?What should I include on my CV?

• Professional Experience– Position title– Facility name– Supervisor– Dates– Brief description of your responsibilities

What should I include on my CV?What should I include on my CV?What should I include on my CV?What should I include on my CV?

• Presentations – Title– Type (in-service, seminar, lecture)

A di– Audience– Location– Date

– “Sexually Transmitted Diseases: A Focus on the New Guidelines”. In-service presentation to family medicine inpatient team, MUSC. Charleston, South Carolina. June 22, 2007

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What should I include on my CV?What should I include on my CV?What should I include on my CV?What should I include on my CV?

• Publications– Newsletters, articles, abstracts– Provide formal citation and bold your name

– Shrader SP, Ragucci KR. Life after the WHI: evaluation of postmenopausal symptoms and use of alternative therapies after discontinuation of hormone therapy. Pharmacotherapy2006;26:1403-09.

• Research/Special Projects

What should I include on my CV?What should I include on my CV?What should I include on my CV?What should I include on my CV?

• Awards and Honors– Title of award

• Rho Chi, Phi Lambda Sigma• Scholarships, other academic awardsp ,

– Date received– Description may be appropriate

What should I include on my CV?What should I include on my CV?What should I include on my CV?What should I include on my CV?

• Service– Professional

• Organization• Years of membership• Offices held; committee work and years

– Community• Description of activities• Dates • Quantify involvement

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What should I include on my CV?What should I include on my CV?What should I include on my CV?What should I include on my CV?

• References– Can state “Available Upon Request” OR

can include references on last page of CVcan include references on last page of CV

– Ask each person prior to listing them– Provide complete and up-to-date contact

information

Where can I learn more?Where can I learn more?Where can I learn more?Where can I learn more?

• http://www.accp.com/stunet/cv.php

30 i i i i CV30 minute presentation on writing CV

Online CV review program

Letter of IntentLetter of IntentLetter of IntentLetter of Intent

• A document outlining an agreement between two or more parties before the agreement is finalized

• A statement of purpose is a brief and focused essay about one's career or research goals and is frequently required forone s career or research goals, and is frequently required for applicants to universities, graduate schools, and professional schools– Required document when applying for admission to most

professional programs in the United States. – Often used as a yardstick to assess the capabilities of a

prospective student/resident in terms of critical thinking, analytical abilities, interests, aims and aspirations.

– Most admissions committees look for a short, crisp and ideologically clear statement of purpose/letter of intent

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Letter of IntentLetter of IntentLetter of IntentLetter of Intent

• Two basic components of letter– Describe your career goals/aspirations and what

you can bring to program/job• Emphasize your unique skills and what sets you apart

– Explain why this particular program/job• Individualize it – don’t send same letter to all

programs/jobs

• Note: Address contact people formally and get degrees, credentials correct

Letter of Intent Letter of Intent -- ExampleExampleLetter of Intent Letter of Intent -- ExampleExample

• First paragraph

I am writing this letter to declare my interest in the pharmacy ti id t th M di l U i it fpractice residency program at the Medical University of

South Carolina. This program was recommended to me initially by one of my former professors and from my own research, I have been impressed with the opportunities that would be afforded to me within your program.

Letter of Intent Letter of Intent -- ExampleExampleLetter of Intent Letter of Intent -- ExampleExample

• Second paragraph

I am pursuing residency training to facilitate both my short and long-term career aspirations. Currently, I work for Kmart as a clinical pharmacist This job provides me theas a clinical pharmacist. This job provides me the opportunity to interact with patients and strengthen my knowledge of primary care specific disease states such as diabetes and hypertension. However, this particular position is limited solely to information distribution and therefore does not afford me the level of professional satisfaction that I desire. My short-term career goals are to obtain a pharmacy practice residency, followed by either a specialty residency

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Letter of Intent Letter of Intent -- ExampleExampleLetter of Intent Letter of Intent -- ExampleExample

• Second paragraph – continued

or fellowship. During this time, I hope to continue to refine my clinical expertise, as well as expand my skills in research and teaching. After completing my post-doctorate training, I

l t k i t t t th f lt f ll fplan to seek appointment to the faculty of a college of pharmacy. In this role, I would hope to teach, conduct research and maintain a clinical practice site.

Letter of Intent Letter of Intent -- ExampleExampleLetter of Intent Letter of Intent -- ExampleExample

• Third paragraphThe program at the Medical University of South Carolina has everything that I am looking for in a pharmacy practice residency. I want to be part of a large residency class, since thi f t t iti f t ki d ll b tithis fosters opportunities for networking and collaboration on projects. I also want a program that offers a diverse selection of elective rotations, as well as numerous specialtyresidencies. Finally, the residency at MUSC has theAcademic Preparation Program, which is a very attractive feature since academia is where I hope to practice eventually.

Letter of Intent Letter of Intent -- ExampleExampleLetter of Intent Letter of Intent -- ExampleExample

• Fourth paragraph

Thank you for considering my candidacy for the pharmacy practice residency at the Medical University of South Carolina Please let me know if there is any additionalCarolina. Please let me know if there is any additional information that you will need at this time.

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Navigating the ACCP WebsiteNavigating the ACCP WebsiteNavigating the ACCP WebsiteNavigating the ACCP Website

Navigating the ACCP WebsiteNavigating the ACCP WebsiteNavigating the ACCP WebsiteNavigating the ACCP Website

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At the Meeting…At the Meeting…At the Meeting…At the Meeting…

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Navigating the ASHP WebsiteNavigating the ASHP WebsiteNavigating the ASHP WebsiteNavigating the ASHP Website

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At the Meeting…At the Meeting…At the Meeting…At the Meeting…

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Questions?Questions?Questions?Questions?

Finding the Right Road: Finding the Right Road: Refining Your Interview SkillsRefining Your Interview Skills

Finding the Right Road: Finding the Right Road: Refining Your Interview SkillsRefining Your Interview Skills

Video Exercise

Finding the Right Road: Refining Your Finding the Right Road: Refining Your Interview SkillsInterview Skills

Finding the Right Road: Refining Your Finding the Right Road: Refining Your Interview SkillsInterview Skills

• Doug Fish, PharmD, FCCP, BCPS(University of Colorado)

• Laura B. Hansen, PharmD, FCCP, BCPS(University of Colorado)

• Cindy O’Bryant, PharmD, BCOP(University of Colorado)

• Rachana J. Patel, PharmD, BCPS(Kaiser Permanente – Colorado)

• Holly J. Phillips, PharmD(University Hospital – Colorado)

• Dennis K. Helling, PharmD, FCCP(Kaiser Permanente – Colorado)

• Brian Hemstreet, PharmD, BCPS(University of Colorado)

• Sunny A. Linnebur, PharmD, BCPS, CGP(University of Colorado)

• Rob MacLaren, PharmD, FCCP (University of Colorado)

(University Hospital Colorado)• Kelly R. Ragucci, PharmD, FCCP,

BCPS, CDE(South Carolina College of Pharmacy)

• Sheryl F. Vondracek, PharmD, FCCP, BCPS(University of Colorado)

• Tom Vondracek, PharmD, BCPS (Exempla St. Joseph Hospital -Colorado)

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Continuing on the Road and Continuing on the Road and Taking Detours: How to Stay on Taking Detours: How to Stay on

Track and What to Do When Track and What to Do When Unexpected Events OccurUnexpected Events Occur

Continuing on the Road and Continuing on the Road and Taking Detours: How to Stay on Taking Detours: How to Stay on

Track and What to Do When Track and What to Do When Unexpected Events OccurUnexpected Events Occur

Holly Phillips PharmDHolly Phillips, PharmDResidency Director

University Hospital – Colorado

Kelly N. Gibson, PharmDErin K. Welch, PharmD

Making the Most of Your Trip: Making the Most of Your Trip: Financial Management 101Financial Management 101

Making the Most of Your Trip: Making the Most of Your Trip: Financial Management 101Financial Management 101gggg

Lance Burch, MBAVice President and Financial Consultant

Charles SchwabDenver, Colorado

Nearing Your Destination: Nearing Your Destination: Selecting a Career PathSelecting a Career Path

Nearing Your Destination: Nearing Your Destination: Selecting a Career PathSelecting a Career Path

Academia Robert L. Talbert, PharmD, FCCP, BCPSUniversity of Texas

Industry Allyn Bandell, PharmDMedImmuneMedImmune

Inpatient Thomas Vondracek, PharmD, BCPSExempla St. Joseph Hospital–Denver, CO

Ambulatory Beverly A. Kroner, PharmD, BCPSKaiser Permanente-Denver, CO

Community Eric Chrisman, PharmDSafeway-Denver,CO

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Pharmacists in Medical Affairs Pharmacists in Medical Affairs and Other Roles in and Other Roles in

Pharmaceutical IndustryPharmaceutical Industry

Pharmacists in Medical Affairs Pharmacists in Medical Affairs and Other Roles in and Other Roles in

Pharmaceutical IndustryPharmaceutical IndustryAllyn Bandell, Pharm.D.

Director, Medical SciencesMedImmune

Adjoint Assistant Professor University of Colorado School of Pharmacy

Clinical InstructorMidwestern University

ObjectivesObjectivesObjectivesObjectives• Increase understanding of pharmaceutical

industry• Develop an appreciation of career

opportunities in industryopportunities in industry • Understand the many roles a clinical

pharmacist has in industry

Pharmaceutical Industry Pharmaceutical Industry OpportunitiesOpportunities

Pharmaceutical Industry Pharmaceutical Industry OpportunitiesOpportunities

Sales and Marketing• Sales Representatives• Division or Area

Managers• Government Affairs

A t M

Medical Affairs• Clinical Scientist• Drug Information• Medical Liaison• Medical Director

• Account Managers• Product Directors• Market Analysis• Health Care Management• Medical Directors• Competitive Intelligence• CEO

• Clinical Investigation• +/- Research and

Development• Pharmacoeconomics/

Healthoutcomes• Drug Safety

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LogisticsLogisticsLogisticsLogistics• What skills and experience does it take to get

into a pharmaceutical industry career path?• How do I break into the industry?• Can you go back?• Can you go back?

The Good the Bad and the UglyThe Good the Bad and the UglyThe Good the Bad and the UglyThe Good the Bad and the Ugly

• The Good– Great career paths– Budgets

• Bad and Ugly– Relocation– Budgets

– Some home based offices– Flexible schedule– Travel– Widespread clinical impact

– Competitive corporate offices

– Travel– Clinically

interchangeable– Layoffs

Additional InformationAdditional InformationAdditional InformationAdditional Information• www.pharmllc.com• Most companies have clinical pharmacists

who work for them, ask your local sales representative for contact information.

• Your professors probably know and even• Your professors probably know and even work with or use an industry-based clinical pharmacist as a resource, reach out to them for a contact.

• Feel free to contact me directly, and I can provide you with some other names and highly biased insights!– [email protected]

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Nearing Your Destination: Nearing Your Destination: Selecting a Career PathSelecting a Career Path

Nearing Your Destination: Nearing Your Destination: Selecting a Career PathSelecting a Career Path

Academia Robert L. Talbert, PharmD, FCCP, BCPSUniversity of Texas

Industry Allyn Bandell, PharmDMedImmuneMedImmune

Inpatient Thomas Vondracek, PharmD, BCPSExempla St. Joseph Hospital–Denver, CO

Ambulatory Beverly A. Kroner, PharmD, BCPSKaiser Permanente-Denver, CO

Community Eric Chrisman, PharmDSafeway-Denver,CO

Asking for Directions: Getting Asking for Directions: Getting Your Questions AnsweredYour Questions Answered

Asking for Directions: Getting Asking for Directions: Getting Your Questions AnsweredYour Questions Answered

• Selecting a Career Path– Academia/Research, Industry, Inpatient,

Ambulatory, Community

O t iti t B ild Y CV• Opportunities to Build Your CV

• Clinical Pearls for Residency

• Surviving Experiential Rotations

• How to Make a Positive First Impression

• Planning Your Financial Future

Continuing on in the Continuing on in the Journey…Journey…

Continuing on in the Continuing on in the Journey…Journey…

Newcomers’ Orientation d R tiand Reception4:30PM

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Rationale for the Development of Targeted Agents:

Improving Specificity, Efficacy, and Safety of Cancer Therapy

D. Ross Camidge, MD, PhDAssistant Professor of Medicine/Oncology

Developmental Therapeutics and Thoracic Malignancies Programs

Associate Director of Thoracic MalignanciesUniversity of Colorado Cancer Center

Agenda

• Anticancer drug overview• Limitations of traditional chemotherapy• Targeted agents and what we mean by that term• Common solid tumor targets and their targeted agents

I t id ith t t d t• Issues to consider with targeted agents

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Cancer: The Role of Drugs

TumorNormal Cancerous change Local treatment(surgery/radiotherapy)

(micro)metastasis

metastasisAdjuvant systemic treatment

for microscopic disease

Systemic treatment

A Brief History of Anticancer Drug Screening Programs

• 1947: Alfred Sloan and Charles Kettering of General Motors founded a private institute to screen synthetic chemicals for anticancer activity on industrial lines

OrganicChemistry

• 1955: National Cancer Institute (NCI) started government funded Cancer Chemotherapy National Service Center

• Late 1950s-1982: NCI and US Department of Agriculture plant screening program

Bacteria/Fungi

NaturalProducts

Cellular damage

p53-dependent transduction

Activation of Bax and Bak

Ligand-dependent death receptor mediated

signal transduction (eg, TRAIL)

DR

5

DR

4

TNFR

1

Fas

Activated caspase 8 and 10 (DISC)

Recruitment of FADDActivation of Bid(Type II cells)

cFLIP

Upregulation of death receptors

BH3-only proteins

p53-independent transduction

Release of mitochondrialcytochrome C

Release of mitochondrialSmac/Diablo

Formation of apoptosome with Apaf-1

Activated effector caspases(caspases 3, 6, and 7)

Activated caspase 9

APOPTOSISNegative regulation of IAPs

(XIAP, cIAP1, cIAP2, survivin)

Apoptosis inhibitionby Bcl-2, Bcl-xl, Mcl-1

IAPs

Common pathway

IAPs=inhibitors of apoptosis; TRAIL=tumor necrosis factor-related apoptosis-inducing ligand.

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Methotrexate, 5-Fluorouracil, 6-Mercaptopurine, 6-Thioguanine

5-Fluorouracil, Gemcitabine, CytarabineAlkylating Agents, Platinums, Anthracyclines,

ET743, Actinomycin D, Mitomycin C

DNA adducts, crosslinks, and intercalation

Nucleotide incorporationNucleotide synthesis

Irinotecan, Etoposide

Taxanes, Vinca Alkaloids

Microtubule-associated processes

DNA-associated processes

Drugs: Traditional Chemotherapy (Screen detected, often DNA as target)

Time (days)

CellsHost

TumorX

It’s no good,We’ll have to quit

XXXTime (days)

Designer Drugs• More differentially

expressed/important targets

Time (days)

Host

Tumor“Targeted” or“Biological”Therapy

Limitations of Traditional Chemotherapy

• Narrow therapeutic margin• Acute and chronic side effects

(eg, myelosuppression + neurotoxicity, nephrotoxicity, alopecia, hand-foot syndrome, phlebitis second malignancies)phlebitis, second malignancies)

• Convergent mechanism of action; cross-resistance common

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1. Drugs isolated after phenotypic screen usually for anti-proliferative endpoint; targets present but may be unknown = traditional chemotherapy

2. Designer drugs isolated based on binding to specific targets thought to be important in cancer:

Si l t d ti i hibit / ll l i hibitSignal transduction inhibitors/cell-cycle inhibitorsAntiangiogenicsPro-apoptotics (and anti–anti-apoptotics)Anti-invasivesEpigenetics Protein micro-environment modulators(‘immune modulators’)

Small molecules (ibs)or

Monoclonal antibodies(mAbs)

The Term “Targeted Therapy”

• Does not mean the drug only goes to the tumor

• Does not mean the drug will work, even if the tumor expresses the target

• Does not mean there will not be side effects

Side Effects and Efficacy (Therapeutic Ratio) Mostly About:

• Whether the target(s) is/are:– Differentially expressed and/or – Differentially important

b t l ti d t…between normal tissues and tumors

However, “targeted agents” or ”biological agents” is what we all understand!

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Major Solid Tumor Targets and Their Currently Approved Targeted Agents

• EGFR: erlotinib, cetuximab, panitumumab

CamidgeOverview

D. FriezeEGFR

• VEGF/VEGFR: bevacizumab (VEGF), sunitinib, sorafenib

• HER2/ErbB2: lapatinib (EGFR/HER2), trastuzumab

S. GoodinVEGF/R

L. MichaudHER2

EGFR=epidermal growth factor receptor; VEGF=vascular endothelial growth factor; VEGFR=VEGF receptor.

EGFEGF

HRG2

3

4

KINASE=Phosphorylates things;Phosphorylated things are active things (usually)

ATP

ADP

Anti-apoptosis (pro-survival)ProliferationOthers: eg, migration

EGFR/ErbB2 Amplification/Mutation

Growth factor

Receptor

Signal TransductionNuclear Events

ErbB2

Monoclonal

EGFR: cetuximab, panatumumabHER2: trastuzumab

EGFR

ErbB2

Small molecule inhibitor

EGFR: erlotinib, gefitinibEGFR/HER2: lapatinib

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Gefitinib (Iressa)/Erlotinib (Tarceva)

• Women, never smokers, Asians…

• 2003: Gefitinib licensed on basis of phase II data

• 2004: Erlotinib licensed similarly• Neither adds to standard chemotherapy for

non–small cell lung cancer (NSCLC) in first-linenon small cell lung cancer (NSCLC) in first line setting

• 2005: Erlotinib prolongs survival compared to placebo (hazard ratio [HR]=0.70, P<0.001); gefitinib does not (HR=0.89, P=0.09)

• June 17, 2005: Gefitinib license restricted to trials or those already on treatment

Erbs and Cancer (EGFR)

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Trastuzumab (Herceptin)

• Monoclonal antibody directed against the HER2 receptor• HER2 upregulated in 20%-30% of breast cancers,

particularly prevalent in aggressive, chemotherapy-resistant disease (eligibility tests)

• Trastuzumab increases the response rate of taxotere or as a single agent in the metastatic settingas a single agent in the metastatic setting

• It is given until disease progression• Adjuvant treatment remarkable!

Disease-Free Survival

and

Dis

ease

Fre

e

1-Year trastuzumab100

908070605040 2-Year

DFS, %Events HR [95% CI] P Value

Observation

% A

live

127127220220127127220220

302010

0

DFS, % HR [ ] P Value

0.5485.877.4

<0.0001[0.43, 0.67]

Months From Randomization0 5 10 15 20 25

No. at Risk1694 1472 1067 629 303 1021693 1428 994 580 280 87

DFS=disease-free survival.

Side Effects of Erb-al Remedies

• HER2 inhibition: Trastuzumab 0.5% severe heart failure (echos)

• EGFR inhibition

Grade 3/4 rash/diarrhea in 7%-9%

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Angiogenesis=new blood vessels

Sorafenib (Nexavar)

Tumor

Sorafenib (Nexavar)Sunitinib (Sutent)

The Bevacizumab Thrill Ride in Lung Cancer

• Randomized phase II study with chemotherapy in NSCLC at 15 mg/kg every 21 days showed longer survival (7.4 vs 4.2 months, P=0.023)

• Risk of death from bleeding: 9%• Eastern Cooperative Oncology Group (ECOG) 4599

interim analysis 2005: 878 patients with NO squamous, brain metastases, or history of gross hemoptysis

• Median survival 12.5 vs 10.2 months, P=0.0075; bleeding death rate approximately 1% with restrictions = new standard of care

• Bevacizumab adds to standard chemotherapy for colorectal cancer and breast cancer, too!

Vascular endothelium Tumor cell

VEGFRVEGF

EGFR:EGFREGFR:HER2 EGFR:HER3/HER4

ras

raf

MEK

ERK

PDGFR c-KITRET

ras

raf

MEK

ERK

• Sorafenib• Multi-targeted kinase: VEGFR2-3, PDGFR β, KIT, FLT-3, B-Raf, C-Raf• Approved by the US Food and Drug Administration (FDA) for renal cancer

(December 2005)• Diarrhea, erythematous skin rash, hand-foot syndrome, fatigue, bleeding,

hypertension• On labs: myelosuppression, hypophosphatemia

PDGFR=platelet-derived growth factor receptor.

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Vascular endothelium Tumor cell

VEGFRVEGF

EGFR:EGFREGFR:HER2 EGFR:HER3/HER4

ras

raf

MEK

ERK

PDGFR c-KITRET

ras

raf

MEK

ERK

• Sunitinib• Multi-targeted kinase: VEGFR1-3, RET, PDGFR α/β, KIT, FLT-3, CSF-1R• Approved by the FDA for imatinib-resistant/intolerant GIST (January 2006)

and renal cancer (January 2006)• Diarrhea, skin and hair discoloration, nausea, mouth irritation, fatigue,

hypertension, bleeding and altered taste• Labs: myelosuppression, altered aspartate/alanine aminotransferase,

altered TSH• Toxicities cumulative (long half-life 40-60 hours, 80-110 hours for active

metabolite)GIST=gastrointestinal stromal tumor; TSH=thyroid-stimulating hormone.

Targeted Therapy Issues

• Identifying who is most/least likely to respond and what is the cut-off for therapeutic intervention

• Dose to maximum tolerated dose or optimal biologically effective dose, on-target or off-target toxicity

• Identification and management of chronic effectsg• Actions on progression after initial benefit• Chronic dosing effects on pharmacokinetic exposure• Combinatorial sequencing with other agents

(chemotherapy, other targeted therapy, radiotherapy)• Multi-targeted/dirty drugs

“Targeted Therapy?”

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QuestionsQuest o s

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Epidermal Growth Factor Inhibitors: Current Clinical Status and New

Developments

Deborah Frieze, PharmD, BCOPClinical Pharmacist, Hematology/Oncology

Seattle Cancer Care AllianceOctober 14, 2007

EGFR Signal Transduction

PI3-K

EGFR

Ligand

STAT3

EGFR-TKKK

pYpY

RAS RAFSOS

GRB2pY

3 Major downstream signaling proteins• MAPK• PI3K• STAT

Survival(anti-apoptosis)

PTEN AKTSTAT3

MEK

Gene transcriptionCell cycle progression

DNA Myc

Myc Cyclin D1JunFos

P P

MAPK

Proliferation /maturation

Chemotherapy /radiotherapyresistance

AngiogenesisMetastasis

CyclinD1

RAS RAF

EGFR=epidermal growth factor receptor; MAPK=mitogen-activated protein kinases; PI3K=phosphatidylinositol 3-kinase; STAT=signal transducers and activators of transcription.www.medscape.com; Mendelsohn J, et al. Semin Oncol. 2006;33:369-385.

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Signal transduction cascade

Signal Transduction Inhibitors

MoAbs• Pros

– Greater specificity– Require lower concentration– Able to cause receptor

internalization

Small molecules• Pros

– Oral– Effective against altered forms

of the receptor– Potential to inhibit more than 1internalization

• Cons– IV only– Potential to induce immune

antibody response– Less effective against altered

receptor

Potential to inhibit more than 1 ErbB receptor

– No immune antibody response

• Cons– Less specificity– Require higher concentration

MoAbs=monoclonal antibodies.Herbst. Int J Radiat Oncol Biol Phys. 2004;59(suppl 2):21-26; Mendelsohn J, et al. Semin Oncol. 2006;33:369-385.

Mechanism of Action

• Cell cycle arrest– Induces G1 phase arrest due to elevated levels of the

CDK2 inhibitor p27 and of hypophosphorylated Rb protein

• Potentiation of apoptosis• Inhibition of angiogenesis• Inhibition of tumor cell invasion and metastasis

– Via inhibition of several MMPs

• Augmentation of the antitumor effects of chemotherapy and radiation therapy

CDK=cyclin-dependent kinase; MMPs=matrix metalloproteinases.

Mendelsohn J, et al. Semin Oncol. 2006;33:369-385.

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FDA-Approved EGFR Inhibitors

Drug Target FDA Indication

Gefitinib EGFR TKI NSCLC*

Erlotinib EGFR TKI NSCLC, pancreatic

EGFR andLapatinib EGFR and HER2 TKI mBC

Cetuximab MoAb mCRC, advanced SCCHN

Panitumumab MoAb mCRC

*For those in trials or who have previously responded.

mBC=metastatic breast cancer; mCRC=metastatic colorectal cancer; NSCLC=non–small cell lung cancer; SCCHN=squamous cell carcinoma of the head and neck; TKI=tyrosine kinase inhibitor.

EGFR Inhibitors in Clinical Development

Drug Target Tumor Target

Nimotuzumab EGFR MoAb NSCLC, SCCHN, breast, glioma, pancreatic

PertuzumabHER2 MoAb

(dimerization with EGFR)

NSCLC, ovarian, breast

Matuzumab Pan-HER MoAb NSCLC, ovarian, stomach, uterine/cervical, pancreatic

Canertinib Pan-HER TKI Ovarian

Vandetanib EGFR and VEGF TKI NSCLC

Zalutumumab EGFR MoAb NSCLC, SCCHN

SCCHN=SCC of the head and neck; VEGF=vascular endothelial growth factor.

EGFR TKIs

• Gefitinib– 250 mg PO daily with or without food– May be dissolved in noncarbonated water– Limited distribution due to ISEL survival outcomes– CYP 3A4 substrate CYP 2C19 and 2D6 inhibitorCYP 3A4 substrate, CYP 2C19 and 2D6 inhibitor

• Erlotinib– 150 mg PO daily (NSCLC)– 100 mg PO daily + gemcitabine (pancreatic cancer)– Take on empty stomach; food increases absorption– CYP 3A4 and 1A2 substrate

ISEL=Iressa Survival Evaluation in Lung Cancer.

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EGFR TKI Counseling Points

• Teratogenic: use birth control while taking these medications and for 2 weeks after completing medication

• Do not take antacids within 2 hours• Several drug interactions; review medications and g

medication changes• Avoid grapefruit or grapefruit juice• If dose is missed, it may be taken later in the day, but

do not take 2 doses in 1 day• Store at room temperature, away from moisture

EGFR MoAbs

• Cetuximab– 400 mg/m2 IV over 120 minutes x1, then 250 mg/m2 IV

over 60 minutes weekly– Premedicate with antihistamine– Administer through 0.22-micron inline filter

• Panitumumab– 6 mg/kg IV every 2 weeks– Doses <1000 mg: dilute in 0.9% NS 100 mL and infuse

over 60 minutes– Doses >1000 mg: dilute in 0.9% NS 150 mL and infuse

over 90 minutes– Administer through 0.2 or 0.22-micron inline filter

Common Adverse Effects

MoAbs• Rash• Paronychial inflammation• Hypomagnesemia• Infusion-related reactions

TKIs• Rash• Diarrhea• Mucositis• Nausea/vomitingInfusion related reactions

• Interstitial lung disease (rare)Nausea/vomiting

• Interstitial lung disease (rare)

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Adverse Effects of EGFR Inhibitors

Basti S. Cancer Nurs. 2007;30:S10-S16.

Dermatological Reactions to EGFR Inhibitors

AE Description Frequency/Onset

RashErythematous maculopapular, follicular, or pustular lesions ±

pruritus or tenderness

60%-80%Onset: 1-3 weeks

Paronychia/Fissuring

Painful periungual granulation-type changes associated with

erythema, swelling, fissuring of lateral nail folds

6%-12%Onset: 2-4 months

Hair Changes

Alopecia and curlier, finer, more brittle hair; trichomegaly and

curling of eyelashes, eyebrows; hypertrichosis of the face

5%-6%Onset: variable

AE=adverse event.Lynch TJ, et al. Oncologist. 2007;12:610-621.

Dermatological Reactions to EGFR Inhibitors (Cont.)

AE Description Frequency/Onset

Dry Skin Diffuse fine scaling4%-35%

Onset: after rash

2% 3%Hypersensitivity Reactions

Flushing, urticaria, anaphylaxis

2%-3%Onset: initial dose of

MoAbs

Mucositis Mucositis, stomatitis, aphthous ulcers

2%-36%Onset: variable

Lynch TJ, et al. Oncologist. 2007;12:610-621.

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Physiology of EGFR Inhibitor–Associated Dermatological Toxicities

• EGFR is expressed in epidermal keratinocytes, sebaceous and eccrine glands, and hair follicle epithelium

• EGFR is key to stimulating epidermal growth, inhibiting differentiation protecting against UVinhibiting differentiation, protecting against UV damage, inhibiting inflammation, and accelerating wound healing

• Inhibition of EGFR alters keratinocyte proliferation, differentiation, migration, and attachment

Lynch TJ, et al. Oncologist. 2007;12:610-621.

NCI-CTCAE Classification System (v.3)AE Grade

1 2 3 4 5

Dry Skin Asymptomatic Symptomatic, not interfering with ADL

Symptomatic, interfering with ADL — —

Macular, papular, or

Macular, papular, or erythema w/ pruritus or other associated

Severe, generalized erythroderma or macular, papular,

Generalized exfoliative,

Rash*p perythema w/o associated symptoms

associated symptoms; localized desquamation or other lesions covering <50% BSA

p por vesicular eruption; desquamation covering >50% BSA

ulcerative, or bullous dermatitis

Death

Rash† Intervention not indicated

Intervention indicated

Associated w/ pain, disfigurement, ulceration, or desquamation

— Death

*Desquamation; †Acne; acneform.ADL=activities of daily living; BSA=body surface area; NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events.http://ctep.cancer.gov/forms/CTCAEv3.pdf.

EGFR-Associated Rash Classification

• NCI-CTCAE most commonly used in trials– Guide to intervention is limited– Rash based on BSA is ineffective– Disfigurement terminology is subjective

• Simpler, EGFR-focused grading system has been p g g ysuggested

– Mild, moderate, or severe

• SERIES Clinic– Used to detect and treat cutaneous/ocular reactions

SERIES=Skin and Eye Reactions to Inhibitors of EGFR and Kinases.

Lynch TJ, et al. Oncologist. 2007;12:610-621; Lacouture ME. Cancer Nurs. 2007;30(4 suppl 1):S17-S26.

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Proposed Definition for EGFR-Associated Cutaneous Toxicities

Mild Moderate Severe

Papulopustular Reaction Localized Generalized Generalized

Pruritus/Tenderness Minimal Mild Severe

Impact on Daily Activities No Minimal Significant

Signs of Superinfection No No Present or

possible

Lynch TJ, et al. Oncologist. 2007;12:610-621.

Management of EGFR Rash

• Nonpharmacological strategies– Minimize exposure to sunlight– Use broad spectrum sunscreen (≥SPF 15)– Moisturize dry areas of the body bid

• Pharmacological optionsPharmacological options– Topical hydrocortisone 1% or 2.5% cream– Topical clindamycin 1% gel– Topical pimecrolimus 1% cream– Doxycycline/minocycline 100 mg PO bid – Methylprednisolone– Dose interruption, reduction, or discontinuation

Lynch TJ, et al. Oncologist. 2007;12:610-621; Lacouture ME. Cancer Nurs. 2007;30(4 suppl 1):S17-S26.

Considerations in Management of EGFR Rash

• Potential complications with use of steroids– Uninterrupted use can increase risk for bacterial or

viral infections– May potentiate the cytotoxic effects in the skin

R f ki li i h b t d• Rare cases of skin malignancies have been reported in patients treated with topical calcineurin inhibitors

• Tetracycline prophylaxis has not been shown to decrease incidence of rash BUT did decrease severity

Lynch TJ, et al. Oncologist. 2007;12:610; Perez-Soler. ASCO. 2007 (abstr 523); Jatoi. ASCO. 2007 (abstr 494).

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Rash as a Surrogate Marker of Efficacy

• Multiple studies in several diseases have shown a positive correlation between rash and response or survival with cetuximab and erlotinib

• Studies with gefitinib have not been consistent• Phase III data of panitumumab in mCRC p

demonstrated increased rash severity correlated significantly with improved median overall survival

Wracker B, et al. Clin Cancer Res. 2007;13:3913-3921; Gibson TB. Clin Colorectal Cancer. 2006;6:29-31.

Rash as a Surrogate Marker of Efficacy

• Median survival by rash grade in erlotinib arm of BR.21 in NSCLC

– Grade 0: 3.3 months– Grade 1: 7.1 months

(P<0.001) bilit

y

(P 0.001)– Grade ≥2: 11.1 months

(P<0.001)

• In PA.3, median survival improved with grade ≥2 vs grade 0 rash

– 10.8 months vs 5.4 months (P<0.001)

Survival (Months)

Surv

ival

Pro

ba

Wracker B, et al. Clin Cancer Res. 2007;13:3913-3921.

Rash as a Surrogate Marker of Efficacy

Analysis of Cetuximab in 4 Phase II Studies

Perez-Soler R, et al. J Clin Oncol. 2005;23:5235-5246; Salt L, et al. Proc Am Soc Clin Oncol. 2003;22:204.

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Rash as a Surrogate Marker of Efficacy

• Should the dose of an EGFR inhibitor be increased until patient has a grade ≥2 rash?

• ECOG 3503: Pilot study of downstream markers of EGFR to predict response to erlotinib

– 118 Patients, erlotinib 150 mg, increased by 25 mg every 2 weeks until grade 2 rash, other toxicities, or 250 mg max dose

– RR=7%, SD=46%, median survival=7.9 months– Grade ≥2 rash improved survival 12.6 months vs 6.4

months (P=0.099)

RR=response rate; SD=stable disease.

Kolesar J, et al. ASCO. 2007 (406).

Predictors of Outcomes to EGFR TKIs

• NSCLC– Somatic mutations of the EGFR gene at exons 18-21,

in particular a deletion at exon 19 (LREA) and a point mutation at exon 21 (L858R), correlate with response to TKIsEGFR t ti lik l t i ti t– EGFR mutations are more likely to occur in patients with adenocarcinoma, females, never-smokers, and patients of Asian descent

– EGFR gene amplification has been associated with survival benefit from erlotinib treatment (P=0.009)

– KRAS mutations have been associated with TKI resistance

Pao W. J Clin Oncol. 2005;23:2556-2568; Shepherd FA, et al. ASCO. 2007 (abstr 402).

Predictors of Outcomes to EGFR TKIs

• NSCLC– Several studies are ongoing to elucidate the role of

EGFR mutations, KRAS mutations, EGFR gene amplification, and other potential molecular predictors of responseiT t t d l t d 31 ti t ith EGFR– iTarget study evaluated 31 patients with EGFRmutations who received gefitinib for first-line treatment of advanced NSCLC

• RR=58%, PFS=11.8 months • 22 Patients had high EGFR gene copy number;

however, RR and PFS did not vary

PFS=progression-free survival.Sequist LV, et al. ASCO. 2007 (abstr 386).

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Predictors of Outcomes to EGFR MoAbs

• CRC– Cetuximab and panitumumab have activity regardless

of EGFR expression– There is no role for EGFR mutations with MoAbs– Studies conflict on whether increased EGFR gene

copy number by FISH predicts response to cetuximab– KRAS mutations are associated with cetuximab

resistance

FISH=fluorescence in situ hybridization.

Finocchiaro G, et al. ASCO. 2007 (abstr 168); Personeni N, et al. ASCO. 2007 (abstr 582).

Summary

• Current EGFR inhibitors have an established role in NSCLC, CRC, SCCHN, and pancreatic cancer

• Ongoing studies are evaluating newer EGFR inhibitors in addition to their use in other malignancies

• Prospective studies are needed to establish best care pfor EGFR toxicities

• Intense research is being done to identify patient subpopulations that are best treated with EGFR inhibitors

• Ongoing studies are evaluating timing and appropriate combinations of these agents

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QuestionsQuestions

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Current Status of Antiangiogenic Agents: Administration and Safety

Susan Goodin, PharmD, FCCP, BCOPDirector, Division of Pharmaceutical Sciences

Associate Professor of MedicineRobert Wood Johnson Medical School

Objectives

• Compare and contrast the mechanism of action of the available agents that target angiogenesis

• Discuss administration issues and recent data with the available antiangiogenesis agents

• Describe the drug interactions associated with the• Describe the drug interactions associated with the antiangiogenesis agents

• Discuss the toxicities associated with the antiangiogenesis agents, as well as their management

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Available Antiangiogenic Agents

• Bevacizumab– Recombinant humanized monoclonal antibody that binds to

vascular endothelial growth factor (VEGF) and prevents the interaction of VEGF to its receptors on the surface of endothelial cells

• Sorafenib– Inhibits Raf-kinase signaling and several angiogenesis-related

growth factors (VEGF receptor [VEGFR], platelet-derived growth factor receptor [PDGFR]-b, Flt3, c-KIT)

• Sunitinib– Inhibits VEGFR, PDGFR-a and PDGFR-b, c-KIT, Flt3, colony-

stimulating factor receptor type 1, and neurotrophic factor receptor

• Temsirolimus– Inhibitor of the mammalian target of rapamycin (mTOR)

Integrins

ILK

Growth Factors

PTENPI3-K

Akt/PKB

LKB1

AMPK

TemsirolimusInhibits Tumor Cell Growth and Angiogenesis

Protein Production

Reduced GeneTranscription

ReducedCell Growth

ReducedProliferation

elF-4E

4E-BP1mTOR

S6K1

FKBP-12

Temsirolimus

Energy

S6P

TSC1/TSC2

Reduced VEGFProduction

Standards for Administration

• Bevacizumab: available as a 25-mg/mL sterile solution for infusion– Recommended dose with bolus irinotecan, 5-fluorouracil,

and folinic acid (IFL) is 5 mg/kg or with FOLFOX4 10 mg/kg, each given every 2 weeks, and with paclitaxel and carboplatin at 15 mg/kg every 3 weeksand carboplatin at 15 mg/kg every 3 weeks

– Initial dose recommended over 90 minutes and, if tolerated, the second infusion over 60 minutes and, if tolerated, the third infusion over 30 minutes

• Sorafenib: available as a 200-mg tablet– Recommended dose is 400 mg twice daily taken either

1 hour before or 2 hours after meals

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Standards for Administration

• Sunitinib: available as a 12.5-mg, 25-mg, and 50-mg capsule– Recommended dose is 50 mg once daily (with or without

food) for 4 weeks, followed by 2 weeks off• Dose increase or decrease of 12.5-mg increments based on

safety and tolerabilitysafety and tolerability

• Temsirolimus: available as a 25-mg/mL solution with diluent for infusion– Recommended dose is 25 mg infused over a 30- to

60-minute period weekly• Premedicate with antihistamine 30 minutes prior

Simplified Administration of Bevacizumab

• Based on the favorable experience with 15 mg/kg over 30 minutes (0.5 mg/kg/minute), alternate infusion rates have been evaluated

• In 202 nonprotocol patients with colorectal cancer, no hypersensitivity reactions (HSRs) were noted in patientshypersensitivity reactions (HSRs) were noted in patients receiving 5 mg/kg over 90-, 60-, or 30-minute infusions

• The standard infusion rate was modified to 30 minutes for all bevacizumab doses, including initial doses, with no HSRs

• In 464 consecutive patients with colorectal cancer treated with 5 mg/kg over 30 minutes, no HSRs occurred

Saltz, et al. J Clin Oncol. 2006;24(suppl 18):156s (abstr 3542).

• Standard infusions were initiated at the infusion rate of 0.5 mg/kg/minute– 5 mg/kg over 10 minutes; 10 mg/kg over 20 minutes;

15 mg/kg over 30 minutes

• The 5 mg/kg dose over 10 minutes was administered

Simplified Administration of Bevacizumab

• The 5-mg/kg dose over 10 minutes was administered in 370 patients for a total of 2,311 doses – 185 Patients were converted from 30-minute infusions

to 10 minute infusions; no HSRs were reported– 177 Patients began therapy over 10 minutes

• 6 (1.6%) Experienced non-serious HSRs

Reidy DL, et al. J Clin Oncol. 2007;25:2691-2695.

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Administration of Oral Agents: The Challenge of Adherence

Reasons for lack of adherences:• Did not like side effects• Wanted a different medication• Could not afford it• To avoid side effects I had heard about• Did not feel it was necessary• Unintentional nonadherence is a passive process;

patient may be careless or forgetful about adherence• Intentional nonadherence is an active process; patient

chooses deliberately to deviate from treatment regimen

Sud A, et al. Ann Pharmacother. 2005;39:1792-1797.

• Refill information can be used as a screening tool for nonadherence

• Direct interview• Tell me how you take your medicine…• How do you schedule your meal and medication times?

Administration of Oral Agents: Pharmacist Assessment of Adherence

• How do you schedule your meal and medication times?• Do you use a pill box or organizer for your medication?• How do you manage to pay for your medication?• If possible, would you like me to simplify your medication

regimen?• If possible, would you like to explore some options for reducing

your out-of-pocket medication expenses?• Show me how you take your current medication…

MacLaughlin EJ, et al. Drugs Aging. 2005;33:231-255.

• Visually and audibly alerts patients they need to take medications and dispenses medications into the tray.

• Two way communicationTwo way communication system

• Holds a one-month supply of up to 10 prescriptions

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Administration Summary

Bevacizumab Sorafenib Sunitinib Temsirolimus

Oral

IV

Daily TherapyDaily x 4 Weeks, Off 2 Weeks

Weekly

Every 2/ Every 3 Weeks

Drug Interactions

• Bevacizumab– No formal interaction studies have been performed

• Sorafenib– Metabolism is principally hepatic by CYP3A4 and

UGT1A9 pathways; sorafenib is an inhibitor ofUGT1A9 pathways; sorafenib is an inhibitor of UGT1A1

• Metabolism unlikely altered by inhibitors of CYP3A4

• Sunitinib– Metabolized by CYP3A4 to an equipotent metabolite

• Dose increase (87.5 mg) when administered concomitantly with CYP3A4 inducers(eg, dexamethasone, St. John’s Wort, phenytoin)

Drug Interactions

• Dose decrease (37.5 mg) when administered concomitantly with CYP3A4 inhibitors(eg, azoles, clarithromycin, grapefruit)

• Temsirolimus– Strong CYP3A4 inhibitors: reduce dose to

12.5 mg/week– Strong CYP3A4 inducers: consider dose increase

to 50 mg/week

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Safety: Bevacizumab

• Asthenia*• Pain*• Headache

• Constipation• Epistaxis• Dyspnea

The most common toxicities of any severity:

• Hypertension*• Diarrhea*• Stomatitis

• Dermatitis• Proteinuria• Leukopenia

*Most common grade 3-4 adverse events.

Safety: Bevacizumab• Hypertension: incidence of 20% to 30%

– Manage with initiation or increase of oral antihypertensive therapy– Blood pressure should be monitored closely and treatment

suspended in the event of uncontrolled hypertension

• Proteinuria: ranges from asymptomatic increases in urine protein (20%) to rare instances of nephrotic syndromes (0.5%)– Monitor urine protein to urine creatinine ratio

• Thromboembolic events: ~2-fold increase– Both venous and arterial events, ranging from catheter-associated

phlebitis to fatal arterial clots– Pooled analysis reveals increase in arterial but not venous

thromboembolism– Increased cerebral infarction, transient ischemic attacks,

myocardial infarctions, and peripheral arterial thrombosis

• Cardiac dysfunction– Ranges from asymptomatic declines in left ventricular

ejection fraction to symptomatic congestive heart failure– Potentiates anthracycline cardiotoxicity?

• Reversible posterior leukoencephalopathy syndrome

Safety: Bevacizumab

– Clinical presentation may include altered mental status, seizure, and cortical visual deficit; hypertension is a risk factor

– Reversible but requires timely correction of underlying causes (blood pressure control and stopping of therapy)

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Safety: Bevacizumab

Black Box Warnings• Gastrointestinal perforation: The incidence in patients

receiving bevacizumab alone or in combination with chemotherapy was 2.4% compared to 0.3% in patients receiving only chemotherapy; the incidence of gastrointestinal perforation ranged from 0% to 3 7%perforation ranged from 0% to 3.7%

• Wound healing: Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving chemotherapy and bevacizumab compared to 4% (1/25) of patients who received chemotherapy alone

• Hemorrhage: Epistaxis and minor mucosal bleeding are most common, occurring in 20% to 40%; life-threatening and fatal hemorrhagic events have been observed

Avoid bevacizumab in patients with:• Cardiac disease – ongoing trial will better define

enhanced risk• Hypertension – no increased risk for hypertension in

patients with baseline history

True or Not?

p y• Central nervous system lesions • Coagulopathy (on anticoagulation?) – no increase in

bleeding in pivotal trials in patients on anticoagulation• Peritoneal metastases – increase in GI perforation?• Recent surgery

Safety: Sorafenib

• Fatigue: 37%• Rash, exfoliative

dermatitis*: 40%• Hand-foot syndrome*:

30%

• Others– Increased amylase and

lipase– Mucositis, stomatitis,

dyspepsia, dysphagiaL k i i

– Self-limited appearing during the first 6 weeks

• Diarrhea: 43%• Hypertension: 17%

– Appears within 3 weeks of therapy

– Leukopenia, anemia, thrombocytopenia, neutropenia

– Hair thinning– Cardiac ischemia or

infarction

*Dose-dependent adverse effects.

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Safety: Sunitinib

• Fatigue (28% to 38%)• Diarrhea (20% to 24%)• Other gastrointestinal

effects (10%)– Nausea dyspepsia

• Cardiac effects– Decreased ejection

fraction (15%)

• Laboratory abnormalities• HypothyroidismNausea, dyspepsia,

stomatitis, vomiting, and constipation

• Skin toxicities– Edema, rash (3%),

hand-foot syndrome (15%)

• Hypertension of all grades (28%)

yp y• Bleeding

Safety: Temsirolimus

• Most common adverse events (30% of patients) with temsirolimus:– Asthenia,* rash, nausea, anorexia, stomatitis, peripheral

edema

• Most common laboratory abnormalities (>30% of patients) with temsirolimus:– Anemia,* hyperglycemia,* hyperlipidemia,

hypertriglyceridemia, elevated alkaline phosphatase, elevated serum creatinine, hypophosphatemia, thrombocytopenia, elevated aspartate aminotransferase, leukopenia

*Grade 3 or 4 toxicity in >10% of patients.

Hudes G, et al. N Engl J Med. 2007;356:2271-2281.

Anti-VEGF Class Toxicities

• Hypertension

• Fatigue

• Increased clotting events

• Bleeding (epistaxis,

• Increased liver function tests

• Pain at tumor sites

• Proteinuriag ( p ,pulmonary hemorrhage, tumor associated)

• Headache

• Hypothyroidism?

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• Simplified administration guidelines for bevacizumab appear safe

• Pharmacist must understand and evaluate adherence issues with patient prescribed oral antiangiogenic agents

Current Status of Antiangiogenic Agents: Administration and Safety

agents • Drug interactions are more common with the

antiangiogenic agents sunitinib and temsirolimus• The safety profiles of the antiangiogenic agents are

similar, indicating mechanism-based toxicities

Questions

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HER-2 Targeted Therapies for Breast Cancer: Focus on Safety

Laura B. Michaud, PharmD, BCOP, FASHPManager, Clinical Pharmacy Services

ObjectivesReview targeted agents currently on the market for breast cancer that target HER2 (e.g., trastuzumab, lapatinib)Compare and contrast different ways to target HER2 and clinical outcomes associated withHER2 and clinical outcomes associated with each type of therapyReview the potential for cardiotoxicity caused by targeted agents and standard chemotherapy currently used for treating breast cancerReview the signs/symptoms, clinical course, management and potential prevention of trastuzumab-induced cardiac dysfunction

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Objectives (con’t)

Discuss the reasons underlying intense concern for this adverse effect Review patient selection in relation to prisk/benefit with trastuzumab therapyFuture directions for HER2-targeted agents

Optimizing current therapiesNew HER2-targeting agents

OverviewReview HER2-targeted therapies

Trastuzumab & lapatinibEfficacy & safety overview

Mechanisms of HER2-related toxicity d i h h li l d i icompared with anthracycline-related toxicity

CardiotoxicityIncidence (risks vs benefits)Risk assessmentManagementPrevention (?)

Future directions

Epidermal Growth Factor Receptor Family

Lin et al. Breast Cancer Res 2004 6:204

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Potential Consequences ofHER Dysregulation

Signaling cascades

HER family

PI3K MAPK

PP AngiogenesisInvasion

cascadesNucleus Gene activation

Cell cycle progression

M G1

SG2

MycFos

Jun

MAPK = mitogen-activated protein kinase.Adapted from Roskoski. Biochem Biophys Res Commun. 2004;319:1-11; Rowinsky. Annu Rev Med. 2004;55:433-457

Survival Apoptosis

Metastasis Proliferation

ErlotinibG fiti ib

LapatinibHKI 272

Selectivity of HER-targeted agents

Targeting the HER Family:Spectrum of Therapies

Cetuximab ABX-EGF

EMD 72000TrastuzumabPertuzumab

Gefitinib HKI-272

HER1 HER2HER1HER2

HER2-Targeted TherapiesTrastuzumab (Herceptin®)

Monoclonal antibody against ECD of HER2 protein receptorVery specific for HER2Very specific for HER2Leads to down-regulation of receptor

Lapatinib (Tykerb®)Dual tyrosine kinase inhibitor against HER2 and EGFR (HER1)Small molecule with intracellular mechanismBlocks down-stream signaling from both receptors

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Trastuzumab (Herceptin®)Humanized MAb

IgG1 backbone (<5% murine region)Binds HER2 w/ high affinity

M h i f tiMechanism of actionAntagonize growth signaling pathway

Down-regulates HER2 receptor proteinEnhance antibody-dependent cellular cytotoxicity (ADCC)Enhance chemotherapy-induced cytotoxicity

Lapatinib Blocks Signaling Through Multiple Receptor Combinations

Blocks signaling throughErbB1 and ErbB2 homodimers and heterodimers

1 + 11 + 1 2 + 22 + 2 1 + 21 + 2

Might also prevent signaling through heterodimers between these receptors and other ErbB family members

Potentially blocks multiple ErbB signaling pathways

Downstream signaling cascadeDownstream signaling cascadeDownstream signaling cascadeDownstream signaling cascade

Efficacy & Safety OverviewTrastuzumab

Single agent activity (~40% CB in MBC)Combined with chemotherapy in MBC

Improves RR, TTP and OS vs chemotherapy aloneCardiac safety questioned (e g drops in LVEF CHF)Cardiac safety questioned (e.g., drops in LVEF, CHF)

Impressive outcomes in early-stage breast cancerLapatinib

Modest single-agent activity (35% PR)Combined with capecitabine in MBC

Improves RR, TTP, and OSSafety concerns: diarrhea, rash, nausea, cardiotoxicity (?)

Studies in early-stage breast cancer ongoingCB = clinical benefit; PR = partial response; MBC = metastatic breast cancer.

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Trastuzumab CardiotoxicityPivotal Trials & Clinical Use in MBC

First recognized during phase III combination trialsStudies halted

Parameter Measured AC1 AC + H1 Pac1 Pac +H1 Doc2 Doc + H2

Cardiac Dysfunction (CREC/NYHA III/IV)

8/3% 27/16% 1/1% 13/2% - -

CREC formed & developed criteria for defining and gradingRetrospective data indicate a fairly high rate

Cardiac events = 28% (LVEF < 50%, LVEF ↓ ≥ 20%, S/Sx CHF)3

Incidence related to previous anthracycline exposure

(CREC/NYHA III/IV)

ASx LVEF ↓ > 15% - - - - 8% 17%

Symptomatic CHF - - - - 0% 2%

1Slamon D, et al. NEJM 2001;344;783-92. 2Marty, et al. JCO 2005;23:4265-74. 3Guarneri V, et al. JCO 2006;24(25):4107-15.

Clinical Characteristics of Drug-Induced Cardiotoxicity

AnthracyclineCorrelates with cumulative doseMethod of administration

TrastuzumabDoes not correlate with cumulative dose or duration of therapy

IrreversibleAssociated with changes in myocardial ultrastructure on biopsy

VacuolizationCardiomyocyte loss

Reversible (partially?)Not associated with ultrastructural changes

Gross pathology appears normalElectron microscope may be able to identify minor cellular changes

Mechanisms of Anthracycline-Related Cardiotoxicity

Doxorubicin Metabolism

Quinone moiety Carbonyl moiety

Semiquinone Doxorubicinol

Free radicals Iron disordersCalcium channel

dysfunctionMitochondrial DNA

deletions or mutations

Acute toxicity(hours-days after)

Sub-acute toxicity (10-24 mos after)

Late toxicity (years after)

?

Menna P et al. Cell Biol Toxicol 2007; Lebrecht D et al. Cardiovasc Toxicol 2007

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Proposed Mechanisms of Trastuzumab-Related Cardiotoxicity

Drug interactions with chemotherapyPharmacokinetics/pharmacodynamics

ADCCHER2 receptor down-regulationInhibition of HER2 signaling in cardiomyocytes (mice)

Early in embryonic development – lethalLate in development – deletion leads to dilated cardiomyopathy later in life

Force T, et al. Nature Rev Cancer 2007;7:332-44.

Effect of Lapatinib on the HeartEffect of Lapatinib on the Heart

Prior therapy

Patients, n (%)Decreased

LVEFAsymptomatic LVEF decrease

Symptomatic LVEF decrease

Anthracyclines (n = 598)

7 (1.2) 5 (0.8) 2 (0.3)

H (w/ chemo or after A) (n = 759) 13 (1.7) 12 (1.6) 1 (0.1)

Neither A nor T(n = 2,201) 38 (1.7) 34 (1.5) 4 (0.2)

Total(N = 3,558)

58 (1.6) 51 (1.4) 7 (0.2)

LVEF = left ventricular ejection fraction

Perez et al. ESMO 2006 (abstr #1420)

ReversibilityChanges in LVEF from Baseline to Retreatment with

Trastuzumab in a Selected Population

Ewer MS and O’Shaughnessy JA. Clin Breast Cancer 2007;7(8):600-7.

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Adjuvant Trastuzumab for Early-Stage Breast Cancer

Five trials now published or presentedNSABP B-31NCCTG N9831 Combined analysisNCCTG N9831HERA TrialBCIRG 006FinHer Trial

Abbreviations: NSABP = National Surgical Breast & Bowel Project; NCCTG = North Central Cancer Treatment Group; HERA = Herceptin Adjuvant trial; BCIRG = Breast Cancer International Research Group; FinHER = Finland Herceptin Study.

Adjuvant Trastuzumab Trials (1)

AC P

PH

R

B31/N9831 (n=3351) 52 weeks

AC

Time

CombinationChemotherapy H

H

Observation

R

HERA (n=1694)

Time4 cycles 12 weeks 40 weeks

At least 4 mo 1 year 1 year

2 years

Adjuvant Trastuzumab Trials (2)AC T

THR

BCIRG 006 (n=3222)52 weeks

ACTC

52 weeks

Time

R

FinHER (n=232)Time

12 weeks 12 weeks 40 weeks

CH

T or V

9 weeks

T or VH

EC

F

9 weeks

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Patient Populations Included in Clinical Trials

NCCTG N9831Initially only node +Amended to include high-risk, node-negative

BCIRG 006Node + or high-risk node-negative (~30%)

FinHerT > 1cm and ER-negativeT > 2 cm and ER/PR +

NSABP B-31Node + only

HERANode + orSentinel node-negativewith ≥ T1c (≈ 30%)

Node + or high-risk node-negative (16%)Any HER2 status included

All patients HER2+ Centrally confirmedIHC = 3+FISH +CISH +

Cardiac Eligibility Criteria in Adjuvant Trastuzumab Trials

TrialBaseline

LVEF

Other Exclusion Criteria

Angina ArrCond Abnl

Valv Dz

Cardio-meg UHTN

H/O MI

H/O CHF

B31/N9831 > LLN X X X X X X X XB31/N9831 > LLN X X X X X X X X

HERA ≥ 55% X X X X X X

BCIRG > LLN X X X X X X X

FinHER NA X X X X

Abbreviations: LVEF = left ventricular ejection fraction; LLN = lower limit of normal for the institution; Arr = arrhythmias requiring medication; Cond Abnl = conduction abnormalities; Valv Dz = valvular disease; Cardio-meg = cardiomegaly; UHTN = uncontrolled hypertension; H/O MI = history of myocardial infarction; H/O CHF = history of congestive heart failure; NA = not available.

Cardiac Monitoring in Adjuvant Trastuzumab Trials

Cardiac Monitoring (LVEF)

B31/N9831 Baseline, after AC (12 weeks), 6, 9, 18 mo after randomization

HERA Baseline, 3, 6, 12, 18, 24, 30, 36, 60 months after randomization

BCIRG 006 Baseline, after 4th & 6th cycle, end of chemo, 3, 12, 36 months after end of chemo

FinHER Baseline, after FEC, 12, 36 months after last chemotherapy

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Evaluating Cardiac Dysfunction in Adjuvant Trastuzumab Trials

CREC Criteria for Diagnosis of Cardiac Dysfunction1 2 3 4

↓ LVEF* Symptomatic Signs of CHF** ↓ LVEF ≥ 5% to < 55% with s/sx or ↓ LVEF ≥ 10% to < 55% w/o s/sx

NYHA Functional ClassificationI II III IV

No limitation

Slight limitation

Marked limitation Inability to carry on any physical activity w/o discomfort

NCI CTC Cardiac Left Ventricular Function (v 2.0)Grade 1 Grade 2 Grade 3 Grade 4

ASx ↓ LVEF ≥ 10% but

< 20%

ASx, LVEF < LLN, ↓ ≥ 20%

CHF responsive to treatment

Severe or refractory CHF or requiring intubation

CREC = Cardiac Review and Evaluation Committee; NYHA = New York Heart Association; NCI CTC = National Cancer Institute Common Toxicity Criteria.* Either global or more severe in septum. ** Including (not limited to) S3, tachycardia, or both.

Clinical Efficacy of Adjuvant Trastuzumab Trials

0 6

0.8

1.0

atio

s

DFSOS

* * * * *

0.0

0.2

0.4

0.6

Haz

ard

Ra

B31/N9831 HERA BCIRG FinHER

* *

* P < 0.01Abbreviations: DFS = disease-free survival; OS = overall survival.1Romond E, et al. N Engl J Med 2005;353(Oct 20):1673-84. 2Smith I, et al. Lancet 2007;369:29-36. 3Slamon D, et al. SABCS 2006;A52. 4Joensuu H, et al. N Engl J Med 2006;354(Feb 23):809-20.

Adjuvant TrastuzumabCardiotoxicity

B-311

n=2043N98311

n=1633HERA2

n=3387BCIRG 0063

n=3222FinHer4

n=232

AC>T vs AC>TH

Obs vs H

AC>T vs AC>TH

AC>T vs TCH

AC>TH vs TCH

D/V vs DH/VH

0.8% vs 2 vs 4 vs 4 vs 20 vs 4 vs 0Cardiotoxicity*

0.8% vs4.1%

2 vs 36 pts

4 vs20 pts

4 vs 4 pts

20 vs 4 pts

4 vs 0pts

* Definition differs in each study.

• NSABP/NCCTG: NYHA Class III/IV CHF or cardiac death at 3y.

• HERA: Symptomatic CHF, including severe.

• BCIRG: Grade 3 or 4 decrease in LVEF.

• FinHer: MI & CHF, all in control. No changes in LVEF.1Romond E, et al. N Engl J Med 2005;353(Oct 20):1673-84. 2Smith I, et al. Lancet 2007;369:29-36. 3Slamon D, et al. SABCS 2006;A52. 4Joensuu H, et al. N Engl J Med 2006;354(Feb 23):809-20.

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Cardiac Tolerability – N9831Cumulative Incidence of Cardiac Events

Time from start of T

AC T+H(n=875)

%

AC T*(n=767)

%

3 months 1.4 0

6 months 1 8 0 26 months 1.8 0.2

1 year 2.5 0.2

2 years 2.5 0.2

3 years 2.5 0.2

Number of events 22 CHF 1 CHF1 cardiac death

*Patients randomized to AC T who received Hwere censored at the date H first administered Perez EA et al. ASCO, 2007 (abstr #512)

Prediction Model for Cumulative Incidence of Cardiac Events (B31)

[7 4 + (0 03xAge) (0 1xLVEF) + (0 68 if on BP Meds)] x100

Cardiac Risk Score =[7.4 + (0.03xAge) - (0.1xLVEF) + (0.68 if on BP Meds)] x100

4.82

Rastogi P, et al. ASCO 2007 (abst #LBA513)

Rastogi P, et al. ASCO 2007 (abst #LBA513)

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Reversibility…

Assessment

Cardiac Event (n=31)

Sx Cardiac Dysfunction

(n=43)ASx Decline in LVEF (n=102)

No follow-up LVEF 7 13 29

B31: Assessment of LVEF ≥ 6 months after Cardiotoxicity

Decrease in LVEF compared to baseline 17 of 24 22 of 30 NA

Recovery of LVEF to baseline 7 of 24 8 of 30 NA

Developed Sx subsequently -- -- 21 of 102

Follow-up LVEF < 50% -- -- 13 of 52

Follow-up LVEF > 50% -- -- 39 of 52

Telli ML, et al. JCO 2007;25:3525-33.

Neoadjuvant TrastuzumabTrial Pts HER2 n Regimen cCR pCR

MDACC Stage II-IIIa FISH+/ IHC 3+

19 P→FEC1 47 2623 P-H→FEC-H1 87 65

22 P-H→FEC-H2 --- 55

NOAH3 Stage IIIFISH+/ IHC 3+

115 AP → P → CMF 58 23

113 AP-H → P-H →CMF-H 69 43

Negative 99 AP → P → CMF 25 17

1Buzdar et al. J Clin Oncol. 2005 Jun 1;23(16):3676-852Buzdar et al. Clin Cancer Res. 2007 Jan 1;13(1):228-333Gianni L et al. ASCO Breast Symposium, 2007 (abstr #144)

MDACC Neoadjuvant TrialDFS

Buzdar et al. Clin Cancer Res. 2007 Jan 1;13(1):228-33

p=0.041

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Adverse EventsCardiac Safety Data

EventsP→FEC

N=19P→FEC + H

N=23P→FEC + H

N=22

Cardiac dysfunction 1 (NY C3) 0 1 (NY C1)

> 10% Decrease in LVEF- Decrease on paclitaxel- Decrease on FEC

505

743

633

Improvement in LVEF f/u 2 3 ?Abnormal Troponin-T 0 1 NE

Buzdar et al. J Clin Oncol. 2005;23:3676-85 and Buzdar et al. ASCO 2005;A5049.

Abbreviations: LVEF = left ventricular ejection fraction; f/u = follow-up; NE = not evaluated.

NOAH TrialCardiac Safety (%)

LVEF Worst Value

HER2 Positive HER2 Negative

With H (n=114) Without H (n=113) (n=97)

No change 75 84 87

Absolute ↓ ≥ 10% < 20% 21 15 12

Absolute ↓ ≥ 20% 2 1 1

CHF responsive to treatment 2 0 0

LVEF = left ventricular ejection fraction; CHF = congestive heart failure.

Gianni L et al. ASCO Breast Symposium, 2007 (abstr #144)

Adjuvant TrastuzumabRisks vs Benefits

Tremendous gains in DFS and OSNot a uniform benefit; some do not benefitMinimal risk, node-negative population?

Wh i h l “ ”?What is the real “cost”?Cardiotoxicity rate “acceptable” for the groupHighly selected populationIndividual risks largely unknown

How to minimize the risks?Optimize trastuzumab therapyAlternatives without cardiotoxicity

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Methods to Modulate Risk of Cardiotoxicity with Anthracyclines

Appropriate risk assessment & screeningLimit life-time cumulative doseModulate pharmacokineticsModulate pharmacokinetics

Goal: lower peak plasma concentrationsFractionate dosing (e.g., daily x 3)Continuous infusions (e.g., over 48-96 hours)

Analogs (e.g., epirubicin, liposomal analogs)Cardioprotectants (e.g., dexrazoxane)

Methods to Modulate Risk of Cardiotoxicity with Trastuzumab

Appropriate risk assessment & screening?

Limit comorbidities?Limit comorbidities?Accurately assess risks and benefits?

Appropriate monitoring?Intervention or discontinuation when necessaryLong-term monitoring and follow-up

Methods to Modulate Risk of Cardiotoxicity with Trastuzumab

Change chemotherapy?Delete anthracyclines?Change to epirubicin?Limit prior exposure to anthracyclines?Sequencing chemotherapy agents?

Change trastuzumab?Duration of therapy? Cumulative dose?Schedule of administration?Sequencing? Concurrent vs sequential?Substitute with another HER2 targeted agent?

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Adjuvant Trastuzumab Trials (1)

AC P

PH

R

B31/N9831 (n=3351) 52 weeks

AC

Third arm:Sequential

trastuzumab

Time

CombinationChemotherapy H

H

Observation

R

HERA (n=1694)

Time4 cycles 12 weeks 40 weeks

At least 4 mo 1 year 1 year

2 years

2-year data2008

Adjuvant Trastuzumab Trials (2)AC T

THR

BCIRG 006 (n=3222)52 weeks

ACTC

52 weeks

Final analysis12/07

SABCS

Time

R

FinHER (n=232)Time

12 weeks 12 weeks 40 weeks

CH

T or V

9 weeks

T or VH

EC

F

9 weeks

Only 9 weeksTrastuzumab

Prevention?Some data with carvedilol to prevent anthracycline-induced cardiomyopathy

Carvedilol 12.5 mg daily vs placebo (n=50)ECHO baseline and after 6 cycles of chemoy

CAF/CEF, CHOP/ABVD, other chemo regimens

Prevented systolic and diastolic dysfunction Mechanisms: antioxidant, blocks down-regulation of SERCA2, inhibition of apoptotic signaling, prevents mitochondrial dysfunction

Kalay N, et al. J Am Coll Cardiol 2006;48(11):2258-62.

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Summarize Trastuzumab Cardiotoxicity

Mechanism differs from anthracyclinesIn early-stage breast cancer

Minimal risk of severe cardiac dysfunctionL t f ll l kiLong-term follow-up lackingPredisposed to future cardiac stressors?

Modulate risks Risk assessment & screeningSequential vs combination chemotherapy?Duration, dose, PK, not a factor?Available cardioprotectants not effective

Future DirectionsFurther analyze and scrutinize adjuvant data with trastuzumabContinue to monitor patients long-termOptimize current knowledge-baseOptimize current knowledge-base

Risk assessment & monitoringClinical trials

Prevention and management strategiesRisk assessment & monitoringNew agents (?)

Pertuzumab (HER dimerization inhibitor – HDI)

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Questions