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

Dott. Giacomo Pelizzari

giacomo.pelizzari@cro.it