Supplementary Appendix

This appendix has been provided by the authors to give readers additional information about their work.

Supplement to: Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011;365:2484-96.

(PDF updated July 28, 2014.) Supplementary Appendix

Supplement to: A Phase III Trial of Bevacizumab in Ovarian Cancer Timothy J Perren et al.

Contents Collaborators Page 2 Trial Management Groups and Committees Page 8 Methods Page 9 Trial conduct Outcome measures and statistical considerations Response and progression definitions RECIST Biological/CA125 progression

Results Page 10 Response PFS sensitivity analyses Biological/CA125 progression Exploratory analyses Overall Survival and Quality of Life Updated Analyses: Overall and Progression-free survival References Page 14

Supplementary Tables and Figures Page 15 Table 1S. Baseline characteristics Table 2S. Best overall response Table 3S. Bivariate analyses of Quality of Life

Figure 1S. Kaplan-Meier plots for progression-free survival censored at last radiological tumor assessment and biological/CA125 progression. Figure 2S. Forest and Kaplan-Meier plots of progression-free survival in subgroups Figure 3S. Global health status score over time Figure 4S. Updated progression-free survival and overall survival by risk group and treatment Figure 5S. Hazard functions for updated progression-free survival and overall survival

1 ICON7: A phase III trial of bevacizumab in ovarian cancer is published in name of all the following collaborators:

AGO-OVAR group: Jacobus Pfisterer, Anja Krüger, Gabriele Elser Ostalb-Klinikum, Frauenklinik, Aalen (Dr Carina Paschold); Praxis Dr. Beha, Amberg (Dr Michaela Beha); Karolinen-Hospital Hüsten, Frauenheilkunde u. Geburtshilfe, Arnsberg (Dr Norbert Peters) ; Klinikum Bayreuth GmbH, Frauenklinik (Pr Augustinus H. Tulusan) ; Campus Virchow Klinikum, Charite, Klinik f. Frauenheilkunde u. Geburtshilfe, Berlin (Pr Jalid Sehouli) ; Ev. Waldkrankenhaus Spandau, Innere Abteilung, Berlin (Dr Jochem Potenberg) ; HELIOS Kliniken GmbH, Klinikum Buch, Frauenklinik, Berlin (Dr Elke Keil) ; Praxisklinik, Berlin (Dr Peter Klare); Klinikverbund Südwest, Kliniken Böblingen, Frauenklinik (Dr Erich Weiss) ; Augusta-Kranken-Anstalt gGmbH, Klinik f. Hämatologie u. internistische Onkologie, Bochum (Pr Dirk Behringer) ; Malteser Krankenhaus, Gynäkologie u. Geburtshilfe, Bonn (Dr Martina Gropp) ; Universitätsklinikum, Zentrum f. Geburtshilfe u. Frauenheilkunde, Bonn (Dr Martin Pölcher) ; Medizinisches Zentrum Bonn - Friedensplatz (Dr Christian Kurbacher) ; Johanniter Krankenhaus, Gynäkologie u. Geburtshilfe, Bonn (Pr Uwe-Jochen Göhring) ; Gemeinschaftspraxis Dr. Hecker und Dr. Lorenz, Braunschweig (Dr Ralf Lorenz) ; Klinikum Bremen-Mitte, Frauenklinik (Pr Willibald Schröder) ; St. Joseph-Stift, Frauenklinik, Bremen (Pr Christiane Frantzen) ; Klinikum Chemnitz gGmbH, Frauenklinik (Dr Petra Krabisch) ; Klinikum Coburg gGmbH, Frauenklinik, (Dr Hermann Zoche) ; Klinikum Darmstadt, Frauenklinik (Dr Sven Ackerman); Klinikum des Landkreises Deggendorf, Frauenklinik (Dr Ronaldo Stuth) ; Städtisches Klinikum, Frauenklinik, Dessau (Dr Inken Achtert) ; St. Johannes Hospital, Frauenheilkunde u. Geburtshilfe, Dortmund (Dr Georg Kunz) ; Universitätsklinikum Carl Gustav Carus, Klinik u. Poliklinik f. Frauenheilkunde u. Geburtshilfe, Dresden (Dr Ulrich Canzler) ; Onkologische Gemeinschaftspraxis, Dresden (Dr Steffen Dörfel) ; Kreisklinik Ebersberg gGmbH, Gynäkologie u. Geburtshilfe (Pr Cornelia Höß) ; Universität Erlangen-Nürnberg, Klinik f. Frauenheilkunde, Erlangen (Pr Matthias W. Beckmann) ; Universitätsklinikum, Frauenklinik, Essen (Dr Pauline Wimberger) ; Elisabeth-Krankenhaus, Klinik f. Gynäkologie u. Geburtshilfe, Essen (Pr Stefan Niesert) ; Klinikum Esslingen, Klinik f. Frauenheilkunde u. Geburtshilfe (Dr Cornelia Kurz) ; Diakonissenanstalt, Frauenklinik, Flensburg (Dr Horst Ostertag) ; Klinikum der J.W. Goethe-Universität, Klinik f. Gynäkologie u. Geburtshilfe, Frankfurt/M. (Dr Lars Hanker) ; Klinikum Frankfurt-Höchst GmbH, Klinik f. Gynäkologie u. Geburtshilfe (Pr Volker Möbus) ;

2 Onkologische Gemeinschaftspraxis, Frankfurt/M. (Pr Hans Tesch) ; Universitäts- Frauenklinik Freiburg (Pr Annette Hasenburg) ; Praxis f. Interdisziplinäre Onkologie u. Hämatologie, Freiburg (Dr Norbert Marschner) ; Kreiskrankenhaus Freudenstadt, Gynäkologie (Andreas Kuznik) ; Klinikum Fürth, Frauenklinik Nathanstift, (Pr Volker Hanf) ; Herz-Jesu-Krankenhaus gGmbH, Frauenheilkunde u. Geburtshilfe, Fulda (Dr Dietrich Mosch) ; Klinikum St. Georg, Franziskus Hospital Harderberg, Gynäkologie, Georgsmarienhütte (Dr Michael Hoedemaker) ; Universitätsklinikum, Zentrum f. Frauenheilkunde u. Geburtshilfe, Gießen (Pr Karsten Münstedt); Kreiskrankenhaus Gifhorn, Gynäkologie (Dr Thomas Dewitz) ; Klinikum Göttingen, Georg-August- Universität, Universitäts-Frauenklinik (Pr Günter Emons) ; Klinikum d. Ernst-Moritz- Arndt-Universität, Klinik u. Poliklinik f. Gynäkologie u. Geburtshilfe, Greifswald (Dr Antje K. Belau) ; Städtisches Klinikum, Frauenklinik, Gütersloh (Dr Joachim Hulde) ; Med. Hochschule Hannover, Frauenklinik (Pr Tjoung-Won Park-Simon) ; Universitätsklinikum Hamburg-Eppendorf, Klinik u. Poliklinik f. Frauenheilkunde u. Geburtshilfe, Hamburg (Dr Sven Mahner) ; Albertinen Krankenhaus, Gynäkologie, Hamburg (Dr Uwe Herwig) ; Asklepios Klinik Nord, Campus Heidberg, Innere Medizin, Hamburg (Dr Peter Müller) ; Klinikum Hanau gGmbH, Frauenklinik (Dr Thomas Müller) ; Henriettenstiftung, Frauenklinik, Hannover (Dr Iris Schrader) ; Ev. Diakoniewerk Friederikenstift, Frauenklinik, Hannover (Dr Jörg Gade) ; Paracelsus- Klinik, Frauenklinik, Henstedt-Ulzburg (Dr Barbara Jahns); Gemeinschaftspraxis f. Gynäkologie, Hildesheim (Dr Christoph Uleer); Klinikum Itzehoe, Klinik f. Frauenheilkunde u. Geburtshilfe (Dr Britta Seifert); Universitätsklinikum, Klinik f. Frauenheilkunde u. Geburtshilfe, Jena (Pr Ingo Runnebaum); St. Vincentius Kliniken gAG, Frauenklinik, Karlsruhe (Dr Anne Stähle); Städtisches Klinikum, Frauenklinik, Karlsruhe (Pr Hans-Ulrich Ulmer); Diakonissenkrankenhaus Karlsruhe, Frauenklinik, Karlsruhe (Dr Gerhard Deutsch); Klinikum Kassel, Frauenklinik (Dr Hans Urbanczyk); Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik f. Gynäkologie u. Geburtshilfe (Dr Felix Hilpert); Klinikum der Universität zu Köln, Klinik u. Poliklinik f. Frauenheilkunde u. Geburtshilfe (Dr Joachim Schneider); Ev. Krankenhaus Köln-Kalk GmbH, Gynäkologie u. Geburtshilfe (Dr Wolfgang Maurer); Klinikum Lahr, Frauenklinik (Dr Daniel Pfisterer); Praxis Vehling-Kaiser Hämatologie/Onkologie, Landshut (Dr Ursula Vehling-Kaiser); Kreiskrankenhaus Leonberg, Frauenklinik (Dr Harald Wolf); St. Vincenz Krankenhaus, Frauenklinik, Limburg (Dr Peter Scheler); St. Elisabethen-Krankenhaus gGmbH, Zentrum Gynäkologie u. Geburtshilfe, Lörrach (Dr Brigitte Schuhmann); Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Klinik f. Frauenheilkunde u. Geburtshilfe (Dr Marc Thill); Städtisches Klinikum, Frauenklinik, Lüneburg (Dr Eric Boetel); Kath. Klinikum, St. Vincenz u. Elisabeth

3 Krankenhaus, Frauenklinik, Mainz (Pr Wolfgang Wiest); Otto-von-Guericke- Universität, Klinik f. Frauenheilkunde u. Geburtshilfe, Magdeburg (Dr Joachim Bischoff); Städtisches Klinikum, Standort Olvenstedt, Klinik f. Hämatologie/Onkologie, Magdeburg (Dr Erika Kettner); Klinikum d. Johannes Gutenberg Universität, Klinik u. Poliklinik f. Geburtshilfe u. Frauenheilkunde, Mainz (Dr Marcus Schmidt); Klinikum Mannheim gGmbH, Universitätsklinikum, Frauenklinik (Pr Marc Sütterlin); Universitätsklinikum Gießen u. Marburg GmbH, Klinik f. Gynäkologie, Gynäkologische Endokrinologie u. Onkologie , Marburg (Dr Klaus Baumann); Klinikum Großhadern, Ludwig-Maximilians-Universität, Frauenklinik, München (Dr Alexander Burges); Klinikum Innenstadt, Ludwig-Maximilians- Universität, Klinik u. Poliklinik f. Frauenheilkunde u. Geburtshilfe, München (Pr Harald Sommer); Städtisches Klinikum Neunkirchen gGmbH, Frauenklinik (Dr Georg-Peter Breitbach); Dietrich-Bonhoeffer-Klinikum, Klink f. Frauenheilkunde u. Geburtshilfe, Neubrandenburg (Katrin Borkowski); Städtisches Kliniken Neuss, Lukaskrankenhaus GmbH, Frauenklinik (Pr Hans-Georg Schnürch); Marienhaus Klinikum, St. Elisabeth Krankenhaus, Klinik f. Gynäkologie u. Geburtshilfe, Neuwied (Pr Richard Berger); Klinikum Offenbach, Klinik f. Gynäkologie u. Geburtshilfe (Dr Jens Kosse); Ortenau Klinikum, St. Josefsklinik, Gynäkologie, Offenburg (Dr Dietmar Schwörer); Asklepios Klinik, Gynäkologie u. Geburtshilfe, Bad Oldesloe (Dr Tobias Zeiser); Klinikum “Ernst-von-Bergmann“, Gynäkologie, Potsdam (Dr Friedrich Dreßler); Klinikum „Dorothea Christiane Erxleben“, Frauenklinik, Quedlinburg (Dr Sven-Thomas Graßhoff); Elblandkliniken Meißen-Radebeul GmbH & Co. KG, Frauenklinik, Radebeul (Dr Barbara Richter); Oberschwaben Klinik, Krankenhaus St. Elisabeth, Studienzentrum, Ravensburg (Dr Gerhard Fischer); Klinikum am Steinenberg, Frauenklinik, Reutlingen (Peter Krieger); Klinikum Südstadt der Hansestadt Rostock, Universitäts-Frauenklinik u. Poliklinik (Pr Bernd Gerber); Klinikum Rosenheim, Klinik f. Gynäkologie u. Geburtshilfe, Rosenheim (Pr Thomas Beck); Kreiskrankenhaus Rottweil, Frauenklinik (Dr Gerhard Bartzke); Gemeinschaftspraxis f. Frauenheilkunde u. Geburtshilfe, Salzgitter (Dr Wolfgang Dietz); Krankenhaus am Rosarium GmbH, Klinik f. Frauenheilkunde u. Geburtshilfe, Sangerhausen (Dr Cornelia Jacob); Leopoldina-Krankenhaus GmbH, Frauenklinik, Schweinfurt (Pr Michael Weigel); St. Marien-Krankenhaus, Frauenklinik, Siegen (Dr Matthias Stamm); Ev. Jung-Stilling-Krankenhaus, Frauenklinik, Siegen (Dr Volker Müller); Kreiskrankenhaus Sigmaringen, Gynäkologie (Dr Peter Krezdorn); Klinikum Schaumburg, Kreiskrankenhaus Stadthagen, Frauenklinik (Dr Johannes Feltz- Süßenbach); Robert-Bosch-Krankenhaus GmbH, Hämatologie/Onkologie, Stuttgart (Pr Walter Aulitzky); Marienhospital, Gynäkologie, Stuttgart (Dr Heinrich Stehle);

4 Kreiskrankenhaus Torgau „Johann Kentmann“ gGmbH, Gynäkologie u. Geburtshilfe (Dr Eike Simon); Hämatologisch-Onkologische Schwerpunktpraxis, Troisdorf (Dr Helmut Forstbauer); Universitäts-Frauenklinik Tübingen (Pr Erich Solomayer); Universitäts-Frauenklinik, Ulm (Pr Rolf Kreienberg); Kreiskrankenhaus Waiblingen, Klinik f. Gynäkologie u. Geburtshilfe (Edina Sulea) Marien-Hospital Witten gGmbH, Frauenklinik (Dr Felix Bartzsch); HSK, Dr. Horst Schmidt Klinik, Klinik f. Gynäkologie u. Gynäkologische Onkologie, Wiesbaden (Dr Philipp Harter); St. Josefs-Hospital, Gynäkologie u. Geburtshilfe, Wiesbaden (Pr Gerald Hoffmann); Klinikum Worms gGmbH, Frauenklinik (Pr Thomas Hitschold); Klinikum der Stadt Wolfsburg, Frauenklinik (Pr Karl Ulrich Petry); Praxis f. Hämatologie u. internistische Onkologie. Wuppertal (Dr Werner Fett); Missionsärztliche Klinik Würzburg gGmbH, Gynäkologie u. Geburtshilfe (Pr Dietmar Kranzfelder);

ANZGOG group: Philip Beale, Julie Martyn, Kim Gillies Australia: Border Medical Oncology (Dr Christopher Steer); Box Hill Hospital (Dr Geraldine Goss); Mercy Hospital for Women (Pr Danny Rischin); Calvary Mater Newcastle Hospital (Dr Tony Bonaventura); Prince of Wales Hospital (Pr Michael Friedlander); Royal Adelaide Hospital (Dr Margaret Davy); Royal Brisbane Hospital (Dr Jeffrey Goh); Royal Hobart Hospital (Dr Rob Mc Intosh); Royal North Shore Hospital (Dr Sally Baron-Hay); Royal Prince Alfred Hospital (Dr Philip Beale); Royal Women s Hospital (Pr Michael Quinn); Sir Charles Gairdner Hospital (Dr Martin BUCK); Wesley Medical Centre (Dr Paul Vasey); Lismore Base Hospital (Dr Adam Boyce); Canberra Hospital (Dr Alison Davis); Cabrini Institute (Dr Gary Richardson) New Zealand: Christchurch Hospital (Dr Bernie Fitzharris); Dunedin Hospital (Dr David Perez); Wellington Hospital (Dr Anne O Donnell)

GINECO group: Pr Eric Pujade Lauraine, Frédéric Marmion, Benedicte Votan Centre Catherine de Sienne Nantes (Dr Alain Lorholary); Institut Bergonié Bordeux (Dr Anne Floquet); Centre François Baclesse Caen (Pr Florence Joly); Centre Alexis Vautrin-Brabois Vandoeuvre-Les-Nancy (Dr Béatrice Weber); Hôpital Hôtel-Dieu Paris (Pr Eric Pujade –Lauraine); Clinique Armoricaine de Radiologie Saint-Brieuc (Dr Anne-Claire Hardy-Bessard); Hôpital Cochin Paris (Pr François Goldwasser); Hôpital Européen Georges Pompidou Paris (Dr Eric Levy); Centre Paul Papin Angers (Dr Rémy Delva); Hôpitaux Civils de Colmar Colmar (Dr Jean-Claude Barats); CRLC Val d’ Aurelle Montpellier (Dr Michel Fabro); Institut Curie Paris (Dr Paul-Henri Couttu); Centre d’Oncologie de Gentilly Nancy (Dr Dominique Spaeth); Centre Léon Bérard Lyon (Dr Isabelle Ray-Coquard); Centre René Huguenin Saint-

5 Cloud (Dr Fawzia Mefti); Hôpital Civil Strasbourg (Pr Jean-Emmanuel Kurtz); Hôpital Tenon Paris (Dr Frédéric Selle); Institut Sainte-Catherine Avignon (Dr Gaëtan De Rauglaudre); Centre René Gauducheau Saint-Herblain (Dr Dominique Berton- Rigaud); Hôpital André Mignot Le Chesnay (Dr Jean-François Geay); Centre Henri Becquerel Rouen (Dr Cécile Guillemet); Clinique Jean Bernard Le Mans (Dr Hugues Bourgeois); Centre Antoine Lacassagne Nice (Dr Véronique Mari); CHD Les Oudairies La Roche-Sur-Yon (Dr Franck Priou); Centre Claudius Regaud Toulouse (Dr Laurence Gladieff); Centre Jean Perrin Clermont-Ferrand (Dr Xavier Durando); Hôpital Saint-Louis Paris (Dr Jean-Louis Misset); Institut Gustave Roussy Villejuif (Dr Catherine Lhomme); Centre Oscar Lambret Lille (Dr Anne Lesoin); Centre Hospitalier des Diaconesses Paris (Dr Anne Plantade); Hôpital Mont-de-Marsan Mont-De- Marsan (Dr Jérôme Dauba) CHRU Lille - Hôpital Huriez Lille (Dr Mohammed Hebbar); Hôpital Foch Suresnes (Dr Mehran Khatibi); Institut Jean Godinot Remis (Pr Hervé Cure)

GEICO group: Andrés Cervantes, Federico Nepote Hospital Clínico Universitario de Valencia (Dr. Andrés Cervantes); Fundación Instituto Valenciano de Oncología(Dr. Andrés Poveda); Hospital Universitario La Fe (Dr. Ana Santaballa); Hospital Ramón y Cajal (Dr. Eva María Guerra); Hospital Universitario Vall de Hebrón (Dr. José María del Campo); Instituto Catalán de Oncología Durán i Reynals (Dr. Beatriz Pardo Burdalo); Hospital de la Santa Creu i Sant Pau (Dr. Belén Ojeda); Corporació Sanitaria Clinic de Barcelona (Dr. Pere Gascón); Hospital Son Llatzer (Dr. Isabel Bover); Hospital Marqués de Valdecilla (Dr. Ana de Juan); Hospital Miguel Servet (Dr. Ana Herrero); Insitituto Catalán de Oncología Girona (Dr. Miguel Beltrán); Hospital Universitario la Paz (Dr. Andrés Redondo)

MRC/NCRI group: Tim Perren, Ann Marie Swart, Emma Hainsworth, Christina Howitt, Julie Bakobaki, Cybil Kwakye, Wendi Qian, Clare Griffin St James University Hospital, Leeds (Dr Timothy Perren); Christie Hospital, Manchester (Dr Jurjees Hasan); Clatterbridge Centre for Oncology, Liverpool (Dr John Green); Clinical Trials Unit, Derriford Hospital (Dr Dennis Yiannakis); Mount Vernon Hospital (Pr Gordon Rustin); Queen Elizabeth Hospital, Gateshead (Dr Raj Naik); Queen Elizabeth The Queen Mother Hospital (Dr Justin Waters); Queen Alexandra Hospital, Portsmouth (Dr Yoodhivir Nagar); University College London Hospital (UCLH), Cancer Clinical Trials Unit (Pr Jonathan Ledermann); Weston Park

6 Hospital (Dr Simon Pledge); Kent Oncology Centre, Maidstone Hospital (Dr Jeff Summers); St Bartholomew’s Hospital (Pr Iain McNeish); Southampton General Hospital (Dr Sajid Durrani); Royal Surrey County Hospital (Dr Sharadah Essapen); Wexham Park Hospital (Dr Marcia Hall); Churchill Hospital, Oxford, (Pr Bass Hassan); Castle Hill Hospital (Dr Penelope O Neill); Queens Hospital (Burton) (Dr Mojca Persic); St Georges Hospital (Dr Fiona Lofts); Sir Bobby Robson Cancer Trials Research Centre, Newcastle (Dr Graham Dark); Yeovil District Hospital (Dr Geoffrey Sparrow); New Cross Hospital (Dr Rozenn Allerton); Ninewells Hospital, Dundee (Dr Michelle Ferguson); The Ipswich Hospital (Dr Jamey Morgan); Nottingham City Hospital (Dr Steven Chan); Cheltenham General Hospital (Dr Radi Counsell); Royal Derby Hospital (Dr Mojca Persic); University Hospital Coventry and Warwickshire (Dr Clive Irwin); Royal Marsden Hospital (London & Sutton) (Pr Martin Gore); Broomfield Hospital (Dr Saad Tahir); Hammersmith Hospital (Dr Sarah Blagden); James Cook University Hospital (Dr Sath Gokul); Poole Hospital (Dr Richard Osbourne); North Devon District Hospital (Dr Mark Napier); Great Western Hospital (Dr Amanda Horne); Royal Cornwall Hospital (Dr Nigel Bailey); Aberdeen Royal Infirmary (Dr Radha Todd); Guys Hospital (Dr Peter Harper); Huddersfield Royal Infirmary (Dr Barbara Crosse); Addenbrookes Hospital (Dr Helena Earl); City Hospital (Dr Ahmed El-Modir); Beatson Oncology Centre (Dr Nick Reed); Leicester Royal Infirmary (Dr Paul Symonds); Velindre Hospital (Dr Malcolm Adams); Queens Hospital, Romford (Dr Mary Quigley); Essex County Hospital (Dr Alan Lamont); Edinburgh Cancer Centre (Dr Charlie Gourley)

NSGO group: Gunnar Kristensen, Gerda Anderson Denmark: Aalborg University Hospital (Dr Bente Lund); Odense University Hospital (Dt Mansoor Mirza; Pr Jørn Herrstedt); Herlev University Hospital (Pr Jørn Herrstedt ,Dr Hanne Havsteen); Regionhospitalet, Herning (Dr Nina Keldsen); Rigshospitalet , Copenhagen University Hospital (Dr Svend Aage Engelholm). Finland: Oulu University Hospital (Dr Ulla Puistola); Turku University Hospital (Dr Seija Grenman); Helsinki University Central Hospital (Dr Arto Leminen). Sweden:Karolinska University Hospital, Stockholm (Dr Bengt Tholander); Lindköping University Hospital (Dr Per Rosenberg); Örebro University Hospital (Pr Bengt Sorbe); Lund University Hospital (Dr Kjell Bergfeldt). Norway: The Norwegian Radium Hospital Oslo (Dr Gunnar Kristensen); Haukeland University Hospital, Bergen (Dr Harald Helland); St Olavs Hospital Trondheim (Dr Ingrid Baasland); Stavanger University Hospital (Dr Bent Fiane).

7 NCIC CTG group: Ralph Meyer, Monica Bacon, Brenda Evans, Mark Carey Dr. H. Bliss Murphy Cancer Centre, NL (Dr Patti Power); QEII Centre for Clinical Research, Halifax (Dr Robert Grimshaw); Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke (Dr Paul Bessette); CHUQ - Hotel-Dieu de Quebec, Quebec (Dr Marie Plante); McGill University - Jewish General Hospital, Montreal (Dr Walter Gotlieb); Hopital Notre-Dame, Montreal (Dr Diane Provencher); The Moncton Hospital, Moncton (Dr Asif Shaikh); Juravinski Cancer Centre, Hamilton (Dr Laurie Elit); Univ. Health Network-OCI/Princess Margaret Hospital, Toronto (Dr Amit Oza); Credit Valley Hospital, Mississauga (Dr Leonard Kaizer); London Regional Cancer Program, East London (Dr Monique Bertrand); Allain Blair Cancer Centre, SK Canada (Dr Haji Chalchal); Cancer Care Manitoba (Dr Robert Lotocki); Tom Baker Cancer Centre N.W.Calgary (Dr Prafull GHATAGE); BCCA - Vancouver Cancer Centre, Vancouver (Dr Anna Tinker); BC Cancer Agency - Fraser Valley Centre (Dr Lee Ann Martin); BCCA-Cancer Ctr. Southern Interior, Kelowna (Dr Susan Ellard); Algoma District Program Sault Area Hospital Ontario (Dr Silvana Spadafora); Cross Cancer Institute, Edmonton (Dr Valerie Capstick).

Trial Management Group : T Perren, A Oza, AM Swart, W Qian, C Griffin, M Parmar, L Farrelly, E Hainsworth, C Kwakye, N Thompson, C Irl, G Jayson, D Stark, M Sculpher, J Pfisterer, G Elser, A Kruger, P Beale, J Martyn, K Gillies, A Cervantes, F Nepote; E Pujade Lauraine, F Marmion, B Votan, M Carey, M Bacon, R Meyer, G Kristensen, G Andersen MRC Clinical Trials Unit Coordination: E Hainsworth, C Kwakye, L Farrelly, AM Swart, W Qian, C Griffin Trial Physicians: F Collinson, S Sim, F al-Terkait Statistical analysis : W Qian, C Griffin, AM Swart, M Parmar. Independent Data Monitoring Committee : R Coleman, W Sauerbrei, U Menon, R Buckstein Trial Steering Committee : C Parker (from Nov 2008), R Rudd, J Whelan (from Nov 2009), D Fink, M Mason (until Nov 2009), P Johnson (until Nov 2008)

8 METHODS

Trial conduct

ICON7 trial is led by the UK Medical Research Council Clinical Trials Unit (MRC CTU). The MRC is the sponsor of the trial. Roche provided bevacizumab and research grants to the MRC. ICON7 was designed by members of the Trial Management Group (TMG) who reviewed and approved the protocol and oversee the ongoing conduct of the trial. Roche members on the TMG contributed to study design and conduct. Data management is conducted by MRC CTU and independent contract research organisations (Covance for all groups except for AGO OVAR, which is managed by Schantl Pharma Services). Roche paid for both independent CROs whose activity was coordinated by MRC CTU through the Trial Management Team. All case report forms (CRF) are 100% source document validated and collected by monitors from Covance or Schantl Pharma. Data collected in the CRFs are entered by Covance. Data transfers from Covance to the MRC CTU are performed regularly. Roche access to ICON7 data is only possible via the MRC CTU. The Serious Adverse Events (SAE) data base, oversight and clinical review of SAE and other safety assessments as well as onward reporting to investigators and authorities are managed by the MRC CTU. The interactive phone and web system for randomisation was provided by S-Clinica. The Independent Data Monitoring Committee regularly reviewed confidential trial data and made recommendations regarding the continuation of the trial to the international Trial Steering Committee. Analysis, preparation of the manuscript, and interpretation were performed independently from the funders and the sponsor (MRC). The writing committee had full access to all study data and had responsibility for the decision to submit for publication. There was no payment by Roche for trial analysis or manuscript writing.

Outcome measures and statistical considerations There was no independent central radiologists’ panel review on progression in ICON7. However, detailed reporting guidelines on tumor assessment have been applied to all centres. The measurements of all lesions according to the RECIST criteria have been collected in the CRFs, which are 100% source data validated. All tumor assessments reported were computationally checked and reviewed by the Chief investigator without knowing the treatment allocation. Queries were raised with individual investigator where necessary.

9

Response and Progression Definitions: Summary of RECIST Guidelines Evaluation of target lesions

Complete Response (CR): Disappearance of all target lesions

Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD

Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started

Evaluation of non-target lesions

Complete Response (CR): Disappearance of all non-target lesions and normalisation of tumour marker level. No evidence of new lesions.

Incomplete Response/ Persistence of one or more non-target lesion(s) or/and maintenance of tumour marker level above the normal limits

Progressive Disease (PD): Unequivocal progression of existing non-target lesions

Biological progression-free interval (PFI bio ) or CA125 progression was calculated from date of randomisation to date of the first CA125 progression 21 or first RECIST progression whichever occurred first ; patients who had died from any cause without CA125/RECIST progression were censored at the date of death; patients alive without CA125/RECIST progression were censored at the date of last CA125 assessment.

RESULTS Response 520 (263 standard, 257 bevacizumab) patients had measurable disease at baseline and received at least one cycle of protocol treatment. Response assessments were unavailable for 23 of these patients. The best overall response was 48% and (67%)

10 in the standard and bevacizumab arms, respectively, a difference of 19% (95% CI, 11% to 28%; p <0.0001) (Table 2S)

PFS sensitivity analyses Sensitivity analyses censoring at last radiological tumor assessment gave similar conclusions for PFS (Fig. 1S a); HR, 0.79; 95% CI, 0.68 to 0.91; p of log-rank test = 0.0010 (non-proportional-hazards detected); restricted mean difference of 1.2 months from 17.8 (standard) to 19.0 (bevacizumab) estimated at 30 months from randomization).

Biological/CA125 progression Isolated CA125 progression occurred in 254 women (117 standard, 137 bevacizumab). 767 women (395 standard, 372 bevacizumab) had CA125 and/or

RECIST progression (PFI bio ). Hazard ratio was 0.83 (95% CI, 0.72 to 0.96; p=0.0093; Fig. 1S b) with medians 16.1 (standard) and 18.9 months (bevacizumab). The (restricted) mean difference was 1.2 months (95% CI, -0.16 to 2.61) from 19.9 (standard) to 21.1 (bevacizumab) months.

Exploratory analyses Exploratory analyses of potential interactions are summarised in Fig 2S. A larger benefit for bevacizumab in women with worse ECOG PS is suggested (interaction p=0.022).

Overall Survival and Quality of life

Overall survival At the time of the protocol designated PFS analysis a total of 241 women had died: 231 (96%) (128 standard, 103 bevacizumab) disease related, 5 treatment related (see safety section), 5 other causes not treatment related and without progression or underlying cause of death from ovarian caner (1 breast cancer, 1 renal failure in standard; 1 pancreatic cancer, 1 metastases to meninges and 1 gastrointestinal haemorrhage in bevacizumab). Comparison of Kaplan-Meier curves gave a HR of 0.81 (95% CI 0.63 to 1.04) with a p value of 0.098 (unstratified log-rank test). At one year the difference in OS is 2.2% (92.7% standard, 94.9% bevacizumab), 95% CI for difference 0.03% to 4.4%.

Quality of life

11 Methods

Health related quality of life (QL) was reported by patients using the EORTC QLQc- 30 and OV28 questionnaires (http://groups.eortc.be/qol/ questionnaires_qlqc30.htm) before each chemotherapy cycle, 6 weekly for the remainder of year 1, then at 15, 18, 21 and 24 months or until progression, and at 36 months from randomisation. The primary QL outcome was global QL, on a translated scale from 0 (worst) to 100 (best). The QL analysis plan (made in 2007) stated a minimum clinically significant difference between groups of 10 points on the Global QL scale. 1-3 Comprehensive contemporary guidelines using a meta-analysis of published data and clinical interpretation to define minimum clinically significant between group differences indicate, for the EORTC QLQ C-30 Global QL scale, a trivial difference is 0 to 4 points, a small difference is 4-7 points, and a moderate difference is 10-15 points. 4

Results 89% of protocol QL data was available for the control arm and 92% for the intervention arm at baseline. Both arms showed improvement in global QL over time (Fig. 3S). No evidence of differences between arms was observed until the end of the chemotherapy. Table 3S indicates that global QL was marginally better in the control arm at the end of chemotherapy (week 18) and at the completion of the active treatment follow-up (end of maintenance bevacizumab in week 54), but there was no clinically significant difference between arms in the change in global QL from baseline.

Discussion Both arms showed improvement in global QL over time. Differences in global QL between arms are consistently present but not considered clinically significant (defined as <10 points).

Updated Analyses: Overall and Progression-free Survival

When ICON7 was designed in 2005, the plan was to use PFS data from ICON7 to support a regulatory submission for the use of bevacizumab for the treatment of first- line ovarian cancer if the primary regulatory outcome of PFS was positive. The regulatory landscape has evolved in both the European Union and in the United States. Regulatory agencies now require interim OS data to be submitted with PFS data in order to assess the risk-benefit of the therapy to the patient. The analyses of

12 immature OS data were therefore performed after a request from regulators via Roche. This request was approved by the TMG, IDMC and TSC.

The understanding of the timing and magnitude of progression and death events according to randomized treatment was explored by the hazard rate functions for PFS and OS (probability of a PFS or OS event over time).

For PFS the peak hazard rate occurred at around 10 months in the standard, and 20 months in the bevacizumab arm, and was similar in magnitude in the two arms (Fig. 5S a). This confirms that the addition of bevacizumab to standard treatment did significantly delay disease progression. However ultimately bevacizumab was not able to prevent progression and the PFS event rates in both arms converged to reach a similar rate around 30 months and thereafter. For the high-risk of progression population (Fig. 5S b), the relative pattern in both arms was very similar to that already described for the whole trial population except they do not appear to converge in the same way, although it should be noted that the number of patients at risk after 30 months is small.

The OS data are immature. The hazard for risk of OS event rate increased with time in both arms and it appears consistently higher in the standard arm than bevacizumab arm, particularly in patient at a high-risk of progression (Fig. 5S c and d). The parallel hazard function curves reflect the proportional-hazards assumptions were not rejected in the OS analyses.

13 References

1. King, M.T. (1996). The interpretation of scores from the EORTC quality of life questionnaire QLQ-C30. Quality of Life Research, 5, 555-567.

2. Osoba, D. et al (1998). Interpreting the significance of changes in health-related quality of life scores. Journal of Clinical Oncology, 16, 139-144.

3. Guidelines for assessing quality of life in EORTC clinical trials. 2002. http://groups.eortc.be/qol/downloads/200203guidelines_qol.pdf

14 Supplementary Tables and Figures

Table 1S. Baseline characteristics

Characteristic Standard (N=764) Bevacizumab (N=764) Age - years Median (range) 57 (18-81) 57 (24-82) Race - n (%) White 737 (96) 730 (96) Asian/Black/Other 27 (4) 34 (4) ECOG PS - n (%) 0 358 (47) 334 (45) 1 354 (47) 366 (49) 2 43 (6) 45 (6) Origin of cancer - n (%) Ovary (epithelial) 667 (87) 673 (88) Fallopian tube 29 (4) 27 (4) Primary peritoneal 56 (7) 50 (6) Multiple sites 12 (2) 14 (2) Histology - n (%) Serous 529 (69) 525 (69) Mucinous 15 (2) 19 (2) Endometrioid 57 (7) 60 (8) Clear cell 60 (8) 67 (9) Mixed 48 (6) 40 (5) Other 55 (7) 53 (7) FIGO stage - n (%) I/IIA 75 (10) 67 (9) IIB/IIC 70 (9) 70 (9) III 14 (2) 18 (2) IIIA 32 (4) 22 (3) IIIB 44 (6) 45 (6) IIIC 432 (57) 438 (57) IV 97 (12) 104 (13) Grade - n (%) Grade 1 – well 56 (7) 41 (5) Grade 2 – moderately 142 (19) 175 (23) Grade 3 – poorly 556 (74) 538 (71) Unknown 10 10 Debulking surgery - n (%) No (inoperable) 17 (2) 13 (2) Yes 747 (98) 751 (98) >1cm residual disease 195 (26) 192 (26) ≤1cm residual disease 552 (74) 559 (74) High-risk of progression (FIGO III>1cm/ IV debulking) – n(%) No 530 (69) 533 (70) Yes 234 (31) 231 (30) GCIG group - n (%) ANZGOG (Australia & New Zealand) 37 (5) 39 (5) AGO-OVAR (Germany) 266 (35) 267 (35) GEICO (Spain) 19 (3) 22 (3) GINECO (France) 98 (13) 98 (13) MRC/NCRI (UK) 187 (24) 188 (25) NCIC CTG (Canada) 61 (8) 57 (7) NSGO (Denmark/Finland/Norway/Sweden) 96 (12) 93 (12) FIGO stage and surgery - n (%) FIGO I-III & residual diseases ≤1cm 508 (66) 518 (68) FIGO I-III & residual disease >1cm 150 (20) 140 (18) FIGO III inoperable or IV 106 (14) 106 (14) Intent to start chemotherapy following surgery - n (%) ≤4 weeks 328 (43) 326 (43) >4 weeks 436 (57) 438 (57)

15

Table 2S. Best overall response for patients with measurable disease at baseline (assessed before cycle 2) and received at least one cycle of protocol treatment

Standard (N=263) Bevacizumab (N=257) Response – n (%) Responders (CR/PR) 118 (48) 168 (67) Non-responders (SD/PD) 129 (52) 82 (33) Unknown 16 7 95% CI for response rate (CR/PR) (%) 41.5-54.0 61.3-73.0 Difference in response rate (%) 19.4 95% CI for difference in response rates 10.9-27.9 P value of Chi-squared test <0.0001

Complete response (CR) (%) 4.8 15.2 95% CI for CR rate (%) 2.2-7.5 10.7-19.7 Partial response (PR) (%) 42.9 52.0 95% CI for PR rate (%) 36.7-49.1 45.8-58.2 Stable disease (SD) (%) 45.7 29.2 95% CI for SD rate (%) 39.5-52.0 23.5-34.8 Progressive disease (PD) (%) 6.5 3.6 95% CI for PD rate (%) 3.4-9.5 1.3-5.9

Table 3S: Bivariate Analyses of Quality-of-Life Baseline 18 weeks 54 weeks 76 weeks Global QL $ 55.7/53.6 71.1/66.9* 74.5/69.5* 73.7/72.6 (Standard/bevacizumab) Φ Global QL change from baseline - 15.7/12.7* 16.8/14.3 16/16 (Standard/Bevacizumab)

$A priori a difference of 10 points was defined as clinically significant 1,3 . Differences of 4-7 points are currently interpreted by clinicians as ‘small’. 4 Φ Individual changes in global QL from baseline of 5-10 points are noticed by patients as small. 2,

*statistically significant at p<0.01

16 Figure 1S. Kaplan-Meier plots for progression-free survival censored at last radiological tumor assessment and PFI bio

a. Progression-free survival by treatment arm b. PFI bio (CA125/RECIST/clinical progression- (sensitivity analysis censoring at last free interval) by treatment arm radiological tumor assessment)

Figure 2S. Forest and Kaplan-Meier plots of progression-free survival in subgroups a. Age

b. ECOG PS

17 c. Origin of cancer

d. Grade

e. FIGO stage

f. Outcome of surgery

18 g. High-risk of progression (FIGO III >1cm residual/IV debulking)

h. Baseline CA125

i. FIGO stage and outcome of surgery

j. Intent to start chemotherapy within 28 days

19 Figure 3S. Global health status score over time (a higher score indicates better Quality of Life)

20 Figure 4S. Updated progression-free survival and overall survival by risk group and treatment

a. Test of Interaction between risk group and treatment b. Updated progression-free survival by risk groups arm on updated progression-free survival

c. Test of interaction between risk group and treatment d. Updated overall survival by risk group arm on updated overall survival

21

Figure 5S. Hazard functions for updated progression-free survival and overall survival a. Progression-free survival hazard function b. Progression-free survival hazard function by risk group

c. Overall survival hazard function d. Overall survival hazard function by risk group

22