Clique para editar o título mestre. Incorporation of bevacizumab in first-line treatment of...

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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]

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)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.


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.



GOG 1111



GOG 1722 IV cisplatin/paclitaxel 18.3 mos 49.7 mos

IP cis/paclitaxel and IV paclitaxel 23.8 mos 65.6 mos





GOG 1111





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%





GOG 1111





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



Addition of biologics to upfront chemotherapy:bevacizumab

Optimal or Suboptimal stage III or IV

Ovarian cancer, peritoneal cancer, tubal cancer

PaclitaxelCarboplatin

Placebo


Bevacizumab


Bevacizumab

Bevacizumab ×15 months

GOG-218GOG-218

Placebo×15 months

Placebo ×15 months

Burger et al, N Engl J Med. 2011

Primary outcome: PFS

Study design

NEJM 365:2473, 2011

3.8 month PFS improvement for bev with chemotherapy and

bev maintenance

NEJM 365:2473, 2011

Primary analysis Updated analysis

No overall survival benefit with addition of bevacizumab

Burger RA et al. N Engl J Med 2011;365:2473-2483

Primary analysis

Updated analysis

Subgroup analysis

NEJM 365:2473, 2011

Toxicities

NEJM 365:2473, 2011

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

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.


ICON7: addition of bevacizumab improvesPFS but no effect on overall survival

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)


Updated Progression-free Survival and Overall Survival Curves

Perren TJ et al. N Engl J Med 2011;365:2484-2496


Unplanned analyses

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

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

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 Paclitaxel3) IP Cisplatin/IV 3hr P/day 8 IP Paclitaxel.All arms contain bevacizumab during chemo and Maintenance.

PFS



GOG 252(NCT00951496)n=1500


PFS

GOG 262 (NCT01167712) n=625

1) Carbo/Pac, 2) Carbo/weekly Pac (both arms all IV)Bevacizumab is optional for both arms

PFS



GOG 252(NCT00951496)n=1500


PFS

GOG 262 (NCT01167712) n=625


PFS

LUME-Ovar 1(NCT01015118) n=1300

1) Carboplatin/Paclitaxel or 2) Carboplatin/Paclitaxel + BIBF1120Eligibility: stage IIB-IV cancer

PFS



GOG 252(NCT00951496)n=1500


PFS

GOG 262 (NCT01167712) n=625


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

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

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