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HER2-Targeted Therapy

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

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  1. HER2-Targeted Therapy THE PROBLEM WITH ‘OFF TARGET’ TOXICITY TO THE HEART Melinda Telli, MD Instructor in Medicine Stanford University 9/12/2008

  2. Overview • Heart Failure & the Elderly • Updated ACC/AHA Heart Failure Staging • The Trastuzumab Story • Risk Versus Benefit Analysis

  3. Cancer patients living longer Long-term toxicities of therapy take on greater significance American Cancer Society 2004

  4. Cardiovascular versus Cancer Deaths by Age United States: 2004; Source: NCHS and NHLBI

  5. Heart failure is primarily a disease of the elderly NHANES: 1999-2004Source: NCHS and NHLBI.

  6. 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

  7. 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

  8. 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

  9. 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

  10. Monoclonal Antibodies Trastuzumab Bevacizumab Cetuximab Panitumumab Small Molecule TKIs Imatinib Gefitinib Erlotinib Lapatinib Sorafenib Sunitinib Dasatinib Tyrosine Kinase Targeted TherapiesThe list keeps growing

  11. The Heartbreak of Success Reports of heart failure begin to emerge Trastuzumab Imatinib LAPATINIB Sunitinib Others???

  12. 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

  13. 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.

  14. First Report of Cardiotoxicity of a Targeted TherapyTRASTUZUMAB

  15. Trastuzumab improves PFS and OS in metastatic breast cancer Slamon et al.: NEJM 2001;344:783-92.

  16. BUT…..EXCESS CARDIOTOXICITY OBSERVED

  17. Independent Cardiac Review & Evaluation Committee (CREC) Seidman A et al: J Clin Oncol 2002; 20:1215-21.

  18. A ‘two-hit’ model of trastuzumab-induced cardiotoxicity • 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

  19. 90 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

  20. Adjuvant Trastuzumab TrialsMAJOR IMPROVEMENTS IN DFS Telli ML et al: J Clin Oncol 25:3525-3533, 2007

  21. Adjuvant Trastuzumab Trials 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”)

  22. 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

  23. 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

  24. Cardiac Monitoring StrategyNSABP B-31 &NCCTG N9831 * Treatment was discontinued if LVEF did not recover to a level above hold criteria after treatment stopped for 4 weeks

  25. Cardiotoxicity in the Adjuvant Trials

  26. Detailed Cardiac Data from NSABP B-31 Cardiac Events Tan Chiu et al: J Clin Oncol 2005;23:7811-9.

  27. Additional B-31 Cardiotoxicity Data • 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

  28. 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

  29. How should we look at benefit vs. risk?

  30. NSABP B-31 Analysis of Benefits vs. Risks at 3 years Telli ML et al: J Clin Oncol 25:3525-3533, 2007

  31. NSABP B-31Cardiac 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

  32. Cardiac Risk Score = 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%

  33. Future Directions 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

  34. Conclusions: Trastuzumab • 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

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