Treatment with programmed-death-1 inhibitors for non-melanoma skin cancer among immunocompromised patients with subgroup analysis of solid organ transplant patients

Abstract

Background

Programmed-cell death protein 1 (PD-1) inhibitors have emerged as a standard of care treatment among advanced-stage or metastatic cutaneous squamous cell carcinoma (cSCC). Immune-compromised patients and particularly solid organ transplant recipients (SOTRs) are considered at high risk for cSCC. When treated with PD-1 inhibitors, the possibility of organ rejection, autoimmune flare, or insufficient response to treatment is feared. As these patients were excluded from past prospective clinical trials, we aim to describe our institute’s experience regarding these patients.

Methods

A retrospective analysis was conducted on cSCC patients treated with PD-1 inhibitors. Comparisons were made between immune-compromised and immune-competent groups, with a subgroup analysis of SOTR.

Results

The study cohort comprised of 133 patients, including 97.8% receiving Cemiplimab with a mean age of 77.2 ± 11.7 years. Immune-compromised patients constituted 26.9% (n = 35) of the cohort, including 10 SOTR (all kidney transplant recipients). Objective response rates (ORRs) and disease control rates (DCR) were comparable between immunocompetent and immunosuppressed patients receiving Cemiplimab (ORR: 76.8% vs 62.9%, P = .12; DCR: 81.1% vs 68.6%, P = .13). SOTR demonstrated an 80% ORR and DCR. Progression-free survival was comparable across all groups. Toxicity rates were similar between immunosuppressed and immunocompetent subgroups (68.6% vs 62.1%, P = .5). Two OTRs (20%) experienced acute graft rejection.

Conclusions

PD-1 inhibitors demonstrate efficacy and safety in immunosuppressed cSCC patients. While effective in SOTR, treatment requires multidisciplinary management due to the potential risk of organ rejection. These findings provide valuable insights into this understudied population and support the use of PD-1 inhibitors in immunosuppressed patients with advanced cSCC.

Implications for practice.

Cutaneous squamous cell carcinoma is the second most common skin cancer worldwide. It is especially common in immune-suppressed patients. In recent years, the use of immune checkpoint inhibitors (ICIs) and specifically Cemiplimab has become a standard of care among inoperable, recurrent, or metastatic patients. However, its use among immune-compromised and specifically solid organ transplant patients is still debatable, as its efficacy and safety were not studied in the prospective trials regarding ICI. Our study demonstrated that ICI among immune-compromised patients is non-inferior compared to immune-competent patients, with similar efficacy profiles, possibly making it a viable option for these patients.

Introduction

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer worldwide. The mainstay of treatment in high-risk localized cases according to the National Comprehensive Cancer Network (NCCN) guidelines is surgical excision when feasible, followed by radiotherapy when indicated.¹

If not amenable to surgery, either due to the patient’s medical background or morbidity, inability to excise the tumor with appropriate margins, expected significant cosmetic deformity, or patient’s preference, per NCCN, the tumor may be handled either by means of definitive intent radiotherapy or by systemic therapy.¹

In recent years, the possibility of immune checkpoint inhibitors (ICIs) treatment has become standard of care as a potent treatment line for patients with inoperable, recurrent, or metastatic cSCC. A prospective phase 2 study trial of 59 patients with advanced cSCC² demonstrated a 47% response rate to the anti-programmed-death 1 (PD-1) agent Cemiplimab. A similar trial of the anti PD-1 agent Pembrolizumab showed a response rate of 34%.³ A pivotal phase 2 trial by Gross et al.⁴ of neo-adjuvant treatment with the ICI Cemiplimab for 79 patients with resectable T2-4 cSCC demonstrated a 51% rate of complete pathological response rate and a further 13% of partial pathological response rate.

ICI mechanism of action involves inhibiting the binding of the PD-1 receptor on T-cell lymphocytes with the Programmed-death 1 ligand on the tumor cell, disabling the tumor cells from inhibition of the immune system response.⁵

The use of ICI among immunocompromised patients is a matter of debate, regarding its effectiveness and safety profile among such patients. For example, solid organ transplant recipients (SOTRs) are at possible risk of transplanted organ failure, as induction of the immune system among these patients can possibly also induce rejection of the transplanted organ.^6,7 For patients suffering from autoimmune disease, exposure to ICI may trigger a flare.⁸

Furthermore, among patients whose immune system is chronically suppressed (such as patients with chronic lymphocytic leukemia (CLL) or other hematologic malignancies, chronic steroid therapy, or other immunomodulation use), the use of ICI may possibly be associated with less effective immune reaction, as the ability to recruit the T-cell lymphocytes against the tumor cells may be limited. This population is naturally not represented in the aforementioned clinical trials.^2-4

Several prospective phase I/II studies attempted to describe cohorts of patients with immunosuppression treated with ICI for various malignancies. In one of the studies, 2 out of 17 patients (12%) experienced allograft rejection.⁹ In a similar phase I study, no rejection events were described among 12 patients.¹⁰ In a study by Schenk et al., 3 out of 8 patients (37.5%) treated with ICI experienced allograft rejection.¹¹ These small prospective series and several other retrospective studies describe different treatment regimens and results,^12-18 and no unequivocal conclusion can be deduced.

In this report, we aim to describe our experience with PD-1 inhibitors for the treatment of advanced and metastatic cSCC in patients with immune suppression, including a subgroup analysis of SOTRs. Additionally, we seek to compare the efficacy and safety profile (including autoimmune phenomena rate) of this treatment in patients with and without immunosuppression. We hypothesize that the effectiveness of the treatment may be limited among immunocompromised patients, but that the safety profile will be similar, if not better, in this group.

Materials and methods

We performed a retrospective review of all consecutive patients treated for locally advanced and metastatic cSCC with ICI at a university-affiliated tertiary care center between 2019 and 2023. We included patients who were treated with ICI either as a first or second-line treatment. Excluded were patients with no sufficient data regarding the treatment modality, or no data regarding follow-up.

The immunosuppression group included 3 main subgroups: SOTRs receiving immunosuppressive medications; patients with hematological diseases including CLL or other hematological malignancies; and patients with rheumatological background or any other autoimmune diseases receiving chronic steroids or other immune modulators.

Data were collected from patients’ medical charts and included demographics, clinical and pathological features, including TNM classification at initial diagnosis and at ICI treatment initiation, preceding and subsequent treatment modalities including surgery, radiotherapy, chemotherapy, and chronic medication treatment including immune-suppressing medications. We described data regarding ICI treatment, including date of treatment initiation and termination, number of treatment cycles, first response to treatment, time to first response, maximal response to treatment and time to maximal response, progression on treatment, and time to progression. Response to treatment was defined as either complete response (CR), partial response (PR), stable disease (SD), or progression of disease (PD), according to the Response Evaluation Criteria in Solid Tumors, version 1.1.¹⁹ Imaging performed to estimate response to treatment included Positron emission tomography and computerized tomography and were reviewed by a dedicated radiologist and nuclear medicine expert in our institute (A.B.A). Objective response rate (ORR) was defined as the rate of patients with either CR or PR out of all patients in the cohort, while disease control rate (DCR) was defined as patients with either CR, PR, or SD out of the entire cohort. Progression-free survival (PFS) was calculated as the time from treatment initiation to evidence of progression (either clinical or by imaging) or to death. Overall survival (OS) data were calculated as the time from treatment initiation to death or last documented follow-up.

Statistical analysis

All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 28.0 (IBM Corp). Results with a P-value of less than .05 were considered statistically significant. Survival analysis was carried out using the Kaplan-Meier estimate, and the Log-rank test was used to determine significance. Pearson chi-square (χ²) was used to test for associations between nominal variables. Comparisons between continuous variables were conducted using the Student’s t-test and Mann-Whitney test.

The study was approved by the Rabin Medical Center ethics board (IRB approval number RMC-21-0515), and informed consent was waived due to the retrospective nature of the study.

Results

Patients

A total of 133 patients with cSCC treated with a PD-1 inhibitor in our institute were included in the study. Of them, 130 (97.8%) were treated with Cemiplimab, and the other 3 patients received Pembrolizumab. Only patients treated with Cemiplimab were included in further analyses. The mean age of all patients at diagnosis was 77.2 ± 11.7 years. One hundred were male (76.9%). A total of 35 (26.9%) patients had an immunosuppression background. Ten of them (28.6%) were kidney transplant recipients receiving immunosuppressing medications, 6 had CLL (17.1%), 9 patients had other hematological malignancies (25.7%), 7 had rheumatological co-morbidity (20%) and received immunosuppressing medications, and 3 more (8.6%) had chronic immune suppression due to other reasons. Further demographic and clinical data are described in Table 1.

Table 1.

Comparison of demographic, clinical, pathological, and treatment characteristics between patients with and without immune suppression treated with Cemiplimab for cSCC.

Variable	No immune suppression N = 95 (%)	Immune suppression background N = 35(%)	P-value
Gender
Female	21 (22.1)	9 (25.7)	.77
Male	74 (77.9)	26 (74.3)
Age at diagnosis of SCC, years	79.8 ± 11.1	73.6 ± 12.2	.007
Age at ICI initiation, years	81.5 ± 10.8	74.9 ± 11.9	.005
Smoking			.8
Yes	22 (23.2)	10 (28.6)
No	68 (71.6)	23 (65.7)
No data	5 (5.3)	2 (5.7)
Origin site			.2
Face other	11 (11.3)	10 (30.6)
Face T zone	9 (9.3)	2 (5.6)
Scalp	20 (20.6)	10 (27.8)
Neck	1 (1)	0
Forearm	4 (4.1)	1 (2.8)
Shoulder	1 (1)	2 (5.6)
Hands	3 (3.1)	0
Trunk	6 (6.2)	0
Lower limb	3 (3.1)	2 (5.6)
Ear	13 (13.4)	3 (8.3)
Other	4 (4.1)	2 (5.6)
No data	20 (22.7)	3 (8.3)
First-line immunotherapy	35 (36.8)	7 (20)	.07
Number of treatment cycles	13 ± 9.5	11.7 ± 9	.48
Mean treatment duration (months)	9.1 + 7.5	9.7 + 8.5	.69
Maximal response			.17
Complete response	33 (34.7)	11 (31.4)
Partial response	40 (42.1)	11 (31.4)
Stable disease	4 (4.2)	2 (5.7)
Progression of disease	18 (19)	11 (31.5)
Overall response rate	73 (76.8)	22 (62.9)	.12
Disease control rate	77(81.1)	24 (68.6)	.13
Time to first response, months	2.5 ± 2.1	3.3 ± 4.3	.19
Time to maximal response, months	6.4 ± 5.5	6.5 ± 6.1	.91
T stage at ICI initiation			.12
T1	6 (6.3)	7 (20)
T2	35 (36.8)	12 (34.3)
T3	20 (21.1)	8 (22.9)
T4	12 (12.6)	1 (2.9)
Tx/unknown	22 (23.2)	7 (20)
N stage at ICI initiation			.48
N0	62 (65.3)	29 (82.9)
N1	7 (7.4)	0
N2	21 (22.1)	6 (17.1)
N3	5 (5.3)	0
Distant metastasis at ICI initiation	10 (10.5)	5 (14.3)	.55

Results with significant P-value < .05 are marked with bold. The ranges described indicate SD.

Abbreviations: cSCC, cutaneous squamous cell carcinoma; ICI, immune checkpoint inhibitor.

Clinical, pathological, and treatment outcome comparison between the immune-suppressed immune-competent patients

When comparing the 2 immune state groups, the immune-suppressed patients’ age of cSCC diagnosis was 6.2 years younger than the immune-competent group (P = .007). The mean age at ICI treatment initiation was 74.9 ± 11.9 among the immune-compromised patients compared with 81.5 ± 10.8 years in the immune-competent group (P = .005).

The mean number of ICI cycles was similar among the immune-competent patients and the immune suppression group (13 ± 9.5 vs11.7 ± 9 cycles, respectively, P = .48). The mean treatment time was also comparable between the groups (9.1 ± 7.5 vs 9.7 ± 8.5 months in the immune-competent and immune-suppressed groups, respectively, P = .69).

We compared the ICI treatment response rate between the 2 groups and found that response rates were similar as the rate of CR was 34.7% and 31.4%, PR rate was 42.1% and 31.4%, and SD rate was 4.2% and 5.7% in the immune-competent and immune-suppressed groups, respectively. The ORR was 76.8% among the immunocompetent and 62.9% in the immune-suppressed groups (P = .12). The DCR was 81.1% among the immune-competent and 68.6% in the immune-suppressed groups (P = .13). No difference regarding PFS was demonstrated between the groups either. The 6-month PFS rate was 85.1% and 82.9% and the 1-year PFS rate was 82% and 79.6% in the immune-competent and immune-compromised groups, respectively (Log-rank P-value = .44) (Figure 1). No significant difference was demonstrated regarding OS either (Figure 1).

Figure 1.

Kaplan-Meier analysis comparing progression-free and overall survival between patients with and without immunosuppression treated with Cemiplimab for cutaneous squamous cell carcinoma.

Comparison of treatment toxicity between the groups

The total rate of treatment toxicity was 62.1% among the immune-competent patients’ group and 68.6% among the immune-compromised patients (P = .5). No difference in the rate of grade 1-2, 3-4, or 5 toxicity was demonstrated between the groups. When comparing specific toxicities, the rate of treatment-related rash was marginally higher among immune-competent patients (14.7% vs 2.9%, P = .06). The rate of treatment-related ageusia was significantly higher among the immune-compromised patients (5.7% vs 0, P = .019), and the rate of weakness was marginally higher among immunocompromised patients (8.6% vs 2.1%, P = .089) (Table S1).

Subgroup analysis of organ transplant recipients and comparison to immune-competent patients

A total of 10 patients underwent solid organ transplants prior to ICI initiation. All were kidney transplants. Table 2 describes data regarding this subgroup and compares it with the immune-competent group. The mean age at cSCC diagnosis was 62.2 ± 7.2 years, significantly younger than the immune-competent patient group (P < .001). The mean age at ICI treatment initiation was 64.3 ± 7.8, also significantly younger than the immune-competent patients (P < .001). The mean time from organ transplantation to ICI treatment initiation was 170 ± 120 months. While 36.8% of immune-competent patients received ICI as primary or as a part of primary treatment for cSCC, ICI was not the first treatment line among any of the SOTRs.

Table 2.

Comparison of demographic, clinical, pathological, and treatment characteristics between organ transplant patients and patients without immune suppression treated with Cemiplimab for cSCC.

Variable	No immune suppression N = 95 (%)	Organ transplant  N = 10(%)	P-value
Gender			.64
Female	21 (22.1)	1 (10)
Male	74 (77.9)	9 (90)
Age at diagnosis of SCC, years	79.8 ± 11.1	62.2 ± 7.2	<.001
Age at ICI initiation, years	81.5 ± 10.8	64.3 ± 7.8	<.001
Smoking			.4
Yes	22 (23.2)	1 (10)
No	68 (71.6)	9 (90)
No data	5 (5.3)	2 (5.6)
Origin site			.04
Face other	11 (11.3)	4 (40)
Face T zone	9 (9.3)	0
Scalp	20 (20.6)	1 (10)
Neck	1 (1)	0
Forearm	4 (4.1)	0
Shoulder	1 (1)	2 (20)
Hands	3 (3.1)	0
Trunk	6 (6.2)	0
Lower limb	3 (3.1)	0
Ear	13 (13.4)	1 (10)
Other	4 (4.1)	1 (10)
No data	20 (22.7)	1 (10)
First-line immunotherapy	35 (36.8)	0	.02
Number of treatment cycles	13 ± 9.5	20.4 ± 17.8	.28
Mean treatment duration (months)	9.1 ± 7.5	13.2 ± 11.1	.29
Maximal response			.76
Complete response	33 (34.7)	5 (50)
Partial response	40 (42.1)	3 (30)
Stable disease	4 (4.2)	0
Progression of disease	18 (19)	2 (20)
Overall response rate	73 (76.8)	8 (80)	.85
Disease control rate	77 (81.1)	8 (80)	.91
Time to first response, months	2.5 + 2.1	2.9 + 4	.28
Time to maximal response, months	6.4 ± 5.5	6.4 + 6.6	.98
T stage			.05
T1	6 (6.3)	3 (30)
T2	35 (36.8)	4 (40)
T3	20 (21.1)	0
T4	12 (12.6)	0
Tx/unknown	22 (23.2)	3 (30)
N stage			.93
N0	62 (65.3)	8 (80)
N1	7 (7.4)	1 (10)
N2	21 (22.1)	1 (10)
N3	5 (5.3)	0
Distant metastasis	10 (10.5)	3 (30)	.09

Results with significant P-value < .05 are marked with bold. The ranges described indicate SD.

Abbreviations: cSCC, cutaneous squamous cell carcinoma; ICI, immune checkpoint inhibitors.

When comparing the response to treatment, no difference was demonstrated, as the ORR was 80% among SOTR compared with 76.8% among immune-competent patients (P = .84), and the DCR rate was also comparable (80% vs 81.1%, P = .94). Regarding PFS, the 6 and 12-month PFS rates were comparable between the subgroups (90% vs 85.1%, 90% vs 82% respectively, Log-rank P-value = .99) (Figure 2). No significant difference regarding OS was demonstrated (Figure 2).

Figure 2.

Kaplan-Meier analysis comparing progression-free and overall survival between organ transplant patients and patients without immunosuppression treated with Cemiplimab for cutaneous squamous cell carcinoma.

Regarding the overall toxicity rate, a marginally higher rate of treatment toxicity was demonstrated among SOTR (90% vs 62.1%, P = .079). However, no case of grade 5 toxicity was recorded in the organ transplant group. The rate of patient-reported fatigue and weakness was significantly higher among the SOTR, and similarly, a significantly higher rate of arthralgia was reported compared with the immune-competent group (20% vs 2.1%, P = .005). Two SOTRs reported ageusia, while no other patients in the entire cohort had similar symptoms, both in the immune-competent and in the other immune-compromised patients (P < .001). Data about treatment-related toxicity and comparison between SOTR and immunocompetent patients are further described in Table S2.

Regarding patients with immune suppression due to other reasons (CLL, other hematologic malignancies, or immunosuppression treatment due to rheumatologic background), the ORR ranged from 43 to 70%, and the toxicity rate was 59.1%, with most of them described as merely 1-2 grade. A description of ICI treatment and prognosis among different immune suppression subgroups is described in Table 3.

Table 3.

Data regarding demographics, treatment with ICI, prognosis, and toxicity regarding different immunocompromised subgroups of patients treated with Cemiplimab for cSCC.

Variable	Organ transplant  N = 10(%)	CLL patients N = 6(%)	Other hematologic malignancies N = 9(%)	Rheumatologic background with IS treatment N = 7(%)
Age at diagnosis of SCC, years	62.2 ±7.2	70.1 ± 9.9	80.6 ± 15.6	79.8 ± 11.7
Age at initiation of ICI, years	64.3 ± 7.8	72 ± 10.4	81.4 ± 10.8	81 ± 11
Number of treatment cycles	20.4 ± 17.8	14.8 ± 8.4	8 ± 9.7	10 ± 7.3
Mean treatment duration (months)	13.2 ± 11.1	16 ± 11.6	7 ± 8.1	8.7 ± 6.5
Maximal response
Complete response	5 (50)	3 (50)	1 (11.1)	2 (28.6)
Partial response	3 (30)	1 (16.7)	5 (55.5)	1 (14.3)
Stable disease	0	0	0	2 (28.6)
Progression of disease	2 (20)	2 (33.3)	3 (33.3)	2 (28.6)
Toxicity	9 (90)	4 (66.7)	4 (44.4)	5 (71.4)
Worst toxicity grade
1-2	8 (80)	2 (33.3)	4 (44.4)	5 (71.4)
3-4	1 (10)	2 (33.3)	0	0
5	0	0	0	0

The ranges described indicate SD.

Abbreviations: cSCC, cutaneous squamous cell carcinoma; CLL, chronic lymphocytic leukemia; ICI, immune checkpoint inhibitors; IS, immune suppression.

In the SOTR subgroup, 2 cases of acute transplant rejection were reported. One of them lost graft function and had to be started on dialysis treatment. The rejection presented 2 weeks after treatment initiation. This patient did not undergo renal biopsy to confirm acute rejection due to a very rapid presentation of rejection. The other patient presented with acute rejection 7 months after ICI initiation, underwent renal biopsy demonstrating both T-cell and antibody-mediated acute rejection, received pulse steroids treatment, and was able to preserve transplant kidney function (although impaired compared to baseline), without needing dialysis treatment. The mean glomerular filtration rate (GFR) prior to ICI initiation was 59.5 mL/min, compared to 37.4 mL/min at the end of treatment (P = .11). Including only the 8 patients who did not experience rejection, the mean GFR prior to ICI treatment was 56 mL/min compared with 43.9 mL/min at the end of treatment (P = .74). Further data regarding the treatment and prognosis of SOTR treated with ICI are described in Tables 4 and 5.

Table 4.

Data regarding transplant treatment and prognosis among 10 kidney transplant patients treated with Cemiplimab for cSCC.

Variable	Organ transplant  N = 10(%)	Patients without organ rejection (N = 8)	Patients with organ rejection (N = 2)
Age at ICI initiation, years	64.3	63.9	65.8
Gender
Female	1(10)	1 (12.5)	0
Male	9 (90)	7 (87.5)	2 (100)
Time from transplantation to ICI initiation, years	13.9	14.4	11.8
Prednisone treatment at ICI initiation	10 (100)	8 (100)	2 (100)
Mean Prednisone dose at ICI initiation, mg	5.7	5.9	5
Mean Prednisone dose at ICI termination, mg	7.8	7.9	7.5
Mean eGFR at ICI initiation, mL/min	59.5	56	73.5
Mean eGFR at ICI termination, mL/min	37.4	43.9	15
Mean time to rejection, months			3.75

Abbreviations: cSCC, cutaneous squamous cell carcinoma; eGFR, estimated glomerular filtration rate; ICI, immune checkpoint inhibitors.

Table 5.

Description of demographic, clinical, pathological, and treatment characteristics among 10 solid organ transplant patients treated with Cemiplimab for cSCC.

Pt #	Gender	Origin site	Time between transplantation and ICI initiation, years	Treatment duration, months	Maximal response	Progression of disease	Adverse event, worse grade	Immune suppression treatment	Transplant rejection
1	Male	Unknown primary	10.3	1	PD	Yes	None	Steroids	No
2	Male	Face	12.3	21.2	PD	Yes	1-2	Steroids, mTORi	No
3	Male	Shoulder	2.6	7.7	CR	No	1-2	Steroids, mTORi	No
4	Male	Shoulder	18.1	3.0	PR	No	1-2	Steroids, CI, mTORi	No
5	Female	Face	8.6	24.5	PR	No	1-2	Steroids	No
6	Male	Scalp	7.1	10.4	CR	No	1-2	Steroids, mTORi	No
7	Male	Face	20	9.8	CR	No	1-2	Steroids, CI	No
8	Male	Ear	36.9	2.1	PR	No	1-2	Steroids, mTORi	No
9	Male	Lip	19.3	19.4	CR	No	3-4	Steroids, mTORi	Yes
10	Male	Face	4.4	34.1	CR	No	1-2	Steroids, mTORi	Yes

Abbreviations: cSCC, cutaneous squamous cell carcinoma; CI, calcineurin inhibitor; CR, complete response; ICI, immune checkpoint inhibitors; mTORi, mammalian target of rapamycin inhibitor; PD, progression of disease; PR, partial response.

Regarding immunosuppressive agents, all patients were treated with steroids before initiation of ICI. Six of them (60%) also received Calcineurin inhibitors and 5 (50%) were treated with mammalian target of rapamycin (mTOR) inhibitors. All patients received at least 2 immunosuppressing agents, and one patient (10%) received 3 medications. During treatment, all patients continued treatment with low-dose steroidal treatment, and the mean Prednisone dose even increased to 7.8 mg from 5.7 mg. Before treatment initiation, mTOR inhibitor treatment was initiated in 2 more patients, and Calcineurin inhibitor treatment was discontinued in 4 patients. Of note, the 2 patients who remained on Calcineurin inhibitor during ICI treatment had both responded to ICI, one defined as CR and the other as PR. Out of the 2 patients who experienced acute rejection, one was treated with steroids and Calcineurin inhibitors (replaced with mTOR inhibitor at initiation of treatment), while the other received a combination of all 3 agents, and the Calcineurin inhibitor treatment was terminated. Data regarding the immunosuppressive treatment of SOTR treated with ICI is further described in Table 5.

Discussion

Our study describes the role of PD-1 inhibitors among immune-suppressed patients with locally advanced inoperable or metastatic cSCC. Our results demonstrate that ICI is an effective and quite safe treatment option among these patients compared with the immune-competent control group. In a subgroup analysis of 10 kidney transplant recipients, a 20% rate of acute rejection was demonstrated, with an otherwise effective treatment profile and a similar toxicity profile to that of the immune-competent group.

Rejection of the transplanted organ is a serious concern for ICI treatment, and previous studies described even higher rates of rejection—around 50%.²⁰ These high figures may reflect older case series, when the common practice was a complete cessation of immunosuppressive treatment or the maintenance of only steroids when ICI was initiated.^14,21 In recent publications—as was also performed in our series—immunosuppression treatment is maintained and modified—including switching from calcineurin inhibitor to mTOR inhibitor and continuation of steroid treatment. This regimen appears to allow the patient to experience the oncologic benefits of ICI therapy on one hand, while still enabling the preservation of the transplant organ on the other.^6,7

When reviewing the literature, there are many case series and case reports focused on SOTR with cSCC treated with ICI and specifically Cemiplimab.^5,12-18,22 A study by Ji et al.¹⁴ reviewed the literature and described a total of 90 SOTR treated with ICI for either Melanoma or cSCC. The ORR described for cSCC patients was 64%, similar to our immunocompromised group and somewhat lower than our SOTR subgroup which had an 80% ORR. They also demonstrated a 37.8% graft rejection rate, that progressed to graft failure in 61.8% of cases. These figures are higher than our 20% rejection rate. Their results showed an association between the number of immunosuppressive agents and the graft rejection rate, and a lower rejection rate among patients treated with mTOR or Calcineurin inhibitors compared with steroids alone.

In our cohort, the policy among kidney transplant patients was usually to switch immunosuppressive agent from calcineurin inhibitor to mTOR inhibitor at ICI initiation while increasing steroid treatment, as studies have shown the mTOR inhibitor’s ability to maintain the anti-neoplastic activity of ICI while possibly providing an anti-tumor effect of its own.^6,7,23,24 While our SOTR cohort included 10 patients, we were able to demonstrate a relatively low acute rejection rate of only 20% with that treatment protocol.

A retrospective multi-center study¹³ described 69 kidney transplant patients treated with ICI for different cancer types, of them 24 had cSCC. The ORR in the cSCC subgroup was 33.3%, significantly lower than that in our cohort of 80% response. This difference can possibly be explained by the more advanced disease stage in the cSCC cohort.

The CONTRAC trial¹⁰ was a phase I open-label study that included SOTR with cSCC who received Cemiplimab with mTOR inhibitor (either Sirolimus or Everolimus) and prednisone. Out of 12 patients recruited to the study, an ORR of 45.5% was described, no cases of organ rejection were recorded and no patient required hemodialysis. Grade 3 adverse events occurred in 5 patients (42%). No grade 4 or 5 events occurred. One patient died as a result of angioedema attributed to mTOR and angiotensin-converting enzyme inhibitor treatment. These prospective study results, even with its small cohort, shed an important light on the feasibility, efficacy, and safety profile of ICI among SOTR. Hopefully, future prospective studies with larger SOTR cohorts will help consolidate the important role of Cemiplimab and ICI in general among cSCC patients with immune suppression background and SOTR specifically.

The limitations of our study include its retrospective nature—possibly subjecting our immunocompromised group to a selection bias—and the single-institute nature of the cohort. Furthermore, our SOTR subgroup included only kidney transplant recipients, limiting the ability to extrapolate our results for other solid organ transplant patients, where replacement therapy such as hemodialysis is not feasible. Even so, we believe that our results mark an important step in the treatment of immune-compromised cSCC patients with ICI, as we demonstrated an optimal response rate with a toxicity profile similar to immunocompetent patients, including among a subgroup of SOTR.

Conclusions

ICI should be considered in the treatment paradigm of immune-suppressed patients with locally advanced cSCC. Our results demonstrate similar efficacy among immune-suppressed patients as among immune-competent patients. Hence, we believe that it can be considered for immune-suppressed patients, while keeping in mind the retrospective nature of our study and the possibility of selection bias in our cohort. Kidney transplant patients may also benefit from ICI when indicated. These patients should be informed about a low but nonnegligible risk for allograft rejection and a need to return to dialysis. Close follow-up by a multidisciplinary team that includes a surgeon, radiation oncologist, medical oncologist, and a nephrologist is warranted for the treatment and follow-up of these patients; switching immunosuppressing agent from Calcineurin to mTOR inhibitor should be strongly considered when ICI treatment is introduced. We encourage further prospective studies on this important subject, including immune-suppressed patients in general and SOTR other than kidney transplant patients specifically.

Author contributions

Eyal Yosefof (Conceptualization, Formal analysis, Writing—original draft), Nofar Edri (Data curation), Idan Ben-Nachum (Data curation), Dan Yaniv (Investigation, Validation, Writing—review & editing), Aviram Mizrachi (Validation, Writing—review & editing), Nethanel Asher (Investigation, Writing—review & editing), Naomi Ben-Dor (Investigation, Writing—review & editing), Avital Ben-Artzi (Data curation), Itamar Averbuch (Data curation, Writing—review & editing), and Noga Kurman (Conceptualization, Methodology, Writing—review & editing)

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflicts of interest

The authors have no conflicts of interest to declare.

Data availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.