HER2-Targeted Therapy THE PROBLEM WITH OFF TARGET TOXICITY TO
THE HEART Melinda Telli, MD Instructor in Medicine Stanford
University 9/12/2008
Slide 4
Overview Heart Failure & the Elderly Updated ACC/AHA Heart
Failure Staging The Trastuzumab Story Risk Versus Benefit
Analysis
Slide 5
Cancer patients living longer Long-term toxicities of therapy
take on greater significance American Cancer Society 2004
Slide 6
United States: 2004; Source: NCHS and NHLBI Cardiovascular
versus Cancer Deaths by Age
Slide 7
NHANES: 1999-2004 Source: NCHS and NHLBI. Heart failure is
primarily a disease of the elderly
Slide 8
Impact of Heart Failure Approximately 80% of patients
hospitalized with heart failure are over 65 Most common Medicare
diagnosis-related group (DRG) One of the largest Medicare
expenditures
Slide 9
Heart disease No symptoms HF Risk Factors No Heart disease No
symptoms Asymptomatic LV dysfunction Refractory HF symptoms Prior
or current HF Symptoms Taking the Congestion Out of Heart Failure
Stages in the evolution of Heart Failure A B C D Hunt SA, et al:
AHA / ACC HF guidelines 2001
Slide 10
Heart disease (any) Hypertension Diabetes, Hyperchol. Family Hx
Cardiotoxins Asymptomatic LV dysfunction Marked symptoms at rest
despite max. therapy Dyspnea, Fatigue Reduced exercise tolerance
Clinical Stages in the Evolution Evolution of Heart Failure A B C D
Hunt SA, et al: AHA / ACC HF guidelines 2001 Trastuzumab,
Anthracyclines 14% in NSABP B-31 4% in NSABP B-31
Slide 11
ACE-i blockers Treat risk factors Avoid toxics ACE-i (selected
pts) In selected patients Palliative therapy Mech. Assist device
Heart Transplant ACE-i blockers Diuretics / Digitalis Stages in the
Evolution of Heart Failure Treatment A B C D Class I indication for
patients with asymptomatic LV dysfunctoin
Slide 12
Tyrosine Kinase Targeted Therapies The list keeps growing
Monoclonal Antibodies Trastuzumab Bevacizumab Cetuximab Panitumumab
Small Molecule TKIs Imatinib Gefitinib Erlotinib Lapatinib
Sorafenib Sunitinib Dasatinib
Slide 13
The Heartbreak of Success Reports of heart failure begin to
emerge Trastuzumab Imatinib LAPATINIB Sunitinib Others???
Slide 14
Determining Extent of the Problem Many trials lack prospective
cardiac monitoring Heart failure difficult to diagnose in the
cancer patient Patients with cardiac comorbidities often excluded
Lack of standardized cardiotoxicity reporting Focus on the most
severe cardiac safety outcomes
Slide 15
How accurate is physician reporting of chemotherapy adverse
effects? A COMPARISON OF PATIENT REPORTED & PHYSICIAN REPORTED
SYMPTOMS 38 65 7765 70 17 30 60 80 60 40 20 0 Fatigue Pain Dyspnea
Insomnia Anorexia Nausea/ Vomiting Diarrhea Constipation Percentage
Physician identified Physician missed Fromme et al: J Clin Oncol
2004; 22(17)3485-3490.
Slide 16
First Report of Cardiotoxicity of a Targeted Therapy
TRASTUZUMAB
Slide 17
Trastuzumab improves PFS and OS in metastatic breast cancer
Slamon et al.: NEJM 2001;344:783-92.
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BUT.. EXCESS CARDIOTOXICITY OBSERVED
Slide 19
Independent Cardiac Review & Evaluation Committee (CREC)
Cardiotoxicity H + ACACH + TT Cardiac dysfunction events, %278131
NYHA Class III/IV CHF, %16421 Seidman A et al: J Clin Oncol 2002;
20:1215-21.
Slide 20
A two-hit model of trastuzumab- induced cardiotoxicity
Trastuzumab -> loss of ErbB2-mediated signalingTrastuzumab ->
loss of ErbB2-mediated signaling Interferes with ability of the
heart to respond to stress When faced with subsequent stress ->
ErbB2-deficient hearts are more susceptible to the cardiotoxic
effects of the stressorWhen faced with subsequent stress ->
ErbB2-deficient hearts are more susceptible to the cardiotoxic
effects of the stressor
Slide 21
Reversible or Just Treatment Responsive? 90 80 70 60 50 40 30
20 10 0 Mean LVEF (%) Following Trastuzumab Therapy (n = 37) Prior
to Trastuzumab Therapy (n = 38) Following Standard Therapy for
Heart Failure (n = 32) Following Trastuzumab Rechallenge (n = 25)
Durand JB, et al: J Clin Oncol 2005;23:7820-7826
Slide 22
Adjuvant Trastuzumab Trials MAJOR IMPROVEMENTS IN DFS Telli ML
et al: J Clin Oncol 25:3525-3533, 2007
Slide 23
Adjuvant Trastuzumab Trials NSABP B-31 & NCCTG N-9831 AC x
4 > Taxol x 4 AC x 4 Taxol x 4 H x 52HERA At least 4 cycles
chemo Observation vs. H 1yr vs. H 2yrs BCIRG 006 AC x 4 Docetaxel x
4 AC x 4 Docetaxel x 4 H x 52 Docetaxel + Carboplatin x 6 + H x 52
(TCH)
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Adjuvant Trastuzumab Trials FinHER Docetaxel x 3 + H x 9 wks
> FEC x 3 Docetaxel x 3 > FEC x 3 Vinorelbine x 3 + H x 9 wks
> FEC x 3 Vinorelbine x 3 > FEC x 3
Slide 25
Prospective Cardiac Monitoring in the Adjuvant Trials Designed
to minimize significant cardiotoxicity Significant cardiac
comorbidities excluded Trials required normal baseline LVEF
Protocol specified cardiac safety analyses
Slide 26
Cardiac Monitoring Strategy NSABP B-31 &NCCTG N9831 Timing
of EvaluationBaseline, post-AC, 6, 9, 18 months from randomization
Criteria for Discontinuation Symptomatic cardiac dysfunction Hold
Criteria*Asymptomatic and: 1. LVEF drop 16% from baseline or 2.
LVEF drop 10-15% from baseline to < LLN * Treatment was
discontinued if LVEF did not recover to a level above hold criteria
after treatment stopped for 4 weeks
Slide 27
Cardiotoxicity in the Adjuvant Trials NSABP B-31NCCTG N9831
HERABCIRG 006 FinHER NYHA III/IV CHF or cardiac death at 3 years:
C: 0.8% H: 4.1% NYHA III/IV CHF or cardiac death at 3yrs: C: 0.3%
H: 3.5% Severe CHF: C: 0% H: 0.6% Grade 3/4 CHF: ACT: 0.3% ACTH:
1.6% TCH: 0.4% CHF/MI: C: 3.4% H: 0%
Slide 28
Detailed Cardiac Data from NSABP B-31 Cardiac Events Tan Chiu
et al: J Clin Oncol 2005;23:7811-9.
Slide 29
Additional B-31 Cardiotoxicity Data Symptomatic CHF not meeting
criteria for a cardiac event: C: 1% H: 5.1% 14% discontinued
trastuzumab secondary to asymptomatic declines in LVEF Tan Chiu et
al: J Clin Oncol 2005;23:7811-9
Slide 30
Follow-up LVEF after Diagnosis of Cardiotoxicity Cardiac Event
Symptoms of CHF Asymptomatic LVEF Tan Chiu et al: J Clin Oncol
2005;23:7811-9
Slide 31
How should we look at benefit vs. risk?
Slide 32
NSABP B-31 Analysis of Benefits vs. Risks at 3 years Survival
Benefit of Trastuzumab Risk of Class III/IV CHF or Cardiac Death
Risk of asymptomatic or symptomatic cardiac dysfunction RR 0.67 ARR
2.5% NNT 40 RR 5.1 AR 4.1% NNH 30.3 RR NA AR 18.9% NNH 5.3 Telli ML
et al: J Clin Oncol 25:3525-3533, 2007
Slide 33
NSABP B-31 Cardiac Risk Score Factors associated with risk of
developing a cardiac event: Use of hypertensive medications Age
>49 Baseline LVEF
