010 Burch - ACCP
Transcript of 010 Burch - ACCP
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.
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
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.
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
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)
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
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
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
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
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.
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
At the Meeting…At the Meeting…At the Meeting…At the Meeting…
Navigating the ASHP WebsiteNavigating the ASHP WebsiteNavigating the ASHP WebsiteNavigating the ASHP Website
At the Meeting…At the Meeting…At the Meeting…At the Meeting…
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)
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
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
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]
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
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
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.
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
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!
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
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)
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%
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.
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?”
QuestionsQuest o s
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.
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.
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.
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)
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.
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.
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).
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.
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).
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
QuestionsQuestions
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
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
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.
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
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
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)
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.
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?
• 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
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
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
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
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.
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
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.
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
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
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.
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)
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
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
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?
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.
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)
Questions