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P PronzatoNapoli, 27.9.2017

INCONTRO NAZIONALE AIOM : INIBITORI DELLE CICLINE

Optimization & Selection

Selection & Optimization

Easy Issues:Do like in the Trial!


JA Beaver, NEJM 2017


CostSubgroups and Limits Sequences

SA Wander, JCO 2017

Subgroups

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

Content

• Choosing among– HT alone– HT alone + CDK4/6 inhibitors– Chemotherapy

• How manage the newer treatments in order to exploit themoptimally

New Foundations

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 Anastrozoleor 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

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

Selection of patients(vs HT or CT)

The Story of Endocrine Sensitivity and Endocrine Resistance

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

Agent Inv Ass PFS (m) ORR (%) (Measurable)

CBR (%)(Measurable)

Ref

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


Agent Inv Ass PFS (m)


CBR (%)(Measurable)

Ref

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

Endocrine High Sensitivity

• Two Groups in which the Performance of HT alone is verygood (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

Endocrine Resistence

• Two Groups in which the Performance of HT alone is verypoor (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


Agent Inv Ass PFS (m)


CBR (%)(Measurable)

Ref

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

PALOMA-3 vs MONARCH-2 vs CONFIRMTRIAL Fulvestrant PFS PRIOR CT FOR

MBC PRIOR AI (%) n. Lines of HT

for MBCRef

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 LeoJCO 2010 & AZ File**

CONFIRMNO PRIOR MBC CT

8.3 no - Di LeoJCO 2010 & AZ File**

* As reported by I Maier at ASCO 2017

Chemotherapy in HER2-/HR+

Performance of CT in the HER2-/HR+ RCTsRegimen 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 - Robert,JCO 2011

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 - Robert,JCO 2011

Paclit + Beva (high risk) 11.1 46 Brodowicz,BJC 2014

Paclit + Beva (low risk) 14.4 35 Brodowicz,BJC 2014

Cape+ Vinor + Beva 9.6 - Welt,BCRT 2016

Why is it so important for SELECTION?

& The challenge in practice

LR/OLIGOMTS METASTASES

HER2+

VERY AGGRNO VERY AGGR

COMBO

MONOCT MONOCT MONOCTHT Res HT Sens

HT +/- BIO HT +/- BIO

HER2-/ HR+

HT +/- BIO

HT +/- BIO

MONOCT

TNBC

Algorithm?Decisional Tree?Flow Chart

Hormonoresistence

No visceral crisis orlife-threatening disease!

HT SENSITIVE

HT RESISTANT

Hormonoresistence


HT SENSITIVE

HT RESISTANT

Risk of Rapid PD Hormonoresistence


Need of Response

HT SENSITIVE

LOW RISK

HT RESISTANT

HIGH RISK

Hormonoresistence


Need of ResponseRisk of Rapid PD

HT SENSITIVE

HT + CDK 4/6 in.

LOW RISK

HT RESISTANT

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

Treatment Optimization(Optimal Treatment

Management after Adoption)

Drug-Drug Interaction

LM Spring, The Oncologist 2017

Toxicity

Presented by S Loibl at ESMO 2017

Management of Neutropenia


Management of Hepatobiliary Toxicity


Management of QTc

AS Clark, ASCO2017

Conclusions

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

Changing Practice?



• Provided that You believe in the clinical value of ORR/ PFS/ CB/ QoL/ delay of CT

Changing Practice?



• And Consider for the Future:– If OS advantage shown in first line every patient to be treated– Much work to do for individuation of subgroups of pts who do not

benefit

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