Novità nel trattamento del carcinoma mammario

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Novità nel trattamento del carcinoma mammario

Prof. Lucia Del Mastro

Breast Unit

Università di Genova

Ospedale Policlinico San Martino – IRCCS Genoa Sassari 21 giugno 2019

UNIVERSITA DEGLI STUDI DI GENOVA

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Disclosure

Relationship Company/Organization

Honorary, consultancy or advisory role Roche – Novartis – Pfeizer – Celgene – Takeda – Ipsen – MSD – Genomic

Health – Eisai – Eli Lilly - Amgen

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Agenda

• Early breast cancer

• Metastatic breast cancer

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Adjuvant treatment decision

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Selection of optimal adjuvant CT

Blum et al, JCO 2017.

Joint analysis of 3 ABC trial TC vs. TaxAC

N=4,242 N+ or high risk N0

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Selection of optimal adjuvant CT

Blum et al, JCO 2017.

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Selection of optimal adjuvant CT: ASCO guidelines

Denduluri N et al, JCO 2016

In patients who can tolerate it, use of a regimen

containing anthracycline-taxane is considered the optimal strategy for adjuvant chemotherapy ,

particularly for high risk patients ^.

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Del Mastro L, ASCO 2019

Extended adjuvant AI studies

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Why Neoadjuvant Systemic Therapy

 No difference in survival comparing patients who have had chemo before or after surgery

 Shrink a large tumor, increasing chances that patient can have breast-

conserving surgery (lumpectomy) rather than mastectomy; potential for less axillary surgery

 Treat patients at high risk for metastatic disease with systemic therapy without delay

 Allows patient and doctor to see if the tumor responds to treatment (and allows to change therapy if not working); “response-guided approach”

 Assessing pathologic response at surgery (residual cancer vs pCR) is

prognostic and can help guide treatment recommendations

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Does pCR predict better outcome in different biologic subsets of breast cancer?

ER+, HER2- G1-2 G3

HER2+

ER+ ER-

Triple Negative

Cortazar et al, Lancet 2014

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Masuda N

Capecitabine group (N=443)

Control Group (N=444) Characteristics

Median age Range

48 25-74

ER+ or PgR+ no. (%) ER-and PgR-

304 (69) 139 (31)

297 (67) 147 (33)

Neoadj CT no. (%) Seq anthra and tax Concurr anthra and tax

357 (81) 63 (14)

372 (84) 53 (12)

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Masuda N

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Does pCR predict better outcome in different biologic subsets of breast cancer?

ER+, HER2- G1-2 G3

HER2+

ER+ ER-

Triple Negative

Cortazar et al, Lancet 2014

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KATHERINE: Trastuzumab Emtansine vs Trastuzumab as Adjuvant Therapy for HER2+ EBC

 International, randomized, open-label phase III study

Patients with HER2+ EBC (cT1-4/N0-3/M0) who had residual invasive disease in breast or axillary nodes after neoadjuvant chemotherapy plus HER2-targeted

therapy* at surgery (N = 1486)

T-DM1

^†

3.6 mg/kg IV Q3W x 14 cycles (n = 743)

Trastuzumab 6 mg/kg IV Q3W x 14 cycles (n = 743)

Slide credit: clinicaloptions.com Geyer. SABCS 2018. Abstr GS1-10. von Minckwitz. NEJM. 2019;380:617.

**Randomization occurred within 12 wks of surgery; radiotherapy and/or endocrine therapy given per local standards. *Minimum** of 9 wks taxane and trastuzumab.

^†

Patients who d/c T-DM1 for toxicity allowed switch to trastuzumab to complete 14 cycles.

Stratified by clinical stage, HR status, single vs dual neoadjuvant HER2-targeted therapy, pathologic nodal status after neoadjuvant therapy

 Primary endpoint: IDFS

 Secondary endpoints including: distant recurrence-free survival, OS,

safety

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KATHERINE: Stratification Factors

Slide credit: clinicaloptions.com Geyer. SABCS 2018. Abstr GS1-10. von Minckwitz. NEJM. 2018;[Epub].

Stratification Factor, n (%) T-DM1 (n = 743) Trastuzumab (n = 743) Clinical stage at presentation

 Operable (cT1-3N0–1M0)

 Inoperable (cT4NxM0 or cTxN2–3M0)

558 (75.1) 185 (24.9)

553 (74.4) 190 (25.6) Hormone receptor status

 ER and/or PgR positive

 ER negative and PgR negative/unknown

534 (71.9) 209 (28.1)

540 (72.7) 203 (27.3) Preoperative HER2-targeted therapy

 Trastuzumab alone

 Trastuzumab + other HER2-targeted agents*

– Trastuzumab + pertuzumab

^†

600 (80.8) 143 (19.2) 133 (17.9)

596 (80.2) 147 (19.8) 139 (18.7) Pathologic nodal status after preoperative therapy

 Node positive

 Node negative/not done

343 (46.2) 400 (53.8)

346 (46.6) 397 (53.4)

*Includes afatinib, dacomitinib, lapatinib, neratinib, pertuzumab.

^†

Not a stratification factor; for informational purposes only.

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KATHERINE: IDFS

First IDFS

Event, % T-DM1 T

Any 12.2 22.2

Distant

recurrence 10.5* 15.9

^†

Locoregional

recurrence 1.1 4.6

Contralateral

breast cancer 0.4 1.3 Death without

prior event 0.3 0.4

6 12 100

80 60 40 20 0

ID FS ( % )

18 24 30 36 42 48 54 60 0

Mos Since Randomization 707

676 681 635

658 594

633 555

561 501

409 342

142 119 255

220 44 38

4 4 743

743 Patients at Risk, n T-DM1

Trastuzumab

Events, n (%) 3-yr IDFS, %

T-DM1 (n = 743) 91 (12.2)

88.3 Trastuzumab (n = 743) 165 (22.2)

77.0 HR: 0.50 (95% CI: 0.39-0.64; P < .001)

CNS events: *5.9% vs

^†

4.3%.

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KATHERINE: Secondary Endpoints

6 12 100

80 60 40 20 0 Freedom From Distant Recurrence (%)

18 24 30 36 42 48 54 60 0

Mos Since Randomization

707 679

682 643

661 609

636 577

564 520

412 359

143 126 254 233

45 41

4 4 743

743 Patients at Risk, n T-DM1 Trastuzumab

Events, n (%)

3-yr event-free rate, %

T-DM1 (n = 743) 78 (10.5)

89.7

Trastuzumab (n = 743) 121 (16.3)

83.0

HR: 0.60 (95% CI: 0.45-0.79)

6 12 100

80 60 40 20 0

OS (%)

18 24 30 36 42 48 54 60 0

Mos Since Randomization

719 695

702 677

693 657

668 635

648 608

508 471

195 175 345 312

76 71

12 8 743

743 Patients at Risk, n T-DM1 Trastuzumab

HR: 0.70 (95% CI: 0.47-1.05; P = .08) Events, n (%)

T-DM1 (n = 743)

42 (5.7)

Trastuzumab (n = 743)

56 (7.5)

Distant Recurrence OS

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Agenda

• Early breast cancer

• Metastatic breast cancer

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MBC in Italy: epidemiology

I numeri del cancro in Italia 2018

11% 12%

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IMpassion130

Schmid P, ESMO 2018 and NEJM 2018

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IMpassion130: second interim OS analysis

Schmid P, ESMO 2018 and NEJM 2018

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Response Rates Across Randomized Phase III Trials of PARP Inhibitors in MBC

Slide credit: clinicaloptions.com

Trial Measurable

Disease, %

PARPi Overall Response, %

CT Overall Response, %

Odds Ratio P Value

OlympiAD

(olaparib) 77.1 59.9 28.8 3.67

EMBRACA

(talazoparib) 77.3 62.6 27.2 4.47

Overall 61.4 27.8 4.15 < .001

Robson. NEJM. 2017;377:523. Litton. NEJM. 2018;379:753. Poggio. ESMO Open. 2018;3:e000361.

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Meta-analysis of Phase III Trials of PARP Inhibitors vs Single-Agent CT in MBC: Survival Outcomes

PFS

Slide credit: clinicaloptions.com Poggio. ESMO Open. 2018;3:e000361.

OS

 Pt population: BRCA-mutant positive/HER2-negative MBC

Trial name HR (95% CI)

OlympiAD EMBRACA Random effect (I-squared = 0%, P = .756)

0.58 (0.43-0.80) 0.54 (0.41-0.79) 0.56 (0.45-0.70)

0.41 1 2.44

Favors PARPi Favors controls

Trial name HR (95% CI)

OlympiAD EMBRACA Random effect (I-squared = 0%, P = .501)

0.90 (0.63-1.29) 0.76 (0.54-1.06) 0.82 (0.64-1.05)

0.54 1 1.85

Favors PARPi Favors controls

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Meta-Analysis of Phase III Trials of PARP Inhibitors vs Single-Agent CT in MBC: PFS by Subgroup

Poggio. ESMO Open. 2018;3:e000361.

HR Negative HR Positive

No Prior Platinum Prior Platinum

Trial name HR (95% CI)

OlympiAD EMBRACA Random effect (I-squared = 31.5%, P = .227)

0.43 (0.29-0.63) 0.60 (0.41-0.87) 0.51 (0.37-0.71)

.29 1 3.45

Favors PARPi Favors controls

OlympiAD EMBRACA Random effect (I-squared = 0%, P = .532)

0.60 (0.43-0.84) 0.52 (0.39-0.71) 0.55 (0.44-0.69)

.39 1 2.56

OlympiAD EMBRACA Random effect (I-squared = 72.2%, P = .058)

0.82 (0.55-1.26) 0.47 (0.32-0.71) 0.62 (0.36-1.07)

0.32 1.00 3.13 Favors PARPi Favors controls

OlympiAD EMBRACA Random effect (I-squared = 0%, P = .764)

0.67 (0.41-1.14) 0.76 (0.40-1.45) 0.70 (0.47-1.05)

0.4 1.0 2.5

Slide credit: clinicaloptions.com

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Novità nel trattamento del carcinoma mammario