pearls from asco and esmo 2015 - over group provider ecm · (advance online publication) 2015 erbb2...

PEARLS FROM ASCO AND ESMO 2015

Giampaolo Bianchini MD

The cell cycle and cyclin-dependent kinases

Ashgar U et al, Nat Rev Drug Discovery 2015

New class of target therapies

Regulation of the G1/S is the focal point of multiple

oncogenic signals

- Multiple oncogenic signals stimulate Cyclin D expression and activation of CDK4/6

- CDK4/6 phosphorylates and inactivates the RB tumor suppressor

- Gene expression via E2F drives progression through S, G2, and M

Inactive RB

Pl3K/Akt

STATs Ras

MAPKs

ER Wnt/β-catenin

HER2

p16

G0/G1

Arrest

Cell CycleProgression

Oncogenic Signals Stimulate CDK4/6

Transcription activated

Palbociclib

Abemaciclib

Ribociclib

CDK4 inhibitors

require functional Rb1

Preferential inhibition of luminal ER+ (and

HER2+) breast cancer cell lines by palbociclib

Finn RS, et al. Breast Cancer Res. 2009;11(5):R77.

Non-luminal/post EMT

Non-luminal

Luminal

HER2 amplified

Immortalized

MCF7-CYP19

0

5000

10000

15000

Control 10nM AD

Palbociclib 25nM

Fulvestrant 3nM

Combination

Treatment

Cells

/well

MCF7-CYP19

10

5000

10000

15000

Control 10nM AD

Palbociclib 25nM

Letrozole 40nM

Combination

TreatmentC

ells

/We

ll

Palbociclib cooperates with Fulvestrant and

Letrozole

Combination benefit

with letrozoleCombination benefit

with fulvestrant

PALOMA3 Study Design

Placebo

(3 wks on/ 1wk off)

+

Fulvestrant†

(500 mg IM q4w)

Palbociclib

(125 mg QD;

3 wks on/1 wk off)

+

Fulvestrant†

(500 mg IM q4w)

†administered on Days 1 and 15 of Cycle 1.

● Visceral metastases

● Sensitivity to prior

hormonal therapy

● Pre-/peri- vs Post-

menopausal

Clinicaltrials.gov NCT01942135

NC Turner et al, ASCO 2015

2:1 Randomization

N=521

Stratification:

• Post-menopausal patients must have progressed on prior aromatase inhibitor therapy.

n=347

n=174

• HR+, HER2– ABC

• Pre-/peri-* or post-menopausal

• Progressed on prior endocrine

therapy:

– On or within 12 mo adjuvant

– On therapy for ABC

• ≤1 prior chemotherapy regimen

for advanced cancer

*All received goserelin.

Demographics and Baseline Tumor Characteristics

Characteristic Palbociclib +

Fulvestrant

(n=347)

Placebo +

Fulvestrant

(n=174)

Median age (range), years 57 (30−88) 56 (29−80)

Receptor status, %

ER+ PR+ 69 64

ER+ PR– 26 28

ECOG performance status, %

0 60 66

1 40 34

Menopausal status,a %

Pre-/peri 21 21

Post 79 79

Visceral metastases,b % 59 60

Number of disease sites, %

1 32 35

2 29 29

3 39 36aBased on randomization; blung, liver, brain, pleural, and peritoneal involvement.

Tumor Characteristics and Prior Treatment

Characteristic Palbociclib +

Fulvestrant

(n=347)

Placebo +

Fulvestrant

(n=174)

Documented sensitivity to prior

hormonal therapy,a %

Yes 79 78

No 21 22

Prior aromatase inhibitor +/- GnRH,b % 85 87

Prior tamoxifen +/- GnRH,b % 61 60

Prior chemotherapy in advanced

setting, %31 36

Prior lines of therapy in advanced

setting, %

0 24 26

1 38 40

2 26 25

≥3 12 9aRelapsed after 24 months of adjuvant endocrine therapy or had clinical benefit to prior therapy in the advanced setting.bAny prior endocrine therapy anytime before study entry.

GnRH=gonatotropin-releasing hormone.



Adverse Events—All Cause

AE, %

Palbociclib + Fulvestrant

(n=345)

Placebo + Fulvestrant

(n=172)

Any

Grade

Grade

3 Grade 4

Any

Grade Grade 3

Grade

4

Any AE 98 59 11 89 16 2

Neutropenia 79 53 9 3 0 1

Leukopenia 46 25 1 4 0 1

Anemia 26 3 0 10 2 0

Thrombocytopenia 19 2 1 0 0 0

Fatigue 38 2 0 27 1 0

Nausea 29 0 0 26 1 0

Headache 21 <1 0 17 0 0

Upper respiratory

infectiona 19 <1 0 16 0 0

Diarrhea 19 0 0 17 1 0

Constipation 17 0 0 14 0 0

Alopecia 15 0 0 6 0 0

0 2 4 6 8 10 12

Time (Month)

0

10

20

30

40

50

60

70

80

90

100

PF

S P

rob

ab

ilit

y (

%)

347 279 132 59 16 6PAL+FUL

174 109 42 16 6 1PCB+FUL

Number of patients at risk

Primary Endpoint: PFS (ITT Population)

CI=confidence interval; HR=hazard ratio; ITT=intent-to-treat; NE=not estimable; PFS=progression-free survival.



Palboci

clib +

Fulvestr

ant

n=347

Placebo

+

Fulvestra

nt

n=174

Median PFS,

months

(95% CI)

9.2

(7.5, NE)

3.8

(3.5, 5.5)

HR (95% CI) 0.422 (0.318, 0.560)

2-sided P

value<0.000001

4.2%

Intrinsec (primary)

resistance

Paloma 1 study: overall results with first line

Palbociclib and letrozole in ER+/HER2- MBC

Finn RS et al, Lancet Oncol, 2015

Intrinsec (primary)

resistance

“Omics” sciences reveal

the molecular landscapes of cancer

Gene mRNA Protein

Genomics Transcriptomics

CGH

arrays

SNP

arrays

Two

channel

arrays

Single

channel

arrays

SELDI-TOF

mass

spectrometry

Whole

genome

Sequencing

DNA

metilation

Epigenomics

Methyl-DIP RNA

sequencing

miRNAs

Regulomics

Microarray

Proteomics

Metabolomics

Metabolite

Mass

spectrometry

“Omics” and computational tools are the

basis for precision medicine

- CONFIDENTIAL -

Regulation of the G1/S is the focal point of multiple

oncogenic signals

- Multiple oncogenic signals stimulate Cyclin D expression and activation of CDK4/6

- CDK4/6 phosphorylates and inactivates the RB tumor suppressor

- Gene expression via E2F drives progression through S, G2, and M

Inactive RB

Pl3K/Akt

STATs Ras

MAPKs

ER Wnt/β-catenin

HER2

p16

G0/G1

Arrest

Cell CycleProgression

Oncogenic Signals Stimulate CDK4/6

Transcription activated

Palbociclib

Abemaciclib

Ribociclib

Paloma 1 Study: benefit from palbociclib

independent of CCND1 and p16 status

ER+/HER2 -

amp CCND1 and/or p16 loss

(high pRb1)

Finn RS et al, Lancet Oncol, 2015

Intertumor heterogeneity, genomics

and precision medicine

The Cancer Genome Atlas Network Nature 2012

Personalized or precision medicine

Unrealistic expectations?

One molecular alteration, one drug?

Precidion medicine in breast cancer

How many “Actionable” alterations?

Arnedos M Nature Review Clinical Oncology

(ADVANCE ONLINE PUBLICATION) 2015

ERBB2

BRCA1

BRCA2

PIK3CA

Tumor addiction to molecular

aberrations is rare

BRAF V600E Mutation

The molecular context matter

Vemurafeninb

Effective in Melanoma (V600E)

Chapman PB N Engl J Med 2011

Vemurafeninb

Ineffective in Colon Cancer (V600E)

Prahallad A Nature 2012

Genomic characterization of brain metastasis

Brastianos PK ECC 2015

Brastianos PK Cancer Discovery 2015

Tumor heterogeneity

Volgelstein B Science 2013

Traget therapies aimed to hit genomic

alterations have to deal with all these

source of heterogeneity

Brain metastasis harbor “clinically actionable mutations”

not detected in primary tumors (phylogenetic trees)



Are there any “brain specific” and really clinically

actionable molecular aberrations?

Distal extracranial metastases are not a reliable surrogate

for actionable mutation in brain metastases



….neither brain metastasis are a reliable

surrogate of distal extracranial metastatsis

Targeted sequencing

of 365 genes

Fabrice A ECC 2015

Which is the new potential therapeutic target?

In some metastatic breast cancers, a disruption of the JAK-STAT

signalling pathway seems to be advantageous for survival

“Selection pressure” and “intratumor heterogeneity”

Spatial and temporal clonal evolution

Zardavas D Nature Review Clinical Oncology 2015

Effects of ER Mutational Status:

emergence of treatment resistance

Ligand-binding domain mutations are frequent in aromatase inhibitor-resistant breast cancer

NeoSphere: study design and pCR results

Gianni L, et al. Lancet Oncol 2012; 13:25–32

HR, hormone receptor;HR-positive = estrogen and/or progesterone receptor-positive;HR-negative = estrogen and progesterone receptor-negative

S

U

R

G

E

R

Y

Study dosing: q3w x 4

Patients withoperable or locally advanced/inflammatoryHER2-positive BC

Chemo-naive & primary tumors >2 cm (N=417)

TD (n=107)trastuzumab (86 mg/kg)docetaxel (75100 mg/m2)

PTD (n=107)pertuzumab (840420 mg) trastuzumab (86 mg/kg) docetaxel (75100 mg/m2)

PT (n=107)pertuzumab (840420 mg)trastuzumab (86 mg/kg)

PD (n=96)pertuzumab (840420 mg)docetaxel (75100 mg/m2)

p = 0.0141

p = 0.0198

p = 0.003bpCR

tpCR

pC

R, %

±9

5%

CI

bp

CR

, % ±

95

% C

I

HR-positive

HR-negative

NeoSphere study design: the adjuvant part of the trial

Gianni L, et al. Lancet Oncol 2012; 13:25–32FEC, 5-fluorouracil, epirubicin, and cyclophosphamide

S

U

R

G

E

R

Y








FEC q3w x 3trastuzumab q3w cycles 5–17


docetaxel q3w x 4 FEC q3w x 3 trastuzumab q3w cycles 5–17


NeoSphere study design: the adjuvant part of the trial

Gianni L, et al. Lancet Oncol 2012; 13:25–32FEC, 5-fluorouracil, epirubicin, and cyclophosphamide

S

U

R

G

E

R

Y










docetaxel q3w x 4 FEC q3w x 3 trastuzumab q3w cycles 5–17


In all arms identical chemotherapy backboneand identical adjuvant trastuzumab after surgery

DFS for TD vs PTD, ITT population

Kaplan–Meier curves are truncated at 60 months (the end of scheduled follow-up). However, summary statistics shown take into account all follow-upTwo late events occurred with PTD: one case of PD at 67 months, and one death due to an unrelated cerebrovascular accident without PD at 72 months

DFS

, %

Months

0

10

30

50

70

80

90

100

20

40

60

0 12 24 36 48 60

n at riskTD 103 92 85 79 77 12PTD 101 96 92 88 85 17

TD

PTD

TD PTD

n=107 n=1075-year DFS, % (95% CI)

81 (72–88) 84 (72–91)

HR (95% CI) 0.60 (0.28–1.27)

• PFS and DFS are in line with the results of the primary endpoint (pCR)

and suggest a persisting benefit of neoadjuvant pertuzumab added to

trastuzumab and docetaxel

Conclusion

Media ReleaseBasel, 31 July 2015

Roche's Perjeta regimen approved in Europe for use before

surgery in combination with trastuzumab and chemotheray

in early stage aggressive HER2-positive breast cancer

Trial-level association between effect of CT and CT plus HER2-directed therapies on pCR and EFS

A, doxorubicin; C, cyclophosphamide; CT, chemotherapy; D, docetaxel; E, epirubicin; LAP, lapatinib; N, vinorelbine; P, pertuzumab; T, trastuzumab; X, capecitabine

HR

fo

r EF

S

OR for pCR

0.0

0.2

0.6

0.8

1.0

1.2

0.4

0.0 0.4 1.2 2.0 2.8 3.60.8 1.6 2.4 3.2

GeparTrio: resp [DAC 6 cycles vs DAC 4 cycles]

GeparQuattro: EC→ DX vs EC → D

NOAH: Neo T → chemo → adj T vs chemo

NeoALTTO: LAP vs T

GeparTrio: non-resp [NX 4 cycles vs DAC 4 cycles]

GeparQuattro: EC → D-X vs EC → D

NeoALTTO: LAP + T vs T

NeoSphere: T + P + chemo vs T + chemo

• Heterogeneity of studies/treatments makes the association weak

Data derived from personal communication of CTNeoBC data byCortazar P, and from Baselga J, et al. Lancet 2012; 379:633–640;

de Azambuja E, et al. Lancet Oncol 2014; 15:1137–1146

CT trials

HER2 therapytrials

Association between immune markers and pCR in the NeoSphere trial

IF.I

STAT1

MHC1

MHC2

CD8

IGG

IFNG

CTLA4

PD1

PDL2

PDL1

-1.5 -1.0 -0.5 0.0 0.5 1.0

Combined Arms A+C+D

Arm B

Higher expression

Higher pCR rate

COMBINED ARMS (TH, HP, TP)ARM THP

Higher expression

Lower pCR rate

pCR by tertile of expression of MHC1

Low.Tertile Int.Tertile High.Tertile

Arm.A

Arm.B

Arm.C

Arm.D

pC

RB

rate

(%

)

020

40

60

80

100


Arm.A

Arm.B

Arm.C

Arm.D

pC

RB

rate

(%

)

020

40

60

80

100


Arm.A

Arm.B

Arm.C

Arm.D

pC

RB

rate

(%

)

020

40

60

80

100


Arm.A

Arm.B

Arm.C

Arm.DpC

RB

rate

(%

)

020

40

60

80

100

TH

THP

HP

TP

T = Docetaxel

H = Trastuzumab

P = Pertuzumab

MHC1 MHC1 MHC1

Recurrence risk

(untreated patients) HIGH INTERMEDIATE LOW

Bianchini G et al SABCS 2015

Group with high TILs (LPBC) do very well with chemotherapy alone

Perez E JAMA Oncology 2015

Cancer immunotherapy: game changer

Couzin-Frankel J Science 2013

The curative potential of immunotherapy

• Pooled OS data for 1,861 patients treated with ipilimumab in phase

II and III studies

Schadendorf D JCO 2015

Ipilimumab long-term survival data

Is melanoma

an unicum?

Raising the bar to curative potential Immunotherapy is game-changer

Rosenberg SA Science Translational Medicine 2012

The immunotherapy tsunami

• Melanoma• Renal cancer (clear cell)• NSCLC – adenocarcinoma and Squamous cell• Small cell lung cancer• Head and neck cancer• Gastric and GE junction• Mismatch repair deficient tumors (colon, cholangiocarcinoma)• Bladder • Hepatocellular carcinoma• Mesothelioma• Hodgkin Lymphoma• Merkel Cell• Triple negative breast cancer• Ovarian• Glioblastoma• Thymoma• Cervical • Diffuse large cell lymphoma• Follicular lymphoma• T-cell lymphoma (CTCL, PTCL)

Minimal to no activity: • Prostate cancer

• MMR+ Colon cancer

• Myeloma

• Pancreatic Cancer

Active

Spectrum of PD-1/PD-L1 Antagonist Activity

Anti-PD1 in TNBC

Nanda R SABCS 2014

Anti-PDLI

ineffective

Different milestones required different clinical trial statistical designs

The “median” is the message The “milestone” is the message

Hellmann MD & Kris MG

Oncotype DX in patients with RS<11

Relevant therapeutic question in ER+/HER2- tumorsWho doesn’t need more treatment

TAM

CMF/TAM

Undue treatment

(overtreatment)

NSABP B-20 trial

Context specific

prognostic markers

Oncotype DX in patients with RS<11

TAILORx trial

ER+/HER2-, node negative

Oncotype DX assay

RS 11-25

R

Chemotherapy and

hormonal treatment

Hormonal

treatment

RS 0-10

Hormonal

Treatment

Patient characteristics according to RS cohorts(0-10 versus 11-25)

Sparano NEJM 2015

DEFS

99.3%

Sparano NEJM 2015

Events rates by histologic grade

Sparano NEJM 2015

This results provide the “prospective validation” for the

“prognostic value of Oncotype DX with score 0 to 10”

“Prospective retrospective” trial design for biomarker validation

• Prospective randomized clinical trials to evaluate the medical utility

of a prognostic or predictive biomarker are the gold standard.

However, such trials are costly and require long period of time

• New guidelines has been suggested for indirect “prospective-

retrospective” designs using archived specimens

Simon R, Paik S Hayes DF. JNCI 2009

My bias

Can multigene-signature be clinical useful for tailoring adjuvant treatment in ER+/HER2- early breast cancer?

• ASCO guidelines (Harris L JCO 2007)

• NCCN guidelines (From 2008)

• National Institute for Health and Care Excellence (NICE)

guidelines (From 2013)

• ESMO guidelines (From 2011)

• St Gallen consensus (From 2011)

• AGO (Gynecologic Oncology Working Group) guidelines (2013)

Recommendation for considering usage of multigene-

signatures in “some patients” with ER+/HER2- tumors

Validation = Fitness for Intended Use

(Simon R.)

Is it about multi-gene signatures against pathologists?

Multi-gene signatures Pathologist

pearls from asco and esmo 2015 - over group provider ecm · (advance online publication) 2015 erbb2...

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