ANCO's San Antonio Breast Cancer Symposium Highlights 2011 Systemic Therapy

Transcription

1 ANCO's San Antonio Breast Cancer Symposium Highlights 2011 Systemic Therapy Robert W. Carlson, M.D. Professor of Medicine Stanford University Robert W. Carlson, M.D. Conflicts of Interest Research support from Sanofi- AvenNs Genentech/Roche AstraZeneca 1

2 Overview Endocrine therapy SWOG S0226 (anastrozole +/- fulvestrant) BOLERO- 2 (exemestane +/- everolimus) Adjuvant bisphosphonates ABCSG- 12 (zoledronate v not) ZoFAST (immediate v delayed zoledronate) NSABP B- 34 (clodronate v placebo) GAIN Trial (ibandronate v not) HER2 targeted therapy Docetaxel/trastuzumab +/- Pertuzumab San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 A phase III randomized trial of anastrozole versus anastrozole and fulvestrant as first-line therapy for postmenopausal women with metastatic breast cancer: SWOG S0226 Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR, Livingston RB, and Hortobagyi GN This presentation is the intellectual property of the author/presenter. Contact them at rsmehta@uci.edu for permission to reprint and/or distribute. 2

3 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Background Anastrozole lowers estrogen levels and fulvestrant down-regulates the estrogen receptor The combination of anastrozole and fulvestrant may be additive in postmenopausal breast cancer Fulvestrant has a high efficacy in low-estrogen in vivo model (Osborne JNCI 1995) The combination of fulvestrant and anastrozole down-regulates several resistance proteins in in vivo model (Macedo et al. Cancer research 2008) This presentation is the intellectual property of the author/presenter. Contact them at rsmehta@uci.edu for permission to reprint and/or distribute. San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 S0226: Main Eligibility Criteria Postmenopausal women with metastatic breast cancer (measurable or non-measurable) ER-positive or PgR-positive by local institutional standards No prior chemotherapy, hormonal therapy, or immunotherapy for metastatic disease Prior adjuvant tamoxifen allowed (stratification factor) Prior adjuvant AI allowed if completed 12 months earlier Neoadjuvant or adjuvant chemotherapy completed more than 12 months prior Patients were not allowed chemotherapy or other hormone therapy while on treatment Must have given informed consent This presentation is the intellectual property of the author/presenter. Contact them at rsmehta@uci.edu for permission to reprint and/or distribute. 3

4 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 S0226: Schema R A N D O M I Z E Arm 1 Anastrozole only: 1 mg PO daily Treat until progression; crossover to fulvestrant strongly encouraged after progression Arm 2 Anastrozole: 1 mg PO daily First cycle of 28 days: Fulvestrant 500mg IM ( 2 x 5 ml) Day 1 Fulvestrant 250mg IM ( 1 x 5 ml) Day 14 Fulvestrant 250mg IM ( 1 x 5 ml) Day 28 Subsequent cycles of 28 days: Fulvestrant 250mg IM ( 1 x 5 ml) Day 28 Treat until progression This presentation is the intellectual property of the author/presenter. Contact them at rsmehta@uci.edu for permission to reprint and/or distribute. San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Patient Characteristics Characteris*c Anastrozole Anastrozole + Fulvestrant Total Randomized Ineligible or withdrew consent 7 (2.0%) 6 (1.7%) 13 (1.8%) Analyzed Age median (range) 65 (36-91) 65 (27-92) 65 (27-92) Prior adjuvant tamoxifen 139 (40.3%) 141 (40.4%) 280 (40.3%) Prior adjuvant chemo 103 (29.9%) 129 (37.0%) 232 (33.4%) Disease characterisncs Measurable 54.5% 53.9% 54.2% Bone only 22.0% 21.5% 21.8% De novo metastanc disease 41.8% 36.0% 38.9% > 10 years since previous dx 26.1% 30.7% 28.4% HER2- posinve 8.5% 10.4% 9.5% Use of adjuvant AI is being determined retrospectively, but only 12 users of adjuvant AI s have been identified. This presentation is the intellectual property of the author/presenter. Contact them at rsmehta@uci.edu for permission to reprint and/or distribute. 4

5 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Progression-free survival Progression-Free Survival in S0226 All eligible patients (n=694) HR = 0.80 (95% CI ) Anastrozole + Fulvestrant (268 events) Anastrozole (297 events) Stratified log-rank p = Median PFS Anastrozole 13.5 mos (95% CI ) Combination 15.0 mos (95% CI ) Months since registration N at risk AN AN + FV This presentation is the intellectual property of the author/presenter. Contact them at rsmehta@uci.edu for permission to reprint and/or distribute. San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Progression-free survival Progression-Free Survival in S0226 Prior adjuvant tamoxifen (n=280) HR = 0.89 (95% CI ) Anastrozole + Fulvestrant (114 events) Anastrozole (119 events) Log-rank p = 0.37 Median PFS Anastrozole 14.1 mos (95% CI ) Combination 13.5 mos (95% CI ) Months since registration N at risk AN AN + FV This presentation is the intellectual property of the author/presenter. Contact them at rsmehta@uci.edu for permission to reprint and/or distribute. 5

6 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Progression-free survival Progression-Free Survival in S0226 No prior adjuvant tamoxifen (n=414) HR = 0.74 (95% CI ) Anastrozole + Fulvestrant (154 events) Anastrozole (178 events) Log-rank p = Median PFS Anastrozole 12.6 mos (95% CI ) Combination 17.0 mos (95% CI ) Months since registration N at risk AN AN + FV This presentation is the intellectual property of the author/presenter. Contact them at rsmehta@uci.edu for permission to reprint and/or distribute. San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Overall Survival HR = 0.81 (95% CI ) Overall Survival in S0226 All eligible patients (n=694) Median OS Anastrozole 41.3 mos (95% CI ) Combination 47.7 mos (95% CI ) Anastrozole + Fulvestrant (154 deaths) Anastrozole (176 deaths) Stratified log-rank p = Months since registration N at risk AN AN + FV This presentation is the intellectual property of the author/presenter. Contact them at rsmehta@uci.edu for permission to reprint and/or distribute. 6

7 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Overall Survival Overall Survival in S0226 Prior adjuvant tamoxifen (n=280) HR = 0.91 (95% CI ) Median OS Anastrozole 44.5 mos (95% CI ) Combination 49.6 mos (95% CI ) Anastrozole + Fulvestrant (63 deaths) Anastrozole (68 deaths) Log-rank p = Months since registration N at risk AN AN + FV This presentation is the intellectual property of the author/presenter. Contact them at rsmehta@uci.edu for permission to reprint and/or distribute. San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Overall Survival Overall Survival in S0226 No prior adjuvant tamoxifen (n=414) HR = 0.74 (95% CI ) Median OS Anastrozole 39.7 mos (95% CI ) Combination 47.7 mos (95% CI ) Anastrozole + Fulvestrant (91 deaths) Anastrozole (108 deaths) Log-rank p = Months since registration N at risk AN AN + FV This presentation is the intellectual property of the author/presenter. Contact them at rsmehta@uci.edu for permission to reprint and/or distribute. 7

8 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Forest Plot PFS treatment hazard ratio with 95% confidence interval Unplanned subset analysis Overall HR = 0.80 Age 65+ Age < 65 HER2-positive HER2-negative Non-visceral Visceral Bone only Non-measurable Measurable 10 years years 0-5 years De novo No prior chemo Prior chemo No prior tam Prior tam Overall Combination better Combination worse Hazard ratio This presentation is the intellectual property of the author/presenter. Contact them at rsmehta@uci.edu for permission to reprint and/or distribute. San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 S0226 Conclusions: The combination of anastrozole and fulvestrant improves PFS and OS, the primary and secondary endpoints, respectively, in first-line therapy of hormone receptor positive breast cancer in postmenopausal women The toxicity of the combination treatment is comparable to single agent treatment though Grade 5 toxicity was seen only with the combination This presentation is the intellectual property of the author/presenter. Contact them at rsmehta@uci.edu for permission to reprint and/or distribute. 8

9 FACT: Open Label, Randomized Phase III F + A vs A at First Relapse in HR+ Breast Cancer J. Bergh et.al. SABCS 2009 N = 514 (256 anastrozole; 258 Anastrozole plus fulvestrant) Fulvestrant Dose = 500 mg IM Day 1, 250 mg Day 14 and Day 28 and 250 mg monthly to progression 2/3 either endocrine therapy naïve or > 12 months from adjuvant endocrine therapy Time to progression HR = 0.99; , p=.91 ObjecNve rate of response RR 33.6%(A) vs 31.8%(A+F); OR 0.92; 95%CI ) No advantage of adding fulvestrant to anastrozole. My Comments S0226 compares combinanon to monotherapy, but not the sequence 41% of anastrozole alone panents did cross- over to fulvestrant alone, but no pre- specified analysis of this subset Greatest benefit in tamoxifen naïve subjects PopulaNon not fully relevant today given AI use in the adjuvant selng FACT trial did not demonstrate a benefit to the combinanon over letrozole Based on conflicnng data of FACT vs. S0226 combinanon should not be viewed as standard of care. 9

10 Overview Endocrine therapy SWOG S0226 (anastrozole +/- fulvestrant) BOLERO- 2 (exemestane +/- everolimus) Adjuvant bisphosphonates ABCSG- 12 (zoledronate v not) ZoFAST (immediate v delayed zoledronate) NSABP B- 34 (clodronate v placebo) GAIN Trial (ibandronate v not) HER2 targeted therapy Docetaxel/trastuzumab +/- Pertuzumab 10

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15 Letrozole +/- Temsirolimus Postmenopausal Advanced breast cancer ER and/or PgR posinve 1 prior chemotherapy for advanced disease No prior endocrine therapy for advanced disease Letrozole 2.5 mg daily (n=556) Letrozole 2.5 mg daily + Temsirolimus 30 mg d1-5 every two weeks (n=556) Chow et al, SABCS 2006 Progression Free Survival Chow et al, SABCS

16 My Comments Exemestane + everolimus with superior DFS No survival data available Everolimus converts a low toxicity therapy to a moderate toxicity therapy Not consistent with letrozole + temsirolimus?prior AI therapy important in efficacy? We need more data Overview Endocrine therapy SWOG S0226 (anastrozole +/- fulvestrant) BOLERO- 2 (exemestane +/- everolimus) Adjuvant bisphosphonates ABCSG- 12 (zoledronate v not) ZoFAST (immediate v delayed zoledronate) NSABP B- 34 (clodronate v placebo) GAIN Trial (ibandronate v not) HER2 targeted therapy Docetaxel/trastuzumab +/- Pertuzumab 16

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23 Overview Endocrine therapy SWOG S0226 (anastrozole +/- fulvestrant) BOLERO- 2 (exemestane +/- everolimus) Adjuvant bisphosphonates ABCSG- 12 (zoledronate v not) ZoFAST (immediate v delayed zoledronate) NSABP B- 34 (clodronate v placebo) GAIN Trial (ibandronate v not) HER2 targeted therapy Docetaxel/trastuzumab +/- Pertuzumab 23

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27 Overview Endocrine therapy SWOG S0226 (anastrozole +/- fulvestrant) BOLERO- 2 (exemestane +/- everolimus) Adjuvant bisphosphonates ABCSG- 12 (zoledronate v not) ZoFAST (immediate v delayed zoledronate) NSABP B- 34 (clodronate v placebo) GAIN Trial (ibandronate v not) HER2 targeted therapy Docetaxel/trastuzumab +/- Pertuzumab NSABP Protocol B-34: A Clinical Trial Comparing Adjuvant Clodronate vs. Placebo In Early Stage Breast Cancer Patients Receiving Systemic Chemotherapy and/or Tamoxifen or No Therapy Final Analysis AHG Paterson 1,2, SJ Anderson 1,3, BC Lembersky 1,4, L Fehrenbacher 1,5, CI Falkson 1,6, KM King 1,7, LM Weir 1,8, AM Brufsky 1,9, S Dakhil 1,10, T Lad 1,11, L Baez-Diaz 1,12, JR Gralow 13, A Robidoux 1,14, EA Perez 15, P Zheng 1,3, CE Geyer 1,16, SM Swain 1,17, JP Costantino 1,3, EP Mamounas 1,18, Norman Wolmark 1,19 1 Na*onal Surgical Adjuvant Breast and Bowel Project (NSABP); 2 Tom Baker Cancer Centre; 3 Biosta*s*cs, University of PiJsburgh Graduate School of Public Health; 4 University of PiJsburgh Cancer Ins*tute School of Medicine; 5 Kaiser Permanente, Northern California; 6 University of Alabama at Birmingham/ECOG; 7 Cross Cancer Ins*tute; 8 Bri*sh Columbia Cancer Agency; 9 University of PiJsburgh/Magee Women's Hospital; 10 Cancer Center of Kansas; 11 Stroger Hospital Cook County MBCCOP; 12 San Juan MBCCOP; 13 University of Washington/SWOG; 14 Centre Hospitalier de l'université de Montréal; 15 Mayo Clinic Jacksonville/NCCTG; 16 University of Texas Southwestern Medical Center; 17 Washington Cancer Ins*tute, Washington Hospital Center; 18 Aultman Health Founda*on; 19 Allegheny General Hospital 27

28 B- 34 Study Design STRATIFICATION Age (< 50, 50) Number of Posi*ve Nodes (0, 1-3, 4+) ER / PgR Status RANDOMIZATION GROUP 1 Clodronate* 1600 mg/day x 3 years GROUP 2 Placebo* x 3 years *At the discre*on of the inves*gator, pa*ents may receive adjuvant systemic chemotherapy and/or tamoxifen, or no adju 100 NSABP Protocol B- 34 Disease- Free Survival % Disease- free Trt N Events Placebo Clodronate HR=0.91 p= Years aler Randomiza*on 28

29 Analyses of Specified Endpoints ENDPOINT Hazard Ratio (HR) 95% confidence interval p-value DFS OS RFI BMFI NBMFI B-34 Post-hoc Analysis Hazard Ratios of Skeletal Metastases between Groups by Age Categories (<50, 50-59, 60+) Pa*ents 60+ at entry Pa*ents at entry Pa*ents <50 at entry HR=0.77 All pa*ents with follow- up Clodronate berer Placebo berer Hazard Ra*o 29

30 B- 34 Post- hoc Analysis Hazard Ra*os of Non- Skeletal Metastases between Groups by Age Categories (<50, 50-59, 60+) Pa*ents 60+ at entry Pa*ents at entry Pa*ents <50 at entry All pa*ents with follow- up HR=0.74 Clodronate berer Placebo berer Hazard Ra*o Conclusions (1) The primary objective of DFS was not met in this low event rate population. The DFS benefit was attenuated due to the equivalent event rates for 2nd primary cancers, contra-lateral cancers and local/regional relapses. 40% of patients did not complete 3 years of study therapy Side-effects/toxicity in the clodronate and placebo groups were low and similar. One case of possible ONJ. Clodronate provided benefit for distant metastases in all protocol pre-defined secondary endpoints having HR reductions of 15% - 26%. 30

31 Conclusions (2) Secondary protocol pre-defined endpoint reductions observed in women 50 years and older were even greater [20% - 39%]: Breast cancer RFI - ages > 50: HR=0.76 (p = 0.05) Bone metastasis-free interval - ages > 50: HR= 0.61 (p = 0.024) Non-bone metastasis-free interval - ages > 50: HR=0.63 (p = 0.015) Overall survival - ages > 50: HR = 0.80 (p = 0.1) 125 deaths in placebo arm vs. 101 deaths in clodronate arm Similar beneficial results in older post-menopausal women are seen in other studies involving bisphosphonates. The vicious cycle hypothesis may require modification in the light of these results. Overview Endocrine therapy SWOG S0226 (anastrozole +/- fulvestrant) BOLERO- 2 (exemestane +/- everolimus) Adjuvant bisphosphonates ABCSG- 12 (zoledronate v not) ZoFAST (immediate v delayed zoledronate) NSABP B- 34 (clodronate v placebo) GAIN Trial (ibandronate v not) HER2 targeted therapy Docetaxel/trastuzumab +/- Pertuzumab 31

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35 My Comments Bisphosphonates prevent BMD loss Heterogeneity among studies of impact on breast cancer disease endpoints Emerging signal that the older postmenopausal panents benefit most Benefits may be impacted by chemotherapy or not Absolute differences in outcome are small, even in the posinve trials. 35

36 Overview Endocrine therapy SWOG S0226 (anastrozole +/- fulvestrant) BOLERO- 2 (exemestane +/- everolimus) Adjuvant bisphosphonates ABCSG- 12 (zoledronate v not) ZoFAST (immediate v delayed zoledronate) NSABP B- 34 (clodronate v placebo) GAIN Trial (ibandronate v not) HER2 targeted therapy Docetaxel/trastuzumab +/- Pertuzumab Baselga J, Cortex J, Kim S- B, Im S- A, Hegg R, Im Y- H, Roman L, Pedrini JL, Pienkowski T, Knor A, Clark E, Benyunes MC, Ross G, Swain SM Pertuzumab plus Tratuzumab plus Docetaxel for MetastaNc Breast Cancer N Engl J Med 2011, published ahead of print December 7,

37 Pertuzumab plus Tratuzumab plus Docetaxel for MetastaNc Breast Cancer: RaNonale Trastuzumab improves outcomes in HER2+ breast cancer Pertuzumab is an ann- HER2 humanized monoclonal annbody that inhibits receptor dimerizanon, especially HER2 with HER3 Pertuzumab + trastuzumab should be complementary Pertuzumab plus Tratuzumab plus Docetaxel for MetastaNc Breast Cancer: Schema MetastaNc breast cancer HER2+ LVEF 50% ECOG status prior endocrine Rx No prior chemo for metastanc disease (Neo)adj chemo/trastuzumab if 12 mos previous Placebo + Trastuzumab 8 mg/kg d1 then 6 mg/kg Docetaxel 75 mg/m 2 Pertuzumab 840 mg d1 then 420 mg Trastuzumab 8 mg/kg d1 then 6 mg/kg Docetaxel 75 mg/m 2 Primary endpoint = Progression- free survival by independent review facility Secondary endpoints = Overall survival, progression- free survival by invesngator, objecnve rate of response, safety N Engl J Med 2011, published ahead of print December 7,

38 Pertuzumab plus Tratuzumab plus Docetaxel for MetastaNc Breast Cancer: PaNent CharacterisNcs Characteris*c Placebo + TH (N=406) Pertuzumab + TH (N=402) Visceral disease 77.8% 78.1% ER- neg and PgR- neg 48.3% 52.7% Prior (neo)adj therapy No Anthracycline Hormone Taxane Trastuzumab 52.7% 40.4% 23.9% 23.2% 10.1% 54.2% 37.3% 26.4% 22.6% 11.7% N Engl J Med 2011, published ahead of print December 7, 2011 Progression- Free Survival N Engl J Med 2011, published ahead of print December 7,

39 Progression- Free Survival: Subgroups N Engl J Med 2011, published ahead of print December 7, 2011 Overall Survival N Engl J Med 2011, published ahead of print December 7,

40 Most Common ToxiciNes, All Grades Event Placebo + TH (%) Pertuzumab + TH (%) Diarrhea Alopecia Neutropenia Nausea Fa*gue Rash Decreased appe*te Mucosal inflamma*on Asthenia Peripheral edema Cons*pa*on Febrile neutropenia Dry skin N Engl J Med 2011, published ahead of print December 7, 2011 Pertuzumab plus Tratuzumab plus Docetaxel for MetastaNc Breast Cancer: Summary AddiNon of pertuzumab to TH improves Progression- free survival Overall survival Increases toxicity of regimen 40

41 My Comments Pertuzumab + trastuzumab + docetaxel more effecnve than trastuzumab + docetaxel in the first line chemotherapy of metastanc HER2+ disease Is the trastuzumab necessary? Await with interest adjuvant trial results! 41