ONCOLOGIA: esperienze cliniche a confronto. Il carcinoma mammario metastatico

ONCOLOGIA: esperienze cliniche a confronto. Il carcinoma mammario metastatico Sequenza ottimale del trattamento Maria Teresa Scognamiglio U.O.C. Clinica Oncologica Chieti-Ortona Chieti 12 novembre 213

Chemotherapy vs EndocrineTherapy Methods Randomized trials of chemotherapy alone vs endocrine therapy alone Results 8 trials identified (N = 817) No significant difference for OS HR:.94 (95% CI:.79-1.12; P =.5) Significant difference favoring chemotherapy for ORR OR: 1.25 (95% CI: 1.1-1.54; P =.4) However the 2 largest trials demonstrated trends in opposite directions Toxicity: little information available on adverse events and QOL Increased toxicity with chemotherapy (nausea, vomiting and alopecia) 3 of 7 trials noted QOL aspects, with differing results Authors conclusions In women with metastatic breast cancer and where hormone receptors are present, a policy of treating first with endocrine therapy rather than chemotherapy is recommended except in the presence of rapidly progressive disease Wilcken N, et al. Cochrane Database Syst Rev. 23:CD2747.

EFECT: Study Design 5 mg Day 1, 25 mg Days 14 & 28, and monthly thereafter Previous nonsteroidal AI failure Fulvestrant loading dose + Placebo for Exemestane (n = 351) Exemestane 25 mg/day orally + Placebo for Fulvestrant (n = 34) Progression Progression Survival Chia S, et al. J Clin Oncol. 28;26:1664-167. Analysis after 58 events (progression or death) Survival

Proportion of Patients Progression-Free Time to Progression (ITT) 1..8.6.4 Fulvestrant Exemestane Fulvestrant Exemestane Median, mos 3.7 3.7 HR:.963 (95% CI:.819-1.133; P =.6531).2 Days Fulvestrant at risk Exemestane at risk 1 2 3 4 5 6 7 8 351 342 5 31 35 1 191 184 Days to Progression 15 127 13 2 89 86 25 67 56 3 46 37 35 29 24 4 23 21 45 13 13 5 1 1 55 4 8 6 4 8 65 2 6 7 2 Chia S, et al. J Clin Oncol. 28;26:1664-167.

Objective Response and Clinical Benefit Rate In population evaluable for response Response, n (%) OR rate (CR + PR) CB rate (OR + SD 24 wks) Fulvestrant (n = 27) Exemestane (n = 27) 2 (7.4) 18 (6.7) 87 (32.2) 85 (31.5) *Analyses are not adjusted for baseline covariates. OR* (95% CI) 1.12 (.578-2.186) 1.3 (.72-1.487) P Value.736.853 Chia S, et al. J Clin Oncol. 28;26:1664-167.

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 = 25) Fulvestrant 5 mg by intramuscular injection Days, 14, 28, and every 28 days thereafter (n = 12) Anastrozole 1 mg/day orally (n = 13) Until disease progression or other event requiring discontinuation Robertson JFR, et al. SABCS 21. Abstract S1-3.

Proportion of Patients Alive and Progression Free FIRST: Fulvestrant Significantly Increased TTP in Secondary Analysis 1..8 Fulvestrant Anastrozole.6.4.2 HR:.66 (95% CI:.47-.92; P =.1) 6 12 18 24 Patients at Risk, n Mos Fulvestrant 12 74 65 52 45 Anastrozole 13 69 55 39 3 Parameter Fulvestrant (n = 12) 3 34 21 36 2 8 42 6 2 Anastrozole (n = 13) Patients progressing, n (%) 63 (61.8) 79 (76.7) Median TTP, mos 23.4 13.1 Clinical benefit rate, % 72.5 67. Robertson JFR, et al. SABCS 21. Abstract S1-3. 48

SWOG S226: 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 = 77) Anastrozole 1 mg/day PO + Fulvestrant 5 mg on Day 1, 25 mg on Days 14 and 28, 25 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 211. Abstract S1-1.

SWOG S226: 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 = 28) Median OS (n = 694), mos No previous adjuvant tamoxifen (n = 414) Previous adjuvant tamoxifen (n = 28) 15. 17. 13.5 47.7 47.7 49.6 Anastrozole HR (95% CI) P Value 13.5.8 (.68-.94).7 12.6.74 (.59-.92).55 14.1.89 (.69-1.15).37 41.3.81 (.65-1.).49 39.7.74 (.56-.98).362 44.5.91 (.65-1.28).59 Mehta RS, et al. SABCS 211. Abstract S1-1.

The PI3K/AKT/mTOR Pathway Oxygen, energy, and nutrients Ras/Raf pathway kinases S6 Cell growth and proliferation Growth factors including IGF-1, VEGF, ErbB TSC2 S6K1 PTEN TSC1 PI3K AKT mtor Protein production Nutrient uptake and metabolism Estrogen receptor 4E-BP1 elf-4e Angiogenesis mtor signaling plays a key role in Cell growth Cell proliferation Regulation of Apoptosis Angiogenesis Lymphocytes Homeostasis Metabolism

BOLERO-2: Study Design Primary endpoint: PFS (investigator assessment) Secondary endpoints: OS, ORR, clinical benefit rate, safety Randomized 2:1; stratified by sensitivity to previous hormonal therapy, presence of visceral metastases Treatment until disease progression or unacceptable toxicity Postmenopausal women with ER-positive advanced breast cancer who progressed on previous nonsteroidal AI therapy* (N = 724) Exemestane 25 mg/day + Everolimus 1 mg/day (n = 485) Exemestane 25 mg/day + Placebo (n = 239) *> 5% of patients in each arm with 3 previous therapies Hortobagyi GN, et al. SABCS 211. Abstract S3-7.

Probability of Event (%) BOLERO-2: Everolimus + Exemestane Improves PFS in HR+ MBC 1 9 8 7 6 5 4 3 2 1 Patients at Risk, n Everolimus 485 Placebo 239 HR:.36 (95% CI:.27-.47; log-rank P <.1) 6 12 18 24 3 36 42 48 54 6 66 72 78 385 168 281 94 21 55 132 33 Central Assessment 12 2 67 11 Wks 43 11 28 6 18 3 Everolimus + exemestane (median PFS: 1.6 mos) Placebo + exemestane (median PFS: 4.1 mos) 9 3 3 1 2 Baselga J, et al. N Engl J Med. 212;366:52-529.

BOLERO-2: Final PFS Analysis (18-Mo Follow-up) PFS, Mos EVE + EXE PBO + EXE HR (95% CI) P Value Local review 7.8 3.2.45 (.38-.54) Central review 11. 4.1.38 (.31-.48) With visceral mets 6.83 2.76.47 (.37-.6) Without visceral mets 9.86 4.21.41 (.31-.55) Bone-only mets 12.88 5.29.33 (.21-.53) Progression after neo/adj therapy 11.5 4.7.39 (.25-.62) <.1 <.1 OS data still not mature (HR:.77; 95% CI:.57-1.4) Most common grade 3/4 AEs were stomatitis (8%), hyperglycemia (5%), fatigue (4%) -- -- -- -- Piccart, M, et al. SABCS 212. Abstract P6-4-2.

BOLERO-2 (12-Mo Follow-up): Safety Adverse Events, % Exemestane + Everolimus (n = 482) Exemestane + Placebo (n = 238) All Grades Grade 3/4 All Grades Grade 3/4 Stomatitis 59 8 11 1 Rash 39 1 6 Fatigue 36 5 27 1 Diarrhea 33 3 19 < 1 Appetite decreased 3 1 12 < 1 Nausea 29 2 28 1 Noninfectious pneumonitis 15 3 Hyperglycemia 14 6 2 < 1 Hortobagyi GN, et al. SABCS 211. Abstract S3-7.

PFS Probability Aromatase Inhibitor + CDK4/6 Inhibitor Improves PFS in ER+ MBC 1..9.8.7.6.5.4.3.2.1 Pts at Risk, n PD 991 + LET LET 2 4 6 8 1 12 14 Mos 84 81 75 57 6 38 53 29 43 22 Finn RS, et al. SABCS 212. Abstract S1-6. 35 17 25 11 Events, n (%) Median PFS, mos (95% CI) HR (95% CI) P value 18 6 PD 991 + LET (n = 84) 21 (25) 26.1 (12.7-26.1) 16 18 2 22 24 26 28 15 5 14 4 9 3 5 3 3 1.37 (.21-.63) <.1 1 1 LET (n = 81) 4 (49) 7.5 (5.6-12.6)

Qual è la sequenza ottimale di trattamento? Prima linea: AI o fulvestrant ; fulvestrant + AI proponibile in pazienti therapy naïve -quale intervallo dalla terapia adiuvante? -associazione o sequenza programmata? Proseguire la terapia endocrina fino alla comparsa di resistenza

Qual è la sequenza ottimale di trattamento? Seconda linea: everolimus + exemestane a progressione da AI non steroideo (se non mts viscerali sintomatiche) Dopo everolimus: monoterapia ormonale o blocco del pathway di PI3K L associazione dell inibitore delle CDK4/6 palbociclib con letrozole in prima linea appare molto promettente; sono in corso studi di fase III

Qual è la sequenza ottimale di trattamento? Seconda linea: everolimus + exemestane a progressione da AI non steroideo (se non mts viscerali sintomatiche) Dopo everolimus: monoterapia ormonale o blocco del pathway di PI3K L associazione dell inibitore delle CDK4/6 palbociclib con letrozole in prima linea appare molto promettente; sono in corso studi di fase III