Nivolumab + Tacrolimus + Prednisone ± Ipilimumab for Kidney Transplant Recipients With Advanced Cutaneous Cancers

Abstract

PURPOSE Cancer-related mortality rates among kidney transplant recipients (KTR) are high, but these patients have largely been excluded from trials of immune checkpoint inhibitors because of immunosuppression and risk of treatment-related allograft loss (TRAL). We conducted a prospective clinical trial testing nivolumab (NIVO) + tacrolimus (TACRO) + prednisone (PRED) ± ipilimumab (IPI) in KTR with advanced cutaneous cancers. METHODS Adult KTR with advanced melanoma or basal, cutaneous squamous, or Merkel cell carcinomas were eligible. Immunosuppression was standardized to TACRO (serum trough 2-5 ng/mL) + PRED 5 mg once daily. Patients then received NIVO 480 mg IV once every 4 weeks. The primary composite end point was partial or complete (tumor) response (CR) or stable disease per RECIST v1.1 without allograft loss at 16W. Patients with progressive disease (PD) could receive IPI 1 mg/kg IV + NIVO 3 mg/kg once every 3 weeks × 4 followed by NIVO. Donor-derived cell-free DNA (dd-cfDNA) levels were measured approximately once every 2 weeks as a potential predictor of allograft rejection. RESULTS Among eight evaluable patients, none met the trial's primary end point. All eight patients experienced PD on NIVO + TACRO + PRED; TRAL occurred in one patient. Six patients then received IPI + NIVO + TACRO + PRED. Best overall responses: two CR (one with TRAL) and four PD (one with TRAL). In total, 7 of 8 pre-NIVO tumor biopsies contained a paucity of infiltrating immune cells. In total, 2 of 5 on-NIVO biopsies demonstrated moderate immune infiltrates; both patients later experienced a CR to IPI + NIVO. In 2 of 3 patients with TRAL, dd-cfDNA elevations occurred 10 and 15 days before increases in serum creatinine. CONCLUSION In most KTR with advanced skin cancer, TACRO + PRED provides insufficient allograft protection and compromises immune-mediated tumor regression after administration of NIVO ± IPI. Elevated dd-cfDNA levels can signal treatment-related allograft rejection earlier than rises in serum creatinine.

Immunotherapy for Advanced Skin Cancer in Kidney Transplant Recipients—The High-Risk Balancing Act

“…Hanna et al enrolled kidney transplant recipients with cSCC, while Schenk et al included kidney transplant recipients with heterogeneous skin cancers. Although the concept of “all comers” may be more generalizable, the variety of tumor types may have influenced the lower response rate.…”

“…Although the concept of “all comers” may be more generalizable, the variety of tumor types may have influenced the lower response rate. Only cSCC achieved CRs in the study by Schenk et al, and CRs was only observed with dual checkpoint inhibition.…”

“…However, in solid organ transplant recipients, immunotherapy is considered a high-risk or salvage option due to the possibility of allograft rejection. The newly published results of the first 2 prospective clinical trials involving immune checkpoint inhibitors in kidney transplant recipients contribute important information to this risk-benefit ratio and may enable more successful use of immunotherapy …”

“…The study by Schenk et al enrolled 12 kidney transplant recipients, of which 8 were evaluable and carried the diagnosis of cSCC, Merkel cell carcinoma or cutaneous melanoma. Patients were transitioned to low-dose tacrolimus (serum trough goal 2-5 ng/mL) and prednisone (5 mg/daily) at enrollment and started taking the PD-1i, nivolumab, within 11 days.…”

Fine-tuning tumor- and allo-immunity: advances in the use of immune checkpoint inhibitors in kidney transplant recipients

“…on eight KTR with advanced skin cancers (melanoma, cSCC, BCC, and Merkel cell carcinoma) treated with nivolumab with or without ipilimumab the patients were maintained on the standardized immunosuppression regimen of tacrolimus (with a target trough level of 2–5 ng/ml) and prednisone 5 mg daily. Out of eight patients enrolled, two experienced allograft rejections after addition of ipilimumab to nivolumab, and the ORR remained 33% [ 62 ].…”