Phase II Randomized Trial on Dose-Escalated Sorafenib vs Best Supportive Care (BSC) in Patients

With Advanced Hepatocellular Carcinoma (HCC) With Disease Progression on Prior Sorafenib Treatment

Pressiani T1, Rimassa L1, Boni C2, Labianca R3, Fagiuoli S3, Ardizzoni A4, Foa P5, Cortesi E6, Porta C7, Artioli F8, Latini L9,

Carnaghi C1, Lutman FR1, Torzilli T1, Tommasini MA1, Cerianl R1,Covini G1, Giordano L1, Locopo N1, Santoro A1.

1Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano (MI), Italy; 2Arcispedale Santa Maria Nuova, Reggio Emilia, Italy; 3Ospedali Riuniti, Bergamo, Italy; 4Azienda Ospedaliero - Universitaria, Parma, Italy; 5Ospedale San Paolo - Polo Universitario, Milano, Italy;6Azienda Policlinico Umberto I, Roma, Italy; 7I.R.C.C.S. Policlinico San Matteo, Pavia, Italy; 8Ospedale B. Ramazzini, Carpi (MO), Italy; 9Ospedale Generale Provinciale, Macerata, Italy.

Study Design

Primary endpoint: PFS

Sorafenib600 mg BID 49 patients

Advanced HCC

Child-Pugh Class A/B

Suitable for systemic treatment

(300 patients)

Sorafenib400 mg BID

PD

BSC52 patients

Randomization1:1

(101 patients)

From April 2007 to July 2008, 300 patients were prospectively treated with sorafenib 400 mg BID. At documented radiological PD, 101 patients (34%) were randomized: 49 patients (48.5%) to increased-dose sorafenib (600 mg BID) + BSC and 52 patients (51.5%) to BSC, respectively

PD=radiological progression, PFS=progression-free survival.

Adapted from Pressiani T et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Baseline Patient Characteristics

No. of Patients(%)

Sorafenibno. (%)

BSC no. (%) P value

Total 101 (100) 49 (48.5) 52 (51.5)Sex .089

Male 83 (82.2) 37 (75.5) 46 (88.5)Female 18 (17.8) 12 (24.5) 6 (11.5)

Child-Pugh Class .113†

A 94 (93.1) 48 (98.0) 46 (88.5)B 7 (6.9) 1 (2.0) 6 (11.5)

Histological subtype* 1.00† Trabecular 80 (79.2) 38 (97.4) 42 (93.33)Mixed 1 (1.0) 0 (0.0) 1 (2.22)Fibrolamellar 3 (3.0) 1 (2.6) 2 (4.44)Missing 17 (16.8)

Extrahepatic spread* .035Yes 69 (68.31) 38 (82.6) 31 (63.3)No 26 (25.74) 8 (17.4) 18 (36.7)Missing 6 (5.94)

Time at first relapse .269≤4 months 49 (48.5) 21 (42.9) 28 (53.9)>4 months 52 (51.5) 28 (57.1) 24 (46.2)

Associations are tested using the Chi-square test.*The sum does not add up to the total due to missing values. †Associations are tested using the Fisher exact test.

Adapted from Pressiani T et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Progression-Free Survival

HR sorafanib vs BSC, 0.67; CI 95%: (0.43-1.06), Pvalue: .089Risk reduction of 33%

All Median (range) Sorafenib Median (range) BSC Median (range)PFS (months) 3.58 (0.26-32.25) 3.91 (0.26-32.25) 2.69 (0.49-19.51)

CI=confidence interval, HR=hazard ratio.Adapted from Pressiani T et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Time to Progression

HR sorafanib vs BSC, 0.59; CI 95%: (0.33-1.05), Pvalue: .070Risk reduction of 41%

All Median (range) Sorafenib Median (range) BSC Median (range)TTP (months) 3.64 (0.62-32.25) 3.97 (0.62-32.2) 2.0 (1.2-19.5)

TTP=time to progression.Adapted from Pressiani T et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Overall Survival (OS)

HR sorafanib vs BSC, 0.71; CI 95% : (0.47-1.08); Pvalue: .107Risk reduction of 29%

All Median (range) Sorafenib Median (range) BSC Median (range)TTP (months) 6.11 (0.26-44.50) 7.55 (0.26-44.50) 5.89 (0.49-26.64)

Adapted from Pressiani T et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Adverse Events

Adverse Events (Grade 3/4) SorafenibNo. (%)

BSC No. (%) Pvalue

Diarrhea 9 (12.2) 6 (11.5) .335Hand foot skin reaction 5 (6.3) 8 (15.4) .437Fatigue 8 (16.3) 4 (7.7) .226Rash 3 (6.1) 4 (7.7) 1.000Weight loss 6 (12.2) 1 (1.9) .055Anemia 4 (8.1) 1 (1.9) .196Stomatitis 5 (6.3) 0 (0.0) .024Cachexia 3 (4.1) 2 (3.8) .672Abdominal pain 4 (8.1) 0 (0.0) .052Nausea and vomiting 2 (3.8) 1 (1.9) .610Encephalopathy 2 (3.8) 0 (0.0) .233Amylase increase 1 (2.0) 1 (1.9) 1.000Thrombocytopenia 1 (2.0) 1 (1.9) 1.000Pain (non abdominal) 1 (2.0) 1 (1.9) 1.000Cardiovascular 1 (2.0) 1 (1.9) 1.000

Adapted from Pressiani T et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Drug Exposure

Adapted from Pressiani T et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

All Patients (300): PFS and OS According to Child-Pugh Class

Median (range)OS PFS

All (months) 9.2 (0.4-46.7) 4.1 (0.4-35.3)n=234 Child-Pugh Class A (months) 10.9 (0.5-46.7) 4.7 (0.5-35.3)n=62 Child-Pugh Class B (months) 4.0 (0.4-27.3) 2.6 (0.4-27.3)

Adapted from Pressiani T et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Conclusions

These results demonstrate that increased-dose sorafenib in HCC patients progressing on standard-dose sorafenib is feasible, with an acceptable safety profile.

Trend toward improved PFS and OS, although not statistically significant, may justify the use of increased or standard dose of sorafenib beyond progression as an active control arm in Phase II – III trials evaluating new drugs as second-line therapy in HCC

Adapted from Pressiani T et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.