Combination Anastrozole and Fulvestrant in Metastatic Breast Cancer: Resurrection of Survival Endpoint Rita Mehta, MD Associate Clinical Professor Division of Hematology/Oncology Department of Medicine November 6th 2012 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. Original Article Combination Anastrozole and Fulvestrant in Metastatic Breast Cancer Rita S. Mehta, M.D., William E. Barlow, Ph.D., Kathy S. Albain, M.D., Ted A. Vandenberg, M.D., Shaker R. Dakhil, M.D., Nagendra R. Tirumali, M.D., Danika L. Lew, M.A., Daniel F. Hayes, M.D., Julie R. Gralow, M.D., Robert B. Livingston, M.D., and Gabriel N. Hortobagyi, M.D. N Engl J Med Volume 367(5):435-444 August 2, 2012 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 6-10, 2011 Epidemiology of breast cancer Female/male ratio 100:1 More than 200,000 women will be Dxd in US >40,000 will die of breast cancer 2nd leading cause of cancer deaths in women This presentation is the intellectual property of the author/presenter. Contact them at rsmehta@uci.edu for permission to reprint and/or distribute. Major Determinants of treatment Staging ER status-Negative and positive HER2 status-Negative and positive This presentation is the intellectual property of the author/presenter. Contact them at rsmehta@uci.edu for permission to reprint and/or distribute. Staging Stage 0 -- carcinoma in situ Stage I – tumor < 2 cm, no nodes Stage II – tumor 2 to 5 cm, +/- nodes Stage III – locally advanced disease, fixed or matted lymph nodes and variable tumor size Stage IV – distant metastases (bone, liver, lung, brain) Estrogen Receptor and Antiestrogen HER2 Over-Expression and Trastuzumab in Breast Cancer San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 6-10, 2011 Background Of all women with breast cancer, 60% have tumors that are positive for hormone receptors; this figure rises to 75% for postmenopausal women with breast cancer Anastrozole lowers estrogen levels and fulvestrant down-regulates the estrogen receptor The combination of anastrozole and fulvestrant may be additive in postmenopausal breast cancer This presentation is the intellectual property of the author/presenter. Contact them at rsmehta@uci.edu for permission to reprint and/or distribute. Preclinical Data Jelovac et al. Can Research 2005 Preclinical Data Anastrozole + fulvestrant down-regulate signaling proteins: Insulin-like growth factor type I receptor β, mitogen-activated protein kinase (MAPK), p-MAPK, AKT, mammalian target of rapamycin (mTOR), p-mTOR, and estrogen receptor α. Macedo et al. Can Research 2008 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. San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 6-10, 2011 S0226: Schema Arm 1 R A N D O M I Z E 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 S0226: Statistical Design • Accrual goal: 690 eligible patients equally allocated and stratified by use of adjuvant tamoxifen • Primary endpoint: Progression-free survival (PFS) – 90% power to detect an increase in median PFS from 10 months (monotherapy) to 13 months (combination) with 2-sided α = 0.05 overall • Planned analyses of the primary endpoint – Two interim analyses at 50% and 75% of the events – Final analysis at 2-sided α = 0.04 • Subset analyses were not planned and are not adjusted for multiplicity • Overall survival is a secondary endpoint 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 Primary Comparisons • Intent-to-treat analysis of eligible patients • Analysis stratified by prior adjuvant tamoxifen • Results as of December 2011: – Population characteristics • 707 patients randomized in the period June 2004 to June 2009 • 694 analyzed excluding 12 ineligible patients and one who withdrew consent – Progression-free survival – Overall survival – Toxicity 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 Crossover • Patients in the anastrozole arm were strongly encouraged to crossover to fulvestrant after progression • After Feb 15, 2011 patients on either arm could crossover to 500 mg fulvestrant dosing after progression • 143 of 345 patients (41%) on anastrozole did crossover to fulvestrant after progression (including 5 who took the 500 mg dosing) • 9 of 349 patients on the combination took 500 mg dosing after progression This presentation is the intellectual property of the author/presenter. Contact them at rsmehta@uci.edu for permission to reprint and/or distribute. Baseline Characteristics of the Patients and the Disease, According to Treatment Group. Mehta RS et al. N Engl J Med 2012;367:435-444. Kaplan–Meier Curves for Progression-free Survival, According to Treatment Group. Mehta RS et al. N Engl J Med 2012;367:435-444 Kaplan–Meier Curves for Overall Survival, According to Treatment Group. Mehta RS et al. N Engl J Med 2012;367:435-444 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 6-10, 2011 Progression-Free Survival in S0226 1.00 No prior adjuvant tamoxifen (n=414) 0.75 Anastrozole + Fulvestrant (154 events) Anastrozole (178 events) Log-rank p = 0.0055 0.50 Median PFS Anastrozole 12.6 mos (95% CI 11.2-15.6) 0.00 0.25 Combination 17.0 mos (95% CI 13.8-19.9) HR = 0.74 (95% CI 0.59-0.92) 0 N at risk AN 208 AN + FV 206 12 24 36 48 Months since registration 60 72 125 113 71 60 6 2 1 0 36 22 16 8 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 in S0226 1.00 Prior adjuvant tamoxifen (n=280) 0.75 Anastrozole + Fulvestrant (114 events) Anastrozole (119 events) Log-rank p = 0.37 0.50 Median PFS Anastrozole 14.1 mos (95% CI 12.0-16.8) 0.25 Combination 13.5 mos (95% CI 11.0-19.3) 0.00 HR = 0.89 (95% CI 0.69 - 1.15) 0 N at risk AN 141 AN + FV 139 12 24 36 48 Months since registration 60 72 74 80 43 32 2 1 1 0 17 17 5 3 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 in S0226 1.00 No prior adjuvant tamoxifen (n=414) 0.50 0.75 Median OS Anastrozole 39.7 mos (95% CI 33.1-43.9) Combination 47.7 mos (95% CI 43.4-58.3) 0.25 HR = 0.74 (95% CI 0.56-0.98) 0.00 Anastrozole + Fulvestrant (91 deaths) Anastrozole (108 deaths) Log-rank p = 0.0362 0 N at risk AN 208 AN + FV 206 12 24 36 48 Months since registration 60 72 190 181 158 139 13 12 1 2 91 77 34 30 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 in S0226 1.00 Prior adjuvant tamoxifen (n=280) 0.50 0.75 Median OS Anastrozole 44.5 mos (95% CI 38.0-54.8) Combination 49.6 mos (95% CI 37.9-71.2) 0.25 HR = 0.91 (95% CI 0.65-1.28) 0.00 Anastrozole + Fulvestrant (63 deaths) Anastrozole (68 deaths) Log-rank p = 0.59 0 N at risk AN 141 AN + FV 139 12 24 36 48 Months since registration 60 72 125 125 101 100 13 10 3 2 54 59 28 24 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 Prior tamoxifen as a predictive factor? • Overall planned analysis is highly significant • Unplanned analysis by prior tamoxifen may suggest benefit only in the tamoxifen naive group • Prior tamoxifen use is confounded with time between adjuvant diagnosis and metastatic diagnosis • Need to better understand other possible predictive factors since the prior tamoxifen factor could be a false lead from an unplanned analysis This presentation is the intellectual property of the author/presenter. Contact them at rsmehta@uci.edu for permission to reprint and/or distribute. Progression-free Survival, According to Subgroups. Mehta RS et al. N Engl J Med 2012;367:435-444 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 6-10, 2011 S0226 Toxicity: Grade 4 and 5 • • • Three patients on the combination had grade 5 toxicities: – two had pulmonary embolism – one had cerebrovascular ischemia Two other patients on the combination had grade 4 toxicities: – one had pulmonary embolism – one had neutropenia and lymphopenia Four patients on anastrozole alone had Grade 4 toxicities (thrombosis/embolism, arthralgia, thrombocytopenia, dyspnea) 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 Toxicity • Grade 3 toxicities: – 46 (13%) on the combination – 38 (11%) on anastrozole alone • Includes musculo-skeletal pain, fatigue, hot flashes, mood alterations and gastrointestinal symptoms with frequency 1-4% • Adverse events did not differ significantly by treatment group • Few patients went off treatment early due to adverse events or side effects (anastrozole alone 4; combination 11) 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 First-Line Hormonal Agent Phase-III Studies in Breast Cancer: Overall Survival Study N OS: Control Arm (months) OS: Experimental Arm (months) HR for OS P-value S0226 NEJM 2012 707 Anastrozole (→fulvestrant (41.3) Anastrozole + Fulvestrant (47.7) 0.81 0.049 Bergh SABCS JCO 2012 514 Anastrozole 1.00 1.00 (38.2) Anastrozole + Fulvestrant (37.8) Nabholtz Eur J C 2003 1021 Tamoxifen (40.1) Anastrozole (39.2) 0.97 ? Mouridsen JCO 2003 916 Tamoxifen (30) Letrozole (34) ? 0.53 Paridaens JCO 2008 371 Tamoxifen (43.3) Exemestane (37.2) 1.04 0.82 Goss JCO 2007 865 Letrozole (34) Toremifen + Atamestane (36) 0.98 0.76 Howell JCO 2004 587 Tamoxifen (38.7) Fulvestrant (36.9) 1.29 0.04 This presentation is the intellectual property of the author/presenter. Contact them at rsmehta@uci.edu for permission to reprint and/or distribute. Table. Comparison of the S0226 and FACT trial. Study S0226 (n=707) FACT (514) Eligibility HR+ metastatic breast cancer, first-line; postmenopausal Progression-free survival 15.0 months vs. 13.5 months favoring fulvestrant arm (HR, 0.80; P=0.0070) 10.8 months vs. 10.2 months ; no difference (HR, 0.99; P=0.91) Overall survival 47.7 months vs. 41.3 months favoring fulvestrant (HR, 0.81; P=0.049) 37.8 months vs. 37.2 months; no difference (HR, 1.0; P=1.00). Prior adjuvant chemotherapy 33% (completion more than 12 months prior) 46% (timing not specified) Cross-over to fulvestrant Strongly encouraged (41% crossed over) Not encouraged Progression within 12 months of prior tamoxifen Low Approximately 30% Intent to Rx Analysis of eligible patients Patient characteristics balanced Patient characteristics balanced? Prior treatment 40% de-novo All in first relapse Prior tamoxifen 140/140 (280); 40% in combination arm. 175 combination/164 mono-therapy (339); 70% in combination arm. HR+ breast cancer after first relapse (local or metastatic); postmenopausal or premenopausal Kaplan–Meier Estimates of Progression-free Survival, According to Whether Patients Were Randomly Assigned to Receive Chemotherapy plus Trastuzumab or Chemotherapy Alone (Panel A), and Whether Chemotherapy Consisted of Either a Combination of an Anthracycline and Cyclophosphamide (Panel B) or Paclitaxel (Panel C). Slamon DJ et al. N Engl J Med 2001;344:783-792. Kaplan–Meier Estimates of Overall Survival, According to Whether Patients Were Randomly Assigned to Receive Chemotherapy plus Trastuzumab or Chemotherapy Alone (Panel A) and Whether Chemotherapy Consisted of Either a Combination of an Anthracycline and Cyclophosphamide (Panel B) or Paclitaxel (Panel C). HR=0.80 Slamon DJ et al. N Engl J Med 2001;344:783-792. ECOG Trial, E2100: The Study Overview • This trial tested the effect of adding bevacizumab, a monoclonal antibody against vascular endothelial growth factor A, to the taxane paclitaxel for the initial treatment of metastatic breast cancer • As compared with paclitaxel alone, the combination increased progression-free survival but not overall survival • The results are a demonstration of the potential benefit of antiangiogenic treatment for breast cancer Survival Analyses HR: 0.60 Miller K et al. N Engl J Med 2007;357:2666-2676 HR: 0.88 CLEOPATRA: The Study Overview •Pertuzumab, an anti-HER2 antibody, recognizes a different epitope of HER2 than does trastuzumab and behaves differently. •In patients with metastatic breast cancer, the combination of the two antibodies plus docetaxel significantly increased progression-free survival. CLEOPATRA: Progression-free Survival, as Assessed at an Independent Review Facility. Baselga J et al. N Engl J Med 2012;366:109-119 Overall Survival. Baselga J et al. N Engl J Med 2012;366:109-119 Which one of the following statements summarizes the results of S0226? A. Combination therapy was associated with increase in progressionfree survival and the effect increased with time B. Combination therapy was associated with increase in progressionfree survival and the effect decreased with time C. Combination therapy was associated with shorter progression-free survival D. There was no difference between the groups with respect to progression-free survival THE STUDY OBJECTIVE, SHOWING A SIGNIFICANT IMPROVEMENT IN THE PRIMARY END POINT OF PROGRESSION-FREE SURVIVAL WITH THE COMBINATION THERAPY, WAS MET (P=0.007 WITH THE USE OF A TWO-SIDED STRATIFIED LOG-RANK TEST). GENERALLY, THE SUPERIORITY OF THE COMBINATION THERAPY OVER ANASTROZOLE ALONE WITH RESPECT TO PROGRESSION-FREE SURVIVAL EMERGED OVER TIME: AT 1 YEAR, THE RATE OF PROGRESSION-FREE SURVIVAL WAS 57% WITH COMBINATION THERAPY AND 56% WITH ANASTROZOLE ALONE; AT 2 YEARS, THE CORRESPONDING RATES WERE 35% AND 28%, AND AT 3 YEARS, THE RATES WERE 25% AND 16% Which one of the following conditions was the most common grade 3 toxic effect observed in S0226? A. Gastrointestinal disturbances B. Hematologic effects C. Musculoskeletal pain D. Thrombosis THE MOST COMMON GRADE 3 TOXIC EFFECTS WERE MUSCULOSKELETAL PAIN (2.8%), INFLUENZA-LIKE SYMPTOMS (2.4%), GASTROINTESTINAL DISTURBANCES (1.5%), AND HEMATOLOGIC EFFECTS (1.5%). Which one of the following characteristics applies to the mechanism of action of fulvestrant? A. It is an aromatase inhibitor. B. It is an estrogen Modulator (SERM). C. It is an estrogen receptor down-regulator (SERD). D. It is a gonadotropin-releasing hormone agonist. FULVESTRANT (FASLODEX, ASTRAZENECA) IS AN ANALOGUE OF ESTRADIOL THAT DOWN-REGULATES THE ESTROGEN RECEPTOR BY DISRUPTING ESTROGEN-RECEPTOR DIMERIZATION AND ACCELERATING DEGRADATION OF THE UNSTABLE FULVESTRANT–ESTROGEN-RECEPTOR COMPLEX.2 THIS EFFECT LEADS TO REDUCED CROSS-TALK BETWEEN THE ESTROGEN RECEPTOR AND ESTROGEN-INDEPENDENT GROWTH FACTOR SIGNALING, THUS DELAYING RESISTANCE TO HORMONE THERAPY. Conclusions The combination of anastrozole and fulvestrant was superior to anastrozole alone or sequential anastrozole and fulvestrant for the treatment of HR-positive metastatic breast cancer, despite the use of a dose of fulvestrant that was below the current standard. The overall survival for combination was statistically superior than for anastrozole alone, despite higher-than-projected survival for anastrozole alone. The combination was not statistically associated with higher toxicity, despite longer time on the combination. Comparison of S0226 (and its subsets) to FACT suggests that benefit of combination decreases with increasing endocrine resistance (acquired or inherent). How to Rx this patient? • Age: 61 (A pt at Hoag) • ER: 95% • PR: 95% • Tumor Type: IDC • Tumor Size: 0.9 cm • Tumor Grade: 2 • HER-2 Neg (FISH) www.adjuvantonline.com. How to Rx this patient? Age: 35 ( a frequent patient at UCI) ER: neg/PR: neg Tumor Type: IDC Tumor Size: >5 cm Tumor Grade: 3 HER-2 pos (FISH); Chemo-sensitive vs chemo-resistant Neoadjuvant Chemotherapy +Trastuzumab Neoadjuvant vs Adjuvant; Pathologic Complete Response in Neoadjuvant (in vivo dynamic lab) vs Survival Endpoint in Adjuvant settings A prem. female with HER2-positive relapsed IBC (2003) Pre Rx Mid Rx Post Rx pCR Pretest probability near 0 in AC resistant tumors, after 5/5 pathologic response, post test probability is not Zero. FDA will not allow indication based on pathologic complete response; July 2004 Young adult with HER2-pos. primary IBC (2003) pCR Annals of Oncology: Trastuzumab in inflammatory breast cancer; Mehta et al. 2008; Patient is the teacher of clinician Neoadjuvant options at UCI • 2003-4:Pilot Study: AC followed by weekly paclitaxel, carboplatin + trastuzumab (TCH) – Sequential TCH reverses anthracycline resistance; – high pathologic complete response will translate into high overall survival; ? – short course of trastuzumab concurrent with optimized chemotherapy is adequate Rx; – minimum anthracycline may be important as it potentially targets cells with topoisomerase-II co-amplified cells in a heterogeneous HER2 population (SWOG, SABCS 2004) • 2004-5: UCI03-70: AC followed by weekly paclitaxel, carboplatin +/- trastuzumab (n=48) - Pathologic complete response following TCH does translate into superior overall survival (SABCS 2008) • 2005-7:UCI 05-38: AC followed by Albumin-paclitaxel, carboplatin +/trastuzumab or bevacizumab (n=43) – Pathologic complete response following dose-dense metronomic chemotherapy translates into high overall survival for triple negative breast cancer (JCO 2008) • 2008-2013: UCI07-61 : Albumin-paclitaxel, carboplatin +/- trastuzumab or bevacizumab (n=100+/120); DD AC is optional Trastuzumab-based combinations • • • • Studies 1 & 2: [NSABP 31 (UCI) and NCCTG] NEJM Oct 2005 After completion of AC, Herceptin weekly taken with Taxol weeks 1-12 followed by Herceptin alone weekly • • • • Study 3: HERA NEJM Oct 2005 After surgery and chemotherapy, Herceptin taken every 3 weeks • • Study 4: Slamon et al. NEJM 2012 After completion of AC, Herceptin weekly taken with Taxotere weeks 1-12 followed by Herceptin alone every 3 weeks • • 52% higher chance of remaining cancer free longer in the group of women who received AC→TH* (n=1872) compared with the group that received AC→T (n=1880) 46% higher chance of remaining cancer free longer in the group of women who received Herceptin alone† (n=1693) compared with the group that did not receive Herceptin (n=1693) 40% higher chance of remaining cancer free longer in the group of women who received AC→TH* (n=1074) compared with the group that received AC→T (n=1073) • Study 4: • After surgery, Herceptin weekly taken with Taxotere and carboplatin weeks 1-18 followed by Herceptin alone every 3 weeks • • 33% higher chance of remaining cancer free longer in the group of women who received TCH† (n=1075) compared with the group that received AC→T (n=1073) Trial Design: Neoadjuvant vs Adjuvant in Triple Negative Breast Cancer • Each 10% increase in pathologic complete response will translate into an absolute 2.6% 3-year survivalTN breast cancer specific calculation • Combination cytotoxic chemotherapy administered in a dose-dense or metronomic schedule remains the standard therapy for early-stage TNBC.[2011 NCI PDQ*] • • Dose-dense and/or metronomic schedules of specific chemotherapies consolidate the chemosensitivity of triple-negative breast cancer: a step toward reversing triple-negative paradox *Mehta RS:. J Clin Oncol 26 (19):, 2008 FDA will allow pathologic complete response rate endpoint for accelerated approval of new drugs 2012. Immediate Goal is to find the driver mutation and treat. Courtesy: Albain Breast Center Team & Collaborators • Campus: Drs. Tromberg, Su, Chen, Nelson (MRI and Laser Optics) • Breast Center: Drs. Butler, Lane and Hsiang • Hematology/Oncology: Drs. Sender, Nelson, Fruehauf, Zell, Nangia, Seery, Fellows • Cancer Center • Radiologists; Drs. Feig and Campbell • Members of IRB/CTPRMC/CRO/CRAC • Nurses • Patients Thank You