Ghassan K Abou-Alfa1, Oscar Puig2, Bruno Daniele3, Masatoshi Kudo4, Philippe Merle5, Joong-Won Park6, Paul Ross7, Jean-Marie Peron8, Oliver Ebert9, Stephen Chan10, Tung Ping Poon11, Massimo Colombo12, Takuji Okusaka13, Baek-Yeol Ryoo14, Beatriz Minguez15, Takayoshi Tanaka16, Toshihiko Ohtomo16, Stacey Ukrainskyj2, Frederic Boisserie2, Olga Rutman2, Ya-Chi Chen2, Chao Xu2, Eliezer Shochat17, Lori Jukofsky2, Bernhard Reis17, Gong Chen2, Laura Di Laurenzio2, Ray Lee2, Chia-Jui Yen18. 1. Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. Electronic address: abou-alg@mskcc.org. 2. Roche Innovation Center New York, Hoffmann-La Roche Inc., USA. 3. G. Rummo Hospital, Benevento, Italy. 4. Kinki University Hospital, Japan. 5. Hopital de la Croix-Rousse, Hepatologie et Gastroenterologie, Lyon, France. 6. National Cancer Center, Republic of Korea. 7. King's College Hospital, United Kingdom. 8. Hopital Purpan, Gastro Enterologie Hepatologie, France. 9. II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Germany. 10. Prince of Wales Hospital, Hong Kong. 11. Queen Mary Hospital, Hong Kong. 12. Fondazione IRCCS Ospedale Maggiore Policlinico, Italy. 13. National Cancer Center Hospital, Japan. 14. Asan Medical Center, Republic of Korea. 15. Liver Unit, Hospital Universitario Vall d́Hebron, Barcelona, Spain. 16. Chugai Pharmaceutical Co. Ltd., Japan. 17. Roche Innovation Center Basel, Hoffmann-La Roche, Switzerland. 18. National Cheng-Kung Univ. Hospital, Taiwan.
Abstract
BACKGROUND & AIMS:Codrituzumab, a humanized monoclonal antibody against Glypican-3 (GPC3) that is expressed in hepatocellular carcinoma (HCC), interacts with CD16/FcγRIIIa and triggers antibody-dependent cytotoxicity. Codrituzumab was studied vs. placebo in a randomized phase II trial in advanced HCC patients who had failed prior systemic therapy. METHODS:Patients with advanced HCC who had failed prior systemic therapy, ⩾18years, Eastern cooperative oncology group (ECOG) 0-1, Child-Pugh A were randomized 2:1 to biweekly codrituzumab 1600mg vs. placebo. Patients were stratified based on GPC3 immunohistochemical expression: 2+/3+, 1+, and 0. Primary endpoint was progression free survival. Secondary endpoints include overall survival (OS), tolerability, pharmacokinetics, and an exploratory endpoint in biomarkers analysis. RESULTS:185 patients were enrolled: 125 receivedcodrituzumab and 60 placebo: Median age 64/63, 85/75% male, 46/42% Asian, ECOG 0 65/63%, 74/77% having vascular invasion and/or extra-hepatic metastasis. 84%/70% had prior sorafenib. Drug exposure was 98.4% of planned dose, with an identical adverse events profile between the 2 groups. The median progression free survival and overall survival in the codrituzumab vs. placebo groups in months were: 2.6 vs. 1.5 (hazard ratios 0.97, p=0.87), and 8.7 vs. 10 (hazard ratios 0.96, p=0.82). Projected Ctrough at cycle 3day 1 based exposure, high CD16/FcγRIIIa on peripheral immune cells, and GPC3 expression in the tumor, were all associated with prolonged progression free survival and overall survival. CONCLUSIONS:Codrituzumab did not show clinical benefit in this previously treated HCC population. Whether higher codrituzumab drug exposure or the use of CD16 and GPC3 as potential biomarkers would improve outcome remain unanswered questions. LAY SUMMARY:Codrituzumab is a manufactured antibody against a liver cancer protein called glypican-3. In this clinical trial, codrituzumab was not found be effective against liver cancer. It was suggested though that a higher dose of codrituzumab or selecting patients with high level of glypican-3 or its mediator CD16 might improve outcome. CLINICAL TRIAL REGISTRATION: This trial is registered at Clinicaltrials.gov (NCT01507168).
RCT Entities:
BACKGROUND & AIMS:Codrituzumab, a humanized monoclonal antibody against Glypican-3 (GPC3) that is expressed in hepatocellular carcinoma (HCC), interacts with CD16/FcγRIIIa and triggers antibody-dependent cytotoxicity. Codrituzumab was studied vs. placebo in a randomized phase II trial in advanced HCC patients who had failed prior systemic therapy. METHODS:Patients with advanced HCC who had failed prior systemic therapy, ⩾18years, Eastern cooperative oncology group (ECOG) 0-1, Child-Pugh A were randomized 2:1 to biweekly codrituzumab 1600mg vs. placebo. Patients were stratified based on GPC3 immunohistochemical expression: 2+/3+, 1+, and 0. Primary endpoint was progression free survival. Secondary endpoints include overall survival (OS), tolerability, pharmacokinetics, and an exploratory endpoint in biomarkers analysis. RESULTS: 185 patients were enrolled: 125 received codrituzumab and 60 placebo: Median age 64/63, 85/75% male, 46/42% Asian, ECOG 0 65/63%, 74/77% having vascular invasion and/or extra-hepatic metastasis. 84%/70% had prior sorafenib. Drug exposure was 98.4% of planned dose, with an identical adverse events profile between the 2 groups. The median progression free survival and overall survival in the codrituzumab vs. placebo groups in months were: 2.6 vs. 1.5 (hazard ratios 0.97, p=0.87), and 8.7 vs. 10 (hazard ratios 0.96, p=0.82). Projected Ctrough at cycle 3day 1 based exposure, high CD16/FcγRIIIa on peripheral immune cells, and GPC3 expression in the tumor, were all associated with prolonged progression free survival and overall survival. CONCLUSIONS:Codrituzumab did not show clinical benefit in this previously treated HCC population. Whether higher codrituzumab drug exposure or the use of CD16 and GPC3 as potential biomarkers would improve outcome remain unanswered questions. LAY SUMMARY:Codrituzumab is a manufactured antibody against a liver cancer protein called glypican-3. In this clinical trial, codrituzumab was not found be effective against liver cancer. It was suggested though that a higher dose of codrituzumab or selecting patients with high level of glypican-3 or its mediator CD16 might improve outcome. CLINICAL TRIAL REGISTRATION: This trial is registered at Clinicaltrials.gov (NCT01507168).
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