Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE)
M Moehler, J Heo, H C Lee, W Y Tak, Y Chao, S W Paik, H J Yim, K S Byun, A Baron, G Ungerechts, D Jonker, L Ruo, M Cho, A Kaubisch, H Wege, P Merle, O Ebert, F Habersetzer, J F Blanc, Olivier Rosmorduc, R Lencioni, R Patt, A M Leen, F Foerster, M Homerin, N Stojkowitz, M Lusky, J M Limacher, M Hennequi, N Gaspar, B McFadden, N De Silva, D Shen, A Pelusio, D H Kirn, C J Breitbach, J M Burke, M Moehler, J Heo, H C Lee, W Y Tak, Y Chao, S W Paik, H J Yim, K S Byun, A Baron, G Ungerechts, D Jonker, L Ruo, M Cho, A Kaubisch, H Wege, P Merle, O Ebert, F Habersetzer, J F Blanc, Olivier Rosmorduc, R Lencioni, R Patt, A M Leen, F Foerster, M Homerin, N Stojkowitz, M Lusky, J M Limacher, M Hennequi, N Gaspar, B McFadden, N De Silva, D Shen, A Pelusio, D H Kirn, C J Breitbach, J M Burke
Abstract
Pexastimogene devacirepvec (Pexa-Vec) is a vaccinia virus-based oncolytic immunotherapy designed to preferentially replicate in and destroy tumor cells while stimulating anti-tumor immunity by expressing GM-CSF. An earlier randomized Phase IIa trial in predominantly sorafenib-naïve hepatocellular carcinoma (HCC) demonstrated an overall survival (OS) benefit. This randomized, open-label Phase IIb trial investigated whether Pexa-Vec plus Best Supportive Care (BSC) improved OS over BSC alone in HCC patients who failed sorafenib therapy (TRAVERSE). 129 patients were randomly assigned 2:1 to Pexa-Vec plus BSC vs. BSC alone. Pexa-Vec was given as a single intravenous (IV) infusion followed by up to 5 IT injections. The primary endpoint was OS. Secondary endpoints included overall response rate (RR), time to progression (TTP) and safety. A high drop-out rate in the control arm (63%) confounded assessment of response-based endpoints. Median OS (ITT) for Pexa-Vec plus BSC vs. BSC alone was 4.2 and 4.4 months, respectively (HR, 1.19, 95% CI: 0.78-1.80; p = .428). There was no difference between the two treatment arms in RR or TTP. Pexa-Vec was generally well-tolerated. The most frequent Grade 3 included pyrexia (8%) and hypotension (8%). Induction of immune responses to vaccinia antigens and HCC associated antigens were observed. Despite a tolerable safety profile and induction of T cell responses, Pexa-Vec did not improve OS as second-line therapy after sorafenib failure. The true potential of oncolytic viruses may lie in the treatment of patients with earlier disease stages which should be addressed in future studies. ClinicalTrials.gov: NCT01387555.
Keywords: Hepatocellular carcinoma; Pexa-Vec; oncolytic immunotherapy; oncolytic vaccinia; sorafenib.
Figures
References
- GLOBOCAN Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012; 2012. doi:10.1094/PDIS-11-11-0999-PDN
- El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:1264. doi:10.1053/j.gastro.2011.12.061.
- Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099–7109. doi:10.1158/0008-5472.CAN-04-1443.
- Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7:3129–3140. doi:10.1158/1535-7163.MCT-08-0013.
- Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163–1173. doi:10.1016/S0140-6736(18)30207-1.
- Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–390. doi:10.1056/NEJMoa0708857.
- 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;10:25–34. doi:10.1016/S1470-2045(08)70285-7.
- Lencioni R, Kudo M, Ye SL, et al. First interim analysis of the GIDEON (Global Investigation of therapeutic decisions in hepatocellular carcinoma and of its treatment with sorafeNib) non-interventional study. Int J Clin Pract. 2012;66:675–683. doi:10.1111/j.1742-1241.2012.02940.x.
- Lencioni R. New data supporting modified RECIST (mRECIST) for hepatocellular carcinoma. Clin Cancer Res. 2013;19:1312–1314. doi:10.1158/1078-0432.CCR-12-3796.
- Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008;100:698–711. doi:10.1093/jnci/djn134.
- Kang YK, Yau T, Park JW, et al. Randomized phase II study of axitinib versus placebo plus best supportive care in second-line treatment of advanced hepatocellular carcinoma. Ann Oncol. 2015;26:2457–2463. doi:10.1093/annonc/mdv388.
- Llovet JM, Decaens T, Raoul JL, et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to Sorafenib or for whom Sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol. 2013;31:3509. doi:10.1200/JCO.2013.49.0219.
- Zhu AX, Park JO, Ryoo BY, 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;16:859–870. doi:10.1016/S1470-2045(15)00050-9.
- Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54–63. doi:10.1056/NEJMoa1717002.
- Bruix J, Qin SK, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56–66. doi:10.1016/S0140-6736(16)32453-9.
- El-Khoueiry AB, Sangro B, Yau T, 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. 2017;389:2492–2502. doi:10.1016/S0140-6736(17)31046-2.
- Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19:940–952. doi:10.1016/S1470-2045(18)30351-6.
- Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20:282–296. doi:10.1016/S1470-2045(18)30937-9.
- Finn RS, Chan SL, Zhu AX, et al. KEYNOTE-240: randomized phase III study of pembrolizumab versus best supportive care for second-line advanced hepatocellular carcinoma. J Clin Oncol. 2017;35(4_suppl):TPS503-TPS503.
- Bell J, McFadden G. Viruses for tumor therapy. Cell Host Microbe. 2014;15:260–265. doi:10.1016/j.chom.2014.01.002.
- Russell SJ, Peng KW, Bell JC. Oncolytic virotherapy. Nat Biotechnol. 2012;30:658–670. doi:10.1038/nbt.2287.
- Kirn DH, Thorne SH. Targeted and armed oncolytic poxviruses: a novel multi-mechanistic therapeutic class for cancer. Nat Rev Cancer. 2009;9:64–71. doi:10.1038/nrc2545.
- Moehler M, Goepfert K, Heinrich B, Breitbach CJ, Delic M, Galle PR, Rommelaere J. Oncolytic virotherapy as emerging immunotherapeutic modality: potential of parvovirus h-1. Front Oncol. 2014;4:92. doi:10.3389/fonc.2014.00092.
- Lichty BD, Breitbach CJ, Stojdl DF, Bell JC. Going viral with cancer immunotherapy. Nat Rev Cancer. 2014;14:559–567. doi:10.1038/nrc3770.
- Kim JH, Oh JY, Park BH, et al. Systemic armed oncolytic and immunologic therapy for cancer with JX-594, a targeted poxvirus expressing GM-CSF. Mol Ther. 2006;14:361–370. doi:10.1016/j.ymthe.2006.05.008.
- Parato KA, Breitbach CJ, Le Boeuf F, et al. The oncolytic poxvirus JX-594 selectively replicates in and destroys cancer cells driven by genetic pathways commonly activated in cancers. Mol Ther. 2012 Apr;20(4):749–758.
- Breitbach CJ, Arulanandam R, De Silva N, et al. Oncolytic vaccinia virus disrupts tumor-associated vasculature in humans. Cancer Res. 2013;73:1265–1275. doi:10.1158/0008-5472.CAN-12-2687.
- Heo J, Reid T, Ruo L, et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med. 2013;19:329–336. doi:10.1038/nm.3089.
- Andtbacka RH, Kaufman HL, Collichio F, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33:2780–2788. doi:10.1200/JCO.2014.58.3377.
- Chen HS, Qin LL, Cong X, et al. Expression of tumor-specific cancer/testis antigens in hepatocellular carcinoma. Zhonghua Gan Zang Bing Za Zhi. 2003;11:145–148.
- Zhao L, Mou DC, Leng XS, Peng J-R, Wang W-X, Huang L, Li S, Zhu J-Y. Expression of cancer-testis antigens in hepatocellular carcinoma. World J Gastroenterol. 2004;10:2034–2038. doi:10.3748/wjg.v10.i14.2034.
- Zhao X, Ogunwobi OO, Liu C, Gaetano C. Survivin inhibition is critical for Bcl-2 inhibitor-induced apoptosis in hepatocellular carcinoma cells. PLoS One. 2011;6:e21980. doi:10.1371/journal.pone.0021980.
- Worns MA, Galle PR. HCC therapies–lessons learned. Nat Rev Gastroenterol Hepatol. 2014;11:447–452. doi:10.1038/nrgastro.2014.10.
- Ringelhan M, Pfister D, O’Connor T, Pikarsky E, Heikenwalder M. The immunology of hepatocellular carcinoma. Nat Immunol. 2018;19:222–232. doi:10.1038/s41590-018-0044-z.
- Sia D, Jiao Y, Martinez-Quetglas I, et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology. 2017;153:812–826. doi:10.1053/j.gastro.2017.06.007.
- Foerster F, Hess M, Gerhold-Ay A, Marquardt JU, Becker D, Galle PR, Schuppan D, Binder H, Bockamp E. The immune contexture of hepatocellular carcinoma predicts clinical outcome. Sci Rep. 2018;8. doi:10.1038/s41598-018-21937-2.
- Liu TC, Hwang T, Park BH, Bell J, Kirn DH. The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma. Mol Ther. 2008;16:1637–1642. doi:10.1038/mt.2008.143.
- Zhu AX, Kudo M, Assenat E, et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. Jama. 2014;312:57–67. doi:10.1001/jama.2014.7189.
- Moehler MH, Zeidler M, Wilsberg V, Cornelis JJ, Woelfel T, Rommelaere J, Galle PR, Heike M. Parvovirus H-1-induced tumor cell death enhances human immune response in vitro via increased phagocytosis, maturation, and cross-presentation by dendritic cells. Hum Gene Ther. 2005;16:996–1005. doi:10.1089/hum.2005.16.996.
- Sieben M, Schafer P, Dinsart C, Galle PR, Moehler M. Activation of the human immune system via toll-like receptors by the oncolytic parvovirus H-1. Int J Cancer. 2013;132:2548–2556. doi:10.1002/ijc.27938.
- Kim MK, Breitbach CJ, Moon A, et al. Oncolytic and immunotherapeutic vaccinia induces antibody-mediated complement-dependent cancer cell lysis in humans. Sci Transl Med. 2013;(5):185ra163.
- Moehler M, Delic M, Goepfert K, et al. Immunotherapy in gastrointestinal cancer: recent results, current studies and future perspectives. Eur J Cancer. 2016;59:160–170. doi:10.1016/j.ejca.2016.02.020.
- Duffy AG, Ulahannan SV, Makorova-Rusher O, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol. 2017;66:545–551. doi:10.1016/j.jhep.2016.10.029.
- Sangro B, Gomez-Martin C, de la Mata M, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013;59:81–88. doi:10.1016/j.jhep.2013.02.022.
- European Association for Study of L, European Organisation for R, Treatment of C EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. Eur J Cancer. 2012;48:599–641. doi:10.1016/j.ejca.2011.12.021.
- Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30:52–60. doi:10.1055/s-0030-1247132.
- Jd Wolchok, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412–7420. doi:10.1158/1078-0432.CCR-09-1624.
- Koren E, Smith HW, Shores E, et al. Recommendations on risk-based strategies for detection and characterization of antibodies against biotechnology products. J Immunol Methods. 2008;333:1–9. doi:10.1016/j.jim.2008.01.001.
Source: PubMed