Phase III Study of Belatacept Versus Cyclosporine in Kidney Transplants from Extended Criteria Donors (BENEFIT‐EXT Study)

Abstract

Recipients of extended criteria donor (ECD) kidneys are at increased risk for graft dysfunction/loss, and may benefit from immunosuppression that avoids calcineurin inhibitor (CNI) nephrotoxicity. Belatacept, a selective costimulation blocker, may preserve renal function and improve long-term outcomes versus CNIs. BENEFIT-EXT (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-EXTended criteria donors) is a 3-year, Phase III study that assessed a more (MI) or less intensive (LI) regimen of belatacept versus cyclosporine in adult ECD kidney transplant recipients. The coprimary endpoints at 12 months were composite patient/graft survival and a composite renal impairment endpoint. Patient/graft survival with belatacept was similar to cyclosporine (86% MI, 89% LI, 85% cyclosporine) at 12 months. Fewer belatacept patients reached the composite renal impairment endpoint versus cyclosporine (71% MI, 77% LI, 85% cyclosporine; p = 0.002 MI vs. cyclosporine; p = 0.06 LI vs. cyclosporine). The mean measured glomerular filtration rate was 4-7 mL/min higher on belatacept versus cyclosporine (p = 0.008 MI vs. cyclosporine; p = 0.1039 LI vs. cyclosporine), and the overall cardiovascular/metabolic profile was better on belatacept versus cyclosporine. The incidence of acute rejection was similar across groups (18% MI; 18% LI; 14% cyclosporine). Overall rates of infection and malignancy were similar between groups; however, more cases of posttransplant lymphoproliferative disorder (PTLD) occurred in the CNS on belatacept. ECD kidney transplant recipients treated with belatacept-based immunosuppression achieved similar patient/graft survival, better renal function, had an increased incidence of PTLD, and exhibited improvement in the cardiovascular/metabolic risk profile versus cyclosporine-treated patients.

Long-Term Outcomes in Belatacept- Versus Cyclosporine-Treated Recipients of Extended Criteria Donor Kidneys: Final Results From BENEFIT-EXT, a Phase III Randomized Study

“…As in prior analyses 28, 29, 30, acute rejection was defined as central biopsy–proven rejection that was either clinically suspected for protocol‐defined reasons or clinically suspected for other reasons and treated. A combined end point comprising time to first occurrence of death, graft loss or estimated GFR (eGFR) <20 mL/min per 1.73 m 2 was examined post hoc .…”

“…These randomized phase III studies compared two belatacept‐based immunosuppressive regimens (more intense [MI] and less intense [LI]) with CsA‐based immunosuppression in adult kidney transplant recipients. In BENEFIT‐EXT, analyses performed at 1, 3 and 5 years after transplant demonstrated that belatacept‐based immunosuppression was associated with similar rates of patient and graft survival and superior renal function versus CsA‐based immunosuppression; however, rates of acute rejection were numerically higher with belatacept‐based treatment 28, 29, 30.…”

Ten-year outcomes in a randomized phase II study of kidney transplant recipients administered belatacept 4-weekly or 8-weekly

“…The comparable rates of acute rejection for belatacept‐based vs CsA‐based immunosuppression were preserved over 10 years: acute rejection rates in the belatacept treatment arms (6%‐7%) were noninferior to that observed in the CsA treatment arm (8%) at 6 months posttransplant in IM103‐100 10. Most acute rejection events in belatacept‐treated patients occur within 6 months of treatment initiation 10, 12, 13. In IM103‐100, most BPAR events in the population at first randomization were reported by month 6 (28 of 41, 68.3%).…”

“…The additional dose in BENEFIT and BENEFIT‐EXT was administered on day 4 posttransplant to optimize saturation of CD80/CD86 ligands and blockade of CD28 activation. Despite these caveats, in analyses performed at 1 and 7 years posttransplant, rates of acute rejection were higher for belatacept‐treated vs CsA‐treated patients participating in BENEFIT12, 14, 15 and similar for belatacept‐treated vs CsA‐treated patients participating in BENEFIT‐EXT 13, 16…”

“…However, it is difficult to compare the results from these phase III studies to IM103‐100 because enrollment to this phase II study was substantially lower and both the definition of acute rejection and the belatacept LI regimen administered were different. With regard to the latter, patients allocated to belatacept LI‐based immunosuppression in IM103‐100 received 5 doses of belatacept 10 mg/kg during the induction phase, while patients randomized to belatacept LI in BENEFIT12 and BENEFIT‐EXT13 received 6 induction doses of belatacept 10 mg/kg. The additional dose in BENEFIT and BENEFIT‐EXT was administered on day 4 posttransplant to optimize saturation of CD80/CD86 ligands and blockade of CD28 activation.…”