Transcript n=1500 1) IV Carboplatin/IV weekly Paclitaxel 2) IP Carboplatin/IV

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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 School
Director/Program Leader, Medical Gynecologic Oncology
Dana-Farber Cancer Institute
Boston MA
Email: [email protected]
Agenda
• State of the art of treatment for newly
diagnosed ovarian cancer
• Upfront bevacizumab trials
• Ongoing studies using bevacizumab and other
anti-angiogenic agents
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.
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)
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.
2Armstrong
Improvements in OS achieved with paclitaxel,
weekly paclitaxel and IP chemotherapy
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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
1
McGuire et al, NEJM 334(1):1-6, 1996, 2 Armstrong DK, et al, NEJM 354(1):34-43, 2006
3 Katsumata et al, Lancet 374(9698):1331-8, 2009, 4 Vergote I et al. NEJM 363(10):943-53, 2010.
Improvements in OS achieved with paclitaxel,
weekly paclitaxel and IP chemotherapy
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
1
McGuire et al, NEJM 334(1):1-6, 1996, 2 Armstrong DK, et al, NEJM 354(1):34-43, 2006
3 Katsumata et al, Lancet 374(9698):1331-8, 2009, 4 Vergote I et al. NEJM 363(10):943-53, 2010.
Improvements in OS achieved with paclitaxel,
weekly paclitaxel and IP chemotherapy
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
Carbo/paclitaxel q 21
17.2 mos
3 yrs 65.1%
Carbo/paclitaxel qwk
28 mos
3 yrs 72.1%
Isonishi et
al3 (all IV)
1
McGuire et al, NEJM 334(1):1-6, 1996, 2 Armstrong DK, et al, NEJM 354(1):34-43, 2006
3 Katsumata et al, Lancet 374(9698):1331-8, 2009, 4 Vergote I et al. NEJM 363(10):943-53, 2010.
Improvements in OS achieved with paclitaxel,
weekly paclitaxel and IP chemotherapy
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
Carbo/paclitaxel q 21
17.2 mos
3 yrs 65.1%
Carbo/paclitaxel qwk
28 mos
3 yrs 72.1%
Surgery, then carbo/paclitaxel
12 mos
29 mos
Carbo/paclitaxel, interval
debulking, then carbo/paclitaxel
12 mos
30 mos
Isonishi et
al3 (all IV)
Neoadjuvant
EORTC
study4
1
McGuire et al, NEJM 334(1):1-6, 1996, 2 Armstrong DK, et al, NEJM 354(1):34-43, 2006
3 Katsumata et al, Lancet 374(9698):1331-8, 2009, 4 Vergote I et al. NEJM 363(10):943-53, 2010.
Addition of biologics to upfront chemotherapy:
bevacizumab
GOG-218
Optimal or Suboptimal
stage III or IV
Ovarian cancer, peritoneal cancer, tubal cancer
Paclitaxel
Paclitaxel
Paclitaxel
Carboplatin Carboplatin Carboplatin
Placebo Bevacizumab Bevacizumab
Placebo
Placebo
×15 months ×15 months
Bevacizumab
×15 months
Primary outcome: PFS
Burger et al, N Engl J Med. 2011
Study design
NEJM 365:2473, 2011
3.8 month PFS improvement
for bev with chemotherapy and
bev maintenance
Primary analysis
Updated analysis
NEJM 365:2473, 2011
No overall survival
benefit with addition of bevacizumab
Primary analysis
Updated analysis
Burger RA et al. N Engl J Med 2011;365:2473-2483
Subgroup analysis
NEJM 365:2473, 2011
Toxicities
NEJM 365:2473, 2011
ICON7
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.
Perren et al, NEJM 2011
ICON7: addition of bevacizumab improves
PFS but no effect on overall survival
Results
A total of 1528 women from 11 countries were enrolled.
Median age was 57 years
90% had epithelial ovarian cancer
70% 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: 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
Updated Progression-free Survival
and Overall Survival Curves
Unplanned
analyses
Perren TJ et al. N Engl J Med 2011;365:2484-2496
Perren et al, NEJM 2011
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 2011
2 Perren et al, NEJM 2011
Other anti-angiogenics
being 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
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
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
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 Paclitaxel
3) IP Cisplatin/IV 3hr P/day 8 IP Paclitaxel.
All arms contain bevacizumab during chemo and Maintenance.
PFS
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 Paclitaxel
3) 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
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 Paclitaxel
3) 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 +
BIBF1120
Eligibility: stage IIB-IV cancer
PFS
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 Paclitaxel
3) 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 +
BIBF1120
Eligibility: stage IIB-IV cancer
PFS
TRINOVA-3
(NCT01493505)
n=2000
1) IV Carbo/Pac + placebo + placebo maintenace for 18 months
2) IV Carbo/Pac/AMG386 plus AMG386 maintenance for 18
months
Eligibility: stage III or IV cancer
PFS
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