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(1)

Terapia sistemica neoadiuvante:

in quali tumori? Quali risultati?

Dott. Giacomo Pelizzari

(2)

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

(3)

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

(4)

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

(5)

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

Surgery

pCR De-Escalation

Strategies

(6)

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

(7)

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

(8)

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?

(9)

Which is the best candidate for neoadjuvant therapy?

(10)

Neoadjuvant chemotherapy

Identifying the best candidate

Cortazar P, et al. Lancet 2014

(11)

Cortazar P, et al. Lancet 2014

Neoadjuvant chemotherapy

Identifying the best candidate

(12)

Cortazar P, et al. Lancet 2014

Neoadjuvant chemotherapy

Identifying the best candidate

(13)

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

(14)

Ellis, et al, JCO 2017

Neoadjuvant chemotherapy

Luminal disease

ITT NO CT

(15)

Recent advances in the neoadjuvant treatment of BC

(16)

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!

(17)

HER2+

(18)

Escalation Neoadjuvant therapy in HR+/HER2+

Phase II/III clinical trials

45% Double HER2 blockage

Harbeck N, et al. The Breast 34 (2017) S99eS103

(19)

Escalation Neoadjuvant therapy in HR-/HER2+

Phase II/III clinical trials

70% Double HER2 blockage

Harbeck N, et al. The Breast 34 (2017) S99eS103

(20)

Neoadjuvant therapy in HER2+

Does Double-blockage improve DFS/EFS?

Courtesy of Cortes J. Presented at ESMO 2018

(21)

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

(22)

Neoadjuvant therapy in HER2+

Concomitant anthracyclines and anti-HER2 therapies?

Buzdar et al. Jama Oncol 2018

(23)

Neoadjuvant therapy in HER2+

De-escalation chemotherapy?

Harbeck N, et al. JCO 2017. Hurvitz S. Lancet Oncol 2017

ADAPT HR+ KRISTINE

(24)

TNBC

(25)

Escalation Neoadjuvant therapy in TNBC

Phase II/III clinical trials

50%

Harbeck N, et al. The Breast 34 (2017) S99eS103

(26)

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 CALGB

40603

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

(27)

Escalation Neoadjuvant therapy

Final results of GeparSixto

Loibl S, et al. Annals of Oncol 2018

DFS OS

(28)

Escalation Neoadjuvant therapy in TNBC

Platinum salts

Poggio et al. Annals of Oncology. 29: 1497–1508, 2018

OR for pCR

(29)

Escalation Neoadjuvant therapy in TNBC

PARP Inhibitors

[1] Rugo HS, et al. NEJM 2016; [2] Loibl et al, Lancet Oncol 2018

(30)

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 CALGB

40603

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?)

(31)

Escalation Neoadjuvant therapy in TNBC

Parp trapping potency

Presented by Litton J at ASCO 2018

(32)

Escalation Neoadjuvant therapy in TNBC

Parp trapping potency

Presented by Litton J at ASCO 2018

(33)

Escalation Neoadjuvant therapy in TNBC

Parp trapping potency

Presented by Litton J at ASCO 2018

(34)

Escalation Neoadjuvant therapy in TNBC

Carboplatin vs Parp Inhibitors

Courtesy of Tutt A, at al. Presented at ESMO 2018

GEPAR-O

LA

Study

(35)

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 CALGB

40603

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±Durv4xAC ±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?)

(36)

Escalating strategies

We have a plan!

RD

surgery

AC  T

Neoadjuvant Follow-up

Adjuvant DFS

+ CT (capecitabine, carboplatin) + Target therapies (PARPi, T-DM1) + ET + CDK4/6i

+ Immunotherapy

(37)

Post-Neoadjuvant therapy

CREATE X

Masuda N, et al. NEJM 2017

(38)

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

Neoadjuvant CT (at least 4xAnthracycline) Surgery Randomization 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)

(39)

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)

(40)

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?

(41)

Ongoing Clinical Trials

Post-Neoadjuvant therapy

Ref. Ph Post-NAT Population Ongoing Post-Neoadjuvant Treatment ECOG-ACRIN III TNBC with RD1 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 RD1 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 RD1

cm or yN12 mm Placebo + ET

Ribociclib 600 mg d1-21 q28 x 26 + ET

(42)

Dott. Giacomo Pelizzari

giacomo.pelizzari@cro.it

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