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. 2021 Jul 1;105(7):1564-1575.
doi: 10.1097/TP.0000000000003394.

Efficacy and Safety of Everolimus With Reduced Tacrolimus in Liver Transplant Recipients: 24-month Results From the Pooled Analysis of 2 Randomized Controlled Trials

Sung-Gyu Lee  1 , Long-Bin Jeng  2 , Faouzi Saliba  3 , Arvinder Singh Soin  4 , Wei-Chen Lee  5 , Paolo De Simone  6 , Frederik Nevens  7 , Kyung-Suk Suh  8 , Lutz Fischer  9 , Dong Jin Joo  10 , John Fung  11 , Jae-Won Joh  12 , Toshimi Kaido  13 , David Grant  14 , Matthias Meier  15 , Barbara Rauer  15 , Carole Sips  15 , Shuhei Kaneko  16 , Gary Levy  17
Affiliations

Efficacy and Safety of Everolimus With Reduced Tacrolimus in Liver Transplant Recipients: 24-month Results From the Pooled Analysis of 2 Randomized Controlled Trials

Sung-Gyu Lee et al. Transplantation. .

Abstract

Background and methods: Data from 2 randomized liver transplant trials (N = 772; H2304 [deceased donor, n = 488], H2307 [living donor, n = 284]) were pooled to further evaluate the efficacy and safety of everolimus with reduced tacrolimus (EVR + rTAC) versus standard tacrolimus (sTAC) regimen at month 24.

Results: EVR + rTAC was comparable to sTAC for composite efficacy failure of treated biopsy-proven acute rejection, graft loss, or death (9.8% versus 10.8%; difference, -1.0%; 95% confidence interval, -5.4 to 3.4; P = 0.641) at month 24. EVR + rTAC was superior to sTAC for the mean change in estimated glomerular filtration rate (eGFR) from randomization to month 24 (-8.37 versus -13.40 mL/min/1.73 m2; P = 0.001). A subanalysis of renal function by chronic kidney disease (CKD) stage at randomization showed significantly lower decline in eGFR from randomization to month 24 for patients with CKD stage 1/2 (eGFR ≥ 60 mL/min/1.73 m2) in EVR + rTAC group versus sTAC (-12.82 versus -17.67 mL/min/1.73 m2, P = 0.009). In patients transplanted for hepatocellular carcinoma (HCC) beyond Milan criteria, HCC recurrence was numerically lower although not statistically significant with EVR + rTAC versus sTAC group (5.9% [1 of 17] versus 23.1% [6 of 26], P = 0.215), while comparable in patients within Milan criteria (2.9% [3 of 102] versus 2.1% [2 of 96], P = 1.000), irrespective of pretransplant alpha-fetoprotein levels.

Conclusions: EVR + rTAC versus sTAC showed comparable efficacy and safety with significantly better renal function, particularly in patients with normal/mildly decreased renal function (CKD stage 1/2) at randomization and a trend toward lower HCC recurrence in patients transplanted with HCC beyond Milan at month 24. Further long-term data would be required to confirm these results.

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Conflict of interest statement

F.S. has received speaker honoraria and/or research grants from Novartis, Astellas, Chiesi, Genzyme, Gilead, AbbVie, Merck, Sharp & Dohme, Pfizer, Gambro and Baxter. P.D.S. is an advisory board member and has received speaker’s fees from Novartis. F.N. has received research grants from Astellas, Ipsen, and MSD and has served as consultant for Gilead, AbbVie, Promethera Biosciences, Durect, Ferring, Gore, Cook Medical, TwinPharma, Ipsen, and Intercept. L.F. has received speaker honoraria (Novartis Pharma, Astellas Pharma), has served as a member of Data and Safety Monitoring Board (Novartis Pharma), and is involved in clinical trials sponsored by Astellas Pharma, Chiesi, Novartis Pharma, and Quark Pharmaceuticals. D.J.J. has received speaker honoraria from Novartis. J.F. has received educational grant from Sanofi and has served as a member of Drug Safety Monitoring Board. M.M., C.S., and S.K. are employees of Novartis. B.R. is an ex-employee of Novartis. G.L. has served as consultant for Astellas, Novartis, Therapure Pharm Inc, Veritas Therapeutics and is a member of scientific advisory board of Singapore MRC. The other authors declare no conflicts of interest.

Figures

None
Graphical abstract
FIGURE 1.
FIGURE 1.
Everolimus (A) and tacrolimus (B) trough concentrations during the study. Values are shown as mean (SD). Shaded areas indicate target ranges. EVR, everolimus; M, month; rTAC, reduced tacrolimus; sTAC, standard tacrolimus; W, week.
FIGURE 2.
FIGURE 2.
Kaplan–Meier plot for proportion of patients free from composite efficacy failure of tBPAR, graft loss, or death. EVR, everolimus; rTAC, reduced tacrolimus; sTAC, standard tacrolimus; tBPAR, treated biopsy-proven acute rejection.
FIGURE 3.
FIGURE 3.
Renal function from baseline to month 24. P value based on the Wilcoxon rank-sum test. BL, baseline; eGFR, estimated glomerular filtration rate; EVR, everolimus; LTx, liver transplantation; M, month; MDRD4, 4-variable modification of diet in renal disease formula; RND, randomization; rTAC, reduced tacrolimus; sTAC, standard tacrolimus; W, week.
FIGURE 4.
FIGURE 4.
Change in eGFR from randomization to month 24 by MELD score at transplant. P value based on the Wilcoxon rank-sum test. Patients with assessments at both randomization and month 24 are included. eGFR, estimated glomerular filtration rate; EVR, everolimus; M, total number of patients; MDRD4, 4-variable modification of diet in renal disease formula; MELD, model for end-stage liver disease; n, number of patients evaluable; rTAC, reduced tacrolimus; sTAC, standard tacrolimus.
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