Session Breast Cancer Alessandra Fabi Il punto di vista dell esperto Roma 6-7.10.2017
The Importance of Understanding What Disease to Treat Cejalvo et al, Cancer Res 2017
Skyline Chaging at evolution of disease Venn diagram of genes that predict overall survival from the data of recurrence when analyzed in primary versus metastatic disease.. Cejalvo et al, Cancer Res 2017
MY OUTLINE The last thought in the first 2 slides HR+ : why cycline? Other? If other What? PI3K in HR+: where we are? Adjuvant therapy in HR+: same tale of metastatic disease? HER2+: beyond adjuvant Trastuzumab
The Precision Medicine and the Better Knowledge of BC Tumor
Yates, ESMO 2017
HR+ : why cycline? Other? If other What?
Finn NEJM 2016 Hortobagji NEJm 2016 Di Leo ESMO 2017 Il Ciclone delle Cicline 24.8 mos vs 14.5 mos 25.3 mos vs 16 mos Reduced Risk PRIMARY of Progression ENDPOINT: PFS 42%- (ITT) 46% Paloma 2 Monaleesa 2 Median PFS abemaciclib + NSAI: not reached placebo + NSAI: 14.7 months HR (95% CI): 0.543 (0.409, 0.723) p =0.000021 Monarch 2
Paloma 2 Monaleesa 2 Finn NEJM 2016 Hortobagji NEJm 2016 Di Leo ESMO 2017 Monarch 2 TREATMENT-EMERGEN (SA FETY POPULATION abemaciclib + NSAI n = 327 Grade, n (%) Any 2 3 4 Any adverse event 322 (98.5) 111 (33.9) 159 (48.6) 21 (6.4) Diarrhea 266 (81.3) 89 (27.2) 31 (9.5) 0 Neutropenia 135 (41.3) 53 (16.2) 64 (19.6) 5 (1.5) Fatigue 131 (40.1) 55 (16.8) 6 (1.8) Nausea 126 (38.5) 36 (11.0) 3 (0.9) Abdominal pain 95 (29.1) 21 (6.4) 4 (1.2) Anemia 93 (28.4) 45 (13.8) 19 (5.8) 0 Vomiting 93 (28.4) 26 (8.0) 4 (1.2) 0 Alopecia 87 (26.6) 5 (1.5) Decreased appetite 80 (24.5) 26 (8.0) 4 (1.2) 0 Leukopenia 68 (20.8) 31 (9.5) 24 (7.3) 1 (0.3)
Cyclines to all HR+ BC peaple in first-line?
Paloma 2 Subgroups
FULV 16,6 mesi ANA 13,8 mesi p = 0,0486 PFS Results Δ 2.8 3.2 m Visceral no visceral
Progression-free survival and overall survival for non-hormonal targeted therapy versus comparator therapy (CT) in HR+MBC (38 studies, n=17,192 pts) CANCER TREAT REV 2017
Hypotesis of Timeline 1 line PD 2 Line PD 3 Line Cycline EVE/EXE Fulvestrant 25 months 10.6 months 4.3 months PFS 39.9 months ( more than 3 years!) Cycline Fulvestrant Eve/Exe 25 months 6.5 months 4.0 months (?) PFS 35.5 months ( more than 3 years!)
II LINE mpfs: 9.5 vs 4.6
MY PERSONAL THOUGHTS First line always cycling in visceral and non-visceral disease, excluding weak, elderly patients with logical problems (faslodex) Chemotherapy only in case of young patients and / or with important bulky disease (bone marrow infiltration, hepatic or pulmonary dysfunction compatible with a treatment) There is no first-line comparison between chemotherapy vs. new target associations There are no second-line sequence sequences after cyclone: Fulvestrant vs Exe / exe (AIOM Lazio proposal!!)
PI3K in HR+: where we are?
PI3k patway activation is common in acquired endocrine resistence Targeting PI3K
Association to AI
COMBO
The translation from metastatic to locally advanced disease
Total pcr rate (%) Total pcr rare (%) EFFICACY: pcr No significant difference was observed for pcr rate overall or in the PIK3CA-MUT subset 10 8 6 4 2 0 All randomized patients Odds ratio=3.07 (95% CI 0.32 29.85) P=0.370 1.8 Taselisib (N=166) 0.6 Placebo (N=168) 10 8 6 4 2 0 Patients withpik3ca-mutant tumors 1.4 Taselisib (N=73) Odds ratio=na (95% CI NA) P=0.480 0 Placebo (N=79)
Still metastatic contrast data My Personal Thoughts Prognostic or predictive factor PI3K or both? LORELEI met its primary endpoint but... Increase in ORR should be balanced with more toxicity: diarrhea (52%), stomatitis (23%) and hyperglicemia (26%). The pcr rate was low with or without the addition of taselisib (4 months of endocrine based therapy): the add on design added mostly toxicity Waiting for SANDPIPER results of taselisib plus fulvestrant and SOLAR 1 of alpelisib (alfa selective PI3K inhibitor) plus fulvestrant
Adjuvant therapy in HR+: same tale of metastatic disease?
Disease Free Survival Overall Survival HR: 0.839 (0.576-1.220) HR: 0.863 (0.523-1.424) Arm Event Total Anastrozole 62 434 Anastrozole + Fulvestrant 49 417 Anastrozole n = 437 Anastrozole + Fulvestrant n = 433 Total n = 870 number at risk 434 417 851 62 49 111 n (%) 372 (85.7) 368 (88.2) 740 (87.0) Arm Event Total Anastrozole 34 434 Anastrozole + Fulvestrant 28 417 Anastrozole n = 437 Anastrozole + Fulvestrant n = 433 Total n = 870 434 417 851 34 28 62 n (%) 400 (92.2) 389 (93.3) 789 (92.7) Study Objectives Primary objective: To compare disease-free survival (DFS) between patients treated with Fulvestrant for 3 years and Anastrozole for 5 years and patients treated with Anastrozole for 5 years. Secondary objectives: To compare breast cancer-specific survival between both treatment arms. To compare time to recurrence (TR) between both treatment arms. To compare overall survival (OS) between both treatment arms. To compare the safety and tolerability profile between both treatment arms.
My Personal Thoughts Dual blockade in ER+ EBC: did we miss an opportunity? Include only high risk patients? > 65% of patients submitted to previous neoadj/adjuvant CT What if 500 mg fulvestrant rather than 250 mg?
HER2+ beyond adjuvant Trastuzumab
ExteNET beyond adjuvant Trastuzumab
Trastuzumab HERA trial update 11 yrs 6.8 % Absolute Benefit in DFS ABSOLUTE BENEFIT OF HERCEPTIN 1 YEAR ExteNET Fu update 5 yrs FOLLOWED BY NERATINIB 1 YEAR 10% 3.2 % Absolute Benefit in DFS
My Personal Thoughts clinically significant benefit, particularly in higher risk, HR+ disease despite limitations due to change in sponsor and initial plan for short FU Diarrhea a limiting factor, reduced significantly with prophylaxis (mandatory component of treatment) Survival data pending Extended therapy for HER2+ disease with neratinib FDA approved in the US
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