1. A randomized, phase III study gemcitabine-paclitaxel-carboplatin (TCG) versus paclitaxel-carboplatin (TC) as first-line treatment of ovarian cancer: survival of FIGO stage I-IIA patients Nordic Society of Gynecologic Oncology () 1. Nordic Society of Gynecologic Oncology (NSGO) Denmark, Finland, Norway, Sweden Denmark, Finland, Norway, Sweden Arbeitsgemeinschaft Gynäkologische Onkologie 2. Arbeitsgemeinschaft Gynäkologische Onkologie () Studiengruppe Ovarialkarzinom (AGO) Studiengruppe Ovarialkarzinom Groupe d’Investigateurs Nationaux pour l’Etude 3. Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (), France des Cancers Ovariens (GINECO), France a GCIG Intergroup Study a GCIG Intergroup Study Jørn Herrstedt 1, Jens Huober 2, Franck Priou 3, Hans-Helge Müller 2, Mark Baekelandt 1, Christian Kurzeder 2, Jacobus Pfisterer 2, Anne Stähle 2, Isabelle Ray-Coquard 3, Andreas du Bois 2 (PI).

2. ADDING A THIRD CYTOSTATIC DRUG TO TC RESULT Triplet combination Gemcitabine AGO-GINECO-NSGO GOG-ANZGOG-MRC Epirubicin 1,2 AGO-GINECO NSGO-EORTC-NCIC-GEICO Peg.-lip. Dox 3 GOG-ANZGOG-MRC Sequential doublet Gemcitabine 3 GOG-ANZGOG-MRC Topotecan 3,4 NCIC-EORTC-GEICO GOG-ANZGOG-MRC Sequential single Topotecan 5 AGO-GINECO negative negative ? negative 1. du Bois A et al. J Clin Oncol 2006;24:1127-35. 2. Kristensen GB et al. J Clin Oncol 2004;22 (suppl):A5003 3. Bookman MA et al. J Clin Oncol 2009;27:1419-1425. 4. Hoskins PJ et al. J Clin Oncol 2008;26(suppl):LBA5505 5. Pfisterer J et al. JNCI 2006;98;1036-45.

3. RANDOMISATIONRANDOMISATION q 21 x 6 Paclitaxel 175 mg/m² d1 Carboplatin AUC 5 d1 q 21 x 6 Gemcitabine800 mg/m²d1+8 Paclitaxel 175 mg/m² d1 Carboplatin AUC 5 d1 STUDY DESIGN

4. Center Interval debulking surgery planned (yes/no) FIGO Stage and Tumor Residuals Stratum 1: FIGO IA/B G3 or IC – IIA Stratum 2:FIGO IIB - IIIC + Tumor residual < 1 cmStratum 2:FIGO IIB - IIIC + Tumor residual < 1 cm Stratum 3: FIGO IV or Tumor residual > 1 cmStratum 3: FIGO IV or Tumor residual > 1 cm STRATIFICATION

5. 1st ENDPOINTOverall Survival in stratum 2+3 2nd ENDPOINTSPFS in stratum 2+3 PFS and OS in stratum 1 PFS and OS in all strata Response Rate Toxicity (NCI/CTC grade 3/4) EORTC QLQ-C 30, QLQ-OV 28 ENDPOINTS

6. PATIENT CHARACTERISTICS

7. RECRUITMENT AND COHORTS Number of patients Recruitment 1742 Analysed for primary endpoint in stratum 2 + 3 1567 Analysed for secondary end- point in stratum 1 175

8. PATIENT CHARACTERISTICS (%) ALL PATIENTS TC N = 882 TCG N = 860 AGE (mean years)58.058.2 PS (ECOG 0/1)91.592.3 STAGE I-IIA (FIGO) IIB-III IV 10.8 73.0 16.2 10.5 73.1 16.4

9. PATIENT CHARACTERISTICS (%) STRATUM 1 TC N = 89 TCG N = 86 AGE (mean years)56.155.9 PS (ECOG 0/1)95.598.8 STAGE IA (FIGO) IB IC IIA 12.4 2.3 56.2 20.2 13.9 1.2 60.5 19.8

10. PATIENT CHARACTERISTICS (%) ALL PATIENTS TC N = 882 TCG N = 860 HISTOLOGY SEROUS ENDOMETROID MUCINOUS 73.7 9.1 4.2 75.1 7.7 3.8 TUMOR POST OP. UNKNOWN MICRO OR 0 CM 0.1-1 CM > 1 CM 9.0 39.2 25.3 26.5 9.0 39.0 24.1 28.0

11. STRATUM 1 TC N = 89 TCG N = 86 HISTOLOGY SEROUS ENDOMETROID MUCINOUS 55.1 16.9 9.0 54.7 20.9 9.3 TUMOR POST OP. UNKNOWN MICRO OR 0 CM 0.1-1 CM > 1 CM 3.3 89.9 4.5 2.3 1.1 95.4 1.2 2.3 PATIENT CHARACTERISTICS (%)

12. FEASIBILITY ALL PATIENTSTC N = 882 TCG N = 860 At least 1 course 874 850 > 6 courses 88.0% 87.2% < 6 courses12.0%12.8%

13. FEASIBILITY STRATUM 1 TC N = 89 TCG N = 86 At least 1 course 89 84 > 6 courses 93.3% 86.9% < 6 courses 6.7%13.1%

14. DOSE DEVIATIONS (%) ALL PATIENTS TC N = 882 TCG N = 860 Interval 28+ days 7.5 11.6 P < 0.0001 > 1 dose reduction on day 1 1.93.4 P < 0.0001 Dose omission gemcitabine day 8 ---46.8

15. DOSE DEVIATIONS (%) STRATUM 1 TC N = 89 TCG N = 86 Interval 28+ days 5.7 8.0 P = 0.1834 > 1 dose reduction on day 1 1.01.9 P < 0.0001 Dose omission gemcitabine day 8 ---40.6

16. RESULTS STRATUM 1

17. PROGRESSION-FREE SURVIVAL (RECIST & CA125) BY THERAPY: STRATUM 1 (FIGO I-IIA) Patients at risk TC89 pts. / 21 evts. median - mos. median - mos. TCG86 pts. / 17 evts. median - mos. median - mos. P r o b a b i l i t y [ months ] HR = 0.85 [95% CI: 0.45-1.61] p = 0.6199 89878279756762574629175100 86797675726758514633154200

18. OVERALL SURVIVAL BY THERAPY STRATUM 1 (FIGO I-IIA) 89888581797573695641236100 86807978757267585238194200 Patients at risk TC89 pts. / 5 evts. median - mos. TCG86 pts. / 10 evts. median - mos. P r o b a b i l i t y [ months ] HR = 2.19 [95% CI: 0.75-6.41] p = 0.1419

19. RESULTS STRATUM 2 +3

20. PROGRESSION-FREE SURVIVAL (RECIST & CA125) BY THERAPY: STRATUM 2+3 (FIGO IIB-IV) [ months ] 7936995113512702251911529543142 7746854833072281851551167236122 Patients at risk HR = 1.17 [95% CI: 1.05-1.31] Logrank test: p = 0.0065 TC793 pts. / 588 evts. median 16.0 [14.9-17.4] mos. median 16.0 [14.9-17.4] mos. TCG774 pts. / 629 evts. median 14.7 [14.0-15.9] mos. median 14.7 [14.0-15.9] mos.

21. OVERALL SURVIVAL BY THERAPY STRATUM 2+3 (FIGO IIB-IV) P r o b a b i l i t y [ months ] TC793 pts. / 401 evts. median 48.9 [43.1-51.2] mos. median 48.9 [43.1-51.2] mos. TCG774 pts. / 404 evts. median 45.8 [40.0-49.5] mos. median 45.8 [40.0-49.5] mos. HR = 1.03 [95% CI: 0.90-1.18] p = 0.6955 Patients at risk 79375070563855748942033822689315 77474069362855448441132220887285

22. TOXICITY ALL PATIENTS

23. Anemia (5168/5067) 1.04.9<.0001 Thrombocytopenia (5168/5068) 1.111.4<.0001 Leukopenia (5168/5067) 9.328.3<.0001 Neutropenia (4905/4882) 32.345.2<.0001 Febrile Neutropenia (5115/5003) 0.41.2<.0001 Inf. without Neutropenia (5122/5009) 0.70.9 0.2705 G-CSF 5.212.5<.0001 EPO 5.612.3<.0001 Antibiotics 3.25.3<.0001 Blood Products 2.39.3<.0001 HEMATOLOGICAL TOXICITIES Grade 3/4 WORST OF ALL COURSES Toxicity (N TC /N TCG ) TC TCG p-value

24. Fatigue (865/840) 7.110.5.0125 Nausea (865/841) 3.24.3.2579 Constipation (865/841) 4.56.5.0672 Neuropathy-motor (865/840) 2.23.0.3139 Neuropathy-sensory (865/840) 6.57.4.4655 Athralgia (865/840) 4.74.1.4871 Myalgia (865/840) 4.73.6.2281 Pain (865/842) 6.16.1.9475 Alopecia grade 2 (859/827) 93.892.9.4330 NON-HEMATOLOGICAL TOXICITIES Grade 3/4 WORST OF ALL COURSES Toxicity (N TC /N TCG ) TC TCG p-value

25. ADDING A THIRD CYTOSTATIC DRUG TO TC RESULT Triplet combination Gemcitabine 3 AGO-GINECO-NSGO GOG-ANZGOG-MRC Epirubicin 1,2 AGO-GINECO NSGO-EORTC-NCIC-GEICO Peg.-lip. Dox 3 GOG-ANZGOG-MRC Sequential doublet Gemcitabine 3 GOG-ANZGOG-MRC Topotecan 3,4 NCIC-EORTC-GEICO GOG-ANZGOG-MRC Sequential single Topotecan 5 AGO-GINECO negative negative 1. du Bois A et al. J Clin Oncol 2006;24:1127-35. 2. Kristensen GB et al. J Clin Oncol 2004;22(suppl)A5003. 3. Bookman MA et al. J Clin Oncol 2009;27:1419-1425. 4. Hoskins PJ et al. J Clin Oncol 2008;26(suppl)LBA5505. 5. Pfisterer J et al. JNCI 2006;98;1036-45.

26. AGO-OVAR Coordinating Group A. Belau(Greifswald) A. Burges(München) U. Canzler(Dresden) A. du Bois - PI (Wiesbaden) M. Gropp(Düsseldorf) P. Harter(Wiesbaden) V. Heilmann(Ulm) F. Hilpert(Kiel) J. Huober(Tübingen) Ch. Jackisch(Marburg) R. Kimmig(Essen) S. Loibl(Frankfurt) H.-J. Lück(Hannover) W. Meier (Düsseldorf) J. Pfisterer(Kiel) B. Richter(Radebeul) B. Schmalfeldt(München) W. Schröder (Bremen) J. Sehouli(Berlin) A. Stähle(Karlsruhe) U. Wagner(Marburg) K. Wollschlaeger(Magdeburg) GINECO A.-C. Hardy-Besard(Saint-Brieuc) F. Joly(Caen) B. Weber(Nancy) E. Lévy(Paris) F. Priou(La-Roch-Sur-Yon) J.-P. Guastalla(Lyon) J. Plaza(Montbéliard) D. Berton-Rigaud(Nantes) S. Abadie-Lacourtoisie(Angers) C. Platini(Metz) F. Mefti(Saint-Cloud) K. Yakendji(Créteil) H. Bourgeois(Poitiers) L. Bastit(Rouen) P. Chinet-Charrot(Rouen) E. Pujade-Lauraine –PI (Paris) Statistics and Data managementStudy OfficeMonitoring AGO-OVARH.-H. MüllerG. Elser, C. AckermannP. Schantl, S. Oxe, S. Bigus M. Hahmann, B. Aminossadati A. Igler, U. WeitzelF. Gottwald, S. Lang, H. Lüers K. Friccius, B. Saile, C. Renné, GINECOD. Paraiso, N. Le FurC. Dumont-PuléoM. Bekhiti, S. Lahmar NSGOR. DePont Christensen G. AndersenC. Ramstad, L. Rosquist, H. Holst Supported by Eli Lilly and Company NSGO J. Herrstedt - PI (Herlev) G. Kristensen (Oslo) J. Kaern (Oslo) T. Skeie-Jensen(Oslo) E. Lorenz(Trondheim) K. Bertelsen(Odense) M. Mirza(Odense) J. Lindegaard(Aarhus) H. Havsteen(Aarhus) E. Aavall-Lundqvist (Stockholm) B. Tholander(Stockholm) M. Kalling(Lund) T. Høgberg(Linkøping) K. Boman(Umeaa) J. Mâenpââ(Tampere) S. Jelic(Beograd) Ljiljana Stamatovic (Beograd) I. Takac(Maribor ) Acknowledgement: Patients, all centres, IDMSC, and…