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HER2 pos. Disease Supportive care

HER2 pos. Disease Supportive care. Hans Wildiers University Hospitals Leuven. HER2 pos. Disease Adjuvant T rastuzumab : HERA (2y vs 1y) Phare (6 mo vs 1y ) NSABP B-31 and NCCTG N9831 (1y vs nil) Metastatic Pertuzumab : Cleopatra HER2 Translational Supportive care

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HER2 pos. Disease Supportive care

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  1. HER2 pos. Disease Supportive care Hans Wildiers University Hospitals Leuven

  2. HER2 pos. Disease • Adjuvant Trastuzumab: • HERA (2y vs 1y) • Phare (6 movs 1y) • NSABP B-31 and NCCTG N9831 (1y vs nil) • Metastatic Pertuzumab: Cleopatra • HER2 Translational • Supportive care • MDS/AML after breast cancer • Neurocognitive impact of adjuvant chemotherapy • Bone

  3. HER2 adjuvant S5-2 HERA TRIAL UPDATE at 8 y FUP Accrual 2001 – 2005 (n=5102) Women with locally determined HER2-positive invasive early breast cancer Surgery + (neo)adjuvant CT ± RT Centrally confirmed IHC 3+ or FISH+ and LVEF ≥ 55% Randomization OBSERVATION n=1698 1 year Trastuzumab 8 mg/kg – 6 mg/kg 3 weekly schedule n=1703 2 years Trastuzumab 8 mg/kg – 6 mg/kg 3 weekly schedule n=1701 After ASCO 2005, option of switch to Trastuzumab Final analysis planned for 725 disease-free survival (DFS) events to obtain 80% power to detect a true hazard ratio of 0.80. CT, chemotherapy; RT, radiotherapy

  4. HER2 adjuvant S5-2 DFS FOR 2 YEARS VS. 1 YEAR TRASTUZUMAB AT 8 YRS MFU 100 89.1% 81.6% 75.8% 86.7% 80 81.0% 76.0% 60 Trastuzumab 2 years Disease-free survival (%) Trastuzumab 1 year 40 20 0 0 1 2 3 4 5 6 7 8 9 Years from randomization

  5. HER2 adjuvant S5-2 DFS BY HORMONE RECEPTOR STATUS AT 8 YRS MFU Hormone receptor positive 92.6% received endocrine therapy Hormone receptor negative 2.8% received endocrine therapy 100 100 90.3% 87.8% 83.1% 80.1% 76.1% 75.4% 89.6% 80 80 82.9% 83.8% 78.9% 77.2% 74.7% 60 60 Disease-free survival (%) Disease-free survival (%) 40 40 Trastuzumab 2 years Trastuzumab 2 years Trastuzumab 1 year Trastuzumab 1 year 20 20 0 0 0 0 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 Years from randomization Years from randomization

  6. HER2 adjuvant S5-2 OS FOR 2 YEARS VS. 1 YEAR TRASTUZUMAB AT 8 YRS MFU 97.4% 100 92.6% 86.4% 96.5% 91.4% 80 87.6% 60 Trastuzumab 2 years Overall Survival (%) Trastuzumab 1 year 40 20 0 0 1 2 3 4 5 6 7 8 9 Years from randomization

  7. HER2 adjuvant S5-2 ADVERSE EVENTS(SAFETY ANALYSIS POPULATION) 1 LVEF < 50% and ≥ 10% below baseline confirmed by repeat assessment, excluding patients with a primary cardiac endpoint. 2NYHA class III or IV, confirmed by a cardiologist, and LVEF < 50% and ≥ 10% below baseline, OR cardiac death.

  8. HER2 adjuvant S5-2 1 YEAR TRASTUZUMAB VS. OBSERVATION: DFS ITT ANALYSES DFS benefit Median follow-up (% follow-up timeafter selective crossover) No. of DFS events 1 year trastuzumab vs observation 0.54 2005 (0%) 127 vs 220 P<0.0001 1 yr MFU 0.64 2006 (4.3%) 218 vs 321 P<0.0001 2 yrs MFU 0.76 2008 (33.8%) 369 vs 458 P<0.0001 4 yrs MFU 0.76 2012 (48.6%) 471 vs 570 P<0.0001 8 yrs MFU Favours 1 year trastuzumab Favours observation 0 1 2 HR (95% CI) Extended from Gianni et al. Lancet Oncol. 2011.

  9. HER2 adjuvant S5-2 1 YEAR TRASTUZUMAB VS. OBSERVATION:OSITT ANALYSES OS benefit Median follow-up (% follow-up timeafter selective crossover) No. of deaths 1 year trastuzumab vsobservation 0.76 2005 (0%) 29 vs 37 P=0.26 1 yr MFU 0.66 2006 (4.1%) 59 vs 90 P=0.0115 2 yrs MFU 0.85 2008 (30.9%) 182 vs 213 P=0.1087 4 yrs MFU 0.76 2012 (45.5%) 278 vs 350 P=0.0005 8 yrs MFU Favours 1 year trastuzumab Favours observation 0 1 2 HR (95% CI) Extended from Gianni et al. Lancet Oncol. 2011.

  10. HER2 adjuvant PHARE*Trial results of subset analysis comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer S5-3 • Protocol of • Herceptin® • Adjuvant with • Reduced • Exposure Xavier Pivot, Gilles Romieu, Marc Debled, Jean-Yves Pierga, Pierre Kerbrat, Thomas Bachelot, Alain Lortholary, Marc Espié, Pierre Fumoleau, Daniel Serin,Jean-Philippe Jacquin, Christelle Jouannaud, Maria Rios, Sophie Abadie-Lacourtoisie, Nicole Tubiana-Mathieu, Laurent Cany, Stéphanie Catala, David Khayat, Iris Pauporté, Andrew Kramar. • *lighthouse in French

  11. HER2 adjuvant S5-3 Study design trastuzumabup to 12 months trastuzumab 6 months R Stratification 1. ER pos / neg 2. Chemo: conco/ seq stop trastuzumab Clinical exam LVEF … 0 3 6 9 12 15 18 21 24 30 mos Mammography Up to 60 mos… R: Randomizationafterinformed consent

  12. HER2 adjuvant S5-3 Statistical Methods • Non inferiority randomized trial • 2% variation in terms of absolute difference of recurrence • The 95% CI HR margins should not cross the 1.15 boundary • 1040 DFS events required for 80% power at 5% level or 4 years of accrual and at least 2 years of follow-up • HR were estimated from the stratified Cox model • Accrual target: 3400 patients

  13. HER2 adjuvant S5-3 Treatment Characteristics

  14. HER2 adjuvant S5-3 DFS Events 42.5mos. median Follow-up

  15. HER2 adjuvant S5-3 Disease Free Survival 97.0 93.8 90.7 87.8 95.5 91.2 87.8 84.9 EventsHR95%CIp-value T 12m 176 T 6m 219 1.28 (1.05 – 1.56) 0.29 * Cox model stratified by ER status and concomitant chemotherapy

  16. HER2 adjuvant S5-3 Primary endpoint scenarios A Equivalent B Superior PHARE trial C D Non Inferior E Inferior .85 1 1.15 1.3 1.45 1.6 HR X Pivot et al, ESMO 2012, LBA5_PR

  17. HER2 adjuvant S5-3 Subanalysis

  18. HER2 adjuvant S5-5 Trastuzumab plus Adjuvant Chemotherapy for HER2-positive Breast Cancer: Final Planned Joint Analysis of Overall Survivalfrom NSABP B-31 and NCCTG N9831 Median follow-up: 8.4 years Definitive survival analysis at 710 OS events Abstract #S5-5 San Antonio Breast Cancer Symposium – December 4-8, 2012

  19. HER2 adjuvant San Antonio Breast Cancer Symposium, December 4-8, 2012 S5-5 N9831/B-31 Disease-Free Survival AC  P+H 81.4% 76.8% 73.7% A  P 64.9% 62.2% N Events AC→P 2018 680 AC→P+H 2028 473 HRadj=0.60 (95% CI: 0.53-0.68) P<0.0001

  20. HER2 adjuvant San Antonio Breast Cancer Symposium, December 4-8, 2012 S5-5 B-31/N9831 Overall Survival 89.8% 87.0% AC  P 90.3% 84.3% 79.4% ∆=2.9% ∆=5.5% ∆=7.6% ∆=8.8% N Events AC→P 2018 418 AC→P+H 2028 286

  21. HER2 metastatic P5-18-26 CLEOPATRA: update Placebo + trastuzumab PD n = 406 Docetaxel*≥ 6 cycles recommended Patients withHER2-positive MBCCentrally confirmed (N = 808) 1:1 Pertuzumab + trastuzumab PD n = 402 Docetaxel*≥ 6 cycles recommended • Primary endpoint: Independently-assessed progression-free survival (PFS) • Collection of tumor tissue (archival in >90%) and serum samples was mandatory • Study dosing q3w:− Pertuzumab/placebo: 840 mg loading dose, 420 mg maintenance− Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance− Docetaxel: 75 mg/m2, escalating to 100 mg/m2 if tolerated 1. Baselga J, et al. SABCS 2011 (Abstract S5-5);2. Baselga J, et al. N Engl J Med 2012; 366: 109–119. * < 6 cycles allowed for unacceptable toxicity or PD; > 6 cycles allowed at investigator discretionHER2, human epidermal growth factor receptor 2; PD, progressive disease

  22. HER2 metastatic P5-18-26 CLEOPATRA: overall survival 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

  23. HER2 metastatic P5-18-26 CLEOPATRA: 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

  24. HER2 metastatic P5-18-01 CLEOPATRA PFS according to age 100 90 80 70 60 Progression-free survival (%) 50 40 30 20 10 0 0 5 10 15 20 25 30 35 Time (months) D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab

  25. HER2 metastatic P5-18-01 CLEOPATRA PFS according to age:Exposure to docetaxel treatment

  26. HER2 metastatic P5-18-01 CLEOPATRA PFS according to age:Ten most common grade ≥3 adverse events overall LVSD, left ventricular systolic dysfunction

  27. HER2 translational S5-7 The HER2 signalling pathway Selection of biomarkers HER ligands (AREG, EGF, TGFα) Y NO RESULTS (except HER2) sHER2 Y IGF1R EGFR HER2 HER3 HER2 ER Grb2 ER Ras Sos PI3K PTEN Sos Shc Grb2 Akt Raf mTOR GSK3 BAD FKHR MEK 1/2 p27 Cell survival MAPK Cyclin D1, E Cell-cycle progression Nucleus Cell proliferation c-myc

  28. HER2 translational • Neosphere: associatonbetweenpCR and immune biomarkersS6-7 • Lapatinibdecreases Ki67 by 27% in HER2 neg tumors in a ‘window of opportunity’ study(mainlyifalso high HER3 expression) PD07-07 • New techniquesforHER2 determination • Next generationsequencingis highly concordant with FISH for HER2, and uncoversactionablegenomicalterationsPD02-07 • MPLA PD02-03, • RNA scope analysis PD02-04 • AQUA: predictstrastuzumab benefit in BCIRG-005/6 PD02-01

  29. HER2 translational S5-6 ActivatingHER2 mutationsin HER2 Gene AmplificationNegativeBreastCancers • HER2 mutationspredominantlyoccur in HER2 gene amplificationnegativepatients. • The majority of HER2 mutations are activatingevents thatcauseoncogenictransformation, thusthey are highlylikelytobe driver events in these breastcancers. • Neratinibis a highly potent, irreversible pan-ErbBtyrosine kinase inhibitor forall of the HER2 mutations (clinical trial has been launched)

  30. AML/MDS S3-5 MDS/AML after BC diagnosis • Previousreports: • NSABP trials: 0,27% after AC at 8y  if RT afterlumpectomy or CSF use. • An “environmental” cancer

  31. AML/MDS S3-5

  32. AML/MDS S3-5 Characteristics of Leukemia cohort

  33. AML/MDS S3-5 Cumulativeincidence of Leukemia Chemo vs no chemo: HR 2,5 p0,007

  34. AML/MDS S3-5 Conclusions • Adjuvantchemotherapy was associatedwith a cumulative10-year incidence of leukemia of ~ 0.5% • Almost half of the events occurredbeyondyear 5 • Radiationaloneappearstobe a risk factor, but maynotaddmuchtopatientsalreadytreatedwithchemotherapy • Leukemia risk was notlimitedto MDS/AML, and cases of high risk lymphoidleukemiawereobserved • Thisstudyhighlights the challenges of studyinginfrequent but important clinical events

  35. chemobrain S6-3 NeurocognitiveImpact in AdjuvantChemotherapyforBreast Cancer LinkedtoFatigue: A ProspectiveFunctional MRI Study • Prospective non-randomizedcomparative trial n=28 n=37 n=32

  36. chemobrain S6-3 • Frontal Brain Activationbygroupand time

  37. chemobrain Resultsandconclusion S6-3 • Neurocognitivealterations in working memory processesandgreaterfatiguewere evident beforeanyadjuvantchemotherapy. • Pre-adjuvant treatment brainalterationsduringworking memory taskpredictseverity of fatiguepost-treatment. • Greaterfatigueacrossallgroups was relatedtoreducedcognitivefunctionover time.

  38. Bone S6-4 Vitamin D, But NotBone Turnover Markers, Predict Relapse In WomenWithEarlyBreastCancer: An AZURETranslationalStudy. And 25HO VitD

  39. Bone S6-4 Prognosticeffect onlyfor25HO VitD

  40. Bone S6-4 Predictiveeffect * 25HO Vit D * CTX, PINP : ZOL benefit NOT predictedbyhigherbone turnover

  41. Bone S3-13-01 LOTUS trial: Prospectivestudy of treatment pattern, effectiveness, andsafety of Zoledronic acid (ZOL) beyond 2y: subgroup analysis of ptswithmetastaticbreastcancer. • Population: 157 pts, 92% continued ZOL only37%receivedper label (q3-4w) • SRE: - SRE rate 0,13 per person yearduring 18 monthstudy (vs 0,13 in 18 monthsbeforeinclusion) - 83% SRE free at 18 months - persistent ZOL therapyper label ≈ lower SRE rate (HR 0,26 p 0,009) • Safety: - renaldeterioration in 6 pts - No symptomatichypoCa (but only 16% taking supplements!) - Acute phasereactions 9,5% - ONJ in 7 pts (4,5%)

  42. Bone Bisphosphonates • Neoadj FEC-paclitaxel +/- ZOL. PD07-05 • randomized trial (n= 182) • pCR 14,9 vs 7,9% (p 0,16) • in postmenopauzal 18,4 vs 5,4% (p 0,15) • iv ZOL vs po ibandronatPD09-07 • randomized trial (n=1405) • MBC withbone metastases • SRE rate per yearlowerfor ZOL (0,44 vs 0,54, p 0,02)

  43. Conclusions HER2 • HER2 adjuvant: • HERA and NSABP B-31/NCCTG N9831 results at 8 yrsFUP show sustained and statistically significant DFS and OS benefit for 1 year trastuzumabversus observation in ITT analyses despite selective crossover. No benefit for extension to 2 years in HERA. • PHARE failed to show that 6 months of trastuzumab is non inferior to 12 months. Subgroup analysis suggested that • Sequential modality for ER negative tumors impacted the overall results. • Results in other groups seemed compatible with non-inferiority hypothesis • 1 year of trastuzumab remains the standard of care as adjuvant therapy for patients with HER2-positive early breast cancer. • HER2 metastatic: • Addition of pertuzumabto trastuzumab and docetaxel improves OS and PFS significantly in HER2-positive first-line without important toxicity aspects.

  44. Conclusions supportive care • Adjuvantchemotherapyis associatedwith a cumulative10-year incidence of leukemiaof ~ 0.5% • Neurocognitivealterations in working memory processesandgreaterfatigueare present beforeanyadjuvantchemotherapy. • Low baseline VitD is associatedwithincreased risk of boneanddistantrecurrence

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