Assessment of Treatment With Sorafenib Plus Doxorubicin vs Sorafenib Alone in Patients With Advanced Hepatocellular Carcinoma: Phase 3 CALGB 80802 Randomized Clinical Trial

Abstract

Importance: Previous communication has reported significant improvement in overall survival (OS) when using doxorubicin plus sorafenib in the treatment of advanced hepatocellular cancer (HCC).

Objective: To determine if doxorubicin added to sorafenib therapy improves OS, with stratification for locally advanced and metastatic disease.

Design, setting, and participants: This unblinded randomized phase 3 clinical trial was led by Alliance in collaboration with Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Canadian Cancer Trials Group, and Southwest Oncology Group. It was launched in February 2010 and completed in May 2015; data were also analyzed during this time frame. Patients with histologically proven advanced HCC, no prior systemic therapy, Child-Pugh grade A score, Eastern Cooperative Oncology Group performance status of 0 to 2 (later amended to 0-1), and adequate hematologic, hepatic, renal, and cardiac function were eligible. The OS primary end point had a final analysis planned with 364 events observed among 480 total patients with 90% power to detect a 37% increase in median OS.

Interventions or exposures: Patients received either 60 mg/m2 of doxorubicin every 21 days plus 400 mg of sorafenib orally twice daily or the sorafenib alone, adjusted to half doses for patients with bilirubin levels of 1.3 to 3.0 mg/dL.

Main outcomes and measures: The primary end point was OS, and progression-free survival (PFS) was a secondary end point.

Results: Of 356 patients included in the study, the mean (SD) age was 62 (10.1) years, and 306 (86.0%) were men. Although it was planned to include 480 patients, the study was halted after accrual of 356 patients (180 patients treated with doxorubicin plus sorafenib and 176 with sorafenib alone) with a futility boundary crossed at a planned interim analysis. Median OS was 9.3 months (95% CI, 7.3-10.8 months) in the doxorubicin plus sorafenib arm and 9.4 months (95% CI, 7.3-12.9 months) in the sorafenib alone arm (hazard ratio, 1.05; 95% CI, 0.83-1.31). The median PFS was 4.0 months (95% CI, 3.4-4.9 months) in the doxorubicin plus sorafenib arm and 3.7 months (95% CI, 2.9-4.5 months) in the sorafenib alone arm (hazard ratio, 0.93; 95% CI, 0.75-1.16). Grade 3 or 4 neutropenia and thrombocytopenia adverse events occurred in 61 (36.8%) and 29 (17.5%) patients, respectively, being treated with doxorubicin plus sorafenib vs 1 (0.6%) and 4 (2.4%) patients treated with sorafenib.

Conclusions and relevance: This multigroup study of the addition of doxorubicin to sorafenib therapy did not show improvement of OS or PFS in patients with HCC.

Trial registration: ClinicalTrials.gov identifier: NCT01015833.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Abou-Alfa reports receiving grants and personal fees from Bayer during the conduct of the study; receiving grants and personal fees from Bristol-Myers Squibb, AstraZeneca, Exelixis, and Eli Lilly, as well as personal fees from Merck and Eisai outside of the submitted work; and was issued a patent (PCT/US2014/031545). Dr Bekaii-Saab reported receiving personal fees from Imugene, Immuneering, Exelixis, Armo, AbbVie, Glenmark, Amgen, and Merck outside of the submitted work; consulting fees from Bayer, Bristol-Myers Squibb, Amgen, Merck, Array BioPharma, Celgene, Incyte, Ipsen, Pfizer, and Genentech/Roche; and research grants from Bayer. Dr El-Khoueiry reports receiving grants from SWOG during the conduct of the study; personal fees from Bristol-Myers Squibb, Bayer, AstraZeneca, Novartis, Genentech/Roche, Merck, Eisai, Exelixis, CytomX, Pieris, EMD Serono, Pfizer, and Agenus; and grants from Astex and AstraZeneca. Dr Harding reports receiving grants from Bristol-Myers Squibb, as well as personal fees from Bristol-Myers Squibb, Eli Lilly, CytomX, and Eisai outside of the submitted work. Dr Kavan reports receiving grants from Jewish General Hospital during the conduct of the study and grants from Bayer outside of the submitted work. Dr Kelley reports receiving grants from Alliance National Clinical Trial Network during the conduct of the study; grants from AstraZeneca, Bristol-Myers Squibb, Bayer, Agios, Adaptimmune, Exelixis, Eli Lilly, Merck, Novartis, QED, and Taiho; and personal fees from Genentech/Roche outside of the submitted work. Dr Knox reports receiving grants from Merck and personal fees from Bristol-Myers Squibb and AstraZeneca outside of the submitted work. Dr Lammers reports receiving personal fees from Pfizer, Merck, Teva, and Sanofi-Aventis outside of the submitted work. Dr Meyerhardt reports receiving personal fees from Ignyta, Taiho, Array BioPharma, and Genentech/Roche outside of the submitted work. Dr O'Reilly reports receiving grants and personal fees from Bristol-Myers Squibb and AstraZeneca, as well as personal fees from Merck outside of the submitted work. Dr Schwartz reported receiving grants from Merck, Novartis, and GlaxoSmithKline, as well as personal fees from Genentech/Roche outside of the submitted work. Dr Tam reports receiving funding from the Canadian Clinical Trials Group during the conduct of the study and grants from Bayer outside of the submitted work. Dr Tan reports receiving grants from the Alliance CALGB Cooperative Group during the conduct of the study. Dr Venook reports receiving grants from the National Cancer Institute during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. Cohort Flowchart

Figure 2.. Overall and Progression-Free Survival

A, The median overall survival was 9.3 months in patients treated with doxorubicin plus sorafenib compared with 9.4 months among those treated with sorafenib alone. B, The median progression-free survival was 4.0 months among patients treated with doxorubicin plus sorafenib compared with 3.7 months among those treated with sorafenib alone.