In a small phase I/II trial reported in the Journal of Clinical Oncology, Schenk et al found that treatment with tacrolimus, prednisone, and nivolumab without or with ipilimumab produced few responses in kidney transplant recipients with advanced skin cancers, with treatment-related allograft loss being a common event.
Study Details
In the U.S. multicenter trial, eight evaluable patients enrolled between November 2019 and August 2021 received low-dose tacrolimus (serum trough goal = 2–5 ng/mL) and prednisone at 5 mg once daily. After confirmation of serum creatinine stability, patients received nivolumab at 480 mg every 4 weeks. The primary composite endpoint was objective response or stable disease without allograft loss at 16 weeks. Patients with progressive disease could receive ipilimumab at 1 mg/kg plus nivolumab at 3 mg/kg every 3 weeks for four cycles, followed by nivolumab at 480 mg every 4 weeks for a total of 96 weeks. Donor-derived cell-free DNA (dd-cfDNA) levels were measured approximately every 2 weeks as a potential predictor of allograft rejection.
Key Findings
None of the eight patients met the primary endpoint: all eight had progressive disease and one had treatment-related allograft loss.
Among six patients subsequently receiving ipilimumab plus nivolumab, two had complete response, including one with allograft loss, and four had progressive disease, including one with allograft loss.
In total, seven of eight tumor biopsies taken before the start of nivolumab therapy contained low levels of infiltrating immune cells. Biopsies in two of five patients taken during nivolumab treatment showed moderate immune infiltrates; these two patients later experienced complete response on ipilimumab plus nivolumab.
In two of the three patients with treatment-related allograft loss, dd-cfDNA elevations occurred 10 and 15 days before increases in serum creatinine, respectively.
Allograft rejection accounted for the majority of grade ≥ 3 treatment-related adverse events. One such event, anemia, was attributed to nivolumab monotherapy; no such events were attributed to ipilimumab plus nivolumab. No treatment-related deaths were reported.
The investigators concluded, “In most kidney transplant recipients with advanced skin cancer, tacrolimus plus prednisone provides insufficient allograft protection and compromises immune-mediated tumor regression after administration of nivolumab without or with ipilimumab. Elevated dd-cfDNA levels can signal treatment-related allograft rejection earlier than rises in serum creatinine.”
Evan J. Lipson, MD, of Johns Hopkins University School of Medicine, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the National Cancer Institute, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Bristol Myers Squibb, and others. For full disclosures of the study authors, visit ascopubs.org.
