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.

Trial registration: ClinicalTrials.gov NCT03816332.

Figure 1:

Durable complete tumor response with preserved allograft function in a 69-year-old male transplant recipient with CSCC of the left temple that had progressed through surgical resections, radiotherapy, carboplatin and cetuximab. He was switched from sirolimus to tacrolimus at trial enrollment. Pre-treatment clinical photograph (A) depicts a locally-destructive tumor with only singular lymphocytes seen on the paired micrograph (AA, AAA). Four weeks after starting nivolumab (NIVO), the tumor had enlarged (B); repeat tumor biopsy revealed 100% residual viable tumor (%RVT) and rare lymphocytes (BB, BBB). The tumor continued to grow and progressive disease was confirmed at 12 weeks (not shown) and the patient was transitioned to ipilimumab (IPI) + NIVO. Three weeks after starting IPI + NIVO, the tumor was clearly regressing (C) and an augmented immune cell infiltrate was observed on tumor biopsy (CC, CCC). By 8 weeks, tumor had regressed markedly (D), and there was 0% RVT seen on tumor biopsy (DD, DDD). The patient experienced a CR at 8 months; scouting biopsies revealed chronic inflammation and fibrosis without evidence of tumor (pathologic complete response). At 16 months the patient continued to experience a complete response without allograft loss (E). Of note, this patient was classified as having experienced primary resistance to NIVO per Society for Immunotherapy of Cancer (SITC) Immunotherapy Resistance Taskforce guidelines. Although the close temporal relationship between the addition of IPI and tumor regression supports a tumor response to combination therapy rather than a delayed response to NIVO alone, it is conceivable that delayed immune reconstitution after adjustment of immunosuppression at trial enrollment played a role. (AA-DD): H&E staining, magnification (from left to right): 110X, 180X, 130X, 130X. IHC duplex stain shows a mixture of CD4 (red)-positive and CD8 (brown)-positive lymphocytes (AAA–DDD), magnification (from left to right): 200X, 160X, 400X, 400X.

Figure 2:

Outcomes of 8 kidney transplant recipients with advanced cancer who received study therapy and were response-evaluable. Patient #4 (cutaneous squamous cell carcinoma): after experiencing PD to study therapy, switched from tacrolimus to sirolimus and received 4 additional doses of IPI+NIVO without tumor response, then received afatinib for <7 days, capecitabine for <7 days, underwent 2 surgical tumor resections, and was alive with an intact allograft at 28.8 months after first dose of NIVO. Patient #3 (Merkel cell carcinoma): following PD to IPI+NIVO+TACRO+PRED, stopped all immunosuppression and received off-protocol NIVO monotherapy, ultimately leading to graft rejection 8 weeks after cessation of study therapy. This patient died from progressive MCC ~7 months after starting trial therapy. (CR, complete tumor response; IPI, ipilimumab; NIVO, nivolumab; PD, progressive disease; PRED, prednisone; TACRO, tacrolimus)

Figure 3:

Elevations in donor-derived cell-free DNA (dd-cfDNA) can be an early indicator of treatment-related allograft rejection. Graph depicts plasma dd-cfDNA elevation 15 days prior to serum creatinine elevation in a 70-year-old male kidney transplant recipient with metastatic melanoma who developed acute T cell-mediated allograft rejection 4 weeks after receiving nivolumab. Dd-cfDNA elevations above the 1% threshold (horizontal dashed line) or >61% increase from baseline indicate likely acute kidney allograft rejection.