Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma

Ghassan K. Abou-Alfa, S. Qin, B. Y. Ryoo, S. N. Lu, C. J. Yen, Y. H. Feng, H. Y. Lim, F. Izzo, M. Colombo, D. Sarker, L. Bolondi, Gina Vaccaro, W. P. Harris, Z. Chen, R. A. Hubner, T. Meyer, W. Sun, J. J. Harding, E. M. Hollywood, J. MaP. J. Wan, M. Ly, J. Bomalaski, A. Johnston, C. C. Lin, Y. Chao, L. T. Chen

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Background: Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme-arginine deiminase- conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy. Methods and patients: Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2: 1 to ADI-PEG 20 18 mg/m2 versus placebo intramuscular injection weekly. The primary end point was overall survival (OS), with 93% power to detect a 4-5.6 months increase in median OS (one-sided α=0.025). Secondary end points included progression-free survival, safety, and arginine correlatives. Results: A total of 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 versus 7.4 for placebo (P=0.88, HR=1.02) and median progression-free survival 2.6 months versus 2.6 (P=0.07, HR=1.17). Grade 3 fatigue and decreased appetite occurred in < 5% of patients. Two patients on ADI-PEG 20 had≥grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 versus 10.4% on placebo, none related to therapy. Post hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion. Conclusion: ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway.

Original languageEnglish (US)
Pages (from-to)1402-1408
Number of pages7
JournalAnnals of Oncology
Volume29
Issue number6
DOIs
StatePublished - Jun 1 2018

Fingerprint

Arginine
Hepatocellular Carcinoma
Patient Care
Placebos
Survival
Disease-Free Survival
Argininosuccinate Synthase
Therapeutics
Citrulline
Intramuscular Injections
Anaphylaxis
Appetite
Enzymes
Hepatitis C
Hepatitis B
Fatigue
Safety
Mortality

Keywords

  • ADI-PEG20
  • Argininosuccinate synthetase
  • ASS1
  • HCC
  • Hepatocellular carcinoma

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma. / Abou-Alfa, Ghassan K.; Qin, S.; Ryoo, B. Y.; Lu, S. N.; Yen, C. J.; Feng, Y. H.; Lim, H. Y.; Izzo, F.; Colombo, M.; Sarker, D.; Bolondi, L.; Vaccaro, Gina; Harris, W. P.; Chen, Z.; Hubner, R. A.; Meyer, T.; Sun, W.; Harding, J. J.; Hollywood, E. M.; Ma, J.; Wan, P. J.; Ly, M.; Bomalaski, J.; Johnston, A.; Lin, C. C.; Chao, Y.; Chen, L. T.

In: Annals of Oncology, Vol. 29, No. 6, 01.06.2018, p. 1402-1408.

Research output: Contribution to journalArticle

Abou-Alfa, GK, Qin, S, Ryoo, BY, Lu, SN, Yen, CJ, Feng, YH, Lim, HY, Izzo, F, Colombo, M, Sarker, D, Bolondi, L, Vaccaro, G, Harris, WP, Chen, Z, Hubner, RA, Meyer, T, Sun, W, Harding, JJ, Hollywood, EM, Ma, J, Wan, PJ, Ly, M, Bomalaski, J, Johnston, A, Lin, CC, Chao, Y & Chen, LT 2018, 'Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma', Annals of Oncology, vol. 29, no. 6, pp. 1402-1408. https://doi.org/10.1093/annonc/mdy101
Abou-Alfa, Ghassan K. ; Qin, S. ; Ryoo, B. Y. ; Lu, S. N. ; Yen, C. J. ; Feng, Y. H. ; Lim, H. Y. ; Izzo, F. ; Colombo, M. ; Sarker, D. ; Bolondi, L. ; Vaccaro, Gina ; Harris, W. P. ; Chen, Z. ; Hubner, R. A. ; Meyer, T. ; Sun, W. ; Harding, J. J. ; Hollywood, E. M. ; Ma, J. ; Wan, P. J. ; Ly, M. ; Bomalaski, J. ; Johnston, A. ; Lin, C. C. ; Chao, Y. ; Chen, L. T. / Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma. In: Annals of Oncology. 2018 ; Vol. 29, No. 6. pp. 1402-1408.
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TY - JOUR

T1 - Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma

AU - Abou-Alfa, Ghassan K.

AU - Qin, S.

AU - Ryoo, B. Y.

AU - Lu, S. N.

AU - Yen, C. J.

AU - Feng, Y. H.

AU - Lim, H. Y.

AU - Izzo, F.

AU - Colombo, M.

AU - Sarker, D.

AU - Bolondi, L.

AU - Vaccaro, Gina

AU - Harris, W. P.

AU - Chen, Z.

AU - Hubner, R. A.

AU - Meyer, T.

AU - Sun, W.

AU - Harding, J. J.

AU - Hollywood, E. M.

AU - Ma, J.

AU - Wan, P. J.

AU - Ly, M.

AU - Bomalaski, J.

AU - Johnston, A.

AU - Lin, C. C.

AU - Chao, Y.

AU - Chen, L. T.

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Background: Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme-arginine deiminase- conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy. Methods and patients: Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2: 1 to ADI-PEG 20 18 mg/m2 versus placebo intramuscular injection weekly. The primary end point was overall survival (OS), with 93% power to detect a 4-5.6 months increase in median OS (one-sided α=0.025). Secondary end points included progression-free survival, safety, and arginine correlatives. Results: A total of 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 versus 7.4 for placebo (P=0.88, HR=1.02) and median progression-free survival 2.6 months versus 2.6 (P=0.07, HR=1.17). Grade 3 fatigue and decreased appetite occurred in < 5% of patients. Two patients on ADI-PEG 20 had≥grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 versus 10.4% on placebo, none related to therapy. Post hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion. Conclusion: ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway.

AB - Background: Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme-arginine deiminase- conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy. Methods and patients: Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2: 1 to ADI-PEG 20 18 mg/m2 versus placebo intramuscular injection weekly. The primary end point was overall survival (OS), with 93% power to detect a 4-5.6 months increase in median OS (one-sided α=0.025). Secondary end points included progression-free survival, safety, and arginine correlatives. Results: A total of 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 versus 7.4 for placebo (P=0.88, HR=1.02) and median progression-free survival 2.6 months versus 2.6 (P=0.07, HR=1.17). Grade 3 fatigue and decreased appetite occurred in < 5% of patients. Two patients on ADI-PEG 20 had≥grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 versus 10.4% on placebo, none related to therapy. Post hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion. Conclusion: ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway.

KW - ADI-PEG20

KW - Argininosuccinate synthetase

KW - ASS1

KW - HCC

KW - Hepatocellular carcinoma

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DO - 10.1093/annonc/mdy101

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