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HER2-Targeted Therapy. THE PROBLEM WITH ‘OFF TARGET’ TOXICITY TO THE HEART Melinda Telli, MD Instructor in Medicine Stanford University 9/12/2008. Overview. Heart Failure & the Elderly Updated ACC/AHA Heart Failure Staging The Trastuzumab Story Risk Versus Benefit Analysis.

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Her2 targeted therapy l.jpg
HER2-Targeted Therapy

THE PROBLEM WITH ‘OFF TARGET’

TOXICITY TO THE HEART

Melinda Telli, MD

Instructor in Medicine

Stanford University

9/12/2008


Overview l.jpg
Overview

  • Heart Failure & the Elderly

  • Updated ACC/AHA Heart Failure Staging

  • The Trastuzumab Story

  • Risk Versus Benefit Analysis


Cancer patients living longer l.jpg
Cancer patients living longer

Long-term toxicities of therapy take on greater significance

American Cancer Society 2004


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Cardiovascular versus Cancer Deaths by Age

United States: 2004; Source: NCHS and NHLBI


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Heart failure is primarily a disease of the elderly

NHANES: 1999-2004Source: NCHS and NHLBI.


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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


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Taking the Congestion

Out of Heart Failure

Stages in the evolution

of Heart Failure

HF Risk Factors

No Heart disease

No symptoms

A

B

Heart disease

No symptoms

Asymptomatic

LV dysfunction

C

Prior or current

HF Symptoms

D

Refractory

HF symptoms

Hunt SA, et al: AHA / ACC HF guidelines 2001


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Trastuzumab, Anthracyclines

A

Hypertension

Diabetes, Hyperchol.

Family Hx

Cardiotoxins

Clinical Stages in the

Evolution

of Heart Failure

B

Heart disease

(any)

4% in NSABP B-31

Asymptomatic

LV dysfunction

C

Dyspnea, Fatigue

Reduced exercise

tolerance

14% in NSABP B-31

D

Marked symptoms

at rest despite

max. therapy

Hunt SA, et al: AHA / ACC HF guidelines 2001


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Treat risk factors

Avoid toxics

ACE-i (selected pts)

A

Stages in the Evolution

of Heart Failure

Treatment

B

ACE-i

 blockers

In selected

patients

C

ACE-i

 blockers

Diuretics / Digitalis

Class I indication for patients with asymptomatic LV dysfunctoin

D

Palliative therapy

Mech. Assist device

Heart Transplant


Tyrosine kinase targeted therapies the list keeps growing l.jpg

Monoclonal Antibodies

Trastuzumab

Bevacizumab

Cetuximab

Panitumumab

Small Molecule TKIs

Imatinib

Gefitinib

Erlotinib

Lapatinib

Sorafenib

Sunitinib

Dasatinib

Tyrosine Kinase Targeted TherapiesThe list keeps growing


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The Heartbreak of Success

Reports of heart failure begin

to emerge

Trastuzumab

Imatinib

LAPATINIB

Sunitinib

Others???


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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


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How accurate is physician reporting of chemotherapy adverse effects?A COMPARISON OF PATIENT REPORTED & PHYSICIAN REPORTED SYMPTOMS

17

60

70

30

77

65

65

38

80

60

Percentage

40

20

0

Pain

Fatigue

Insomnia

Anorexia

Nausea/

Vomiting

Dyspnea

Diarrhea

Constipation

Physician missed

Physician identified

Fromme et al: J Clin Oncol 2004; 22(17)3485-3490.



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Trastuzumab improves PFS and OS in metastatic breast cancer effects?

Slamon et al.: NEJM 2001;344:783-92.


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BUT….. effects?EXCESS CARDIOTOXICITY OBSERVED


Independent cardiac review evaluation committee crec l.jpg
Independent Cardiac Review & Evaluation Committee (CREC) effects?

Seidman A et al: J Clin Oncol 2002; 20:1215-21.


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A ‘two-hit’ model of trastuzumab-induced cardiotoxicity effects?

  • Trastuzumab -> 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 stressor


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90 effects?

80

70

60

50

40

30

20

10

0

Mean LVEF (%)

Prior to

Trastuzumab

Therapy

(n = 38)

Following

Standard Therapy

for Heart Failure

(n = 32)

Following

Trastuzumab

Rechallenge

(n = 25)

Following

Trastuzumab

Therapy

(n = 37)

Reversible or Just Treatment Responsive?

Durand JB, et al: J Clin Oncol 2005;23:7820-7826


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Adjuvant Trastuzumab Trials effects?MAJOR IMPROVEMENTS IN DFS

Telli ML et al: J Clin Oncol 25:3525-3533, 2007


Adjuvant trastuzumab trials l.jpg
Adjuvant Trastuzumab Trials effects?

NSABP B-31 & NCCTG N-9831

AC x 4 > Taxol x 4

AC x 4  Taxol x 4H x 52

HERA

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 effects?

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


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Prospective Cardiac Monitoring effects?in the Adjuvant Trials

  • Designed to minimize significant cardiotoxicity

  • Significant cardiac comorbidities excluded

  • Trials required normal baseline LVEF

  • Protocol specified cardiac safety analyses


Cardiac monitoring strategy nsabp b 31 ncctg n9831 l.jpg
Cardiac Monitoring Strategy effects?NSABP B-31 &NCCTG N9831

* Treatment was discontinued if LVEF did not recover to a level above hold

criteria after treatment stopped for 4 weeks



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Detailed Cardiac Data from NSABP B-31 effects?Cardiac Events

Tan Chiu et al: J Clin Oncol 2005;23:7811-9.


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Additional B-31 Cardiotoxicity Data effects?

  • Symptomatic CHF not meeting criteria for a cardiac event:

    C: 1%

    H: 5.1%

  • 14% discontinued trastuzumab secondary toasymptomatic declines in LVEF

Tan Chiu et al: J Clin Oncol 2005;23:7811-9


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Follow-up LVEF after Diagnosis of Cardiotoxicity effects?

Cardiac Event Symptoms of CHF Asymptomatic ↓ LVEF

Tan Chiu et al: J Clin Oncol 2005;23:7811-9



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NSABP B-31 effects?Analysis of Benefits vs. Risks at 3 years

Telli ML et al: J Clin Oncol 25:3525-3533, 2007


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NSABP B-31 effects?Cardiac Risk Score

Factors associated with risk of developing a cardiac

event:

  • Use of hypertensive medications

  • Age >49

  • Baseline LVEF <54

    Risk Score = 100 x 7.4(0.03 x Age) – (0.10 + baseline LVEF) + (0.68 x C)

    4.82

    C = HTN medication status: none = 0; yes = 1

    Rostagi P, Adjuvant Breast Oral Session, ASCO 2007


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Cardiac Risk Score = effects? 82

3-year predicted incidence of symptomatic heart failure/cardiac death 10%

NSABP B-31Cardiac Risk Score

Example:

62 yo woman on antihypertensive medication

Baseline LVEF = 60%


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Future Directions effects?

PREVENTION

  • Pre-emptive use of ACE inhibitors or beta-blockers in may prevent cardiotoxicity

    EARLY DETECTION

  • Cardiac biomarkers may help identify high risk patients

    • Troponin

    • BNP


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Conclusions: Trastuzumab effects?

  • Symptomatic heart failure in up to 4% in adjuvant trials

  • Asymptomatic declines in LVEF much more common

  • Less cardiotoxicity with non-anthracycline containing TCH regimen

  • No cardiotoxicity observed in FinHER

  • Need to consider absolute benefits vs. risks