Βασικές αρχές ορμονοθεραπείας Κάθε ασθενής με ορμονοευαίσθητο καρκίνο μαστού δικαιούται να ξεκινήσει με ορμονικό χειρισμό εκτος και αν πάσχει από επιθετική παρεγχυματική νόσο (VISCERAL CRISIS) Κλινικοί παράγοντες ορμονοευαισθησίας μεγάλο DFS, μεταστάσεις σε λεμφαδένες ή οστά, υψηλά επίπεδα έκφρασης ER ή και PR, εμφάνιση αντίδρασης flare μετα τη θεραπεία Παράγοντες αντοχής στην ορμονοθεραπεία : υπερέκφραση (HER2)
SERMS (Selective Estrogen Receptor Modulators) ΤΑΜΟΞΙΦΑΙΝΗ, ΤΟΡΕΜΙΦΑΙΝΗ Aromatase inhibitors decrease circulating levels of estrogen by blocking the action of the enzyme aromatase, which converts androgens into estrogens. ΑΝΑΣΤΡΑΖΟΛΗ, ΛΕΤΡΟΖΟΛΗ, ΕΞΕΜΕΣΤΑΝΗ FULVESTRANT - blocks ER dimerization and promotes ER degradation
Αναστολείς αρωματάσης vs ταμοξιφαίνη Μετα-ανάλυση 1. Υπεροχή σε συνολική επιβίωση (relative hazard 0.89, 95% CI 0.80-0.99) για τους αναστολείς αρωματάσης τρίτης γενεάς σε θεραπεία πρώτης γραμμής 2. Υπεροχή σε συνολική επιβίωση έναντι προγεστερόνης σαν θεραπεία 2 ης και 3 ης γραμμής (relative hazard 0.86, 95% CI 0.79-0.94)
ΘΕΡΑΠΕΙΑ ΠΡΩΤΗΣ ΓΡΑΜΜΗΣ ΘΕΡΑΠΕΊΑ ΔΕΥΤΕΡΗΣ ΓΡΑΜΜΗΣ San Antonio Breast Cancer Conference 2010,2011 ECCO/ESMO 2011 ASCO 2011
ΜΕΛΕΤΗ TANDEM (anastrozole + herceptin vs anastrozole Lapatinib + letrozole vs letrozole Αποτέλεσμα: διπλασιασμος του PFS και στις δύο μελέτες Για γυναίκες (HER2) + ορμονοευαίσθητη νόσο προτείνεται αντι HER 2 θεραπεία (Grade 1A).
ΘΕΡΑΠΕΙΑ ΠΡΩΤΗΣ ΓΡΑΜΜΗΣ
FIRST: Study Design Randomized, open-label phase II trial Primary endpoint: CBR, defined as CR, PR, or SD for 24 wks Postmenopausal women with previously untreated hormone receptor positive advanced breast cancer (N = 205) Fulvestrant 500 mg by IM injection on Days 0, 14, 28, and every 28 days thereafter (n = 102) Anastrozole 1 mg/day PO (n = 103) Until disease progression or other event requiring discontinuation Robertson JFR, et al. SABCS 2010. Abstract S1-3.
FIRST: Comparable Clinical Benefit Rate Observed in Primary Analysis Outcome Fulvestrant (n = 102) Anastrozole (n = 103) OR (95% CI) P Value Absolute Difference, % (95% CI) Clinical benefit rate, % 72.5 67.0 1.30 (0.72-2.38).386 5.6 (-7.8 to 15.8) Robertson JF, et al. J Clin Oncol. 2009;27:4530-4535.
Parameter Fulvestrant (n = 102) Anastrozole (n = 103) Patients progressing, n (%) 63 (61.8) 79 (76.7) Median TTP, mos 23.4 13.1 HR (95% CI) 0.66 (0.47-0.92); P =.01 Robertson JFR, et al. SABCS 2010. Abstract S1-3.
FIRST: No Difference in Response to Subsequent Endocrine Therapy Patients Receiving Subsequent Endocrine Therapy, % Fulvestrant (n = 34) Anastrozole (n = 50) Achieved CR/PR 8.8 14.0 Achieved clinical benefit 41.2 42.0 Robertson JFR, et al. SABCS 2010. Abstract S1-3.
SWOG S0226: Study Design Primary endpoint: PFS Secondary endpoints: OS, Safety Stratified by previous adjuvant tamoxifen Treatment until disease progression Postmenopausal women with hormone receptor positive MBC (N = 707) Anastrozole 1 mg/day PO + Fulvestrant 500 mg on Day 1, 250 mg on Days 14 and 28, 250 mg every 28 days thereafter (n = 355) Anastrozole 1 mg/day PO (n = 352) Women with progression encouraged to cross over to receive fulvestrant Mehta RS, et al. SABCS 2011. Abstract S1-1.
SWOG S0226: PFS and OS Overall and by Previous Adjuvant Tamoxifen Endpoint Anastrozole + Fulvestrant Median PFS (n = 694), mos No previous adjuvant tamoxifen (n = 414) Previous adjuvant tamoxifen (n = 280) Median OS (n = 694), mos No previous adjuvant tamoxifen (n = 414) Previous adjuvant tamoxifen (n = 280) Mehta RS, et al. SABCS 2011. Abstract S1-1. Anastrozole HR (95% CI) P Value 15.0 13.5 0.80 (0.68-0.94) 17.0 12.6 0.74 (0.59-0.92) 13.5 14.1 0.89 (0.69-1.15) 47.7 41.3 0.81 (0.65-1.00) 47.7 39.7 0.74 (0.56-0.98) 49.6 44.5 0.91 (0.65-1.28).007.0055.37.049.0362.59
SWOG S0226: Unplanned Subset Analysis of PFS Overall HR: 0.80 Age 65+ yrs Age < 65 yrs HER2 positive HER2 negative Nonvisceral Visceral Bone only Nonmeasureable Measureable 10 yrs+ 5-10 yrs 0-5 yrs De novo No previous chemo Previous chemo No previous tam Previous tam Overall Combination better Combination worse Mehta RS, et al. SABCS 2011. Abstract S1-1. 0.4 0.6 0.8 1.0 1.2 1.4 1.6 HR
SWOG S0226: συμπεράσματα Σε μετεμμηνοπαυσιακές γυναίκες η θεραπεία 1 ης γραμμής με το συνδ. Anastrozole + fulvestrant αύξησε σημαντικά το PFS και OS έναντι της μονοθεραπείας με anastrozole Ανάλυση υποπληθ. Έδειξε πιθανό όφελος στην ομάδα που δεν είχε πάρει adj. tamoxifen Παρενέργεις ίδιες και στις 2 ομάδες S0226 efficacy findings differ from those of FACT study, which demonstrated a similar median TTP and OS with anastrozole plus fulvestrant vs anastrozole alone (2) 1. Mehta RS, et al. SABCS 2011. Abstract S1-1. 2. Bergh J, et al. SABCS 2009. Abstract 23
ΘΕΡΑΠΕΙΑ ΔΕΥΤΕΡΗΣ ΓΡΑΜΜΗΣ (ΠΡΟΗΓΟΥΜΕΝΗ ΕΚΘΕΣΗ ΣΕ ΑΝΑΣΤΟΛΕΙΣ ΑΡΩΜΑΤΑΣΗΣ ΣΑΝ 1 Η ΓΡΑΜΜΗ)
ΘΕΡΑΠΕΙΑ ΔΕΥΤΕΡΗΣ ΓΡΑΜΜΗΣ
CALGB 40302: Study Design Randomized, double-blind, placebo-controlled phase III trial Primary endpoint: PFS Stratified by previous tamoxifen treatment and presence of bone disease Postmenopausal women with hormone receptor positive advanced breast cancer with previous AI exposure (N = 267) Lapatinib* 1500 mg PO QD on Days 1-28 + Fulvestrant (n = 133) Placebo on Days 1-28 + Fulvestrant (n = 134) *Lapatinib dose adjustment for toxicity permitted. Fulvestrant administered by IM injection at 500 mg on Day 1, 250 mg on Days 15 and 28, and 250 mg every 28 days thereafter. Burstein HJ, et al. SABCS 2010. Abstract PD-05-01.
Endpoint, Mos Lapatinib + Fulvestrant Placebo + Fulvestrant Log Rank P Value Median PFS 5.2 4.0.94 Median OS 22.3 21.9.64 Burstein HJ, et al. SABCS 2010. Abstract PD-05-01.
Grade 3 Adverse Events, % Lapatinib + Fulvestrant (n = 133) Placebo + Fulvestrant (n = 134) Any 22 0 Diarrhea 9 0 Fatigue 4 0 Acneiform rash 4 0 Transaminitis 3 0 Dyspnea 2 0 Burstein HJ, et al. SABCS 2010. Abstract PD-05-01.
Randomized, controlled phase II trial Primary endpoint: CBR at 6 mos (CR + PR + SD) Stratified by primary vs secondary hormone resistance* Patients with HER2- negative, hormone receptor positive metastatic breast cancer with previous AI exposure (N = 111) Everolimus 10 mg/day + Tamoxifen 20 mg/day (n = 54) Tamoxifen 20 mg/day (n = 57) *Primary resistance: relapse during adjuvant AI therapy or progression during first 6 mos of initiating AI for metastatic disease. Secondary resistance: late relapse (at or after 6 mos) or previous response to AI therapy for metastatic breast cancer and subsequent progression. Bachelot T, et al. SABCS 2010. Abstract S1-6.
22 Strong Evidence Links Hormone Resistance to Cross-Talk Between Signal Transduction Pathways and ER Signaling IGF-1R, EGFR ER PI3K RAS E ER AKT TSC2TSC1 RAF MEK mtor ERK E ER Cell proliferation 22 Yue W. J Steroid Biochem Mol Biol. 2007; 106:102-110.
Everolimus (RAD001) Απο του στόματος ισχυρός αναστολέας του mammalian target of rapamycin (mtor) Έχει έγκριση για renal cell carcinoma Έχεί δείξει δραστηριότητα σε in vitro μοντέλα ορμονοαντοχής 1 Έχει δείξει δράση σε πρώιμε κλινικές δοκιμές 2,3 Αυξάνει σημαντικά τη δράση της λετροζόλης σε neoadjuvant θεραπεία 4 1. Boulay 23 A et al. Clin Cancer Res. 2005; 11:5319-5328. 2. Ellard SL et al. J Clin Oncol. 2009; 27:4536-4541. 3. Awada A et al. 2. Eur J Cancer. 2008; 44:84-91. 4. Baselga J et al. J Clin Oncol. 2009; 27:2630-2637.
TAMRAD Protocol Τυχαιοποιημένη μελέτη φάσης II Ασθενείς με μεταστατικό καρκίνο και προηγούμενη θεραπεία με αναστολείς αρωματάσης A: Tamoxifen 20 mg/d (TAM) B: Tamoxifen 20 mg/d + RAD001 10 mg/d (TAM + RAD) Διαστρωμάτωση : πρωτογενής ή δευτερογενής ορμονική αντίσταση Πρωτογενής : υποτροπή κατά τη διάρκεια της συμπληρωματικής θεραπείας με ΑA; Πρόοδος νόσου μεσα σε 6 μήνες από την έναρξη θεραπείας με AΑ σε μεταστατική νόσο Δευτερογενής : καθυστερημένη υποτροπή ( 6 μήνες) ή προηγούμενη ανταπόκριση και επακόλουθη πρόοδος σε μεταστατική νόσο με αγωγή με ΑΑ No crossover planned 24 AI = aromatase inhibitor.
Key Inclusion Criteria Menopausal condition Hormone-receptor positive and HER2 negative With or without measurable disease Treated with AIs in the adjuvant and/or metastatic setting May have received tamoxifen in the adjuvant setting May have received chemotherapy in the adjuvant/metastatic setting
Statistical Consideration Primary endpoint : Clinical benefit rate (CBR) at 6 months (CR + PR + SD at 6 months) Secondary endpoints Time to disease progression Overall survival Objective response rate Toxicity Translational studies Simon two-stage minimax design, with alpha = 5% and power = 90% 26 CR = complete response; PR = partial response; SD = stable disease.
Study Status as of September 2011 111 patients included (March 2008/May 2009) Final analysis: May 2011 Median follow-up 24 month Overall survival update: September 2011 Translational research Initial tumor samples from 48 patients mtor pathway markers by immunohistochemistry (IHC) ps6k; 4EBP1 Mutational analysis PI3K, exon 9 and 20; KRAS exon 2 27
Patient Characteristics TAM n = 57 TAM + RAD n = 54 Median age, years (range) 66 (42-86) 62.5 (41-81) Median duration of metastatic disease, months (range) 14.4 (0.7-102) 13.2 (1.2-94.8) Disease stage, n (%) Bone Bone only Visceral 3 or more Previous anti-aromatase treatment, n (%) Adjuvant only Metastatic only Adjuvant + metastatic 45 (78.9) 14 (24.6) 28 (49.1) 16 (28.1) 20 (35.1) 33 (57.9) 4 (7) 41 (75.9) 16 (29.6) 31 (57.4) 13 (24.1) 17 (31.5) 33 (61.1) 4 (7.4) Previous adjuvant TAM treatment, n (%) 24 (42.1) 18 (33.3) Previous chemotherapy, n (%) Adjuvant Metastatic 32 (56.1) 15 (26.3) 25 (46.3) 13 (24.1) Primary hormone resistance, n (%) 28 (49.1) 26 (49.1) Secondary hormone resistance, n (%) 29 (50.9) 27 (50.9)
TTP Probability CBR, % of Patients (95% CI) Clinical Benefit Rate and Time to Progression (TTP) Clinical benefit rate P = 0.045 (exploratory analysis) 70 60 50 40 30 20 10 0 42.1% (29.1-55.9) TAM 61.1% (46.9-74.1) TAM + RAD Time to progression TAM: 4.5 months TAM + RAD: 8.6 months HR (95% CI) = 0.54 (0.36-0.81) P = 0.0021 (exploratory analysis) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 At risk 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Months 57 44 30 24 22 16 13 11 7 6 4 2 2 1 0 0 54 45 39 34 28 26 25 20 19 17 14 10 3 3 2 1 TAM TAM + RAD
Overall Survival (as of September 2011) No crossover was planned or allowed. TAM TAM + RAD At risk 57 54 56 54 54 53 53 52 52 50 56 50 44 50 43 50 39 47 37 47 37 47 36 44 32 38 26 33 20 28 16 22 8 15 6 10 5 8 2 3 1 0
Clinical Benefit in Selected Subgroup CBR, n (%) TAM n = 57 TAM + RAD n = 54 ALL 24/57 (42.1) 33/54 (61.1) Visceral metastases No visceral metastases Previous adjuvant tamoxifen No previous adjuvant tamoxifen Previous metastatic chemotherapy No previous metastatic chemotherapy Primary hormone resistance Secondary hormone resistance 11/28 (39.3) 13/29 (44.8) 9/24 (37.5) 15/33 (45.5) 4/15 (26.7) 20/42 (47.6) 10/28 (35.7) 14/29 (48.3) 19/31 (61.3) 14/23 (60.9) 12/18 (66.7) 21/36 (58.3) 6/13 (46.2) 27/41 (65.9) 12/26 (46.2) 20/27 (74.1) 31
TTP Probability TTP Probability Time to Progression as a Function of Intrinsic Hormone Resistance 1.0 Primary resistance TAM: 3.8 months TAM + RAD: 5.4 months HR = 0.70 (0.40-1.21) P = NS (exploratory analysis) Secondary resistance TAM: 5.5 months TAM + RAD: 14.8 months HR = 0.46 (0.26-0.83) P = 0.0087 (exploratory analysis) 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 TAM TAM + RAD 0 6 12 18 24 30 Months 0 6 12 18 24 30 Months
Primary resistance Survival as a Function of Intrinsic N (%) of events TAM: 15 (54%) TAM + RAD: 12 (46%) HR = 0.73 (0.34-1.55) P = 0.41 (exploratory analysis) Hormone Resistance 1,0 Probability of Survival 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 TAM TAM + RAD 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 Months 33 Secondary resistance N (%) of events TAM: 16 (55%) TAM + RAD: 4 (15%) HR = 0.21 (0.07-0.63) P = 0.002 (exploratory analysis)
34 PI3K and KRAS Mutational Status Mutational analysis was performed for PI3K and KRAS in 48 patients (primary tumor) PI3K, exon 9 mutation: 1/48 (2%) PI3K, exon 20 mutation: 2/47 (4.2%) KRAS mutation: 4/48 (8.3%) Incidence of PI3K and KRAS mutation was lower than expected; no statistical analysis was performed
35 mtor Activation Biomarker Assessed in 35 patients (primary tumor) Cut-off (high/low) as the median percentage of marked cell ps6k 4EBP +
Treatment Effect as a Function of Biomarker Expression (TTP) 36 High ps6k Low ps6k TAM TAM + RAD
Treatment Effect as a Function of Biomarker Expression (TTP) High 4EBP Low 4EBP TAM TAM + RAD
Adverse Events Incidence, n (%) TAM n = 57 TAM + RAD n = 54 Grade Any 3/4 Any 3/4 Most Common Adverse Events (AEs) Fatigue Stomatitis Rash Anorexia Diarrhea Nausea Vomiting Pneumonitis Thromboembolic Pain 30 (52.6) 4 (7.0) 4 (7.0) 10 (17.5) 5 (8.8) 20 (35.1) 7 (12.3) 2 (3.5) 4 (7.0) 49 (90.7) 6 (10.5) 0 0 2 (3.5) 0 0 2 (3.5) 2 (3.5) 4 (7.0) 10 (18.5) 39 (72.2) 30 (55.6) 24 (44.4) 23 (42.6) 21 (38.9) 19 (35.2) 9 (16.7) 9 (16.7) 5 (8.8) 44 (81.5) 3 (5.6) 6 (11.1) 2 (3.7) 4 (7.4) 1 (1.9) 2 (3.7) 0 1 (1.9) 3 (5.6) 5 (9.3) Dose reduction due to AE 0 (0) 11 (20) Treatment discontinuation due to AE 4 (7.0) 12 (22) 38
Συμπεράσματα In this randomized phase II trial of an mtor inhibitor and anti-estrogen combination in AI-pretreated patients: CBR, TTP, and survival increased with the addition of everolimus to tamoxifen compared with tamoxifen alone CBR: 61 vs 42 % TTP: HR = 0.54; 95% CI, 0.36-0.81 Survival: HR = 0.45; 95% CI, 0.24-0.81 Clinical benefit may favor patients with secondary hormone resistance Preliminary results of translational analysis show a possible correlation between biomarkers of mtor activation and everolimus efficacy Toxicity was manageable and consistent with previous studies 39
AMG 479: Background IGF-1R widely expressed transmembrane tyrosine kinase Activates PI3-kinase/AKT and Ras/MAP signal transduction cascades upon IGF-1 or IGF-2 binding Coexpressed with ER in a subset of ER-positive breast cancers Increased signaling may drive resistance to hormonal therapy AMG 479: investigational monoclonal IGF-1R antibody Inhibits IGF-1 and IGF-2 binding to IGF-1R Kaufman PA, et al. SABCS 2010. Abstract S1-4.
AMG 479: Study Design Randomized, placebo-controlled, double-blind phase II trial Primary endpoint: PFS Randomized 2:1; stratified by exemestane vs fulvestrant and disease extent Postmenopausal women with hormone receptor positive metastatic or locally advanced breast cancer with history of disease progression on endocrine therapy (N = 156) AMG 479 12 mg/kg IV every 2 wks + Exemestane or Fulvestrant* (n = 106) Placebo IV every 2 wks + Exemestane or Fulvestrant* (n = 50) Until disease progression *Exemestane or fulvestrant selected by investigator. Exemestane dosed at 25 mg/day PO. Fulvestrant dosed at 500 mg on Day 1, 250 mg on Days 15, 29, and every 4 wks thereafter, by IM injection. Kaufman PA, et al. SABCS 2010. Abstract S1-4.
AMG 479: Treatment History Characteristic, % AMG 479 (n = 106) Previous chemotherapy Placebo (n = 50) Adjuvant setting 49 46 Metastatic setting 18 18 Previous radiotherapy 84 82 Previous hormone therapy 1 regimen 100 100 Adjuvant setting 75 74 Metastatic setting 52 58 Kaufman PA, et al. SABCS 2010. Abstract S1-4.
Patients Event Free (%) AMG 479 Had No Significant Effect on PFS Outcome, Mos AMG 479 (n = 106) Placebo (n = 50) HR* (80% CI) P Value 100 80 Median PFS 3.9 5.7 1.17 (0.91-1.50).435 60 40 20 0 Placebo AMG 479 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Patients at Risk, n 50 50 36 33 106 102 72 64 30 50 27 47 24 42 24 40 19 35 18 30 Mos 11 20 9 15 6 12 5 8 5 8 4 4 3 4 1 3 1 3 1 0 1 0 21 *Stratified by endocrine therapy + extent of disease. Stratified log rank test. Kaufman PA, et al. SABCS 2010. Abstract S1-4.
AMG 479: Response Rates Among Pts With Measureable Disease at Baseline Response, % AMG 479 (n = 63) Placebo (n = 32) CBR 35 31 Best response CR 0 0 PR 8 13 SD 24 wks 27 19 SD < 24 wks 21 34 PD 35 34 Unevaluable 10 0 Kaufman PA, et al. SABCS 2010. Abstract S1-4.
ΕCCO ESMO 2011 Everolimus in combination with exemestane for postmenopausal women with advanced breast cancer who are refractory to letrozole or anastrozole: results of the BOLERO-2 phase III trial J. Baselga, M. Campone, T. Sahmoud, M. Piccart, H. Burris, H. Rugo, S. Noguchi, M. Gnant, P. Mukhopadhyay, G. Hortobagyi On behalf of the BOLERO-2 Investigators
Crosstalk between ER and mtor Signaling mtorc1 activates ER in a ligand-independent fashion 1 Estradiol suppresses apoptosis induced by PI3K/mTOR blockade 2 Hyperactivation of the PI3K/mTOR pathway is observed in endocrineresistant breast cancer cells 3 mtor is a rational target to enhance the efficacy of hormonal therapy 1. Yamnik, RL. J Biol Chem 2009; 284(10):6361-6369. 2. Crowder, RJ. Cancer Res 2009;69:3955-62. 3. Miller, TW. J Clin Invest 2010; 120(7):2406-2413. 46
Ph II Neoadjuvant Letrozole ± Everolimus: Proof of Concept N= 270 Postmenopausal ER+ early breast cancer Everolimus 10 mg/day + Letrozole 2.5 mg/day Placebo + Letrozole 2.5 mg/day Surgery ORR Biomarkers: D14 and surgical specimen Results: Significantly higher response rate (primary endpoint) Everolimus arm 68% vs placebo arm 59% Significantly greater decrease in Ki67 proliferation index Everolimus arm 57% vs placebo arm 30% Baselga J. 2009. J Clin Oncol 2009;27:2630-7.
BOLERO-2: Trial Design N = 724 Postmenopausal ER+ HER2- ABC refractory to letrozole or anastrozole 2 1 Everolimus 10 mg/day + Exemestane 25 mg/day (N = 485) Placebo + Exemestane 25 mg/day (N = 239) PFS OS ORR Bone Markers Safety PK Stratification: 1. Sensitivity to prior hormonal therapy 2. Presence of visceral disease No cross-over ABC: advanced breast cancer, NSAI: non steroidal aromatase inhibitors, HER2-: human epidermal growth factor receptor 2 negative; PFS: progression-free survival; PK: pharmacokinetics 48 Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
BOLERO-2: Baseline Characteristics Characteristic Everolimus + Exemestane (N=485), % Placebo + Exemestane (N=239), % Median age (range), years 62 (34, 93) 61 (28, 90) Race Caucasian 74 78 Asian 20 19 Performance status 0 60 59 Liver involvement 33 30 Lung involvement 29 33 Measurable disease a 70 68 a All other patients had 1 bone lesion. Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
Therapy BOLERO-2: Prior Therapy Everolimus + Exemestane (N=485), % Placebo + Exemestane (N=239), % Sensitivity to prior hormonal therapy 84 84 Last treatment: LET/ ANA 74 75 Last treatment Adjuvant 21 16 Metastatic 79 84 Prior tamoxifen 47 49 Prior fulvestrant 17 16 Prior chemotherapy for metastatic BC 26 24 Number of prior therapies: 3 54 53 LET: letrozole, ANA: anastrozole 50 Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
BOLERO-2 Primary Endpoint: PFS Local Assessment Everolimus 485 398 294 212 144 108 75 51 34 18 8 3 3 0 Placebo 239 177 109 70 36 26 16 14 9 4 3 1 0 0 Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
Probability of Event (%) BOLERO-2 Primary Endpoint: PFS Central Assessment HR = 0.36 (95% CI: 0.27 0.47) 100 Log rank P value = 3.3 x 10-15 80 EVE + EXE: 10.6 Months PBO + EXE: 4.1 Months 60 40 20 0 Everolimus + Exemestane (E/N=114/485) Placebo + Exemestane (E/N=104/239) 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Time (weeks) No. of Patients Still at Risk: Everolimus485 385 281 201 132 102 67 43 28 18 9 3 2 Placebo 239 168 94 55 33 20 11 11 6 3 3 1 0 0 52 Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
Subgroups (N) All (724) Age <65 (449) 65 (275) Region Asia (137) Europe (275) North America (274) Other (38) Sensitivity to prior hormonal therapy Yes (610) No (114) Visceral metastasis Yes (406) No (318) Last therapy Aromatase inhibitor (532) Antiestrogen (122) Other (70) Last therapy setting Metastatic (586) Adjuvant (138) Prior chemotherapy Adjuvant only (306) Metastatic (186) None (232) BOLERO 2: PFS Subgroup Analyses Favors EVE + EXE Favors PBO + EXE 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 Hazard Ratio Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
BOLERO-2: Overall Response Rate and Clinical Benefit Rate by Local Assessment P < 0.0001 P < 0.0001 Presented 54by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
BOLERO-2: Overall Survival As of PFS interim analysis: 83 deaths 10.6% in everolimus arm 13.0% in placebo arm OS interim analysis after 173 events OS final analysis at 392 events 80% power to detect 26% reduction in hazard ratio (0.74) 55 Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
BOLERO-2: Most Common G3/4 AEs Everolimus + Exemestane (N = 482), % All Grades Grade 3 Grade 4 Placebo + Exemestane (N = 238), % All Grades Grade 3 Grade 4 Stomatitis 56 8 0 11 1 0 Fatigue 33 3 <1 26 1 0 Dyspnea 18 4 0 9 1 <1 Anemia 16 5 <1 4 <1 <1 Hyperglycemia 13 4 <1 2 <1 0 AST 13 3 <1 6 1 0 Pneumonitis 12 3 0 0 0 0 AE: Adverse Event; AST: Aspartate aminotransferase 56 Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
Probability of Event, % Global Health Status EORTC-QLQ30 QoL Scale Score: Time to 5% deterioration 100 90 80 70 60 HR = 0.91 (95% CI: 0.68 1.20) Log rank P value = 0.217 EVE + EXE: 4.5 months PBO + EXE: 4.4 months 50 40 30 20 10 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 No. of patients still at risk Everolimus 485 404 236 Placebo 239 190 94 Everolimus + Exemestane (E/N = 226/485) Placebo + Exemestane (E/N = 98/239) Time, weeks 161 112 84 56 62 41 23 13 37 23 18 12 9 5 2 1 2 1 0 0 0 0 57 Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
BOLERO-2: Συμπεράσματα Η προσθήκη του everolimus στην εξεμεστάνη παρατείνει το PFS σε ασθενείς με μεταστατικό καρκίνο του μαστού ER+ HER2- ανθεκτικού σε αρχικό ορμονικό χειρισμό με μη στεροειδικούς ΑΑ Local: median 6.9 vs 2.8 months, HR = 0.43, P < 0.0001 Central: median 10.6 vs 4.1 months, HR = 0.36, P < 0.00 Κλινική ωφέλεια παρατηρήθηκε σε όλες τις υποομάδες Οι παρενέργεις ήταν οι αναμενόμενες με βάση την ήδη υπάρχουσα εμπειρία με το everolimus και περι λαμβάνει τη στοματίτιδα, κόπωση, και υπεργλυκαιμία. Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
BOLERO-2: Συμπεράσματα Το Everolimus είναι ο πρώτος παράγοντας που φαίνεται ότι ενισχύει την κλινική ωφέλεια της ορμονικής θεραπείας σε ανθεκτικό ER+ καρκίνο του μαστού Τα αποτελέσματα της μελέτης θα μπορούσαν να αλλάξουν την ήδη υπάρχουσα κλινική πρακτική για τον μεταστατικό καρκίνου του μαστού με θετικούς ορμονικούς υποδοχείς. Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
Entinostat: Epigenetic Modulation of Hormonal Therapy in Breast Cancer AI resistance characterized by estrogenindependent growth of breast cancer cells Mechanisms of resistance may include decreased ER expression and increased growth factor signaling (eg, via HER2) Entinostat, a selective HDAC inhibitor, associated with increased expression of ERα and aromatase in preclinical studies ERα and aromatase upregulation sensitizes breast cancer cells to effects of estrogen and AI therapy Sabnis GJ, et al. Cancer Res. 2011;71:1893-1903.
ENCORE 301: Study Design Primary endpoint: PFS Secondary endpoints: ORR, clinical benefit rate Treatment until disease progression or unacceptable toxicity Postmenopausal women with ERpositive advanced breast cancer who progressed on previous nonsteroidal AI therapy (N = 130) Exemestane 25 mg/day + Entinostat 5 mg/wk (n = 64) Exemestane 25 mg/day + Placebo (n = 66) Yardley DA, et al. SABCS 2011. Abstract PD01-04.
ENCORE 301: PFS Overall and by Subgroup Median PFS, Mos Exemestane + Entinostat (n = 64) Exemestane + Placebo (n = 66) ITT population 4.28 2.27 Patient subgroups Per protocol population 4.74 2.20 Visceral involvement 4.28 2.20 PgR positive 4.28 1.97 AI sensitivity Sensitive 4.87 3.36 Resistant 3.72 1.78 Setting of AI progression Adjuvant 3.49 1.78 Advanced 4.87 2.27 HR (95% CI) 0.73 (0.49-1.09)* 0.74 (0.49-1.13) 0.69 (0.42-1.14) 0.66 (0.42-1.04) 0.90 (0.55-1.45) 0.61 (0.30-1.25) 0.61 (0.21-1.72) 0.78 (0.51-1.19) *P =.06. Statistically significant based on protocol-defined 1-sided significance level (P =.10). Yardley DA, et al. SABCS 2011. Abstract PD01-04.
Adverse Events, % Exemestane + Entinostat (n = 64) Exemestane + Placebo (n = 66) All Grades Grade 3/4 All Grades Grade 3/4 Fatigue 46 13 26 3 Nausea 40 5 15 2 Weight loss 17 0 18 0 Anemia 19 2 12 3 Back pain 14 0 17 2 Dyspnea 3 11 19 Arthralgia 11 2 17 0 Diarrhea 16 0 12 2 Constipation 10 0 15 2 Neutropenia 25 13 0 0 Peripheral edema 21 0 5 0 Vomiting 21 5 5 0 Thrombocytopenia 17 0 6 2 Pain 16 2 6 2 Yardley DA, et al. SABCS 2011. Abstract PD01-04.
ENCORE 301: Συμπεράσματα Ο συνδυασμός exemestane με entinostat παρατείνει σημαντικά τη διάμεση PFS σε μετεμμηνοπαυσιακές γυναίκες με μεταστατικό καρκίνο μαστού που προοδευσε μετα από ΑΑ Το όφελος παρατηρήθηκε σε όλες τις υποομάδες Yardley DA, et al. SABCS 2011. Abstract PD01-04.
ΟΡΜΟΝΟΕΥΑΙΣΘΗΤΟΣ ΚΑΡΚΙΝΟΣ ΜΑΣΤΟΥ - ΣΥΜΠΕΡΑΣΜΑΤΑ Σε HER 2 + νόσο προτείνεται προσθήκη αντι ΗΕR 2 παράγοντα (grade 1A) Για μεταεμμηνοπαυσιακές γυναίκες προτείνεται θεραπεία με αναστολείς αρωματάσης 3 ης γενιας, με αναστραζόλη ή λετροζόλη ή εξεμεστάνη για πρωτο ορμονικό χειρισμό (Grade 1A). Σαν θεραπεία 2 ης γραμμής φαίνεται ότι η προσθήκη του everolimus σε ορμονικό παράγοντα αυξάνει το PFS και ίσως αποτελέσει την επόμενη λογική επιλογή θεραπείας