Welcome! Please take a moment to complete the short - PowerPoint PPT Presentation

jaafar
slide1 n.
Skip this Video
Loading SlideShow in 5 Seconds..
Welcome! Please take a moment to complete the short PowerPoint Presentation
Download Presentation
Welcome! Please take a moment to complete the short

play fullscreen
1 / 65
Download Presentation
Welcome! Please take a moment to complete the short
61 Views
Download Presentation

Welcome! Please take a moment to complete the short

- - - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

  1. Welcome! • Please take a moment to complete the short • pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities.

  2. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: • Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

  3. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: • DebuTripathy, MD: Consultant:Clovis Oncology; Clinical Investigator:Piramal Pharmaceuticals • Kathy Miller, MD: Speaker/Consultant:Genentech/Roche; Consultant: AstraZeneca, Bristol-Myers Squibb

  4. Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz: Nothing to Disclose Michelle Melisko, MD: Speaker:Agendia,Genentech/Roche, Novartis, Bristol-Myers Squibb. Clinical Investigator: Amgen, AstraZeneca, Celldex.

  5. Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: • Review the recently updated clinical practice guidelines for HER2-positive breast cancer • Discuss recent data with HER2-targeted agents in the neoadjuvant and adjuvant settings and choose the optimal treatment for patients with early-stage HER2-positive breast cancer and patients with abnormal cytogenetics • Assess the various treatment strategies for patients with locally advanced or metastatic HER2-positive breast cancer • Identify eligibility criteria and the status of currently accruing clinical trials in HER2-positive breast cancer and counsel patients accordingly

  6. Paper Audience Response Questions • During the course of the program Audience Response Questions will be asked to determine the current knowledge of the audience • These questions will not be graded and are for outcomes purposes only • Please record your answers on your evaluation form located in your packet

  7. HER2 Oncogene: A Biological Target • Increased Aggressiveness • Shortened Survival • Hormonal Resistance HER2 gene amplification HER2 protein overexpression

  8. HRG AR HRG EGF TGF HER Family Ligands and Signaling HER3 HER2 HER1/EGFR HER4 X TK TK TK PI3K/AKT Ras/MEK/MAPK (STAT) Proliferation Migration Differentiation Apoptosis P P CoA CoR TF

  9. EARLY STAGE/ADJUVANT THERAPY

  10. Adjuvant Trastuzumab Trial Designs

  11. In favor of T In favor of Obs. 0 1 2 Summary of Trastuzumab AdjuvantTrial DFS Benefits Dahabreh IJ, et al. The Oncologist2008 ;13(6): 620-630

  12. NSABP/NCCTG Update – Disease-Free Survival Median F/U 3.9 years HR=0.52, P<.001 Years From Randomization Perez EA, et al. J Clin Oncol. 2011;29(25):3366-3373.

  13. NSABP/NCCTG Update – Overall Survival Median F/U 3.9 years HR=0.61, P<.001 Years From Randomization Perez EA, et al. J Clin Oncol. 2011;29(25):3366-3373.

  14. BCIRG 006 Study – Final Analysis Slamon D, et al. Presented at: 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, TX; Slamon D, et al. N Engl J Med. 2011;365(14):1273-1283.

  15. Concurrent vs Sequential Therapy: N9831 Trial Perez EA, et al. J Clin Oncol. 2011;29(25):3366-3373.

  16. HERA Trial Update – Median F/U 4 YearsDisease-Free Survival, Censored for Crossover Unadjusted HR censored for crossover = 0.69 P<.0001 Gianni L, et al. Lancet Oncol.2011;12(3):236-244.

  17. Clinical Cardiomyopathy From Trastuzumab Adjuvant Trials BaselineLVEF, % >55 >50 >50 >50 CHF, % Cardiacdeath, n 10 10 110 000 00 Trial HERA B31 N9831 BCIRG 006 FinHer Arm Control H 1 year ACPACPH ACPACPHACPH ACDACDHTCH No HH 02.1 0.83.8 0.32.8 3.3 0.62.00.4 10 Any Chemo H = Trastuzumab; A = Doxorubicin; C = Cyclophosphamide; P = Paclitaxel; D = Docetaxel. Smith I, et al. Lancet. 2007;369(9555):29-36; Perez EA, et al. J Clin Oncol. 2008;26(8):1231-1238;Slamon D, et al. N Engl J Med. 2011;365(14):1273-1283.; Rastogi S, et al. Cardiovasc Drugs Ther. 2007;21(6):415-422;Rastogi S, et al. J ClinOncol. 2007; 25 (964S; LBA513)

  18. Case A 59-year-old postmenopausal woman undergoes a left lumpectomy and sentinel node biopsy for a 2.2-cm grade II infiltrating ductal cancer that is ER/PR+ and HER2+ (FISH ratio 3.7). Neither of 2 sentinel nodes examined contain tumor. Chest x-ray and serum chemistries including liver function test are normal. A cardiac ejection fraction by MUGA scan is normal at 56%.

  19. ARS Question 1 What would you recommend for this patient? An aromatase inhibitor (AI) for 5 years plus trastuzumab for 1 year Docetaxel and cyclophosphamide for 4 cycles followed by an AI for 5 years Docetaxel, carboplatin, and trastuzumab for 6 cycles with trastuzumab for 1 year and an AI for 5 years Doxorubicin plus cyclophosphamide followed by paclitaxel with trastuzumab, with trastuzumab for 1 year and an AI for 5 years

  20. ARS Question 1 Response What would you recommend for this patient? An aromatase inhibitor (AI) for 5 years plus trastuzumab for 1 year Docetaxel and cyclophosphamide for 4 cycles followed by an AI for 5 years Docetaxel, carboplatin, and trastuzumab for 6 cycles with trastuzumab for 1 year and an AI for 5 years–Reasonable choice Doxorubicin plus cyclophosphamide followed by paclitaxel with trastuzumab, with trastuzumab for 1 year and an AI for 5 years

  21. HERA and BCIRG 006 trials enrolled patients with node-negative HER2+ breast cancer • In the HERA study, patients had to have tumor >1cm if node-negative (one third of all patients) • In the BCIRG 006 study, high-risk node negative cases were enrolled, defined as tumor >2 cm, or ER- and PR-negative or histologic grade 2 or 3 (29% of patients enrolled) • Subset analysis of these trials have shown a statistically significant reduction in risk of recurrence in node-negative patients, but as expected, the absolute magnitude of risk reduction is lower compared to that of node-positive patients. • In this case, the patient would have been eligible for either of these trials and therefore would be expected to derive a benefit from chemotherapy plus trastuzumab. Given the smaller benefit, the regimen with lower cardiac toxicity (TCH) would be preferable.

  22. Exploratory DFS Subgroup Analysis (ITT):1-year Trastuzumab vs Observation – HERA Trial Subgroup (No. patients) No. eventsT vs obs HR (95% CI) Region of the world Europe, Canada, SA, Australia, NZ (2438) 161 vs 235 0.66 (0.54, 0.81) Asia Pacific, Japan (405) 21 vs 37 0.53 (0.31, 0.90) Eastern Europe (369) 23 vs 36 0.54 (0.32, 0.91) Central + South America (189) 13 vs 13 0.98 (0.45, 2.11) Age at randomisation <35 years (253) 19 vs 31 0.57 (0.32, 1.01) 35-49 years (1508) 89 vs 150 0.54 (0.42, 0.70) 50-59 years (1096) 71 vs 97 0.71 (0.52, 0.97) >60 years (544) 39 vs 43 0.91 (0.59, 1.41) Menopausal status at randomisation Premenopausal (491) 43 vs 49 0.80 (0.53, 1.21) Uncertain (1373) 70 vs 135 0.48 (0.36, 0.64) Postmenopausal (1535) 105 vs 137 0.75 (0.58, 0.97) Nodal status Neoadjuvant CT (372) 39 vs 50 0.66 (0.43, 1.00) Negative (1099) 34 vs 58 0.59 (0.39, 0.91) 1-3 positive nodes (976) 50 vs 80 0.61 (0.43, 0.87) >4 positive nodes (953) 95 vs 132 0.64 (0.49, 0.83) All patients (3401) 218 vs 321 0.64 (0.54, 0.76) 1.0 0.0 0.5 1.5 Overall Result HR Smith I, et al. Lancet. 2007;369(9555):29-36.

  23. BCIRG 006 Trial, Node-Negative Subset Disease-Free Survival Slamon D, et al. Presented at: 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, TX (Abstr 62); Slamon D, et al. N Engl J Med. 2011;365(14):1273-1283.

  24. BCIRG 006 Trial, Node-Negative Subset Overall Survival Slamon D, et al. Presented at: 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, TX (Abstr 62); Slamon D, et al. N Engl J Med. 2011;365(14):1273-1283.

  25. ARS Question 2 The patient is treated with AC → paclitaxel with trastuzumab and completes the chemotherapy portion of therapy without any problems. Trastuzumab is planned for a total trastuzumab duration of 1 year. What would you recommend at this point? Initiation of radiation therapy to the left breast and continuation of trastuzumab, with hormonal therapy after radiation Initiation of radiation therapy to the left breast and continuation of trastuzumab, with hormonal therapy after trastuzumab Initiation of radiation therapy to the left breast and resumption of trastuzumab and hormonal therapy after radiation Initiation of radiation therapy to the left breast and resumption of trastuzumab after radiation, with hormonal therapy after trastuzumab

  26. ARS Question 2 Response What would you recommend at this point? Initiation of radiation therapy to the left breast and continuation of trastuzumab, with hormonal therapy after radiation–Reasonable choice Initiation of radiation therapy to the left breast and continuation of trastuzumab, with hormonal therapy after trastuzumab Initiation of radiation therapy to the left breast and resumption of trastuzumab and hormonal therapy after radiation Initiation of radiation therapy to the left breast and resumption of trastuzumab after radiation, with hormonal therapy after trastuzumab

  27. The NCCTG N9831 and NSABP B-31 trials were designed to allow radiation following chemotherapy as indicated by standard of care to overlap with the administration of trastuzumab • Hormonal therapy was to be given as standard of care following chemotherapy and to overlap with the administration of trastuzumab • This patient would receive radiation as standard of care following a lumpectomy and hormonal therapy based on ER and PR positivity. Analysis of adverse events based on radiation therapy in the N9831 did not show a difference in cardiac adverse events or other adverse events.

  28. Cardiac Adverse Events With or Without RT: N9831 HR RT vs No RT/Unknown = 0.7; P=.21 Halyard MY, et al. J Clin Oncol. 2009;27(16):2638-2644.

  29. ARS Question 3 • Three months after completion of chemotherapy as trastuzumab therapy is ongoing, a follow-up cardiac ejection fraction (EF) is found to be 45%. The patient has no cardiac symptoms and has a normal cardiac examination along with an excellent performance status. • What would you recommend? • Permanent discontinuation of trastuzumab • Continuation of trastuzumab with a recheck of EF in 1 month • Continuation of trastuzumab with the addition of a beta blocker and angiotensin converting enzyme inhibitor with a recheck of EF in 1 month • Discontinuation of trastuzumab with a recheck of EF in 1 month and restarting trastuzumab if EF recovers to more than 50%

  30. ARS Question 3 Response • What would you recommend? • Permanent discontinuation of trastuzumab • Continuation of trastuzumab with a recheck of EF in 1 month • Continuation of trastuzumab with the addition of a beta blocker and angiotensin converting enzyme inhibitor with a recheck of EF in 1 month • Discontinuation of trastuzumab with a recheck of EF in 1 month and restarting trastuzumab if EF recovers to more than 50%–Reasonable choice

  31. Cardiac dysfunction is seen at a rate of 3-10% and is usually subclinical, with clinical signs of congestive heart failure seen at a rate of 0.5-3.8%. Cardiac function usually recovers over time and the long-term consequences are still unknown. The guidelines for evaluating cardiac status is empiric and based on the design of most adjuvant trials. These trials required normal EF prior to initiation of trastuzumab (usually defined as EF >50%), and monitoring every 3 months. For clinical congestive heart symptoms, immediate EF evaluation is recommended to verify cardiac cause, with permanent discontinuation of trastuzumab. For asymptomatic decreases in cardiac function, guidelines are recommended (see next slide) that the trials used for holding trastuzumab and rechecking, with restarting once criteria for continuation are met.

  32. Asymptomatic PatientsRules for Trastuzumab Continuation Based on Serial LVEF Used in Trials Within Normal Limits 1-5% below LLN 6% below LLN Absolute Decrease of <10% Absolute Decrease of 10-15% Absolute Decrease of 16% Relationship of LVEF to LLN Cont. Cont. Cont.* Cont. Hold * Hold * Hold * Hold * Hold * * Repeat LVEF assessment after 4 weeks - If criteria for continuation met – resume trastuzumab - If 2 consecutive holds, or total of 3 holds occur – discontinue trastuzumab Romond EH, et al. N Engl J Med. 2005; 353: 1673-84; Russell S, et al. J Clin Oncol. 2010;28(21):3416-3421; Procter M, et al. J Clin Oncol. 2010;28(21):3422-3428.

  33. METASTATIC BREAST CANCER

  34. Trastuzumab Increases Time to Progression in HER2(+) MBC 1.0 Trast + CT (n=235) Median TTP = 7.4 mon 0.8 CT alone (n=234) Median TTP = 4.6 mon 0.6 Probability 0.4 0.2 P<.001 0.0 0 5 10 15 20 25 Months Slamon DJ, et al. N Engl J Med. 2001;344(11):783-792.

  35. Trastuzumab Added to ChemoRxImproves Survival in MBC RR=0.76 P=.025 Slamon DJ, et al. N Engl J Med. 2001;344(11):783-792.

  36. Lapatinib + capecitabine Capecitabine No. of pts 160 161 Progressed or died* 45 (28%) 69 (43%) 90 Median TTP, wk 19.7 36.9 80 Hazard ratio (95% CI) 0.51 (0.35, 0.74) 70 P value (log-rank, 1-sided) .00016 60 50 40 30 20 10 0 Lapatinib Increases Time to ProgressionAfter Trastuzumab 100 % of patients free from progression* 0 10 20 50 30 60 40 70 Time (weeks) * Censors 4 patients who died due to causes other than breast cancer. Geyer CE, et al. N Engl J Med. 2006;355(26):2733-2743.

  37. Trastuzumab Remains Effective After Disease Progression 2-sided p: OR: 0.011 CB: 0.0068 75.3% (64.2-84.4) 54 (42.1-65.7) NC>24wks 48.0 (36.5-59.7) CR: 2.7% PR: 24.3% CR: 7.7% PR: 40.3% 27.0 (17.3-38.6) CR+PR von Minckwitz G, et al. J Clin Oncol. 2009;27(12):1999-2006.

  38. Combined HER2 Blockade Improves PFS After Progression on Trastuzumab 100 80 60 Cumulative % Alive without Progression 40 28% 20 L L+T 13% 0 0 10 20 30 40 50 60 Time from Randomization (wks) Blackwell KL, et al. J ClinOncol. 2010; 28 (7): 1124-30.

  39. Updated Overall Survival in ITT Blackwell KL, et al.J ClinOncol. 2012 Jun 11 [Epub ahead of print].

  40. Novel Agents: HER2 HER1/2 TKIHKI-272, BIBW 2992, PKI-166, EKB-569 Pan HER TKI Canertinib, BMS-599626 HER1/2/VEGFR TKI XL647, AEE788 HER2 dimerization inhibitor Pertuzumab Bispecific antibody Ertumaxomab, MM111 Conjugated antibodies Trastuzumab-MCC-DM1, trastuzumab-A-Z-CINN 310-paclitaxel Targeted nanoparticles MM302 HSP90 inhibitors Tanespimycin, alvespimycin, CNF2024, IPI-504, AUY922, SNX5422 IGF-1R inhibitors (mAb, TKI) CP-751871, EM164, IMC-A12, NVP-ADW742, INSM-18 HDAC inhibitors Vorinostat, LBH589, PXD101, NVP-LAQ824, depsipeptide, CI-994, MS-275 PI3K inhibitors SF1126, BEZ235, XL147, XL765, GDC-0941 Akt inhibitors Perifosine, XL418 mTOR inhibitors Rapamycin (sirolimus), temsirolimus, everolimus, deforolimus HER2 vaccines

  41. Investigating T-DM1 (EMILIA): Study Design • Primary endpoints: PFS (independently assessed), OS, safety • Secondary endpoints: PFS (investigator assessment), ORR, OS, duration of response, time to symptom progression Stratified by World region, number of prior chemo regimens for MBC, or unresectable LABC, presence of visceral disease Trastuzumab-DM1 3.6 mg/kg q3wIV (n=495) Treatment until disease progression or unacceptable toxicity Women with HER2+ unresectable LABC or MBC (N=991) Capecitabine 1,000 mg/m2 orally bid, days 1-14, q3w + Lapatinib 1,250 mg/day orally qd (n=496) T-DM1= Trastuzumab-DM1 Blackwell KL, et al. Presented at: 2012 Annual ASCO meeting; Abstract LBA1, Abstract S5-5.

  42. T-DM1 Demonstrated Improved Efficacy over Capecitabine + Lapatinib Blackwell KL, et al. Presented at: 2012 Annual ASCO meeting; Abstract LBA1, Abstract S5-5.

  43. Case 38-year-old patient presented with inflammatory ER-negative/PgR-negative/HER2-positive breast cancer. She was treated with neoadjuvant AC >TH followed by mastectomy (achieved a pCR) and radiation therapy. She completed 1 year of trastuzumab. Now, 2 years later, she has disease progression with lung metastases. Biopsy of the largest lesion (2.5 cm) confirms recurrent disease that remains ER-/PgR-/HER2+ by FISH with ratio 8.9. She has a cough but is not SOB. ECOG PS = 1. Her main goal in therapy is to maximize response and PFS.

  44. ARS Question 4 Which treatment would you recommend? • Rechallenge with trastuzumab + capecitabine • Lapatinib + capecitabine • Lapatinib + paclitaxel • Trastuzumab + lapatinib • Trastuzumab + pertuzumab + docetaxel

  45. ARS Question 4 Response Which treatment would you recommend? • Rechallenge with trastuzumab + capecitabine–Reasonable choice • Lapatinib + capecitabine–Reasonable choice • Lapatinib + paclitaxel–Incorrect answer • Trastuzumab + lapatinib–Reasonable choice • Trastuzumab + pertuzumab + docetaxel–Reasonable choice. On June 8, 2012, the FDA approved pertuzumabfor use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease

  46. Pertuzumab and Trastuzumab: Complementary Mechanisms of Action Trastuzumab: • Inhibits ligand-independent HER2 signaling • Activates ADCC • Prevents HER2 ECD shedding Pertuzumab: • Inhibits ligand-dependent HER2 dimerization and signaling • Activates ADCC HER2 HER 1/3/4 Trastuzumab Pertuzumab Dimerization domain Subdomain IV Baselga J, et al. Presented at: 34th Annual San Antonio Breast Cancer Symposium; December 6-11, 2011; San Antonio, TX. Abstract S5-5; Baselga J, et al. J ClinOncol. 2010;28(7):1138-1144.

  47. Pertuzumab Activity: Baselga J, et al. J Clin Oncol. 2010;28(7):1138-1144.

  48. CLEOPATRA: Study Design • Primary endpoint: PFS (independently assessed) • Secondary endpoints: PFS (investigator assessment), ORR, OS, Safety Stratified by geographic region and previous (neo)adjuvant chemotherapy Trastuzumab 6 mg/kg q3w* + Docetaxel 75-100 mg/m2 q3w† + Pertuzumab 420 mg q3w‡ (n = 402) Women with previously untreated, HER2-positive locally recurrent/metastatic breast cancer (N = 808) Treatment until disease progression or unacceptable toxicity Trastuzumab 6 mg/kg q3w* + Docetaxel 75-100 mg/m2 q3w† + Placebo q3w (n = 406) * Trastuzumab 8 mg/kg loading dose given. † Minimum of 6 docetaxel cycles recommended; <6 cycles permitted for unacceptable toxicity or PD. ‡ Pertuzumab 840 mg loading dose given. Baselga J, et al. N Engl J Med. 2012; 366 (2): 109-19.

  49. CLEOPATRA: Independently Assessed PFS 100 Ptz + T + D: median 18.5 months Pbo + T + D: median 12.4 months 90 80 70 60 50 Progression-free survival (%) 40 HR = 0.62 95% CI 0.51-0.75 P<.0001 30 20 10 0 0 5 10 15 20 25 30 35 40 Time (months) No. at risk Ptz + T+ D Pbo + T + D 402 406 345 311 287 209 139 93 88 42 32 17 10 7 0 0 0 0 Stratified by prior treatment status and region. Baselga J, et al. N Engl J Med. 2012; 366 (2): 109-19.