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Clique para editar o título mestre
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Incorporation of bevacizumab in first-line treatment of advanced ovarian cancer: results
and indications
Ursula Matulonis, M.D.Associate Professor of Medicine, Harvard Medical SchoolDirector/Program Leader, Medical Gynecologic Oncology
Dana-Farber Cancer InstituteBoston MA
Email: [email protected]
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Agenda• State of the art of treatment for newly
diagnosed ovarian cancer• Upfront bevacizumab trials• Ongoing studies using bevacizumab and other
anti-angiogenic agents
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Basic principles of management
• Surgery ideally performed by a gynecologic oncologist1
• Staging: involves: --histologic diagnosis--establishes stage --removal of bulk tumor (debulking)--careful inspection of all peritoneal surfaces--inspection/palpation of retroperitoneal nodes +/- removal
• Extent of debulking is what is left behind after surgery.• >1 cm of residual tumor is termed “suboptimal” debulking• ≤1 cm is termed “optimal” debulk• These distinctions are important for prognosis and treatment planning• For neoadjuvant treatment: histological diagnosis should be made by FNA
or core biopsy of a solid mass; 3 cycles of platinum/taxane chemotherapy, interval cytoreduction, then completion of 6 cycles total of treatment.
1Elit et al, Gynecologic Oncology 87(3):260-7, 2002.
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Standard of Care for pts with advanced epithelial
ovarian cancer: 20121
• If optimally cytoreduced (i.e. ≤ 1cm tumor remaining), options are: *Placement of an IP port and IP/IV tx2, *IV carboplatin/paclitaxel (q21d or weekly paclitaxel)*Clinical trial.
• If suboptimally cytoreduced, options are: *IV carboplatin/paclitaxel (q21d or weekly paclitaxel)*clinical trial
• Neoadjuvant chemotherapy3 has demonstrated equivalent results to upfront cytoreduction → chemotherapy
• IV carboplatin and paclitaxel dosing is: Carboplatin AUC 6 via Cockgroft Gault and Paclitaxel 175 mg/m2
1NCCN ovarian cancer guidelines, nccn.org (2012 version)2Armstrong DK, et al, N Engl J Med 354(1):34-43, 2006. 3Vergote I et al. N Engl J Med. 2010 Sep 2;363(10):943-53.
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Study Study Arms Median PFS Median OS
GOG 1111
(all IV)Cisplatin/cyclophosphamide 13.3 mos 24.8 mos
Cisplatin/paclitaxel 18 mos 36.9 mos
Improvements in OS achieved with paclitaxel,weekly paclitaxel and IP chemotherapy
1 McGuire et al, NEJM 334(1):1-6, 1996, 2 Armstrong DK, et al, NEJM 354(1):34-43, 20063 Katsumata et al, Lancet 374(9698):1331-8, 2009, 4 Vergote I et al. NEJM 363(10):943-53, 2010.
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Study Study Arms Median PFS Median OS
GOG 1111
(all IV)Cisplatin/cyclophosphamide 13.3 mos 24.8 mos
Cisplatin/paclitaxel 18 mos 36.9 mos
GOG 1722 IV cisplatin/paclitaxel 18.3 mos 49.7 mos
IP cis/paclitaxel and IV paclitaxel 23.8 mos 65.6 mos
Improvements in OS achieved with paclitaxel,weekly paclitaxel and IP chemotherapy
1 McGuire et al, NEJM 334(1):1-6, 1996, 2 Armstrong DK, et al, NEJM 354(1):34-43, 20063 Katsumata et al, Lancet 374(9698):1331-8, 2009, 4 Vergote I et al. NEJM 363(10):943-53, 2010.
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Study Study Arms Median PFS Median OS
GOG 1111
(all IV)Cisplatin/cyclophosphamide 13.3 mos 24.8 mos
Cisplatin/paclitaxel 18 mos 36.9 mos
GOG 1722 IV cisplatin/paclitaxel 18.3 mos 49.7 mos
IP cis/paclitaxel and IV paclitaxel 23.8 mos 65.6 mos
Isonishi et al3 (all IV)
Carbo/paclitaxel q 21 17.2 mos 3 yrs 65.1%
Carbo/paclitaxel qwk 28 mos 3 yrs 72.1%
Improvements in OS achieved with paclitaxel,weekly paclitaxel and IP chemotherapy
1 McGuire et al, NEJM 334(1):1-6, 1996, 2 Armstrong DK, et al, NEJM 354(1):34-43, 20063 Katsumata et al, Lancet 374(9698):1331-8, 2009, 4 Vergote I et al. NEJM 363(10):943-53, 2010.
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Clique para editar o título mestre
Study Study Arms Median PFS Median OS
GOG 1111
(all IV)Cisplatin/cyclophosphamide 13.3 mos 24.8 mos
Cisplatin/paclitaxel 18 mos 36.9 mos
GOG 1722 IV cisplatin/paclitaxel 18.3 mos 49.7 mos
IP cis/paclitaxel and IV paclitaxel 23.8 mos 65.6 mos
Isonishi et al3 (all IV)
Carbo/paclitaxel q 21 17.2 mos 3 yrs 65.1%
Carbo/paclitaxel qwk 28 mos 3 yrs 72.1%
Neoadjuvant EORTC study4
Surgery, then carbo/paclitaxel 12 mos 29 mos
Carbo/paclitaxel, interval debulking, then carbo/paclitaxel
12 mos 30 mos
Improvements in OS achieved with paclitaxel,weekly paclitaxel and IP chemotherapy
1 McGuire et al, NEJM 334(1):1-6, 1996, 2 Armstrong DK, et al, NEJM 354(1):34-43, 20063 Katsumata et al, Lancet 374(9698):1331-8, 2009, 4 Vergote I et al. NEJM 363(10):943-53, 2010.
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Addition of biologics to upfront chemotherapy:bevacizumab
Optimal or Suboptimal stage III or IV
Ovarian cancer, peritoneal cancer, tubal cancer
PaclitaxelCarboplatin
Placebo
PaclitaxelCarboplatin
Bevacizumab
PaclitaxelCarboplatin
Bevacizumab
Bevacizumab ×15 months
GOG-218GOG-218
Placebo×15 months
Placebo ×15 months
Burger et al, N Engl J Med. 2011
Primary outcome: PFS
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Study design
NEJM 365:2473, 2011
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3.8 month PFS improvement for bev with chemotherapy and
bev maintenance
NEJM 365:2473, 2011
Primary analysis Updated analysis
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No overall survival benefit with addition of bevacizumab
Burger RA et al. N Engl J Med 2011;365:2473-2483
Primary analysis
Updated analysis
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Subgroup analysis
NEJM 365:2473, 2011
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Toxicities
NEJM 365:2473, 2011
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Women with stage II through IV ovarian cancer were randomized to:
1) Carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg per square meter of body-surface area), given every 3 weeks for 6 cycles
OR
2) Carboplatin + paclitaxel plus bevacizumab (7.5 mg per kilogram of body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease.
Outcome measures included progression-free survival (primary endpoint) and interim overall survival.
Not blinded and no placebo.
ICON7
Perren et al, NEJM 2011
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ResultsA total of 1528 women from 11 countries were enrolled. Median age was 57 years90% had epithelial ovarian cancer70% had stage IIIC or IV ovarian cancer.
Progression-free survival (restricted mean) at 36 months was 20.3 months with standard therapy, as compared with 21.8 months with standard therapy plus bevacizumab (HR 0.81; 95% confidence interval, 0.70 to 0.94; P=0.004)
So, 1.5 month PFS difference. NO overall survival benefit.
Perren et al, NEJM 2011
ICON7: addition of bevacizumab improvesPFS but no effect on overall survival
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ICON7: toxicities
Bevacizumab was associated with more toxic effects:
5 pt deaths in study overall: 4 in bev arm (2 GIP, 1 intracranial bleeding and 1 of neutropenic sepsis).
Specific toxicities: -Hypertension of grade 2 or higher: (18% bev vs. 2% with chemotherapy alone).
-Thromboembolic events of grade 3 or higher (7% with bevacizumab vs. 3% with standard)
-Bleeding was higher with bevacizumab (mostly grade 1 mucocutaneous bleeding) - Higher # of GIP’s in the bev group (10 pts in bev arm versus 3 pts in non bev arm)
Perren et al, NEJM 2011
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Updated Progression-free Survival and Overall Survival Curves
Perren TJ et al. N Engl J Med 2011;365:2484-2496
Perren et al, NEJM 2011
Unplanned analyses
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Bevacizumab for newly diagnosed advanced ovarian cancer
• Gastrointestinal events and hypertension were higher in bevacizumab arms1,2
• To date, no overall survival advantage has been observed with addition of bevacizumab to upfront carboplatin and paclitaxel chemotherapy1,2
• Thus, our group does not use bevacizumab for newly diagnosed ovarian cancer
1Burger et al, NEJM 20112 Perren et al, NEJM 2011
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Other anti-angiogenicsbeing tested for newly diagnosed
ovarian cancer
• AMG386 is a first in class, peptide-Fc fusion protein (peptibody) that neutralizes the interaction between Tie2 receptor and angiopoietin 1 and angiopoietin 2.
AMG386 targets a parallel angiogenic pathway from VEGFR.
• BIBF1120 (nintedanib) is an oral anti-angiogenic TKI with activity against VEGFR, PDGFR, and FGFR
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AMG386: results in recurrent cancer
AMG386 has been tested in a randomized phase II study of weekly paclitaxel plus AMG386 versus weekly paclitaxel alone in patients with recurrent platinum resistant ovarian cancer. Pts were randomized 1:1:1: to either AMG 10mg/kg, 3 mg/kg or placebo.
Results: Non-significant prolongation of PFS from 4.6 mos for paclitaxel and placebo to 7.2 mos for paclitaxel and AMG386 at a dose of 10mg/kg (p = 0.23).
Karlan et al, JCO 2012
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BIBF1120: results in recurrent ovarian cancer
• BIBF1120:Tested in a double-blinded randomized phase II study versus placebo for up to 9 months in patients with recurrent ovarian cancer whose cancer responded to the most recent chemotherapy in the second-line or greater setting.
36 week PFS rates were 16.3% and 5.0% in the BIBF 1120 and placebo groups, respectively (hazard ratio, 0.65; 95% CI, 0.42 to 1.02; P = .06).
OS not different between both arms: HR for OS was 0.84 (95% CI, 0.51 to 1.39; P = .51).
Ledermann et al, JCO 2011
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Ongoing studies testing anti-angiogenics in newly diagnosed ovarian cancer
Study Agents being tested Primary Endpoint
GOG 252(NCT00951496)n=1500
1) IV Carboplatin/IV weekly Paclitaxel 2) IP Carboplatin/IV weekly Paclitaxel3) IP Cisplatin/IV 3hr P/day 8 IP Paclitaxel.All arms contain bevacizumab during chemo and Maintenance.
PFS
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Ongoing studies testing anti-angiogenics in newly diagnosed ovarian cancer
Study Agents being tested Primary Endpoint
GOG 252(NCT00951496)n=1500
1) IV Carboplatin/IV weekly Paclitaxel 2) IP Carboplatin/IV weekly Paclitaxel3) IP Cisplatin/IV 3hr P/day 8 IP Paclitaxel.All arms contain bevacizumab during chemo and Maintenance.
PFS
GOG 262 (NCT01167712) n=625
1) Carbo/Pac, 2) Carbo/weekly Pac (both arms all IV)Bevacizumab is optional for both arms
PFS
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Ongoing studies testing anti-angiogenics in newly diagnosed ovarian cancer
Study Agents being tested Primary Endpoint
GOG 252(NCT00951496)n=1500
1) IV Carboplatin/IV weekly Paclitaxel 2) IP Carboplatin/IV weekly Paclitaxel3) IP Cisplatin/IV 3hr P/day 8 IP Paclitaxel.All arms contain bevacizumab during chemo and Maintenance.
PFS
GOG 262 (NCT01167712) n=625
1) Carbo/Pac, 2) Carbo/weekly Pac (both arms all IV)Bevacizumab is optional for both arms
PFS
LUME-Ovar 1(NCT01015118) n=1300
1) Carboplatin/Paclitaxel or 2) Carboplatin/Paclitaxel + BIBF1120Eligibility: stage IIB-IV cancer
PFS
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Ongoing studies testing anti-angiogenics in newly diagnosed ovarian cancer
Study Agents being tested Primary Endpoint
GOG 252(NCT00951496)n=1500
1) IV Carboplatin/IV weekly Paclitaxel 2) IP Carboplatin/IV weekly Paclitaxel3) IP Cisplatin/IV 3hr P/day 8 IP Paclitaxel.All arms contain bevacizumab during chemo and Maintenance.
PFS
GOG 262 (NCT01167712) n=625
1) Carbo/Pac, 2) Carbo/weekly Pac (both arms all IV)Bevacizumab is optional for both arms
PFS
LUME-Ovar 1(NCT01015118) n=1300
1) Carboplatin/Paclitaxel or 2) Carboplatin/Paclitaxel + BIBF1120Eligibility: stage IIB-IV cancer
PFS
TRINOVA-3 (NCT01493505) n=2000
1) IV Carbo/Pac + placebo + placebo maintenace for 18 months2) IV Carbo/Pac/AMG386 plus AMG386 maintenance for 18 months Eligibility: stage III or IV cancer
PFS
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Conclusions
• Bevacizumab added to upfront chemotherapy for newly diagnosed ovarian cancer patients prolongs PFS but does not prolong overall survival.
• Other agents are undergoing phase III testing