Clinical Conundrums: Choosing the Best Management Approaches in Patients With Ovarian Cancer
Thomas J. Herzog, MDDirector, Division of Gynecologic OncologyColumbia University College of Physicians and SurgeonsNew York, New York
This program is supported by an educational grant from
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Controversies in the Treatment of Newly Diagnosed Ovarian Cancer
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Ovarian Cancer: Initial Chemotherapy
Standard frontline chemotherapy is paclitaxel 175 mg/m2 plus carboplatin AUC 6-7, every 21 days for 6 cycles
Result of several studies over last decade
– GOG 111[1] and OV 10[2]: paclitaxel/cisplatin vs cyclophosphamide/cisplatin
– GOG 158[3] and AGO OVAR-3[4]: carboplatin instead of cisplatin
1. McGuire WP, et al. N Engl J Med. 1996;334:1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92:699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21:3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95:1320-1329.
What About Alternative Taxane Therapy?
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
*Similar results for patients with CA-125 elevation only.
Vasey P, et.al. J Natl Cancer Inst. 2004;96:1682-1691.
SCOTROC: Clinical Response*
Outcome, % Paclitaxel/Carboplatin(n = 296)
Docetaxel/Carboplatin(n = 300)
CR 28 28
PR 31 30
ORR 59 59
NC 27 29
PD 10 9
Missing/not evaluable 4 4
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
SCOTROC: Toxicity
Vasey P, et.al. J Natl Cancer Inst. 2004;96:1682-1691.
Adverse Event, % Paclitaxel/Carboplatin
Docetaxel/Carboplatin
P Value
Hematologic toxicity (grades 3-4 )
Neutropenia 84 94 < .001
Thrombocytopenia 10 9 .595
Anemia 8 11 .112
Platelets 11 10 .27
Neuropathy (grades 2-4) 30 11 < .001
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
JGOG: Dose-Dense Wkly Paclitaxel in Stage II-IV
Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy
Accrual: 637 patients (631 intent to treat)
R
ICarboplatin AUC 6Paclitaxel 180 mg/m2 wk x 3
x 6-9
IICarboplatin AUC 6Paclitaxel 80 mg/m2 wk x 3
x 6-9
Katsumata N, et al. Lancet. 2009;374:1331-1338.
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JGOG: Dose-Dense Wkly Paclitaxel
OS at 3 yrs: wkly (72.1%) > 3 wkly (65.1%); HR: 0.75 (95% CI: 0.57-0.98; P = .03)
Treatment Arm n Median PFS (mos)
P Value
Carboplatin AUC 6Paclitaxel 180 mg/m2 3 x wkly
319 17.2.015 (HR: 0.714 (95% CI: 0.581-
0.879)Carboplatin AUC 6Paclitaxel 80 mg/m2/wk x 3
312 28.0
Katsumata N, et al. Lancet. 2009;374:1331-1338.
Will Adding a Third Drug Help?
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GOG0182: Pac/Carbo vs Triplet or Sequential Doublet Combinations (Ph III) Paclitaxel/carboplatin x 8 (control)
Paclitaxel/carboplatin/gemcitabine x 8
Paclitaxel/carboplatin/PLD (4) x 8
Topotecan/carboplatin x 4 paclitaxel/carboplatin x 4
Gemcitabine/carboplatin x 4 paclitaxel/carboplatin x 4
Closed to accrual September 1, 2004
Bookman MA, et al. J Clin Oncol. 2009;27:1419-1425.
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GOG0182-ICON5: PFS
Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Bookman MA, et al. J Clin Oncol. 2009;27:1419-1425.
1.00
0.75
0.50
0.25
00 12 24 36 48 60 72
Pro
po
rtio
n o
f P
atie
nts
A
chie
vin
g P
FS
Mos Since Randomization
CPCPGCPDCT → CPCG → CP
TreatmentCPCPGCPDCT → CPCG → CP
Cancer178177199174173
Prog686687663687688
Total864864862861861
HR1.0081.0060.9841.0661.037
(95% CI)Reference Arm(0.924-1.143)(0.884-1.095)(0.958-1.186)(0.932-1.253)
P
.610
.796
.239
.503
Events Adjusted HR
Patients at risk, n
864864862861861
565579574547563
284275277259255
174153162154153
8068636778
2727322723
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
GOG0182-ICON5: Overall Survival
1.00
0.75
0.50
0.25
00 12 24 36 48 60 72
Pro
po
rtio
n o
f P
atie
nts
A
chie
vin
g O
S
Mos Since Randomization
CPCPGCPDCT → CPCG → CP
TreatmentCPCPGCPDCT → CPCG → CP
Alive391399424394361
Dead473465438477500
Total864864862861861
HR1.0001.0060.9621.0611.114
(95% CI)Reference arm(0.895-1.144)(0.836-1.085)(0.925-1.194)(0.982-1.264)
P
.923
.462
.447
.093
Events Adjusted HR
Patients at Risk, n
864864862861861
780780762778773
625622592593589
426424425423395
203214209200203
7270807366
Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Bookman MA, et al. J Clin Oncol. 2009;27:1419-1425.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Other Recent 3-Drug Frontline Trials
1. Du Bois A, et al. J Clin Oncol. 2006;24:1127-1135. 2. Kristensen G, et al. ASCO 2002. Abstract 805. 3. Scarfone G, et al. ASCO 2006. Abstract 5003. 4. Pfisterer J, et al. J Natl Cancer Inst. 2006;98:1036-1045.5. Herrstedt J, et al. ASCO 2009. Abstract LBA5510. 6. Hoskins PJ, et al. ASCO 2008. Abstract LBA5505.
Group(s) Standard Arm Experimental Arm (s) N Benefit
AGO/GINECO[1] Paclitaxel/carboplatin (TC) TC epirubicin 1282 NS
NSGO/EORTCNCIC CTG[2]
Paclitaxel/carboplatin (TC) TC epirubicin 888 NS
Bolis[3] Paclitaxel/carboplatin (TC) TC topotecan 326 NS
AGO/GINECO[4] Paclitaxel/carboplatin (TC) TC → topotecanconsolidation
1308 NS
AGO/GINECONSGO[5]
Paclitaxel/carboplatin (TC) TC gemcitabine 1742 NS
NCIC CTGEORTC/GEICO[6]
Paclitaxel/carboplatin (TC) Cis topotecan → TC 819 NS
What About IP Therapy?
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Role of IP Chemotherapy: Optimally Debulked Ovarian Cancer
1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK, et al. N Engl J Med. 2006;354:34-43.
GOG 104[1]
Improved outcome in CTX cisplatin-treated patients when cisplatin given IP (relative risk: 0.76)
GOG 114[2] Improved outcome in patients when cisplatin administered IP (relative risk: 0.78)
GOG 172[3]
Improved outcome in patients when paclitaxel and cisplatin administered IP(relative risk: 0.73)
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
GOG 172: Survival
Copyright © 2006 Massachusetts Medical Society. All rights reserved. Armstrong DK, et al. N Engl J Med. 2006;354:34-43.
Outcome IV IP RR P Value
Median PFS, mos 18.3 23.8 0.80 .05
Visible 15.4 18.3 0.81
Micro 35.2 37.6 0.80
Median OS, mos 49.7 65.6 0.75 .03
Visible 39.1 52.6 0.77
Micro 78.2 NA 0.69
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
GOG 172: Survival
Outcome IV IP RR P Value
Median PFS, mos 18.3 23.8 0.80 .05
Visible 15.4 18.3 0.81
Micro 35.2 37.6 0.80
Median OS, mos 49.7 65.6 0.75 .03
Visible 39.1 52.6 0.77
Micro 78.2 NA 0.69
Copyright © 2006 Massachusetts Medical Society. All rights reserved. Armstrong DK, et al. N Engl J Med. 2006;354:34-43.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
GOG 172: OS
Mos of Study
Pro
po
rtio
n S
urv
ivin
g
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 6 12 18 24 30 36 42 48 54 60
IP therapy
IV therapy
P = .03
Copyright © 2006 Massachusetts Medical Society. All rights reserved. Armstrong DK, et al. N Engl J Med. 2006;354:34-43.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
IP Compared With IV Chemotherapy Phase III Trials
GOG 104[1] GOG 114[2] GOG 172[3]
1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK, et al. N Engl J Med. 2006;354:34-43.
25
20
15
10
5
0Alberts Markman Armstrong
PFS: % increase
OS: % increase
Will Adding a Targeted Therapy Help?
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
GOG 218
OvCa III/IV
Subopt
Paclitaxel 175 mg/m2/3 hrsCarboplatin AUC 6
q21d x 6 Bevacizumab* Day 1 x 5
begin cycle 2
Paclitaxel 175 mg/m2/3 hrsCarboplatin AUC 6
q21d x 6Placebo Day 1 x 5
begin cycle 2
Paclitaxel 175 mg/m2/3 hrsCarboplatin AUC 6
q21d x 6Bevacizumab* Day 1 x 5
begin cycle 2
PI: Burger RA
Placeboq 21d
x 15 mos
Placeboq 21d
x 15 mos
Bevacizumab*q 21d
x 15 mos
*Bevacizumab 15 mg/kg IVClinicalTrials.gov. NCT00262847.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
ICON 7 (Frontline European Trial)
Stages I-IV ovarian and peritoneal cancer
– Stratified according to stage, optimal status region or country
Carboplatin AUC 6 + Paclitaxel 175 mg/m2/3 hrs q21d x 6
Carboplatin AUC 6 + Paclitaxel 175 mg/m2/3 hrs q21d x 6 + Bevacizumab at 7.5 mg/kgfollowed by Bevacizumab 7.5 mg/kg q21d x 12 mos
Accrual goal: 1444 patientsPrimary endpoint: PFSOther endpoints: OS (10 mos), RR, Toxicity
Translational Research
Tissue and serum markers of angiogenesis
Genomics
DCE-MRI
Quality of life
Health economics
ClinicalTrials.gov. NCT00483782.
RANDOMIZE
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Observation
Erlotinib 150 mg/day for up to 2 yrs or until PD
Stage Ic to IV epithelial ovarian cancer, having achieved CR/PR/SD on platinum-based chemo
(6-9 courses)
N = 830Endpoints: PFS and OSRecruitment completed, study ongoing
First-line Maintenance (EORTC) With Translational Substudy
ClinicalTrials.gov. NCT00263822.
RANDOM I Z E
Prognostic Factors in Ovarian Cancer
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Age, Yrs Median PFS, Mos
P Value Median OS, Mos
P Value
< 40 21.8 .03 60.1 < .001
40-50 17.8 47.9
50-59 17.5 47.7
60-69 16.8 44.5
≥ 70 15.8 36.6
Age and Ovarian Cancer Outcome
Winter WE III, et al. J Clin Oncol. 2007;25:3621-3627.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Disease Residual Median PFS, Mos
P Value Median OS, Mos
P Value
Microscopic 33.0 < .001 71.9 < .001
0.1-1 cm 16.8 42.4
> 1 cm 14.1 35.0
Other Prognostic Factors: Debulking Status
Winter WE III, et al. J Clin Oncol. 2007;25:3621-3627.
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Histology Median PFS, Mos
P Value Median OS, Mos
P Value
Serous 16.9 .006 45.1 < .001
Endometrioid 24.8 56.0
Clear cell 11.4 24.0
Mucinous 10.5 14.8
Other Prognostic Factors: Histology
Winter WE III, et al. J Clin Oncol. 2007;25:3621-3627.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Elderly Patients: Prognostic Analysis
Patient Characteristic HR 95% CI P Value
Age (continuous) 1.07 1.01-1.13 .013
Stage (IV vs III) 3.05 1.58-5.89 .001
Performance score (2-3 vs 0-1) 1.84 0.97-3.51 .064
Symptoms of depression 5.20 2.46-10.99 < .001
Paclitaxel-based chemotherapy(CP vs CC combination)
2.14 1.10-4.15 .025
Trédan O, et al. Ann Oncol. 2007;18:256-262.
Analysis of 2 consecutive trials from the Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens
This table reports the prognostic factors of poorer survival identified in theproportional hazards model (Cox Regression Model)
Does Having a BRCA Mutation Affect Ovarian Cancer Prognosis?
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Ovarian Cancer Relapse: Effect of BRCA Mutations Retrospective cohort study that
included 933 consecutive ovarian cancers at a single institution
Patients restricted to women of Jewish origin (N = 189)
– 88 cases with evidence of germline foundation mutation in BRCA 1 or BRCA2
– Remaining 101 cases included in comparison group
Mean age of diagnosis significantly younger for BRCA1 vs BRCA 2 (54 vs 62 yrs, P = .04)
Median time to recurrence higher in hereditary group vs nonhereditary group (14 vs 7 mos, P < .001)
Improved survival in hereditary group vs nonhereditary group (P = .004)
BRCA mutation status indep. prognostic variable in stage III disease (P = .03)
Boyd J, et al. JAMA. 2000;283:2260-2265.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Ovarian Cancer Survival: Effect of BRCA Mutations 71 Jewish women with epithelial
ovarian cancer tested for 3 BRCA founder mutations; 32 patients analyzed for in vitro chemoresistance
34 pts (48%) had germline BRCA mutations
Disease developed at a younger age in pts with BRCA mutation vs those without (50 vs 59 yrs, P = .001)
Higher response rates to primary therapy in pts with BRCA mutations vs those without (P = .001)
In vitro chemoresistance predicted tumor response to platinum therapy in pts with BRCA mutation (P = .001)
Improved OS in pts with BRCA mutation at advanced stage vs those without (91 vs 54 mos, P = .046)
Longer DFI with BRCA mutation (49 vs 19 mos, P .016)
Cass I, et al. Cancer. 2003;97:2187-2195.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
BRCA1 and BRCA2 Mutated Ovarian Carcinomas BRCA1 and BRCA2 are critical proteins in DNA repair via
homologous recombination
BRCA-associated cancers develop after a deletion or mutation of the wild-type allele
Normal nonmalignant cells retain the wild-type allele and intact BRCA function
Cells defective in BRCA1 or BRCA2 are more sensitive to ionizing radiation and platinum compounds
BRCA-deficient cells are dependent on an alternate, PARP-dependent DNA repair pathway
Ongoing and Recently Completed Clinical Trials in Ovarian Cancer
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Ovarian, peritoneal or FT cancerStages II-IIIOptimal not required
GOG 9917[1]
IV Paclitaxel 135 mg/m2/3 hrs on Day 1IP Carboplatin (dose esc) on Day 1
q3wks x 6
GOG 9916[2]
IV Paclitaxel 135 mg/m2/3 hrs on Day 1 or IV Docetaxel 100 mg/m2/1 hr on Day 1
Followed byIP Carboplatin (dose esc) on Day 1
IP Paclitaxel 60 mg/m2 on Day 8 q3wks x 6-8
GOG Phase I Trials: IP Carboplatin-Based Regimens
Ovarian, peritoneal or FT cancerstages III-IIIOptimal not requiredOvarian CS allowed
Expanded cohorts with bevacizumab ongoing for both trials cohorts with bevacizumab ongoing for both trials
1. ClinicalTrials.gov. NCT00079430. 2. ClinicalTrials.gov. NCT00085358.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
PORT
PK
C
PK
Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6
SLO
PK
Debulkandport
Carboplatin AUC 6
Paclitaxel 60 mg/m2T
IV
IP
Bevacizumab 15 mg/kg
Courtesy of C. Krasner
Dana Farber/Inter-SPORE Treatment Schema
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
GOG Ovarian Strategy: 252, 262
252Optimal
(≤ 1 cm residual)
262 (under development)Suboptimal
(> 1 cm residual)
IV Paclitaxel 135 mg/m2 on Day 1IP Cisplatin 75 mg/m2 on Day 2IP Paclitaxel 60 mg/m2 on Day 8IV Bevacizumab 15 mg/kg
IV Paclitaxel 80 mg/m2 wklyIP Carboplatin AUC 6IV Bevacizumab 15 mg/kg
IV Paclitaxel 80 mg/m2 wklyIV Carboplatin AUC 6 q3wksIV Bevacizumab 15 mg/kg q3wks
IV Paclitaxel 175 mg/m2
IV Carboplatin AUC 6IV Bevacizumab 15 mg/kg
Bevacizumab q 3 wkMaintenance x 22
Control/Experimental
ClinicalTrials.gov. NCT00951496.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Every 3 WksCarboplatin AUC 5
Paclitaxel 175 mg/m2
Confirmation Trial
WklyCarboplatin AUC 2Paclitaxel 60 mg/m2
MITO7500 patients
ClinicalTrials.gov. NCT00660842.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
ClinicalTrials.gov. NCT00989651.
GOG 9923Phase A (cycle repeated q21d for a total of 6 cycles) Phase B
*Bevacizumab started in cycle 2.†ABT-888 will be dose escalated according to the schedule below to determine the MTD; a feasibility phase will follow. During the dose-escalation phase, patients will be enrolled in cohorts of 3 patients each alternating between regimens 1 and 2. During the feasibility phase, 11 additional patients will be enrolled in regimen 1, followed by 11 in regimen 2, with an additional 16 patients following per regimen, if necessary according to the statistical design.
Eligible PatientsNewly diagnosed epithelial ovarian, fallopian tube, or
primary peritoneal cancer FIGO stage II-IV defined surgically
Regimen 1 (Phase A)Paclitaxel 175 mg/m2 on Day 1Carboplatin AUC 6 on Day 1
Bevacizumab 15 mg/kg on Day 1*ABT-888 BID on Days 1-21†
Regimen 2(Phase A)Paclitaxel 80 mg/m2 on Days 1, 8, 15
Carboplatin AUC 6 on Day 1Bevacizumab 15 mg/kg on Day 1*
ABT-888 BID on Days 1-21†
Bevacizumab will be continued as maintenance for cycles 7-22
q21d
ABT-888 Dose Escalation ScheduleDose Level ABT-888 Dose, mg (oral, BID)Level -1 20 mgLevel 1 30 mgLevel 2 50 mgLevel 3 80 mgLevel 4 100 mgLevel 5 150 mgLevel 6 200 mg
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
ClinicalTrials.gov. NCT00993655.
OV.21: Optimally Debulked Patients After Neoadjuvant Chemotherapy
Stratification and Randomization
Phase II Portion
Arm 1IV Paclitaxel 135 mg/m2
on Day 1 + IV Carboplatin AUC 5 (measured GFR) or AUC 6 (calculated GFR) on
Day 1; IV Paclitaxel 60 mg/m2 on Day 8; cycles given q21d
x 3 cycles
Arm 2IV Paclitaxel 135 mg/m2
on Day 1 + IP Cisplatin 75 mg/m2 on Day 1; IP
Paclitaxel 60 mg/m2 on Day 8; cycles given q21d x 3 cycles
Arm 3IV Paclitaxel 135 mg/m2
on Day 1 + IP Carboplatin AUC 5 (measured GFR) or AUC 6 (calculated GFR) on
Day 1; IP Paclitaxel 60 mg/m2 on Day 8; cycles given q21d
x 3 cycles
Assess Phase II Outcomes(Sample Size = 150)
Proceed to Phase III Portion
Relevance of CA-125 Levels: Placing Novel Data Into Clinical Context
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Background: Recurrent Ovarian Cancer
Nearly 70% of advanced stage cancers relapse
Treatment of recurrent disease is complex with a myriad options
Elevation of CA-125 levels may be first indication of recurrent disease
Marker reliability may be extraneously influenced by biologics
Emerging data to inform clinicians on the role of observation vs treatment
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Current Questions in Recurrent Disease
How do you define recurrence?
– Physical exam
– Imaging
– Chemical
When do you treat?
– Symptoms
– Imaged lesions
– Chemical
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Ovarian Carcinoma: CA-125
Serum glycoprotein (OC-125)
Discovered during a search to boost an immunotherapy (Corynebacterium parvum)[1]
Blood test introduced in 1981
– Present in 82% ovarian cancers; 1% in controls[2]
CA-125 cloned in 2001[3]
– Mapped to chromosome 19 (p13.3)
– Gene: MUC16
– Very large molecule
1. Bast RC, et al. J Clin Invest. 1981;68:1331-1337. 2. Bast RC, et al. N Engl J Med. 1983;309:883-887.3. Yin BW, et al. J Biol Chem. 2001;276:27371-27375.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
CA-125: Uses
Detection
CA-125CA-125CA-125CA-125
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
CA-125 Level Variation in Ovarian Cancer
Characteristic Variation (N = 25)
Analytical imprecision, % 12.1
Intraindividual biological variation, % 24.0
Interindividual biological variation, % 43.1
Index of individuality 0.62
Tuxen MK, et al. Scand J Clin Lab Invest. 2000;60:713-721.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
CA-125Doubling Median: 1.5 mos
CA-125 “lead time”: 3 mos
Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Rustin GJ, et al. J Clin Oncol. 2001;19:4054-4057.
Recurrent Ovarian Cancer: Diagnosis
25
20
15
10
5
0
Pat
ien
ts (
n)
-12 -11-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12
Mos From Clinical Progression
12
13
13 3
24 4
7
16
20
7
31 1 1
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
EORTC 55955: Schema
Previous ovarian, PP, tubal cancer
Previous platinum chemoNormal CA-125 following
first treatment
Conventional Surveillance (“Early”)
Blinded CA-125 q3mos
Monitored CA-125 (“Delayed”)If elevated, repeat in 4 wks
Confirmed elevation promptsChemotherapy
RANDOMIZE
Accrual goal: 1400
Objectives: OS, TFS, QoL
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
0
0.25
0.50
0.75
1.00
Pro
po
rtio
n A
live
No
t S
tart
ed S
eco
nd
-Lin
e C
hem
oth
erap
y
264 177 116 91 69 56 49 42 33Delayed265 23 16 14 11 11 10 10 9Early
Patients at Risk, n
0 3 6 9 12 15 18 21 24
Mos Since Randomization
When to Treat?
Median, MosEarly 0.8Delayed 5.6HR: 0.29 (95% CI: 0.24-0.35; P < .00001)
Rustin G, et al. ASCO 2009. Abstract 1. Reprinted with permission from the author.
Time From Randomization to Second-Line Chemotherapy
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
264 236 203 167 129 103 69 53 38 31 19265 247 211 165 131 94 72 51 38 31 22
Rustin G, et al. ASCO 2009. Abstract 1. Reprinted with permission from the author.
DelayedEarlyPatients at Risk, n
Mos Since Randomization
Pro
po
rtio
n S
urv
ivin
g
6 12 18 24 30 36 42 48 54 60
HR: 1.00 (95% CI: 0.82-1.22; P = .98)
Abs diff at 2 yrs: -0.1% (95% CI diff: -6.8, 6.3%)
Early Delayed
0
0.25
0.50
0.75
1.00
0
Overall Survival
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Primary Treatment
End of FrontlineTherapy
0 Mos 6 Mos 12 Mos
Refractory Resistant Sensitive
Our patient
Platinum Sensitivity
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Pros & Cons of Treating CA-125 Increase
Cons
Potential Rx of false positives
No improvement in OS
Exhaust treatment options
Toxicity
Impaired QoL
Cost
No ideal agent available
May be homeopathic only
Pros
Stay ahead of disease
Improve survival?
Prevent symptoms
Maximize QoL
“Active approach” to care
Intuitive to do something
Minimize patient anxiety
Avoids patient “relocating”
Shortens visit time
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Modifying Influences on Clinical Practice
Applicability of UK to US3rd Party Payers
New AgentsAdvocacy Groups
CA-125 and Rustin Data
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Intervention
Paracentesis First-line treatment for ascites in ovarian cancer patients 1]
Most patients need regular paracentesis[2]
Pleurx catheter Enables patients to manage drainage from pleural effusion at home and reduces risk for septic complications[3]
IP chemotherapy Associated with many complications and toxicities[4]
Bevacizumab IP administration shown be safe and effective when administered to palliate symptoms in patients with refractory malignant ascites[5]
Catumaxomab Trifunctional anti-EpCAM x anti-CD3 antibody Associated with significant reduction in ascites flow rate in
ovarian cancer patients[6] and with longer puncture-free survival and time to next paracentesis[7]
1. Sehouli J. Symptomorientierte Therapien: Aszites. In: Multimodales Management des Ovarialkarzinoms. Sehouli J andLichtenegger W (eds.). Bremen: UNI-MED, pp. 129-134, 2006. 2. Adam R, Adam Y. J Am Coll Sur. 2004;198: 999-1011.3. Iyengar T, Herzog TJ. Am J Hosp Pallit Care. 2002;19:35-38. 4. Woopen H, Sehouli J. Anticancer Res. 2009;29:3353-3360.5. El-Shami, et al. ASCO 2007. Abstract 9043. 6. Burges A, et al. Clin Cancer Res. 2007;13:3899-3905. 7. Heiss MM, et al. Int J Cancer. 2010 Apr 27 [Epub ahead of print].
Management of Ascites
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Conclusions: CA-125 in Ovarian Cancer
Nearly 70% of advanced stage cancers relapse
Many patients will have relevant marker—usually first sign of recurrence with 3 mos of lead time
Marker reliability influenced by biologics
Traditional monitoring paradigms have been challenged by recent phase III data
Reconciling contemporary data with needs of providers and patients during era of economic restraint remains problematic
Is UK data completely applicable to all non-UK populations?
Best Management Approaches for Patients With Platinum-Sensitive Recurrent Disease
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Recurrent Ovarian Cancer: Effect of Platinum-Free Interval and Survival
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
Response, % 9 24 35 52 62
Day
sP
ercentag
e
Pujade-Lauraine E, et al. ASCO 2002. Abstract 829.
1000900800700600500400300200100
0
100908070605040302010
0
Who Are the Best Candidates?
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Secondary Cytoreduction: Patients With Short PFIs Do Not Benefit? Patients (N = 106)
– Optimal (no visible tumor): 82%
– All cisplatin based
– PFI: 6 mos
Time to second surgery: 16.8 mos (range: 6-109)
6-12 mos13-36 mos> 36 mos
Eisenkop SM, et al. Cancer. 2000;88:144-153.
1.00.90.8
0.70.60.50.4
0.30.2
0.10
0 12 24 36 48 60 72 84 96
Survival Time (Mos)
Cu
mu
lati
ve S
urv
ival
PFI = Platinum-free intervalPFI = Platinum-free interval
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
AGO DESKTOP OVAR II: Design
ECOG performance score: 0
No residuals after primary surgery (or, if unknown, initially FIGO I/II)
Absence of ascites > 500 mL
Predictive score positive (all items) ?
Yes
Surgery is planned?
Yes
Laparotomy
Platinum-based combination chemotherapy
No (basic collective 1)
No
Only descriptive analysis of further therapy
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Complete resection in 76% of the study collective = AGO score could predict complete resection in at least 2 out of 3 patients
DESKTOP
Hypothesis
AGO DESKTOP OVAR II: Surgical ResultsFrequency of complete resection by applying the AGO score
100
90
80
70
60
50
40
30
20
10
0Score Positive:
All PatientsScore Positive:First Relapse
Score Positive:Second Relapse
75 7668
Harter P, et al. Ann Surg Oncol. 2006;13:1702-1710.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
A randomized trial evaluating cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer
Stratified byplatinum-free interval 6-12 vs > 12 mos,first-line platinum-
based chx: yes vs no
RANDOMIZE
Cytoreductivesurgery
Platinum-basedchemotherapy*recommended
*Recommended platinum-based chemotherapy regimens:
Carboplatin/paclitaxel
Carboplatin/gemcitabine
Carboplatin/pegliposomal doxorubicin
Or other platinum combinations in prospective trials
No surgery
AGO-OVAR DESKTOP III (Protocol AGO- OVAR OP.4)
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Recurrent ovarian and peritoneal primary cancer TFI > 6 mos
Surgical candidate?
Yes No
Randomize Randomize
Surgery No surgery CarboplatinPaclitaxel
CarboplatinPaclitaxel
Bevacizumab
Maintenancebevacizumab
To chemotherapy randomization
GOG 213
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Refractory
PREVIOUS
TREATMENT
Resistant
Sensitive
0 3 6 12 18 24
Time to Recurrence (Mos)
Very sensitive
Recurrent Ovarian Cancer: Definition of Disease Sensitivity
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
1978
Cis
plat
in
Car
bopl
atin
Altr
etam
ine
Pac
litax
elTo
pote
can
Lipo
som
al d
oxor
ubic
in (P
LD)
(acc
eler
ated
)Li
poso
mal
dox
orub
icin
(ful
l)
Gem
cita
bine
(with
car
bopl
atin
)
2006
1989
1990
1992
1996
1999
2005
2009
Trab
ecte
din;
EU
onl
y
(with
PLD
)
FDA-Approved Drugs in Ovarian Cancer
1964
Mel
phal
anD
oxor
ubic
in
1974
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Decreased toxicity Decreased toxicity
Prolonged platinum-free intervalProlonged platinum-free interval
Alternative mechanism of actionAlternative mechanism of action
Potential Advantages to Nonplatinum Agents in Intermediately Sensitive Disease
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Positive Trials in Recurrent Ovarian Cancer Paclitaxel vs topotecan[1,2]
Topotecan vs pegylated liposomal doxorubicin (PLD)[3,4]
Platinum vs platinum + paclitaxel[5]
Carboplatin vs carboplatin + gemcitabine[6]
Carboplatin + PLD vs carboplatin + paclitaxel[7]
PLD vs PLD + trabectedin[8]
1. ten Bokkel Huinink WW, et al. J Clin Oncol. 1997;15:2183-2193. 2. ten Bokkel Huinink WW, et al. Ann Oncol. 2004;15:100-103. 3. Gordon AN, et al J Clin Oncol. 2001;19:3312-3322. 4. Gordon AN, et al. Gynecol Oncol. 2004;95:1-8. 5. Parmar MK, et al. Lancet. 2003;361:2099-2106. 6. Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. 7. Vasey P, et al. ECCO ESMO 2009. Abstract 18LBA. 8. Monk BJ, et al. ESMO 2008. Abstract LBA4
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Platinum vs Platinum + Paclitaxel
N = 802 (776 evaluable)
Platinum Platinum +Paclitaxel
P Value
Platinum sensitive, %
100 100
Response rate, %
54 66 .06
Median PFS, mos
9 12 .0004
Median OS, mos
24 29 .02
Parmar MK, et al. Lancet. 2003;361:2099-2106.Parmar MK, et al. Lancet. 2003;361:2099-2106.
SurvivalSurvival
PFSPFS1.0
0.8
0.6
0.4
0.2
00 1 2 3 4
Yrs From Randomization
Pro
po
rtio
n S
urv
ivin
g
Pro
gre
ssio
n F
ree Paclitaxel plus platinum
Conventional treatmentHR: 0.76 (0.66-0.89;P = .004)
1.0
0.8
0.6
0.4
0.2
00 1 2 3 5
Yrs From Randomization
Pro
po
rtio
n S
urv
ivin
g Paclitaxel plus platinum
Conventional treatmentHR: 0.82 (0.69-0.97; P = .023)
4
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
ICON 4: “A Mixed Bag”
Entry Criteria
TFI (median): not statedTFI > 12 mos for 75% (both arms)
*4% > 2.
Site Accrual Met?
PreviousTaxane?
TFI, Mos PreviousChemo
Meas. Disease
RelapseCriteria
MRC-CTU
Yes Not req. > 6 > 1* Not req. CA-125
IRFMN Yes Not req. > 12 1 Required Meas.
AGO No Required > 6 1 Not req. Meas.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Gemcitabine 1000 mg/m² Days 1, 8 Carboplatin AUC 4 Day 1
q3w for 6 cycles*
Carboplatin AUC 5 Day 1 q3w for 6 cycles*
Stratified by:
Platinum-free interval (6-12 or > 12 mos)
Type of first-line platinum therapy (platinum/paclitaxel or other platinum therapy)
Bidimensionally measurable disease (yes or no)
*Patients were treated for 6 cycles in the absence of progressive disease or unacceptable toxicity.
At investigator discretion, benefiting patients could receive a maximum of 10 cycles.
RA
ND
OM
IZE
D
Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707.
Phase III Trial of Carboplatin/Gemcitabine:
Study Design
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Median PFSGemcitabine/
Carboplatin, MosCarboplatin, Mos
Progression-free interval
(6-12 mos)7.9 5.2
Progression-free interval
(> 12 mos)9.7 6.7
Previous platinum and paclitaxel 9.7 5.9
Previous platinum (no paclitaxel)
7.6 5.7
American Society of Clinical Oncology. ASCO Virtual Meeting 2003; Abstract and presentation 5005, slides 13-16.
Phase III Registration Trial Carbo/Gem: Prespecified Subgroup Analysis for PFS
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
PLD 30 mg/m² 90-min infusion followed by
Trabectedin* 1.1 mg/m² 3-hr infusion q3w
PLD 50 mg/m2 90-min infusion q4w
RANDOMIZATION
OVA-301: Study Design
*Premedication with dexamethasone is required.
Monk BJ, et al. J Clin Oncol. June 1, 2010 [Epub ahead of print].
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
OVA-301: PFS Primary Endpoint by Independent Radiologist—Measurable*
PFS events: 389HR: 0.79 (0.65-0.96; P = .0190)# censored: 256
Trabectedin + PLD 7.3 mosPLD 5.8 mos
*27 subjects nonmeasurable (9 trab + PLD [2 not treated], 18 PLD [1 not treated])
Pa t
ien
ts (
%)
PFS (Mos)
Monk BJ, et al. J Clin Oncol. June 1, 2010 [Epub ahead of print].
100
90
80
70
60
50
40
30
20
10
00 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Patients at Risk, nPLDTrabectedin/PLD
317328
208225
139176
93121
5486
3563
2233
1422
613
410
07
06
04
00
00
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
PFS events: 226HR: 0.73 (0.56-0.95; P = .0170)# censored: 191
Trabectedin + PLD 9.2 mos
PLD 7.5 mos
Su
bje
cts
(%
)
*9 not treated and 18 nonmeasurable.
100
90
80
70
60
50
40
30
20
10
00 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Patients at Risk, nPLDTrabectedin/PLD
202215
138164
102133
71102
4572
3056
1730
1120
513
310
07
06
04
00
00
PFS (Mos)
OVA-301: PFS (PFI > 6 Mos) by Independent Radiologist (All Measurable* Subjects)
Monk BJ, et al. J Clin Oncol. June 1, 2010 [Epub ahead of print].
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Favorable Opinion for Trabectedin by EMEA September 24, 2009: The EMEA Committee for Medicinal
Products for Human Use (CHMP) adopted a positive opinion to recommend the variation to the terms of the marketing authorization for the medicinal product trabectedin. The CHMP adopted a new indication as follows:
– “[Trabectedin] in combination with pegylated liposomal doxorubicin (PLD) is indicated for the treatment of patients with relapsed platinum-sensitive ovarian cancer”
EMEA. Available at: http://www.emea.europa.eu/pdfs/human/opinion/Yondelis_60855009en.pdf.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
OVA-301: Results Among Partially Sensitive Subpopulation
Poveda A, et al. ASCO 2010. Abstract 5012.
Measure Trabectedin + PLD PLD P Value
Response rate,* % 33 15 .0041
Median PFS,* mos 7.4 5.5 .00152 (HR, 0.65)
Median OS, mos 20.7 17.2 .0090 (HR, 0.59)
Time from randomization to subsequent platinum-based therapy, mos
15.3 11.6 .0093 (HR, 0.60)
*By independent radiologist review
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
PLD + Carbo in Ovarian Cancer Pts Who Recur Within 6-12 Mos: Phase II Study PLD 30 mg/m2 followed by carboplatin AUC 5 mg/mL/min every 4 wks
N = 54
75% received at least 6 cycles
RECIST RR: 46% (4% CR and 42% PR)
– Additional 33% experiencing disease stabilization > 6 mos
CA-125 RR: 66% (28% CR and 38% PR)
– Additional 18% experiencing disease stabilization > 6 mos
Median TTP: 10.0 mos (range: 1.5-25.0)
Median OS: 19.1 mos (range: 2.2-38.9)
Most frequent adverse effects were neutropenia, thrombocytopenia, and constipation
Power P, et al. Gynecol Oncol. 2009;114:410-414.
CALYPSO TrialCarboplatin + PLD vs
Carboplatin + Paclitaxel in Relapsed, Partially Platinum-
Sensitive Ovarian CancerPaul Vasey
on behalf of all GCIC collaboratorsECCO ESMO 2009
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
CALYPSO Study Schema
International, Intergroup, Open-label, Randomized Phase III Study
Ovarian cancer in relapse > 6 mos
after first- or second-line platinum + taxane
chemotherapy
RANDOMIZE
Experimental arm: CDPLD 30 mg/m2 IV Day 1
Carboplatin AUC 5 Day 1
q28 days x 6 courses*
Control arm: CPPaclitaxel 175 mg/m2 IV Day 1
Carboplatin AUC 5 Day 1
q21 days x 6 courses*
*Or progression in patients with SD or PR.
Stratification
Center
Measureable disease(yes vs no)
Therapy-free interval(6-12 mos vs > 12 mos)
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Accrual
AGO-OVAR (Germany), GINECO (France, Switzerland, Turkey, Saudi Arabia), NSGO (Denmark, Finland, Norway, Sweden), NCIC-CTC (Canada), ANZGOG (Australia, New Zealand), AGO (Austria), EORTC (Netherlands, Belgium, Spain), MITO (Italy), MANGO (Italy)
Treatment Total
Therapy-Free Interval CD, n (%) CP, n (%)
6-12 mos 161 (35) 183 (36) 344 (35)
> 12 mos 305 (65) 326 (64) 631 (65)
Vasey P, et al. ECCO ESMO 2009. Abstract 18LBA.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Progression-Free Survival (ITT):Primary Endpoint
Vasey P, et al. ECCO ESMO 2009. Abstract 18LBA. Reprinted with permission from the author.
CD CP
Median PFS, mos 11.3 9.4
HR (95% CI) 0.82 (0.72-0.94)
Log-rank P value (superiority)
.005
P value (noninferiority) < .001
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24 30
Pro
po
rtio
n n
ot
Pro
gre
ssin
g
Mos From Randomization
CP
CD
Patients at Risk, nCDCP
467509
397405
188152
6045
2010
42
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
CD CP
Median PFS, mo 9.4 8.8
HR (95% CI) 0.73 (0.58, 0.90)
Log-rank P-value (superiority)
0.004
P-value (non-inferiority) <0.001
PFS 6-12 Month Segment
Vasey P, et al. ECCO ESMO 2009. Abstract 18LBA. Reprinted with permission from the author.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Cediranib (AZD 2171)*
Cediranib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, and c-kit
Blocking VEGFR-2 inhibits VEGF signaling, angiogenesis, and tumor growth
Highly potent
Orally bioavailable
Toxicity: hypertension, fatigue, diarrhea, nausea
Wedge SR, et al. Cancer Res. 2005;65:4389-4400.
*AZD 2171 is an investigational agent.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Cediranib (AZD 2171)*
Phase II study in recurrent EOC or peritoneal or fallopian tube cancer
N = 46
RR: 8 (17%; 95% CI: 7.6% to 30.8%)
– All PRs, no CRs
Median PFS: 5.2 mos
Median OS not reached
Grade 4 toxicities
– CNS hemorrhage (n = 1)
– Hypertriglyceridemia/hypercholesterolemia/elevated lipase (n = 1)
– Dehydration/elevated creatinine (n = 1)
Grade 3 toxicities (> 20% of pts)
– Hypertension (46%)
– Fatigue (24%)
– Diarrhea (13%)
Grade 2 hypothyroidism occurred in 43% of patients
No bowel perforations or fistulas occurredMatulonis UA , et al. J Clin Oncol.
2009;27:5601-5606.
*AZD 2171 is an investigational agent.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Patients with platinum-sensitive ovarian cancer
Relapsed > 6 mos following first-line platinum-based
treatment
Measurable disease
(N = 33)*
*Planned: phase II (N = 300), phase III (N = 2000).
Platinum-based chemotherapy(± taxane) q21 days x 6 cycles+ oral Cediranib daily during
chemo, then 18 mos of Placebo
Platinum-based chemotherapy(± taxane) q21 days x 6 cycles
+ Placebo
Platinum-based chemotherapy (± taxane) q21 days x 6 cycles+ oral Cediranib during chemoand until progression or 18 mos
Randomized 2:3:3
ClinicalTrials.gov. NCT0000544973.
ICON 6 (Second-Line European Trial)
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Recurrent Ovarian and Peritoneal Primary Cancer TFI > 6 mos
Surgical Candidate?
Yes No
Randomize Randomize
Surgery No Surgery CarboplatinPaclitaxel
CarboplatinPaclitaxel
Bevacizumab
MaintenanceBevacizumab
To Chemotherapy Randomization
GOG 213
ClinicalTrials.gov. NCT00565851.
Management of Patients in Challenging Clinical Situations: Platinum Resistance and Other Clinical Scenarios
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Case #3: Treatment History
Symptoms
Diagnosis
Staging
?5
mos
Progression
Now What?
Primary Chemo x 6
RecurrentChemo x 6
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Treatment Considerations
Recognize her situation is not curable but treatable
Survey carefully for pre-existing toxicities
Assess her likelihood for response
Develop your approach:
– Standard: NCCN guidelines
– Experimental: Clinical study
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Practice Guidelines (2010)
Pts with PD, SD, or persistent disease receiving primary chemotherapy should receive
– Supportive care
– Recurrence therapy
– Referral to a clinical trial
Pts achieving CR and relapse within 6 mos following chemotherapy OR pts with stage II-IV disease with PR should receive
– Observation
– Recurrence therapy (such as with non-platinum-based single agent therapy)
– Referral to a clinical trial
NCCN Clinical Practice Guidelines in Oncology. Ovarian Cancer v.2.2010. NCCN Clinical Practice Guidelines in Oncology. Ovarian Cancer v.2.2010.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
NCCN. Clinical Practice Guidelines in Oncology. Ovarian Cancer v.2.2010.
Practice Guidelines (2010): Recurrence Therapies — Preferred Regimens Cytotoxic regimens
Targeted therapy: Bevacizumab
Platinum-resistant diseaseSingle-agent (non-platinum based)PLDDocetaxelGemcitabineEtoposide (oral)PemetrexedTopotecanPaclitaxel (wkly)
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
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 platinum-sensitive subgroup
PLD Paclitaxel 214 22 vs 22 NS 46 vs 56 NS All pts taxane-naive
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 trialAll 3rd line
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Chemoresistant Queue GOG126: Taxanes
Drug Study N RR, % PFS (mos) OS (mos)
Docetaxel 126-L 58 22 2.1 12.7
Paclitaxel wkly 126-N 48 21 3.6 NS
nab-paclitaxel 126-R 51 23 4.5 17.4
Paclitaxel poliglumex
186-C 49 16 2.8 15.4
Controversial: Taxane-free interval – effect not observed in GOG 126-L
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Pemetrexed
Anti-folate
– Approved in malignant mesothelioma and advanced or metastatic NSCLC
– Enters via reduced folate carrier and a selective high capacity transporter
– Active against DHFR, TS, GARFT
Phase II study
– GOG 126-Q
N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-
yl)ethyl]benzoyl]-L-glutamic acid
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Pemetrexed in Ovarian Cancer
GOG 126-Q Characteristic Tox Heme (Gr 3/4)
N 48 ANC: 42%
Patients Plat-R, measurable RBC: 15%
No. of chemo lines 1 Platelets: 13%
Regimen 900 mg/m2 IV (21 d) Constitutional: 15%
Response (%) Non-Heme (Gr 3/4)
CR+PR 1(2%)+9(19%): 21% GI/Nausea: 15%
SD 17 (35%) Neuro: 10%
PFS/OS 2.8 mos/11.4 mos Alopecia (Gr 2): 10%
Miller DS, et al. ASCO 2009. Abstract e16507.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Chemotherapy vs Hormones
PFS
Chemotherapy (PLD vs Pac-Wkly)
Tamoxifen
OS
Chemotherapy (PLD vs Pac-Wkly)
Tamoxifen
328 d vs 278 dP = .56
87 d vs 62 dP = .024
Kristensen GB, et al. IGCS 2008. Abstract 2008_1175.Kristensen GB, et al. IGCS 2008. Abstract 2008_1175.
N = 241 platinum/taxane-resistant
0 10 20 30 40months
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40months
0.00
0.25
0.50
0.75
1.00
50
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
PLD + Trabectedin vs PLD: Phase III Registration Trial Recurrent ovarian cancer
– One prior regimen
– Evaluable and measurable disease
– Platinum sensitive and resistant
Accrual goal: 650 patients
Primary endpoint: OS
Other endpoints: PFS, RR, safety
Translational research– Pharmacokinetics
– Pharmacogenomics
– Pharmacoeconomics
– Quality of life
– Circulating tumor cells
RANDOMIZE
PLD 50 mg/m2 q 4 wks
PLD 30 mg/m2 + q3 weeksTrabectedin 1.1 mg/m2
Monk BJ, et al. J Clin Oncol . June 1, 2010 [Epub ahead of print].
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
OVA-301: PFS (TFI < 6 mos)
Trabectedin+PLD4.0 mos
PLD3.7 mos
PFS events: 163HR: 0.95 (0.70-1.30)P =.7540# censored: 65
Progression-free survival (months)RR: 12% vs 13% (rad review)
0 4 8 14 280
10
50
70
1.00
90
80
60
20
30
40
262422201816121062
Per
cen
t o
f S
ub
jec
ts
No. Subjects at Risk
PLDTrabectedin/PLD
115 37 9 3 0000011552270113 43 14 2 00000001371961
Monk BJ, et al. J Clin Oncol. June 1, 2010 [Epub ahead of print].
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
GOG 170 Series: Track Record
Response Rate (%)Response Rate (%)
PF
S ≥
6 (
%)
PF
S ≥
6 (
%)
Bevacizumab
VorinostatVorinostatLapatinibLapatinib
GefitinibGefitinibImatinibImatinib
SorafenibSorafenib TemsirolimusTemsirolimus
EnzastaurinEnzastaurinMifepristoneMifepristone
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Phase II Studies of Bevacizumab in Recurrent Ovarian CancerMeasure, % Cannistra et al[1]
(N = 44)Garcia et al[2]
(N = 70)Burger et al[3]
(N = 62)
Previous regimens
1 100% 34%
2 52% 66%
3 48%
Response rate
CR 0% 0% 3%
PR 16% 24% 18%
Gastrointestinal perforations 11% 6% 0%
Arterial thrombosis 7% 4% 0%
Bevacizumab-related deaths 7% 4% 0%
1. Cannistra SA, et al. J Clin Oncol. 2007;25:5180-5186. 2. Garcia AA, et al. J Clin Oncol. 2008;26:76-82.3. Burger RA, et al. J Clin Oncol. 2007;25:5165-5171.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Platinum-Sensitivity and Bevacizumab
Parameter Wald P HR (95% CI)
GOG PS > 0 vs 0
0.25 1.49 (0.76-2.9)
Plat-S Y vs N
0.47 0.80 (0.44-1.46)
Age 0.91 1.0 (0.98-1.02)
Prior chemo 2 vs 1
0.12 0.62 (0.33-1.14)
0 6 12 24 30Time Since Start of Bevacizumab +
Cyclophosphamide Treatment (months)
0
0.1
0.4
0.8
1.0
18
0.20.3
0.5
0.6
0.9
0.7
Est
ima
ted
Pro
bab
ilit
y o
fP
rog
ress
ion
-Fre
e S
urv
ival
Platinum-sensitive (n=42)Platinum-resistant (n=28)All patients (n=70)Log-rank P=.004
Burger RA, et al. J Clin Oncol. 2007;25:5165-5171. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Garcia AA, et al. J Clin Oncol. 2008;26:76-82. Garcia AA, et al. J Clin Oncol. 2008;26:76-82. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.
GOG-170D (Burger et al.) (Garcia, et al.)
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Toxicity from Target and Off Target Constituents Hypertension
– CNS
Proteinuria
Cardiac:
– CHF
– Conduction abnormalities
Endocrine
– Thyroid
VTE
– Arterial and venous
Hemorrhage
GI toxicity
– Perforation
– Fistula
Dermatologic
– Rash
– Wound disruption
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Extraluminal Air
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Morbid situation
– Mortality > 50%
– Challenging counseling due to several factors such as disease status, patient’s intentions, clinical condition at presentation
Management approach (discontinue agent) and:
– Non-interventional: comfort care
– Conservative care: observation, nutritional support, octreotide, drains, antibiotics
– Surgical: intestinal resection/bypass, stomata…
(~5% incidence in recurrent population)
Treatment-Emergent Toxicity: Perforation
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Poly (ADP-Ribose) Polymerase (PARP)
If PARP is inhibited, SSB repair prevented, leading to increased double strand DNA breaks
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Clinical Activity: Phase I
Fong PC, et al. ASCO 2008. Abstract 5510.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Phase II Trial Olaparib in BRCA-Deficient Recurrent Ovarian Cancer: Efficacy
Audeh MW, et al. ASCO 2009. Abstract 5500.
Patients with confirmed BRCA 1/2 mutation, recurrent (stage IIIB/IIIC/IV) ovarian cancer after failure of ≥ 1 platinum-based chemotherapy
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
PARPi Trials: Ongoing/Planned
17 ovarian trials listed on Clinicaltrials.gov Web site
PARP agents
– AG014699
– Olaparib
– BSI-201
– MK4827
– ABT-888
Single agent and in combination with chemo
Populations
– Known BRCA germline
– High grade serous
– 20-30% HR dysfunction
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Investigational Agents
Biologics
AMG-386 (Tie2)
Pazopanib
BIBF-1120
IMC-1121B
Fosbretabulin
IMC-3G3
IGF-1R inhibitors
Rapalogs
PARPi
Chemotherapy and Others
Epothilones
– Ixabepilone
BMP-1350 (karenitecan)
NKTR-102
EC-145
Farletuzumab
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
NKTR-102: Peg-Irinotecan
Data on file. Nektar Therapeutics.
Platinum-resistant
ovarian cancer patients
(N = 70)
Primary Endpoint: Objective response
rate (GCIG)
145 mg/m2 q14d
145 mg/m2 q21d
Stage I N = 20/ regimen
Stage 2 N = 15/ regimen
Prior to entering the study:77% of patients in first stage progressed within 3 months of the last platinum dose
44% of patients in the first stage progressed within 3 weeks of the last platinum dose
Response Measure, % Confirmed Response
q14d q21d
GCIG response rate (RECIST and CA-125) 32 (6/19) 35 (7/20)
RECIST response rate 21 (4/19) 22 (4/18)
Preliminary results from first 39 patients in study*
*Full results for 71 patients to be presented at ASCO Annual Meeting, Sunday, June 6, 2010, 11:15 am (Vergote I, et al, Abstract 5013).
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
Utilizing the Folate Receptor: EC145
Folate-Vinca conjugate
Relevant for imaging targeting and therapy
Reddy JA, et al. Cancer Res. 2007;67:4434-4442.
clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer
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
Naumann W, et al. ASCO 2010. Abstract LBA5012b.
Arm PFS HR P
PLD 11.7 wks - -
PLD+EC145 24.0 wks 0.497 0.014
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Developmental Strategies
Chemotherapy with biologics
Chemotherapy combinations
Biological combinations
Patient profiling – biomarker driven design
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Recommendations: Therapy
My bias would be to first consider a clinical trial such as 126 series or biologic 170-series
Off-protocol: a taxane vs PLD vs topotecan
– Decision based on antecedent toxicity, patient schedule preference, insurance
In the absence of CR or toxicity, treat to progression
– Wait for definitive evidence of progression
– CA-125 trends may be discordant to efficacy determination
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