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Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX
Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf
Professor
Gynecologic 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 Staging Stage 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 Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = 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 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 Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = 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 R
A
N
D
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M
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E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = 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-carboplatin PC = paclitaxel-carboplatin SCOTROC = 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-carboplatin PC = paclitaxel-carboplatin Regimen I (control)
Paclitaxel 175 mg/m2 IV (3 h) d 1
Carboplatin AUC 6 IV d 1 Regimen II (triplet A)
Paclitaxel 135 mg/m2 IV (3 h) d 1
Carboplatin AUC 5 IV d 1
Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B)
Paclitaxel 135 mg/m2 IV (3 h) d 1
Carboplatin AUC 5 IV d 1
Doxil 30 mg/m2 IV d 1
Every other cycle Regimen IV (sequential module A)
Carboplatin AUC 5 IV d 3
Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A)
Carboplatin AUC 6 IV d 8
Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B)
Paclitaxel 175 mg/m2 IV (3 h) d 1
Carboplatin AUC 6 IV d 1 Regimen V (sequential module B)
Paclitaxel 175 mg/m2 IV (3 h) d 1
Carboplatin 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 interval
Regimens 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 1.000
16.4 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 = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI)
40.0 1.000
40.4 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 = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual
EOC, PPC cancer Paclitaxel
Carboplatin
Placebo Paclitaxel
Carboplatin
Bevacizumab Paclitaxel
Carboplatin
Bevacizumab Bevacizumab
×16 cycles GOG 218 N = 2,000 patients
Survival, PFS primary endpoints
Biologic & QOL endpoints Placebo
×16 cycles Placebo
×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS 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 Cancer IDS = Interval Debulking Surgery SLS = 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 crossover
Paclitaxel 175 mg/m2 Day 1 Single-agent crossover
Gemcitabine 1000 mg/m2 Days 1, 8 Elective T 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 GC
Gemcitabine 1000 mg/m2 Days 1, 8
+ Carboplatin AUC 5 Day 1
x 6 cycles every 21 days Induction TC
Paclitaxel 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. *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. 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 1
every 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 Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging
Primary cytoreduction Interval
Cytoreduction Progression Chemo #2 Chemo #3+ Supportive
Care Death Consolidation/
Maintenance Cure Secondary
Cytoreduction Second-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 tomography
MRI = 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 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 Cancer Effect of Platinum-Free Interval on Response Rate 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 P
R
I
M
A
R
Y
T
R
E
A
T
M
E
N
T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition 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 plus
platinum
chemotherapy R
A
N
D
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M
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Z
E Prior 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 (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum;
PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 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 17 Plat 410 157 45 17 7 Years from randomization 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 risk Pac-Plat 392 306 167 96 43 Plat 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 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group;
Pac = paclitaxel; Plat = platinum R A N D O M I Z E 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 = carboplatin
Gem = gemcitabine
PFI = 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 GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 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 60 54 48 42 36 30 24 Proportion Surviving 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 = Arbeitsgemeinschaft
Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer
Platinum Sens.
Stratify:
< 0.5 cm
> 0.5-2 cm
R
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N
D
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E PLD
30 mg/m2
Carboplatin AUC = 5
q 28 days x 6 Paclitaxel 175 mg/m2
Carboplatin AUC = 5
q 21 days x 6 GCIG = Gynecologic Cancer Intergroup
PFS = progression-free survival
PLD = 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 relapse after 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. 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 Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP
mos
>12
>12
>12
>17.5
>36
>24
12-24
>24
Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival
Author
Janicke
Segna
Zang
Gadducci
Eisenkop
Munkarah
Scarabelli
Tay
Total/Range
Year
1992
1993
2000
2000
2000
2001
2001
2002
N
30
100
60
30
114
25
148
46
553 Survival
Median
mos
16
16.6
13
21
16.8
26
13-26 TTP
mos
<12
<12
<12
<17.5
<12
<24
<12
<12
Survival
Median
mos
8
8.8
8
15
25
42
12
6
6-42 Survival
Median
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 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 Group TFI = treatment-free interval Effect of Platinum-Free Interval on Response Rate 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/comm
126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive
126-C Hexamethylmelamine 3/30 (10%) Inactive
126-D Pyrazoloacridine 2/24 (8.4%) Inactive
126-E PSC833 + paclitaxel 1/16 (6%) Inactive
126-G CI-958 1/25 (4%) Inactive
126-H Topotecan (24 h) 1/25 (4%) Inactive
126-I 9-amino-camptothecin 8/58 (14%) Moderate
126-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 group Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm
126-K Oxaliplatin 1/25 (4%) Inactive
126-L Gemcitabine/CDDP 9/57 (16%) Moderate
126-M Ixabepilone 7/50 (14%) Moderate
126-N Paclitaxel weekly 10/48 (21%) Active
(post-paclitaxel)
126-O Triapine-CDDP Not Feasible
126-P Paclitaxel & Celecoxib Closed Early
126-Q Pemetrexed 10/48 (21%) Active
126-R Abraxane Accrual in Progress Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = 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. 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. *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 rate GOG Experience GOG 160: Trastuzumab
GOG 170
Human 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 Active
Too Early
Active GOG = Gynecologic Oncology Group Antiangiogenic Agents in Testing for Treatment of Ovarian Cancer Agent Targets
Ligand binding:
Bevacizumab VEGF-A
VEGF-Trap VEGF-A, -B, -C, -D, -E, PIGF-1 and -2
Receptor binding:
Volociximab 51 integrin
IMC-1121B VEGFR-2
Receptor tyrosine kinase inhibition:
Valatanib VEGFR-1, -2, -3, PDGFR, and c-kit
Sunitinib PDGFR, VEGFR-1, -2, -3, c-kit, Flt-3
AMG-706 VEGFR-1, -2, -3, PDGFR, and c-kit
Sorafenib Raf, VEGFR-2, -3, Flt-3, c-kit, PDGFR-
Non-receptor kinase inhibition:
Temsirolimus, everolimus mTOR
Enzastaurin 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 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 Agents Targeting the VEGF Pathway VEGFR-2 VEGFR-1 Endothelial Cell Small-Molecule Inhibitors VEGF Soluble VEGFRs
(VEGF-TRAP) Podar K, et al. Blood. 2005;105(4):1383-1395. VEGF = vascular endothelial growth factor
VEGFR = 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 = immunoglobulins
GI = gastrointestinal
TE = thromboembolism Phase II Studies of Bevacizumab in Ovarian Cancer 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 response
GI = gastrointestinal
PR = partial response GI Perforations with Bevacizumab in Ovarian Cancer Han E, et al. Gynecol Oncol. 2007;105(1):3-6. GI = gastrointestinal NCI Registered Phase II Trials:
Anti-VEGF + Cytotoxic * Front Line
**Carboplatin and Paclitaxel Bev = bevacizumab; Carbo = carboplatin
Gem = gemcitabine; IP = intraperitoneal
Mab = monoclonal antibody; Ox = Oxaliplatin; VEGF = vascular endothelial growth factor NCI Registered Phase II Trials: VEGF + EGFR Inhibitors Bev = bevacizumab
EGFR = epidermal growth factor receptor
Mab = monoclonal antibody
VEGF = vascular endothelial growth factor 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 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 Patients Surviving (%) 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 20 Time (Mos) Patients Without PD (%) 2 6 14 18 16 8 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. 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 20 Time (Mos) Patients Surviving (%) 2 6 14 18 16 8 12 Patients with 1 previous therapy (n = 16) Patients with 2 previous therapies (n = 14) P = .043 by log-rank test Refractory P
R
I
M
A
R
Y
T
R
E
A
T
M
E
N
T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition 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
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