Everolimus e la ridefinizione del paradigma nel trattamento delle pazienti con carcinoma mammario ER+/HER2-
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1 Everolimus e la ridefinizione del paradigma nel trattamento delle pazienti con carcinoma mammario ER+/HER2- VINCENZO ADAMO UOC Oncologia Medica AOOR Papardo-Piemonte - Università degli Studi di Messina
2 Breast Cancer Intrinsic Subtypes: A Spectrum Hayes D. et al, JCO 2012
3 Classifications by Biologic Subtypes: Molecular Portrait of Breast Cancers SørlieT, et al. Proc Natl Acad Sci USA. 2001;98(19): Prat A, et al. Breast Cancer Res. 2010;12(5):R68
4 SystemicTreatment Approaches for ER+,HER2- MBC Metastatic Breast Cancer ER+ and HER2 negative Only Bone Metastases Limited visceral metastases Slow disease progression Endocrine-responsive Hormonal Therapy??? Exstensive metastases Visceral disease Rapid Progression No-response to hormonotherapy Chemotherapy Response Non response No Progression Progression of disease If disease PD, second-line HT If disease PD, third-line HT Second-line of chemotherapy Third-line of chemotherapy
5 The Problem in ER+, HER2 neg Tumors is Endocrine Therapy Resistance About 50% of hormone receptor-positive breast cancers are de novo resistant to endocrine therapy Almost all patients with advanced disease will develop acquired resistance to endocrine therapies The mechanisms of de novo and acquired resistance are likely similar, but are not completely understood
6 Signal Transduction Pathways & ER signaling RTKs: EGFR, HER2, IGF1-R ER Src CoA PTEN ER P PI3K Ras TSC1/2 AKT MAPK mtor signaling plays E=oestrogen E S6KI ER P ER P mtor P P P ER CoA P P CoA a key role in Cell growth Cell proliferation Regulation of - Apoptosis - Angiogenesis - Metabolism EREs P AP-1/SP-1 CoA Figure adapted from Wander SA, et al. J Clin Invest. 2011;121: ; Osborne CK, et al. Annu Rev Med. 2011;62: ; Yamnik RL, et al. J Biol Chem. 2009;284: TFs-REs
7 The PI3K/AKT/mTOR Pathway Genetically Altered or Mutated Frequently
8 PIK3CA Mutation the Most Common Mutation in Breast Cancer Cancer Genome Atlas Network. Nature. 2012;490(7418):61-70.
9 Rationale for PI3K/mTOR inhibitors in HR+ HER2- MBC Baselga J et al. The Oncologist (suppl 1):12 19
10 mtor Inhibition in Breast Cancer mtor Mammalian target of rapamycin Allosteric inhibitors Sirolimus (rapamycin) Everolimus (RAD001) Temsirolimus Low activity as single agents in pretreated metastatic disease Everolimus PO RR 12% Temsirolimus IV RR 9.2% Zoncu R, et al. Nat Rev Mol Cell Biol. 2011;12(1): Ellard SL, et al. J Clin Oncol. 2009;27(27): Chan C, et al. J Clin Oncol. 2005;23(23):
11 Everolimus Selectively Hits mtor
12 Cell proliferation (absorbance 540 nm) mtor Inhibition Combines Effectively With Hormonal Therapy in BC Interaction between mtor and ERa Growth factors mtor S6K MDA-MB- 231 T47D * MCF7 * ZR-75-1 E Ser 167 P ERα Transcription ER-Responsive Element 4-HT, 4-hydroxytamoxifen. 12 Control Rapamycin 0.1μM 4-HT 0.1μM 4-HT+ rapamycin *P < 0.05, 2-tailed paired Student t test. Cell proliferation Yamnik RL et al. J Biol Chem. 2009;284(10): ; Johnston SR. Clin Cancer Res. 2005;11(2 Pt 2):889S-899S.
13 Biology of breast cancer inhibition of multiple pathways RTKs: EGFR, HER2, IGF1-R Endocrine therapy E ER Src CoA TSC1/2 S6KI ER PTEN ER PI3K AKT P P mtor Ras MAPK P P mtor inhibitor We have entered a new era where endocrine therapy can be combined with targeted therapy E=oestrogen P ER EREs P CoA P P ER P CoA AP-1/SP-1 Figure adapted from Wander SA, et al. J Clin Invest. 2011;121: ; Osborne CK, et al. Annu Rev Med. 2011;62: ; Yamnik RL, et al. J Biol Chem. 2009;284: CoA TFs-REs
14 Phase II Neoadjuvant Letrozole +/- Everolimus (RAD001) Breast Cancer Study Newly diagnosed, untreated patients with ER+ localized breast cancer likely to benefit from hormonal therapy Palpable tumor: >2 cm diameter Baselga J, et al. J Clin Oncol. 2009;27(16):
15 Targeting mtor to Enhance Endocrine Therapy ORR, overall response rate; USS, ultrasound Baselga J, et al. J Clin Oncol. 2009;27(16):
16 TAMRAD Primary Endpoint: clinical benefit rate (CBR) Bachelot T, et al. J Clin Oncol. 2012;30(22):
17
18 TAMRAD: Results Time to Progression Overall Survival Bachelot T et al., J Clin Oncol 2012;30: ;
19 TAMRAD Who to Select for Everolimus? Primary resistance Secondary resistance Bachelot T et al., J Clin Oncol 2012;30: ;
20 Randomized Phase III Trial Exemestane ± RAD001 in Postmenopausal with ER+ HER2-LABC/MBC Refractory to Letrozole or Anastrozole (BOLERO-2) BOLERO-2 N = 724 Postmenopausal women Advanced Breast Cancer NSAI-refractory disease Recurrence during/within 12 mo of adjuvant treatment or Progression during/within 1 mo of treatment for advanced disease Primary Endpoint: PFS by local assessment R 2:1 Baselga J, et al. N Engl J Med. 2012;366(6): Everolimus 10 mg PO daily + Exemestane 25 mg PO daily Placebo 10 mg PO daily + Exemestane 25 mg PO daily Key Baseline Characteristics Median age, years 62 Race, % Caucasian Asian Visceral involvement, % 56 Bone metastases, % 77 n = 485 n = 239
21 Probability of Event, % Probability of Event, % BOLERO-2 Efficacy PFS Local* PFS Central* 100 HR = 0.45 (95% CI: ) Log-rank P value: < HR = 0.38 (95% CI: ) Log-rank P value: < EVE + EXE: 7.82 months PBO + EXE: 3.19 months 80 EVE + EXE: months PBO + EXE: 4.14 months Time, weeks Time, weeks Final PFS Analysis: 18-month Median Follow-up Abbreviation: CI, confidence interval; HR, hazard ratio; PBO, placebo; PFS, progression-free survival. 1.Baselga J, et al. N Engl J Med. 2012;366(6): *Piccart 2.Piccart M, et M, al. et ASCO al. 2012; Cancer Abstract Res ;72(Suppl 24): Abstract P
22 BOLERO-2 (18-mo f/up): PFS Benefits Were Comparable In Patients With (A) Visceral Metastases, (B) Without Visceral Metastases, and (C) With Bone-Only Metastases Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival. Piccart M, et al. SABCS 2012; poster P ; Campone M, et al. ESMO 2012; abstract 324PD (poster discussion)
23 Everolimus modulates bone turnover markers
24 Common Adverse Events Bolero-2 vs Tamrad Everolimus + Exemestane (N=482), % Placebo + Exemestane (N=238), % Everolimus+ Tamoxifene (N=54),% Tamoxifene Alone (N=57),% Grade Grade Grade Grade All 3 4 All 3 4 All 3/4 All 3/4 Stomatitis < Rash Fatigue 33 3 < Diarrhea 30 2 <1 16 < Nausea 27 <1 < Appetite decreased Non-infectious pneumonitis* NR NR NR NR Hyperglycemia* 13 4 <1 2 <1 0 NR NR NR NR 1.Baselga J, et al. N Engl J Med. 2012; ; 2. Bachelot T. et al. J Clin Oncol 2012;
25
26 can you predict who benefit from mtor inhibitors in the clinic
27 Probability of Progression-Free Survival Correlation of molecular alterations with efficacy of everolimus in HR+, HER2- ABC: results from BOLERO NGS = 227 ITT = Time, days Population N (% ITT) N Events (%) EVE.ITT EVE.NGS PBO.ITT PBO.NGS PFS (months) Median (95%CI) ITT EVE (60.4%) 7.8 ( ) ITT PBO (82.4%) 3.2 ( ) NGS EVE 157 (32.4%) 94 (59.9%) 7.0 ( ) NGS PBO 70 (29.3%) 59 (84.3%) 2.6 ( ) Abbreviations: CI, confidence interval; EVE, everolimus; HR, hazard ratio; ITT, intent to treat; NGS, next generation sequencing ; PBO, placebo; PFS, progression-free survival. Hortobagyi et al. Poster discussion ASCO 2013 No major baseline clinical and demographic differences observed between ITT and NGS populations Clinical efficacies are comparable between the populations HR (95%CI) 0.45 ( ) 0.40 ( )
28 Frequency of Genetic Alterations in Key Pathways Gene % PIK3CA 47.6 CCND TP FGFR MCL MYC 14.1 CDH MDM GNAS 7.5 ARID1A 6.2 PTEN 5.7 AKT1 5.7 MAP2K4 5.3 MDM2 4.4 RUNX1 4.4 ESR Tumor samples Mutation type Missense NS_FS_Splice_Indel Amplification Loss Hortobagyi et al. Poster discussion ASCO 2013
29 Impact on Treatment by Genetic Status The Most Frequently Altered Single Genes and Pathways Alt : PIK3CA WT : PIK3CA Alt : PI3K WT : PI3K Alt : CCND1 WT : CCND1 Alt : Cell Cycle WT : Cell Cycle Alt : TP53 WT : TP53 Alt : p53 WT : p53 Alt : FGFR1 WT : FGFR1 Alt: FGFR1/2 WT : FGFR1/2 Positive treatment effect in favor of everolimus across the various genetic marker subgroups Pathway composition PI3K: PIK3CA, PTEN, AKT (PIK3CA Alt: 47.6%, total alteration: 55.5%) Cell Cycle: CCND1, CDK4, CDK6, CDKN2A, CDKN2B, (CCND1 Alt: 31.3%, total alteration: 35.7%) p53: TP53, MDM2, MDM4 (TP53 Alt: 23.3%, total alteration: 36.1%) FGFR1/2: FGFR1, FGFR2 (FGFR1 Alt: 18.1%, total alteration: 21.1%) HR of NGS population Genetically altered (Alt) log 10 (hazard) Wild Type (WT) EVE+EXE better Hortobagyi et al. Poster discussion ASCO 2013
30 Probability of Progression-Free Survival Greater PFS Benefit With EVE in Patients With Minimal Alterations in PIK3CA/PTEN/CCND1 or FGFR1/ EVE.PI3K/FGFR/CCND1_.WT/single EVE.PI3K/FGFR/CCND1_.multiple PBO.PI3K/FGFR/CCND1_.WT/single PBO.PI3K/FGFR/CCND1_.multiple HR (95% CI): 0.27 ( ) Time, days Abbreviations: CI, confidence interval; EVE, everolimus; HR, hazard ratio; PBO, placebo; PFS, progression-free survival; WT, wild type. Hortobagyi et al. Poster discussion ASCO 2013
31 Predictive markers of everolimus efficacy in HR+,HER2- MBC: Final results of the TAMRAD trial translational study Treilleux I et al., poster discussion ASCO 2013
32 TTP in Subgroup defined by differential expression of tested biomarker Treilleux I et al., poster discussion ASCO 2013
33 Treatment effect as a function of PI3K, LKB1,p4EBP-1 expression (TTP)
34 How it changed the treatment in patients with ER+ and HER2 negative Rowan T. Chlebowski Clin Breast Cancer Jun;13(3):159-66
35 BOLERO-4 Everolimus + Letrozole, 1 st -line ER + mbc Primary endpoint: First PFS Secondary endpoints: Second PFS, ORR, CBR, Safety, OS, Stomatitis (severity and duration) Progression 1 Progression 2 N = 100 Postmenopausal ER+ HER2- mbc If NSAI as adjuvant, recurrence >1 year after end of adjuvant Everolimus + Letrozole + Dexamethasone oral solution vs. SOC for stomatitis Everolimus + Exemestane
36 Everolimus + Exemestane vs Everolimus vs Capecitabine pts 300 pts Final Analysis Stratification: Visceral metastases, prior use of chemotherapy in the metastatic setting (one line) Trial aims at estimation of hazard ratio and confidence limits. N = 300 Postmenopausal ER + HER2 ABC After recurrence or progression on letrozole or anastrozole Everolimus + Placebo (N = 100) Everolimus + Exemestane (N = 100) Capecitabine 1250mg BID (N = 100) PFS OS, ORR, CBR, Safety, PK, Biomarker
37 CONCLUSIONS The data from this trial will provide efficacy and safety information on EVE in combination with ongoing adjuvant ET (AIs or ER- modulators) versus ET alone in patients with high risk ER+ HER2 early BC.
38 38 Presentation Title Presenter Name Date Subject
39 39 Presentation Title Presenter Name Date Subject Business Use Only
40 Everolimus in combination with chemotherapy Trial Subtype Drugs Treatments Phase N NCT MBC Triple-Negative HER2-negative Everolimus Cisplatin Paclitaxel 1/2 55 NCT as First-Line Chemotherapy HER2-negative Everolimus Paclitaxel Bevacizumab NCT Current Neoadjuvant Chemotherapy (GeparQuinto) HER2-negative or HER2-positive Everolimus Epirubicin Cyclophosphamide Docetaxel Bevacizumab Paclitaxel Trastuzumab Lapatinib NCT Advanced or Metastatic HER2-negative Everolimus Albumin-bound Paclitaxel 1/2 72 Yardley DE, Breast Cancer: Basic and Clinical Research 2013:7 7 22
41 Take home messages The strategy of combining mtor inhibitors with ET, targeted agents or cytotoxic chemo could be produce signals of antitumor activity or could delay the development of resistance to these agents. Selective patient criteria and rational selection of combination therapies may enhance the success of mtor therapies Surely we must wait the information emerging from the many ongoing clinical trials of mtor combinations in MBC.
42 Signaling of the PI3K/AKT/mTOR Pathway and Targeted Drugs Rodon J, et al. Nat Rev Clin Oncol. 2013;10(3):
43
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