10.5826/dpc.1304a251
Introduction of immunotherapy has radically changed the therapeutic scenario in patients affected by locally advanced and/or metastatic cutaneous squamous cell carcinoma patients. If it is well consolidated the role of immunotherapy in the setting of a disease not amenable to curative surgery and/or radiation, how to integrate immune checkpoint inhibitors in the curative setting is still under evaluation. Surgery combined or not with adjuvant radiotherapy remains the mainstay of curative treatment in localized cutaneous squamous cell carcinoma; however, promising data with neoadjuvant or perioperative immunotherapy could pave the way towards a treatment de-escalation according to the response achieved. On the other side, data on adjuvant treatment with pembrolizumab and cemiplimab after surgery and radiation are still awaited. Several questions related to the activity and safety of immunotherapy in real world setting still remain without answer, and several points need to be better explored. In the current review we will explore the updated literature on the use of immunotherapy in cutaneous squamous cell carcinoma, and we will show the current challenges in its use.
text/xml
2160-9381
3740
en
Paolo Bossi
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
Neoadjuvant Treatment
Advanced Cutaneous Squamous Cell Carcinoma Management in Immunotherapy Era: Achievements and New Challenges 
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Review
2023-10-31
2023-08-04
2023-10-31
2024-01-16
e2023251
Dermatol Pract Concept
Introduction of immunotherapy has radically changed the therapeutic scenario in patients affected by locally advanced and/or metastatic cutaneous squamous cell carcinoma patients. If it is well consolidated the role of immunotherapy in the setting of a disease not amenable to curative surgery and/or radiation, how to integrate immune checkpoint inhibitors in the curative setting is still under evaluation. Surgery combined or not with adjuvant radiotherapy remains the mainstay of curative treatment in localized cutaneous squamous cell carcinoma; however, promising data with neoadjuvant or perioperative immunotherapy could pave the way towards a treatment de-escalation according to the response achieved. On the other side, data on adjuvant treatment with pembrolizumab and cemiplimab after surgery and radiation are still awaited. Several questions related to the activity and safety of immunotherapy in real world setting still remain without answer, and several points need to be better explored. In the current review we will explore the updated literature on the use of immunotherapy in cutaneous squamous cell carcinoma, and we will show the current challenges in its use.
Paolo Bossi
2023/10/31
10.5826/dpc.1304a251
e2023251
Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano; Department of Biomedical Sciences, Humanitas University, Milan, Italy
2160-9381
Neoadjuvant Treatment
en
e2023251
Müller K, Karrer S, Szeimies RM, Steinbauer J, Kohl E, Steinbauer D, et al. Quality of life assessment in patients with nonmelanoma skin cancer - psychometric validation of the EORTC QLQ-C30 questionnaire: Validation of EORTC QLQ-C30 in patients with NMSC. JDDG J Dtsch Dermatol Ges. 2017 Nov;15(11):1090–100.
Advanced Cutaneous Squamous Cell Carcinoma Management in Immunotherapy Era: Achievements and New Challenges 
https://dpcj.org/index.php/dpc/article/download/3740/2328
  Advanced Cutaneous Squamous Cell Carcinoma
 Management in Immunotherapy Era: Achievements
              and New Challenges
                                   Luigi Lorini1*, Andrea Alberti2*, Paolo Bossi1,3


1 Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy
2 Medical Oncology Unit, Department of Medical & Surgical Specialties, Radiological Sciences & Public Health, University of Brescia,
  ASST Spedali Civili, Brescia, Italy
3 Department of Biomedical Sciences, Humanitas University, Milan, Italy
* Both authors equally contributed for the paper



Key words: Cutaneous Squamous Cell Carcinoma; Immunotherapy; Frail Patients; Neoadjuvant Treatment
Citation: Lorini L, Alberti A, Bossi P. Advanced CSCC Management in Immunotherapy Era: Achievements and New Challenges.
Dermatol Pract Concept. 2023;13(4):e2023251. DOI: https://doi.org/10.5826/dpc.1304a251
Accepted: August 9, 2023; Published: October 2023
Copyright: ©2023 Lorini et al. This is an open-access article distributed under the terms of the Creative Commons
Attribution-NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted
noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing Interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding Author: Luigi Lorini, Via Alessandro Manzoni, 56, 20089, Rozzano (MI), Italy. Telephone: +390282242;
Email: luigi.lorini@cancercenter.humanitas.it




  ABSTRACT             Introduction of immunotherapy (IT) has radically changed the therapeutic scenario in patients af-
                       fected by locally advanced and/or metastatic cutaneous squamous cell carcinoma (cSCC) patients. If
                       it is well consolidated the role of immunotherapy in the setting of a disease not amenable to curative
                       surgery and/or radiation, how to integrate immune checkpoint inhibitors in the curative setting is
                       still under evaluation. Surgery combined or not with adjuvant radiotherapy remains the mainstay of
                       curative treatment in localized cSCC; however, promising data with neoadjuvant or perioperative im-
                       munotherapy could pave the way towards treatment de-escalation according to the response achieved.
                       On the other side, data on adjuvant treatment with pembrolizumab and cemiplimab after surgery and
                       radiation are still awaited. Several questions related to the activity and the safety of immunotherapy
                       in the real-world setting still remain without answer, and several points need to be better explored. In
                       the current review we will explore the updated literature on the use of immunotherapy in cSCC, and
                       we will show the current challenges in its use.




Review | Dermatol Pract Concept. 2023;13(4):e2023251                                                                                   1
Immunological Status of cSCC                                       Lessons Learned: How to Position
and Differences With BCC                                           Immunotherapy in Advanced cSCC
Cutaneous squamous-cell carcinoma (cSCC) is the second             Immune checkpoint inhibitors (ICIs) have shown efficacy in
most common skin cancer after basal-cell carcinoma (BCC) [1].      the treatment of advanced cSCC. Two phase II trials inves-
BCC-to-SCC prevalence ratio range between 1:1 and 10:1,            tigated the efficacy of pembrolizumab in cSCC, the KEY-
depending on the population evaluated, as for example solid        NOTE 629 trial and CARSKIN, both open-label, single-arm,
organ transplant recipients were there is an higher incidence      multicenter design. In KEYNOTE 629, most patients (87%)
rates of cSCC than BCC [2]. Long-term sun exposure is re-          had received one or more prior systemic therapies or ra-
sponsible for the DNA damage from ultraviolet (UVA and             diotherapy (RT) (74%). In the entire study population, the
UVB) radiation exposure and it is the major risk factor for        objective response rate (ORR) was 34%, with complete
both histotypes; BCC is caused by intensive UV exposure in         (CRR) and partial response (PRR) rates reported in 4% and
childhood/adolescence, while cSCC is related to cumulative         31%, respectively. Among the cohort of 36 patients with
UV exposure over decades [1]. Both BCC and cSCC harbor a           confirmed disease response, about two-thirds (69%) had
high tumor mutational burden, which likely results in higher       a durable response of more than 6 months. At the median
levels of tumor neoantigens that may be targeted by the im-        follow-up of 10 months, the median progression free sur-
mune system. The gene signature in cSCC is characterized by        vival (PFS) was 7 months and the 1-year overall survival
NOTCH family genes mutations in 22%-86%, RAS pathway               (OS) 60% [10]. In the investigator-initiated CARSKIN trial,
mutations in quite 5-50%, and aberrant activation of the epi-      where only treatment-naïve patients were enrolled, the
dermal growth factor receptor (EGFR) and Fyn Src-family            ORR, CRR, and PRR in the entire study population was
tyrosine kinase is common [3]. Tumor suppressor genes like         42%, 7%, and 35% respectively [11]. In the expansion co-
p53 are more frequently altered in cSCC, with 19% mutations        hort, the ORR was higher among patients with PD-L1 pos-
at a UV-signature hotspot in KNSTRN gene [3]. Furthermore,         itive disease (55%) than those with negative PD-L1 (17%)
the strong link between immunosuppression and the risk of          (P = 0.02). In the primary cohort, after a median follow-up
cSCC indicates that natural immuno-surveillance plays an           of 22.4 months, none of the 16 responders had subsequent
important role in controlling this type of cancer; in cSCC         disease progression; median PFS and OS were 7 and 25
the most relevant is the promotion of an immuno-tolerant           months, respectively [11].
microenvironment [4]. This occurs through cytokine manip-             The efficacy of cemiplimab was studied in a phase
ulation (increased secretion of IL-6, IL-10, and TGF-beta;         I multi-cohort study and followed up in the phase II
consumption of IL-2) that promotes the infiltration of             EMPOWER-CSCC 1 study; both studies had an open-label
T-reg cells, myeloid-derived suppressor cells (MDSCs), and         multicenter design [12–16]. The EMPOWER-CSCC study
other cell types, such as mature dendritic cells, that inhibit     treated patients with cemiplimab 3 mg/kg and included 3
the function of cytotoxic T-cells. These cells can then actively   parallel treatment groups; group 1 included patients with
suppress the proliferation of CD4+ and CD8+ T lymphocytes          metastatic cSCC, while group 2 included patients with lo-
that would otherwise recognize tumor antigens [4,5]. cSCC          cally advanced cSCC; in both groups, cemiplimab was ad-
also upregulates the expression of immune checkpoint mol-          ministered at a dose of 3 mg/kg. In group 3 patients with
ecules such as PD-1 and PD ligand 1 (PD-L1) that promote           metastatic cSCC were treated with cemiplimab 350 mg
peripheral T cell depletion [6].The immunogenicity of cSCC         [12–14]. ORR was observed in 50.8%, 44.9% and 46.4%
and BCC is different, as witnessed by the higher infiltra-         of patients in groups 1, 2, and 3, respectively; with a me-
tion of CD8+ T cells and CD68+ macrophages in cSCC [7];            dian time to response lower than 2 months. After a median
also, BCC shows lower expression of immune checkpoints             follow-up of 18.5, 15.5, and 17.3 months in the 3 groups,
compared to cSCC [8].                                              the response observed with cemiplimab in patients with ad-
    Some cSCC cases are associated with high-risk types of         vanced cSCC appeared durable; the median duration of re-
HPV, particularly HPV-16, differently from what happens in         sponse (DOR) was not reached in the group 1, while was
BCC, where the association with the infection is less relevant.    41.9 and 41.3 months in group 2 and 3, respectively. The
HPV-positive cSCC tends to exhibit a more immunologically          median OS was 57.7 and 48.4 months in group 1 and 3, and
active profile compared to HPV-negative cSCC [9]. This is          not reached in group 2.
thought to be due to the expression of viral antigens, which          Cemiplimab and pembrolizumab have been approved
can trigger an immune response against the tumor. It is im-        (from FDA and EMA the first, from FDA the second one) for
portant to note that while cSCC often exhibits an immune-          locally advanced and metastatic squamous cell carcinoma of
inflamed phenotype, there can be considerable heterogeneity        the skin, which is not a candidate for curative surgery or
in the immunological status among individual tumors.               curative RT.



2                                                                             Review | Dermatol Pract Concept. 2023;13(4):e2023251
Challenges for the Use                                            receive nivolumab or nivolumab plus ipilimumab followed
                                                                  by surgery, combined or not with RT. A deep or partial
of Immunotherapy in cSCC
                                                                  pathological response (less of 10% or from 10% to 50% of
Neoadjuvant Use of Immunotherapy                                  remaining viable tumor cells in the surgical pathology sam-
Despite optimal loco-regional treatment, up to 30% of pa-         ple), or a clinically complete response has been assessed in
tients with loco-regional advanced cSCC recur, and in up to       50% and 61% of cases with nivolumab or nivolumab plus
5% disease become no longer amenable to curative treat-           ipilimumab, respectively.
ment, with a consequent worsening in prognosis [17]. More-           Despite optimal results reported with neoadjuvant strate-
over, in case of advanced disease, where the feasibility of a     gies, two main questions remain open, thus deserving further
surgery is considered “borderline” (combined or not with          trials to be better explored.
RT) there would be a high risk of R1 resection; also, surgical       Firstly, is it possible to de-escalate treatment in IT re-
interventions in some advanced cSCC may cause significant         sponders? In the trial by Ferrarotto et al 55% of the patients
disfigurement and functional morbidity, with consequent           did not receive preplanned adjuvant RT, due to p
                                                                                                                 ­ athological
impact on patient quality of life, social and working activi-     response, thus questioning if preoperative treatment may
ties. Thus, given the activity of anti PD-1 agents in advanced    ­select responsive patients to reduce treatment intensity [18].
disease [10,13] and the somewhat suboptimal results of sur-       Surgery remains the cornerstone of the treatment, as it allows
gical strategies in advanced cases, there is a strong rationale   eradicating potential resistant clones and permits to perform
for the introduction of anti PD-1 agents in the neoadjuvant       a clear evaluation of response to IT, where radiological im-
setting.                                                          aging is not so effective.
    Ferrarotto et alperformed a pilot phase II single arm            However, it is an open issue if surgery needs to be lim-
study of neoadjuvant cemiplimab in loco-regionally ad-            ited to “remnant” disease after neoadjuvant treatment, or if
vanced resectable head and neck (HN) cSCC [18]. Twenty            it should encompass the whole area where the tumor was
newly diagnosed or recurrent stage III-IVa (M0) cSCC of           present before treatment. A new concept of de-escalation
the HN region received 2 cycles of cemiplimab, with/with-         is being explored by the DESQUAMATE ongoing trial
out adjuvant RT. Even if the clinical response rate was 30%,      (NCT05025813). This trial is evaluating a de-escalation
one half of the patients reported a pathological complete         approach on loco-regionally advanced cSCC candidate to
response (pCR) and 20% a major pathological response              surgical exeresis and post-operative RT. Patients are treated
(MPR). The 12 months disease specific survival, disease free      with four cycles of neoadjuvant pembrolizumab and, if re-
survival and OS were 95%, 89%, and 95% respectively.              staging imaging and biopsy are negative, they avoid surgery
Gross et alconducted a phase 2 single arm study on stage          and continue with pembrolizumab for further 17 cycles.
II, III, IV (M0) cSCC [19]. The 79 patients enrolled received        Secondly, the patient selection. Up to 10% of patients
anti PD-1 cemiplimab 350 mg flat dose for up to 4 cycles be-      experiences a progressive disease as the best response to neo-
fore undergoing surgery combined or not with RT. Fifty-one        adjuvant treatment, with a consequent risk to overcome the
percent of patients reported a pCR and 13% a MPR, while           feasibility and the efficacy of the surgery, and patients may
the response according to RECIST 1.1 was 68%. To note, 5          lose the opportunity to be curatively treated [18,19]. Gene
patients with partial response at imaging did not undergo         expression studies revealed an inflamed tumor microenviron-
surgical resection, thus being considered as not pathological     ment in patients with pathological response, with an enrich-
responders.                                                       ment cluster of memory CD8+ T-cell in pCR patients [18].
    At the recent American Society of Clinical Oncology           PDL1 expression and TMB cannot be considered as opti-
(ASCO) annual meeting, Ascierto et al presented the data          mal predictive biomarkers. Responders were identified in
of the NEOCESQ study, a phase 2 single arm trial [20]. The        both PDL1 positive or negative patients, even if lower PDL1
23 enrolled patients, affected by stage III-IV (M0) surgi-        expression was associated with lower pCR; the tumor mu-
cally resectable cSCC, received cemiplimab for two cycles         tational burden (TMB) was not associated with tumor re-
prior to surgery, and for one year after surgery. pCR was         sponse [19].
obtained in 39% of patients, while MPR, defined as pCR
or near pCR with 10% remaining viable tumor cells in the          Adjuvant Immunotherapeutic Treatment
surgical pathology sample, in 48% of the cases. The study         In the case of high-risk cSCC, there is a need to reduce the
is still ongoing, further activity and translational data are     risk of recurrence after surgery.
awaited (NCT04632433). Zuur et al (NCT04620200) con-                 The C-POST trial (NCT0396004) is an ongoing ran-
ducted a phase 2, double arm, randomized trial and enrolled       domized, placebo-controlled, double-blind, multicenter
40 patients affected by cSCC with an indication for extensive     phase 3 study to evaluate cemiplimab as adjuvant treatment
and/or mutilating surgery [21]. Patients were randomized to       for patients with high-risk cSCC, based on surgical and



Review | Dermatol Pract Concept. 2023;13(4):e2023251                                                                           3
clinicopathologic findings. Patients enrolled must have at         patients, overall response rate was 50% and at the data cut
least one of the following high-risk features: (1) nodal dis-      off no responder had progressed [27]. Several reports in liter-
ease with (a) extracapsular extension (ECE) and at least one       ature warned about the high rates (around 40%) of allograft
node ≥20 mm or (b) at least three lymph nodes positive on          rejection in patients with cancer who were treated with an
surgical pathology report, regardless of ECE; (2) in-transit       immune checkpoint inhibitor, leading to organ failure in
metastases; (3) T4 lesion; (4) perineural invasion; and (5)        71% of the patients who experienced rejection [24].
recurrent cSCC with at least one other risk factor. Patients          Because of the high risk of allograft loss and the poor
receive adjuvant cemiplimab for up to 1 years and the trial        data of clinical benefit, the use of ICI should be clearly dis-
has disease-free survival as its primary objective.                cussed with the patient before the initiation of treatment,
    The KEYNOTE 630 (NCT03833167) is a similar phase               and these patients should be monitored closely for signs of
3 trial in which patients at high risk of recurrence (defined      rejection.
as having one or more high risk features) after surgery and
RT are randomized to receive either pembrolizumab or pla-          Real Life Experiences
cebo for up to 1 year. The primary efficacy end point is the       Next to evidence reported by clinical trials, data about cemi-
investigator-assessed and biopsy-confirmed recurrence-free         plimab activity in real life are available, especially for sub-
survival.                                                          groups of patients who have not been included in clinical
    The optimal duration of adjuvant treatment to elicit           trials because of active autoimmune disease, concomitant
treatment efficacy without increasing toxicities is so far not     malignancies, and those receiving high dose corticosteroids,
clear. One year duration is based on trials in other diseases,     as well as patients with performance status greater than 1.
such as melanoma [22]; however, in the context of disease          The results in terms of treatment responses are in line with
with high response to IT, a shorter period may be enough.          clinical trial data. On the contrary, frail patients with poor
Moreover, it is to be clarified if the highest benefit can be IT   performance status responded less well. Notably, PFS and
seems to be more active in surgery naïve patients [10,11];         OS did not differ according to cSCC stage, prior systemic
thus, a neoadjuvant or even a perioperative approach, in case      treatment status or immune status. The safety profile of
of borderline surgical resectable disease may be the preferred     cemiplimab in these series was comparable with what was
option, also in order also to de-escalate post-operative treat-    reported in clinical trials. Most adverse events (AEs) were
ment in case of response.                                          manageable, except for patients (7% - 10%) who required
                                                                   cemiplimab discontinuation [28–31].
Treatment of Solid Organ Transplant Patients
The state of immune tolerance induced by broad immuno-             Frail Patients
suppression to prevent allograft rejection leads to an in-         cSCC patients are usually frail, with critical social condi-
creased risk of the development of cSCC. Both CTLA-4 and           tions, and often with advanced age. In the real life study
PD-1/PD-L1 play a key role in immuno-tolerance required            published by Baggi et al, median age was 79 years old, thus
for allograft survival [23,24]. In a preclinical study, the in-    physicians frequently face with the issue to whether treat or
jection of anti-CTLA-4 immunoglobulin in the perioperative         not some patients who could be borderline for comorbidities
period led to acute rejection of liver allograft but did not       and/or frailty [28]. IT has comparable activity and toxicity in
have any effect on graft survival when it was injected after       younger and older patients, but the question remains how to
the establishment of peripheral tolerance [23]. On the con-        identify older and frailer patients at higher risk for toxicities.
trary, the early infusion of anti PD-1 antibodies prevented        In oncology, the comprehensive geriatric assessment (CGA)
the induction of peripheral tolerance, and infusion at a later     is a multidimensional evaluation of the overall fitness of an
stage led to complete loss of allograft [23,25,26]. This has not   older adult to tolerate a proposed cancer treatment plan and
been proved in humans and prospective data from clinical           follow up. Screening tools to select frail patients that may
trials go not in this direction. Recently, Hanna et al presented   benefit from CGA exists, such as G-8 and VES 13 [32–34].
the CONTRACT-1 study results, the first prospective study          Little data exists about the role of CGA and health-related
using the PD-1 inhibitor cemiplimab for kidney transplant          outcomes in older adults receiving IT, either single-agent or
recipients, with advanced, incurable cutaneous squamous            in combination [35]. The ELDERS prospective study eval-
cell carcinoma [27]. Twelve patients have been enrolled 3-31       uated the role of the G8 scale screening and of the CGA
years after transplant and a standardized immunosuppres-           in predicting immuno-related toxicities [36]: on 140 pa-
sion therapy with mTOR inhibitors and prednisone taper-            tients (lung cancer 53% and melanoma 47%), a positive G8
ing has been established during the treatment. At a median         screening correlated with a higher rate of hospital admission,
follow-up of 6.3 months (range < 1-24.9), no patients ex-          and with a higher risk of death. In a prospective study on
perienced kidney allograft rejection or loss. Of 8 evaluable       70 years older melanoma patients who underwent IT [37],



4                                                                               Review | Dermatol Pract Concept. 2023;13(4):e2023251
frail patients, identified with G8 screening tools, seems to       integrations, the cutoff for treatment de-escalation, the long-
not have an increased risk of immuno-related toxicities if         term QoL and the affordability of this treatment in the con-
compared with their younger counterparts; however, they            text of an aging population.
have a higher risk of hospital admission due to toxicities and
an higher proportion of treatment interruption.
   CGA and frailty assessment before starting IT is of out-        References
most importance in such a complex population as cSCC
                                                                    1. Rogers HW, Weinstock MA, Feldman SR, Coldiron BM. Inci-
patients. Prospective trials evaluating the role of CGA, spe-          dence Estimate of Nonmelanoma Skin Cancer (Keratinocyte
cifically on cSCC, are advocated to better understand how              Carcinomas) in the US Population, 2012. JAMA Dermatol.
to select elderly frail patients that may benefit from IT, or          2015;151(10):1081. DOI: 10.1001/jamadermatol.2015.1187.
to evaluate how an early supportive intervention on frail              PMID: 25928283.
                                                                    2. Madeleine MM, Patel NS, Plasmeijer EI, et al. Epidemiology
patients may be of benefit in reverting some conditions as
                                                                       of keratinocyte carcinomas after organ transplantation. Br J
malnutrition, depression, risk of infections, and possible
                                                                       Dermatol. 2017;177(5):1208–1216. DOI: 10.1111/bjd.15931.
ameliorating the performance status.                                   PMID: 28994104.
                                                                    3. Li X, Zhao S, Bian X, Zhang L, Lu L, Pei S, et al. Signatures of
Quality of Life (QoL)                                                  EMT, immunosuppression, and inflammation in primary and re-
                                                                       current human cutaneous squamous cell carcinoma at single-cell
In advanced cSCC treated with cemiplimab, the improve-
                                                                       resolution. Theranostics. 2022;12(17):7532–49. DOI: 10.7150/
ment in Global Health Status (GHS)/QoL is an early event,
                                                                       thno.77528. PMID: 36438481. PMCID: PMC9691356.
starting from the 2nd cycle and lasting all treatment. The me-      4. Lai C, August S, Albibas A, et al. OX40+ Regulatory T Cells in
dian time to first clinically meaningful improvement for pain             Cutaneous Squamous Cell Carcinoma Suppress Effector T-Cell
is 2.1 months and this is significantly improved in responders            Responses and Associate with Metastatic Potential. Clin Cancer
versus non responders (P < 0.0001) [38]. Overall, studies on              Res. 2016;22(16):4236–4248. DOI: 10.1158/1078-0432.CCR-
                                                                          15-2614. PMID: 27034329. PMCID: PMC4987192.
IT in advanced cSCC showed a benefit on QoL and on symp-
                                                                    5.    Bluth MJ, Zaba LC, Moussai D, et al. Myeloid Dendritic
toms both with cemiplimab and pembrolizumab [10,11,13].
                                                                          Cells from Human Cutaneous Squamous Cell Carcinoma Are
However, a well-conducted systematic review [39], showed                  Poor Stimulators of T-Cell Proliferation. J Invest Dermatol.
heterogeneity across cited studies regarding the use of qual-             2009;129(10):2451–2462. DOI: 10.1038/jid.2009.96. PMID:
ity of life assessment scales, with low possibility to compare            19387481. PMCID: PMC2846605.
results. Various assessment tools exist to evaluate specifically    6.    Slater NA, Googe PB. PD-L1 expression in cutaneous squa-
                                                                          mous cell carcinoma correlates with risk of metastasis: PD-L1
QoL in cSCC, such as the Skin Cancer Index, Dermatology
                                                                          expression in cutaneous squamous cell carcinoma. J Cutan
Life Quality Index, the FACE-Q Skin Cancer Module, the
                                                                          Pathol. 2016;43(8):663–670. DOI: 10.1111/cup.12728. PMID:
SCQOLIT, and the Basal and Squamous Cell Carcinoma                        27153517.
Quality of life questionnaire [40-44]. The EORTC QLQ                7.    Frohwitter G, Kerta M, Vogl C, et al. Macrophage and T-Cell
C-30, has been used for cSCC patients but may lack sensitiv-              Infiltration and Topographic Immune Cell Distribution in
ity [45]. It should be considered that all these questionnaires           Non-Melanoma Skin Cancer of the Head and Neck. Front
                                                                         ­Oncol. 2022;12:809687. DOI: 10.3389/fonc.2022.809687.
have been developed before the introduction of IT in cSCC,
                                                                          PMID: 35463364. PMCID: PMC9022069.
thus they might not well address the QoL of such patients.
                                                                    8.    Costache M, Georgescu TA, Oproiu AM, et al. Emerging con-
Considering the high activity of IT in cSCC, and the possi-               cepts and latest advances regarding the etiopathogenesis, mor-
bility to reach long survival (74% alive at 2 years) [38], it is          phology and immunophenotype of basal cell carcinoma. Rom J
of importance to reach QoL data from real-life cohorts, in                Morphol Embryol. 2018;59(2):427-433. PMID: 30173247.
order to better address patients issues during their treatment      9.    Tampa M, Mitran CI, Mitran MI, et al. The Role of Beta HPV
                                                                          Types and HPV-Associated Inflammatory Processes in Cutaneous
and in the long-term follow-up.
                                                                          Squamous Cell Carcinoma. J Immunol Res. 2020;2020:5701639.
                                                                          DOI: 10.1155/2020/5701639. PMID: 32322596. PMCID:
Conclusions                                                               PMC7165336.
                                                                   10.    Hughes BGM, Munoz-Couselo E, Mortier L, et al. Pembroli-
Treatment of advanced cSCC has dramatically evolved in the                zumab for locally advanced and recurrent/metastatic cutaneous
last years and the huge benefits of IT in recurrent and/or                squamous cell carcinoma (KEYNOTE-629 study): an open-label,
metastatic setting have allowed designing new approaches                  nonrandomized, multicenter, phase II trial. Ann Oncol.
                                                                          2021;;32(10):1276-1285. DOI: 10.1016/j.annonc.2021.07.008.
in other disease settings. In the next few years, we will ob-
                                                                          PMID: 34293460.
tain the results of ongoing trials with the use of IT in neoad-
                                                                   11.    Maubec E, Boubaya M, Petrow P, et al. Phase II Study of Pem-
juvant and adjuvant settings, and new scenarios will open.                brolizumab As First-Line, Single-Drug Therapy for Patients With
The revolution of the treatment of advanced cSCC will how-                Unresectable Cutaneous Squamous Cell Carcinomas. J Clin
ever be accompanied by several questions about the best



Review | Dermatol Pract Concept. 2023;13(4):e2023251                                                                                   5
      Oncol. 2020;38(26):3051–3061. DOI: 10.1200/JCO.19.03357.           23. Judge TA, Wu Z, Zheng XG, et al. The role of CD80, CD86, and
      PMID: 32730186.                                                        CTLA4 in alloimmune responses and the induction of long-term
12.   Migden MR, Rischin D, Schmults CD, et al. PD-1 Blockade                allograft survival. J Immunol. 1999;162(4):1947-1951. PMID:
      with Cemiplimab in Advanced Cutaneous Squamous-Cell Car-               9973463.
      cinoma. N Engl J Med. 2018;379(4):341–351. DOI: 10.1056/           24. Kumar V, Shinagare AB, Rennke HG, et al. The Safety and Ef-
      NEJMoa1805131. PMID: 29863979.                                         ficacy of Checkpoint Inhibitors in Transplant Recipients: A
13.   Migden MR, Khushalani NI, Chang ALS, et al. Cemiplimab in              Case Series and Systematic Review of Literature. Oncologist.
      locally advanced cutaneous squamous cell carcinoma: results            2020;25(6):505–514. DOI: 10.1634/theoncologist.2019-0659.
      from an open-label, phase 2, single-arm trial. Lancet Oncol.           PMID: 32043699. PMCID: PMC7288631.
      2020;21(2):294–305. DOI: 10.1016/S1470-2045(19)30728-4.            25. Aguirre LE, Guzman ME, Lopes G, Hurley J. Immune Check-
      PMID: 31952975. PMCID: PMC7771329.                                     point Inhibitors and the Risk of Allograft Rejection: A Compre-
14.   Guminski AD, Lim AML, Khushalani NI, et al. Phase 2 study              hensive Analysis on an Emerging Issue. Oncologist. 2019;24(3):
      of cemiplimab, a human monoclonal anti-PD-1, in patients (pts)         394–401. DOI: 10.1634/theoncologist.2018-0195. Epub 2018
      with metastatic cutaneous squamous cell carcinoma (mCSCC;              Nov 9. PMID: 30413665. PMCID: PMC6519766.
      Group 1): 12-month follow-up. J Clin Oncol. 2019;37:15_suppl:      26. Li W, Zheng XX, Kuhr CS, Perkins JD. CTLA4 Engagement
      9526-9526. DOI: 10.1200/JCO.2019.37.15                                 is Required for Induction of Murine Liver Transplant Sponta-
15.   Migden MR, Schmults C, Khushanlani N, et al. 814P Phase II study       neous Tolerance. Am J Transplant. 2005;5(5):978–986. DOI:
      of cemiplimab in patients with advanced cutaneous squamous             10.1111/j.1600-6143.2005.00823.x. PMID: 15816877.
      cell carcinoma (CSCC): Final analysis from EMPOWER-CSCC-1          27. Hanna GJ, Dharaneeswaran HJ, Giobbie-Hurder A, Harran JJ,
      groups 1, 2 and 3. Ann Oncol. 2022;33suppl_7): S356-S409.              Liao Z, Pai L, et al. Cemiplimab for kidney organ transplant
      DOI: 10.1016/annonc/annonc1059.                                        recipients with advanced cutaneous squamous cell carcinoma:
16.   Owonikoko TK, Papadopoulos KP, Johnson ML, et al. Phase                CONTRAC-1. J Clin Oncol. 2023;41(16_suppl):9519–9519.
      I study of cemiplimab, a human monoclonal anti-PD-1, in pa-        28. Baggi A, Quaglino P, Rubatto M, et al. Real world data of ce-
      tients with unresectable locally advanced or metastatic cutane-          miplimab in locally advanced and metastatic cutaneous squa-
      ous squamous cell carcinoma (CSCC): Longer follow-up efficacy            mous cell carcinoma. Eur J Cancer. 2021;157:250–258. DOI:
      and safety data. Ann Oncol. 2018;29:x25. DOI:https://doi                 10.1016/j.ejca.2021.08.018. PMID: 34536948.
      .org/10.1093/annonc/mdy487.002.                                    29.   Quaglino P, Baggi A, Depenni R, et al. 833P Longer follow up
17.   Porceddu SV, Bressel M, Poulsen MG, et al. Postoperative                 of a real-world study of cemiplimab in advanced cutaneous
      Concurrent Chemoradiotherapy Versus Postoperative Radio-                 squamous cell carcinoma: Focus on late toxicities and long term
      therapy in High-Risk Cutaneous Squamous Cell Carcinoma of                benefit. Ann Oncol. 2022;33:S929–S930. DOI: 10.1016/annonc
      the Head and Neck: The Randomized Phase III TROG 05.01                   /annonc1059.
      Trial. J Clin Oncol. 2018;36(13):1275–1283. DOI: 10.1200           30.   Salzmann M, Leiter U, Loquai C, Zet al. Programmed cell death
      /JCO.2017.77.0941. PMID: 29537906.                                       protein 1 inhibitors in advanced cutaneous squamous cell carci-
18.   Ferrarotto R, Amit M, Nagarajan P, et al. Pilot Phase II Trial           noma: real-world data of a retrospective, multicenter study. Eur
      of Neoadjuvant Immunotherapy in Locoregionally Advanced,                 J Cancer. 2020;138:125–1232. DOI: 10.1016/j.ejca.2020.07.029.
      Resectable Cutaneous Squamous Cell Carcinoma of the Head                 PMID: 32882466.
      and Neck. Clin Cancer Res. 2021;27(16):4557–4565. DOI:             31.   Hober C, Fredeau L, Pham-Ledard A, et al. Cemiplimab for Lo-
      10.1158/1078-0432.CCR-21-0585. PMID: 34187851. PMCID:                    cally Advanced and Metastatic Cutaneous Squamous-Cell Car-
      PMC8711237.                                                              cinomas: Real-Life Experience from the French CAREPI Study
19.   Gross ND, Miller DM, Khushalani NI, et al. Neoadjuvant                   Group. Cancers (Basel). 2021;13(14):3547. DOI: 10.3390/can-
      Cemiplimab for Stage II to IV Cutaneous Squamous-Cell Carci-             cers13143547. PMID: 34298764. PMCID: PMC8305372.
      noma. N Engl J Med. 2022;387(17):1557–1568. DOI: 10.1056           32.   Extermann M, Hurria A. Comprehensive Geriatric Assessment
      /NEJMoa2209813. PMID: 36094839. PMCID: PMC9844515.                       for Older Patients With Cancer. J Clin Oncol. 2007;25(14):
20.   Ascierto PA, Bossi P, Mandalà M, et al. NEO-CESQ study: Neo-             1824–1831. DOI: 10.1200/JCO.2007.10.6559. PMID: 17488980.
      adjuvant plus adjuvant treatment with cemiplimab in surgically     33.   Martinez-Tapia C, Canoui-Poitrine F, Bastuji-Garin S, et al. Op-
      resectable, high risk stage III/IV (M0) cutaneous squamous               timizing the G8 Screening Tool for Older Patients With Cancer:
      cell carcinoma. J Clin Oncol. 2023;41(16_suppl):9576–9576.               Diagnostic Performance and Validation of a Six-Item Version.
      DOI:10.1200/JCO.2023.41.16_suppl.9576.                                   Oncologist. 2016;21(2):188–195. DOI: 10.1634/theoncologist
21.   Zuur CL, Breukers S, Machuca-Ostos M, et al. Towards organ               .2015-0326. PMID: 26764250. PMCID: PMC4746091.
      preservation and cure via 2 infusions of immunotherapy only, in    34.   Castagneto B, Di Pietrantonj C, Stevani I, et al. The impor-
      patients normally undergoing extensive and mutilating curative           tance of negative predictive value (NPV) of vulnerable elderly
      surgery for cutaneous squamous cell carcinoma: An investigator-          survey (VES 13) as a pre-screening test in older patients with
      initiated randomized phase II trial—The MATISSE trial. J Clin            cancer. Med Oncol. 2013;30(4):708. DOI: 10.1007/s12032-013
      Oncol. 2023;41(16_suppl):9507–9507.                                      -0708-3. PMID: 23996243.
22.   Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant                35.   Tagliamento M, Frelaut M, Baldini C, et al. The use of immu-
      Pembrolizumab versus Placebo in Resected Stage III Mela-                 notherapy in older patients with advanced non-small cell lung
      noma. N Engl J Med. 2018;378(19):1789–1801. DOI: 10.1056                 cancer. Cancer Treat Rev. 2022;106:102394. DOI: 10.1016/j
      /NEJMoa1802357. PMID: 29658430.                                          .ctrv.2022.102394. PMID: 35472632.




6                                                                                      Review | Dermatol Pract Concept. 2023;13(4):e2023251
36. Gomes F, Lorigan P, Woolley S, et al. A prospective cohort study              with skin diseases. Br J Dermatol. 2018;178(1):161–175.
    on the safety of checkpoint inhibitors in older cancer patients – the         DOI: 10.1111/bjd.15853. PMID: 28762236.
    ELDERS study. ESMO Open. 2021;6(1):100042. DOI: 10.1016/j               42.   Lee EH, Klassen AF, Cano SJ, Nehal KS, Pusic AL. FACE-Q Skin
    .esmoop.2020.100042. PMID: 33516147. PMCID: PMC7844568.                       Cancer Module for measuring patient-reported outcomes fol-
37. Bruijnen CP, Koldenhof JJ, Verheijden RJ, et al. Frailty and                  lowing facial skin cancer surgery. Br J Dermatol. 2018;179(1):
    checkpoint inhibitor toxicity in older patients with melanoma.                88–94. DOI: 10.1111/bjd.16671. PMID: 29654700. PMCID:
    Cancer. 2022;128(14):2746–2752. DOI: 10.1002/cncr.34230.                      PMC6115303.
    PMID: 35439334. PMCID: PMC9325486.                                      43.   Burdon-Jones D, Gibbons K. The Skin Cancer Quality of Life
38. Rischin D, Khushalani NI, Schmults CD, Guminski AD, Chang                     Impact Tool (SCQOLIT): a validated health-related quality of
    ALS, Lewis KD, et al. Phase II study of cemiplimab in patients (pts)          life questionnaire for non-metastatic skin cancers: A quality
    with advanced cutaneous squamous cell carcinoma (CSCC): Lon-                  of life impact tool for non-metastatic skin cancers. J Eur Acad
    ger follow-up. J Clin Oncol. 2020;38(15_suppl):10018–10018.                   Dermatol Venereol. 2013;27(9):1109–1113. DOI: 10.1111/j
39. Starkings R, Shilling V, Jenkins V, Fallowfield L. A structured               .1468-3083.2012.04669.x. PMID: 22909179.
    review of quality of life in advanced and high-risk cutaneous           44.   Waalboer-Spuij R, Hollestein L, Timman R, Poll-Franse L,
    squamous cell carcinoma shows the need for more studies and                   ­Nijsten T. Development and Validation of the Basal and Squa-
    better measures. Skin Health Dis. 2021;1(3):e39. DOI: 10.1002                  mous Cell Carcinoma Quality of Life (BaSQoL) Questionnaire.
    /ski2.39. PMID: 35663134. PMCID: PMC9060136.                                   Acta Derm Venereol. 2018;98(2):234–239. DOI: 10.2340
40. Gibbons E, Casañas i Comabella C, Fitzpatrick R. A structured                  /00015555-2806. PMID: 28952653.
    review of patient-reported outcome measures for patients with           45.    Müller K, Karrer S, Szeimies RM, et al. Quality of life assessment
    skin cancer, 2013. Br J Dermatol. 2013;168(6):1176–1186. DOI:                  in patients with nonmelanoma skin cancer - psychometric val-
    10.1111/bjd.12310. PMID: 23488455.                                             idation of the EORTC QLQ-C30 questionnaire: Validation of
41. Basra MKA, Salek MS, Fenech D, Finlay AY. Conceptualization, de-               EORTC QLQ-C30 in patients with NMSC. J Dtsch Dermatol
    velopment and validation of T-QoL© (Teenagers’ Quality of Life):               Ges. 2017;15(11):1090-1100. DOI: 10.1111/ddg.13357. PMID:
     a patient-focused measure to assess quality of life of adolescents           29106018.




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