Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE)

被引：105

作者：

Moehler, M. ^{[1
]}

Heo, J. ^{[2
,3
]}

Lee, H. C. ^{[4
]}

Tak, W. Y. ^{[5
]}

Chao, Y. ^{[6
]}

Paik, S. W. ^{[7
]}

Yim, H. J. ^{[8
]}

Byun, K. S. ^{[9
]}

Baron, A. ^{[10
]}

Ungerechts, G. ^{[11
,12
]}

Jonker, D. ^{[13
]}

Ruo, L. ^{[14
]}

Cho, M. ^{[15
]}

Kaubisch, A. ^{[16
]}

Wege, H. ^{[17
]}

Merle, P. ^{[18
]}

Ebert, O. ^{[19
]}

Habersetzer, F. ^{[20
,21
]}

Blanc, J. F. ^{[22
]}

Rosmorduc, Olivier ^{[23
]}

Lencioni, R. ^{[24
]}

Patt, R. ^{[25
]}

Leen, A. M. ^{[26
]}

Foerster, F. ^{[1
]}

Homerin, M. ^{[27
]}

Stojkowitz, N. ^{[28
]}

Lusky, M. ^{[29
]}

Limacher, J. M. ^{[27
]}

Hennequi, M. ^{[30
]}

Gaspar, N. ^{[31
]}

McFadden, B. ^{[32
]}

De Silva, N. ^{[33
]}

Shen, D. ^{[33
]}

Pelusio, A. ^{[33
]}

Kirn, D. H. ^{[34
]}

Breitbach, C. J. ^{[33
]}

Burke, J. M. ^{[33
]}

机构：

[1] Johannes Gutenberg Univ Mainz, Dept Med 1, Univ Med Ctr, Mainz, Germany

[2] Pusan Natl Univ, Coll Med, Busan, South Korea

[3] Pusan Natl Univ Hosp, Med Res Inst, Busan, South Korea

[4] Univ Ulsan, Asan Med Ctr, Coll Med, Ulsan, South Korea

[5] Kyungpook Natl Univ, Sch Med, Med Ctr, Daegu, South Korea

[6] Taipei Vet Gen Hosp, Dept Oncol, Taipei, Taiwan

[7] Sungkyunkwan Univ, Samsung Med Ctr, Dept Med, Sch Med, Seoul, South Korea

[8] Korea Univ, Dept Internal Med, Ansan Hosp, Ansan, South Korea

[9] Korea Univ, Dept Internal Med, Coll Med, Seoul, South Korea

[10] Calif Pacific Med Ctr, Dept Med, San Francisco, CA USA

[11] Natl Ctr Tumor Dis NCT, Dept Med Oncol, Heidelberg, Germany

[12] Heidelberg Univ Hosp, Heidelberg, Germany

[13] Univ Ottawa, Ottawa Hosp Res Inst, Ottawa, ON, Canada

[14] McMaster Univ, Juravinski Hosp & Canc Ctr, Dept Surg, Hamilton, ON, Canada

[15] Pusan Natl Univ, Dept Internal Med, Yangsan Hosp, Busan, South Korea

[16] Montefiore Med Ctr, Dept Med, New York, NY USA

[17] Univ Med Ctr Hamburg Eppendorf, Dept Med Gastroenterol & Hepatol, Hamburg, Germany

[18] Croix Rousse Hosp, Hepatol Unit, Lyon, France

[19] Tech Univ, Klinikum Rechts Isar, Klin & Poliklin Innere Med 2, Munich, Germany

[20] Hop Univ Strasbourg, IHU Strasbourg, Pole Hepatodigestif, INSERM 1110, Inserm, France

[21] Univ Strasbourg, Inserm, France

[22] CHU Bordeaux, Hepatogastroenterol & Digest Oncol Dept, Bordeaux, France

[23] Sorbonne Univ, Hop Paul Brousse, AP HP, Villejuif, France

[24] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA

[25] Rad MD, New York, NY USA

[26] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[27] Transgene SA, Med Affairs, 400 Bd Gonthier dAndernach,Parc Innovat, F-67405 Illkirch Graffenstaden, France

[28] Transgene SA, Clin Operat, 400 Bd Gonthier dAndernach,Parc Innovat, F-67405 Illkirch Graffenstaden, France

[29] Transgene SA, Program Management, 400 Bd Gonthier dAndernach,Parc Innovat, F-67405 Illkirch Graffenstaden, France

[30] Transgene SA, Biostat, 400 Bd Gonthier dAndernach,Parc Innovat, F-67405 Illkirch Graffenstaden, France

[31] SillaJen Inc, Ain Assays, San Francisco, CA USA

[32] SillaJen Inc, Analyt Dev & Qual Control, San Francisco, CA USA

[33] SillaJen Inc, Clin, San Francisco, CA USA

[34] SillaJen Inc, San Francisco, CA USA

来源：

ONCOIMMUNOLOGY | 2019年 / 8卷 / 08期

关键词：

Hepatocellular carcinoma; Pexa-Vec; sorafenib; oncolytic immunotherapy; oncolytic vaccinia; MODIFIED RECIST MRECIST; 2ND-LINE TREATMENT; CLINICAL-TRIAL; DOUBLE-BLIND; CANCER; JX-594; THERAPY; PLACEBO; HEPATITIS; TARGETS;

D O I：

10.1080/2162402X.2019.1615817

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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-naive 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

引用

页数：11

共 48 条

[21] Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial [J].

Kudo, Masatoshi ;

Finn, Richard S. ;

Qin, Shukui ;

Han, Kwang-Hyub ;

Ikeda, Kenji ;

Piscaglia, Fabio ;

Baron, Ari ;

Park, Joong-Won ;

Han, Guohong ;

Jassem, Jacek ;

Blanc, Jean Frederic ;

Vogel, Arndt ;

Komov, Dmitry ;

Evans, T. R. Jeffry ;

Lopez, Carlos ;

Dutcus, Corina ;

Guo, Matthew ;

Saito, Kenichi ;

Kraljevic, Silvija ;

Tamai, Toshiyuki ;

Ren, Min ;

Cheng, Ann-Lii .

LANCET, 2018, 391 (10126) :1163-1173

[22]

Lencioni R, 2012, Int J Clin Pract, V66, P675, DOI 10.1111/j.1742-1241.2012.02940.x

[23] New Data Supporting Modified RECIST (mRECIST) for Hepatocellular Carcinoma [J].

Lencioni, Riccardo .

CLINICAL CANCER RESEARCH, 2013, 19 (06) :1312-1314

[24] Modified RECIST (mRECIST) Assessment for Hepatocellular Carcinoma [J].

Lencioni, Riccardo ;

Llovet, Josep M. .

SEMINARS IN LIVER DISEASE, 2010, 30 (01) :52-60

[25] Going viral with cancer immunotherapy [J].

Lichty, Brian D. ;

Breitbach, Caroline J. ;

Stojdl, David F. ;

Bell, John C. .

NATURE REVIEWS CANCER, 2014, 14 (08) :559-567

[26] The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma [J].

Liu, Ta-Chiang ;

Hwang, Taeho ;

Park, Byeong-Ho ;

Bell, John ;

Kirn, David H. .

MOLECULAR THERAPY, 2008, 16 (09) :1637-1642

[27] Sorafenib in advanced hepatocellular carcinoma [J].

Llovet, Josep M. ;

Ricci, Sergio ;

Mazzaferro, Vincenzo ;

Hilgard, Philip ;

Gane, Edward ;

Blanc, Jean-Frederic ;

Cosme de Oliveira, Andre ;

Santoro, Armando ;

Raoul, Jean-Luc ;

Forner, Alejandro ;

Schwartz, Myron ;

Porta, Camillo ;

Zeuzem, Stefan ;

Bolondi, Luigi ;

Greten, Tim F. ;

Galle, Peter R. ;

Seitz, Jean-Francois ;

Borbath, Ivan ;

Haussinger, Dieter ;

Giannaris, Tom ;

Shan, Minghua ;

Moscovici, Marius ;

Voliotis, Dimitris ;

Bruix, Jordi .

NEW ENGLAND JOURNAL OF MEDICINE, 2008, 359 (04) :378-390

[28] Design and endpoints of clinical trials in hepatocellular carcinoma [J].

Llovet, Josep M. ;

Di Bisceglie, Adrian M. ;

Bruix, Jordi ;

Kramer, Barnett S. ;

Lencioni, Riccardo ;

Zhu, Andrew X. ;

Sherman, Morris ;

Schwartz, Myron ;

Lotze, Michael ;

Talwalkar, Jayant ;

Gores, Gregory J. .

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2008, 100 (10) :698-711

[29] 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].

Llovet, Josep M. ;

Decaens, Thomas ;

Raoul, Jean-Luc ;

Boucher, Eveline ;

Kudo, Masatoshi ;

Chang, Charissa ;

Kang, Yoon-Koo ;

Assenat, Eric ;

Lim, Ho-Yeong ;

Boige, Valerie ;

Mathurin, Philippe ;

Fartoux, Laetitia ;

Lin, Deng-Yn ;

Bruix, Jordi ;

Poon, Ronnie T. ;

Sherman, Morris ;

Blanc, Jean-Frederic ;

Finn, Richard S. ;

Tak, Won-Young ;

Chao, Yee ;

Ezzeddine, Rana ;

Liu, David ;

Walters, Ian ;

Park, Joong-Won .

JOURNAL OF CLINICAL ONCOLOGY, 2013, 31 (28) :3509-+

[30] Immunotherapy in gastrointestinal cancer: Recent results, current studies and future perspectives [J].

Moehler, Markus ;

Delic, Maike ;

Goepfert, Katrin ;

Aust, Daniela ;

Grabsch, Heike I. ;

Halama, Niels ;

Heinrich, Bernd ;

Julie, Catherine ;

Lordick, Florian ;

Lutz, Manfred P. ;

Mauer, Murielle ;

Alsina Maqueda, Maria ;

Schild, Hansjoerg ;

Schimanski, Carl C. ;

Wagner, Anna-Dorothea ;

Roth, Arnaud ;

Ducreux, Michel .

EUROPEAN JOURNAL OF CANCER, 2016, 59 :160-170

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