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Building on the Success of Targeted Therapies in Metastatic Disease

Building on the Success of Targeted Therapies in Metastatic Disease Harold J. Burstein, MD, PhD Assistant Professor of Medicine Department of Oncology Dana-Farber Cancer Institute Boston, Massachusetts Trastuzumab Monoclonal antibody binding to HER2/neu (erbB2) receptor

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Building on the Success of Targeted Therapies in Metastatic Disease

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  1. Building on the Success of Targeted Therapies in Metastatic Disease Harold J. Burstein, MD, PhD Assistant Professor of Medicine Department of Oncology Dana-Farber Cancer Institute Boston, Massachusetts

  2. Trastuzumab • Monoclonal antibody binding to HER2/neu (erbB2) receptor • Standard treatment (in combination with chemotherapy) for HER2-positive metastatic breast cancer for past 7 years • Reduces the risk of recurrent HER2-positive disease by ~50% • Cardiotoxicity the most important adverse event • Trastuzumab + paclitaxel: 13% • Trastuzumab + anthracycline: 27% • Piccart-Gebhart MJ. 42nd ASCO; June 2-6, 2006. Education Session.

  3. Bevacizumab Targets tumor angiogenesis—the formation of new blood vessels necessary to support tumor growth and metastasis—by inhibiting vascular endothelial growth factor, an important signaling molecule in regulating this process1,2 1. Cross MJ, Claesson-Welsh L. Trends Pharmacol Sci. 2001;22:201. 2. Brown JM, Giaccia AJ. Cancer Res. 1998;58:1408.

  4. Bevacizumab + Paclitaxel Phase III Trial The addition of bevacizumab (BEV) to paclitaxel (PAC) doubled the response rate and extended progression-free survival by almost 5 months, compared with paclitaxel alone PAC Alone PAC/BEV(n = 316) (n = 330) Response rate (%) 14.2 28.2 Progression-free survival (mo) 6.1 10.97 Miller KD, et al. 41st ASCO; May 13-17, 2005.

  5. Bevacizumab + PaclitaxelToxicities • 13% of patients receiving bevacizumab developed hypertension requiring treatment • Serious bleeding events were rare and not substantially increased with addition of bevacizumab • There was a significant increase in grade 3 neuropathy from 13.6% with paclitaxel alone to 19.9% in the combination arm • Chemotherapy-related toxicities were mild and did not interfere with therapy Miller KD et al. 41st ASCO; May 13-17, 2005. Abstract.

  6. ASCO 2006—New Trastuzumab Combination Regimens in Metastatic/Recurrent Disease • Trastuzumab + vinorelbine • Trastuzumab + bevacizumab • Trastuzumab + docetaxel +/- carboplatin • Trastuzumab + heat shock protein inhibitor

  7. Trastuzumab + Vinorelbine vs Trastuzumab + TaxaneHER2+ Metastatic Breast Cancer Trastuzumab/ Trastuzumab/ Vinorelbine Taxane* n = 41 n = 40 P-Value Response rate (strict criteria) 51% 40% .37 Response rate (unconfirmed) 66% 58% .50 Median time to 8.5 6.0 .09 Progression (mo) Weekly trastuzumab + vinorelbine is at least as effective as weekly trastuzumab/taxane * Paclitaxel (n=14), docetaxel (n=24), or paclitaxel/carboplatin (n=2) at discretion of treating oncologist. Burstein HJ, et al. 42nd ASCO; June 2-6, 2006. Abstract 650.

  8. Trastuzumab + Vinorelbine vsTrastuzumab + Taxane Time to Tumor Progression (TTP) Courtesy of Burstein HJ, et al. 42nd ASCO; June 2-6, 2006. Abstract 650. Poster Session. 1.0 - 0.8 - 0.6 - 0.4 - 0.2 - 0.0 - Median TTP: A (Trast + Vln) B (Trast + Tax) Probability Log-rank P = .20 0 2 18 4 6 8 14 10 16 12 Months

  9. Trastuzumab + Vinorelbine vs Trastuzumab + TaxaneToxicities • Generally similar • Trastuzumab + vinorelbine • Greater myelosuppression • Trastuzumab + taxane • Greater hair loss, nail changes, rash, and fluid retention • Cardiotoxicity <5% in all groups Burstein HJ, et al. 42nd ASCO; June 2-6, 2006. Abstract 650. Poster Session.

  10. Trastuzumab + BevacizumabRelapsed/Metastatic HER2+ Disease • First report of 2 humanized monoclonal antibodies in humans • Phase 1 (9 patients) • 2 complete responses; 3 partial responses; 2 stable disease (>6 mo) • Phase II ongoing (16 patients with response) • 8 partial responses; 6 stable disease Rugo HS. 42nd ASCO; June 2-6, 2006. Education Session.

  11. Trastuzumab (T) + Docetaxel (D) +/- Carboplatin (C)Phase III Trial in HER2+ Metastatic Breast Cancer TD TDC n = 131 n = 131 P-Value Median time to tumor progression (mo)* 11.1 10.4 .57 Objective response rate 73% 73% Duration of response (mo) 10.7 9.4 Median overall survival (mo) Not reached 41.7 Clinical benefit 67% 67% * Primary end point No increase in benefit with the addition of carboplatin to trastuzumab + docetaxel Forbes JF, et al. 42nd ASCO; June 2-6, 2006. Abstract LBA516.

  12. Trastuzumab + Heat Shock Protein (HSP) Inhibitor • Chaperone protein is required for maturation and stabilization of certain client proteins, including HER2 • Inhibition of HSP90 chaperone function induces degradation of client protein • Phase I trial of KOS-953, an HSP90 inhibitor, plus trastuzumab: 17 HER2+ patients with trastuzumab-resistant metastatic breast cancer • 1 partial response, 3 minimal response, 5 prolonged (>4 mo) stable disease • Phase II trial under way Modi S, et al. 42nd ASCO; June 2-6, 2006. Abstract 501.

  13. Trastuzumab Resistance • Virtually all HER2+ metastatic breast cancers develop resistance • Adjuvant trastuzumab reduces the annual hazard rate by 1/2, ie, 1/2 of recurrences are not prevented Sledge GW. 42nd ASCO; June 2-6, 2006. Education Session.

  14. Possible Causes of Trastuzumab Resistance • Suboptimal drug delivery • Altered target expression • Altered target • Modified target-regulating proteins • Alternative pathway signaling Sledge GW. 42nd ASCO; June 2-6, 2006. Education Session.

  15. Overcoming Trastuzumab Resistance • Block the HER pathway(s) at other points • Block other growth factor receptor pathways (HER1, IGF-1R) • Block angiogenesis Sledge GW. 42nd ASCO; June 2-6, 2006. Education Session.

  16. Lapatinib Dual inhibitor targeting both erbB1 (or epidermal growth factor) and erbB2 (or HER2/neu) receptors

  17. LapatinibMechanism of Action Lapatinib and Trastuzumab:Potential for Synergy Rugo HS. 42nd ASCO; June 2-6, 2006. Education Session. Phase I trial: Storniolo, SABC 2005 Trastuzumab Lapatinib Downstream signaling cascade Cell Division/Tumor Growth Maximum inactivation of ErbB2 Pathway • ErbB2 receptor • Truncated Erb2 receptor • ErbB1/ErbB2 heterodimes

  18. Lapatinib+Capecitabine vs Capacitabine in Trastuzumab-Resistant DiseaseTime to Tumor Progression Lapatinib/ Capecitabine Capecitabine n = 160 n = 161 Progressed or died 45 (28%) 69 (43%) Median TTP (wk) 36.9 19.7 Hazard ratio (95% CI) 0.51 (0.35, 0.74) P-value (log rank, 1-sided) .00016 Geyer CE, et al. Presented at 42nd ASCO; June 2-6, 2006. Special Session.

  19. Lapatinib + Capecitabine vs Capecitabinein Trastuzumab-Resistant DiseaseBrain Metastasesas Site of Progression Lapatinib/ Capecitabine Capecitabine n = 160 n = 161 Patients with CNS metastases at baseline 2 2 Patients with CNS relapse* 4 11 Patients with CNS as only site of relapse 3 10 *P-value (Fisher’s exact, 2-sided) = .110 Geyer CE, et al. 42nd ASCO; June 2-6, 2006. Special Session.

  20. Lapatinib + Capecitabine vs Capacitabinein Trastuzumab-Resistant DiseaseAdverse Events(AEs) • Similar rates for all AEs and serious AEs • Most common AEs: diarrhea, PPE, rash, and/or skin reactions • AEs leading to discontinuation of study medication • Lapatinib + capecitabine: 22 (14%) • Capecitabine: 16 (11%) • Cardiac events • 4 lapatinib + capecitabine; 1 capecitabine • All asymptomatic (grade 2) • No withdrawals due to decreased LVEF • 1 treatment-related death in capecitabine arm PPE = palmar-plantar erythrodysesthesia; LVEF = left ventricular ejection fraction. Geyer CE, et al. 42nd ASCO; June 2-6, 2006. Special Session.

  21. Lapatinib + Capecitabine vs Capecitabinein Trastuzumab-Resistant DiseaseSummary Compared with capecitabine alone, lapatinib + capecitabine results in • Significantly longer time to tumor progression • Fewer CNS metastases • Comparable safety

  22. Lapatinib in Brain Metastases • Approximately 1/3 of women with HER2+ metastatic breast cancer develop CNS metastases • Apparently higher incidence of CNS metastases in women treated with trastuzumab • Trastuzumab is not thought to cross the blood-brain barrier • Phase II trial of lapatinib monotherapy in CNS metastases • 39 patients with CNS metastases that developed on trastuzumab (38 of whom progressed after prior radiation) • 2 partial responses by RECIST • 8 progression-free in CNS at 16 weeks • Volumetric declines >30% in 4 patients; declines of 10% to 30% in an additional 6 patients • RECIST = Response Evaluation Criteria in Solid Tumors. • Lin NU, et al. 42nd ASCO; June 2-6, 2006. Abstract 503.

  23. Lapatinib Monotherapyin Inflammatory Breast Cancer Cohort A: Cohort B: erbB2+ erbB1+/erbB2- (n = 24) (n = 12) Partial response 62% 8.3% erbB2 overexpression, but not erbB1 expression alone, predicts for sensitivity to lapatinib in inflammatory breast cancer Spector NL, et al. 42nd ASCO; June 2-6, 2006. Abstract 502

  24. Conclusions Targeted therapy has assumed a prominent role in the treatment of breast cancer • Three targeted agents—trastuzumab, bevacizumab, and lapatinib—have demonstrated impressive activity in metastatic breast cancer • Trastuzumab + vinorelbine has proven at least as efficacious as trastuzumab + taxane-based treatment • The combination of 2 targeted agents—trastuzumab and bevacizumab—shows promising early results

  25. Conclusions(cont’d) New agents and approaches continue to expand the benefit of targeted therapy • Inhibition of heat shock protein (HSP) chaperone function by a HSP90 inhibitor induces degradation of HER2 and may increase efficacy of trastuzumab when used in a combination regimen • Lapatinib is effective in treating trastuzumab-resistant tumors; early results indicate that it may be beneficial in treating CNS metastases and inflammatory breast cancer, as well

  26. Getting the Most Out of Targeted Therapy Francisco J. Esteva, MD, PhD Associate Professor of MedicineBreast Medical OncologyThe University of TexasM.D. Anderson Cancer CenterHouston, Texas

  27. Trastuzumab in Early-Stage Disease

  28. HERA Trial Design Women with locally determined HER2 + invasive early breast cancer Surgery + (neo)adjuvant CT ± RT Centrally confirmed IHC 3+ or FISH+ and LVEF ≥ 55% Randomization Observation 1 year trastuzumab8 mg/kg 6 mg/kg3 weekly schedule 2 year trastuzumab8 mg/kg 6 mg/kg3 weekly schedule X After ASCO 2005,option of switchto trastuzumab HERA Trial2-Year Follow-Up CT = chemotherapy; RT = radiotherapy; IHC = immunohisochemistry; FISH = fluorescence in situ hybridization; LVEF = left ventricular ejection fraction. Smith IE. Presented at 42nd ASCO; June 2-6, 2006.

  29. HERA TrialDisease-Free Survival (ITT) Median Follow-Up 2 years ITT = intent to treat; DFS = disease-free survival; HR = hazard ratio; CI = confidence interval. Smith IE. 42nd ASCO; June 2-6, 2006. 100806040200 1 year trastuzumab 6.3% Observation Patients (%) 3-yearDFS HR P-Value Events 95% Cl 80.6 218 0.64 0.54, 0.76 <.0001 74.3 321 24 12 18 30 0 6 36 Months from Randomization 1703 1591 1434 1127 742 383 140 No.at risk 1698 1535 1330 984 639 334 127

  30. HERA TrialOverall Survival (ITT) Median Follow-Up 2 Years ITT = intent to treat; OS = overall survival; HR = hazard ratio; CI = confidence interval. Smith IE. 42nd ASCO; June 2-6, 2006. 100806040200 1 year trastuzumab 2.7% Observation Patients (%) 3-yearOS HR P-Value Events 95% Cl 92.4 59 0.66 0.47, 0.91 .0115 89.7 90 24 12 18 30 0 6 36 Months from Randomization 1703 1627 1498 1190 794 407 146 No.at risk 1698 1608 1453 1097 711 366 139

  31. HERA TrialCardiac Safety Number Patients (%) Observation Trastuzumab: 1 y n = 1708 n = 1678 Cardiac death 1 (0.1) 0 (0.0) Severe CHF (NYHA III and IV) 0 (0.0) 10 (0.6) Symptomatic CHF 3 (0.2) 36 (2.1) Confirmed significant LVEF drop 9 (0.5) 51 (3.0) CHF = congestive heart failure; NYHA = New York Heart Association; LVEF = left ventricular ejection fraction. Smith IE. 42nd ASCO; June 2-6, 2006.

  32. HERA TrialSummary • Trastuzumab following adjuvant chemotherapy significantly improves overall survival (HR 0.66) in women with early-stage HER2+ breast cancer • Gain in disease-free survival after 1 year median follow-up is maintained after 2 years median follow-up • Risk of cardiac toxicity remains low HR=hazard ratio Smith IE. 42nd ASCO; June 2-6, 2006.

  33. Identification of Patients Likely to Benefit • Balancing risk and benefit • Using biomarkers to predict response • Trastuzumab • Anti epidermal growth factor receptor therapy

  34. Trastuzumab for All HER2+ Patients? • Adjuvant trastuzumab results in significant reduction of recurrence in high-risk HER2+ breast cancer patients • However, trastuzumab is associated with significant cardiac toxicity • What is the risk of adverse effects vs survival benefit of trastuzumab in patients with low risk of recurrence and/or high risk of cardiac toxicity? Gupta AK, et al. 42nd ASCO; June 2-6, 2006. Abstract 6022.

  35. Low Risk of Recurrence and/or High Risk of Toxicity Cumulative Cardiac 10-y 10-y Patient Treatment Toxicity (%) QALYs DFS (%) Cardiac Deaths (%) 50 y CT 0.8 20.61 70.2 0.06 2 cm node+ CT+T 6 25.34 81.9 0.68 ER/PR- EF 60% 70 y CT 0.8 13.58 62.1 0.06 2 cm node- CT+T 20 14.18 66.8 2.03 ER/PR- EF 50% QALYs = quality adjusted life years; DFS = disease-free survival; CT = chemotherapy; T= trastuzumab; ER = estrogen receptor; PR = progesterone receptor; EF = ejection fraction. Gupta AK, et al. 42nd ASCO Abstracts. J Clin Oncol. 2006;24:Abstract 6022. Reprinted with permission from the American Society of Clinical Oncology.

  36. Conclusions • The addition of trastuzumab to standard chemotherapy is more beneficial than standard chemotherapy alone in most cases, including elderly patients with node-negative disease and those at increased risk of cardiac toxicity • However, incremental benefit decreases with increasing age, higher risk of cardiac toxicity, and lower risk of recurrence Gupta AK, et al. 42nd ASCO Abstracts. J Clin Oncol. 2006;24:Abstract 6022. Reprinted with permission from the American Society of Clinical Oncology.

  37. Change in Serum HER2 and Outcome Change in HER2 Serum Levels DR TTP OS from Baseline ORR (median/d) (median/d) (median/d) <20% decrease 28.4% 230 182 593 >20% decrease 56.5% 369 320 898 P value <.001 .008 <.001 .018 Patients with <20% decrease in serum HER2 have decreased benefit from trastuzumab and should be considered for additional HER2-targeted therapies ORR = objective response rate; DR = duration of response; TTP = time to tumor progression; OS = overall survival. Ali SM, et al. 42nd ASCO Abstracts. J Clin Oncol. 2006;24:Abstract 500. Reprinted with permission from the American Society of Clinical Oncology.

  38. ER+/PR- Status • Compared with ER+/PR+ disease, ER+/PR- breast cancer has • Lower response rate to estrogen deprivation • Worse prognosis • May be dependent on other signaling pathways ER = estrogen receptor; PR = progesterone receptor. Finn RS, et al. 42nd ASCO; June 2-6, 2006. Abstract 514.

  39. ER+/PR- Breast Cancer and EGFR Inhibition • Presurgical exposure to short-term gefitinib, an EGFR inhibitor, in 43 patients with operable breast cancer • Tissue obtained at surgery • ER+/PR- tumors more likely to show molecular growth inhibition • ER+/PR+ tumors more likely to show molecular growth proliferation • Conclusions • ER+/PR- breast cancer is growth factor dependent • ER+/PR- patients may be more likely to benefit from EGFR inhibition ER = estrogen receptor; PR = progesterone receptor; EGFR = epidermal growth factor receptor. Finn RS, et al. 42nd ASCO; June 2-6, 2006. Abstract 514.

  40. EGFR Expression and Tumor Characteristics • Comparision of EGFR+ and EGFR- tumors in 2567 patients • EGFR+ tumors were more common in patients who were • Younger (<50 y)1 • Premenopausal1 • Black2 • EGFR expression was associated with • Larger tumors1 • Aneuploidy1 • High S-phase fraction1 • Nodal involvement3 • EGFR+ tumors were more likely to be HER2+1, but less likely to be ER+1 and PR+1 1P <.0001 2P = .005 3P = .009 EGFR = epidermal growth factor receptor; ER = estrogen receptor; PR = progesterone receptor. Rimawi MF, et al. 42nd ASCO; June 2-6, 2006. Abstract 513.

  41. EGFR Expression and Prognosis • 1256 treated patients;1 1068 untreated patients2 • In treated patients, EGFR expression was negatively correlated with • DFS (P = .001) • 0S (P = .001) • No relationship was found between EGFR status and DFS or OS in untreated patients EFGR expression is associated with significant resistance to adjuvant hormonal therapy and chemotherapy. Blocking EFGR activity may help to overcome this resistance in selected patients 1 Systemic chemotherapy and/or hormonal therapy 2 No systemic therapy EGFR = epidermal growth factor receptor; DFS = disease-free survival; OS = overall survival. Rimawi MF, et al. 42nd ASCO; June 2-6, 2006. Abstract 513.

  42. Cost-Effectiveness of Trastuzumab—Model 1 • Cost-effectiveness of adding trastuzumab to standard adjuvant therapy (doxorubicin, cyclophosphamide, and paclitaxel) • Based on Markov model with 3 disease states • Disease-free survival • Recurrence • Death • Costs included • Testing for HER2 status • Drug and administration costs for trastuzumab • Cardiac monitoring • Treatment of cardiac toxicity • Treatment following recurrence • End-of-life costs for dying patients Garrison LP Jr, et al. 42nd ASCO; June 2-6, 2006. Abstract 6023.

  43. Cost-Effectiveness of Trastuzumab—Model 1(cont’d) • Patient: 50 year-old woman • Efficacy based on NCCTG N9831 and NSABP B-31 trials; projections to recurrence and death based on literature (Lancet, 2005) • With trastuzumab • Lifetime cost per QALY gained: $27,800 (range: $17,900 to $39,100) • Projected life expectancy 3 years longer (trastuzumab: 19.4 years; without trastuzumab: 16.4 years) • Additional cost of adding trastuzumab: $46,300 • Expected gain of 1.28 QALY • Cost/QALY = $36,100 Utility/cost ratio of adding trastuzumab is below that of many treatments used for oncology patients. Garrison LP Jr, et al. 42nd ASCO; June 2-6, 2006. Abstract 6023.

  44. Cost-Effectiveness of Trastuzumab in Early-Stage and Metastatic Breast Cancer—Model 2 Comparison of • Cost per relapse prevented by adjuvant chemotherapy (docetaxel, paclitaxel, filgrastim) vs • Cost per relapse prevented by adjuvant trastuzumab Wilson E, et al. 42nd ASCO; June 2-6, 2006. Abstract 6081.

  45. Cost-Effectiveness of Trastuzumab in Early-Stage and Metastatic Breast Cancer—Model 2(cont’d) Trastuzumab Docetaxel Paclitaxel Filgrastim Reduction in relapse 50% 7%1 5%2 4%3 Cost per relapse prevented € 147,000 € 126,000 € 148,000 € 231,000 Adjuvant trastuzumab is more cost-effective than adjuvant paclitaxelor filgrastim 1 BCIRG 001 2 CALGB 9344 3 CALGB 9741 Wilson E, et al. 42nd ASCO; June 2-6, 2006. Abstract 6081.

  46. Cost-Effectiveness of Trastuzumab in Early-Stage and Metastatic Breast Cancer—Model 2(cont’d) Conclusions • Assuming no retreatment with trastuzumab, adjuvant trastuzumab appears to be a relatively cost-effective means of reducing relapses • Possibility of a shorter treatment regimen (FinnHER study) should result in even greater cost-effectiveness Wilson E, et al. 42nd ASCO; June 2-6, 2006. Abstract 6081.

  47. Conclusions • Initial gains in disease-free survival and overall survival observed with trastuzumab in early-stage breast cancer continue to be sustained after median follow-up of 2 years • Trastuzumab is cost-effective in reducing relapse and compares favorably with many treatments used for oncology patients • Clinical benefit and cost-effectiveness can be increased with the use of biomarkers to identify patients most likely to benefit from targeted therapies

  48. Adverse Events andTargeted Therapy Maureen Major, RN, MS Clinical Nurse Specialist Department of Nursing Memorial Sloan-Kettering Cancer Center New York, New York

  49. Adverse Events • Cardiac toxicity • Osteoporosis

  50. = Doxorubicin/cyclophosphamide 60/600 mg/m2 q3wk x 4 = Paclitaxel 175 mg/m2 q3wk x 4 = Paclitaxel 80 mg/m2 qwk x 12 = Trastuzumab 4 mg/kg loading  2 mg/kg qwk x 51 NCCTG N9831 Trial Designs NCCTG N9831 Arm A Arm B Arm C NCCTG = North Central Cancer Treatment Group. N9831 PI. EA Perez. With permission from Romond E. ASCO 2005; May 13–17, 2005. Oral Presentation.

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