TY - JOUR
T1 - A phase II and biomarker study of sorafenib combined with modified FOLFOX in patients with advanced hepatocellular carcinoma
AU - Goyal, Lipika
AU - Zheng, Hui
AU - Abrams, Thomas A.
AU - Miksad, Rebecca
AU - Bullock, Andrea J.
AU - Allen, Jill N.
AU - Yurgelun, Matthew B.
AU - Clark, Jeffrey W.
AU - Kambadakone, Avinash
AU - Muzikansky, Alona
AU - Knowles, Michelle
AU - Galway, Aralee
AU - Afflitto, Anthony J.
AU - Dinicola, Caroline F.
AU - Regan, Eileen
AU - Hato, Tai
AU - Mamessier, Emilie
AU - Shigeta, Kohei
AU - Jain, Rakesh K.
AU - Duda, Dan G.
AU - Zhu, Andrew X.
N1 - Funding Information:
We thank Mrs. Anna Khachatryan (Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital) for technical support for biomarker studies. This study was funded by Bayer. L. Goyal received the NIH Loan Repayment Program Award and the NIH GI SPORE Award. R.K. Jain and D.G. Duda were supported by NIH P01-CA080124. K. Shigeta was supported by a fellowship from Uehara Foundation. E. Mamessier received a grant from the Philippe Foundation and Canceropole PACA.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Purpose: Sorafenib is a standard first-line treatment for advanced hepatocellular carcinoma (HCC). The phase III SHARP trial showed a median time-to-progression (mTTP) of 5.5 months, overall response rate (ORR) of 2%, and median overall survival (mOS) of 10.7 months with sorafenib. FOLFOX4 has shown modest activity in advanced HCC. We evaluated the combination of sorafenib and modified (m)FOLFOX in a single-arm, multicenter phase II study. Patients and Methods: The study included Child–Pugh A patients with advanced HCC and no prior systemic therapies. Patients received sorafenib 400 mg twice a day for 2 weeks, followed by concurrent mFOLFOX [5-fluorouracil (5-FU) 1,200 mg/m2/day for 46 hours, leucovorin 200 mg/m2, and oxaliplatin 85 mg/m2 biweekly]. The primary endpoint was mTTP with an alternative hypothesis of 7 months, and secondary endpoints included ORR, mOS, and circulating biomarkers. Results: The study enrolled 40 patients: HCV/EtOH/HBV, 43%/28%/13%; Child–Pugh A5, 70%. Notable grade 3/4 adverse events (AE) included AST/ALT elevation (28%/ 15%), diarrhea (13%), hyperbilirubinemia (10%), hand–foot syndrome (8%), and bleeding (8%). mTTP was 7.7 months [95% confidence interval (CI): 4.4–8.9], ORR 18%, and mOS 15.1 months (7.9–16.9). Sorafenib þ mFOLFOX increased plasma PlGF, VEGF-D, sVEGFR1, IL12p70, and CAIX and CD4þ and CD8þ effector T lymphocytes and decreased plasma sVEGFR2 and s-c-KIT and regulatory T cells (Tregs). Shorter TTP was associated with high baseline sVEGFR1. Shorter TTP and OS were associated with increases in Tregs and CD56Dim natural killer (NK) cells after sorafenib alone and plasma sMET after combination treatment (all P < 0.05). Conclusions: Sorafenib þ mFOLFOX met the prespecified endpoint with encouraging efficacy but moderate hepatotoxicity. Thus, this regimen may be effective in select patients with adequate liver reserve. Biomarker evaluations suggested a correlation between time-to-progression (TTP) and angiogenic biomarkers and circulating Tregs.
AB - Purpose: Sorafenib is a standard first-line treatment for advanced hepatocellular carcinoma (HCC). The phase III SHARP trial showed a median time-to-progression (mTTP) of 5.5 months, overall response rate (ORR) of 2%, and median overall survival (mOS) of 10.7 months with sorafenib. FOLFOX4 has shown modest activity in advanced HCC. We evaluated the combination of sorafenib and modified (m)FOLFOX in a single-arm, multicenter phase II study. Patients and Methods: The study included Child–Pugh A patients with advanced HCC and no prior systemic therapies. Patients received sorafenib 400 mg twice a day for 2 weeks, followed by concurrent mFOLFOX [5-fluorouracil (5-FU) 1,200 mg/m2/day for 46 hours, leucovorin 200 mg/m2, and oxaliplatin 85 mg/m2 biweekly]. The primary endpoint was mTTP with an alternative hypothesis of 7 months, and secondary endpoints included ORR, mOS, and circulating biomarkers. Results: The study enrolled 40 patients: HCV/EtOH/HBV, 43%/28%/13%; Child–Pugh A5, 70%. Notable grade 3/4 adverse events (AE) included AST/ALT elevation (28%/ 15%), diarrhea (13%), hyperbilirubinemia (10%), hand–foot syndrome (8%), and bleeding (8%). mTTP was 7.7 months [95% confidence interval (CI): 4.4–8.9], ORR 18%, and mOS 15.1 months (7.9–16.9). Sorafenib þ mFOLFOX increased plasma PlGF, VEGF-D, sVEGFR1, IL12p70, and CAIX and CD4þ and CD8þ effector T lymphocytes and decreased plasma sVEGFR2 and s-c-KIT and regulatory T cells (Tregs). Shorter TTP was associated with high baseline sVEGFR1. Shorter TTP and OS were associated with increases in Tregs and CD56Dim natural killer (NK) cells after sorafenib alone and plasma sMET after combination treatment (all P < 0.05). Conclusions: Sorafenib þ mFOLFOX met the prespecified endpoint with encouraging efficacy but moderate hepatotoxicity. Thus, this regimen may be effective in select patients with adequate liver reserve. Biomarker evaluations suggested a correlation between time-to-progression (TTP) and angiogenic biomarkers and circulating Tregs.
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U2 - 10.1158/1078-0432.CCR-18-0847
DO - 10.1158/1078-0432.CCR-18-0847
M3 - Article
C2 - 30190369
AN - SCOPUS:85059462821
VL - 25
SP - 80
EP - 89
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 1
ER -
