Efficacy and Safety of Bavituximab in Combination with Sorafenib in Advanced Hepatocellular Carcinoma: A Single-Arm, Open-Label, Phase II Clinical Trial
Bavituximab, an immunomodulator, targets phosphatidylserine (PS), a membrane lipid externalized on tumor and endothelial cells in response to sorafenib.
The objective of this phase II study was to assess the efficacy of combination bavituximab and sorafenib in advanced hepatocellular carcinoma (HCC).
In this single-arm phase II study, patients with HCC determined to be unresectable with Eastern Cooperative Oncology Group (ECOG) score ≤ 2, Child–Pugh score A/B7 received intravenous bavituximab 3 mg/kg weekly and oral sorafenib 400 mg twice daily until disease progression or intolerable toxicity. We investigated time to progression (TTP) for patients receiving combination bavituximab and sorafenib compared with that for sorafenib-only historical controls.
In total, 38 patients were accrued. The median follow-up was 6.1 months. Patient characteristics were as follows: median age 61 years; male 82%; hepatitis C virus 79%; Black 39%, Hispanic 26%, White 29%; previous treatment 39%; macrovascular invasion 84%; and extrahepatic metastases 24%. The median TTP was 6.7 months (95% confidence interval [CI] 4–17). The median overall survival was 6.1 months (95% CI 5–8), and the median disease-specific survival was 8.6 months (95% CI 6–14). Two patients experienced partial responses; none had a complete response. The disease control rate was 58%. Treatment-related adverse events were observed in 63% of patients, with the most commonly reported therapy-related symptoms being diarrhea (32%), fatigue (26%), and anorexia (24%).
The efficacy of adding bavituximab to sorafenib for the treatment of advanced HCC was inconclusive; however, the combination regimen did not exacerbate toxicities associated with single-agent sorafenib.
Compliance with Ethical Standards
This work was supported by Peregrine Pharmaceuticals, Inc.
Conflict of interest
AAM, HZ, YA, JD, and ACY have no conflicts of interest that might be relevant to the contents of this manuscript. MSB has served in a consulting/advisory role for Cegene, Ipsen, Genentech/Roche, Guardant Health, and Boston Biomedical; on a speaker’s bureau for Ipsen, Genentech/Roche, and Bristol-Myers Squibb; and has received research funding from Gelgene, Bristol-Myers Squibb, AstraZeneca/MedImmune, Merk Serono, Agios, Five Prime Therapeutics, MedImuune, Tolero Pharmaceuticals, ArQule, Genetech, Sillajen, and CASI Pharmaceuticals. AGS has served in a consultant/advisory role for Eisai, Exelixis, Bayer, and BMS and on a speaker’s bureau for Bayer and BMS.
- 1.Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the Global Burden of Disease Study. JAMA Oncol. 2017;3:524–48.PubMedCentralGoogle Scholar
- 2.European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer. EASL–EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56:908–43.Google Scholar
- 12.Riedl S, Rinner B, Asslaber M, Schaider H, Walzer S, Novak A, et al. In search of a novel target—Phosphatidylserine exposed by non-apoptotic tumor cells and metastases of malignancies with poor treatment efficacy. Biochim Biophys Acta BBA Biomembr. 2011;1808:2638–45.Google Scholar
- 15.He J, Yin Y, Luster TA, Watkins L, Thorpe PE. Antiphosphatidylserine antibody combined with irradiation damages tumor blood vessels and induces tumor immunity in a rat model of glioblastoma. Clin Cancer Res Off J Am Assoc Cancer Res. 2009;15:6871–80.Google Scholar
- 18.Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest. 1998;101:890–8.PubMedPubMedCentralGoogle Scholar
- 20.Chen X, Doffek K, Sugg SL, Shilyansky J. Phosphatidylserine regulates the maturation of human dendritic cells. J Immunol Baltim Md. 1950;2004(173):2985–94.Google Scholar
- 25.R Core Team. R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2015. https://www.R-project.org/.
- 26.Plummer M, Best N, Cowles K, Vines K. CODA: convergence diagnosis and output analysis for MCMC. R News. 2006;6:7–11.Google Scholar
- 36.Kudo M, Finn RS, Qin S, Han K-H, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet Lond Engl. 2018;391:1163–73.Google Scholar
- 40.Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012;30:2046–54.PubMedGoogle Scholar
- 43.Zhu AX, Park JO, Ryoo B-Y, Yen C-J, Poon R, Pastorelli D, et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015;16:859–70.PubMedGoogle Scholar
- 47.El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet Lond Engl. 2017;389:2492.Google Scholar
- 49.Kelley RK, Abou-Alfa GK, Bendell JC, Kim T-Y, Borad MJ, Yong W-P, et al. Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): phase I safety and efficacy analyses. J Clin Oncol. 2017;35:4073.Google Scholar
- 50.Gray MJ, Gong J, Hatch MMS, Nguyen V, Hughes CCW, Hutchins JT, et al. Phosphatidylserine-targeting antibodies augment the anti-tumorigenic activity of anti-PD-1 therapy by enhancing immune activation and downregulating pro-oncogenic factors induced by T-cell checkpoint inhibition in murine triple-negative breast cancers. Breast Cancer Res BCR. 2016;18:50.PubMedGoogle Scholar
- 52.Monzon JG, Hay AE, McDonald GT, Pater JL, Meyer RM, Chen E, et al. Correlation of single arm versus randomised phase 2 oncology trial characteristics with phase 3 outcome. Eur J Cancer Oxf Engl. 1990;2015(51):2501–7.Google Scholar