Download Time (months)

Open Issue in Oncology: new
drugs for GI, Ovarian and lung
cancer
Roma 21/05/2016
Domenica Lorusso
Gynecologic Oncologic Unit
National Cancer Institute-Milan
The angiogenesis in ovarian cancer:
bevacizumab and beyond
Minimal improvement in ovarian cancer mortality rates
– no new front-line therapy for >20 years
Alkylating agents
(melphalan or
cyclophosphamide)
Platinum-based
therapy
Platinum/taxane
therapy
Mortality per 100,000 women
20
Front line
15
10
PLD and
trabectedin
Platinum-based
therapy
5
Paclitaxel, gemcitabine,
doxorubicin, topotecan
0
1975
1985
1995
Year
Recurrent
2005
Jemal et al. CA Cancer J Clin 2009
The challenge of going beyond carboplatin/paclitaxel: key
trials worldwide
Trial
1995
GOG-0162
AGO-GINECO
324
1,282
Regimens compared
Outcome
Cis + either 24 h or 96 h pac
Efficacy similar
Carbo/pac vs carbo/pac/epirubicin
No benefit of a third agent
MITO-1
273
Carbo/pac x6  topo x4 or surveillance
No PFS benefit with topo
maintenance
GOG-0172
429
IV cis/IV pac vs IP cis/IP pac
IP has better efficacy/worse
toxicity and QoL
GCIG
887
Carbo/pac vs carbo/pac/epirubicin
No benefit of a third agent
Carbo/pac  topo x4 or surveillance
No benefit of topo maintenance
277
Cis/pac  pac x3 vs x12 cycles in
patients in CR
PFS improved with pac x12
cycles/no OS difference in a
selected patient population
4,312
Carbo/pac vs carbo/pac/gem (2
regimens) vs carbo/pac/topo vs
carbo/pac/PLD
No benefit of a third agent
819
Carbo/pac x8 vs cis/topo x4 
carbo/pac x4
Efficacy similar; tolerability better
with carbo/pac
1,742
Carbo/pac vs carbo/pac/gem
No benefit of a third agent
AGO-GINECO
GOG-0178
GOG-0182
OV16
2010
n
AGO-OVAR9
1,308
Carbo = carboplatin; cis = cisplatin; CR = complete response; cyclo = cyclophosphamide; gem =
gemcitabine; IP = intraperitoneal; IV = intravenous; pac = paclitaxel; PLD = pegylated liposomal
doxorubicin; topo = topotecan
Ovarian cancer is not a single disease
70 %
5%
2%
Romero I et al. Endocrinology 2012; 153: 1593-1602
15%
5%
Ovarian Cancer - not one disease<br />Outcome depends on histiotype
© Colombo, IEO 2015
Progress in the Management of Ovarian
Cancer: Evolution Over 40 Years
Five-year
15%
survival
Key
advances
in chemotherapy
30%
40%
?50%?
First use
of oral
PARPi
First use
of
cisplatin
1970
First use
of
carboplatin
1980
First use
of
Paclitaxel
First reports
of
bevacizumab
1990
2000
Positive evidence
for weekly
paclitaxel in first
line
2010
Four positive trials with antiangiogenic
agents in front line
Can we choose which anti-angiogenic drug ?
1st line
Concomitant +
Maintenance
GOG 218
1st line
Maintenance
ICON7
OVAR 16
Not approved
Bevacizumab
Pazopanib
Not approved
OVAR12
Nintedanib
Two positive trials with bevacizumab
in front line
Overall Survival
Deaths
1-Year Survival
Arm I
CP
(n = 625)
Arm II
CP + Bev
(n = 625)
Arm III
CP + Bev  Bev
(n = 623)
156 (25.0%)
150 (24.0%)
138 (22.2%)
90.6%
90.4%
91.3%
Events were observed in ~ 24% of patients at the time of database lock.
Burger RA et al. Proc ASCO 2010;Abstract LBA1.
OS estimate
OS benefit is suggested with chemotherapy + Avastin and continued
single-agent Avastin in stage IV disease
CPP
CPB
CPB15
93 (61)
99 (60)
81 (49)
1.0
Deaths, n
(%)
32.8
32.9
40.6
0.8
Median
survival
(months)
0.98
(0.74–1.31)
0.72
(0.53–0.97)
HR
(95% CI)
0.6
0.4
CPP (n=153)
CPB15 (n=165)
CPB15+ (n=165)
0.2
0.0
0
CPP
CPB
CPB15
153
165
165
12
144
149
154
Randall, et al. SGO 2013: Abstract 80
Randall, et al. SGO 2013: Abstract 80
129
142
144
24
113
117
130
95
104
117
36
Time (months)
72
73
83
42
44
57
28
30
37
48
15
15
21
60
5
10
10
3
3
3
72
0
1
0
0
0
0
Chemotherapy + Avastin with continued single-agent
Avastin improves progression-free interval
– The proportion of patients progression-free 6 and 12 months
after last dose of carboplatin is increased with Avastin-based
therapy (70.6 vs 52.7) at 6 months and (41.7 vs 25.9) at 12
GOG analysis
months
65.6
70.6
52.7
41.7
32.1
25.9
14.0
8.4
9.2
Randall, et al. SGO 2013: Abstract 287
Randall, et al. SGO 2013: Abstract 287
© Colombo, IEO 2015
A GiNECO study:Therapy-free
Recurrent
Ovarian
Cancer:
Population
Interval and Efficacy
Characteristics
Survival
Response
P
Rate6 (%)
R (days)
3
0
12
100
1000
I
M
A Refractory
80
800
R
Y
LA SENSIBILITA’ AL PLATINO E’
T
H
E
R
A
P
Y
Overall
Survival
UNA VARIABILE CONTINUA!!!
Resistant 60
600
400
40Partially Sensitive
217
200
366
PFS
Fully Sensitive
166
90
0-3/Pr
Response
Rate
32
20
9
0
24 months
18
0-3
3-6
6-9
9-12 12-18 ≥18
Therapy-free interval (months)
© Colombo, IEO 2015
Pisano et al. Ther Clin Risk Manag. 2009;5:421-426; Gadducci et al. Anticancer Res. 2001;21:3525-3533.
STUDIO AURELIA
ASCO 2012
Sopravvivenza globale: popolazione generale
Sopravvivenza globale: w paclitaxel
100
75
Overall survival (%)
Overall survival (%)
Events, n (%)
75
50
25
0
0
12
Time (months)
18
24
Median OS,
months (95% CI)
HR (unadjusted)
(95% CI)
50
CT
(N=55)
BEV + CT
(N=60)
41 (75)
36 (60)
13.2
(8.2‒19.7)
22.4
(16.7‒26.7)
0.65
(0.42‒1.02)
25
0
0
6
12
18
24
30
36
ESMO 2013
TRINOVA-1
Weekly paclitaxel
Recurrent partially
platinum sensitive or
resistant OC, PP, FTC,
(PFI <12 months,
>6months after the
beginning of the firstline platinum-based
chemotherapy)
Radiographically
evaluable disease,
documented PD
Prev Chemo <3
Toxicity <G3
n=900
Placebo IV qw
to progression
Weekly paclitaxel
AMG-386 IV 15 mg/kg qw to
progression
Primary endpoint: PFS
Secondary endpoints: OS, ORR, DOR, CA125 response
rate, safety and tolerbality of AMG386, PK of AMG386
ClinicalTrials.gov. Identifier NCT01204749
Progression-free Survival
(Primary Analysis)
Events, n (%)
Median PFS, months
Pac + Placebo
(n = 458)
Pac + Trebananib
(n = 461)
361 (79)
310 (67)
5.4
7.2
HR = 0.66 (95% CI, 0.57–0.77)
P (stratified log rank) < 0.001
Presented by Monk BJ at European Cancer Congress
European Journal of Cancer 49; suppl 3, Sept 2013 LBA 41
MITO-11: A randomized multicenter phase II trial testing the addition of pazopanib to weekly paclitaxel in platinum-resistant or -refractory advanced ovarian cancer (AOC).
Presented By Sandro Pignata at 2014 ASCO Annual Meeting
Progression-free survival
Presented By Sandro Pignata at 2014 ASCO Annual Meeting
Overall survival
Presented By Sandro Pignata at 2014 ASCO Annual Meeting
Can we choose which anti-angiogenic drug ?
2st line resistant
Concomitant +
Maintenance
Aurelia
Not
approved
Trinova
1
Bevacizumab
Trebananib
MITO
11
Not approved
Pazopanib
STUDI RANDOMIZZATI DI FASE III SULLE
COMBINAZIONI A BASE DI PLATINO NELLA
RECIDIVA PLATINO SENSIBILE DI
CARCINOMA DELL’OVAIO
Autore
Trattamento
PFS HR
OS HR
Tossicita’
Parmar 2003
CBDA vs
CBDA+TAX
0.76
0.82
Neurotossicita
Alopecia
Reazioni
allergiche
Pfisterer
2006
CBDA vs
CBDA+GEM
0.72
0.96
Mielotossicita
Reazioni
allergiche
Pujade 2010
CBDA+TAX vs
CBDA+PLD
0.82
0.99
Piastrinopenia
PPE
Proportion surviving progression-free
GOG-0213: primary analysis of PFS
0.8
Carboplatin +
Paclitaxel
(n=337)
Carboplatin +
Paclitaxel +
Avastin
(n=337)
Events, n (Total)
304
296
Median (months)
10.4
13.8
HR, adj. (95% CI)
0.614 (0.522–0.722)
p-value
0.6
0.4
p<0.0001*
39% reduction
in risk of PD or death
0.2
0.0
0
•
12
Coleman, et al. SGO 2015 (Abstract 3)
24
36
48
60
GOG-0213: primary analysis of OS
Carboplatin +
Paclitaxel
(n=337)
Carboplatin +
Paclitaxel +
Avastin
(n=337)
Events, n
214
201
Median (months)
37.3
42.2
1.0
Proportion surviving
0.8
HR, adj. (95% CI)
2 tailed p-value
0.6
0.4
0.829 (0.683–1.005)
p=0.056
17% reduction in risk of death
5-month difference in median overall
survival, favouring Avastin arm
0.2
0.0
0
•
12
Coleman, et al. SGO 2015 (Abstract 3)
24
36
Time (months on study)
48
60
Randomised double-blind phase III trial of
cediranib (AZD 2171) in relapsed platinum
sensitive ovarian cancer: Results of the ICON6
trial.
Ledermann JA, Perren T, Raja FA, Embleton AC, Rustin GJS,
Jayson G, Kaye SB, Swart AM, Vaughan M, Hirte H
on behalf of the ICON 6 Collaborators
(NCRN, NCIC-CTG, ANZGOG, GEICO)
An academic sponsored GCIG trial
Progression-free survival – arms A vs. C
1.00
Maintenance
PFS events, n (%)
Chemo.
Maint.
112 (94.9)
139 (84.8)
8.7
11.1
Median, months
Chemotherapy
0.75
Log-rank test
p=0.00001
HR (95% CI)
0.57 (0.45 – 0.74)
Test for non-proportionality p=0.024
Restricted means, months
0.50
9.4
12.5
Restricted mean survival time increases by
3.1 months with maintenance treatment
0.25
0.00
0
3
6
9
12
Months
15
18
21
24
.
Chemo 118
Maint.. 164
90
148
24
65
8
21
3
7
Overall survival
Maintenance
1.00
Restricted mean survival time increases
by 2.7 months with maintenance
treatment (over two years)
Chemotherapy
0.75
Chemo.
Maint.
OS events, n (%)
63 (53.3)
75 (45.7)
Median, months
20.3
26.3
0.50
0.25
Log-rank test
p=0.042
HR (95% CI)
0.70 (0.51 – 0.99)
Test for non-proportionality p=0.0042
0.00
Restricted means, months
0
6
17.6
20.3
12
18
24
30
46
89
27
48
11
22
Months
.
Chemo. 118
Maint 164
.
106
159
89
139
Can we choose which anti-angiogenic drug ?
2st line sensitive
Concomitant +
Maintenance
Ocean
/GOG213
Not
yet6approved
Icon
Bevacizumab
Cediranib
Ruolo essenziale del VEGF nell’ovaio:
fisiologia e patologia
Moghaddam, et al. Cancer Metastasis Rev 2012
Single Agent Activity of Bevacizumab
Tumor Type
Dose
ORR (PR+CR)
Ovarian Cancer
15mg/kg q3wk
16-21%
Renal Cell
10mg/kg q2wk
10%
Met Breast Cancer
3-20mg/kg q2wk
7%
NHL
10mg/kg q2wk
5%
CRC
10mg/kg q2wk
3%
HRPC
10mg/kg q2wk
0%
GOG Phase II Response Rates
What is Post Progression Survival (PPS)?
 Post Progression Survival: Time from disease progression till death
 OS = PFS + PPS
Start
Progression
Death
OS
PFS
33
PPS
PPS influences chance to translate PFS into OS
benefit
•
•
OS = PFS + SPP ( Survival Post Progression)
As SPP increases, comparable OS benefit needs very large sample
If PPS = 2 months
PFS and OS benefit = 3mo
Patients needed to demonstrate significant OS = 350
Control Arm
Active Arm
PFS 3 mo
PPS
2 mo
PFS 6 mo
Total OS = 5 mo
PPS
2 mo
Total OS = 8 mo
If PPS = 24 months
PFS and OS benefit = 3mo
Patients needed to demonstrate significant OS = 2440
Control Arm
Active Arm
34
PFS 3 mo
PFS 6 mo
PPS 24 mo
Total OS = 27 mo
PPS 24 mo
Total OS = 30 mo
Can we choose which patients
to treat with bevacizumab?
Bevacizumab more active in high risk
patients?
Trial
Chemotherapy
Bevacizumab
PFS HR
GOG-02181
(n=1873)
Paclitaxel
Carboplatin
Concurrent and
maintenance
15 mg/kg q3w
(3-arm placebo)
0.72
ICON72
(n=1528)
Paclitaxel
Carboplatin
Concurrently only
7.5 mg/kg q3w
(2 arm)
0.81
Platinum resistant
Aurelia3
(n=361)
Caelyx
Topotecan
Paclitaxel
Concurrent
10 mg/kg q2w
(2 arm)
0.48
Platinum sensitive
OCEANS4
(n=484)
Gemcitabine
Carboplatin
Concurrent
15 mg/kg q3w
(2 arm)
0.48
First line
Second line
1. Burger et al. N Engl J Med 2011
2. Perren et al. N Engl J Med 2011
3. Pujade-Laurain et al. J Clin Oncol 2012
4. Aghajanian et al. J Clin Oncol 2012
Can we choose which patients?
Subgroup efficacy
Amit Oza, ECC 2013
Pujade-Lauraine, ESGO 2013
Interpretation
of results
Type of
analyses
Which data should we consider when
making treatment decisions?
Primary analyses
ITT population
Pre-specified
Primary objective is shown
Subgroup analyses
Pre-specified (stratified)
Subgroup analyses
Exploratory
Post-hoc
Primary endpoint is met
Primary endpoint is met
Assessment whether
consistent treatment
effects have been observed
across pre-specified
subgroups
Assessment whether
consistent treatment
effects have been
observed across
post-hoc subgroups
Hypothesis generating
ICON7: OS per risk groups
Subgroup analyses were not preplanned
in the protocol
Data from low-risk patients are immature
(37% events)
Elaborato da Oza, et al. ECC 2013 (abstract LBA6)
Oza et al is available at: http://eccamsterdam2013.eccoorg.eu/Amsterdam2013/Webcasts%20Photos/ WebcastDetail.aspx?webcasturl=http://www.ecco-org.eu/webcasts/ecco17/SP0993/SP0993.flv , Last access 28/03/2014
ICON 7
PFS: Stage IIIB-IV
PFS: Stage IIIB-IV, No residual
Antonio Gonzales-Martin, ASCO 2015, Abstract 5548
How reliable is the definition of risk based
on residual tumor after primary surgery?
Correlation between surgical evaluation and postsurgery CT scan
Chi, et al.
52%
Sala et al.
59%
Lorusso et al
20%
Int J Gynecol
Cancer 2010
Int J Gynecol
Cancer 2011
Oncology 2014
© Colombo, IEO 2015
• Avastin, in combination with carboplatin and paclitaxel is
indicated for the front-line treatment of advanced (FIGO
stages III B, III C and IV) epithelial ovarian, fallopian tube, or
primary peritoneal cancer
• Avastin is administered in addition to carboplatin and
paclitaxel for up to 6 cycles of treatment followed by continued
use of Avastin as single agent until disease progression or for
a maximum of 15 months or until unacceptable toxicity,
whichever occurs earlier
• The recommended dose of Avastin is 15 mg/kg of body
weight given once every 3 weeks as an intravenous infusion
In the era of personalised medicine…
Is there any group of patients obtaining the most benefit
from bevacizumab according to a molecular profile?
Women with
Ovarian Cancer
Molecular Classification of HGS Ovarian
Cancer
TCGA
Tothill, et al
Cancer
Genome
Atlas Research
474, 2011
The Cancer Genome The
Atlas
Research
Network,
Nature.Network.
2011 JunNature
29;474(7353):609-15
Presented by: Boris Winterhoff
ICON7: retrospective molecular TCGA
subgroup analyses by the AGO group
1.0
Mesenchymal
Bevacizumab
Control
0.8
0.6
0.4
0.2
0
11.8
0
12
21.9
24
Time (months)
36
48
Proportion alive without
progression
Proportion alive without
progression
Proliferative
1.0
Bevacizumab
Control
0.8
0.6
0.4
0.2
0
12.4
0
1.0
Bevacizumab
Control
0.8
0.6
0.4
0.2
0
17.0
0
12
20.8
24
Time (months)
24
Time (months)
36
48
Differentiated
36
48
Proportion alive without
progression
Proportion alive without
progression
Immunoreactive
12
20.6
1.0
Bevacizumab
Control
0.8
0.6
0.4
0.2
0
17.9
0
21.6
12
24
Time (months)
36
Proliferative and mesenchymal subtypes appeared to benefit most from the addition of bevacizumab
Winterhoff, et al. ASCO 2014
100
80
“Immune subgroup”
41% (n=116)
CP
CP + bev
60
40
20
00
18.5
10
35.8
20
30
40
Time (months)
50
PFS probability (%)
PFS probability (%)
ICON7: histological subgroup analyses using
retrospective 63-gene immune signature
100
80
60
40
20
00
60
12.3
10
Test for interaction, p=0.015
100
80
60
40
Univariate
HR 2.00 (1.11–3.61), p=0.022
20 Multivariate HR 2.37 (1.27–4.41), p=0.007
00
10
20
30
40
50
Time (months)
OS probability (%)
“Immune subgroup”
41% (n=116)
OS probability (%)
“Pro-angiogenic subgroup”
59% (n=168)
60
17.4
20
30
40
Time (months)
50
60
“Pro-angiogenic subgroup”
59% (n=168)
100
80
60
40
20
00
Univariate
HR 1.19 (0.80–1.78), p=0.386
Multivariate
HR 1.10 (0.73–1.66), p=0.637
10
20
30
40
Time (months)
Test for non-proportionality negative in both molecular subgroups
50
60
Gourley, et al. ASCO 2014
BEVACIZUMAB AND BRCA MUTATED PATIENTS
George J et al Clinical Cancer Res 2013
© Colombo, IEO 2015
GOG 218: Mutation in BRCA e response to Bev
Norquist AACR 2015
© Colombo, IEO 2015
PFS: Five candidate BMs (median cut-off)
Presented By Michael Birrer at 2015 ASCO Annual Meeting
PFS by CD31 (median cut-off)
Presented By Michael Birrer at 2015 ASCO Annual Meeting
For how long should maintenance
bevacizumab be continued ?
© Colombo, IEO 2015
53
PFS in ROSiA and ICON7 (ITT populations)
Caveats
• Differing tumour assessment schedules
• Prior neoadjuvant chemotherapy permitted in ROSiA
Estimated probability of PFS
1.00
0.75
0.50
ROSiA
BEV 15 (or 7.5) mg/kg +
CP
ICON7
BEV 7.5 mg/kg
+ CP1,2
0.25
19.3
25.5
0
0
3
6
9
12
15
18 21 24 27
Time (months)
30
33
36
39
42
45
1Avastin
CP = carboplatin + paclitaxel
2Roche
SmPC;
data on file 2012 (ICON7 CSR addendum).
54
PFS in ROSiA and ICON7 according to ‘MRC’ risk status
High
(N=468)
ICON7
ICON7
nonhigh
high risk
riska
(N=516)
(N=248)21
Non-high
risk
(N=553)
324 (69)
266
204 (50)
(82)
234 (42)
18.3
(16.8–20.6)
25.9
16.0
(23.6–NE)
32.0
(30.9–40.2)
riska
PFS
1.00
Events, n (%)
Estimated probability of PFS
Median PFS,
months (95% CI)
0.75
0.50
Caveats
• Differing tumour assessment
schedules
• Prior neoadjuvant
chemotherapy permitted in
ROSiA
0.25
16.0
0
0
3
6
9
12
15
18.3
25.9
18 21 24 27
Time (months)
NE = not estimable
aFIGO stage III and >1 cm residual disease or any FIGO stage IV or no debulking surgery.
30
32.0
33
36
39
1Gonzalez-Martin
2Unpublished
42
45
A, et al. ASCO 2015
data, courtesy of MRC
AGO-OVAR 17
Design
Bevacizumab 15 mg/kg q21 days
Paclitaxel 175 mg/m²
Carboplatin AUC5 q21 days
1:1
15 Months
= 22 Courses
R
N = 900
Bevacizumab 15 mg/kg q21 days
Paclitaxel 175 mg/m²
Carboplatin AUC5 q21 days
Strata
Residual tumor (yes vs no)
FIGO Stage (IIB-III vs IV)
Group
30 Months
= 44 Courses
National Institutes of Health. Available at: http://clinicaltrials.gov/show/NCT01462890. Accessed: 6 February 2013.
Any other choice for the future ?
High grade serous ovarian cancer:
Potential benefit of PARP inhibition in 50%
Not
‘BRCA-ness’ is frequent
HRD in ovarian cancer
Cancer Genome Atlas Research Network. Nature. 2011;474(7353):609-615.
HRD
SOLO-1 Trial
BRCAm Population Only
First-line maintenance
344 patients
Olaparib
PFS/PFS2/OS + QoL
Randomization
2:1
Response to
platinum-based
chemotherapy
Placebo
Cediranib and olaparib have synergistic activity in vitro
Presented By Joyce Liu at 2014 ASCO Annual Meeting
Primary Outcome: Cediranib/olaparib significantly increased PFS compared to olaparib alone
Presented By Joyce Liu at 2014 ASCO Annual Meeting
Paola 1: Study Design
Bevacizumab is not provided
© Colombo, IEO 2015
Recurrent platinum sensistive trial
Randomised Trial of Cediranib and Olaparib
Maintenance in Patients
with Relapsed Platinum Sensitive Ovarian
Cancer
Shibani Nicum and Jonathan Ledermann
For the NCRI Clinical Studies Group
MITO-16/MaNGO OV-2: Avastin plus chemotherapy at progression after
front-line Avastin plus chemotherapy in platinum sensitive
Carboplatin
PLD or gemcitabine or paclitaxel
1:1
Carboplatin
PLD or gemcitabine or paclitaxel
Avastin15mg/kg q3w
until PD
• Primary endpoint: PFS
• Secondary endpoint: OS
• 60 Italian centres involved and involvement of others European groups (ENGOT –
Italy, Germany, France, Greece, Switzerland) (sponsor: INT Napoli)
Principal investigators: Sandro Pignata, Nicoletta Colombo
x 6 – 8 cycles
Stage IIIB–IV EOC, FT or PPC
progressing or recurring at least
6 months after
front-line chemotherapy
plus Avastin
(n≈400)
TREATMENT ALGORYTMS IN RECURRENT
OVARIAN CANCER
 Treatment according to histotype is the future!
 Antiangiogenic agents and parp inhibitors are changing the
natual history of ovarian cancer disease.
 The best treatment algorytm is the one which allows patients to
receive all the available and effective treatment options.
 The future is very dynamic!!!!