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

Disclosure

Relationship Company/Organization

Honorary, consultancy or advisory role Roche – Novartis – Pfeizer – Celgene – Takeda – Ipsen – MSD – Genomic Health – Eisai – Eli Lilly - Amgen

Agenda

• Early breast cancer

• Metastatic breast cancer

Adjuvant treatment decision

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

Selection of optimal adjuvant CT

Blum et al, JCO 2017.

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.

Del Mastro L, ASCO 2019

Extended adjuvant AI studies

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

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

Masuda N

Capecitabine group (N=443)

Control Group (N=444)

Characteristics

Median age Range

48 25-74

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)

Masuda N

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

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

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.

KATHERINE: IDFS

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

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

IDFS

(%

)

18 24 30 36 48 42 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%.

KATHERINE: Secondary Endpoints

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

6 12

100

80

60

40

20

0

Fre

edo

m F

rom

Dis

tan

t R

ecu

rre

nce

(%

)

18 24 30 36 48 42 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 48 42 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

Agenda

• Early breast cancer

• Metastatic breast cancer

MBC in Italy: epidemiology

I numeri del cancro in Italia 2018

11% 12%

IMpassion130

Schmid P, ESMO 2018 and NEJM 2018

IMpassion130: second interim OS analysis

Schmid P, ESMO 2018 and NEJM 2018

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.

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

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

Trial name HR (95% CI)

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 Favors PARPi Favors controls

Trial name HR (95% CI)

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

Trial name HR (95% CI)

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 Favors PARPi Favors controls

Slide credit: clinicaloptions.com

Trial name HR (95% CI)

OlympiAD

EMBRACA

Random effect (I-squared = 0%, P = .671)

0. 44 (0.25-0.77)

0.38 (0.26-0.55)

0.40 (0.29-0.54)

Meta-Analysis of Phase III Trials of PARP Inhibitors vs CT in MBC: Time to Clinically Meaningful QOL Deterioration

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

.25 1 4 Favors PARPi Favors controls

Conclusions Early breast cancer

‒ Biology is the main driver for treatment choice

‒ Benefit of dose-dense CT

‒ Neoadjuvant CT as the preferred approach for TN and HER2 +

Metastatic breast cancer

‒ Atezolizumab in PDL1+ TNBC

‒ CDK4-6 inhibitors + ET are standard first line treatment in HR+ patients

‒ PARP inhibitors in BRCA+

‒ “Cure” for selected subgroups of HER2+ MBC patients?