Drug Combination May Benefit Patients with Transplanted Kidneys, Advanced Skin Cancers

putilov_denis/AdobeStock

Organ transplant recipients are at a much greater risk for skin cancer than are members of the general population, and balancing cancer treatment with organ preservation in these patients presents a challenge.¹ To address this, investigators recently performed a clinical trial to test a novel drug combination designed to fight advanced skin cancers while minimizing damage to transplanted kidneys in a small patient population.²

The investigators, led by Evan Lipson, MD, an associate professor of oncology at the Johns Hopkins University School of Medicine and Kimmel Cancer Center, used a combination of 2 immune-suppressing drugs (low-dose tacrolimus and prednisone) to protect the transplanted kidney and either 1 or 2 cancer-checkpoint inhibitors (nivolumab, ipilimumab) in a phase 1-2 study of 8 patients.

The patients had advanced melanoma, cutaneous squamous cell carcinoma, or Merkel cell carcinoma, and had either previously received standard, nonimmune-based therapies or were ineligible for them. All participants had previously received a kidney transplant and had adequate kidney function when they enrolled in the study. The average time from kidney transplantation to trial initiation was 13 years.

“To our knowledge, this study is the first to prospectively test whether low-dose tacrolimus [...] and prednisone can preserve a patient’s transplanted kidney while also allowing immune checkpoint inhibitor-mediated tumor regression in kidney transplant recipients with advanced skin cancers,” said Lipson in a Johns Hopkins news release.³

Study methods and results

The patients’ immunosuppression regimen was standardized to tacrolimus and prednisone 5 mg once daily. Patients then received nivolumab 480 mg by IV once every 4 weeks.

The primary composite end point was partial or complete tumorresponse or stable disease without allograft loss at 16 weeks. Patients with progressive disease could receive ipilimumab 1 mg/kg by IV andnivolumab 3 mg/kg once every 3 weeks × 4 followed by nivolumab. Donor-derived cell-free DNA levels were measured approximately once every 2 weeks as a potential predictor of allograft rejection.

None of the patients met the trial's primary end point, the investigators reported. All 8 patients experienced disease progression on nivolumab + tacrolimus + prednisone.

Treatment-related allograft loss occurred in 1 patient. Six patients received ipilimumab + nivolumab + tacrolimus + prednisone. After adding the second checkpoint inhibitor to the regimen, 2 of 6 patients experienced a complete response, meaning their tumors fully regressed.

The investigators concluded that in most kidney transplant recipients with advanced skin cancer, tacrolimus + prednisone provides insufficient allograft protection and compromises immune-mediated tumor regression after administration of nivolumab ± ipilimumab.

These results have led to the initiation of a follow-up study to test a different combination of immune-based therapies in this patient population, according to Johns Hopkins. The follow-up trial will pair prednisone with the immunosuppressive drug sirolimus in addition to nivolumab and ipilimumab, given concurrently, the university reported.

“The immune suppression we chose prevented nivolumab (anti-PD-1) from working at full effectiveness, but didn’t fully protect the kidney either,” said Lipson in the news release.

“We also learned that the immune system really started attacking cancer only when we added the second checkpoint inhibitor.”

The study was published in the Journal of Clinical Oncology.

References

1. Andrus E. Investigation of risk factors for metastatic cutaneous squamous cell carcinoma in organ transplant recipients. Dermatology Times. October 27, 2023. Accessed March 1, 2024. https://www.dermatologytimes.com/view/investigation-of-risk-factors-for-metastatic-cutaneous-squamous-cell-carcinoma-in-organ-transplant-recipients
2. Kara M. Schenk et al. Nivolumab + Tacrolimus + Prednisone ± Ipilimumab for kidney transplant recipients withadvanced cutaneous cancers. JCO. JCO.23.01497. DOI:10.1200/JCO.23.01497
3. Johns Hopkins Medicine. Immunotherapy combination may benefit patients with transplanted kidneys and advanced skin cancers. News release. February 28, 2024. Accessed March 1, 2024. https://www.eurekalert.org/news-releases/1035948