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

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

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

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

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

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

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

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

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

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

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

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

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.

16. First Report of Cardiotoxicity of a Targeted Therapy TRASTUZUMAB

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

18. BUT….. EXCESS CARDIOTOXICITY OBSERVED

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.

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

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

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

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”)

24. 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

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

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

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%

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

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

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

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

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

33. NSABP B-31 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 4.82 C = HTN medication status: none = 0; yes = 1 Rostagi P, Adjuvant Breast Oral Session, ASCO 2007

34. NSABP B-31 Cardiac Risk Score Example: 62 yo woman on antihypertensive medication Baseline LVEF = 60% Cardiac Risk Score = 82 3-year predicted incidence of symptomatic heart failure/cardiac death  10%

35. 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

36. 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 Conclusions: Trastuzumab