1 / 70

Howard A. Burris III, MD, FACP Chief Medical Officer and Director of Drug Development

Managing HER2- Positive Breast Cancer in the Metastatic Setting: The Evolution of Targeted Therapies. Howard A. Burris III, MD, FACP Chief Medical Officer and Director of Drug Development Sarah Cannon Research Institute Memphis, TN Lee Schwartzberg, MD Medical Director, West Clinic

jera
Download Presentation

Howard A. Burris III, MD, FACP Chief Medical Officer and Director of Drug Development

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Managing HER2- Positive Breast Cancer in the Metastatic Setting: The Evolution of Targeted Therapies Howard A. Burris III, MD, FACP Chief Medical Officer and Director of Drug Development Sarah Cannon Research Institute Memphis, TN Lee Schwartzberg, MD Medical Director, West Clinic Chief, Division of Hematology/Oncology Professor of Medicine University of Tennessee Health Science Center Memphis, TN

  2. Breast Cancer Mortality Breast cancer mortality has dropped by nearly one-third since 1990 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Lancet. 2011. 1

  3. HER2+ Breast Cancer Subtypes ER+/PR+/HER2+ ER+/PR-/HER2+ ER-/PR+/HER2+ ER-/PR-/HER2+ N=114,786 ~21% HER2+ ~79% HER2- 7.1% 10.8% Breakdown of the 21% HER2+ 3.3% 0.5% Bauer K., Cancer. 2010;10:228. 2

  4. Survival for HER2+ Subtypes • Clinical and pathologic features and survival of the four subtypes were compared • In ER/PR+,HER2-, chemotherapy conferred significant overall survival advantages • Subtype comparison revealed statistically significant differences in outcomes Onitilo A. Clin Med Res Opin. 2009;7(2):4-13. 3

  5. Signal Transduction by the HER Family Promotes Proliferation, Survival, and Invasiveness Receptor-specific ligands HER2 HER1, HER2, HER3, or HER4 HER3 HER4 HER2 VEGF HER1 (EGFR) PI3K P SOS Plasma membrane P Tyrosine kinase domains RAS P Akt RAF P MAPK MEK Cytoplasm Cell proliferation Cell survival Cell mobility and invasiveness Nucleus 4 Transcription Ross JS, et al. The Oncologist. 2009;14:320-368.

  6. ‘0’ (negative) ‘1+’ (negative) ‘2+’ (equivocal) ‘3+’ (positive) HER2 gene no amplification FISH negative HER2 gene amplificationFISH positive Current Assays of HER2/neu Immunohistochemistry Fluorescence in situ hybridization (FISH) Murthy SS, et al. Indian J Pathol Microbiol. 2011;54(3):532-538.

  7. Optimal Testing Algorithm Immunohistochemistry (IHC) Breast Cancer Specimen (invasive component) HER2 testing by validated IHC assay for HER2 protein expression Positive for HER2 protein expression IHC 3+ (defined as uniform intense membrane staining of >30% of invasive tumor cells) Negative for HER2 protein expression IHC 0 or 1+ Equivocal for HER2 protein expression IHC 2+ Test with validated assay for HER2 gene amplification Positive for HER2 gene amplification Negative for HER2 gene amplification Equivocal HER2 gene amplification (Patients with HER2/CEP17 ratio ≥2.0 were eligible for the adjuvant trastuzumab trials)

  8. Optimal Testing Algorithm FISH Breast Cancer Specimen HER2 gene amplification FISH positive HER2 gene no amplification FISH negative HER2 testing by validated FISH assay for HER2 gene amplification Positive for HER2 gene amplification (FISH ratio >2.2 or HER2 gene copy >6.0) Equivocal for HER2 gene amplification (FISH ratio 1.8-2.2 or HER2 gene copy 4.0-6.0) Negative for HER2 gene amplification (FISH ratio <1.8 or HER2 gene copy <4.0) Count additional cells for FISH or retest, or test with HER2 IHC Equivocal HER2 gene amplification result (Patients with HER2/CEP17 ratio ≥2.0 were eligible for the adjuvant trastuzumab trials)

  9. HER2+ Metastatic Disease Case Review Treatment of a 53-Year-Old Woman With HER2-Positive Metastatic Inflammatory Breast Cancer • A 53-year-old woman presents with T4 N2 M0 ER–/PR–/HER2+ (by fluorescence in situ hybridization) right inflammatory breast cancer • She is treated with preoperative doxorubicin/cyclophosphamide (AC) chemotherapy with minimal response in the breast and axilla and in the diffuse erythema in the skin of the left breast • Her disease is not operable with expectation of clear margins 8

  10. Polling Question 1 Which Neoadjuvant Treatment Would You Recommend? Please see the multiple answer options on the right and select an answer. Once you submit your answer, your answer selection will be compared with your peers’ responses. The best answer(s) will be discussed in the subsequent slides and commentary. 9

  11. Discussion Case Review – Progression I Howard A. Burris III, MD, FACP Lee Schwartzberg, MD

  12. Case Review – Progression I The patient is subsequently treated with 3 cycles of preoperative weekly paclitaxel/trastuzumab with no response, followed by worsening erythema extending onto her chest wall below her breast and ipsilateral and contralateral supraclavicular fossa. 11

  13. Polling Question 2 Which Treatment Would You Recommend for Case Progression I ? Please see the multiple answer options on the right and select an answer. Once you submit your answer, your answer selection will be compared with your peers’ responses. The best answer(s) will be discussed in the subsequent slides and commentary. 12

  14. Discussion Case Review – Progression II Howard A. Burris III, MD, FACP Lee Schwartzberg, MD

  15. Case Review – Progression II • The patient is treated with capecitabine/lapatinib for 6 cycles, with improvement in the erythema and a 30% reduction in tumor volume in breast and all nodal metastatic disease • She undergoes a left modified radical mastectomy and has diffuse residual disease in her breast and axilla with diffuse skin and tumor lymphovascular invasion • The margins of resection are clear • She receives radiation therapy and resumes capecitabine/lapatinib postoperatively; however, she develops signs of coronary spasm that require discontinuation of capecitabine 14

  16. Polling Question 3 Which Treatment Do You Recommend for Case Progression II? Please see the multiple answer options on the right and select an answer. Once you submit your answer, your answer selection will be compared with your peers’ responses. The best answer(s) will be discussed in the subsequent slides and commentary. 15

  17. Discussion Case Review – Progression III Howard A. Burris III, MD, FACP Lee Schwartzberg, MD

  18. Case Review – Progression III • The patient continues lapatinib/trastuzumab for 9 months and then develops progressive disease over the right chest wall as well as bilateral supraclavicular adenopathy • Restaging reveals new pulmonary metastases • Her physician is interested in enrolling her in a trial evaluating investigational HER2-targeted agents and refers her to the ongoing phase IB trial of trastuzumab emtansine (T-DM1)/paclitaxel/pertuzumab 17

  19. Polling Question 4 Which of the Following Statements Regarding Novel HER2-Targeted Agents Is Correct? Please see the multiple answer options on the right and select an answer. Once you submit your answer, your answer selection will be compared with your peers’ responses. The best answer(s) will be discussed in the subsequent slides and commentary. 18

  20. Discussion Howard A. Burris III, MD, FACP Lee Schwartzberg, MD

  21. P P P P P P P P Targeted Agents for HER2+ Breast Cancer Trastuzumab Bevacizumab VEGF T-DM1 Pertuzumab EGFR HER2 VEGFR PI3-K Akt/PKB Lapatinib PTEN mTOR Neratinib 4E-BP1 elF-4E S6K1 Protein synthesis Cell growth, proliferation, survival, metastasis, angiogenesis

  22. Proposed Mechanisms of Action of Trastuzumab Spector N., J Clin Oncol.2009;27:5838.

  23. HER2 Targeting With Trastuzumab Has Changed the Natural History of HER2-Positive Advanced Breast Cancer 1991-2007 Dawood S., et al. J Clin Oncol.2009;28:92.

  24. Polling Question 5 With which of the following statements regarding HER2+ MBC do you agree? Please see the multiple answer options on the right and select an answer. Once you submit your answer, your answer selection will be compared with your peers’ responses. The best answer(s) will be discussed in the subsequent slides and commentary. 23

  25. Trastuzumab in First-Line Treatment AC, anthracycline + cyclophosphamide; Anas, anastrozole; T, paclitaxel; D, docetaxel; EC, epirubicin + cyclophosphamide; H, trastuzumab; mo, months; PFS, progression-free survival; OS, overall survival; RR, response rate; TTP, time to progression; VH, vinorelbine + trastuzumab; *statistically significant 1. Slamon DJ, et al. N Engl J Med. 2001:344(11):783-792; 2. Vogel CL, et al. J Clin Oncol. 2002;20:719-726; 3. Burstein HJ, et al. J Clin Oncol. 2003;21(15):2889-2895; 4. Marty M, et al. J Clin Oncol. 2005;23(19):4265-4274; 5. Kaufman B, et al. J Clin Oncol. 2009;27(33):5529-5537; 6. Valero V, et al. J Clin Oncol. 2011;29:149-156.

  26. NCCN Guidelines Preferred agents for trastuzumab-exposed HER2 + disease • Lapatinib + capecitabine • Trastuzumab + other first-line agents • Trastuzumab + capecitabine • Lapatinib + trastuzumab National Comprehensive Cancer Network (NCCN) Breast Cancer Guidelines, 2012 available at www.nccn.org.

  27. Phospholipid cell membrane Lapatinib PTEN Ras Shc P13K Grb2 Raf So8 pAkt pErk Lapatinib: Targeting HER2 and EGFR • Lapatinib oral tyrosine kinase inhibitor of ErbB1 and ErbB2 • Blocks signaling through EGFR and HER2 homodimers and heterodimers • May also prevent signaling between ErbB1/ErbB2 and other ErbB family members Rusnak DW, et al. Mol Cancer Ther. 2001;1:85-94; Xia W, et al. Oncogene. 2002;21:6255-6263.

  28. Randomized Phase III Study EGF10015 • Progressive, HER2+ MBC or LABC • Previously treated with anthracycline, taxane, and trastuzumab* • No prior capecitabine R A N D O M I Z E Lapatinib 1250 mg poqd continuously + Capecitabine 2000 mg/m2/d po days 1-14 q 3 wk • Stratification: • Disease sites • Stage of disease Capecitabine 2500 mg/m2/d po days 1-14 q 3 wk Patients on treatment until progression or unacceptable toxicity, then followed for survival N=528 * Trastuzumab must have been administered for metastatic disease Geyer C, et al. N Engl J Med. 2006;355:2733-2743.

  29. Lapatinib + Capecitabine Capecitabine Progression-Free Survival Lapatinib + Capecitabine Capecitabine 100 Cumulative Progression-Free Survival(%) No. of pts 160 161 90 Progressed or died 45 (28%) 73 (45%) Median PFS, wk 36.9 17.9 80 Hazard ratio (95% CI) 0.48 (0.33, 0.70) 70 P-value (log-rank, 1-sided) 0.000045 60 50 40 30 20 10 0 10 20 30 0 50 70 40 60 Time (weeks) Geyer C, et al. N Engl J Med. 2006;355:2733-2743.

  30. Lapatinib + Capecitabine Capecitabine Overall Survival: Capecitabine ± Lapatinib 100 Cumulative Survival (%) 90 80 70 60 50 Lapatinib + Capecitabine Capecitabine 40 No. of pts 160 161 30 Deaths 29 (18%) 29 (18%) Median OS NR NR 20 Hazard ratio (95% CI) 0.93 (0.55, 1.59) 10 P-value (log-rank, 2-sided) 0.800 0 0 10 20 30 40 50 60 70 80 90 Time (weeks) Geyer C, et al. N Engl J Med. 2006;355:2733-2743.

  31. OS With Lapatinib ± Trastuzumab in MBC 100 80% 80 56% 70% 60 Alive without Progression (Cumulative %) 6 Month OS 40 41% L L + T 12 Month OS 20 0 0 5 10 15 20 25 30 35 Months From Randomization Patients at Risk, n L L + T 148 148 121 102 88 65 64 47 43 28 25 13 1 Blackwell KL, et al. San Antonio Breast Cancer Symposium (SABCS) 2009. Abstract 61.

  32. Neo-ALTTO: Study Design Invasive operable HER2+ BC T>2 cm (inflammatory BC excluded) LVEF50% N=450 lapatinib lapatinib paclitaxel R A N D O M I Z E S U R GE R Y FEC X 3 trastuzumab trastuzumab paclitaxel • Stratification: • T≤5 cm vs. T>5 cm • ER or PgR + vs. ER & PgR – • N 0-1 vs N≥2 • Conservative surgery or not lapatinib lapatinib trastuzumab trastuzumab paclitaxel + 12 wks 6 wks 34 weeks 52 weeks of anti-HER2 therapy Baselga J, et al. SABCS 2010.

  33. 70 P=0.0001 P=0.001 60 50 51.3% 46.9% P=0.34 P=0.13 40 (%) Response 30 29.5% 27.6% 24.7% 20 20.0% 10 0 L T L+T L T L+T N=154 N=149 N=152 N=150* N=145* N=145* pCR Pathologic Complete Response tpCR Locoregional (total) pCR Neo-ALLTO: Pathologic Response L, lapatinib; T, trastuzumab; L+T, lapatinib plus trastuzumab; pCR, pathologic complete response. * Excludes 15 patients with non-evaluable nodal status Baselga J, et al. SABCS 2010.

  34. Investigational Anti-HER2 Agents

  35. Polling Question 6 Which of the following have demonstrated benefit in patients with HER2+ MBC who experienced disease progression on trastuzumab? Please see the multiple answer options on the right and select an answer. Once you submit your answer, your answer selection will be compared with your peers’ responses. The best answer(s) will be discussed in the subsequent slides and commentary. 34

  36. Polling Question 7 Which of the following is true of trastuzumab-DM1? Please see the multiple answer options on the right and select an answer. Once you submit your answer, your answer selection will be compared with your peers’ responses. The best answer(s) will be discussed in the subsequent slides and commentary. 35

  37. Trastuzumab-DM1

  38. T-DM1 Selectively Delivers a Highly Toxic Payload to HER2-Positive Tumor Cells • Trastuzumab-like activity by binding to HER2 • Targeted intracellular delivery of a potent antimicrotubule agent, DM1 T-DM1 binds to the HER2 protein on cancer cells Receptor-T-DM1 complex is internalized into HER2-positive cancer cell Potent antimicrotubule agent is released once inside the HER2-positive tumor cell

  39. Trastuzumab-TDM1 • Trastuzumab-DM1 (T-DM1) is a novel anti-HER2 antibody drug conjugate in development for treatment of HER2-positive metastatic breast cancer (MBC).T-DM1 combines the HER2-targeting properties of trastuzumab2 with targeted delivery of a highly potent anti-microtubule derivative, DM1 • T-DM1 binds to HER2 with an affinity similar to that of trastuzumab. • It is hypothesized that after binding to HER2, T-DM1 undergoes receptor-mediated internalization, 7 resulting in intracellular release of DM1.

  40. TDM1 Versus Trastuzumab + Docetaxel 1st line HER2-positive, recurrent locally advanced BC or MBC (n=137) T-DM1 3.6 mg/kg Q3W until PD 1:1 Trastuzumab 8 mg/kg dose; 6 mg/kg Q3W + Docetaxel 75 or 100 mg/m2 Q3W Crossover T-DM1 PD • Randomized, phase II, international, open-label study • HER2-positive, measurable disease required • Stratification factors • World region, prior adjuvant trastuzumab therapy, disease-free interval • Primary endpoints: PFS by INV, safety • Key secondary endpoints: ORR, clinical benefit, OS, QOL, symptom control Perez EA, et al. ESMO 2010. Abstract LBA3.

  41. T-DM1 Versus Trastuzumab (T) + Docetaxel (D) in HER2-Positive MBC With No Prior Chemotherapy for MBC † Most common AEs, any grade, T + D: alopecia: 66.2%, neutropenia: 57.4%, diarrhea: 45.6% — these were 1.5%, 7.5%, and 10.4% in pts receiving T-DM1. Most common AEs, any grade, T-DM1: nausea: 47.8%, fatigue: 46.3%, pyrexia: 35.8% — these were 39.7%, 46.2%, and 20.6% in pts receiving T + D. Perez EA, et al. Proc ESMO 2010. Abstract LBA3.

  42. T-DM1 Activity: Improved PFS 15 P=0.035 10 Median Progression-Free Survival (months) 14.2 9.2 5 0 T-DM1 trastuzumab + docetaxel HER2+ locally advanced or metastatic Treatment with T-DM1 reduced the probability of disease progression or death by 41% compared with Trastuzumab + Docetaxel HR=0.59, P=0.035 Hurvitz S, et al. ECCO-ESMO 2011. Abstract 5001. 41

  43. EMILIA (TDM4370g) Phase III Study: T-DM1 Versus Lapatinib/Capecitabine in HER2+ MBC PD or unacceptable toxicity Patients with HER2+ locally advanced or metastatic breast cancer following treatment with a taxane and trastuzumab (N=980) T-DM1 q3w(n=490) Lapatinib + Capecitabine q3w(n=490) • Primary endpoint: PFS by IRF, OS, safety • Secondary endpoints: QoL (FACT B), DOR, PFS by investigator assessment ClinicalTrials.gov. NCT00829166.

  44. Phase III MARIANNE Study: T-DM1 ± Pertuzumab in HER2+ MBC PD Trastuzumab + Taxane (n=364) Patients with HER2+, previously untreated MBC (N=1092) T-DM1 + Pertuzumab (n=364) • Primary endpoints: PFS as assessed by IRF, AEs • Superiority design with a noninferiority analysis • Interim futility analysis: option to drop experimental arm • Secondary endpoints: OS, TTF by IRF, ORR, CBR, DOR T-DM1 + Placebo (n=364) ClinicalTrials.gov. NCT01120184.

  45. HER2-Targeted Therapy With Pertuzumab • Monoclonal antibody and pan-HER inhibitor • Binds to a distinct epitope on the HER2 extracellular domain • Prevents dimerization Pertuzumab Trastuzumab Fisher, et al. J. Mol. Biol. 2010;402:217-229.

  46. Pertuzumab Recognizes Different Epitopes HER2 Ligand-binding domain (inactive) Pertuzumab Trastuzumab Cell membrane Tyrosine kinase domain

  47. Preferentially inhibits ligand-independent HER2 signaling Prevents shedding of HER2 ECD Flags cells for destruction by the immune system Inhibits formation of HER2 dimer pairs Suppresses multiple HER signaling pathways, leading to a more comprehensive blockade of HER2-driven signaling Flags cells for destruction by the immune system Pertuzumab Demonstrates Synergistic Activity With Trastuzumab HER2 receptor Pertuzumab Trastuzumab Dimerization domain of HER2 Subdomain IV of HER2 Junttila, et al. Cancer Cell. 2009.

  48. HER2:HER3 Dimers May Provide an Escape Mechanism From Trastuzumab Homodimers Heterodimers HER1:HER2 HER4:HER4 HER1:HER3 HER1:HER4 HER3:HER3 HER2:HER3 HER2:HER2 HER2:HER4 HER1:HER1 HER3:HER4 + + + + + + + + + + + + + + + Signaling activity Tzahar E., et al. Mol Cell Biol. 1996. Sergina NV, et al. Nature. 445:437-441.

  49. CLEOPATRA: Phase III Trial Evaluating Adding Pertuzumab N=808 HER2-positive Metastatic Breast Cancer Primary Outcome: Progression-Free Survival First-Line MBC Could have received prior adjuvant trastuzumab Treatment A: 400 patients Docetaxel* + Trastuzumab + Pertuzumab R Treatment B: 400 patients Docetaxel* + Trastuzumab + Placebo  First-Line HER2-positive MBC 1:1 randomization stratification by (1. pretreated or de novo, 2. region) * At least 6 cycles of docetaxel Baselga J, et al. N Engl J Med. 2012;366:109-119.

  50. CLEOPATRA: Response Data 100 4.2 5.5 90 80 70 ORR: 69.3% CR ORR: 80.2% 65.2 60 74.6 PR 50 Patients (%) SD 40 PD 30 Not evaluable 20 20.8 14.6 10 1.5 1.5 8.3 3.8 0 Trastuzumab + Docetaxel + Pertuzumab (n=343) Trastuzumab + Docetaxel + Placebo (n=336) Baselga J, et al. N Engl J Med. 2012;366:109-119.

More Related