Assessment of Treatment With Sorafenib Plus Doxorubicin vs Sorafenib Alone in Patients With Advanced Hepatocellular Carcinoma: Phase 3 CALGB 80802 Randomized Clinical Trial | Gastroenterology | JAMA Oncology | JAMA Network
[Skip to Navigation]
Figure 1.  Cohort Flowchart
Cohort Flowchart
Figure 2.  Overall and Progression-Free Survival
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.

Table 1.  Patient Demographics and Disease Characteristics by Treatment Arm
Patient Demographics and Disease Characteristics by Treatment Arm
Table 2.  Observed Treatment Responses (RECIST 1.1) by Regimen
Observed Treatment Responses (RECIST 1.1) by Regimen
1.
Llovet  JM, Ricci  S, Mazzaferro  V,  et al; SHARP Investigators Study Group.  Sorafenib in advanced hepatocellular carcinoma.  N Engl J Med. 2008;359(4):378-390. doi:10.1056/NEJMoa0708857PubMedGoogle ScholarCrossref
2.
Cheng  AL, Kang  YK, Chen  Z,  et al.  Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.  Lancet Oncol. 2009;10(1):25-34. doi:10.1016/S1470-2045(08)70285-7PubMedGoogle ScholarCrossref
3.
Yeo  W, Mok  TS, Zee  B,  et al.  A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma.  J Natl Cancer Inst. 2005;97(20):1532-1538. doi:10.1093/jnci/dji315PubMedGoogle ScholarCrossref
4.
Richly  H, Henning  BF, Kupsch  P,  et al.  Results of a phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors.  Ann Oncol. 2006;17(5):866-873. doi:10.1093/annonc/mdl017PubMedGoogle ScholarCrossref
5.
Abou-Alfa  GK, Johnson  P, Knox  JJ,  et al.  Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial.  JAMA. 2010;304(19):2154-2160. doi:10.1001/jama.2010.1672PubMedGoogle ScholarCrossref
6.
Zelen  M.  The randomization and stratification of patients to clinical trials.  J Chronic Dis. 1974;27(7-8):365-375. doi:10.1016/0021-9681(74)90015-0PubMedGoogle ScholarCrossref
7.
Miller  AA, Murry  DJ, Owzar  K,  et al.  Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301.  J Clin Oncol. 2009;27(11):1800-1805. doi:10.1200/JCO.2008.20.0931PubMedGoogle ScholarCrossref
8.
Lacouture  ME, Wu  S, Robert  C,  et al.  Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib.  Oncologist. 2008;13(9):1001-1011. doi:10.1634/theoncologist.2008-0131PubMedGoogle ScholarCrossref
9.
Lan  KKG, DeMets  DL.  Discrete sequential boundaries for clinical trials.  Biometrika. 1983;70(3):659-663. doi:10.2307/2336502Google ScholarCrossref
10.
O’Brien  PC, Fleming  TR.  A multiple testing procedure for clinical trials.  Biometrics. 1979;35(3):549-556. doi:10.2307/2530245PubMedGoogle ScholarCrossref
11.
Eisenhauer  EA, Therasse  P, Bogaerts  J,  et al.  New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).  Eur J Cancer. 2009;45(2):228-247. doi:10.1016/j.ejca.2008.10.026PubMedGoogle ScholarCrossref
12.
Kaplan  EL, Meier  P.  Nonparametric estimation from incomplete observations.  J Am Stat Assoc. 1958;53(282):457-481. doi:10.1080/01621459.1958.10501452Google ScholarCrossref
13.
Mantel  N.  Evaluation of survival data and two new rank order statistics arising in its consideration.  Cancer Chemother Rep. 1966;50(3):163-170.PubMedGoogle Scholar
14.
Peto  R, Peto  J.  Asymptotically efficient rank invariant test procedures.  J R Stat Soc [Ser A]. 1972;135(2):185-207. doi:10.2307/2344317Google ScholarCrossref
15.
Harrington  D. Linear rank tests in survival analysis. In: Armitage  P, Colton  T, eds.  Encyclopedia of Biostatistics. Cambridge, England: Wiley Interscience; 2005.
16.
Cox  DR.  Regression models and life-tables.  J R Stat Soc B. 1972;34(2):187-220.Google Scholar
17.
Abou-Alfa  GK, Schwartz  L, Ricci  S,  et al.  Phase II study of sorafenib in patients with advanced hepatocellular carcinoma.  J Clin Oncol. 2006;24(26):4293-4300. doi:10.1200/JCO.2005.01.3441PubMedGoogle ScholarCrossref
18.
Olweny  CL, Toya  T, Katongole-Mbidde  E, Mugerwa  J, Kyalwazi  SK, Cohen  H.  Treatment of hepatocellular carcinoma with adriamycin: preliminary communication.  Cancer. 1975;36(4):1250-1257. doi:10.1002/1097-0142(197510)36:4<1250::AID-CNCR2820360410>3.0.CO;2-XPubMedGoogle ScholarCrossref
19.
Brown  KT, Do  RK, Gonen  M,  et al.  Randomized trial of hepatic artery embolization for hepatocellular carcinoma using doxorubicin-eluting microspheres compared with embolization with microspheres alone.  J Clin Oncol. 2016;34(17):2046-2053. doi:10.1200/JCO.2015.64.0821PubMedGoogle ScholarCrossref
20.
McCubrey  JA, Steelman  LS, Abrams  SL,  et al.  Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance.  Adv Enzyme Regul. 2006;46:249-279. doi:10.1016/j.advenzreg.2006.01.004PubMedGoogle ScholarCrossref
21.
Alavi  AS, Acevedo  L, Min  W, Cheresh  DA.  Chemoresistance of endothelial cells induced by basic fibroblast growth factor depends on Raf-1-mediated inhibition of the proapoptotic kinase, ASK1.  Cancer Res. 2007;67(6):2766-2772. doi:10.1158/0008-5472.CAN-06-3648PubMedGoogle ScholarCrossref
22.
Song  S, Wientjes  MG, Gan  Y, Au  JL.  Fibroblast growth factors: an epigenetic mechanism of broad spectrum resistance to anticancer drugs.  Proc Natl Acad Sci USA. 2000;97(15):8658-8663. doi:10.1073/pnas.140210697PubMedGoogle ScholarCrossref
23.
Schneider  C, Wallner  M, Kolesnik  E,  et al.  The anti-cancer multikinase inhibitor sorafenib impairs cardiac contractility by reducing phospholamban phosphorylation and sarcoplasmic calcium transients.  Sci Rep. 2018;8(1):5295. doi:10.1038/s41598-018-23630-wPubMedGoogle ScholarCrossref
24.
Abou-Alfa  GK, Zhao  B, Capanu  M,  et al Tumor necrosis as a correlate for response in subgroup of patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib  [ESMO abstract 547P].  Ann Oncol. 2008:19(suppl 8):viii178.Google Scholar
25.
Petrick  JL, Kelly  SP, Altekruse  SF, McGlynn  KA, Rosenberg  PS.  Future of hepatocellular carcinoma incidence in the United States forecast through 2030.  J Clin Oncol. 2016;34(15):1787-1794. doi:10.1200/JCO.2015.64.7412PubMedGoogle ScholarCrossref
Original Investigation
September 5, 2019

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

Author Affiliations
  • 1Memorial Sloan Kettering Cancer Center, New York, New York
  • 2Weill Cornell Medical College, Cornell University, New York, New York
  • 3Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota
  • 4Princess Margaret Cancer Centre, Toronto, Ontario, Canada
  • 5Montefiore Medical Center, New York, New York
  • 6Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina
  • 7Thomas Jefferson University, Philadelphia, Pennsylvania
  • 8Washington University School of Medicine, St Louis, Missouri
  • 9McGill University, Montreal, Quebec, Canada
  • 10Ottawa Hospital, Ottawa, Ontario, Canada
  • 11Meharry Medical College, Nashville, Tennessee
  • 12Mayo Clinic, Scottsdale, Arizona
  • 13Tom Baker Cancer Centre, Calgary, Alberta, Canada
  • 14Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco
  • 15Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles
  • 16Kaiser Permanente Vallejo Medical Center, Vallejo, California
  • 17Columbia University Medical Center, New York–Presbyterian Hospital, New York, New York
  • 18West Virginia University Cancer Institute, Morgantown
  • 19Brigham and Women's Hospital, Boston, Massachusetts
  • 20Dana-Farber Cancer Institute, Boston, Massachusetts
JAMA Oncol. 2019;5(11):1582-1588. doi:10.1001/jamaoncol.2019.2792
Key Points

Question  Does adding doxorubicin to sorafenib therapy improve overall survival in patients with advanced hepatocellular cancer?

Findings  This phase 3 clinical trial randomized 356 eligible patients to treatment with doxorubicin plus sorafenib vs sorafenib alone. Results demonstrated no difference in median overall survival (9.3 months for the doxorubicin plus sorafenib arm and 9.4 months for the sorafenib arm).

Meaning  The addition of doxorubicin to sorafenib therapy did not improve overall survival and resulted in higher toxicity; the combination of doxorubicin and sorafenib should not be used for the treatment of advanced hepatocellular cancer.

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

Introduction

The tyrosine kinase inhibitor sorafenib was shown in 2 randomized phase 3 clinical trials to lead to superior overall survival (OS) compared with placebo in the treatment of patients with advanced hepatocellular carcinoma (HCC).1,2 Doxorubicin has also been considered an effective systemic therapy for HCC.3 A phase 1 clinical trial proved the feasibility and tolerability of sorafenib in combination with doxorubicin.4 A randomized, double-blind, phase 2 study of doxorubicin plus sorafenib and doxorubicin plus placebo followed and demonstrated a significant improvement in OS with doxorubicin plus sorafenib.5 Cancer and Leukemia Group B (CALGB), now part of the Alliance for Clinical Trials in Oncology, designed CALGB 80802 to determine if doxorubicin plus sorafenib improved survival compared with the single agent sorafenib in the treatment of advanced HCC.

Methods

This Alliance-led National Clinical Trials Network multigroup trial was approved by the institutional review boards at all sites and/or the National Cancer Institute (NCI) central institutional review board and was registered at ClinicalTrials.gov (NCT01015833). The study was conducted in accordance with the US Department of Health and Human Services guidelines. Written informed consent was obtained from all patients. The Alliance Data and Safety Monitoring Board (DSMB) reviewed this trial semiannually for toxic effects and scheduled interim efficacy analyses. The trial protocol is available in Supplement 1.

Patients’ Eligibility

Patients with measurable, histologically proven, locally advanced (with disease not amenable to curative interventions) or metastatic HCC who had received no prior systemic therapy for HCC were eligible. Patients with known central nervous system tumors, including brain metastases, were ineligible. In view of the differing causes and backgrounds of HCC, ethnicity was reported by participants. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 to 2 (later amended to 0-1), Child-Pugh grade A score status, an absolute neutrophil count of 1500/mm3 or greater, a platelet count of 75 × 109/L or greater, a hemoglobin level of 8.5 g/dL or greater, and a prothrombin time–international normalized ratio of 1.7 or less. Patients who were therapeutically anticoagulated were allowed to participate provided that no prior evidence of underlying abnormality in prothrombin time–international normalized ratio existed. Adequate hepatic (bilirubin, ≤3 mg/dL; alanine transaminase and aspartate aminotransferase, ≤5 × upper limit of normal) and renal (serum creatinine, ≤1.5 × upper limit of normal or creatinine clearance, ≥60 cc/min) function were required.

Any hypertension must have been well controlled (<140/90 mm Hg). Patients with known history of congestive heart failure greater than New York Heart Association class II, cardiac arrhythmias requiring antiarrhythmic therapy other than beta blockers or digoxin, or myocardial infarction within 6 months prior to study entry were not eligible. Patients were required to have an absolute left ventricular ejection fraction (LVEF) of 45% or greater or the normal lower limit of the specific institution at which they were seen.

Patients could have had prior liver-directed treatment provided there was a measurable target lesion that had not been subjected to local therapy and/or progressed since last treatment. Such therapy must have been completed 4 or more weeks prior to study entry. Patients having undergone liver transplantation were not eligible.

Current antiviral therapy was allowed except for interferon. Patients with known HIV were not eligible.

Treatment and Dose Modifications

All patients received sorafenib and were randomly assigned on a 1:1 basis to receive doxorubicin or not using a permuted block allocation procedure.6 Randomization was stratified by extent of disease (locally advanced vs metastatic). Hepatitis status (no hepatitis, hepatitis B, hepatitis C, or hepatitis B and C) was considered as a covariate. Patients received either 60 mg/m2 of doxorubicin intravenously every 21 days (1 cycle) for a maximum total dose of 360 mg/m2, plus 400 mg of sorafenib orally twice daily or 400 mg of sorafenib orally twice daily alone. Three dose reductions were allowed for doxorubicin (45, 30, and 22.5 mg/m2) and 2 for sorafenib (400 mg daily and 400 mg every other day) for drug-related toxic effects based on the NCI Common Toxicity Criteria, version 4.0.

Patients with bilirubin levels between 1.3 and 3.0 mg/dL received either 30 mg/m2 of doxorubicin intravenously every 21 days for a maximum of 360 mg/m2 plus 400 mg of sorafenib orally once daily or 400 mg of sorafenib orally once daily.7 Only 1 dose reduction was allowed for doxorubicin (22.5 mg/m2) and sorafenib (400 mg every other day) for drug-related toxic effects.

After the maximal doxorubicin dose, patients continued treatment with single-agent sorafenib. In approved circumstances when a patient was benefitting from therapy and continued to have normal ejection fraction, treatment with doxorubicin was allowed up to a maximum total dose of 450 mg/m2, following which sorafenib could be continued as a single agent. Cardiac function was followed with multigated acquisition scans obtained at baseline before start of doxorubicin therapy and every 3 cycles, then every cycle after the cumulative dose reached 360 mg/m2. Patients were removed from protocol therapy in cases of clinical heart failure (eg, left ventricular systolic dysfunction  ≥ grade 3) or LVEF value decline by a relative 20% from baseline (eg, a decline in LVEF from 55% to 44%).

Specific sorafenib dose modifications were implemented for hypertension (eTable 1 in Supplement 2). Specific sorafenib dose modifications were used for hand-foot skin reaction, palmar-plantar erythrodysesthesia (eTable 2 in Supplement 2),8 and for hepatic toxicity (eTable 3 in Supplement 2).

If dose reductions beyond the lowest dose level were required, or either agent was held for more than 3 weeks, all protocol therapy was to be discontinued.

Disease Assessments and Follow-up

Patients were evaluated at the start of every cycle. Imaging was performed every 2 cycles. Posttreatment survival and progression follow-up was conducted every 3 months for 1 year, then every 6 months until 3 years after registration. Survival follow-up was conducted through available means, including but not limited to clinic visits, phone calls, and death reports.

Statistical Methods

Efficacy analysis was based on an intent-to-treat principle with all eligible patients belonging to the treatment arm in which they were randomized. The primary outcome measure was OS, defined as the time from the date of randomization to the date of death due to any cause. Patients who were alive at the primary analysis time were censored at the time they were last known to be alive. Assuming a median OS of 10.7 months in the sorafenib alone group, 480 patients enrolled over 2 years and followed up for 15 months were required to achieve 90% power to detect a 37% increase in median OS in the sorafenib plus doxorubicin arm (ie, 10.7-14.7 months; hazard ratio [HR], 0.73), using stratified log-rank test at a 1-sided significance level of α = .05. A total of 364 deaths were expected at the time of the final analysis. Formal interim analyses for OS began when 15% of expected events were observed and subsequently occurred every 6 months. Futility interim analyses based on the OS end point were conducted using a confidence interval approach. The Lan-DeMets boundaries9 and O’Brien-Fleming10 analogue were used to test the superiority and futility hypotheses at each interim (1-sided α = .05). A preplanned early-stopping analysis based on progression-free survival (PFS) was conducted when 130 events were observed, which provided 90% power to detect a 50% increase in median PFS (ie, 4.0-6.0 months in the sorafenib alone and sorafenib plus doxorubicin arms, respectively [HR, 0.66]), at a 1-sided significance level α = .15. If PFS was not statistically superior on the sorafenib plus doxorubicin arm vs the sorafenib alone arm at α = .15, the trial would have closed to further accrual. Cardiac toxicity was monitored by a formal statistical plan among patients randomized to treatment with sorafenib plus doxorubicin beginning when 33 patients were enrolled on the combination treatment arm and subsequently every 6 months coinciding with Alliance DSMB meetings. Cardiac toxicity was defined as the development of a grade 3 or higher decrease in ejection fraction per Common Terminology Criteria for Adverse Events, version 4.0.

Secondary end points were PFS, time to progression (TTP), and response by Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.11 The PFS was defined as time from randomization to disease progression or death due to any cause. The TTP was measured from randomization to documented disease progression, and patients who died without progression were censored at time of death. For both PFS and TTP, patients lost to follow-up were censored at the date of their most recent disease assessment (or contact).

The Kaplan-Meier method was used to estimate the distributions of time-to-event end points.12 Stratified log-rank test was used to compare time-to-event end points between treatment groups.13-15 A stratified Cox proportional hazards regression model was used to estimate HRs and 95% CIs.16 For all analyses regarding time-to-event end point (eg, log-rank test and Cox model), extent of disease (locally advanced vs metastatic) was included as the stratification factor for controlling confounding effect. Hepatitis status was considered as a covariate. A P < .05 level was considered statistically significant. Data collection and statistical analyses were conducted by the Alliance Statistics and Data Center. Data quality was ensured by review of data by the Alliance Statistics and Data Center and by the study chairperson (G.K.A.) following Alliance policies. All analyses were based on the study database frozen on December 19, 2017. Analyses were performed by using SAS, version 9.4 (SAS Institute Inc.).

Correlative Studies

A series of correlative studies were planned and are being completed. These include the evaluation of tumor necrotic areas using a new volumetric method of assessing nonviable tumor as a correlate for response,17 the effect of sorafenib on hepatitis C viral titers, quasispecies in patients with virologic failure, and correlation with radiologic evaluation. Results from these studies will be reported separately.

Results
Study Population

Patient enrollment began February 15, 2010, and was halted on May 21, 2015, per recommendation of the DSMB after the fifth interim analysis demonstrated a low probability that OS of the combination group would surpass that of the sorafenib alone group. A total of 356 patients were enrolled from Alliance, Eastern Cooperative Oncology Group (now part of the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network), National Cancer Institute of Canada (now Canadian Cancer Trials Group), and Southwest Oncology Group sites. All results are based on an intent-to-treat population of 356 patients (Figure 1). A total of 180 patients were randomized to the doxorubicin plus sorafenib arm and 176 to the sorafenib alone arm. All patients were evaluated for the toxicity analysis. Baseline demographic and disease characteristics of randomized patients are summarized in Table 1 and were similar between the 2 study arms.

Dose and Duration of Therapy

In the doxorubicin plus sorafenib arm, the median total dose of doxorubicin administered was 237.5 mg (range, 0-1036 mg) given over a median of 3 cycles (range, 1-22 cycles), and the median daily dose of sorafenib was 433 mg (range, 19-895 mg). In the sorafenib arm, the mean daily dose was 495 mg (range, 38-994 mg). The median duration of treatment was 8.9 weeks (range, 0.6-71.3 weeks) in the doxorubicin plus sorafenib arm and 11.7 weeks (range, 0.6-223.4 weeks) in the sorafenib arm.

Overall Survival

A total of 302 deaths (154 in the doxorubicin plus sorafenib arm and 148 in the sorafenib alone arm) were observed after a median follow-up of 36.1 months. The median OS was 9.3 months (95% CI, 7.3-10.8 months) in patients treated with doxorubicin plus sorafenib compared with 9.4 months (95% CI, 7.3-12.9 months) among those who received sorafenib alone. The stratified HRs were 1.05 (95% CI, 0.83-1.31; P = .68) and 1.03 (95% CI, 0.82-1.29; P = .83) without and with adjustment by hepatitis status, respectively (Figure 2A).

Progression-Free Survival

The preplanned PFS interim analysis was completed per protocol in July 2013 after the first 170 patients were enrolled and 130 PFS events were observed. At that time, median PFS for patients randomized to the doxorubicin plus sorafenib arm was 4.5 months (95% CI, 2.6-6.0 months) and median PFS for patients randomized to the sorafenib alone arm was 3.5 months (95% CI, 2.6-5.0 months). The 1-sided log-rank P value was .12, which is significant at α = .15 level. This satisfied the preplanned threshold for activity of the doxorubicin plus sorafenib arm, and the study continued accrual. With updated database information available as of December 2017, the median PFS was 4.0 months (95% CI, 3.4-4.9 months) among patients treated with doxorubicin plus sorafenib compared with 3.7 months (95% CI, 2.9-4.5 months) among those who received sorafenib alone. The HR estimated by Cox model was 0.93 (95% CI, 0.75-1.16) with stratified log-rank test (P = .54) (Figure 2B).

Time to Progression

The Kaplan-Meier estimate of the median TTP was 4.7 months (95% CI, 4.1-5.6 months) in patients treated with doxorubicin plus sorafenib compared with 4.2 months (95% CI, 3.4-5.4 months) for those who received sorafenib alone. The HR estimated by Cox model was 0.92 (95% CI, 0.71-1.18) with log-rank test (P = .49).

Response Rate

There was 1 complete response in the doxorubicin plus sorafenib arm. Partial response was noted in 14 (9.3%) patients in the doxorubicin plus sorafenib arm, and 8 (5.4%) in the sorafenib alone arm (χ24, 3.21; P = .52). Table 2 shows the detailed RECIST response data. There was no significant difference in tumor response between the doxorubicin plus sorafenib and sorafenib alone arms.

Toxic Events

Grade 3 or 4 neutropenia and thrombocytopenia 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, respectively, taking sorafenib; nonhematologic adverse events were comparable (138 [83.1%] and 118 [76.9%] patients, respectively). Observed nonhematologic grade 3 and 4 toxicities that occurred with an incidence of more than 4% in at least one arm included fatigue (21 [12.6%] patients in the doxorubicin plus sorafenib arm, and 17 [10.1%] in the sorafenib only arm), hypertension (8 [4.8%] and 23 [13.6%] patients), hand-foot skin reaction (22 [13.3%] and 24 [14.2%] patients), nausea (11 [6.6%] and 12 [7.1%] patients), mucositis (15 [9.0%] and 4 [2.4%] patients), abdominal pain (8 [4.8%] and 14 [8.3%] patients), and diarrhea (12 [7.2%] and 12 [7.1%] patients) (eTable 4 in Supplement 2).

Grade 3 and 4 cardiac toxic events were limited to patients in the doxorubicin plus sorafenib arm. Left ventricular systolic dysfunction and decreased ejection fraction rates were noted in 5 (3.0%) and 8 (4.8%) patients taking doxorubicin plus sorafenib, respectively.

Of 46 deaths (22 in the doxorubicin plus sorafenib arm and 24 in the sorafenib arm), 7 in the doxorubicin plus sorafenib arm, and 3 in the sorafenib arm, were possibly related to treatment.

Discussion

This phase 3 randomized clinical trial evaluating the addition of doxorubicin to sorafenib in the treatment of advanced HCC is a landmark study. It represents, to our knowledge, the first US national effort of a phase 3 clinical trial for advanced HCC that was led by the Alliance National Clinical Trials Network group collaborating successfully with Eastern Cooperative Oncology Group–American College of Radiology Imaging Network, Canadian Cancer Trials Group, and Southwest Oncology Group. This is also to our knowledge the first published product of collaborative work of the NCI Hepatobiliary Task Force that was established around the same time with oversight from the NCI Gastrointestinal Cancer Steering Committee.

This study demonstrates that the addition of doxorubicin to sorafenib treatment does not improve OS and also strongly suggests that doxorubicin does not have a role as a systemic therapy for patients with advanced HCC.18 This also substantiates a previous finding that the addition of doxorubicin to therapy does not improve outcomes when combined with locoregional intrahepatic embolization.19

The experimental arm was designed following the results from a randomized phase 2 trial3 that combined doxorubicin and sorafenib based on laboratory evidence of the deactivation of the multidrug resistance pathway by the Ras/Raf/MEK/ERK pathway20 and bFGF-mediated activation of Raf-1 promoting the formation of antiapoptotic Raf-1 and ASK1 complex, induced by anthracyclines.21,22 The OS for those on sorafenib monotherapy was in the expected range (9.4 months), but the patients receiving the doxorubicin and sorafenib combination had a survival of just 9.3 months; that contrasts with the OS of 13.7 months in the cohort of patients treated with doxorubicin and sorafenib in the preceding randomized phase 2 trial.5

Although this study, like almost every other contemporary study in HCC, was restricted to patients who could have no worse than Child-Pugh grade A cirrhosis, HCC is a very heterogeneous disease, and similar patient populations can have very different outcomes (eg, the SHARP North American/European and the Asia-Pacific sorafenib phase III trials).1,2

After 130 (of the planned 480) patients experienced disease progression, a statistically significant difference in PFS favoring the doxorubicin plus sorafenib arm was mandatory for the study to continue accrual. The study met that metric, yet with continued accrual, OS did not prove to be any better when accrual was complete.

The doxorubicin plus sorafenib combination can be added to a long list of phase 2 treatments in any cancer that were not sustained in phase 3 trials. Beyond the possible confounders listed above, it appears that the toxicity of doxorubicin was a major factor despite the observed adverse events of both doxorubicin and sorafenib as previously noted,3 with an observed and expected increase in the rates of grade 3 or greater adverse events for the doxorubicin plus sorafenib arm compared with the sorafenib alone arm. The increased rate of doxorubicin-associated cardiac toxic events in this study was not unexpected, and it is unclear whether it was attributable to a sorafenib-induced increase in doxorubicin area under the curve or to other factors.23

Limitations

Regardless of the outcome, this study has certain limitations. Raf inhibition of sorafenib may play a limited role compared with other attributes of the drug that would not necessarily support the combination. It is also a reminder of the criticality of phase 3 trials in the setting of promising phase 2 data.5 Despite the detailed descriptors of the study population with Child-Pugh scores, further details delineating portal vein thrombosis among others would have been helpful. The relatively low median daily dose of sorafenib and starting dose based on bilirubin level may also explain the poor outcome of the study.

Conclusions

Despite the negative outcomes of this study, the data obtained from patients enrolled in the sorafenib control arm are of key importance. They will help provide insights into a series of correlative research questions that are being studied that will provide data pertinent to patients with HCC. Ongoing planned analyses include a prospective evaluation of radiographic tumor necrosis for association with treatment response building on prior studies,17,24 studies of hepatitis C viral load and quasispecies changes on therapy, and baseline platelets level and correlation with biology and outcome,18 as described in the methods section.

The study is timely considering the continued rising incidence of HCC in the United States25 and the critical need for better treatments for patients with advanced HCC.

Back to top
Article Information

Accepted for Publication: May 10, 2019.

Published Online: September 5, 2019. doi:10.1001/jamaoncol.2019.2792

Correction: This article was corrected on October 10, 2019, to correct Dr Harding’s middle initial.

Corresponding Author: Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center, 300 E 66th St, New York, NY 10065 (abou-alg@mskcc.org).

Author Contributions: Dr Abou-Alfa had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Abou-Alfa, Knox, Niedzwiecki, Kavan, El-Khoueiry, Schwartz, Goldberg, Bertagnolli, O'Reilly, Venook.

Acquisition, analysis, or interpretation of data: Abou-Alfa, Shi, Knox, Kaubisch, Niedzwiecki, Posey, Tan, Kavan, Goel, Lammers, Bekaii-Saab, Tam, Rajdev, Kelley, El Dika, Zemla, Potaracke, Balletti, Harding, Suga, Schwartz, Goldberg, Bertagnolli, Meyerhardt, O'Reilly, Venook.

Drafting of the manuscript: Abou-Alfa, Shi, Niedzwiecki, Kavan, Lammers, El Dika, Zemla, Potaracke, Schwartz, O'Reilly, Venook.

Critical revision of the manuscript for important intellectual content: Abou-Alfa, Shi, Knox, Kaubisch, Niedzwiecki, Posey, Tan, Kavan, Goel, Lammers, Bekaii-Saab, Tam, Rajdev, Kelley, Zemla, Balletti, El-Khoueiry, Harding, Suga, Schwartz, Goldberg, Bertagnolli, Meyerhardt, O'Reilly, Venook.

Statistical analysis: Abou-Alfa, Shi, Niedzwiecki, Kavan, Zemla, O'Reilly.

Obtained funding: Abou-Alfa, Schwartz, Bertagnolli, O'Reilly, Venook.

Administrative, technical, or material support: Abou-Alfa, Knox, Goel, Lammers, Bekaii-Saab, Rajdev, El Dika, Zemla, Potaracke, Schwartz, Goldberg, Bertagnolli, O'Reilly, Venook.

Study supervision: Abou-Alfa, Knox, Lammers, Tam, El-Khoueiry, Suga, Schwartz, Goldberg, Bertagnolli, O'Reilly, Venook.

Other—enrolled patients: Kaubisch.

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.

Funding/Support: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health (U10CA180821 and U10CA180882 to the Alliance for Clinical Trials in Oncology; U10CA077202, U10CA180820, U10CA180830, U10CA189859, U10CA180888, and UG1CA189821). The work was also supported in part by Bristol-Myers Squibb and Sanofi.

Role of the Funder/Sponsor: The National Cancer Institute of the National Institutes of Health reviewed and approved the design and conduct of the study. Bristol-Myers Squibb and Sanofi had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Meeting Presentation: These data were previously presented at the American Society of Clinical Oncology Annual Meeting; June 3–7; Chicago, Illinois.

Data Sharing Statement: See Supplement 3.

Additional Contributions: The authors thank the following investigators and institutions who participated in this study: Kendrith Rowland and the Carle Cancer Center NCI Community Oncology Research Program in Urbana, Illinois (UG1CA189861); Gary Schwartz and the Columbia University Minority Underserved NCORP in New York, New York (UG1CA189960); Howard Gross and the Dayton NCI Community Oncology Research Program in Dayton, Ohio (UG1CA189957); Gregory Masters and the Delaware/Christiana Care NCI Community Oncology Research Program in Newark, Delaware (UG1CA189819); Bret Friday and the Essentia Health NCI Community Oncology Research Program in Duluth, Minnesota (UG1CA189812); Jeffrey Berenberg and the Hawaii Minority Underserved NCORP in Honolulu, Hawaii (UG1CA189804); James Wade and they Heartland Cancer Research NCORP in Decatur, Illinois (UG1CA189830); Jeffrey Kirshner and the Hematology Oncology Associates of Central New York–East Syracuse in East Syracuse, New York; the Hematology Oncology Associates of Ohio and Michigan PC; Robert Behrens and the Iowa-Wide Oncology Research Coalition NCORP in Des Moines, Iowa (UG1CA189816); the Kansas City CCOP; Steven Alberts and the Mayo Clinic LAPS in Rochester, Minnesota (U10CA180790); Filipa Lynce and the MedStar Georgetown University Hospital in Washington, DC; Philip Lammers and the Meharry Medical College in Nashville, Tennessee; Michael Morris of the Memorial Sloan Kettering Cancer Center LAPS in New York, New York (U10CA180791); Daniel Anderson and the Metro Minnesota Community Oncology Research Consortium in Saint Louis Park, Minnesota (UG1CA189863); Jeffrey Giguere and the NCORP of the Carolinas (Greenville Health System NCORP) in Greenville, South Carolina (UG1CA189972); John Ellerton and the Nevada Cancer Research Foundation NCORP in Las Vegas, Nevada (UG1CA189829); Zoneddy Dayao and the New Mexico Minority Underserved NCORP in Albuquerque, New Mexico (UG1CA189856); the Northern Indiana Cancer Research Consortium in South Bend, Indiana; Daniel Budman and the Northwell Health NCORP in Lake Success, New York (UG1CA189850); John Cole and the Ochsner NCI Community Oncology Research Program in New Orleans, Louisiana (UG1CA189870); Claire Verschraegen and The Ohio State University Comprehensive Cancer Center LAPS in Columbus, Ohio (U10CA180850); Ellis Levine and the Roswell Park Cancer Institute LAPS in Buffalo, New York (U10CA180866); Preston Steen and the Sanford NCI Community Oncology Research Program of the North Central Plains in Sioux Falls, South Dakota (UG1CA189825); Marvin Feldman and the Sinai Hospital of Baltimore in Baltimore, Maryland; James Atkins and the Southeast Clinical Oncology Research Consortium NCORP in Winston-Salem, North Carolina (UG1CA189858); Charalambos Andreadis and the UCSF Medical Center–Mount Zion in San Francisco, California; Thomas Shea and the UNC Lineberger Comprehensive Cancer Center LAPS in Chapel Hill, North Carolina (U10CA180838); Hedy Kindler and the University of Chicago Comprehensive Cancer Center LAPS in Chicago, Illinois (U10CA180836); John Quigley and the University of Illinois in Chicago, Illinois; Laith Abushahin and the University of Iowa/Holden Comprehensive Cancer Center in Iowa City, Iowa; Bruce Peterson and the University of Minnesota/Masonic Cancer Center in Minneapolis, Minnesota; Puja Nistala and the University of Missouri Ellis Fischel Cancer Center in Columbia, Missouri; Apar Ganti and the University of Nebraska Medical Center in Omaha, Nebraska; Adam Asch and the University of Oklahoma Health Sciences Center LAPS in Oklahoma City, Oklahoma (U10CA180798); Steven Ades and the University of Vermont College of Medicine in Burlington, Vermont; Nancy Bartlett and the Washington University Siteman Cancer Center LAPS in St Louis, Missouri (U10CA180833); Scott Tagawa and the Weill Medical College of Cornell University in New York, New York; and Shaker Dakhil and the Wichita NCI Community Oncology Research Program in Wichita, Kansas (UG1CA189808).

References
1.
Llovet  JM, Ricci  S, Mazzaferro  V,  et al; SHARP Investigators Study Group.  Sorafenib in advanced hepatocellular carcinoma.  N Engl J Med. 2008;359(4):378-390. doi:10.1056/NEJMoa0708857PubMedGoogle ScholarCrossref
2.
Cheng  AL, Kang  YK, Chen  Z,  et al.  Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.  Lancet Oncol. 2009;10(1):25-34. doi:10.1016/S1470-2045(08)70285-7PubMedGoogle ScholarCrossref
3.
Yeo  W, Mok  TS, Zee  B,  et al.  A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma.  J Natl Cancer Inst. 2005;97(20):1532-1538. doi:10.1093/jnci/dji315PubMedGoogle ScholarCrossref
4.
Richly  H, Henning  BF, Kupsch  P,  et al.  Results of a phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors.  Ann Oncol. 2006;17(5):866-873. doi:10.1093/annonc/mdl017PubMedGoogle ScholarCrossref
5.
Abou-Alfa  GK, Johnson  P, Knox  JJ,  et al.  Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial.  JAMA. 2010;304(19):2154-2160. doi:10.1001/jama.2010.1672PubMedGoogle ScholarCrossref
6.
Zelen  M.  The randomization and stratification of patients to clinical trials.  J Chronic Dis. 1974;27(7-8):365-375. doi:10.1016/0021-9681(74)90015-0PubMedGoogle ScholarCrossref
7.
Miller  AA, Murry  DJ, Owzar  K,  et al.  Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301.  J Clin Oncol. 2009;27(11):1800-1805. doi:10.1200/JCO.2008.20.0931PubMedGoogle ScholarCrossref
8.
Lacouture  ME, Wu  S, Robert  C,  et al.  Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib.  Oncologist. 2008;13(9):1001-1011. doi:10.1634/theoncologist.2008-0131PubMedGoogle ScholarCrossref
9.
Lan  KKG, DeMets  DL.  Discrete sequential boundaries for clinical trials.  Biometrika. 1983;70(3):659-663. doi:10.2307/2336502Google ScholarCrossref
10.
O’Brien  PC, Fleming  TR.  A multiple testing procedure for clinical trials.  Biometrics. 1979;35(3):549-556. doi:10.2307/2530245PubMedGoogle ScholarCrossref
11.
Eisenhauer  EA, Therasse  P, Bogaerts  J,  et al.  New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).  Eur J Cancer. 2009;45(2):228-247. doi:10.1016/j.ejca.2008.10.026PubMedGoogle ScholarCrossref
12.
Kaplan  EL, Meier  P.  Nonparametric estimation from incomplete observations.  J Am Stat Assoc. 1958;53(282):457-481. doi:10.1080/01621459.1958.10501452Google ScholarCrossref
13.
Mantel  N.  Evaluation of survival data and two new rank order statistics arising in its consideration.  Cancer Chemother Rep. 1966;50(3):163-170.PubMedGoogle Scholar
14.
Peto  R, Peto  J.  Asymptotically efficient rank invariant test procedures.  J R Stat Soc [Ser A]. 1972;135(2):185-207. doi:10.2307/2344317Google ScholarCrossref
15.
Harrington  D. Linear rank tests in survival analysis. In: Armitage  P, Colton  T, eds.  Encyclopedia of Biostatistics. Cambridge, England: Wiley Interscience; 2005.
16.
Cox  DR.  Regression models and life-tables.  J R Stat Soc B. 1972;34(2):187-220.Google Scholar
17.
Abou-Alfa  GK, Schwartz  L, Ricci  S,  et al.  Phase II study of sorafenib in patients with advanced hepatocellular carcinoma.  J Clin Oncol. 2006;24(26):4293-4300. doi:10.1200/JCO.2005.01.3441PubMedGoogle ScholarCrossref
18.
Olweny  CL, Toya  T, Katongole-Mbidde  E, Mugerwa  J, Kyalwazi  SK, Cohen  H.  Treatment of hepatocellular carcinoma with adriamycin: preliminary communication.  Cancer. 1975;36(4):1250-1257. doi:10.1002/1097-0142(197510)36:4<1250::AID-CNCR2820360410>3.0.CO;2-XPubMedGoogle ScholarCrossref
19.
Brown  KT, Do  RK, Gonen  M,  et al.  Randomized trial of hepatic artery embolization for hepatocellular carcinoma using doxorubicin-eluting microspheres compared with embolization with microspheres alone.  J Clin Oncol. 2016;34(17):2046-2053. doi:10.1200/JCO.2015.64.0821PubMedGoogle ScholarCrossref
20.
McCubrey  JA, Steelman  LS, Abrams  SL,  et al.  Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance.  Adv Enzyme Regul. 2006;46:249-279. doi:10.1016/j.advenzreg.2006.01.004PubMedGoogle ScholarCrossref
21.
Alavi  AS, Acevedo  L, Min  W, Cheresh  DA.  Chemoresistance of endothelial cells induced by basic fibroblast growth factor depends on Raf-1-mediated inhibition of the proapoptotic kinase, ASK1.  Cancer Res. 2007;67(6):2766-2772. doi:10.1158/0008-5472.CAN-06-3648PubMedGoogle ScholarCrossref
22.
Song  S, Wientjes  MG, Gan  Y, Au  JL.  Fibroblast growth factors: an epigenetic mechanism of broad spectrum resistance to anticancer drugs.  Proc Natl Acad Sci USA. 2000;97(15):8658-8663. doi:10.1073/pnas.140210697PubMedGoogle ScholarCrossref
23.
Schneider  C, Wallner  M, Kolesnik  E,  et al.  The anti-cancer multikinase inhibitor sorafenib impairs cardiac contractility by reducing phospholamban phosphorylation and sarcoplasmic calcium transients.  Sci Rep. 2018;8(1):5295. doi:10.1038/s41598-018-23630-wPubMedGoogle ScholarCrossref
24.
Abou-Alfa  GK, Zhao  B, Capanu  M,  et al Tumor necrosis as a correlate for response in subgroup of patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib  [ESMO abstract 547P].  Ann Oncol. 2008:19(suppl 8):viii178.Google Scholar
25.
Petrick  JL, Kelly  SP, Altekruse  SF, McGlynn  KA, Rosenberg  PS.  Future of hepatocellular carcinoma incidence in the United States forecast through 2030.  J Clin Oncol. 2016;34(15):1787-1794. doi:10.1200/JCO.2015.64.7412PubMedGoogle ScholarCrossref
×