novità nel trattamento del carcinoma mammario · 2019. 9. 25. · novità nel trattamento del...
TRANSCRIPT
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?