1. No category

Current options and future opportunities in
platinum-resistant ovarian cancer
Aknar Calabrich
AMO
LACOG CONFERENCE 2013
Current options and future opportunities in
platinum-resistant ovarian cancer
Aknar Calabrich
AMO
Abril, 2013
PFS in Advanced Ovarian Cancer
Du Bois et al. Cancer 2009
100
90
80
70
60
50
40
30
20
10
1000
900
800
700
600
500
400
300
200
100
0
0
0-3 Prog
0-3 Non-PD
3-12 Mos
12-18 Mos
18+ Mos
PFS, days
90
176
174
275
339
OS, days
217
375
375
657
957
9
24
35
52
62
Response, %
Percentage
Days
Recurrent Ovarian Cancer: Effect of PlatinumFree Interval and Survival
Pujade-Lauraine E, et al. ASCO 2002. Abstract 829.
Treatment History
Progression
Diagnosis
Symptoms
Primary
Chemo x 6
Recurrent
Chemo x 6
Staging
Now What?
5
mos
?
Practice Guideline 2013
Patients who progress on two consecutive therapy
regimens without evidence of clinical benefits
have diminished likelihood of benefitting from
additional therapy.
Single-agent non-platinumbased if platinum resistant
Docetaxel
Etoposide, oral
Gemcitabine
Liposomal doxorubicin
Paclitaxel, weekly
Topotecan
Summary of Phase III Single-Agent Trials:
Recurrent Ovarian Cancer
Drug A
Drug B
N
TTP (wks)
P
OS (wks)
P
Comment
Topotecan
Paclitaxel
226
23 vs 14
NS
61 vs 43
NS
50% Cross-over
Paclitaxel
(bolus)
Paclitaxel
(weekly)
208
38 vs 26
NS
34 vs 59
NS
Less toxicity w/
weekly
Oxaliplatin
Paclitaxel
86
12 vs 14
NS
42 vs 37
NS
74% platinum
resistant
PLD
Topotecan
481
16 vs 17
NS
60 vs 57
NS
54% platinum
resistant; OS
benefit in platinumsensitive subgroup
PLD
Paclitaxel
214
22 vs 22
NS
46 vs 56
NS
All pts taxanenaive
Topotecan
Treosulfan
357
22 vs 12
.001
56 vs 48
.02
2nd – 3rd line
therapy
PLD
Gemcitabine
195
16 vs 13
NS
59 vs 55
NS
PLD
Gemcitabine
153
16 vs 20
NS
55 vs 50
NS
56% platinum
resistant
PLD or
Topotecan
Canfosfamide
461
19 vs 9
< .01
59 vs 37
(PLD: 62 vs Topo: 47)
< .0001
ASSIST-1 trial
All 3rd line
PLD + Trabectedin vs PLD:
Phase III Registration Trial
• Recurrent ovarian cancer R
A
– One prior regimen
N
– Evaluable and measurable D
disease
O
– Platinum sensitive and
M
I
resistant
Z
Accrual goal: 650 patients E
•
• Primary endpoint: OS
• Other endpoints: PFS, RR,
safety
PLD 30 mg/m2 + q3 weeks
Trabectedin 1.1 mg/m2
PLD 50 mg/m2 q 4 wks
Translational research
– Pharmacokinetics
– Pharmacogenomics
– Pharmacoeconomics
– Quality of life
– Circulating tumor cells
Monk BJ, et al. J Clin Oncol, 2010.
OVA-301: PFS (TFI < 6 mos)
1.00
Percent of Subjects
90
PFS events: 163
HR: 0.95 (0.70-1.30)
P =.7540
# censored: 65
80
70
60
50
40
Trabectedin+PLD
4.0 mos
30
PLD
3.7 mos
20
10
0
0
2
4
6
37
43
22
19
RR: 12% vs 13% (rad review)
No. Subjects at Risk
PLD
Trabectedin/PLD
115 70
113 61
8 10 12 14 16 18 20 22
Progression-free survival (months)
9
14
5
7
5
13
3
2
1
0
1
0
0
0
0
0
24
26
28
0
0
0
0
0
0
Monk BJ, et al. J Clin Oncol. 2010
Other Potentially Active Agents
Single agents
Hormonal Therapy
•
•
•
•
•
•
•
•
•
•
•
•
Altretamine
Capecitabine
Cyclophosphamide
Ifosfamide
Irinotecan
Melphalan
Oxaliplatin
Anastrozole
Letrozole
Leuprolide acetate
Megestrol acetate
Tamoxifen
Chemotherapy vs Hormones
N = 241 platinum/taxane-resistant
PFS
1.00
0.75
0.50
87 d vs 62 d
P = .024
Tamoxifen
0.25
Chemotherapy
(PLD vs Pac-Wkly)
0.75
Chemotherapy
(PLD vs Pac-Wkly)
0.50
OS
1.00
328 d vs 278 d
P = .56
0.25
Tamoxifen
0.00
0.00
0
10
20
months
30
40
0
10
20
30
months
40
50
Kristensen GB, et al. IGCS 2008. Abstract 2008_1175.
What Is Ovarian Cancer?
Picture clipping
Different diseases
Different diseases
Bowtell D 2010
Altered pathways in HGS-OvCa
GOG 170 Series: Track Record
Bevacizumab
PFS
Sorafenib
Temsirolimus
Dasatinib
Imatinib
Gefitinib
Mifepristone
Enzastaurin Trastuzumab
Lapatinib
Vorinostat
Response Rate (%)
Role of VEGF throughout ovarian cancer development
creates rationale for its inhibition
• VEGF promotes angiogenesis in
early-stage ovarian cancer1
Ascites
– VEGF transduction can transform
peritoneal vessels causing ascites
development2,4,5
•
positive correlation between ascites
volume and VEGF expression in
preclinical models6,7
• Clinically, VEGF expression is
associated with ovarian cancer
recurrence8
10
Ascites (mL)
– VEGF enhances permeability of
750
500
5
VEGF (ng/mL)
normal ovarian epithelium into
ascites-producing cancers2,3
VEGF
250
0
0
0 4
11
18
24
34
Time (days)
1. Hefler, et al. Clin Cancer Res 2007; 2. Ramakrishnan, et al. Angiogenesis 2005; 3. Schumacher, et al. Cancer Res 2007; 4.
Zhang, et al. Am J Pathol 2002; 5. Trinh, et al. BJC 2009; 6. Belotti, et al. Cancer Res 2003
7. Alvarez, et al. Clin Cancer Res 1999; 8. Hazelton, et al. Clin Cancer Res 1999
Anti-VEGF agents
Anti-VEGF therapies in ovarian cancer
Target
Class
Agent
Phase
VEGF-A
MoAb
Bevacizumab
III
VEGR
Soluble decoy
receptor
VEGF trap
II/III
VEGFR2
MoAb
Ramucirumab
II
VEGFR + PDGFR
TKI
Sunitinib
II
VEGFR, PDGFR, Raf
TKI
Sorafenib
II
VEGFR + PDGFR
TKI
Motesanib
II
VEGFR, EGFR, RET
TKI
Vandetanib
II
VEGFR + PDGFR
TKI
Pasopanib
III (ongoing)
VEGFR + PDGFR + FGFR
TKI
Cediranib
III (ongoing)
VEGFR + PDGFR + FGFR
TKI
BIBF 1120
III (ongoing)
Ligand
Receptor
AURELIA trial design
Platinum-resistant OCa
• ≤2 prior anticancer regimens
• No history of bowel
obstruction/abdominal
fistula, or clinical/
radiological evidence of
rectosigmoid involvement
• PD ≤ 6 mos after ≥ 4 cycles
platinum-based therapy
Chemotherapy
Treat to
PD/toxicity
Optional BEV
monotherapyc
BEV 15 mg/kg q3wb
+ chemotherapy
Treat to
PD/toxicity
Investigator’s
choice
(without BEV)
R
1:1
Stratification factors:
Chemotherapy options (investigator’s choice):
•
Chemotherapy selected
•
Paclitaxel 80 mg/m2 days 1, 8, 15, & 22 q4w
•
Prior anti-angiogenic therapy
•
•
Treatment-free interval
(<3 vs 3‒6 months from previous
platinum to subsequent PD)
Topotecan 4 mg/m2 days 1, 8, & 15 q4w
(or 1.25 mg/m2, days 1–5 q3w)
•
PLD 40 mg/m2 day 1 q4w
PD = progressive disease; PLD = pegylated liposomal doxorubicin
aEpithelial ovarian, primary peritoneal or fallopian tube cancer
bOr 10 mg/kg q2w
c15 mg/kg q3w, permitted on clear evidence of progression
Baseline characteristics: Generally balanced between
arms, some differences between cohorts
Characteristic, %
Median age, years
(range)
Age ≥65 years
Histology at diagnosisa
Serous/adenocarcinoma
Clear cell
FIGO stage III/IV
Grade at diagnosis
1
2
3
Missing
2 prior chemotherapy regimens
PFI <3 monthsb
ECOG PS
0
1
2
Weekly paclitaxel
CT
BEV + CT
(N=55)
(N=60)
60
60
(25‒80)
(25‒79)
25
42
PLD
CT
BEV + CT
(N=64)
(N=62)
62
63.5
(32‒77)
(39‒78)
34
48
Topotecan
CT
BEV + CT
(N=63)
(N=57)
61
60
(35‒84)
(26‒80)
43
26
87
6
87
88
3
87
77
9
81
85
2
90
87
5
89
88
2
96
5
31
45
18
51
27
12
30
52
7
55
27
6
22
63
9
33
20
2
24
58
16
26
27
3
27
63
6
46
25
4
35
47
14
40
26
49
40
7
63
30
3
59
34
6
55
32
13
54
40
5
61
35
4
PFI = platinum-free interval. aMultiple answers possible. bFrom last platinum to subsequent PD
Progression-free survival: Overall population
Estimated probability
1.0
Events, n (%)
Median PFS, months (95%
CI)
HR (not stratified)
(95% CI)
Log-rank p-valuea
0.8
0.6
BEV + CT (N=179)
166 (91)
3.4
(2.2‒3.7)
135 (75)
6.7
(5.7‒7.9)
0.48
(0.38‒0.60)
<0.001
a2-sided, not
stratified
0.4
0.2
3.4
0
0
No. at risk:
CT
BEV + CT
CT
(N=182)
182
179
6.7
6
93
140
37
88
12
20
49
8
18
18
Time (months)
1
4
1
1
24
0
1
30
0
0
Median duration of follow-up: 13.9 months (CT arm) vs 13.0 months (BEV + CT arm)
Summary of best overall response rates (RECIST, CA125 criteria or both)
22.9a
[3.9–41.8]
60
CT
51,7
Patients (%)
50
40
BEV + CT
18.3a
[9.6–27.0]
p<0.001
30,9
30
28,8
10.4a
[–2.4 to 23.2]
18,3
20
19.5a
[6.7–32.3]
22,8
12,6
7,9
10
3,3
0
Overall population
Weekly paclitaxel
cohort
aDifference in
PLD cohort
Topotecan cohort
overall response rate; 95% CI with Hauck–Anderson continuity correction
Adverse events
Additional grade ≥3 adverse events in ≥2% of
patients in either arm
18
≈
CT (n=181)
BEV + CT (n=179)
16
Patients (%)
14
12
10
8
6
≈
4
2
0
HFS = hand-foot syndrome
aPreferred terms. bIncludes abdominal pain upper
≈ ≈
Conclusions
• AURELIA is the first randomized phase III trial
in platinum-resistant OC to demonstrate:
– Benefit with biologic therapy
– Benefit with a combination regimen versus
monotherapy
– Bevacizumab combined with chemotherapy
should be considered an option
in platinum-resistant ovarian cancer
Anti-VEGF to treat malignant ascites
• Intravenous aflibercept for treatment of
recurrent symptomatic malignant ascites in
patients with advanced ovarian cancer: a
phase 2, randomised, double-blind, placebocontrolled study
• Malignant ascites
• Fatal bowel perforation
Lancet Oncol. 2012 Feb;13(2):154-62
Poly (ADP-Ribose) Polymerase (PARP)
If PARP is inhibited, SSB
repair prevented, leading
to increased double strand
DNA breaks
PARP inhibition and tumor-selective synthetic
lethality
DNA damage (SSBs)
PARP
PARP inhibition
DNA replication
(accumulation of DNA DSBs)
Normal cell
with functional HR
pathway
HR-deficient tumor
cell (e.g. BRCA 1/2-/-)
HR-mediated
DNA repair
Cell survival
Cell death
Impaired HRmediated
DNA repair
Tumor-selective cytotoxicity
DSB, double-strand break; HR, homologous recombination; SSB, single-strand break
Farmer H et al. Nature 2005;434:917–921 . Bryant HE et al. Nature 2005;434:913–917 . McCabe N et al. Cancer Res 2006;66:8109–8115
Olaparib in platinum-sensitive ovarian
cancer
Olaparib
Placebo
N° of event: total patients (%)
60:136 (44)
93:129 (72)
Median PFS (months)
8.4
4.8
Proportion of patients
progression
rogression free
1.0
0.8
HR 0.35 (CI 95% 0.25-0.49)
p<0.00001
0.6
0.4
0.2
Treatment
Olaparib
Placebo
0
3
6
9
12
15
18
Time from randomization (months)
Ledermann et al. N Engl J Med. 2012
Does platinum free interval affect response to PARPi?
Results from Phase I expansion cohort
•
•
50 patients, all but two with ovarian cancer and BRCA mutations received olaparib 20 mg
BID continuously
ORR RECIST or GCIC: 20/50 (40%)
Fong et al. JCO 2010
Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in
BRCA-deficient advanced ovarian cancer
Olaparib
400 mg bid
(n=33)
Olaparib
100 mg bid
(n=24)
Response by RECIST, n (%)*
Platinum-sensitive
Platinum-resistant
11 (33)
1/7 (14)
10/26 (38)
3 (13)
2/8 (25)
1/16 (6)
Response by RECIST and/or
GCIC, n (%)
20 (61)
4 (17)
290 (126-513)
269 (169-288)
5.8
1.9
Median DOR (range) †
Median PFS months
*Confirmed responses; there were an additional 3 unconfirmed responders in the 400 mg cohort (unconfirmed ORR 42%)
†Duration of
response is underestimated as some patients are still responding
Lancet. 2010 Jul 24;376(9737):245-51
Iniparibe
Platinunsensitive
Platinumresistant
n
40
32
RR
65%
25%
PFS
9.5m
6,44m
• Phase II trial
• carboplatin+gemcitabin+
iniparib (BSI-201)
Penson et al. ASCO 2011
Birrer et al. ASCO 2011
Developmental Strategies
•
•
•
•
Chemotherapy with biologics
Chemotherapy combinations
Biological combinations
Patient profiling – biomarker driven design
Target Agents in Development for Advanced Ovarian
Cancer
• AMG-386 (Tie2)
• mTOR inhibitors
• Pazopanib
• EGFR inhibitors
• BIBF-1120
• Aurora kinase inhibitors
• IMC-1121B
• Fosbretabulin
• IMC-3G3
• IGF-1R inhibitors
• Rapalogs
• PARPi
• PDGR inhibitors
• Imatinib
• Cediranib
• Her-2 receptior antagonist
Chemotherapy and Others in Development for
Advanced Ovarian Cancer
• Epothilones
– Ixabepilone
– Patupilone
• BMP-1350 (karenitecan)
• NKTR-102
• EC-145
• Farletuzumab
• Canfosfamide
Utilizing the Folate Receptor: EC145 Vintafolide
• Folate-Vinca
conjugate
• Relevant for imaging
targeting and therapy
Reddy JA, et al. Cancer Res. 2007;67:4434-4442.
EC145: Novel Folate Receptor Targeted
Therapeutic
• Randomized Phase II, Platinum-resistant ovarian
• Prior therapy: no more than 2 priors
• Regimen:
– PLD 50 mg/m2 IBW q 28 days
– PLD 50 mg/m2 IBW q 28 days + EC145 2.5 mg weeks 1 and 3 (cycle:
28 days)
• Toxicity similar in both arms: total AEs, SAEs, TETs
Arm
PFS
HR
P
PLD
11.7 wks
-
-
PLD+EC145
24.0 wks
0.497
0.014
Naumann W, et al. ASCO 2010. Abstract LBA5012b.
PROCEED
• A Randomized Double-Blind Phase 3 Trial Comparing EC145 and Pegylated
Liposomal Doxorubicin (PLD/Doxil®/Caelyx®) in Combination Versus PLD in
Participants With Platinum-Resistant Ovarian Cancer
• Primary endpoint: PFS
Platinum-resistant OC
• Participants must have
primary or secondary
platinum-resistant ovarian
cancer
• ≤2 prior anticancer regimens
• Participants must have
primary or secondary
platinum-resistant ovarian
cancer
• Exclusion criteria: PD ≤ 6 mos
after of first dose of initial
platinum-based therapy
Doxo lipossomal +
Placebo
R
Doxo lipossomal +
EC145
Saracatinib and Paclitaxel in Platinum-resistant Ovarian
Cancer (SaPPrOC)
• A Randomised Placebo-controlled Trial of Saracatinib (AZD0530) Plus
Weekly Paclitaxel in Platinum Resistant Ovarian, Fallopian Tube or Primary
Peritoneal Cancer
• Primary endpoint: PFS
Platinum-resistant OC
• Participants must have
primary or secondary
platinum-resistant ovarian
cancer
• At least 2 lines prior
hemotherapy
• Exclusion criteria: previous
weekly paclitaxel
Paclitaxel + Placebo
R
Paclitaxel + Saracatinib
TRINOVA-2: Trebananib in Ovarian Cancer-2
• A Phase 3, Randomized, Double-Blind Trial of Pegylated Liposomal
Doxorubicin (PLD) Plus AMG 386 or Placebo in Women With Recurrent
Partially Platinum Sensitive or Resistant Epithelial Ovarian, Primary
Peritoneal, or Fallopian Tube Cancer
• Primary endpoint: PFS
Platinum-resistant OC
• Subjects with platinum-free
interval (PFI) < 12 months
from their last platinum
based therapy
• one prior platinum-based
chemotherapeutic regimen
for management of primary
disease containing
carboplatin, cisplatin, or
another organoplatinum
compound.
• ≤2 prior anticancer regimens
Doxo lipossomal +
Placebo
R
Doxo lipossomal + AMG
386
Summary and Future Directions
• Despite the many advances in therapeutic
options for recurrent ovarian cancer, many
controversies remain
• Finding the optimal treatment paradigms for
ovarian cancer patients will remain the goal
for improving outcomes
• Understanding of molecular basis of ovarian
cancers helps to develop rational treatments
Summary and Future
Directions
• Despite the many advances in therapeutic
options for recurrent ovarian cancer, many
controversies remain
• Finding the optimal treatment paradigms for
ovarian cancer patients will remain the goal
for improving outcomes
• Understanding of molecular basis of ovarian
cancers helps to develop rational treatments
THANK YOU!