NE Oncology Issue – September 2011

Background

Results from the OCEANS trial build on findings from two previous phase III studies in newly diagnosed ovarian cancer, GOG 0218 and ICON7.1,2 Both of these studies showed that front-line bevacizumab in combination with standard chemotherapy, followed by continued use of bevacizumab alone, significantly increased progression-free survival (PFS) compared with chemotherapy alone.1,2

These new results of OCEANS (a double-blind, placebo-controlled phase III study of platinumsensitive patients) — presented by Aghajanian and colleagues at ASCO 2011 — assessed the therapeutic impact of bevacizumab in combination with carboplatin (C) and gemcitabine (G), followed by single agent bevacizumab on progressive disease (PD). Results demonstrated that bevacizumab provided a statistically significant and clinically relevant benefit when added to chemotherapy in patients with recurrent, platinum-sensitive epithelial ovarian (EOC), primary peritoneal (PPC), and fallopian tube cancer (FTC).3

Study design

  • The trial included women with recurrent, platinumsensitive EOC, PPC, or FTC who had received no prior chemotherapy for recurrent ovarian cancer, and no prior bevacizumab.
  • Patients had an ECOG performance status of 0–1 and no measurable disease.
  • Patients were randomized in equal numbers (n = 242) to receive six to 10 cycles of standard chemotherapy (C and G) plus either bevacizumab 15 mg/kg every 3 weeks (Arm B), or a placebo (Arm A) concurrently, followed by maintenance treatment with single-agent bevacizumab (15 mg/kg) or placebo, respectively, until progressive disease (PD) or toxicity.
  • The primary endpoint was investigator assessed PFS.
  • Secondary endpoints were overall response rate (ORR), overall survival (OS), duration of response, and safety.
  • PFS was also assessed an independent review committee.
  • The final analysis of OS is not yet mature, and is planned when 353 events are observed.

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Key findings

  • A total of 484 patients (242 per arm) were enrolled from April 2007 to January 2010.
  • Patient characteristics were matched in study arms:
    • Approximately one-third of patients were aged 65 years and older.
    • Approximately 40% of patients had a platinum-free interval of six to 12 months, and 60% at more than 12 months.
  • After a median follow up of 24 months, bevacizumab plus CG followed by single agent bevacizumab upon PD significantly increased PFS compared with CG alone (median 12.4 months versus median 8.4 months, HR = 0.484 (95% CI: 0.388–0.605), p <0.0001). There was clear separation of the curves at approximately two months. (Figure 1)
  • A subgroup analysis of PFS showed notable consistency among the subgroups: all demonstrated that bevacizumab plus chemotherapy improves PFS versus chemotherapy alone.
  • Patients in the bevacizumab group had a statistically significant increase in ORR (78.5% versus 57.4%, p <0.0001).
  • The duration of responses was 10.4 months versus 7.4 months in the control arm (HR = 0.534 [95% CI: 0.408–0.698], p <0.0001, compared for descriptive purposes only).
  • Although OS results are not yet mature, an interim analysis showed a trend favouring bevacizumab, with a median OS of 35.5 months, compared with 29.9 months for placebo (HR = 0.751 (95% CI: 0.537–1.052); p = 0.094). (Figure 2)
  • The safety data was consistent with the known bevacizumab side effect profile. (Table 1)
    • Serious adverse events (SAEs) occurred in 25% of patients who received placebo, and in 35% of patients who received bevacizumab.
    • Grades 3 to 5 adverse events (AEs) of special interest occurred in 62% of patients who received placebo, and in 74% patients who received bevacizumab.
    • There was one study death in each arm.
    • For AEs of special interest hypertension and proteinuria were more common in the bevacizumab arm, and the rate of neutropenia and febrile neutropenia were the same in each arms.
    • There were no gastrointestinal perforations noted during the study period.

Key conclusions

  • In this phase III trial, bevacizumab was shown to provide a statistically significant and clinically relevant benefit when added to chemotherapy in patients with recurrent, platinum sensitive EOC, PPC, and FTC, when compared with chemotherapy alone.
  • Improvements were seen in PFS, ORR, and duration of response.
  • Additional data are required to more fully evaluate OS.
  • Safety data are consistent with those seen with trials of bevacizumab in that there were no GI perforations and no new safety signals arose as a result of this trial.
  • This is the first trial of its kind that demonstrates a clinical benefit in these types of cancers after treatment with bevacizumab.
  • Results suggest that this regimen should be considered a new option for patients with recurrent platinum-sensitive ovarian cancer, in which there are currently limited treatment options available.

References: 1. Burger RA, Brady MF, Bookmanet MA et al. Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal (PPC) or Fallopian tube cancer (FTC): A Gynaecologic Oncology Group study. J Clin Oncol 2010;28:946s (Abstract LBA1). 2. Perren T, Swart AM, Pfistere J, et al. ICON7: A phase III Randomised Gynaecologic Cancer InterGroup (GCIG) trial of concurrent bevacizumab and chemotherapy followed by maintenance bevacizumab in women with newly diagnosed epithelial ovarian (EOC), primary peritoneal (PPC) or fallopian tube cancer (FTC). ESMO 2010 (Abstract LBA4). 3. Aghajanian C, Finkler NJ, Rutherford T, et al. 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). J Clin Oncol (ASCO Annual Meeting Abstracts) 2011;29: LBA5007.

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Canadian Perspectives

dr-lachance
Silvy Lachance, MD, FRCPC, CSPQ
Dr. Silvy Lachance is currently a hematologist, clinical researcher, and Director of the Stem Cell Transplant Program at the MaisonneuveRosement Hospital in Montreal, Quebec, and Professor of Medicine and Director of the Fellowship Program in Stem Cell Transplantation at the University of Montreal. In 1995, Dr. Lachance established the first Stem Cell Transplant Unit at the University Health Centre (CUSE) in Sherbrooke, Quebec. She joined the Hematology and Oncology Division of the Montreal General Hospital as a transplant physician in 1997 and became an Associate Professor of Medicine at McGill University in 2005, holding both positions until 2006. Dr. Lachance has served as chair of the Continuing Medical Education Committee of the Quebec Association of Hematologists and Oncologists, and is currently treasurer of the executive committee. She has also served as chair of the jury for the hematology specialty exam board of the Collège des Médecins du Québec (CMQ). Her research interests include stem cell transplant, graft-versus-host-disease, and lymphoproliferative disorders.

dr-petrella
Teresa Petrella, BSc, MD, MSc, FRCPC
Teresa Petrella is a Medical Oncologist at the Odette Cancer Centre (OCC) in Toronto, Canada and an Assistant Professor at the University of Toronto. Dr. Petrella has a BSc in Molecular Biology from the University of Western Ontario and she completed her MD at Queen’s University. Her Internal Medicine and Medical Oncology training was at McMaster University. She subsequently completed a fellowship in Melanoma and Breast Cancer at the Toronto Sunnybrook Regional Cancer Centre along with a Masters degree in Health Research Methodology at McMaster University. She was the recipient of a CIHR/CAMO award for her research in vaccine therapy in combination with interferon for melanoma patients. Dr. Petrella joined the staff at OCC in 2002 and became the head of the Melanoma Site Group. She also chairs the Provincial Guidelines Melanoma Disease Site Group Program in Evidence Based Care the National Cancer Institute of Canada (NCIC) Melanoma Clinical Trials Group. Her research interests are in melanoma and breast cancer and she is currently the Principal Investigator for several multicentre trials investigating novel therapies in melanoma.