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 (SAFETY 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 = 161

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 3 Line PD

PFS 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

1.80.6

0

2

4

6

8

10

Taselisib(N=166)

Placebo(N=168)

Tota

l pC

R r

ate

(%)

All randomized patients

Odds ratio=3.07

(95% CI 0.32–29.85)

P=0.370

1.4

00

2

4

6

8

10

Taselisib(N=73)

Placebo(N=79)

Tota

l pC

R r

are

(%)

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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