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Optimizing Treatment for Her 2 Positive Metastatic Breast Cancer Patients

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  1. Optimizing Treatment for Her 2 Positive Metastatic Breast Cancer Patients Sunil Verma MD, MSEd, FRCPC Medical Oncologist Chair, Breast Medical Oncology Sunnybrook Odette Cancer Centre Associate Professor, University of Toronto

  2. Her 2 Story Poor Prognostic Marker

  3. Outline First Line Treatment Second Line Treatment and Beyond Individualized Approach An Algorithm and Concluding Remarks

  4. Outline First Line Treatment Second Line Treatment and Beyond Individualized Approach An Algorithm and Concluding Remarks

  5. Trastuzumab prolongs overall survival in HER2-positive MBC 100 Chemotherapy (n = 234) Chemotherapy + trastuzumab (n = 235) RR = 0.80 (95% CI = 0.64,1.00) p = 0.046 80 Overall survival (%) 60 40 Median OS: 20.3 months Median OS: 25.1 months 20 0 0 5 15 25 35 45 Time (months after enrolment) Adapted from Slamon DJ, et al. N Engl J Med 2001; 344:783–792. OS was a secondary endpoint in the study Chemotherapy = either doxorubicin or epirubicin + cyclophosphamide or paclitaxelOS, overall survival; RR, relative risk of death

  6. First Line Treatment Approach (2001-2011) • A number of effective options with chemo and anti-her2 • Taxanes and Herceptin • Vinorelbine and Herceptin • Capecitabine and Anti-Her2 • Doublet chemo with Her 2 generally not used • Select group of patients may benefit from an anti-Her2 and anti-estrogen approach

  7. Recent Achievements in Her 2 positive MBC First Line • MA.31 • Taxane + H vs. Taxane + L • CLEOPATRA • Chemo + H vs. Chemo +H+P

  8. Gelmon et. al ASCO 2012

  9. Gelmon et. al ASCO 2012

  10. CLEOPATRA study design PD Placebo + trastuzumab n=406 Docetaxel≥6 cycles recommended Patients withHER2-positive MBCcentrally confirmed (N=808) 1:1 PD Pertuzumab + trastuzumab n=402 Docetaxel≥6 cycles recommended Randomization was stratified by geographic region and prior treatment status (neo/adjuvant chemotherapy received or not) HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; PD, progressive disease Swain et al. SABCS 2012 Poster P5-18-26 .

  11. CLEOPATRA: Significantly higher response rate with pertuzumab and trastuzumab H, trastuzumab; P, pertuzumab; T, docetaxel Adapted from Baselga J, et al. N Engl J Med 2012; 366:109–119.

  12. Updated Kaplan-Meier curves of investigator-assessed PFS 100 Ptz + T + D: median 18.7 months ∆=6.3 months Pla+ T + D: median 12.4 months 90 80 70 60 Progression-free survival (%) HR=0.6995% CI 0.58−0.81 50 40 30 20 10 0 0 5 10 15 20 25 30 35 40 45 50 Time (months) n at risk Ptz + T + D 402 341 284 218 178 108 67 34 8 0 0 Pla+ T + D 406 329 223 148 110 72 42 26 8 0 0 D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Swain et al. SABCS 2012 Poster P5-18-26 .

  13. Kaplan-Meier curves of the confirmatory overall survival analysis 1 year 94% 100 2 years 90 89% 81% 3 years HR=0.6695% CI 0.52−0.84 p=0.0008 80 70 66% 69% 60 Overall survival (%) 50 50% 40 30 Ptz + T + D: 113 events; median not reached 20 Pla+ T + D: 154 events; median 37.6 months 10 0 0 5 10 15 20 25 30 35 40 45 50 55 Time (months) n at risk Ptz + T + D 402 387 371 342 317 230 143 84 33 9 0 0 Pla+ T + D 406 383 350 324 285 198 128 67 22 4 0 0 Stopping boundary for concluding statistical significance at this second interim analysis was p≤0.0138 D, docetaxel; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Swain et al. SABCS 2012 Poster P5-18-26 .

  14. Breast cancer therapies following discontinuation of study treatment in patients who had withdrawn from study treatment Swain et al. SABCS 2012 Poster P5-18-26 .

  15. Adverse events (all grades) with ≥25% incidence or ≥5% difference between arms Highlighted are adverse events with ≥5% higher incidence Swain et al. SABCS 2012 Poster P5-18-26 .

  16. Cardiac adverse events * In patients with post-baseline assessment LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction Swain et al. SABCS 2012 Poster P5-18-26 .

  17. T-DM1Mechanism of Action KADCYLA is a HER2-targeted antibody and microtubule inhibitor conjugate consisting of • HERCEPTIN, a humanized anti-HER2 IgG1 monoclonal antibody • DM1, a cytotoxic microtubule inhibitor derived from maytansine • on average, KADCYLA has 3.5 DM1 molecules per antibody • MCC, a stable thioether linker, covalently linking HERCEPTIN to DM1 Cytotoxic agent (DM1) Stable linker Emtansine Antibody (HERCEPTIN) DM: derivative of maytansine MCC: 4-[N-maleimidomethyl] cyclohexane-1-carboxylate KADCYLA Product Monograph. Hoffmann-La Roche Limited. September 11, 2013. Swanton C, Johnston SR, editors. Handbook of Metastatic Breast Cancer, 2nd ed. Informa Healthcare, New York, 2012.

  18. T-DM1Retains Activity of Herceptinf In vitro studies in human breast cancer cells that overexpress HER2 have shown that, like HERCEPTIN, KADCYLA • Binds subdomain IV of the HER2 extracellular domain • Inhibits HER2 signaling • Mediates antibody-dependent cell-mediated cytotoxicity (ADCC) • Inhibits shedding of the HER2 extracellular domain KADCYLA Product Monograph. Hoffmann-La Roche Limited. September 11, 2013.

  19. T-DM1Intracellular Delivery of DM1 HER2 KADCYLA has the additional MOA of DM1. Upon binding to HER2, KADCYLA undergoes • Receptor-mediated internalization • Subsequent lysosomal degradation • Intracellular release of DM1-containing cytotoxic catabolites • DM1 binding to tubulin, disrupting microtubule networks in the cell, resulting in cell cycle arrest and apoptotic cell death KADCYLA DM1 release* Inhibition of tubulin polymerization Lysosomal degradation Internalization *The primary DM1-containing cytotoxic catabolite released is lysine-MCC-DM1. KADCYLA Product Monograph. Hoffmann-La Roche Limited. September 11, 2013. LoRousso PM, et al. Clin Cancer Res 2011.

  20. PDa PDa PHASE II STUDY T-DM1 vs. Docetaxel and Trastuzumab T-DM1 3.6 mg/kg q3w IV (n=67) HER2-positive, recurrent locally advanced breast cancer or MBC (N=137) 1:1 Trastuzumab 8 mg/kg loading dose; 6 mg/kg q3w IV + Docetaxel 75 or 100 mg/m2 q3w (n=70) Crossover to T-DM1 (optional) Hurvitz, et al., JCO, 2013

  21. Objective Response by Investigator Patients With Measurable Disease at Baseline aOne patient was not included in the efficacy analysis due to study site withdrawal. bDefined as complete or partial response based on RECIST 1.0 determined on 2 consecutive tumor assessments at least 4 weeks apart. cDefined as objective response any time during the study or maintained stable disease for at least 6 months from randomization. Hurvitz, et al., JCO, 2013 Hurvitz SA, et al. Abstract 5.001. ESMO 2011.

  22. Progression-Free Survival by InvestigatorRandomized Patients 1.0 0.8 0.6 0.4 0.2 0.0 Trastuzumab + docetaxel (n=70) T-DM1 (n=67) Proportion progression-free 0 2 4 6 8 10 12 14 16 18 20 Time (months) Number of patients at risk T+D 70 66 63 53 43 27 12 4 2 2 0 T-DM1 67 60 51 46 42 35 22 15 6 3 0 Hazard ratio and log-rank P value were from stratified analysis. Hurvitz, et al., JCO, 2013

  23. MARIANNE: A clinical trial of pertuzumab and T-DM1 in first-line metastatic breast cancer Pertuzumab + T-DM1 Placebo + T-DM1 HER2-positive, progressive or recurrent, locally advanced or untreated MBC (N = 1092) R Trastuzumab + taxane (docetaxel or paclitaxel) T-DM1 ± pertuzumab: blinded, placebo-controlled Trastuzumab + taxane: open-label 2010 2011–2012 2013 Last patient inQ2 2012 First patient in July 2010 Figure adapted from: http://clinicaltrials.gov/ct2/show/NCT01120184; Roche. Data on file

  24. SummaryFirst Line The standard of care should consist of pertuzumab and trastuzumab along with docetaxel (?other taxane alternative) T-DM1 looks very promising in the first line and may be suited for selected patients • Not candidates for chemotherapy • DFI < 6 months • Contraindication to taxanes

  25. Future QuestionsFirst Line Can we combine Pertuzumab and Herceptin with other partners • Other taxanes • Other chemotherapies (Vinorelbine/Capecitabine) • Other biologics – T-DM1/Bevacizumab Developing effective drugs that can target brain metastases Duration of targeted therapy for those responding

  26. Outline First Line Treatment Second Line Treatment and Beyond Individualized Approach An Algorithm and Concluding Remarks

  27. Second Line(2006-2010) • There is continued benefit of trastuzumab beyond progression • Capecitabine and Trastuzumab • There is benefit of Lapatinib in combination with Capecitabine upon progression on Trastuzumab

  28. Recent Achievements in Her 2 positive MBC Second Line and Beyond • EGF 104900 • L+ H vs L alone • EMILIA • T-DM1 vs Cape + L • Bolero-3 • Vinorelbine + H + Everolimus vs. Vinorelbine + H

  29. Trastuzumab and Lapatinib

  30. Trastuzumab and LapatinibOverall Survival

  31. EMILIA Study Design • HER2-positive LABC or MBC (N=980) • Prior taxane and trastuzumab • Progression on metastatic treatment or within 6 months of adjuvant treatment T-DM1 3.6 mg/kg q3w IV PD 1:1 Capecitabine 1000 mg/m2 PO bid, days 1–14, q3w + Lapatinib 1250 mg/day PO qd PD Verma et al NEJM 2012

  32. Verma et al NEJM 2012

  33. EMILIA: Overall Survival Verma et al NEJM 2012

  34. EMILIAAdverse Events Verma et al NEJM 2012

  35. TH3RESA Study Schema HER2-positive (central) advanced BCa (N=600) ≥2 prior HER2-directed therapies for advanced BC Prior treatment with trastuzumab, lapatinib, and a taxane T-DM1 3.6 mg/kg q3w IV (n=400) PD 2 Treatment of physician’s choice (TPC)b (n=200) 1 T-DM1c (optional crossover) PD a Advanced BC includes MBC and unresectable locally advanced/recurrent BC. b TPC could have been single-agent chemotherapy, hormonal therapy, or HER2-directed therapy, or a combination of a HER2-directed therapy with a chemotherapy, hormonal therapy, or other HER2-directed therapy. c First patient in: Sep 2011. Study amended Sep 2012 (following EMILIA 2nd interim OS results) to allow patients in the TPC arm to receive T-DM1 after documented PD. d Excluding single-agent hormonal therapy. BC, breast cancer; IV, intravenous; ORR, objective response rate; PD, progressive disease; q3w, every 3 weeks. Stratification factors: World region, number of prior regimens for advanced BC,dpresence of visceral disease Co-primary endpoints: PFS by investigator and OS Key secondary endpoints: ORR by investigator and safety Wildiers H, et al. ECC 2013; Abstract 15LBA. .

  36. PFS by Investigator Assessment 1.0 0.8 0.6 Proportion progression-free 0.4 0.2 0.0 0 2 4 6 8 10 12 14 Time (months) No. at risk: TPC 198 120 62 28 13 6 1 0 T-DM1 404 334 241 114 66 27 12 0 Median follow-up: TPC, 6.5 months; T-DM1, 7.2 months. Unstratified HR=0.521 (P<0.0001). Wildiers H, et al. ECC 2013; Abstract 15LBA. .

  37. First Interim OS Analysis 1.0 Observed 21% of targeted events 0.8 0.6 Proportion surviving 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 Time (months) No. at risk: TPC 198 169 125 80 51 30 9 3 0 T-DM1 404 381 316 207 127 65 30 7 0 44 patients in the TPC arm received crossover T-DM1 treatment after documented progression. Unstratified HR=0.57 (P=0.004). Wildiers H, et al. ECC 2013; Abstract 15LBA. .

  38. The PI3K pathway and Breast Cancer Constitutive activation of the PI3K pathway is frequent. PI3K pathway activation conveys malignant transformation, cell growth and invasion, tumor neoangiogensis and resistance towards anti-cancer treatments. Known mechanisms of PI3K pathway activation include activating mutations of RTKs, gain-of-function mutation of the PIK3CA gene, and loss-of-function mutations of PTEN. HER2/HER3 PI3K Ras Raf PIP3 PTEN PDK1 Akt TORC2 MEK Tuberin Tuberin Tuberin Tuberin Erk Rheb Rsk TORC1 S6K 4EBP1 S6

  39. O’Regan R, et al. ASCO 2013; Abstract 505. Not for distribution. O Regan ASCO 2013

  40. O’Regan R, et al. ASCO 2013; Abstract 505. Not for distribution. O Regan ASCO 2013

  41. SummarySecond Line and Beyond T-DM1 offers significant clinical benefit and superior toxicity profile and is very effective for second line Her 2 + treatment Patients progressing on T-DM1 still may derive a benefit from ongoing systemic tx with chemo with anti-Her 2 approaches The role of Lapatinib has evolved and now is generally considered in third or later lines of treatment. One may consider earlier use if: • Progressive brain metastases despite radiation • Lack of response to first/second line of herceptin • ? Biomarkers – p95 still needs to be validated

  42. Future Questions Is there a benefit of Pertuzumab or T-DM1 (along with other partners) beyond progression? What is the effect on tumor biology once patients progress on Pertuzumab/T-DM1? • What are potential targeted agents that may help overcome resistance? What will be the role of PI3K inhibitors in second line + treatment? Who are the ideal patients for dual targeted treatment alone?

  43. Outline First Line Treatment Second Line Treatment and Beyond Individualized Approach An Algorithm and Concluding Remarks

  44. Personalized Factors to Consider Hormone Receptor Status Prior Adjuvant Trastuzumab CNS Metastases Biomarkers

  45. Hormone Receptor Status CLEOPATRAOverall survival in predefined subgroups Favorspertuzumab Favorsplacebo n HR 95% CI All 808 0.66 0.52‒0.84 NoYes 432 0.66 0.47‒0.93376 0.66 0.46‒0.94 Prior (neo)adjuvant chemotherapy EuropeNorth AmericaSouth AmericaAsia 306 0.72 0.48‒1.07 135 0.68 0.36‒1.28 114 0.55 0.31‒0.98253 0.64 0.41‒1.00 Region <65 years≥65 years <75 years≥75 years 681 0.70 0.53‒0.91127 0.51 0.27‒0.95789 0.66 0.52‒0.8519 0.72 0.15‒3.50 Age group WhiteBlackAsianOther 480 0.70 0.51‒0.9530 0.52 0.14‒1.91261 0.66 0.43‒1.0337 0.29 0.06‒1.43 Race Visceral diseaseNon-visceral disease 630 0.57 0.44‒0.74178 1.42 0.71‒2.84 Disease type 388 0.73 0.50‒1.06408 0.57 0.41‒0.79 PositiveNegative ER/PgR status IHC 3+ 721 0.66 0.51‒0.85 HER2 status FISH-positive 767 0.67 0.52‒0.86 0 1 2 3 4 5 ER, estrogen receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; PgR, progesterone receptor Swain et al. SABCS 2012 Poster P5-18-26 .

  46. Hormone Receptor Status EMILIAOverall Survival Subgroup Analyses Hazard ratio 0.2 0.5 1 2 5 aDefined as any systemic therapy including endocrine and chemotherapy. NR, not reached. From confirmatory OS analysis; data cut-off July 31, 2012. Verma et al. ESMO 2012; Oral Abstract #LBA12

  47. Prior Trastuzumab CLEOPATRA: Independently assessed PFS by prior trastuzumab therapy in patients with (neo)adjuvant therapy CI, confidence interval; PFS, progression-free survival Adapted from Baselga J, et al. N Engl J Med 2012; 366:109–119.

  48. Prior Trastuzumab CLEOPATRA:Overall survival subgroup analyses An exploratory subgroup analysis was performed for patients who had received prior neoadjuvant and/or adjuvant trastuzumab therapy (88 patients). • The observed hazard ratio of 0.68 (95% CI 0.30−1.55) indicates overall survival benefit in the pertuzumab arm Swain et al. SABCS 2012 Poster P5-18-26 .

  49. Prior Trastuzumab EMILIA: Progression-Free Survival Subgroup Analyses Cap + Lap T-DM1 Baseline characteristic T-DM1 better Cap + Lap better Totaln Median,mos Median,mos HR(95% CI) All pts 991 6.4 9.6 0.66 (0.56, 0.78) Age <65 yrs 853 6.0 9.8 0.62 (0.52, 0.74) ≥65 yrs 138 8.1 7.0 1.06 (0.68, 1.66) ER and PR status ER+ and/or PR+ 545 7.1 9.0 0.72 (0.58, 0.91) ER− and PR− 426 5.6 10.3 0.56 (0.44, 0.72) Line of therapya First 118 5.7 10.8 0.51 (0.30, 0.85) Second 361 6.8 9.6 0.69 (0.53, 0.91) Third 512 6.5 9.0 0.69 (0.55, 0.86) 0.2 0.5 1 2 5 Hazard ratio Data cut-off Jan 14, 2012 HRs were from unstratified analysis. aDefined as any systemic therapy, including endocrine or chemotherapy. Verma et al. N Eng J Med 2012 (incl. supplementary appendix) Blackwell et al. ASCO 2012; Abst #LBA1

  50. Prior Trastuzumab EMILIA: Overall Survival Subgroup Analyses Hazard ratio 0.2 0.5 1 2 5 aDefined as any systemic therapy including endocrine and chemotherapy. NR, not reached. From confirmatory OS analysis; data cut-off July 31, 2012. Verma et al. ESMO 2012; Oral Abstract #LBA12