Ottimizzazione del trattamento e selezione dei pazienti

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Ottimizzazione del trattamento e selezione delle pazienti

P Pronzato

Napoli, 27.9.2017

INCONTRO NAZIONALE AIOM : INIBITORI DELLE CICLINE

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Optimization & Selection

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Selection & Optimization

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Easy Issues:

Do like in the Trial!

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Easy Issues:

Do like in the Trial!

JA Beaver, NEJM 2017

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Easy Issues:

Do like in the Trial!

Cost

Subgroups and Limits Sequences

SA Wander, JCO 2017

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Subgroups

RS Finn Lancet Oncol 2015; RS Finn, Breast Cancer Res 2016; A Di Leo, ESMO 2017

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Subgroups

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Subgroups

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Subgroups

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Content

• Choosing among – HT alone

– HT alone + CDK4/6 inhibitors – Chemotherapy

• How manage the newer treatments in order to exploit them

optimally

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New Foundations

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RELEVANT TRIALS (HTs & HT+TARGET) in HER2-/HR+

phase HT Target T Setting Ref

FALCON ³ Anastrozole or

Fulvestrant - HS ^Robertson,Lancet Oncol 2016

PALOMA-1 ² Letrozole Palbociclib HS ^Finn,Lancet Oncol 2015

PALOMA-2 ³ Letrozole Palbociclib HS ^Finn,_{NEJM 2016}

PALOMA-3 ³ Fulvestrant Palbociclib HR ^Turner,_{NEJM 2015}

MONALEESA-2 ³ Letrozole Ribociclib HS Hortobagyi,

NEJM 2016

MONARCH-2 ³ Fulvestrant Abemaciclib HR ^Sledge,_{JCO 2017}

MONARCH-3 ³ Anastrozole

or Letrozole Abemaciclib HS ^DiLeo,_{ESMO 2017}

BOLERO-2 ³ Exemestane Everolimus HR Baselga,

NEJM 2012

BELLE-2 ³ Fulvestrant Buparlisib HR ^Baselga,Lancet Oncol 2017

BELLE-3 ³ Fulvestrant Buparlisib HR ^DiLeo,_{SABCS 2016}

FERGI ² Fulvestrant Pictilisib HR ^Krop,Lancet Oncol 2016

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MAIN RESULTS OF RELEVANT TRIALS

HT Inv Ass PFS

(mos) ORR (%)

(Measurable) CBR (%)

(Measurable) Ref

PALOMA-2 (HS) Letro

24.8

^{vs 14.5}

42

^{vs 35}

85

^{vs 70} ^Finn,NEJM 2016

PALOMA-3 (HR) Fulv

9.6

^{vs 4.6}

19

^{vs 9}

67

^{vs 40} ^Turner,NEJM 2015

MONALEESA-2 (HS) Letro NR vs 14.7 53 vs 37 80 vs 73 Hortobagyi, NEJM 2016

MONARCH-2 (HR) Fulv 16.4 vs 9.3 48 vs 21 73 vs 52 ^Sledge,_{JCO 2017}

MONARCH-3 (HS) NSAI NR vs 14.7 53 vs 31 78 vs 69 ^{Di Leo,}_{ESMO 2017}

BOLERO-2 (HR) Exe

6.9

^{vs 2.8}

13

^{vs 2*} ^- Baselga, NEJM 2012

BELLE-2 (HR) Fulv

6.9

^{vs 5}

11

^{vs 7**} ^- ^Baselga,Lancet Oncol 2017

* H Burris, SABCS 2013

* ITT population

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MAIN RESULTS OF RELEVANT TRIALS

HT Inv Ass PFS

(mos) ORR (%)

24.8

^{vs 14.5}

42

^{vs 35}

85

^{vs 70} ^Finn,NEJM 2016

9.6

^{vs 4.6}

19

^{vs 9}

67

6.9

^{vs 2.8}

13

^{vs 2*} ^- Baselga, NEJM 2012

6.9

^{vs 5}

11

* ITT population

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MAIN RESULTS OF RELEVANT TRIALS

HT Inv Ass PFS

(mos) ORR (%)

24.8

^{vs 14.5}

42

^{vs 35}

85

^{vs 70} ^Finn,NEJM 2016

9.6

^{vs 4.6}

19

^{vs 9}

67

6.9

^{vs 2.8}

13

^{vs 2*} ^- Baselga, NEJM 2012

6.9

^{vs 5}

11

* ITT population

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Selection of patients

(vs HT or CT)

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The Story of Endocrine Sensitivity and

Endocrine Resistance

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Performance of HT alone in the HER2-/HR+ RCTs

Agent Inv Ass PFS (m) ORR (%)

Anastrozole (FALCON)

13.8 36 74

^Robertson,Lancet Oncol 2016

Letrozole (PALOMA -1)

10.2 33 58

^Finn,Lancet Oncol 2015

Letrozole (PALOMA-2)

14,5 35 70

^Turner,NEJM 2015

Letrozole (MONALEESA)

14,7 31 73

Hortobagyi,

NEJM 2016

Letrozole (MONARCH-3)

14.7 31 69

^{Di Leo,}ESMO 2017

Exemestane (BOLERO-2)

2.8 2 -

^Baselga,NEJM 2012

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Performance of HT alone in the HER2-/HR+ RCTs

Agent Inv Ass PFS

(m) ORR (%)

Fulvestrant (FALCON) 16.6 40 78 ^Robertson,Lancet Oncol 2016

Fulvestrant (PALOMA-3) 4.6 9 40 ^Turner,_{NEJM 2015}

Fulvestrant (MONARCH-2) 9.3 21 52 ^Sledge,_{JCO 2017}

Fulvestrant (BELLE-2) 5 7 - ^Baselga,Lancet Oncol 2017

Fulvestrant (BELLE-3) (PI3KCA wt/ mut) 2.7/ 1.4 2.1 15.4 ^{Di Leo,}_{SABCS 2016} Fulvestrant (FERGI- part 1) 5.1 6.3 17.7 ^Krop,Lancet Oncol 2016

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Endocrine High Sensitivity

• Two Groups in which the Performance of HT alone is very good (ORR >30%; CBR >60%; PFS >12 mos)

– Not Previously treated by HT

– Treated by Adjuvant Tam and Relapsed >12 months

JFR Robertson, Lancet Oncol 2016; RS Finn, Lancet Oncol 2015; RS Finn NEJM 2016 See also N Turner, Lancet 2016

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Endocrine Resistence

• Two Groups in which the Performance of HT alone is very poor (ORR <10%; CBR < 40%; PFS <5 mos)

– Pts in PD during NSAI or shortly after adjuvant AI withdrawal

– Pts progressing under or <6 months after withdrawal of adjuvant TAM

J Baselga, NEJM 2012; IE Krop, Lancet Oncol 2016; J Baselga, Lancet Oncol 2017 See also N Turner, Lancet 2016

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Performance of HT alone in the HER2-/HR+ RCTs

Agent Inv Ass PFS

(m) ORR (%)

Fulvestrant (FALCON) 16.6 40 78 ^Robertson,Lancet Oncol 2016

Fulvestrant (PALOMA-3) 4.6 9 40 ^Turner,_{NEJM 2015}

Fulvestrant (MONARCH-2) 9.3 21 52 ^Sledge,_{JCO 2017}

Fulvestrant (BELLE-2) 5 7 - ^Baselga,Lancet Oncol 2017

Fulvestrant (BELLE-3) (PI3KCA wt/ mut) 2.7/ 1.4 2.1 15.4 ^{Di Leo,}_{SABCS 2016} Fulvestrant (FERGI- part 1) 5.1 6.3 17.7 ^Krop,Lancet Oncol 2016

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PALOMA-3 vs MONARCH-2 vs CONFIRM

TRIAL Fulvestrant PFS PRIOR CT FOR

MBC PRIOR AI (%) n. Lines of HT

for MBC Ref

PALOMA- 3

4.6 Yes (36.2%) 86.8 Any

^TurnerNEJM 2015

MONARCH -2

9.3 no 66.8* 1

^SledgeASCO 2017* & JCO

2017

CONFIRM

PRIOR MBC CT

4.9 yes -

^{Di Leo}JCO 2010 & AZ File**

CONFIRM

NO PRIOR MBC CT

8.3 no -

^{Di Leo}JCO 2010 & AZ File**

* As reported by I Maier at ASCO 2017

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Chemotherapy in HER2-/HR+

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Performance of CT in the HER2-/HR+ RCTs

Regimen Inv Ass PFS (m) ORR (%)

(Measurable)

Ref

Capecitabine

6.2 -

^Robert,JCO 2011

Paclitaxel

9.1 -

^Miles,EJC 2017

Tax/Anthra

8.2 -

^Robert,^{JCO 2011}

Cape + Beva

9.2 -

Cape + Beva

8.8 -

^Welt,BCRT 2016

Cape + Beva (high risk)

8.3 30

^Brodowicz,BJC 2014

Cape + Beva (low risk)

11.5 28

^Brodowicz,^{BJC 2014}

Paclitaxel + Beva

11.2 -

^Miles,EJC 2017

Tax/Anthra + Beva

10.3 -

Paclit + Beva (high risk)

11.1 46

Paclit + Beva (low risk)

14.4 35

Cape+ Vinor + Beva

9.6 -

^Welt,^{BCRT 2016}

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Why is it so important for SELECTION?

& The challenge in practice

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LR/OLIGOMTS METASTASES

HER2+

VERY AGGR NO VERY AGGR

COMBO

MONOCT MONOCT MONOCT

HT Res HT Sens HT +/- BIO HT +/- BIO HER2-/ HR+

HT +/- BIO HT +/- BIO MONOCT

TNBC

Algorithm?

Decisional Tree?

Flow Chart

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Hormonoresistence

No visceral crisis or life-threatening disease!

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SENSITIVEHT

RESISTANTHT

Hormonoresistence

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SENSITIVEHT

RESISTANTHT

Risk of Rapid PD Hormonoresistence

Need of Response

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SENSITIVEHT

LOW RISK

RESISTANTHT

HIGH RISK

Hormonoresistence

Need of Response

Risk of Rapid PD

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SENSITIVEHT

HT + CDK 4/6 in.

LOW RISK

RESISTANTHT

HIGH RISK

HT + CDK 4/6 in. or HT + EVE Chemotherapy Chemotherapy

Hormonoresistence

Need of Response

HT + CDK 4/6 in. or HT + EVE

Risk of Rapid PD

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Treatment Optimization (Optimal Treatment

Management after Adoption)

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Drug-Drug Interaction

LM Spring, The Oncologist 2017

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Drug-Drug Interaction

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Drug-Drug Interaction

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Drug-Drug Interaction

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Toxicity

Presented by S Loibl at ESMO 2017

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Management of Neutropenia

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Management of Hepatobiliary Toxicity

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Management of QTc

AS Clark, ASCO2017

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Conclusions

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Changing Practice?

• Incorporate CDK/6 inhibitors + HT at some point in the treatment sequence of HER2-/HR+ MBC

• Not every patient in I line must receive CDK/6 inhibitors + HT

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Changing Practice?

• Incorporate CDK/6 inhibitors + HT at some point in the treatment sequence of HER2-/HR+ MBC

• Not every patient in I line must receive CDK/6 inhibitors + HT

• Provided that You believe in the clinical value of ORR/ PFS/

CB/ QoL/ delay of CT

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