PI3K and beyond - onkopedia.com · Stratification by PI3K pathway* and visceral disease status Postmenopausal women with HR+/HER2 – locally advanced or metastatic breast cancer

PI3K and beyond

1.10.2017

Wolfgang Janni

Universitätsfrauenklinik, Universität Ulm

Disclosures

Research Grants and/or honoraria from:Sanofi-Aventis, Novartis, Roche, Pfizer, AstraZeneca, Chugai, GSK, Eisai, Cellgene, Johnson&Johnson

PI3K and beyond

- Landscape endokrine Therapie

metastasierter Brustkrebs

- PI3K-Inhitoren – aktuelle Datenlage

- PARP-Inhibition

- Ausblick

PI3K and beyond




- PARP-Inhibition

- Ausblick

In der Therapieentscheidung die richtige Balance finden

Die Lebensqualität muss

im Vordergrund stehen,

und somit die

Verträglichkeit der

Therapie

Effektivität Nebenwirkungen

Die Behandlung von

metastasiertem

Brustkrebs kann die

Erkrankung

stabilisieren, aber nicht

heilen

Faktoren, die die Therapieentscheidung bei Auftreten von Fernmetastasen beeinflussen

Alter, PS,

Begleiterkrankungen

Krankheits-Charakteristika Patientenprofil

Sozio-ökonomische und

psychologische Faktoren

(z.B. Entfernung zum

Krankenhaus; Kosten)

Menopausenstatus

Patientenpräferenz(z.B. oral vs i.v.Behandlung)

Agressivität der Erkrankung

Leidensdruck

Vortherapien und

Therapieansprechen

ER/PgR, HER2 Rezeptor

Status

Krankheitsfreies

Intervall

Vorausgehende adjuvanteTherapie

Leitlinien, Zugang und Therapiekosten

Faktoren, die die Therapieentscheidung bei Auftreten von Fernmetastasen beeinflussen

Alter, PS,

Begleiterkrankungen

Krankheits-Charakteristika Patientenprofil

Sozio-ökonomische und

psychologische Faktoren

(z.B. Entfernung zum

Krankenhaus; Kosten)

Menopausenstatus

Patientenpräferenz(z.B. oral vs i.v.Behandlung)

Agressivität der Erkrankung

Leidensdruck

Vortherapien und

Therapieansprechen

ER/PgR, HER2 Rezeptor

Status

Krankheitsfreies

Intervall

Vorausgehende adjuvanteTherapie

Leitlinien, Zugang und Therapiekosten

1896: Ovarektomie

(Beatson)

1922: Radiomenolyse

1940: Östrogene

1951: Adrenalektomie

1960: Androgene

1971: Tamoxifen

1985: GnRH-Analoga

1998: Aromatase-Hemmer

2000: Östrogenrezeptor-

Downregulator

Seit 2010:

Kombinationstherapien

Gene transcription

Growth factor

receptorEstradiol

mTOR inhibitors

Estrogen receptor down-regulator

PI3K inhibitors

Estrogen receptor modulator

Aromatase inhibitors

PI3K

AKTER

GRB2

P

P

P P

ER

CoA

ER CoA

AP1

P

CoA

TFs

EREs AP1/SP1 TFs-REs

PER

S6KI

SOSShc

Rb

E2F E2F

Cyclin D

CDK4/6

PP P

PP

Cyclin D

CDK4/6

CDK4/6 inhibitors

P P

mTOR

Ras

Raf

MEK

MAPKEstablished

Targets

Innovative

Therapeutic Targets

Weiterentwicklung der endokrinen Therapie –

intrazelluläre Signalwege

Gene transcription

Growth factor

receptorEstradiol

mTOR inhibitors

Estrogen receptor down-regulator PI3K inhibitors

Estrogen receptor modulator

Aromatase inhibitors

PI3K

AKTER

GRB2

P

P

P P

ER

CoA

ER CoA

AP1

P

CoA

TFs

EREs AP1/SP1 TFs-REs

PER

S6KI

SOSShc

Rb

E2F E2F

Cyclin D

CDK4/6

PP P

PP

Cyclin D

CDK4/6

CDK4/6 inhibitors

P P

mTOR

Ras

Raf

MEK

MAPKEstablished

Targets

Innovative

Therapeutic Targets

Weiterentwicklung der endokrinen Therapie –

intrazelluläre Signalwege

PI3K and beyond




- PARP-Inhibition

- Ausblick

PI3K- Phosphoinositid-3-Kinasen

• Heterodimere aus regulatorischer (p85α) und katalytischer (p110α)

Untereinheit; p110α kodiert durch PIK3CA

• Involviert in Zellwachstum, Zellproliferation, Migration,

Differenzierung, Überleben und Zelladhäsion

PIK3CA-Mutationen sehr häufig in MammaCa (20-40%) (Isakoff et al. 2005)

Baselga 2011, The Oncologist

Courtesy T. Fehm

PI3K/mTOR und CDK4/6 Pathways

PI3K

RTK

ER

Estrogen

PIP2

PIP3

PTEN

AKT

mTORC1

mTORC2

Cyclin D

CDK4/6

RTKs can be

overexpressed

or overactivated

in cancer

PTEN (tumor suppressor)

mutation or loss of expression

(13%) are also detected in

luminal A BC1

PIK3CA mutation is the

most frequent genetic

alteration (45–49% of

luminal A BC)1

Cyclin D1 amplification (29–58%)

CDK4 amplification (14–25%),

CDK6 amplification (17%), and loss of

p16 (49%) are detected in BC1,2

BC, breast cancer; CDK, cyclin dependent kinase; ER, estrogen receptor; mTOR, mammalian target of rapomycin; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase PIP2, phosphatidylinositol 4,5-biphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog; RTK, receptor tyrosine kinase.1. The Cancer Genome Atlas Network. Nature. 2012; 490:61–70; 2. Geradts J, Wilson PA, Am J Pathol. 1996:149:15–20.

PI3K Inhibitoren in Phase III Testung

IC50, half maximal inhibitory concentration; Ki, inhibitor constant.

1. Maira SM et al. Mol Cancer Ther. 2012;11:317–28; 2. Folkes AJ et al. J Med Chem 2008;51:5522–5532;

3. Fritsch CM et al. Cancer Res. 2012;72: Abstract 3748; 4. Olivero et al. AACR 213; Abstract DDT02-01.

Buparlisib Alpelisib Taselisib

Pan-Class I

PI3K inhibitor1

Isoform-specific

PI3K inhibitor3

Isoform-specific

PI3K inhibitor4

α β γ δ α

IC50

(nM)52 166 262 116 IC50 5 nM

α

Ki 0.2 nM

Pictilisib

Pan-Class I

PI3K inhibitor2

α β γ δ

3 33 3 75

Vier PI3K-Inhibitoren derzeit in Phase III Testung





Buparlisib

Pan-Class I

PI3K inhibitor1

α β γ δ

IC50

(nM)52 166 262 116

Pictilisib

Pan-Class I

PI3K inhibitor2

α β γ δ

3 33 3 75






IC50

(nM)52 166 262 116

Pictilisib

Pan-Class I

PI3K inhibitor2

α β γ δ

3 33 3 75


Fazit Pictilisib-Kombinationstherapien

• Nebenwirkungen mit Pictilisib typisch für

Pan-PI3K-Inhibitoren

• Met. Brustkrebs:

• Numerischer PFS-Zugewinn, aber

moderat und nicht signifikant

• PI3K-Mutation nicht prädiktiv

• Neo-Adjuvant:

• Signifikant höherer und

eindrucksvoller Abfall von Ki67 mit

Pictilisib, aber keine

Überlebensdaten

• PI3K-Mutation nicht prädiktiv





Buparlisib

Pan-Class I

PI3K inhibitor1

α β γ δ

IC50

(nM)52 166 262 116 3 33 3 75


This presentation is the intellectual property of the author/presenter. Contact them at [email protected] for permission to reprint and/or distribute.

San Antonio Breast Cancer Symposium – December 8–12, 2015

PIK3CA Status in Circulating Tumor DNA Predicts Efficacy of

Buparlisib Plus Fulvestrant in Postmenopausal Women With

Endocrine-resistant HR+/HER2– Advanced Breast Cancer:

First Results From the Randomized, Phase III BELLE-2 Trial

José Baselga,1 Seock-Ah Im,2 Hiroji Iwata,3 Mark Clemons,4 Yoshinori Ito,5 Ahmad Awada,6 Stephen Chia,7

Agnieszka Jagiełło-Gruszfeld,8 Barbara Pistilli,9 Ling-Ming Tseng,10 Sara Hurvitz,11 Norikazu Masuda,12 Javier Cortés,13

Michele De Laurentiis,14 Carlos L. Arteaga,15 Zefei Jiang,16 Walter Jonat,17 Soulef Hachemi,18 Sylvie Le Mouhaër,18

Emmanuelle Di Tomaso,19 Patrick Urban,20 Cristian Massacesi,18 Mario Campone21

1Memorial Sloan Kettering Cancer Center, New York, NY; 2Seoul National University College of Medicine, Seoul, Republic of Korea; 3Aichi Cancer Center, Nagoya, Japan; 4Ottawa Hospital Research Institute, Ottawa, Canada;

5Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan; 6Institut Jules Bordet, Brussels, Belgium; 7BC Cancer Agency, Vancouver, Canada; 8Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology (MCMCC), Warsaw, Poland;

9Ospedale di Macerata, Macerata, Italy; 10Taipei Veterans General Hospital, Taipei, Taiwan; 11UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA; 12National Hospital Organization Osaka National Hospital, Osaka, Japan; 13Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain;

14Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy; 15Vanderbilt-Ingram Cancer Center, Nashville, TN; 16Beijing 307 Hospital of PLA, Beijing, China; 17University Hospital Schleswig-Holstein, Kiel, Germany; 18Novartis Pharma S.A.S., Paris, France; 19Novartis Institutes for BioMedical Research, Cambridge, MA;

20Novartis Pharma AG, Basel, Switzerland; 21Institut de Cancérologie de l’Ouest – René Gauducheau Centre de Recherche en Cancérologie, Nantes, France

34



BELLE-2 Study Design and Endpoints

35

BELLE-2: ClinicalTrials.gov NCT01610284.

AI, aromatase inhibitor; BEAMing, beads, emulsification, amplification, and magnetics; ctDNA, circulating tumor DNA; HER2–, human epidermal growth factor receptor 2 negative;

HR+, hormone receptor-positive; PFS, progression-free survival; PI3K, phosphatidylinositol 3-kinase.

*PI3K pathway activation (activated, non-activated, unknown) was assessed in archival tumor tissue provided at screening, defined as PIK3CA mutation by Sanger sequencing (any

mutations in exons 1, 7, 9, or 20) and/or loss of PTEN expression by immunohistochemistry (1+ expression in <10% of cells); †ctDNA PIK3CA status was assessed by BEAMing technology.

Primary Endpoints

• PFS in the main population (PI3K activated

and non-activated, excluding status unknown*)

• PFS in the PI3K activated group*

(PIK3CA mutation and/or PTEN loss in

archival tissue)

• PFS in the full population (local assessment)

Key Secondary Endpoint

• Overall survival

Other Secondary Endpoints

• Overall response rate

• Clinical benefit rate

• Safety, pharmacokinetics, quality of life

Exploratory Endpoint

• PFS by ctDNA PIK3CA mutation status†

Randomization (1:1)

Stratification by PI3K pathway* and visceral disease status

Postmenopausal women with HR+/HER2– locally advanced or

metastatic breast cancer that progressed on/after AI therapy

N=1147

Buparlisib (100 mg/day)

+ fulvestrant (500 mg)

n=576

Placebo


n=571



BELLE-2 Safety Profile Was Characterized by Hyperglycemia,

Transaminitis, Rash, and Mood Disorders

• Serious adverse events occurred in 23.4% of patients in the buparlisib arm vs 15.8% in the placebo arm

• 12 on-treatment deaths (2.1%) were reported in each arm in the full population, the majority due to disease progression

36

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Buparlisib + Fulvestrant

n=573

Placebo + Fulvestrant

n=570

Adverse event, % All grades Grade 3 Grade 4 All grades Grade 3 Grade 4

Total 99.5 63.2 14.1 93.0 27.4 4.6

Increased ALT 40.1 18.7 6.8 6.8 1.1 0

Increased AST 37.3 15.0 3.0 9.3 2.8 0

Hyperglycemia 43.1 15.2 0.2 7.7 0.2 0

Rash 32.1 7.7 0.2 6.3 0 0

Anxiety 22.3 5.2 0.2 8.2 0.9 0

Fatigue 31.9 4.9 0 23.9 1.6 0

Depression 26.2 3.7 0.7 8.9 0.4 0

Diarrhea 34.2 3.7 0 14.6 1.1 0

Asthenia 20.1 2.8 0 10.5 1.1 0

Stomatitis 21.6 2.1 0 6.5 0.5 0

Nausea 38.7 1.7 0 23.2 1.4 0

Decreased appetite 29.8 1.6 0 11.1 0.2 0



BELLE-2 Met the Primary Endpoint for Statistically Significant

PFS Improvement in the Full and Main Population

• A similar PFS improvement was observed in the main population (HR 0.80 [95% CI: 0.68–0.94]; one-sided P value 0.003)

• Follow-up for OS analysis is ongoing, with a pre-specified target of 588 deaths in the full population

– At the time of primary PFS analysis, OS data were immature (281 deaths in the full population), with a trend in favor of the buparlisib arm

37

CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

Full Population

(N=1047)

Buparlisib +

Fulvestrant

n=576

Placebo +

Fulvestrant

n=571

Median PFS,

months (95% CI)

6.9

(6.8–7.8)

5.0

(4.0–5.2)

HR (95% CI) 0.78 (0.67–0.89)

One-sided

P value<0.001

Pro

bab

ilit

y o

f

Pro

gre

ssio

n-f

ree S

urv

ival, %

Time (Months)

100

60

0

80

40

20

0 4 8 14 182 6 10 12 16 20 26 3022 24 28

Buparlisib + fulvestrant (n/N=349/576)

Placebo + fulvestrant (n/N=435/571)



PFS Increase in the PI3K Activated Group Was

Not Statistically Significant

38

*PFS in the PI3K activated group was tested at a one-sided α=0.01 level of significance.

CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; PI3K, phosphatidylinositol 3-kinase.

PI3K Activated

Group (N=372)

Buparlisib +

Fulvestrant

n=188

Placebo +

Fulvestrant

n=184

Median PFS,

months (95% CI)

6.8

(4.9–7.1)

4.0

(3.1–5.2)

HR (95% CI) 0.76 (0.60–0.97)

One-sided

P value*0.014

Time (Months)

Pro

bab

ilit

y o

f

Pro

gre

ssio

n-f

ree S

urv

ival, %

100

60

0

80

40

20

0 4 8 14 182 6 10 12 16 20 26 3022 24 28





Buparlisib and Fulvestrant Produced a Clinically Meaningful

PFS Improvement in Patients With ctDNA PIK3CA Mutations

39

CI, confidence interval; ctDNA, circulating tumor DNA; HR, hazard ratio; PFS, progression-free survival.

ctDNA PIK3CA Mutant

n=200

Buparlisib +

Fulvestrant

n=87

Placebo +

Fulvestrant

n=113

Median PFS, months

(95% CI)

7.0

(5.0–10.0)

3.2

(2.0–5.1)

HR (95% CI) 0.56 (0.39–0.80)

One-sided nominal P value <0.001

Pro

bab

ilit

y o

f

Pro

gre

ssio

n-f

ree S

urv

ival, %

Time (Months)

100

60

0

80

40

20

0 4 8 14 182 6 10 12 16 20 22





Buparlisib and Fulvestrant Produced a Clinically Meaningful

PFS Improvement in Patients With ctDNA PIK3CA Mutations

40

CI, confidence interval; ctDNA, circulating tumor DNA; HR, hazard ratio; PFS, progression-free survival.

ctDNA PIK3CA Mutant

n=200

Buparlisib +

Fulvestrant

n=87

Placebo +

Fulvestrant

n=113

Median PFS, months

(95% CI)

7.0

(5.0–10.0)

3.2

(2.0–5.1)

HR (95% CI) 0.56 (0.39–0.80)

One-sided nominal P value <0.001

ctDNA PIK3CA

Non-mutant

n=387

Buparlisib +

Fulvestrant

n=199

Placebo +

Fulvestrant

n=188

Median PFS, months

(95% CI)

6.8

(4.7–8.5)

6.8

(4.7–8.6)

HR (95% CI) 1.05 (0.82–1.34)

One-sided nominal P value 0.642

Pro

bab

ilit

y o

f

Pro

gre

ssio

n-f

ree S

urv

ival, %

Time (Months)

100

60

0

80

40

20

0 4 8 14 182 6 10 12 16 20 26 2822 24



Pro

bab

ilit

y o

f

Pro

gre

ssio

n-f

ree S

urv

ival, %

Time (Months)

100

60

0

80

40

20

0 4 8 14 182 6 10 12 16 20 22





41

BELLE-3: A Phase III Study of Buparlisib and Fulvestrant

in Postmenopausal Women With HR+, HER2–, AI-treated,

Locally Advanced or Metastatic Breast Cancer, Who

Progressed On or After mTOR Inhibitor-based Treatment

Angelo Di Leo,1 Keun Seok Lee,2 Eva Ciruelos,3 Per Lønning,4 Wolfgang Janni,5 Ruth O’Regan,6

Marie-Ange Mouret Reynier,7 Dimitar Kalev,8 Daniel Egle,9 Tibor Csőszi,10 Roberto Bordonaro,11

Thomas Decker,12 Vivianne CG Tjan-Heijnen,13 Sibel Blau,14 Alessio Schirone,15 Denis Weber,16

Mona El-Hashimy,17 Bharani Dharan,17 Dalila Sellami,17 Thomas Bachelot18

1Ospedale Misericordia e Dolce, Prato, Italy; 2National Cancer Center, Gyeonggi-do, Republic of Korea; 3Hospital Universitario 12 de Octubre, Madrid, Spain; 4Haukeland University Hospital, Bergen, Norway; 5Universitätsklinikum Ulm, Ulm, Germany; 6University of Wisconsin-Madison, Madison, WI;

7Centre Jean Perrin, Clermont-Ferrand, France; 8Medical University of Varna, Varna, Bulgaria; 9Medizinische Universität Innsbruck, Innsbruck, Austria; 10JNSZ Megyei Hetényi Géza Kórház-Rendelőintézet, Szolnok, Hungary; 11ARNAS Garibaldi, Catania, Italy;

12Onkonet – Onkologie Ravensburg, Ravensburg, Germany; 13Maastricht University Medical Center+, Maastricht, The Netherlands; 14Rainier Hematology-Oncology/Northwest Medical Specialties, Tacoma, WA;

15Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy; 16Novartis Pharma AG, Basel, Switzerland; 17Novartis Pharmaceuticals Corporation, East Hanover, NJ; 18Centre Léon Bérard, Lyon, France



42

• Tumor assessments were performed every 6 weeks

• 90% power to detect a 33% risk reduction in PFS (disease progression or death)

at one-sided α=0.025, based on the observation of 313 PFS events

BELLE-3 Study Design and Endpoints

Randomization (2:1)

Stratified by visceral

disease status

Buparlisib (100 mg/day)


n=289

Placebo


n=143

Primary endpoint

• PFS (locally assessed per

RECIST v1.1)

Key secondary endpoint

• OS

Other secondary endpoints

• PFS by PIK3CA status (ctDNA)

• OS by PIK3CA status (ctDNA)

• ORR and CBR in the full

population and by PIK3CA

status (ctDNA)

• Safety, pharmacokinetics,

quality of life

• Postmenopausal women with

HR+/HER2–, AI-pretreated,

locally advanced or

metastatic breast cancer

• Progression on or after

an mTOR inhibitor as

last line

of treatment

• N=432

AI, aromatase inhibitor; CBR, clinical benefit rate; ctDNA, circulating tumor DNA; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RECIST, Response Evaluation Criteria In Solid Tumors.BELLE-3: ClinicalTrials.gov NCT01633060.



43

CharacteristicBuparlisib +

Fulvestrant (n=289)

Placebo +

Fulvestrant (n=143)

All Patients

(N=432)

Median age, years (range) 60 (32–84) 62 (37–79) 61 (32–84)

≥3 metastatic sites, % 64 67 65

Visceral metastases, % 73 72 73

Prior chemotherapy for

metastatic disease, %36 34 35

≥2 lines of endocrine therapy for

metastatic disease, %

(Prior fulvestrant was not permitted)

70 66 69

Key Patient and Tumor Characteristics



44

• PFS results by independent central review were consistent with local assessment:

– HR 0.57 (95% CI: 0.44–0.74; one-sided p<0.001)

Progression-free Survival per Investigator Assessment

(Primary Endpoint)

CI, confidence interval; HR, hazard ratio.

6-month PFS rate:

31% vs. 20%

100

80

60

40

20

0

0 4 82 6 10 12 14 16 18 20 22 24 26

Time, Months

Pro

ba

bilit

y o

f

Pro

gre

ss

ion

-fre

e S

urv

iva

l, %

Full Population

(N=432)

Buparlisib +

Fulvestrant

n=289

Placebo +

Fulvestrant

n=143

Median PFS,

months (95% CI)

3.9

(2.8–4.2)

1.8

(1.5–2.8)

HR (95% CI) 0.67 (0.53–0.84)

One-sided p-value <0.001



45

Subgroup Analyses of PFS

ECOG, Eastern Cooperative Oncology Group; ER+, estrogen receptor-positive; PgR–, progesterone receptor-negative; PgR+, progesterone receptor-positive.

Hazard ratio for PFS (95% CI)

<65 years (n=274) 0.69 (0.51–0.92)

≥65 years (n=158) 0.63 (0.42–0.93)

0 (n=264) 0.58 (0.43–0.78)

1 or 2 (n=163) 0.80 (0.54–1.18)

(Neo)adjuvant setting only (n=189) 0.67 (0.47–0.96)

Metastatic setting (n=152) 0.74 (0.50–1.11)

None (n=91) 0.59 (0.36–0.96)

1 (n=103) 0.53 (0.33–0.87)

2 (n=219) 0.72 (0.52–0.99)

≥3 (n=110) 0.73 (0.46–1.16)

ER+, PgR+ (n=343) 0.66 (0.50–0.85)

ER+, PgR– (n=85) 0.70 (0.42–1.18)

Clinical benefit (n=284) 0.75 (0.57–1.00)

No clinical benefit (n=148) 0.47 (0.32–0.71)

Favors Buparlisib + Fulvestrant Favors Placebo + Fulvestrant

0.25 0.5 0.75 1 1.5 2

Age

ECOG performance status

Prior

chemotherapy

Hormone receptor status

Sensitivity to last

endocrine therapy +

mTOR inhibitor

Prior lines of therapy



46

Progression-free Survival by PIK3CA Status

100

80

60

40

20

0

20181614121086420 262422

100

80

60

40

20

0

20181614121086420

Pro

ba

bil

ity o

f P

FS

, % Tissue (mutant)

Buparlisib +

Fulvestrant

Placebo +

Fulvestrant

Median PFS,

months (95% CI)

4.7

(2.9–6.7)

1.4

(1.4–2.2)

HR (95% CI) 0.39 (0.23–0.65); p<0.001

PCR, polymerase chain reaction; WT, wild-type.p-values are one-sided.

100

80

60

40

20

0

2620181614121086420 2422

Pro

ba

bil

ity o

f P

FS

, %

100

80

60

40

20

0

20181614121086420 262422

Primary tumor

tissue (PCR)

N=321

PIK3CA mutant:

34%

Time, Months Time, Months

Tissue (WT)Buparlisib +

Fulvestrant

Placebo +

Fulvestrant

Median PFS,

months (95% CI)

2.8

(2.0–3.7)

2.7

(1.4–2.9)

HR (95% CI) 0.83 (0.60–1.14); p=0.117

ctDNA (WT)Buparlisib +

Fulvestrant

Placebo +

Fulvestrant

Median PFS,

months (95% CI)

3.9

(2.8–4.3)

2.7

(1.5–3.6)

HR (95% CI) 0.73 (0.53–1.00); p=0.026

ctDNA (mutant)Buparlisib +

Fulvestrant

Placebo +

Fulvestrant

Median PFS,

months (95% CI)

4.2

(2.8–6.7)

1.6

(1.4–2.8)

HR (95% CI) 0.46 (0.29–0.73); p<0.001

ctDNA samples

at study entry

(BEAMing)

N=348

PIK3CA mutant:

39%

Mutant Wild-type



47

• One confirmed case of Hy’s Law was observed in the buparlisib + fulvestrant arm

• Three cases of suicidal attempt were reported in the buparlisib + fulvestrant arm vs none in the placebo + fulvestrant arm

Adverse Events (≥10% of Patients) Regardless of Relationship to

Study Treatment

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Buparlisib + Fulvestrant

n=288

Placebo + Fulvestrant

n=140

Adverse event, % All Grades Grade 3/4 All Grades Grade 3/4

Total 98 62 91 34

ALT increased 39 22 7 3

AST increased 37 18 10 3

Hyperglycemia 36 12 3 0

Nausea 34 1 18 2

Diarrhea 26 3 9 1

Fatigue 23 4 19 1

Depression 21 1 8 0

Anxiety 18 1 10 0

Asthenia 17 2 10 0

Decreased appetite 16 1 6 1

Dizziness 12 1 7 0

Hypertension 12 6 6 4

Rash 12 2 2 0

Stomatitis 10 1 4 0

Fazit Buparlisib-Kombinationstherapien

• Nebenwirkungen von Buparlisib führen

dazu, dass die Substanz trotz zweier

positiver Studien nicht weiter verfolgt wird

• Nebenwirkungen der Pan-PI3KIs im

Vergleich zu CDKIs ungünstig

• Inkonsistente Daten zur prädiktiven

Bedeutung der PI3K-Mutation

• Liquid Biopsy (ctDNA) womöglich besser,

als Primärtumor?

DETECT study concept

CTC Biomaterial Program in the Detect-Trials

Which cells are responsiblefor progression?

S1 – Damage responseS2 – EMT and stem cell markersS3 – Protein pathway activation

EpCAM-positive AND –negative CTCs

LiquidBiopsy

Tumor heterogeneity

Resistanceto therapy

Hypothesis-driven analysis of molecular targets

Individualized treatment of advanced breast cancer

Translational research program of DETECT CTC- Project aims -

S5 – Circulating nucleic acids(miRNA, ctDNA)

S4 – Disseminated cancer cellsin bone marrow

S6 – Selection of mutations in CTCs

Which biomarker is the best predictor for response to therapy?

Funded by theGerman Cancer Foundation 1,7 Mio€

Strength of DETECT CTC- Concerted exploitation of blood samples -

PI3K and beyond




- PARP-Inhibition

- Ausblick

OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients with HER2-negative metastatic breast cancer and a germline BRCA mutation

Presented By Mark Robson at 2017 ASCO Annual Meeting

OlympiAD study design


Patient characteristics


Primary endpoint: progression-free survival by BICR


Overall survival (interim analysis; 46% data maturity)


Objective response by BICR


Subgroup analyses: PFS by BICR


Time to deterioration of global HRQoL


Slide 24


Persönliches Fazit Olaparib ABC

• Überzeugende Daten zu Olaparib nun nach

dem Ovarial-Ca auch beim Mamma-Ca bei

gBRCA-Mutation

• Zulassung wird sicher kommen

• Für ca. 10% der Patientinnen eine wichtige

Option

• Adjuvante Studie in Rekrutierung

Praxis: umsetzen – abwarten –

nicht umsetzen

PI3K and beyond




- PARP-Inhibition

- Ausblick

Ongoing Clinical Trials of Investigational SERDs in HR+,

HER2– ABC

65

Agent Phase Treatment Prior Treatment

Target

N

Primary

Endpoint

RAD19013,4 1 Monotherapy Progression or

recurrence with ET

75 MTD

AZD94962,5 1 Monotherapy Progression or

recurrence with ET

150 Safety and

tolerability

GDC-08106,7 2 FUL vs

GDC-0810

Progression or

recurrence on AI

152 PFS

1/2 GDC-0810 +

PAL ± LHRH

agonist

Progression or

recurrence on ET

195 RP2D, MTD,

CBR

LSZ1028 1 LSZ102 alone;

LSZ102 + RIBO;

LSZ102 + BYL

Progression or

recurrence with ET

150 Incidence of

DLT; safety,

tolerability

ABC, advanced breast cancer; AI, aromatase inhibitor; ANA, anastrozole; BYL, alpelisib; CBR, clinical benefit rate; DLT, dose-limiting toxicity; ET, endocrine therapy; FUL, fulvestrant;

HER2–, human epidermal growth factor receptor-2–negative; HR+, hormone receptor-positive; LHRH, luteinizing hormone-releasing hormone; MTD, maximum tolerated dose; OS, overall

survival; ORR; objective response rate; PAL, palbociclib; PFS, progression-free survival; RP2D, recommended phase 2 dose; RIBO, ribociclib; SERD, selective estrogen receptor down-

regulator/degrader.

1. Garner F, et al. Anticancer Drugs. 2015;26(9):948-956; 2. Hamilton, E, et al. SABCS 2016. Abstract P6-12-03 [poster]; 3. Kakalamani, et al. SABCS 2016. Abstract P2-08-06 [poster];

4. NCT02338349; 5. NCT02248090; 6. NCT02569801; 7. NCT01823835; 8. NCT02734615.

In clinical practice,

the utility of fulvestrant

is limited by method

of administration

(intramuscular

injection)1

Oral SERDs are

currently being

investigated for

postmenopausal

women with HR+ ABC1,2

Immunomodulation in Breast Cancer

66

T cellDendritic cell

T cell Tumor

cell

T cell Tumor cell

Tumor Microenvironment

Activation(cytokines, lysis,

proliferation,

migration to tumor)

In breast cancer

Tumor-infiltrating lymphocytes and PD-L1 expression are associated with better outcome1

Myeloid-derived suppressor cells are linked to high risk of nodal metastases2

Immune checkpoint inhibition

regimens can result in

• Late responses and

unconventional kinetics of

response

• Long duration of remissions

• Ability to re-respond to therapy

after progression

• Immune-related AEs

AE, adverse event; PD-L1, programmed death ligand-1.

1. Schalper KA, et al. Clin Cancer Res. 2014;20(10):2773-2782; 2. Yu J, et al. J Immunol. 2013;190(7):3783-3797.

T cell

Dendritic

cell

BlockadeBlockade

Ongoing Clinical Trials of Immune Checkpoint Inhibitors

(Phase 1/2 in HR+ ABC)

67

Study Phase N

Endpoints

Primary Secondary

Cohort 2: Pembrolizumab + antiestrogen therapy

(anastrozole, letrozole, or exemestane) in HR+,

HER2− MBC (NCT02648477a)

2 ≈ 56ORR and

safety

CBR, DOR,

TTF, PFS, OS

Anti–PD-L1 antibody (durvalumab) + anti–CTLA-4

antibody (tremelimumab) in HR+, HER2– BC

(NCT03132467)1 ≈ 15

Safety,

feasibility—

Neoadjuvant pembrolizumab + decitabine followed by

standard neoadjuvant chemotherapy for HER2– locally

ABC (NCT02957968)2 ≈ 50

Safety, TIL

levels

pCR, cCR,

residual

disease, TIL

infiltration

Cohort 3: Safety study of nivolumab + nab-paclitaxel ±

gemcitabine in recurrent MBC (NCT02309177)1 ≈ 40 Safety

PFS, OS, DCR,

ORR, DoR

ABC, breast cancer; AE, adverse event; CBR, clinical benefit rate; cCR, clinical complete response; DCR, disease control rate;; DOR, duration of response; HR+, hormone receptor-positive;

HER2–, human epidermal growth factor receptor-2–negative; MBC, metastatic breast cancer; ORR, overall response rate; OS, overall survival; pCR, pathological complete response;

PD-1, programmed death-1; PFS, progression-free survival; PK, pharmacokinetics;; TIL, tumor infiltrating lymphocyte; TTF, time to treatment failure.a This is a combined trial in TNBC and HR+ HER2– BC, with 2 cohorts.

Available from clinicaltrials.gov.

Fazit: PI3K-Inhibitoren and beyond…

- PI3K-Inhibitoren beim HR-pos metastasierten Brustkrebs wirksam

– sowohl primär, als auch in der endokrinen Therapieresistenz

- Pan-PI3K-Inhibitoren wegen hoher Toxizität vermutlich nicht

praxistauglich

- Datenlage zur Rolle der PI3K-Mutation unklar – liquid biopsy

womöglich besser

- Beyond ist jetzt: Olaparib beim BRCA-ass. Met. Brustkrebs

einsetzbar

- Further beyond: we‘ll see…..

Documents

PI3K and beyond - onkopedia.com · Stratification by PI3K pathway* and visceral disease status Postmenopausal women with HR+/HER2 – locally advanced or metastatic breast cancer