Alessandra Fabi
Il punto di vista dell’esperto
Roma 6-7.10.2017
Session Breast Cancer
The Importance of Understanding What Disease to Treat
Cejalvo et al, Cancer Res 2017
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
Skyline Chaging at evolution of disease
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?
Paloma 2 Monaleesa 2
24.8 mos vs 14.5 mos 25.3 mos vs 16 mos
PRIMARY ENDPOINT: PFS (ITT)
Median PFS
abemaciclib + NSAI: not reached placebo + NSAI: 14.7 months HR (95% CI): 0.543 (0.409, 0.723)
p =0.000021
PFS benefit confirmed by blinded independent central review: HR (95% CI): 0.508 (0.359, 0.723); p=0.000102
Il Ciclone delle Cicline
Monarch 2
Finn NEJM 2016
Hortobagji NEJm 2016 Di Leo ESMO 2017
Reduced Risk of Progression 42%- 46%
TREATMENT-EMERGENT ADVERSE EVENTS (SA FETY POPULATION)≥ 20% OCCURRENCE
Grade, n (%) Any 2 3 4 Any 2 3 4
Any adverse event 322 (98.5) 111 (33.9) 159 (48.6) 21 (6.4) 145 (90.1) 61 (37.9) 32 (19.9) 3 (1.9)
Diarrhea 266 (81.3) 89 (27.2) 31 (9.5) 0 48 (29.8) 11 (6.8) 2 (1.2) 0
Neutropenia 135 (41.3) 53 (16.2) 64 (19.6) 5 (1.5) 3 (1.9) 1 (0.6) 1 (0.6) 1 (0.6)
Fatigue 131 (40.1) 55 (16.8) 6 (1.8) — 51 (31.7) 20 (12.4) 0 —
Nausea 126 (38.5) 36 (11.0) 3 (0.9) — 32 (19.9) 1 (0.6) 2 (1.2) —
Abdominal pain 95 (29.1) 21 (6.4) 4 (1.2) — 19 (11.8) 4 (2.5) 2 (1.2) —
Anemia 93 (28.4) 45 (13.8) 19 (5.8) 0 8 (5.0) 2 (1.2) 2 (1.2) 0
Vomiting 93 (28.4) 26 (8.0) 4 (1.2) 0 19 (11.8) 3 (1.9) 3 (1.9) 0
Alopecia 87 (26.6) 5 (1.5) — — 17 (10.6) 0 — —
Decreased appetite 80 (24.5) 26 (8.0) 4 (1.2) 0 15 (9.3) 2 (1.2) 1 (0.6) 0
Leukopenia 68 (20.8) 31 (9.5) 24 (7.3) 1 (0.3) 4 (2.5) 1 (0.6) 0 1 (0.6)
placebo + NSAI n = 1 61 abemaciclib + NSAI
n = 327
• Infections and infestations (grouped as system organ class) were reported in 128 (Any: 39.1%, G3: 4.0%, G4: 0.9%) patients in the abemaciclib arm and 46 (Any: 28.6%, G3: 2.5%, G4: 0.6%) in the placebo arm.
• 1 patient experienced non-serious febrile neutropenia in the abemaciclib arm.
• Venous thromboembolic events occurred in 16 (4.9%) of patients in the abemaciclib arm versus 1 (0.6%) in the placebo arm.
Paloma 2 Monaleesa 2
Monarch 2
Finn NEJM 2016
Hortobagji NEJm 2016 Di Leo ESMO 2017
Cyclines to all HR+ BC peaple in first-line?
Paloma 2 Subgroups
Visceral no visceral
FULV 16,6 mesi ANA 13,8 mesi p = 0,0486
Δ 3.2 m
PFS Results
Δ 2.8 m
CANCER TREAT REV 2017 Progression-free survival and overall
survival for non-hormonal targeted therapy versus comparator therapy (CT)
in HR+MBC (38 studies, n=17,192 pts)
Cycline EVE/EXE Fulvestrant
25 months 10.6 months 4.3 months
PD
1 line 2 Line
PD
3 LinePFS 39.9 months ( more than 3 years!)
Cycline Fulvestrant Eve/Exe
25 months 6.5 months 4.0 months (?)
Hypotesis of Timeline
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?
Targeting PI3K
PI3k patway activation is common in acquired endocrine resistence
Association to AI
COMBO
The translation from metastatic to locally advanced disease
EFFICACY: pCR
1.8
0.6 0
2 4 6 8 10
Taselisib
(N=166) Placebo
(N=168)
Total pCR rate (%)
All randomized patients
Odds ratio=3.07 (95% CI 0.32–29.85)
P=0.370
1.4 0 0
2 4 6 8 10
Taselisib
(N=73) Placebo
(N=79)
Total pCR rare (%)
Patients withPIK3CA-mutant tumors
Odds ratio=NA (95% CI NA)
P=0.480
No significant difference was observed for pCR rate overall or in the PIK3CA-MUT subset
My Personal Thoughts
❊ Still metastatic contrast data
❊ 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?
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.
Study Objectives
Overall Survival
Anastrozole n = 437
Anastrozole + Fulvestrant n = 433
Total n = 870
Total number at risk 434 417 851
Events 34 28 62
Censored n (%) 400 (92.2) 389 (93.3) 789 (92.7)
HR: 0.863 (0.523-1.424)
Arm Event Total
Anastrozole 34 434
Anastrozole + Fulvestrant 28 417
Disease Free Survival
Anastrozole n = 437
Anastrozole + Fulvestrant n = 433
Total n = 870
Total number at risk 434 417 851
Events 62 49 111
Censored n (%) 372 (85.7) 368 (88.2) 740 (87.0)
HR: 0.839 (0.576-1.220)
Arm Event Total
Anastrozole 62 434
Anastrozole + Fulvestrant 49 417
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
ExteNET Fu update 5 yrs
3.2 % Absolute Benefit in DFS
ABSOLUTE BENEFIT OF HERCEPTIN 1 YEAR FOLLOWED BY NERATINIB 1 YEAR
10%
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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