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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
Landscape of Systemic Therapy for
Ovarian Cancer 2019
–Primary Therapy-Keiichi Fujiwara, MD, PhD
Saitama Medical University International Medical Center, Japan
GCIG Chair
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
• Astra Zeneca
• Pfizer
• MSD
• Clovis
Disclosure
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
• Consensus Statement from 5th Ovarian Cancer Consensus Conference
2015
‒ 3-weelky carboplain and paclitaxel remain the standard chemotherapy drugs for first-line therapy in advanced stage ovarian cancer
‒ Acceptable alternative schedules, and routes of delivery include
• 1) weekly intravenous paclitaxel in combination with 3-weekly intravenous carboplatin
• 2) the addition of bevacizumab to the standard chemotherapy drugs after primary surgery
• 3) intraperitoneal platinum-based chemotherapy after primary surgery with <1 cm residual disease
Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
Introduction and Background
Karam et al, Ann Oncol, 2017. 28(4): p. 711-717.
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
• Consensus Statement from 5th Ovarian Cancer Consensus Conference
2015
‒ 3-weelky carboplain and paclitaxel remain the standard chemotherapy drugs for first-line therapy in advanced stage ovarian cancer
‒ Acceptable alternative schedules, and routes of delivery include
• 1) weekly intravenous paclitaxel in combination with 3-weekly intravenous carboplatin
• 2) the addition of bevacizumab to the standard chemotherapy drugs after primary surgery
• 3) intraperitoneal platinum-based chemotherapy after primary surgery with <1 cm residual disease
Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
Introduction and Background
Karam et al, Ann Oncol, 2017. 28(4): p. 711-717.
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
• JGOG3016 (Katsumata, Lancet Oncol, 2013. 14(10): p. 1020-6)
‒ DDW Pac + 3W Carbo > 3W Pac + 3W Carbo
• MITO-7 (Pignata, Lancet Oncol, 2014. 15(4): p. 396-405)
‒ W Pac + W Carbo = 3W Pac +3W Carbo
• GOG262 (N Engl J Med, 2016. 374(8): p. 738-48)
‒ DDW Pac + 3W Carbo + Bev = 3W Pac + 3W Carbo + Bev
(Bev was optional)
‒ DDW Pac + 3W Carbo > 3W Pac + 3W Carbo (Subset Analysis)
• ICON-8
‒ DDW Pac + 3W Carbo = 3W Pac + 3W Carbo
‒ W Pac + W Carbo = 3W Pac + 3W Carbo
Weekly Paclitaxel
DDW: dose-dense weekly
W: weekly
3W: 3-weekly
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ICON 8B
MRC Clinical Trials Unit at UCL
• Accrual began 6th June 2011 and ICON8 pathway closed to recruitment 28th November 2014 • Final recruitment figure = 1566• UK= 1397, ANZGOG= 70, GICOM= 43, KGOG= 32, ICORG= 24• Primary PFS analysis presented at ESMO 2017. Conclusions: although weekly dose-dense
chemotherapy can be delivered successfully as first-line EOC treatment without substantial toxicity increase, it does not significantly improve PFS compared to standard 3-weekly CT.
Arm 1 Arm 2 Arm 3
StandardWeekly
paclitaxelWeekly carbo-
paclitaxelTotal Patients N=522 N=523 N=521
Progressions 330 (63%) 335 (64%) 338 (65%)
Median PFS 17.9 months 20.6 months 21.1 months
Log rank (vs Arm1) p=0.45 p=0.56
HR vs Arm 1(97.5% CI)
0.92(0.77, 1.09)
0.94(0.79, 1.12)
Restricted means 24.4 months 24.9 months 25.3 months
ICON8 Progression Free Survival
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
• JGOG3016 (Katsumata, Lancet Oncol, 2013. 14(10): p. 1020-6)
‒ DDW Pac + 3W Carbo > 3W Pac + 3W Carbo
• MITO-7 (Pignata, Lancet Oncol, 2014. 15(4): p. 396-405)
‒ W Pac + W Carbo = 3W Pac +3W Carbo
• GOG262 (N Engl J Med, 2016. 374(8): p. 738-48)
‒ DDW Pac + 3W Carbo + Bev = 3W Pac + 3W Carbo + Bev
(Bev was optional)
‒ DDW Pac + 3W Carbo > 3W Pac + 3W Carbo (Subset Analysis)
• ICON-8
‒ DDW Pac + 3W Carbo = 3W Pac + 3W Carbo
‒ W Pac + W Carbo = 3W Pac + 3W Carbo
Weekly Paclitaxel
DDW: dose-dense weekly
W: weekly
3W: 3-weekly
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
• Consensus Statement from 5th Ovarian Cancer Consensus Conference
2015
‒ 3-weelky carboplain and paclitaxel remain the standard chemotherapy drugs for first-line therapy in advanced stage ovarian cancer
‒ Acceptable alternative schedules, and routes of delivery include
• 1) weekly intravenous paclitaxel in combination with 3-weekly intravenous carboplatin
• 2) the addition of bevacizumab to the standard chemotherapy drugs after primary surgery
• 3) intraperitoneal platinum-based chemotherapy after primary surgery with <1 cm residual disease
Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
Introduction and Background
Karam et al, Ann Oncol, 2017. 28(4): p. 711-717.
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
• GOG218 (Burger, N Engl J Med, 2011. 365(26): p. 2473-83)
Addition of Bevacizumab
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
• ICON7 (Perren, N Engl J Med, 2011. 365(26): p. 2484-96)
Addition of Bevacizumab
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
• ICON7 Sub-analysis (Oza, Lancet Oncol 2015; 16: 928–36)
Addition of Bevacizumab
All Patients
HR 0.99 (0.85-1.14), p=0.85
High Risk Patients
HR 0.78 (0.63-0.97) p=0.03
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
Addition of Bevacizumab
in Recurrent Ovarian Cancer GOG213 Trial
Coleman, Lancet Oncol, 2017. 18(6): p. 779-791
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
• PFS: Improved
• OS: Not improved in all patient population
But improved in high-risk patient population
• In consideration with the improvement of OS in GOG213
trial for recurrent ovarian cancer patients, addition of
bevacizumab may be a reasonable choice of treatment for
high risk patient population
Addition of Bevacizumab
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
• Consensus Statement from 5th Ovarian Cancer Consensus Conference
2015
‒ 3-weelky carboplain and paclitaxel remain the standard chemotherapy drugs for first-line therapy in advanced stage ovarian cancer
‒ Acceptable alternative schedules, and routes of delivery include
• 1) weekly intravenous paclitaxel in combination with 3-weekly intravenous carboplatin
• 2) the addition of bevacizumab to the standard chemotherapy drugs after primary surgery
• 3) intraperitoneal platinum-based chemotherapy after primary surgery with <1 cm residual disease
Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
Introduction and Background
Karam et al, Ann Oncol, 2017. 28(4): p. 711-717.
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
• IP Cisplatin (Int J Gynecol Cancer, 2007. 17(1): p. 1-20)
‒ GOG104, GOG114, GOG172
• IP Cisplatin > IV Cisplatin
• IP Carboplatin
‒ GOG252 (Walker, JCO in press)
• IP Carbo with Bev = IV Carbo with Bev
‒ OV21 (Provencher, Ann Oncol, 2018. 29(2): p. 431-438)
• IP Carbo > IV Carbo
‒ iPocc (Fujiwara, Jpn J Clin Oncol, 2011. 41(2): p. 278-82)
• IP Carbo ? IV Carbo
• HIPEC (N Engl J Med, 2018. 378(14): p. 1363-1364)
‒ Will be discussed extensively in this symposium
Intraperitoneal (IP) Chemotherapy
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iPocc paclitaxel
Carboplatin
Cisplatin
IV
IP
Bevacizumab
GOG252
NCIC OV21/GCIG
Day 1 8 15
NACT+
IDS
PDSOptimal
Suboptimal
PDSOptimal
Suboptimal
A
B
C
D
E
F
G
H
Fujiwara,
Expert Opin Pharmacother.
2013 Sep;14(13):1797-806.
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
Bevacizumab 15 mg/kg IV on day 1 for cycles 7-22
GOG 252
R
A
N
D
O
M
I
Z
E
Paclitaxel 135 mg/m² IV over 3 hours day 1
Cisplatin 75 mg/m² IP on day 2
Paclitaxel 60 mg/m² IP on day 8
Bevacizumab 15 mg/kg IV on day 1 beginning on cycle 2
Paclitaxel 80 mg/m² IV over 1 hour days 1, 8, and 15
Carboplatin AUC 6 IP on day 1
Bevacizumab 15 mg/kg IV on day 1 beginning on cycle 2
Paclitaxel 80 mg/m² IV over 1 hour days 1, 8, and 15
Carboplatin AUC 6 IV on day 1
Bevacizumab 15 mg/kg IV on day 1 beginning on cycle 2
Phase A: Cycles 1-6*
*Continue regimen every 3 weeks for six cycles of
chemotherapy and a total of 22 cycles including
bevacizumb unless toxicity or progression intervenes.
Phase B: Cycles 7-22*
IV carbo Arm 1
IP cisplatin Arm 3
IP carbo Arm 2
Walker, JCO in Press
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
Stage II or III Optimally Debulked
Progression-Free Survival by Treatment Group
461 387 244 169 111 37 0
464 391 262 177 125 39 0
456 372 255 168 120 34 0
123
0 12 24 36 48 60 72
Months on Study
0.0
0.2
0.4
0.6
0.8
1.0
Prop
ortio
n Su
rvivin
g Pr
ogre
ssio
n-Fr
ee 3: Cis(IP)+T+Bev
2: Crb(IP)+T+Bev
1: Crb(IV)+T+Bev
Treatment Group
27.8456307
28.7464300
26.8461303
Median(mos)TotalEvents
0 12 24 36 48 60 72
Months on Study
0.0
0.2
0.4
0.6
0.8
1.0
Prop
ortio
n Su
rvivin
g Pr
ogre
ssio
n-Fr
ee 3: Cis(IP)+T+Bev
2: Crb(IP)+T+Bev
1: Crb(IV)+T+Bev
Treatment Group
27.8456307
28.7464300
26.8461303
Median(mos)TotalEvents
GOG252
Walker, JCO in Press
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
OV21/PETROC: Schema (2 stage study)
ELIGIBILITY
• EOC, fallopian tube or
primary peritoneal
cancer
• Clinical FIGO stage IIB-
IV AT DIAGNOSIS
• Neoadjuvant platinum-
based chemotherapy
• Resected to optimal
<1cm
R
A
N
D
O
M
I
Z
A
T
I
O
N
Carboplatin AUV5/6* IV Day 1
Paclitaxel 135 mg/m2 IV 1Day 1
Paclitaxel 60 mg/m2 IV 1Day 8
Q 21 days X 3 cycles
Cisplatin 75 mg/m2 IP Day 1
Paclitaxel 135 mg/m2 IV Day 1
Paclitaxel 60 mg/m2 IP Day 8
Q 21 days x 3 cycles
Carboplatin AUC 5/6* IP Day 1
Paclitaxel 135 mg/m2 IV Day 1
Paclitaxel 60 mg/m2 IP Day 8
Q 21 days x 3 cycles
ARM 1
ARM 2
ARM 3
Stratification variables:
• Cooperative group
• Residual disease: macroscopic vs. microscopic
• Reason for NACT: non-resectable disease vs. other
• Timing of IP catheter insertion: intra-operative vs. postoperative
* AUC 5 (measured GFR)/AUC 6 (calculated GFR)
1:1:1
Provencher, Ann Oncol, 2018. 29(2): p. 431-438
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
PD Rate at 9 Months Following Randomization (Per-Protocol)
PD Rate at 9 Months Following Randomization (ITT)
Provencher, Ann Oncol, 2018. 29(2): p. 431-438
Limitations; Phase 2 setting, Lack of power for PFS or OS.
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
Ovarian,
Peritoneal, Tubal
Cancer
Stage II-IV
Optimal &
Suboptimal
IDS Allowed
R
Paclitaxel 80 mg/m2 Days 1, 8, 15 IV
Carboplatin AUC6 IV
q3w, 6-8 cycles
Paclitaxel 80 mg/m2 Days 1, 8, 15 IV
Carboplatin AUC6 IP
q3w 6-8 cycles
Total Sample Size 655WITHOUT Bevacizumab
iPocc Trial Design
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy iPocc Trial (GOTIC-001/JGOG3019)
Total 655: Singapore 32, KGOG 10, NZ 4, USA 4, Hong Kong 2
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary TherapyIP Therapy and BRCA Status
Lisnock et al. BJC 2013
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
• IP Cisplatin showed improvement of survival over IV Cisplatin but not
over IV Carboplatin (current standard).
• IP Cisplatin showed significant improvement of OS in patients with BRCA
mutations.
‒ Implication of benefit in combination with PARP inhibitor in the future.
• IP Carboplatin was NOT inferior to IP Cisplatin and superior to IP Cisplatin
in terms of toxicity
‒ GOG252 Trial
‒ OV21 Trial
• Results of iPocc trial will finalize the discussion of IP Carboplatin whether
the result is positive or negative.
Intraperitoneal (IP) Chemotherapy Summary
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
• For Platinum Sensitive Recurrent Patients
‒ PARP inhibitors showed improvement of PFS compared to the placebo
• Olaparib
• Niraparib
• Rucaparib
• For Primary Treatment
‒ Olaparib showed significant improvement of PFS as a maintenance therapy after platinum-based chemotherapy
PARP Inhibitor
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
SOLO-1 Trial Design
Randomise 2:1
at end of
chemotherapy
N=344
Olaparib 300mg
bid
until
progression
Placebo bid
until
progression
Newly
diagnosed
Stage III-IV
CR/PR/no
evidence of
disease
upon
completion
of 1st line
platinum
PF
S
OSuntil progression
(Max. 2 yrs for CR)
Primary Endpoint:
PFS (RECIST, BICR)
Key Secondary Endpoints
• OS, PFS2
• TFST, TSST, TDT
• HRQoL
• Safety
Moore, N Engl J Med, 2018. 379(26): p. 2495-2505
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
Moore, N Engl J Med, 2018. 379(26): p. 2495-2505
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
• Nausea/Vomiting
• Fatigue
• Anemia
• Diarrhea/Constipation
• Dysgeusia
• Arthralgia
• Abdominal Pain
• Neutropenia
Etc.
Toxicities of Olaparib
Moore, N Engl J Med, 2018. 379(26): p. 2495-2505
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
For Olaparib
• Ovarian cancer Patients
‒ with germline BRCA mutation
‒ With somatic BRCA mutation
For BRCAnalysis CDx test
• To identify patients with germline BRCA mutated ovarian
cancer patients
FDA Approval
(https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm628876.htm
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
• With Antiangiogenics
‒ Bevacizumab
‒ Cediranib (for recurrent ovarian cancer)
• With Immune Checkpoint Inhibitors
‒ PD-1 Antibody
‒ PD-L1 Antibody
FUTURE
Combination of PARP Inhibitor with Other Agents
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
First-lineTreatment
First-lineMaintenance
PDL1/L1i
Avelumab + chemo
JAVELIN 100
PARPi
Veliparib + chemoVELIA
Olaparib,
SOLO-1gBRCA
PARPi + VEGFi
Olaparib + BevPAOLA-1
Rucaparib + Bev
MITO25
tBRCA, HRD+
PARPi + PD1/L1i
Atezo + Bev + chemo; IMagyn50
VEGFi + PD1/L1iVEGFi
Bev + chemoGOG-218
Bev + chemoICON7
Ovarian Cancer Targeted Therapy Landscape Overview
NiraparibPRIMA
Modified from Meet the Professor; ASCO 2017 By Dr. Mirza MR
Avelumab + chemo +Talazoparib
JAVELIN PARP 100
VEGFi + PD1/L1i + PARPi
Rucaparib + NivolmabATHENA
Pembro + chemo +Olaparib
ENGOT- ov43
Durvalmab + Bev + chemo +
OlaparibDuo-O
TSR-042 + Bev + chemo +
Niraparib
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
PAOLA -1 Study design
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CP
c
Primary debulking Interval debulking
CP
c
cPembro + Olaparib
CP: Carboplatin / Paclitaxel
Pembro 200mg iv q
3wk 2y Start at cycle
2
Olaparib 300 mg BID,
till PD (2Y is NED after
CP)
Placebo
Placebo + Placebo
sBRCAwt or unknown
Arm 1 (Control)
Arm 3
R 1:1:1
N ≈ 1086
CP
c
cPembro + Placebo Arm 2
Bevacizumab allowed; to be specified in advance; randomization to be stratified by use of bev or not
First biopsy for somatic BRCA testing (taken at PDS or laparoscopy or core,…)
Randomization before cycle 2 if not somatic mutated in BRCA
Stratification: 1. Bev use 2. PDS R0; PDS R>0; NACT->IDS
3. PD-L1 status (CPS < or >= 10)
Trial setting: Ovary/newly diagnosed
Sponsor(s): MSD
Planned No. of patients: 1086
FPI: expected Q4 2018
Co-primary Endpoints: PFS (by PI) and OS
STUDY DESIGN
Activating Trials – status update
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GOG 3020 (NCT03522246)Maintenance Rucaparib +/- Nivolumab
ATHENA
Ongoing Trials – status update
(Global)
CO-338-087/GOG-3020/ENGOT-ov45 (Joint International Steering Committee)
Open: MAR 2017
Status: Ongoing Accrual
Target: 1000 pts
Notes: Monk B and Kristeleit, for GOG-F and ENGOT
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy
• Mainstay of primary systemic therapy for ovarian cancer remains
paclitaxel and carboplatin administering every 3 weeks.
• Maintenance therapy with olaparib after chemotherapy dramatically
improved the PFS.
‒ Role of PARPi on OS still unknown.
‒ Long term adverse effect of PARPi still unknown.
• Multiple trials for combination of PARPi is ongoing.
‒ With antiangiogenics
‒ With immuno-checkpoint inhibitors
Summary
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Landscape of Systemic Therapy for Ovarian Cancer 2019
Primary Therapy