Characterization of PIK3CA and PIK3R1 somatic mutations in ...
PEARLS FROM ASCO AND ESMO 2015 - Over Group Provider ECM · (ADVANCE ONLINE PUBLICATION) 2015 ERBB2...
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PEARLS FROM ASCO AND ESMO 2015
Giampaolo Bianchini MD
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The cell cycle and cyclin-dependent kinases
Ashgar U et al, Nat Rev Drug Discovery 2015
New class of target therapies
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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
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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
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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
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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.
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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.
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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.
Clinicaltrials.gov NCT01942135
NC Turner et al, ASCO 2015
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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
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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.
Clinicaltrials.gov NCT01942135
NC Turner et al, ASCO 2015
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
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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
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“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 -
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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
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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
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Intertumor heterogeneity, genomics
and precision medicine
The Cancer Genome Atlas Network Nature 2012
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Personalized or precision medicine
Unrealistic expectations?
One molecular alteration, one drug?
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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
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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
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Genomic characterization of brain metastasis
Brastianos PK ECC 2015
Brastianos PK Cancer Discovery 2015
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Tumor heterogeneity
Volgelstein B Science 2013
Traget therapies aimed to hit genomic
alterations have to deal with all these
source of heterogeneity
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Brain metastasis harbor “clinically actionable mutations”
not detected in primary tumors (phylogenetic trees)
Brastianos PK ECC 2015
Brastianos PK Cancer Discovery 2015
Are there any “brain specific” and really clinically
actionable molecular aberrations?
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Distal extracranial metastases are not a reliable surrogate
for actionable mutation in brain metastases
Brastianos PK ECC 2015
Brastianos PK Cancer Discovery 2015
….neither brain metastasis are a reliable
surrogate of distal extracranial metastatsis
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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
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“Selection pressure” and “intratumor heterogeneity”
Spatial and temporal clonal evolution
Zardavas D Nature Review Clinical Oncology 2015
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Effects of ER Mutational Status:
emergence of treatment resistance
Ligand-binding domain mutations are frequent in aromatase inhibitor-resistant breast cancer
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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
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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
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)
FEC q3w x 3trastuzumab q3w cycles 5–17
FEC q3w x 3trastuzumab q3w cycles 5–17
docetaxel q3w x 4 FEC q3w x 3 trastuzumab q3w cycles 5–17
FEC q3w x 3trastuzumab q3w cycles 5–21
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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
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)
FEC q3w x 3trastuzumab q3w cycles 5–17
FEC q3w x 3trastuzumab q3w cycles 5–17
docetaxel q3w x 4 FEC q3w x 3 trastuzumab q3w cycles 5–17
FEC q3w x 3trastuzumab q3w cycles 5–21
In all arms identical chemotherapy backboneand identical adjuvant trastuzumab after surgery
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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)
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• 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
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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
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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
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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
Low.Tertile Int.Tertile High.Tertile
Arm.A
Arm.B
Arm.C
Arm.D
pC
RB
rate
(%
)
020
40
60
80
100
Low.Tertile Int.Tertile High.Tertile
Arm.A
Arm.B
Arm.C
Arm.D
pC
RB
rate
(%
)
020
40
60
80
100
Low.Tertile Int.Tertile High.Tertile
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
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Group with high TILs (LPBC) do very well with chemotherapy alone
Perez E JAMA Oncology 2015
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Cancer immunotherapy: game changer
Couzin-Frankel J Science 2013
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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?
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Raising the bar to curative potential Immunotherapy is game-changer
Rosenberg SA Science Translational Medicine 2012
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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
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Anti-PD1 in TNBC
Nanda R SABCS 2014
Anti-PDLI
ineffective
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Different milestones required different clinical trial statistical designs
The “median” is the message The “milestone” is the message
Hellmann MD & Kris MG
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Oncotype DX in patients with RS<11
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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
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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
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Patient characteristics according to RS cohorts(0-10 versus 11-25)
Sparano NEJM 2015
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DEFS
99.3%
Sparano NEJM 2015
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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”
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“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
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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.)
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Is it about multi-gene signatures against pathologists?
Multi-gene signatures Pathologist