Immune Checkpoint Inhibitor Therapy Seen Feasible After Kidney Transplant

Continuing regular immunosuppression does not appear to diminish the efficacy of immune checkpoint inhibitors in kidney transplant recipients with incurable, locally advanced cancer or defined metastatic solid tumors, according to a small phase I study.

Furthermore, organ rejection among those patients was lower than observed in previously published studies, reported Robert P. Carroll, MBChB, of Royal Adelaide Hospital in Australia, and colleagues in The Lancet Oncology.

Nine of the 17 patients in the study achieved a response when treated with checkpoint inhibition, a rate similar to those reported in the general population of patients with cancer, Carroll and his colleagues observed. In addition, just two (12%) of the patients developed allograft rejection, only one of whom did not respond to anti-rejection therapy and progressed to terminal allograft failure.

Moreover, no patient experienced irretrievable allograft failure without evidence of tumor response, which was the study’s composite primary endpoint.

“Without formalized prospective studies, organ transplant recipients are likely to be excluded from effective treatment with immune checkpoint inhibitors in clinical practice,” wrote Carroll and his colleagues. Results of this study, however, suggest that “[a]ssessment of immunological risk and immunosuppression drug regimen before and during checkpoint inhibition can lead to acceptable outcomes.”

In addition to the overall response rate described above:

• Complete responses were seen in four (24%) of the patients, including one (6%) patient with microsatellite instability-high colorectal cancer, and three (18%) patients with squamous cell carcinoma of the head and neck.
• Partial responses were observed in five (29%) patients, including three (18%) patients with squamous cell carcinoma of the head and neck, one (6%) patient with bladder cancer, and one (6%) patient with hepatocellular carcinoma.
• The mean duration of response was 27.7 months.
• Nine patients died, with a median overall survival of 3.2 months (95% CI 0.8–not reached) among all participants. All but two of the deaths occurred in the first 4 months.
• There were 12 disease progression events, with a median progression-free survival of 2.5 months (95% CI 1.1–not reached).

Not only was irretrievable allograft loss in the absence of tumor response not seen, but neither was allograft rejection without allograft loss and no evidence of tumor response. One patient had allograft rejection without allograft loss with tumor response, and one patient had allograft loss with tumor response.

Carroll’s group also noted that measuring urinary inflammatory chemokine IP-10 might be useful in identifying kidney transplant recipients who may be at risk of rejection after exposure to immune checkpoint inhibitor.

There were no treatment-related deaths or treatment-related serious adverse events. The most common grade 3 or grade 4 adverse events were decreased lymphocyte count in four patients, fever or infection in four patients, decreased hemoglobin in three patients, and increased creatinine in three patients.

This multicenter, single-arm trial took place across three hospitals in Australia, and enrolled 22 participants from 2017 to 2021. It included patients 18 years or older with incurable, locally advanced cancer or defined metastatic solid tumors who were eligible if they had a creatinine concentration of less than 180 mmol/L, no or low concentrations of donor-specific HLA antibodies, and an ECOG status of 0–2. Patients were to receive the checkpoint inhibitor nivolumab (Opdivo), although one patient ended up receiving avelumab (Bavencio) and another was given cemiplimab (Libtayo).

Of these 22 patients, four chose not to proceed in the trial. An additional patient had disease progression and died before receiving the first checkpoint inhibitor infusion. That left 17, with median age 67, two-thirds of them men. The trial was stopped prematurely due to the difficulties associated with running a clinical trial during COVID-19 pandemic.

Nivolumab was given at 3 mg/kg by IV infusion every 14 days for five cycles, and then at a fixed dose of 480 mg every 28 days for up to two years. Dosing schedules for avelumab and cemiplimab were not reported. Patients received a mean of three infusions, and the median follow-up was 28 months.

Of the 17 patients in the analysis, 16 had either a ECOG 0 or 1 status. Tumor types were varied and included six patients with cutaneous squamous cell carcinoma of the head and neck, three with squamous cell carcinoma of the head and neck/oropharynx, two with renal tract carcinoma, two with Merkel cell carcinoma, and one each with non-small cell lung cancer, melanoma, hepatocellular carcinoma, and colorectal cancer.

In a commentary accompanying the study, Céleste Lebbé, MD, PhD, of AP-HP Saint-Louis Hospital in Paris, and three colleagues noted that the inclusion of a wide variety of cancers, “with a possible bias toward malignancies that are highly responsive to checkpoint inhibitors,” was a methodological limitation of the study, as was the fact that most patients — including seven who had nodal metastases — were given their first-line systemic therapy.

“These limitations should prompt caution in the comparison of efficacy across studies and encourage the design of tumor-specific trials,” they wrote.