Terapia sistemica neoadiuvante:
in quali tumori? Quali risultati?
Dott. Giacomo Pelizzari
Neoadjuvant Treatment
A window of opportunity
Rational:
Historically proposed to enable breast-conserving surgery in stage II-III, in
particular for triple negative and HER2-positive EBC
Neoadjuvant Treatment
A window of opportunity
Rational:
Historically proposed to enable breast-conserving surgery in stage II-III, in
particular for triple negative and HER2-positive EBC ➥ this strategy could fail in reducing the mastectomy rate!
Criscitiello C, et al. European Journal of Cancer 97 (2018) 1-6
Neoadjuvant Treatment
A window of opportunity
Rational:
Historically proposed to enable breast-conserving surgery in stage II-III, in
particular for triple negative and HER2-positive EBC ➥ this strategy could fail in reducing the mastectomy rate!
In vivo evaluation of tumor dynamic response as early outcome
Neoadjuvant Treatment
A window of opportunity
Rational:
Historically proposed to enable breast-conserving surgery in stage II-III, in
particular for triple negative and HER2-positive EBC ➥ this strategy could fail in reducing the mastectomy rate!
In vivo evaluation of tumor dynamic response as early outcome ➥ Tailored post-neoadjuvant treatment
Neoadjuvant
Treatment
NO pCR Escalation
Strategies
Surg
ery
pCR De-Escalation
Strategies
Pathological complete response Definition and clinical meaning
Clinical meaning of pCR:
Achievement of pCR at time of surgery is correlated with favourable patient
outcome in all breast cancer subtype: prognostic relevance
Cortazar P, et al. Lancet 2014
Neoadjuvant Treatment
A window of opportunity
Rational:
Historically proposed to enable breast-conserving surgery in stage II-III, in
particular for triple negative and HER2-positive EBC ➥ this strategy could fail in reducing the mastectomy rate!
In vivo evaluation of tumor dynamic response as early outcome ➥ Tailored post-neoadjuvant treatment
Ideal scenario for drug development and biomarker discovery ➥ shorter follow-ups and smaller sample sizes
➥ translational research
Cortazar P, et al. Lancet 2014
Surrogate endpoint:
pCR has been proposed as a surrogate endpoint for prediction of long-term
clinical benefit, such as DFS and OS
SURROGACY
➥ Incremental gains of pCR should also result in a significant extensions of
survival outcomes at trial-level comparison of different treatmets
Prognostic relevance of pCR Enough for surrogacy?
Which is the best candidate for neoadjuvant therapy?
Neoadjuvant chemotherapy Identifying the best candidate
Cortazar P, et al. Lancet 2014
Cortazar P, et al. Lancet 2014
Neoadjuvant chemotherapy Identifying the best candidate
Cortazar P, et al. Lancet 2014
Neoadjuvant chemotherapy Identifying the best candidate
Curigliano G, et al, Annals of Oncology 28: 1700–1712, 2017
“The Panel strongly endorsed the use of neoadjuvant therapy for
stage II or III, HER2 positive or triple-negative breast cancer as the
preferred initial treatment approach, particularly when there is any
suggestion that treatment response might enable de- escalation of
surgery or radiotherapy”
Neoadjuvant chemotherapy Identifying the best candidate
Ellis, et al, JCO 2017
Neoadjuvant chemotherapy Luminal disease
ITT NO CT
Recent advances in the neoadjuvant treatment of BC
Escalating strategies
pCR
surgery
AC T Observation
Neoadjuvant Follow-up
DFS
+ CT (capecitabine, carboplatin)
+ Bevacizumab
+ Double HER2-blockage
+ PARPi
+ ET + CDK4/6i
+ Immunotherapy
We have a plan!
HER2+
Escalation Neoadjuvant therapy in HR+/HER2+ Phase II/III clinical trials
45% Double HER2 blockage
Harbeck N, et al. The Breast 34 (2017) S99eS103
Escalation Neoadjuvant therapy in HR-/HER2+ Phase II/III clinical trials
70% Double HER2 blockage
Harbeck N, et al. The Breast 34 (2017) S99eS103
Neoadjuvant therapy in HER2+ Does Double-blockage improve DFS/EFS?
Courtesy of Cortes J. Presented at ESMO 2018
Neoadjuvant therapy in HER2+ Do we need anthracyclines?
Schneeweiss A, et al. Annals of Oncology 24: 2278–2284, 2013. Van Ramshorst et al. ASCO 2017
Neoadjuvant therapy in HER2+ Concomitant anthracyclines and anti-HER2 therapies?
Buzdar et al. Jama Oncol 2018
Neoadjuvant therapy in HER2+ De-escalation chemotherapy?
Harbeck N, et al. JCO 2017. Hurvitz S. Lancet Oncol 2017
ADAPT HR+ KRISTINE
TNBC
Escalation Neoadjuvant therapy in TNBC Phase II/III clinical trials
50%
Harbeck N, et al. The Breast 34 (2017) S99eS103
Escalation Neoadjuvant therapy Platinum salts
Ref. Pop. Escalation Neoadjuvant Treatment Pz pCR HR DFS HR OS
Gepar IV
2010[1,2]
T≥2 cm,
or ER–,
or
ER+N+
4xEC 4xT
4xEC 4xTCape
4xEC 4xT 4xCape
471
471
479
22.3%
19.5%
22.3% ns
0.92 ns
0.97 ns
0.93
ns
0.97
ns
Gepar VI
2014[3,4,5]
TNBC
sub.
18wPacli/nPLD +Bev
18wPacli/nPLD/Cb1.5AUC +Bev
157
158
42.7%
53.2%*
0.56*
0.10
ns
CALGB40603
2015[6,7]
TNBC 12wPacli 4xddAC ±Bev
12wPacli+4xCb6AUC 4xddAC ±Bev
212
221
41%
54%*
0.84 ns
1.15
ns
[1] von Minckwitz, et al. JCO 2010; [2] von Minckwitz, et al. Ann Oncol 2014
[3] von Minckwitz, et al. Lancet Oncology 2014; [4] von Minckwitz, et al. ESMO 2017
1. [5] Loibl S, et al. Annals of Oncol 2018; [6] Sikov W, et al. JCO 2015; [7] Sikov W, et al. SABCS 2015
Escalation Neoadjuvant therapy Final results of GeparSixto
Loibl S, et al. Annals of Oncol 2018
DFS OS
Escalation Neoadjuvant therapy in TNBC Platinum salts
Poggio et al. Annals of Oncology. 29: 1497–1508, 2018
OR for pCR
Escalation Neoadjuvant therapy in TNBC PARP Inhibitors
[1] Rugo HS, et al. NEJM 2016; [2] Loibl et al, Lancet Oncol 2018
Escalation Neoadjuvant therapy Clinical trials
Ref. Pop. Escalation Neoadjuvant Treatment Pz pCR HR DFS HR OS
Gepar IV
2010[1,2]
T≥2 cm,
or ER–,
or
ER+N+
4xEC 4xT
4xEC 4xTCape
4xEC 4xT 4xCape
471
471
479
22.3%
19.5%
22.3% ns
0.92 ns
0.97 ns
0.93
ns
0.97
ns
Gepar VI
2014[3,4,5]
TNBC
sub.
18wPacli/nPLD +Bev
18wPacli/nPLD/Cb1.5AUC +Bev
157
158
42.7%
53.2%*
0.56*
0.10
ns
CALGB40603
2015[6,7]
TNBC 12wPacli 4xddAC ±Bev
12wPacli+4xCb6AUC 4xddAC ±Bev
212
221
41%
54%*
0.84 ns
1.15
ns
ISPY-2
2016[8]
TNBC
sub.
12wPacli 4xddAC
12wPacli+4xCb6AUC+Veliparib 4xddAC
21
39
26%
51%*
- -
BRIGHTNES
S
2017[9]
TNBC 12wPacli 4xddAC
12wPacli+Cb 4xddAC
12wPacli+Cb+Veliparib 4xddAC
158
160
361
31%
57.5%*
53.2%*
[1] von Minckwitz, et al. JCO 2010; [2] von Minckwitz, et al. Ann Oncol 2014
[3] von Minckwitz, et al. Lancet Oncology 2014; [4] von Minckwitz, et al. ESMO 2017
[5] Loibl S, et al. Annals of Oncol 2018; [6] Sikov W, et al. JCO 2015; [7] Sikov W, et al. SABCS 2015
[8] Rugo HS, et al. NEJM 2016; [9] Loibl et al, Lancet Oncol 2018
1. Escalation-NeoAdjuvant therapy increases pCR from 30-40% to 55%
2. Lack of proven survival benefit.
3. Patient selection (gBRCAm?)
Escalation Neoadjuvant therapy in TNBC Parp trapping potency
Presented by Litton J at ASCO 2018
Escalation Neoadjuvant therapy in TNBC Parp trapping potency
Presented by Litton J at ASCO 2018
Escalation Neoadjuvant therapy in TNBC Parp trapping potency
Presented by Litton J at ASCO 2018
Escalation Neoadjuvant therapy in TNBC Carboplatin vs Parp Inhibitors
Courtesy of Tutt A, at al. Presented at ESMO 2018
GEPAR-OLA Study
Escalation Neoadjuvant therapy Clinical trials
Ref. Pop. Escalation Neoadjuvant Treatment Pz pCR HR DFS HR OS
Gepar IV
2010[1,2]
T≥2
cm, or
ER–,
or
ER+N+
4xEC 4xT
4xEC 4xTCape
4xEC 4xT 4xCape
471
471
479
22.3%
19.5%
22.3%
ns
0.92 ns
0.97 ns
0.93
ns
0.97
ns
Gepar VI
2014[3,4,5]
TNBC
sub.
18wPacli/nPLD +Bev
18wPacli/nPLD/Cb1.5AUC +Bev
157
158
42.7%
53.2%*
0.56*
0.10
ns
CALGB40603
2015[6,7]
TNBC 12wPacli 4xddAC ±Bev
12wPacli+4xCb6AUC 4xddAC ±Bev
212
221
41%
54%*
0.84 ns
1.15
ns
ISPY-2
2016[8]
TNBC
sub.
12wPacli 4xddAC
12wPacli+4xCb6AUC+Veliparib 4xddAC
21
39
26%
51%*
- -
BRIGHTNESS
2017[9]
TNBC 12wPacli 4xddAC
12wPacli+Cb 4xddAC
12wPacli+Cb+Veliparib 4xddAC
158
160
361
31%
57.5%*
53.2%*
-
GeparNuevo[10]
TNBC 12wNabPacli 4xAC
12wNabPacli ±Durv 4xAC ±Durv
Durvx2w+12wNabPacli±Durv4xAC ±Durv
44.2%
53.4%
61vs41
%
-
[1] von Minckwitz, et al. JCO 2010; [2] von Minckwitz, et al. Ann Oncol 2014
[3] von Minckwitz, et al. Lancet Oncology 2014; [4] von Minckwitz, et al. ESMO 2017
[5] Loibl S, et al. Annals of Oncol 2018; [6] Sikov W, et al. JCO 2015; [7] Sikov W, et al. SABCS 2015
[8] Rugo HS, et al. NEJM 2016; [9] Loibl S, et al. Lancet Oncol 2018; Loibl S, et al. ASCO 2018
1. Escalation-NeoAdjuvant therapy increases pCR from 30-40% to 55%
2. Lack of proven survival benefit.
3. Patient selection (gBRCAm?)
Escalating strategies
We have a plan!
RD
surgery
AC T
Neoadjuvant Follow-up
DFS Adjuvant
+ CT (capecitabine, carboplatin)
+ Target therapies (PARPi, T-DM1)
+ ET + CDK4/6i
+ Immunotherapy
Post-Neoadjuvant therapy CREATE X
Masuda N, et al. NEJM 2017
CREATE X
Masuda N, et al. NEJM 2017
Trial Design
-HER2
negative
-Stage I-IIIB
-Age 20-74yr
-ECOG 0-1
NO pCR
Stratification:
ER- vs ER+
Age >50
Taxane use
N0 vs N1 vs N2
Fluorouracil use
Center
Standard treatment
Observation
Capecitabine 1250 mg/mq BD
d1-14 q21 x6-8 cycles
Ne
oa
dju
va
nt
CT
(at
least 4xA
nth
racycline)
Surg
ery
Random
ization 1
:1
End Points & Statistical Analysis:
Primary end point: DFS
Secondary end point: OS, Safety
With a power of the 80%, and a type I error set at
0.05, to see the hypothesized 0.74 hazard for
recurrence, second cancer or death, the required
sample size was estimated to be 900 patients.
Follow-up: 5 years.
Prespecified subgroup analysis (TNBC)
CREATE X
Masuda N, et al. NEJM 2017
Results
• mFU: 3.9 years
All comers:
• 3-year DFS rate:
82.2% vs 73.9% with
Cape
• 5-year OS rate: 89.2%
vs 83.6% with Cape
• HR for recurrence 0.70
(0.53-0.92; P=0.01)
• HR for death 0.59
(0.39-0.90; P=0.01)
TNBC:
• 5-year DFS rate:
69.8% vs 56.1% with
Cape
• 5-year OS rate: 78.8%
vs 70.3% with Cape
• HR for recurrence 0.58
(0.39-0.87)
• HR for death 0.52
(0.30-0.90)
CREATE X Conclusions
Capecitabine showed effectiveness as adjuvant treatment in patients with residual
disease after neoadjuvant therapy:
Methodological issues Previous trials in the adjuvant setting were negative (FINXX, GEICAM).
Statistical enrichment? In the FINXX trial, an exploratory analysis in the TNBC
subgroup showed that TX/CEX was more effective than T/CEF.
Treatment sequence? In preclinical models, agents such as paclitaxel,
cyclophosphamide increase cancer thymidine-phosphorylase concentration.
In subgroup analysis the survival benefit was significative only among TNBC patients.
Applicability issues Concern about the applicability and safety among non-Asian population.
Japanase have a 36% lower Cmax and 24% lower AUC than Caucasian.
The study dose was 1250mg/mq BD (Tolerability?).
Clinical issues Tailored therapies or Clinical Trials are preferred in this setting. Precision medicine?
Post-Neoadjuvant Carboplatin?
Warnings about Capecitabine use in adjuvant setting.
DPYD variants.
About 20% pts discontinued, 30% had dose reduction.
Off-lable?
Ongoing Clinical Trials Post-Neoadjuvant therapy
Ref. Ph Post-NAT Population Ongoing Post-Neoadjuvant Treatment
ECOG-ACRIN III TNBC with RD1 cm 4xCis 75mg/mq q21
4xCb6AUC q21
6xCape 1000mg/mq BID d1-14 q21
A-BRAVE III TNBC with RD Observation
Avelumab 10 mg/kg IV q14 x 1 yr
SWOG S1418 III TNBC with RD1 cm or yN+
Observation
Pembrolizumab 200 mg q21 x 1yr
OlympiA III HER2– BC with gBRCAm Placebo
Olaparib 300 mg BID x 1yr
KATHERINE III HER2+ BC with RD Trastuzumab 6 mg/kg q21 x14
TDM-1 3.6 mg/kg q21 x14
PENELOPE-B III HR+/HER2– BC with RD and
CPSEG≥3, or 2 if ypN+
Placebo + ET
Palbociclib 125 mg d1-21 q28 x 13 + ET
CLEE011G2301
III HR+/HER2– BC with RD1
cm or yN12 mm
Placebo + ET
Ribociclib 600 mg d1-21 q28 x 26 + ET