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 )

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.

Hepatocellular carcinomaBCLCC B or CPS 0-1CHILD APl > 90 000/mm³Bilirubin Total ≤ 1.5N

R

Sorafenib 400mg BIDn= 44

Sorafenib 400mg BID+ GEMOX (D1-D14)n= 39Gemcitabine 1000mg/m²L-OHP 100mg/m²

Stratification• CLIP score 0-1 vs 2-3• Cirrhosis vs non cirrhosis

Phase II Randomized 2 staged study

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))

Hepatocellular carcinomaBCLCC B or CPS 0-1CHILD APl > 90 000/mm³ Bilirubin Total ≤ 1.5N

R

Sorafenib 400mg BIDn= 44

Sorafenib 400mg BID+ GEMOX (D1-D14)n= 39Gemcitabine 1000mg/m²L-OHP 100mg/m²

Phase II Randomized 2 staged study

Principal Endpoint: Progression Free survival (PFS) at 4 monthsN= 78 valuable patients (39 by arm); ≥ 24 patients/ 39 non progressive at 4 months in experimental armH0<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

signalling pathway analysis

Patient population (Baseline)Sorafenib (n = 44) (%)

Sorafenib + GEMOX (n = 39) (%)

p

Age Median Range

62.5(39-78)

65(47-79)

ns

Gender Male Female

38(86%)6(14%)

36(92%)3(8%)

ns

Performance Status (PS) 0 1

31(71%)13(29%)

28(72%)11(28%)

ns

Cirrhosis (presence) 26(62%) 23(62%) ns

Pre treatment (surgery, RFA,TACE) 24(55%) 22(56%) ns

Portal Vein Thrombosis (presence) 11(25%) 11(28%) ns

CLIP Score 0-1 2-3

20(46%)24(54%)

20(51%)29(49%)

ns

Tumor Site Liver only Liver + Distant metastasis

17(39%)27(61%)

9(23%)30(77%)

ns

SorafenibTreatment Compliance

Sorafenib (n=44)

Sorafenib + GEMOX (n=39)

Cycle Number Median Range

3504

(1-29)

3304

(1-27)

Duration (month) Median Range

3.9 (0.9-26.6)

4.1(0.9- 27.4)

Dose intensity (mg/Day)

606 668

Relative Dose Intensity (%)

<80% ≥ 80%

75.8

54.545.5

81.5

4159

Gemox Sorafenib + GEMOX (n=39)

Cycle Number Median Range

2757

(1-12)

Relative Dose Intensity (%) Gemcitabine Oxaliplatine

7868

Toxicity Profile/patientSorafenib

(n=44) Sorafenib + GEMOX

(n=39) p

Grade 3 Grade 4 Grade 3 Grade 4

Neutropenia (%) 0 0 18 5 0.001

Thrombocytopenia (%) 0 0 28 5 <0.001

Asthenia (%) 7 0 20 0 0.06

Diarrhea (%) 9 0 18 0 0.234

Hand Foot syndrome (%) 18 0 5 0 0.03

Grade 2 Grade 3 Grade 2 Grade 3

Sensitive Neuropathy (Grade 2/3) (%) 0 0 8 2 0.029

ALL Toxicities (Grade ≥ 3) (%) 71 76 0.505

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)

Treatment Efficacy (Evaluable Population RECIST 1.0)

Sorafenib (n=44)

Sorafenib + GEMOX (n=39)

Response Rate, n (%) RP SD PD NE

4 (9%)27 (61%)9 (21%)4 (9%)

6 (16%)24 (61%) 8 (21%)

1 (2%)

Disease Control Rate, n (%) 31 (70%) 30 (77%)

Sorafenib (n=44)

Sorafenib + GEMOX (n=39)

PFS at 4 months, n (%)

24 (54%) 25 (64%)

Principal Endpoint: Progression Free survival (PFS) at 4 monthsN= 78 valuable patients (39 by arm); ≥ 24 patients/ 39 non progressive at 4 months in experimental arm

Treatment Efficacy

Sorafenib (n = 44)

Sorafenib + GEMOX (n = 39)

PFS, Median [90% IC] 4.6 [3.9-6.2] 6.2 [3.8-6.8]

OS, Median [90% IC] 13.0 [10.4- 22.2] 13.5 [7.5-19.1]

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)

Progression Free Survival0

25

50

75

100

Su

rviv

al

Ra

te (

%)

19 5 2 1 0Gemox+Sorafenib

18 5 3 1 0Sorafenib

Number at risk

6 12 18 24 30

Months

Sorafenib : 4.6 mois [IC90% : 4-6]Sorafenib+ Gemox : 6.2 mois [IC90% : 4-7] p( log rank)=0,684

Overall Survival0

2550

75100

su

rviv

al

Ra

te (

%)

36 18 9 5 0Gemox+Sorafenib

29 14 7 3 1Sorafenib

Number at risk

6 12 18 24 30

Months

Sorafenib : 13,0 months [IC90% : 10-22]Sorafenib + GEMOX : 13.5 months [IC90% : 7-19]p( log rank)=0,114

ConclusionSorafenib 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.