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Hepatocellular carcinoma BCLCC B or C PS 0-1 CHILD A Pl > 90 000/mm³ Bilirubin Total ≤ 1.5N

Sorafenib alone or in combination with Gemcitabine and oxaliplatin (GEMOX) in the first-line treatment of advanced hepatocellular carcinoma: final analysis of the randomized phase II GoNext trial (PRODIGE 10 ).

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Hepatocellular carcinoma BCLCC B or C PS 0-1 CHILD A Pl > 90 000/mm³ Bilirubin Total ≤ 1.5N

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  1. Sorafenib alone or in combination with Gemcitabine and oxaliplatin (GEMOX) in the first-line treatment of advanced hepatocellular carcinoma: final analysis of the randomized phase II GoNexttrial (PRODIGE 10 ) E Assenat (1-3), V Boige (2), S Thezenas (3), GP Pageaux (1), JM Peron (4), Y Becouarn (5), JF Seitz (6), P Merle (7), JF Blanc (8), O Bouche (9), M Ramdani(10), C Fiess (3), M Ychou (3) (1) CHU Montpellier St Eloi; (2) IGR Villejuif ; (3) ICM Montpellier; (4) Toulouse; (5) Bordeaux Bergonié; (6) Marseille; (7) Lyon ; (8) CHU Bordeaux St Andre ; (9) Reims; (10) Beziers.

  2. Phase II Randomized 2 stagedstudy Hepatocellular carcinoma BCLCC B or C PS 0-1 CHILD A Pl > 90 000/mm³ Bilirubin Total ≤ 1.5N Sorafenib 400mg BID n= 44 R Sorafenib 400mg BID + GEMOX (D1-D14) n= 39 Gemcitabine 1000mg/m² L-OHP 100mg/m² Dec 2008 to Oct 201, 10 French centers N = 94 patients screened Screen Failure: (Refusal (2); 2nd Cancer (1); Bilirubin Total <1.5N(2); Low platelet < 90 000(2); Child B (2); Renal failure before treatment(1), Death before treatment (1)) • Stratification • CLIP score 0-1 vs 2-3 • Cirrhosis vs non cirrhosis

  3. Phase II Randomized 2 stagedstudy Hepatocellular carcinoma BCLCC B or C PS 0-1 CHILD A Pl > 90 000/mm³ Bilirubin Total ≤ 1.5N Sorafenib 400mg BID n= 44 R Sorafenib 400mg BID + GEMOX (D1-D14) n= 39 Gemcitabine 1000mg/m² L-OHP 100mg/m² Principal Endpoint: Progression Free survival (PFS) at 4 months N= 78 valuable patients (39 by arm); ≥ 24 patients/ 39 non progressive at 4 months in experimental arm H0<50%; H1≥70%; α=10%; 1-β=90% Tumor assesment / 8 weeks. RECIST 1.0 • Secondary End points: • Response Rate and Disease Control Rate (RECIST 1.0);Toxicity; PFS; OS • m RECIST assessment (central review); Pharmacocinetic (Sorafenib); Blood/Tumor VEGF signallingpathwayanalysis

  4. Patient population (Baseline)

  5. TreatmentCompliance Sorafenib Gemox

  6. Toxicity Profile/patient • Comparable Severe toxicity (Global, Asthenia, Diarrhea…) • More Haematological, Sensitive neuropathy in Sorafenib + GEMOX arm • More HFS in Sorafenib alone arm • One toxic death in Sorafenib alone arm (Pneumocystis)

  7. TreatmentEfficacy(Evaluable Population RECIST 1.0) Principal Endpoint: Progression Free survival (PFS) at 4 months N= 78 valuable patients (39 by arm); ≥ 24 patients/ 39 non progressive at 4 months in experimental arm

  8. Treatment Efficacy 2nd Line Treatment • In Sorafenib alone arm: 24 Patients (55%) 2nd Line treatment : • Gemox (n= 10); Brivanib (BRISK PS study) (n= 6); Everolimus (EVOLVE study) (n=4); TACE(n=2), RFA (n=1), Radiotherapy (n=1) • In Sorafenib + gemox arm: 15 patients (38%) 2nd Line treatment: • Adriamycin (n= 5); 5FU (n=2); Etoposide CDDP(n=1); Irinotecan (n=1); Sorafenib (n=4); Everolimus (EVOLVE study) (n= 2)

  9. Progression Free Survival Sorafenib : 4.6 mois [IC90% : 4-6] Sorafenib+ Gemox : 6.2 mois [IC90% : 4-7] p( log rank)=0,684 100 75 50 Survival Rate (%) 25 0 6 12 18 24 30 Months Number at risk Sorafenib 18 5 3 1 0 Gemox+Sorafenib 19 5 2 1 0

  10. OverallSurvival Sorafenib : 13,0 months [IC90% : 10-22] Sorafenib + GEMOX : 13.5 months [IC90% : 7-19] p( log rank)=0,114 100 75 survival Rate (%) 50 25 0 6 12 18 24 30 Months Number at risk Sorafenib 29 14 7 3 1 Gemox+Sorafenib 36 18 9 5 0

  11. Conclusion • Sorafenib plus GEMOX regimen has acceptable tolerance in pre treated, HCC CHILD A BCLCC B or C patients • Sorafenib plus GEMOX regimen met its primary endpoint (4-month PFS ≥ 50%). • Moreover, in this randomized trial Response Rate, median PFS and OS are encouraging compared to the literature data. • Exploratory analyses are underway to try to identify patient subgroups most willing to derive benefit from this regimen. 

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