Immunotherapy in Kidney Transplant Patients - the Final Frontier for ICI?

A handful of questions are as old as time. Is consciousness real? What happens after death? Is the universe truly infinite? And can immunotherapy be used in transplant patients without destroying their grafts? You know, questions of equal importance.

The safety of immunotherapy in patients with transplants is one of the last remaining unanswered questions in this space. Given the life-altering consequences of a transplant, both medically and financially - a renal transplant is much less expensive than lifelong intermittent dialysis, for example - every effort should be made to preserve these precious organs. In addition, transplant patients are frequently on intense immunosuppressive regimens, calling the efficacy of immunotherapy into question.

It remains unknown who would win: immune checkpoint inhibitors, or the immunosuppressive regimens used to preserve transplants.

We may have gained our first inkling to the safety of immunotherapy in a very small selection of renal transplant patients. Published in the Journal of Clinical Oncology in January 2024, the phase I study by Hanna, Dharanesswaran, Giobbie-Hurder et al. examined the use of cemiplimab in renal transplant recipients with unresectable or metastatic cutaneous squamous cell cancer (cSCC).

This is particularly important because the risk of developing cSCC is more than 60 times higher in transplant patients and accounts for 40% of all malignancies in this population. In addition, the volume of cSCC is frequently much greater in transplant patients, meaning that after a certain point, surgical or radiotherapy-based management is no longer feasible or effective.

Cemiplimab is a very effective treatment for patients with locally advanced or metastatic cSCC. A study of patients with metastatic cSCC by Migden et al (NEJM 2018), demonstrated a 50% response rate, with 82% of patients continuing on treatment at time of data cutoff. Another study in the locally advanced cSCC population (Migden et al., Lancet Oncology, 2020) demonstrated a complete response rate of 13%, and an objective response rate of 44%.

The study was a phase I, single-arm, single-centre, nonrandomised trial conducted at the Dana-Farber Cancer Institute in Boston. Patients with locoregionally advanced unresectable, incurable or metastatic cSCC with a history of kidney transplantation (≥6 months prior to enrolment). Initially, patients who received allogeneic stem-cell transplants were also eligible, but this arm was closed due to lack of recruitment.

The primary endpoints for this study were safety and toxicity, with a specific focus on kidney allograft rejection or loss. A rejection rate exceeding 60% was considered unacceptable. Associations between PD-L1 expression, tumour mutational burden (TMB) and treatment response was an exploratory endpoint.

Key inclusion criteria were:

• ECOG PS ≤2

• Adequate organ function, including eGFR ≥30mL/min/1.73m2 if serum creatinine were above institutional ULN

• Urine protein:creatinine ratio <0.5g/g creatinine

• Not taking antiproliferative immunosuppressive medications at time of screening

Any amount of previous systemic or radiation therapy was permitted, but patients could not have previously received immunotherapy.

Prior to enrolment, patients were transitioned from their existing immunosuppressive regimen to an mTOR inhibitor such as sirolimus or everolimus, with goal trough levels of 4-6ng/mL in combination with 10mg daily prednisolone. After target mTOR levels were achieved, patients received cemiplimab 350mg every 21 days until disease progression, toxicity or withdrawal of consent, for up to 2 years. In addition, patients received prednisolone 40mg daily from the day prior to immunotherapy to day 3 (D3) of the new cycle. Doses were weaned to 20mg on D4-6, then back to the baseline dose of 10mg daily.

Overall, 12 patients were enrolled in the trial. The median age was 62.5, and 10 out of 12 patients were male. Almost all patients (92%) were caucasian, and most patients had an ECOG PS of 0-1 (10/12, 84%). The median baseline eGFR was 49mL/min/1.73m2. The most common type of immunosuppressive agents taken prior to enrolment were calcineurin inhibitors, such as cyclosporin or tacrolimus.

Adverse events (AE) of any grade occurred in 10 patients, with 5 patients experiencing Grade 3 or higher adverse events. One patient discontinued therapy due to toxicity. The most common AE of any grade was fatigue (7 patients), while one patient suffered G3 diarrhoea, lung infection, skin infection, upper respiratory infection (secondary to COVID-19), metabolic acidosis and hyperkalaemia.

No kidney allograft rejection events were observed during the study, nor were any significant elevations in creatinine noted. No patients required haemodialysis, but two patients developed hypoperfusion events and one developed allograft pyelonephritis. In addition, one patient died due to facial swelling from everolimus and an angiotensin-converting enzyme (ACE) inhibitor, resulting in respiratory failure. This AE was deemed unlikely to be due to cemiplimab.

Image courtesy of Journal of Clinical Oncology

Five of the 11 evaluable patients responded (ORR 46%). This included three complete responses (CR) and two partial responses (PR). Two patients also demonstrated stable disease per RECIST1.1, leading to a total clinical benefit rate of 64%. Median duration of response was 11.4 months. At time of data cutoff, three patients remained on study.

Image courtesy of Journal of Clinical Oncology

The median progression-free (PFS) and overall survival (OS) was 22.5 months, with a 3-month OS estimate of 72%. Among patients who progressed on study, the median time to progression was 1.4 months (range <1-2.1 months). Five patients (42%) had died at the time of data cutoff.

Among the exploratory biomarker assessments, there did not appear to be significant association between PD-L1 tumour proportion scores, as four patients who responded has TPS of 0-1. The median TMB value was higher among responders (80 vs 38, p=0.05).

So what does this all mean?

The Bottom Line

First, the Dana-Farber investigators must be commended for this study. Enrolling such complex patients with multiple medical issues for clinical trials is notoriously difficult, so this study represents a significant achievement. It is likely the first prospective study of immunotherapy use in a kidney transplant cohort, and the complete absence of kidney rejection events is very encouraging. The combination of pulsed prednisolone and an mTOR inhibitor could represent a practical regimen for transplant recipients with cancer.

However, there are always considerations. Most obviously, it was a very small population recruited from a single centre, with only eleven patients evaluable for data. Wider recruitment would be difficult, with challenges in consent, logistics and medical management among these complex patients. However, the small numbers do make it difficult to draw wide-ranging conclusions from the data.

In addition, the study only enrolled patients with renal transplants; while kidneys remain the most common transplanted major organ by a significant margin, it would be impossible to extrapolate these data to recipients of other organ transplants, such as recipients of donated livers, pancreases or hearts.

In a similar vein, it is impossible to extrapolate the available data to other types of immunotherapy in other cancer contexts where immunotherapy may be used, such as lung cancer or melanoma. Specific studies in these populations would be required before any conclusions could be made.

Ultimately, if confronted with a patient with a dual diagnosis of cancer and a previous organ transplant, treatment decisions must be made on an individual patient basis in close consultation with the patient’s home transplant team. While this study proposes a regimen that could minimise the risk of graft rejection, patients would still require intense monitoring for immune-mediated complications and transplant dysfunction. Ideally larger studies would be required, but as mentioned before, these would be exceptionally difficult to complete.

Sources

Hanna GJ, Dharanesswaran H, Giobbie-Hurder A et al. Cemiplimab for Kidney Transplant Recipients With Advanced Cutaneous Squamous Cell Carcinoma. J Clin Oncol. 42: 1021-1030. https://doi.org/10.1200/JCO.23.01498

Migden MR, Rischin D, Schmults CD et al. PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma. N Engl J Med. 2018; 379:341-351. DOI:10.1056/NEJMoa1805131

Migden MR, Khushalani NI, Change ALS et al. Cemiplimab in locally advanced cutaneous squamous cell carcinoma: results from an open-label, phase 2, single-arm trial. Lancet Oncol. 2020. https://doi.org/10.1016/S1470-2045(19)30728-4