judith k. wolf, md professor department of gynecologic oncology university of texas m.d. anderson...
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Judith K. Wolf, MDJudith K. Wolf, MDProfessor • Department of Gynecologic Oncology • University Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TXof Texas M.D. Anderson Cancer Center • Houston, TX
Treatment of Ovarian Cancer21st Century and Beyond
Judith K. WolfProfessorGynecologic Oncology
Ovarian Cancer: 2010• 1/71 lifetime risk1
• 5-year survival rates (by year of diagnosis)2
– 1990-1992 42.5%– 1993-1995 43.5%– 1996-2003 45%
• Mortality relatively unchanged but statistically significant improvement in 5-year survival rates
1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007.
2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007.
Ovarian Cancer StagingStage I - Limited to ovaries
A. Unilateral ovary
B. Bilateral ovaries
C. Positive cytology
Stage II - Limited to pelvis
A. Extends to uterus or tubes
B. other pelvic organs
C. Positive cytology
Stage III – Spread to upper abdomen or regional lymph nodes
A. Microscopic spread
B. Macroscopic < 2 cm
C. Macroscopic > 2 cm
Stage IV - Spread outside peritoneum, pleura or parenchymal
liver metastases
Ovarian Cancer FIGO Staging System
Stage Description Incidence Survival
I Confined to ovaries 20% 73%
II Confined to pelvis 5% 45%
III Confined to abdomen/ 58% 21%lymph nodes
IV Distant metastases 17% <5%
Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France.
Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007.
FIGO = International Federation of Gynecology and Obstetrics
Ovarian Cancer Surgical Debulking and Staging
Exploration
Washings/Ascites
(Staging)
TAH/BSO
Biopsies(Staging)
Goals (Debulking)•Assessment of extent of disease
•Optimal tumor reduction
TAH = total abdominal hysterectomy
BSO = bilateral salphingo-oophorectomy
First-line Therapy – Standard Treatment Options
Platinum + Taxane Chemotherapy(Carboplatin + Paclitaxel)
Surgery with maximum cytoreduction effort <1cm
residual disease
Chemotherapy• Standard front-line chemotherapy in the US today
is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles
• Result of several studies over last decade
– GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin
– GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin
1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6.2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200.4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329.
GOG = Gynecologic Oncology GroupAGO = ArbeitsgemeinschaftGynaekologische Onkologie
The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma
Study # Pts RegimenMedian PFS
(mo)Median OS
(mo)
GOG 1321
377III suboptimal-IV
Cisplatin/Paclitaxel (24 h) x 6
14.1 26.3
Cisplatin 100 mg/m2 x 6 16.4 30.2Paclitaxel 200 mg/m2 (24 h)* 10.8 25.9
ICON32
2074I-IV
Carboplatin/Paclitaxel (3 h)
17.3 36.1
Carboplatin or CAP 16.1 35.4
CAP = cyclophosphamide, doxorubicin, cisplatinGOG = Gynecologic Oncology GroupICON = International Collaborative Ovarian Neoplasm Group OS = overall survivalPFS = progression-free survival
1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515.
*CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001
The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma
Study # Pts Regimen Median PFS (mo) Median OS (mo)
GOG 1581
792III optimal
Cisplatin 75 mg/m2
Paclitaxel 135 mg/m2 (24 h)19.4 48.8
Carboplatin AUC 7.5Paclitaxel 175 mg/m2 (3 h) *
20.7 56.7
* RR progression 0.88 (95% CI) and RR death 0.86 (95% CI)
HR =0.86(99% CI)
AGO2 798IIB-IV
Cisplatin 75 mg/m2
Paclitaxel 185 mg/m2 (24 h)19.1 44.1
Carboplatin AUC 6Paclitaxel 185 mg/m2 (3 h)
17.2 43.3
HR = 1.050 (95% CI)
HR =1.045 (95% CI)
More toxicity with the cisplatin regimens
1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329.
AGO = Arbeitsgemeinschaft Gynaekologische OnkologieCI = confidence intervalGOG = Gynecologic Oncology GroupHR = hazard ratio; OS = overall survivalPFS = progression-free survivalRR = relative risk
• Ovarian cancer stage Ic-IV
• Primary peritoneal cancer
• N = 1077
Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h)Q3W x 6
Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h)Q3W x 6
RANDOMIZE
SCOTROC: Trial
Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691.
SCOTROC = Scottish Randomized Trial in Ovarian CancerQ3W = once every 3 weeks
SCOTROC: Results
Parameter DC PC
Response (standard) 59% 60%
Response (CA-125) 76% 77%
Progression-free survival 15 mos 14.8 mos
Overall survival at 24 months 64% 69%
Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691.
DC = docetaxel-carboplatinPC = paclitaxel-carboplatinSCOTROC = Scottish Randomized Trial in Ovarian Cancer
SCOTROC: Conclusion• PC vs DC: PC the Standard
– Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia
– Differences in neurotoxicity related to taxane in each regimen should be reversible
– Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin
– Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity
Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691.
DC = docetaxel-carboplatinPC = paclitaxel-carboplatin
Regimen I (control)Paclitaxel 175 mg/m2 IV (3 h) d 1Carboplatin AUC 6 IV d 1
Regimen II (triplet A)Paclitaxel 135 mg/m2 IV (3 h) d 1Carboplatin AUC 5 IV d 1Gemcitabine 800 mg/m2/d IV d 1, 8
Regimen III (triplet B)Paclitaxel 135 mg/m2 IV (3 h) d 1Carboplatin AUC 5 IV d 1Doxil 30 mg/m2 IV d 1 Every other cycle
Regimen IV (sequential module A)Carboplatin AUC 5 IV d 3Topotecan 1.25 mg/m2/d IV d 1-3
Regimen V (sequential module A)Carboplatin AUC 6 IV d 8Gemcitabine 1000 mg/m2/d IV d 1, 8
Regimen IV (sequential module B)Paclitaxel 175 mg/m2 IV (3 h) d 1Carboplatin AUC 6 IV d 1
Regimen V (sequential module B)Paclitaxel 175 mg/m2 IV (3 h) d 1Carboplatin AUC 6 IV d 1
Randomization• All patients• Equal proportions on
each regimen• Primary end points:
PFS, OS, RR
GOG 182-ICON5 International Study for Stage III/IV
Regimens I, II, and III: 8 cycles, 21-d cycle intervalRegimens IV and V: 4 cycles, 21-d cycle interval
Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002.
GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate
GOG0182-ICON5: Progression-Free Survival
Median PFS and HR (95% CI)
16.1 1.00016.4 0.990 (0.884-1.107)16.4 0.998 (0.891-1.117)15.3 1.094 (0.979-1.224)15.4 1.052 (0.940-1.176)
Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002.
C = carboplatinD = pegylated liposomal doxorubicinG = gemcitabineP = paclitaxel; PFS = progression-free survivalT = topotecan
GOG0182-ICON5: Overall Survival
Median OS and HR (95% CI)
40.0 1.00040.4 0.978 (0.838-1.141)42.8 0.972 (0.832-1.136)39.1 1.068 (0.918-1.244)40.2 1.035 (0.888-1.206)
Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002.
C = carboplatinD = pegylated lipososomal doxorubicinG = gemcitabineP = paclitaxel; 0S = overall survivalT = topotecan
Current GOG Frontline Trial
> Microscopic residual > Microscopic residual EOC, PPC cancerEOC, PPC cancer
PaclitaxelPaclitaxelCarboplatinCarboplatin
PlaceboPlacebo
PaclitaxelPaclitaxelCarboplatinCarboplatin
BevacizumabBevacizumab
PaclitaxelPaclitaxelCarboplatinCarboplatin
BevacizumabBevacizumab
Bevacizumab ×16 cycles
GOG 218GOG 218
N = 2,000 patientsSurvival, PFS primary endpoints
Biologic & QOL endpoints
Placebo×16 cycles
Placebo ×16 cycles
EOC = epithelial ovarian cancerFT = fallopian tubeGOG = Gynecologic Oncology GroupPFS = progression-free survivalPPC = primary peritoneal cancerQOL = quality of life
IDS AllowedIDS With
Response or Stable Disease
Repeat ChemotherapySLS allowed
Repeat ChemotherapySLS allowed
EORTC-55971
The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007.
EORTC = European Organisation for Research and Treatment of CancerIDS = Interval Debulking SurgerySLS = Second-Look Surgery
Cytoreductive Surgery+
3 Courses Platinum-Based Chemotherapy
Upfront Debulking Surgery vs Neoadjuvant Chemotherapy
Stage IIIc or IV Epithelial Ovarian Carcinoma
3 Courses Platinum-Based Chemotherapy
GC vs TC Induction Regimens Followed by T Consolidation: Study Design
Gordon A, et al. ASCO 2008. Abstract 5536.
Anything other than CR(PR, SD, PD)
Anything other than CR(PR, SD, PD)
Clinical CR
Single-agent crossoverPaclitaxel 175 mg/m2 Day 1
Single-agent crossoverGemcitabine 1000 mg/m2 Days 1,
8
ElectiveT Consolidation Therapy
Paclitaxel 135 mg/m2 every 28 days for 12 cycles
Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal,
or fallopian tube carcinoma
Induction GCGemcitabine 1000 mg/m2 Days 1,
8 + Carboplatin AUC 5 Day 1
x 6 cycles every 21 days
Induction TCPaclitaxel 175 mg/m2 Day 1+ Carboplatin AUC 6 Day 1
x 6 cycles q 21 days
GC vs TC Induction Regimens Followed by T Consolidation: Response Rates
Gordon A, et al. ASCO 2008. Abstract 5536.
Best response, n (%)Induction
GC(n = 66)
Induction TC
(n = 58)
P Value
CR* 30 (45.5) 26 (44.8)
PR 13 (19.7) 12 (20.7)
SD 5 (7.6) 8 (13.8)
PD 6 (9.1) 4 (6.9)
Data not available 12 (18.2) 8 (13.8)
ORR (CR + PR) 43 (65.2) 38 (65.5) .999
DCR (CR + PR + SD) 48 (72.7) 46 (79.3) .410
*CR required a normalized CA-125.
GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity
Gordon A, et al. ASCO 2008. Abstract 5536.
Toxicity, n (%)Induction
GC(n = 219)
Induction TC
(n = 220)P Value
Hematologic
G3/4 thrombocytopenia
88 (40.2)55 (25.1)
30 (13.6)10 (4.5)
.0001
G3/4 anemia 52 (23.7) 20 (9.1) .0001
Nonhematologic
G2 neuropathy 24 (11.0) 43 (19.5) .0165
G2 alopecia 79 (36.1) 110 (50.0) .0038
Platelet transfusion 7 (3.2) 0 (0) .0073
Conventional vs Dose-Dense TC (NOVEL): Study Design
Ovarian epithelial, primary peritoneal, or fallopian tube cancer with
FIGO stage II-IV
Conventional TC (c-TC)Paclitaxel 180 mg/m2 Day 1 +Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles
Dose-dense weekly TC (dd-TC)Paclitaxel 80 mg/m2 Days 1, 8, 15 +
Carboplatin AUC 6.0 Day 1every 21 days for 6-9 cycles
Dose-dense weekly TC (dd-TC)Paclitaxel 80 mg/m2 Days 1, 8, 15 +
Carboplatin AUC 6.0 Day 1every 21 days for 6-9 cycles
Stratified by residual disease ≤ 1 cm vs > 1 cm;
FIGO stage II vs III vs IV;histology: clear cell/mucinous vs serous/others
Isonishi S, et al. ASCO 2008. Abstract 5506.
P = .72
Evaluated by WHO criteria
Conventional vs Dose-Dense TC (NOVEL): Clinical Responses
MeasurablePatients, %
c-TC(n = 135)
dd-TC(n = 147)
Objective response 53 56
• CR 16 20
• PR 38 36
NC 31 29
PD 7 3
NE 9 12
Isonishi S, et al. ASCO 2008. Abstract 5506.
Treatment n Event Median PFS,
mosP Value HR 95 %CI
c-TC 319 200 17.2
dd-TC 312 160 28.0 .0015 0.714 0.581-0.879
Conventional vs Dose-Dense TC (NOVEL): PFS
0.0
0.2
0.4
0.6
0.8
1.0
0 12 30 54Mos From Randomization
Pro
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0.1
0.3
0.5
0.7
0.9
6 18 4224 4836
Isonishi S, et al. ASCO 2008. Abstract 5506.
dd-TCc-TC
Ovarian Carcinoma: Clinical Course
SymptomsSymptoms
Diagnosis
Chemotherapy #1Chemotherapy #1
StagingPrimary cytoreduction
Interval Cytoreduction
Progression
Chemo #2Chemo #2 Chemo #3+Chemo #3+
SupportiveCare
Death
Consolidation/Maintenance
Consolidation/Maintenance
Cure
SecondaryCytoreductionSecond-Look
Goals of Treatment:Relapsed Ovarian Cancer
• Prolong Survival
• Delay Time to Progression
• Control Disease-Related Symptoms
• Minimize Treatment-Related Symptoms
• Maintain or Improve Quality of Life
Issues Impacting Therapy for Recurrent Ovarian Cancer
• Treatment-free interval– Impact of consolidation/maintenance therapy
• Number of prior regimens– Response to prior therapy
• Toxicity from prior therapy– Prior use of growth factors– Transfusion requirements– Neuropathy
• Volume and site(s) of disease– Ascites/GI symptoms– Performance status
Surveillance Options for Ovarian Cancer Patients in Remission• Second-look laparotomy
• Physical examination– Include pelvic examination
• CA-125
• Imaging– CT scan– MRI?– PET scan?
CT = computed tomographyMRI = magnetic resonance imaging PET = positron emission tomography
Ovarian Cancer:How is Relapse Defined?
• Continuous rise in CA-125
• CA-125 above 100
• Radiographic recurrence
• Symptomatic recurrence
• Physical examination findings
• Combination of above
Population Study Treatment PFS
Optimal St III GOG 114 IV Carb & Pac, IP Cis 28 mos
GOG 172 IV Pac, IP Cis & Pac 24 mos
GOG 158 IV Pac & Carb 21 mos
GOG 114 IV Pac & Cis 22 mos
GOG 158 IV Pac & Cis 19 mos
GOG 172 IV Pac & Cis 18 mos
Suboptimal III & IV GOG 111 IV Pac & Cis 18 mos
GOG 162 IV Pac Cis 12 mos
GOG 152 IV Pac Cis 11 mos
Stage IC-IV SCOTROC Doc Carbo 15 mos
Stage IC-IV SCOTROC Pac Carbo 15 mos
All Stage III & IV GOG 182 IV Pac/Carbo x 8 16 mos
When Does Ovarian Cancer Recur?
Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel;GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel
Active Agents in Ovarian CancerFDA approved
Altretamine Carboplatin Cisplatin
Gemcitabine/
Carboplatin
Paclitaxel Pegylated liposomal doxorubicin
Topotecan
Not FDA approved, compendium listed
Chlorambucil Cyclophosphamide Docetaxel
Doxorubicin Epirubicin Etoposide
5-FU/LV Gemcitabine Ifosfamide
Irinotecan Melphalan Methotrexate
Thiotepa Vinorelbine
Not FDA approved, not compendium listed
Aromatase inhibitors Bevacizumab Pemetrexed
Tamoxifen
Effect of Platinum-Free Intervalon Response Rate% Response to Second-line
Platinum Therapy
Platinum-Free Interval (mos) Markman Gore Blackledge
0-617%
10%
7-12 27% 29%
13-1833% 27%
63%
19-24 94%
>24 59% 57%
Non-Platinum Therapy
15%
20%
30%
30%
Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211.Blackledge G, et al. Br J Cancer. 1989;59:650-653.
Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211.Blackledge G, et al. Br J Cancer. 1989;59:650-653.
Refractory
PRI
MARY
TREATMENT
Resistant
Sensitive
0 3 6 12 18 24Months
“Very Sensitive”
Ovarian Cancer at First RelapseDefinition of Sensitivity
Defined as measurable recurrence, not biochemical (CA-125) recurrence
ICON 4 Schema
• Relapsed ovarian or primary
• Peritoneal requiring chemotherapy
• Previous platinum-based chemotherapy
Conventional platinum-based chemotherapy
Paclitaxel plusplatinum chemotherapy
RANDOMIZEPrior chemotherapy
• Carboplatin (31%)• Paclitaxel/platinum (40%)• Other (30%)
TFI > 12 months for 75%
Parmar MK, et al. Lancet. 2003;361:2099-2106.ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval
ICON 4 Response
Plat (n = 128)
Pac-Plat (n = 119)
CR or PR 54% 66%
(Difference of 12%; 95% CI -0.1% to 24%; p=0.06)
CR = complete response; ICON = International CollaborativeOvarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response;
CR = complete response; ICON = International CollaborativeOvarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106.
Pro
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pro
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0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4
Patients at risk Pac-Plat 392 179 52 25 17Plat 410 157 45 17 7
Years from randomization
Pac-PlatPlat
Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001)
Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%)
Ovarian Carcinoma: ICON 4 Progression-Free Survival
Parmar MK, et al. Lancet. 2003;361:2099-2106.ICON = International Collaborative Ovarian Neoplasm Group;Pac = paclitaxel; Plat = platinum
Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023)
Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%)
Patients at riskPac-Plat 392 306 167 96 43Plat 410 295 150 68 33
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4Years from randomization
Pro
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Pac-PlatPlat
ICON 4: Overall Survival
Parmar MK, et al. Lancet. 2003;361:2099-2106.ICON = International Collaborative Ovarian Neoplasm Group;Pac = paclitaxel; Plat = platinum
RANDOMIZE
Gemcitabine 1,000 mg/m2
days 1 + 8 Plus
Carboplatin AUC 4 day 1
every 21 days × 6
• Recurrent ovarian cancer
• 6+ months after platinum
• Strata
– PFI (6 - 12, >12 months)
– 1st-line therapy (platinum ± paclitaxel)
– Measurable vs evaluable
• Primary endpoint = PFS
Gem/Carbo vs Carbo: Design
Carboplatin AUC 5 day 1
every 21 days × 6
Carbo = carboplatinGem = gemcitabinePFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707.
AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival
0 3 6 9 12 15 18 21 24 27 30 33 36 39
0.0
0.2
0.4
0.6
0.8
1.0
Progression-Free Survival Time (mo)
Pro
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-Fre
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rob
ab
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y
GCb: median = 8.6 mo Censoring: 12.4%
Cb: median = 5.8 moCensoring: 12.9%
Cb Arm (N=178)
GCb Arm (N=178)
Log-rank p-value = 0.0038
Unadjusted HR = 0.72 (0.57 to 0.90)
Adjusted HR* = 0.71 (0.57 to 0.89)
* Adjusted for PFI, Tumor size
Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707.AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin
AGO OVAR 2.5 Efficacy Results:
Overall Survival
0.0
0.8
0.2
0.3
0.4
0.5
0.6
0.7
0.9
1.0
0.1
0 6 12 18 60544842363024
Pro
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Months
Median = 18.0 mo Censoring: 18.5%
Median = 17.3 mo Censoring: 22.5%
Cb Arm (N=178)
GCb Arm (N=178)
* Adjusted for PFI, Tumor size and performance status
Log-rank p-value = 0.7349
Unadjusted HR = 0.96 (0.75 to 1.23)
Adjusted* HR = 0.92 (0.72 to 1.16)
Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707.
AGO = ArbeitsgemeinschaftGynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin
GCIG CALYPSO Trial
Ovarian CancerPlatinum Sens.Stratify:< 0.5 cm> 0.5-2 cm
RANDOMIZE
PLD30 mg/m2
Carboplatin AUC = 5q 28 days x 6
Paclitaxel 175 mg/m2
Carboplatin AUC = 5q 21 days x 6
GCIG = Gynecologic Cancer IntergroupPFS = progression-free survivalPLD = pegylated liposomal doxorubicin
Accrual Completed (Target accrual 864 pts)
PFS 1° endpoint
Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale
• FRA is overexpressed in most EOC; largely absent from normal tissue
• Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models
• Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC
MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design
Patients with platinum-sensitive EOC in first relapseafter first remission of 6-18 months duration
with evaluable disease by CA125(Enrolled N = 58;eligible n = 54)
Asymptomatic relapse
Single-agent Farletuzumab until progression
(n = 28)
Original Carbo/Taxane regimen+ Farletuzumab for 6 cycles
(n = 26)
Symptomatic relapse
Compare lengths of first and second remissions
Farletuzumab maintenance Rx for responders
Single-agent ORR Combination ORR
Armstrong DK, et al. ASCO 2008. Abstract 5500.
All arms
MORAb-003: 100 mg/m2 weekly
– Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2
Combination therapy arm every 21 days x 6 cycles
Carboplatin: AUC 5-6
Taxane
–Paclitaxel 175 mg/m2 over 3 hours or
–Docetaxel 75 mg/m2
MORAb-003-002 Phase II: Treatment Arms
Armstrong DK, et al. ASCO 2008. Abstract 5500.
Comparison of First vs Second Remission Length: n = 6
Data as of May 5, 2008.
Subject 1st Remission, Mos
2nd Remission, Mos
Status
1 8.3 19.5+ Still in remission
2 10.8 19.1+ Still in remission
3 10.1 15.8+ Still in remission
4 9.5 9.6+ Still in remission
5 8.2 8.2 Relapsing
6 6.5 7.8+ Still in remission
Armstrong DK, et al. ASCO 2008. Abstract 5500.
MORAb-003-002 Clinical Responses by RECIST (Combination Therapy)
Best response• CR: 7.4%• PR: 62.9%• SD: 25.9%• PD: 3.7%
• Based on all scans submitted as of December 3, 2007 (~ 30%)
• By independent central reader
• MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm
ORR: 70.3% Patient benefit: 96.3%
Armstrong DK, et al. ASCO 2008. Abstract 5500.
Secondary Cytoreduction
• Controversial
• Inconsistent definitions
• Benefit appears confined to patients likely to respond to additional chemo:
• >12 month PFI• Isolated site of
recurrence• Disease completely
resectable
KidneyKidney
Resected LiverResected LiverDiaphragmDiaphragm
KidneyKidney
Vena CavaVena Cava
Tumor MassTumor Mass
Renal VeinRenal Vein
PFI = progression-free interval
TTP
mos>12>12>12
>17.5>36>24
12-24>24
Ovarian Cancer Secondary Cytoreduction:
Post-Surgery SurvivalAuthor
JanickeSegnaZangGadducciEisenkopMunkarahScarabelliTay
Total/Range
Year
19921993200020002000200120012002
N
301006030
11425
14846
553
SurvivalMedian
mos16
16.61321
16.8
26
13-26
TTP
mos<12<12<12
<17.5<12<24<12<12
SurvivalMedian
mos8
8.88
152542126
6-42
SurvivalMedian mos (P)
29 (0.002)22.9 (0.007)
12 (0.02)25 (0.04)
56.8 (0.005)57 (NS)
32 (0.001)39 (0.001)
12-56
TTP = time to progressionTTP = time to progression
GOG 213- PI Robert Coleman
Surgical
Candidate?
Recurrent ovarian or peritoneal cancer
TFI >6 mos
YES
NO
Surgery
No surgery
Carboplatin + Paclitaxel Carboplatin + Paclitaxel
+ Bevacizumab
+ Bevacizumab Maintenance
Randomize to Chemotherapy
GOG = Gynecologic Oncology GroupTFI = treatment-free interval
Effect of Platinum-Free Intervalon Response Rate% Response to Second-line
Platinum Therapy
Platinum-Free Interval (mos) Markman Gore Blackledge
0-617%
10%
7-12 27% 29%
13-1833% 27%
63%
19-24 94%
>24 59% 57%
Non-Platinum Therapy
15%
20%
30%
30%
Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211.Blackledge G, et al. Br J Cancer. 1989;59:650-653.
Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211.Blackledge G, et al. Br J Cancer. 1989;59:650-653.
Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer
Study Agents Response/comm126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive126-C Hexamethylmelamine 3/30 (10%) Inactive126-D Pyrazoloacridine 2/24 (8.4%) Inactive126-E PSC833 + paclitaxel 1/16 (6%) Inactive126-G CI-958 1/25 (4%) Inactive126-H Topotecan (24 h) 1/25 (4%) Inactive126-I 9-amino-camptothecin 8/58 (14%)
Moderate126-J Docetaxel 13/58 (22%) Active
(post-paclitaxel)
Bookman MA. Semin Oncol 2002;29(suppl 1):20-31.CDDP = c/s-diamminedichloroplatinum (cisplatin)GOG = gynecologic oncology groupCDDP = c/s-diamminedichloroplatinum (cisplatin)GOG = gynecologic oncology group
Recent Phase II GOG Studies in Platinum-Resistant Ovarian CancerStudy Agents Response/comm126-K Oxaliplatin 1/25 (4%) Inactive126-L Gemcitabine/CDDP 9/57 (16%) Moderate126-M Ixabepilone 7/50 (14%)
Moderate126-N Paclitaxel weekly 10/48 (21%) Active
(post-paclitaxel)126-O Triapine-CDDP Not Feasible126-P Paclitaxel & Celecoxib Closed Early126-Q Pemetrexed 10/48 (21%) Active126-R Abraxane Accrual in Progress
Bookman MA. Semin Oncol 2002;29(suppl 1):20-31.CDDP = c/s-diamminedichloroplatinum (cisplatin)GOG = gynecologic oncology groupCDDP = c/s-diamminedichloroplatinum (cisplatin)GOG = gynecologic oncology group
Pemetrexed in Platinum-Resistant EOC: Phase II GOG Study Schema
Miller DS, et al. ASCO 2008. Abstract 5524.
Day -7
Folic acid,
Vitamin B12
Day -6
Folic acid
Day -5
Stop NSAID, folic acid
Days -4,-3Folic acid
Day -2
Stop NSAID,
folic acid
Day -1
Dexamethasone, folic acid
Day 1
Chemotherapy, dexamethasone
, folic acid
Day 2
Dexamethasone,
folic acid
Patients with persistent or recurrent platinum-resistant EOC or primary peritoneal cancer who have failed on
higher priority treatment protocols
Pemetrexed 900 mg/m2 IV every 21 days for 1 cycle; patients who have received previous radiotherapy will initiate
pemetrexed at level I reduction dose until disease progression or adverse effect prohibits further therapy
Phase II GOG Study Evaluation of Pemetrexed: Clinical Responses
Miller DS, et al. ASCO 2008. Abstract 5524.
Category No. of Cases Pts, %
Response
• CR 1 2.1
• PR 9 18.8
• SD 17 35.4*
• Increasing disease
18 37.5
• Not evaluable 3 6.3
Total 48 100
*1 patient remains on therapy.
Cochrane Review of Tamoxifen for Relapsed Ovarian Cancer
• 13 studies (11non-randomized series, 1 non-randomized phase II and 1 randomized trial)
• 59 of 568 women (10.4%) treated with tamoxifen achieved an objective response (RR)– RR varied from 0% to 56%– Stable disease, for variable periods of 4 weeks or
more, in 109 of 356 (30.6%) from 8 studies– Not enough data to assess duration of RR, survival, or
the effect of tamoxifen on quality of life
• No reliable data from randomized controlled trials
Williams CJ. Cochrane Database Syst Rev. 2000;(2):CD001034. RR = response rateRR = response rate
GOG Experience• GOG 160: Trastuzumab
• GOG 170Human Interleukin-12 (170B) Lapatinib (170G)
Gefitinib (170C) Vorinostat (170H)
Bevacizumab (170D) Temsirolimus (170I)
Imatinib (170E) Enzastaurin (170J)
Bay 43-9006 (170F) Mifepristone (170K)
Ongoing GOG Phase II Effort
Insufficiently ActiveToo EarlyActive
GOG = Gynecologic Oncology Group
Antiangiogenic Agents in Testing for Treatment of Ovarian Cancer
Agent TargetsLigand binding:
Bevacizumab VEGF-AVEGF-Trap VEGF-A, -B, -C, -D, -E, PIGF-1 and -2
Receptor binding:Volociximab 51 integrinIMC-1121B VEGFR-2
Receptor tyrosine kinase inhibition:Valatanib VEGFR-1, -2, -3, PDGFR, and c-kitSunitinib PDGFR, VEGFR-1, -2, -3, c-kit, Flt-3AMG-706 VEGFR-1, -2, -3, PDGFR, and c-kitSorafenib Raf, VEGFR-2, -3, Flt-3, c-kit, PDGFR-
Non-receptor kinase inhibition:Temsirolimus, everolimus mTOREnzastaurin PKC- Dasatinib Src kinase
EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; mTOR = mammalian target of rapamycin; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; VEGF = vascular endothelial growth factor
EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; mTOR = mammalian target of rapamycin; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; VEGF = vascular endothelial growth factor
Rationale for Targeting VEGF in Treatment of Epithelial
Ovarian Cancer• Human tumors
– VEGF over-expressed in epithelial ovarian cancers, associated with
• Ascites formation• Malignant progression• Poor prognosis
• Preclinical models of solid tumors – Anti-VEGF therapy:
• Slowing of tumor progression• Resolution of malignant effusions• Synergy with cytotoxic agents
Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345.Burger RA. J Clin Oncol. 2007;25(20):2902-2908. VEGF = vascular endothelial growth factor VEGF = vascular endothelial growth factor
Agents Targeting the VEGF Pathway
VEGFR-2VEGFR-1
PPPPPP
PPPPPPPP
PP
Endothelial Cell Small-Molecule Inhibitors
Anti-VEGFR Antibodies
VEGFAnti-VEGF Antibodies(bevacizumab)
Soluble VEGFRs
(VEGF-TRAP)
Podar K, et al. Blood. 2005;105(4):1383-1395.VEGF = vascular endothelial growth factorVEGFR = VEGF receptor VEGF = vascular endothelial growth factorVEGFR = VEGF receptor
Bevacizumab - Toxicity• Proteinuria (usually G1 – G2)
• Muco-cutaneous hemorrhage– Common – G1 epistaxis
– Rare (possibly life-threatening) G2-G4 tumor site hemorrhage (primarily lung cancer trials)
• Arterial thromboembolism– Uncommon (3% - 5%)
– Risk factors: age > 65, prior arterial TE
– Risk of venous thromboembolism not increased
• GI perforation – wound healing– Perforation uncommon (2% - 4% in solid tumor population)
– Wound dehiscence rate 1%
Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345.Burger RA. J Clin Oncol. 2007;25(20):2902-2908.
G1, G2 = immunoglobulinsGI = gastrointestinalTE = thromboembolism
G1, G2 = immunoglobulinsGI = gastrointestinalTE = thromboembolism
Phase II Studies of Bevacizumabin Ovarian Cancer
Cannistra 2007
Burger2007
Garcia2008
Number of Pts 44 62 70
Prior Regimens2= 52%3= 48%
1= 34%2 = 66%
Median = 2Range 1-3
Response Rate 16% (PRs)18% (PRs)3% (CRs)
24% (PRs)
GI Perforations 11% 0% 6%
Arterial Thromboembolism
7% 0% 4%
Deaths 7% 0% 4%
Cannistra SA, et al. J Clin Oncol. 2007;25(33):5180-5186.Burger RA, et al. J Clin Oncol. 2007;25(33):5165-5171.Garcia AA, et al. J Clin Oncol. 2008;26(1):76-82.
Cannistra SA, et al. J Clin Oncol. 2007;25(33):5180-5186.Burger RA, et al. J Clin Oncol. 2007;25(33):5165-5171.Garcia AA, et al. J Clin Oncol. 2008;26(1):76-82.
CR = complete responseGI = gastrointestinalPR = partial response
CR = complete responseGI = gastrointestinalPR = partial response
GI Perforations with Bevacizumabin Ovarian Cancer
Study GI (Gastrointestinal) Perforations
Burger (GOG 170D) 0/62 (0)
Garcia (ASCO 2005) 2/29 (6.9)
Cannistra (ASCO 2006) 5/44 (11.4)
Wright (ASCO 2006) 4/62 (6.5)
Friberg (ASCO 2006) 2/13 (15.4)
Monk (Gyn Oncol 2006) 1/32 (3.1)
Wright (Cancer 2006) 2/23 (8.7)
Bidus (Gyn Oncol 2006) 0/3 (0)
Penson (ASCO 2006) 0/30
Total 16/298 (5.4%)
Han E, et al. Gynecol Oncol. 2007;105(1):3-6. GI = gastrointestinalGI = gastrointestinal
NCI Registered Phase II Trials:Anti-VEGF + Cytotoxic
Protocol Drug Class PI Status
MDA-2006-0329 AVE-0005 - Docetaxel Receptor Coleman Active
NCT00129727* Bev (+CT**) MAb Penson Active
TEACO* Bev + Ox/Docetaxel MAb Herzog Active
MCC-105366c Bev + Docetaxel MAb Wenham Active
ALSSOPR0501 Bev + Paclitaxel Protein-Bound
MAb Schwartzberg Active
NCT00343044 Bev + Topotecan MAb McGonigle Active
NCT00267696 Bev + Carbo/Gem MAb Copeland Active
AVF3953 Bev + IV Paclitaxel/IP Bev
MAb McMeekin Active
NCT00418093 Bev + Ox/Gem MAb Horowitz Active
* Front Line**Carboplatin and Paclitaxel
Bev = bevacizumab; Carbo = carboplatinGem = gemcitabine; IP = intraperitonealMab = monoclonal antibody; Ox = Oxaliplatin; VEGF = vascular endothelial growth factor
Bev = bevacizumab; Carbo = carboplatinGem = gemcitabine; IP = intraperitonealMab = monoclonal antibody; Ox = Oxaliplatin; VEGF = vascular endothelial growth factor
NCI Registered Phase II Trials:VEGF + EGFR Inhibitors
Protocol Drug Class PI Status
NCIBev +Erlotinib MAb
Friberg Active
NCT00130520 Alberts Active
NCT00520013 Bev +/- Erlotinib Consolidation
MAb Campos Active
Bev = bevacizumabEGFR = epidermal growth factor receptor Mab = monoclonal antibodyVEGF = vascular endothelial growth factor
Bev = bevacizumabEGFR = epidermal growth factor receptor Mab = monoclonal antibodyVEGF = vascular endothelial growth factor
Protocol Drug Target(s) PI StatusGOG 170-J Enzastaurin
(TKI)PKC -b Usha Suspended
NCT00391118 CT +/- [Enzastaurin Enzastaurin]
(Not Listed) Active
GOG 170-EImatinib (TKI) PDGF-R
SchilderCompleted
NCT00039585 Kohn
NCT00516841 Volociximab (MAb)
51 IntegrinMultiple Active
NCT00479817 AMG 386 (Peptibody)
Angiopoietins(Not Listed) Active
NCI Registered Phase II Trials:Other Anti-Angiogenic Agents
CT = chemotherapy; GOG = gynecologic oncology group; EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; TKI = tyrosine kinase inhibitor
CT = chemotherapy; GOG = gynecologic oncology group; EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; TKI = tyrosine kinase inhibitor
Bev + Topotecan in Platinum Refractory Ovarian Cancer: Study
Design
McGonigle KF, et al. ASCO 2008. Abstract 5551.
Platinum-refractory OC; recurrence
< 6 mos of platinum therapy; received max of 2 previous
chemotherapy regimens
(N = 40)
Bevacizumab 10 mg/kg Days 1, 15 + Topotecan
4 mg/m2
Days 1, 8, 15 for 28-day cycles
PD as defined by RECIST criteria
Excessive toxicity according to
prespecified criteria
Toxicity requiring topotecan delay
> 2 weeks or bevacizumab delay
> 2 months
Topotecan-related toxicities requiring > 2 dose reductions
Treatment continued until
1 of the following events
Single arm, 2-site phase II trial
OS: Patients With Platinum-Resistant Ovarian Cancer (N = 30)
McGonigle KF, et al. ASCO 2008. Abstract 5551.
0.0
.25
.50
.75
1.0
Pat
ien
ts S
urv
ivin
g (
%)
Time (Mos)
0 2 4 6 8 10 12 14 16 18 20
Bev + Topotecan
PFS in Patients Receiving Bev + Topotecan by No. of Prior Regimens
McGonigle KF, et al. ASCO 2008. Abstract 5551.
0.0
.25
.50
.75
1.0
0 4 10 20Time (Mos)
Pat
ien
ts W
ith
ou
t P
D (
%)
2 6 14 18168 12
Patients with 1 previous therapy (n = 16)
Patients with 2 previous therapies (n = 14)
P = .040 by log rank test
Best Response of Bev + Topotecan by No. of Prior Regimens
McGonigle KF, et al. ASCO 2008. Abstract 5551.
No. of Previous Regimens
Best Response (N =24)
PR or SD PD Total
1 previous chemotherapy
5 9 14
2 previous chemotherapies
8 2 10
Total 13 11 24
OS in Patients Receiving Bev + Topotecan by No. of Prior Regimens
McGonigle KF, et al. ASCO 2008. Abstract 5551.
0.0
.25
.50
.75
1.0
0 4 10 20Time (Mos)
Pat
ien
ts S
urv
ivin
g (
%)
2 6 14 18168 12
Patients with 1 previous therapy (n = 16)
Patients with 2 previous therapies (n = 14)
P = .043 by log-rank test
Refractory
PRI
MARY
TREATMENT
Resistant
Sensitive
0 3 6 12 18 24Months
“Very Sensitive”
Ovarian Cancer at First RelapseDefinition of Sensitivity
Defined as measurable recurrence, not biochemical (CA-125) recurrence
• Drugs active in platinum-resistant disease
• Single agent regimens
• Treatment to progression, unacceptable toxicity, or clinical complete remission with each regimen
• Sequential use of agents with goal of palliation
Platinum-Resistant Recurrence