Gynecologic CancerASCO/ONS Highlights 2011

Association of Northern California Oncologists

Lee-may Chen, MDProfessor of Clinical Obstetrics, Gynecology, &

Reproductive SciencesDivision of Gynecologic Oncology

UCSF Helen Diller Family Comprehensive Cancer Center

Objectives

Review, summarize, and interpret new advances and implement changes in the treatment of gynecologic malignancies presented at the 2011 ASCO Annual Meeting

New Advances in Gyn Malignancies

Biological targets

Angiogenesis: Bevacizumab, Cabozantinib, Sorafenib, Aflibercept, Temsirolimus

DNA damage repair: Olaparib, Iniparib

Folate receptor: Farletuzemab

Trabecditin

Pegylated liposomal doxorubicin and carboplatin (C-PLD) versus paclitaxel and carboplatin (C-P) in platinum-sensitive ovarian cancer (OC) patients (pts): Treatment at recurrence

and overall survival (OS) final analysis from CALYPSO phase III GCIG trial

Phase III trial comparing pegylated liposomal doxorubicin & carboplatin with paclitaxel & carboplatin, n=976, 4/05-10/07Median PFS: 11.3mo vs 9.4mo, HR 0.82, p=0.005

Most patients received subsequent treatment, but there was an imbalance of crossover: C-PLD P, 34%, C-P PLD, 57%

Median follow-up: 40mo.Median OS: 30.7mo vs 33.0mo, HR 0.99, p=0.87

Conclusion: Crossover treatment rate was higher in C-P, OS was similar

Pujade-Lauraine et al, J Clin Oncol 2010Abstract No: 5052

OCEANS: A randomized, double-blinded, placebo-controlled phase III trial of chemotherapy with or without

bevacizumab (BEV) in patients with platinum-sensitive recurrent epithelial ovarian (EOC), primary peritoneal

(PPC), or fallopian tube cancer (FTC).

C Aghajanian, NJ Finkler, T Rutherford, DA Smith, J Yi, H Parmar, LR Nycum, MA Sovak

Memorial Sloan-Kettering Cancer Center, New York, NY; Florida Hospital Gynecologic Oncology, Florida Hospital Cancer Institute, Orlando, FL; Yale University School of Medicine, New Haven, CT; Northwest Cancer Specialists, Vancouver, WA; Genentech Inc., South San Francisco, CA; Forsyth Regional Cancer Center, Winston-Salem, NC

Abstract No: LBA5007

OCEANS: Rationale

BevacizumabA humanized anti-VEGF monoclonal antibodySingle-agent activity in recurrent ovarian cancer

21% response rate in 2nd/3rd line treatment

Carboplatin & Gemcitabine Improved response rate and PFS over single agent

Carboplatin47% vs 31% ORR, p=0.00168.6 vs 5.8mo PFS, HR 0.72 (p=0.0031)

Burger et al, J Clin Oncol 2007Pfisterer et al, J Clin Oncol, 2006

Abstract No: LBA5007

OCEANS: Treatment exposure

Median # cycles CG+Pl CG+Bev

(n=233) (n=247)

Chemotherapy 6 6

(1-10) (1-10)

Bevacizumab/Placebo 10 12

(1-36) (1-43)Abstract No: LBA5007

Abstract No: LBA5007

OCEANS: Toxicities

AEs of special interest CG+Pl CG +Bevn=233 n=247

Neutropenia, > gr3 56 58Febrile neutropenia 2 2Hypertension, > gr3 <1 17Fistula/abscess <1 2GI perforation 0 0Proteinuria 1 9

2 GI perforations 69d after bevacizumab23% of discontinuation in CG + Bev were due to HTN, proteinuria

Abstract No: LBA5007

OCEANS: Conclusions

Carboplatin, gemcitabine, & bevacizumab, followed by bevacizumab until progression provides a clinically meaningful benefit over chemotherapy alone in platinum-sensitive recurrent ovarian carcinoma.

ORR: 78.5% vs 57.4%, p< 0.0001PFS: 12.4mo vs 8.4mo, HR 0.48, p< 0.0001OS: 35.5mo vs 29.9mo, HR 0.75, p=0.094, not yet mature

Safety data

A new option for recurrent platinum-sensitive ovarian carcinoma

Abstract No: LBA5007

Result of interim analysis of overall survival in the GCIG ICON7 phase III randomized trial of bevacizumab in women

with newly diagnosed ovarian cancer

ICON7: High risk and advanced ovarian cancer treated with debulking surgery, then: Taxol/Carboplatin x 6 cycles, followed by bevacizumab through 18 cycles versus no further treatment

N=1528, 12/06-2/09PFS: 19.0mo vs 17.3mo, HR 0.81, p=0.0041

Median follow-up: 28 mo. Overall HR 0.84, p=0.099Suboptimal Stage III + Stage IV OS: 36.6mo vs 28.8mo, HR 0.64, p=0.0022

Conclusion: Overall trend for improvement by adding Bev

Abstract No: LBA5006

Phase II randomized placebo-controlled study of olaparib (AZD2281) in patients with platinum-sensitive relapsed

serous ovarian cancer (PSR SOC)

JA Ledermann, P Harter, C Gourley, M Friedlander, IB Vergote, GJS Rustin, C Scott, W Meier, R Shapira-Frommer, T Safra, D Matei, E Macpherson, C Watkins, J Carmichael, U Matulonis

UCL Cancer Institute and UCL Hospitals, London, United Kingdom; Kliniken Essen Mitte, Essen, Germany; Edinburgh Cancer Research UK Centre, Edinburgh, United Kingdom; Department of Medical Oncology, Prince of Wales Hospital and Prince of Wales Clinical School, UNSW, Sydney, Australia; University Hospital Leuven, Leuven, Belgium; Mount Vernon Cancer Centre, Middlesex, United Kingdom; The Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria, Australia; Evangelical Hospital, Düsseldorf, Germany; Oncology Institute, Chaim Sheba Medical Center, Ramat-Gan, Israel; Department of Oncology, Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel; Indiana University Simon Cancer Center, Indianapolis, IN; AstraZeneca, Macclesfield, United Kingdom; Dana-Farber Cancer Institute, Boston, MA

Abstract No: 5003

PARP Inhibitors

Selectively potent in BRCA1/2 deficient tumors

33-41% RR in Phase II study in recurrent ovarian cancer

24% RR in BRCA1/2 intact ovarian cancer

Audeh et al, Lancet 2010Gelmon et al, ASCO 2010

Olaparib Maintenance

Platinum sensitive recurrent ovarian carcinoma with stable complete/partial response

2 or more prior platinum-containing regimensStratified by time to progression and response in last

platinum regimen, Jewish descentBRCA testing not required

Olaparib: 400mg PO BID vs Placebo

Evaluation for progression by RECIST criteriaPrimary objective: PFS

Abstract No: 5003

Olaparib Maintenance: Results

n=26516 countriesMedian PFS: 8.4mo vs 4.8mo, HR 0.35, p <

0.00001Median TTP: 8.3mo vs 3.7mo

50% olaparib, 16% placebo patients remain on treatment

Abstract No: 5003

Olaparib Maintenance: Toxicities

Adverse events Placebo Olaparibn=129 n=136

Nausea 35% 68%Fatigue 38% 49%Vomiting 14% 32%Anemia 5% 17%

9 patients on olaparib had > gr3 fatigue & 7 patients had > gr3 anemia4 patients on placebo had > gr3 fatigue & 4 patients had > gr3 abdominal painThe majority of AEs were grade 1 or 2

Abstract No: 5003

Olaparib Maintenance: Conclusions

Maintenance treatment with olaparib provided a significant improvement in progression-free survival in platinum-sensitive recurrent ovarian carcinoma.

PFS: 8.4mo vs 4.8mo, HR 0.35, p< 0.00001TTP: 8.3mo vs 3.7mo, HR 0.35, p<0.00001OS: not yet mature

Well tolerated

A new option for maintenance treatment in recurrent platinum-sensitive ovarian carcinoma

Abstract No: 5003

Iniparib

A phase II trial of iniparib (BSI-201) in combination with gemcitabine/carboplatin (GC) in patients with platinum-sensitive recurrent ovarian cancer

n=41, 71% ORR, 9.4mo PFS

A phase II trial of iniparib (BSI-201) in combination with gemcitabine/carboplatin (GC) in patients with platinum-resistant recurrent ovarian cancer

n=48, 32% ORR, 5.9mo PFS

Conclusions: Activitity without unexpected toxicities

Abstract No: 5004Abstract No: 5005

Effect of screening on ovarian cancer mortality in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer

randomized screening trial

SS Buys, E Partridge, A Black, C Johnson, L Lamerato, C Isaacs, D Reding, R Greenlee, B Kessel, M Fouad, D Chia, L Ragard, J Rathmell, P Hartge, P Pinsky, G Izmirlian, J Xu, P Prorok, CD Berg

Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT; University of Alabama at Birmingham, Birmingham, AL; National Cancer Institute, Bethesda, MD; Henry Ford Health System, Detroit, MI; Henry Ford Hospital, Detroit, MI; Lombardi Comprehensive Cancer Center, Washington, DC; Marshfield Clinic Research Foundation, Marshfield, WI; Marshfield Medical Center, Marshfield, WI; Pacific Health Research Education Institute, Honolulu, HI; Minority Health and Health Disparities Research Center, Birmingham, AL; Department of Pathology and Laboratory Medicine, Los Angeles, CA; Westat, Inc., Rockville, MD; Information Management Services, Inc., Bethesda, MD; Division of Cancer Prevention, NCI, Bethesda, MD

Abstract No: 5001

PLCO: Background

11/93-7/01, n=78,216 women ages 55-74

10 centers nationally

Intervention: baseline, then annual CA125 (5 yrs) and transvaginal ultrasound (3 yrs)

Abstract No: 5001

PLCO: Patient Characteristics

Abstract No: 5001

88% White27% Prior hysterectomy54% Prior oral contraceptive pill use63% Prior hormone therapy9% Nulliparous4% Prior breast cancer17% Family history of breast or ovarian cancer

85% 73% compliance with screening

PLCO: Results

CA125: 1.4-1.8% positive screenTransvaginal ultrasound: 2.9-4.6% positive screen

Ovarian cancers diagnosed212 cases in screening arm

(5.7 per 10,000 person years), 77% Stage III/IV176 in usual care arm

(4.7 per 10,000 person years), 78% Stage III/IVRR 1.21, 95% CI 0.99-1.48

Abstract No: 5001

PLCO: Results

Ovarian cancer deaths118 in screening arm (3.1 per 10,000 person years)100 in usual care (2.6 per 10,000 person years)RR 1.18, 95% CI 0.82-1.71

All cause mortality, RR 1.01, 95% CI 0.96-1.06

Abstract No: 5001

PLCO: Results

3285 false positive CA125/ultrasound tests1080 (32.9%) underwent surgery222 distinct major complications 20.6 complications per 100 surgical procedures

-Infection, Surgical, Cardiovascular or pulmonary

Oophorectomy procedures1771 (7.7%) in screening arm1304 (5.8%) in usual care armRR 1.33, 95% CI 1.24-1.43

Abstract No: 5001

PLCO: Conclusions

Annual CA125 and transvaginal ultrasound screening does not reduce disease-specific mortality in average risk postmenopausal women.

Screening does increase invasive medical procedures, with associated harms and complications.

Abstract No: 5001

Ovarian Cancer Management

Suspicious MassSuspicious SymptomsHereditary Risks

Examination, Imaging, CA125 Laparotomy vs laparoscopy

StagingCytoreductionBx Neoadjuvant chemotherapy

IV Chemotherapy, possible dose denseIV/IP ChemotherapyPossible Interval debulking surgery

Clinical follow-upMaintenance chemotherapy

Screening

Recurrence therapy

ASCO 2011: Gyn Takeaway

OCEANS: Consider bevacizumab in recurrent ovarian cancer

PARP inhibitors: Consider olaparib for maintenance in ovarian cancer

Screening: Annual CA125 & USN ineffective for detecting ovarian cancer in low risk women