10.5826/dpc.1304a252
For patients with advanced BCC, including locally advanced or metastatic BCC not amenable to curative surgery or radiotherapy, hedgehog pathway inhibitors (HHI) vismodegib and sonidegib are approved as first-line systemic treatment. Results from clinical trials highlight that the overall discontinuation rate of HHI treatment varies from 88% to 92% with vismodegib and is approximately 92% with sonidegib, and half of patients will discontinue HHI after approximately 8 to 12 months. The main factors weighing in on the decision to discontinue HHI, include efficacy (tumor response), adverse events and patient decision. In clinical practice, some of the patients that stop HHI may be re-evaluated if the tumor becomes amenable to surgery, or restart HHI at a later time, while others will need to switch to immunotherapy, depending on the reasons for HHI discontinuation. In this review, we revisit the therapeutic decisions considering a switch from HHI to immunotherapy with anti-PD-1 agent cemiplimab and we highlight the place of cemiplimab in the therapeutic ladder for patients with advanced BCC. We discuss the evidence on the efficacy and safety of anti-PD-1 agents as second-line systemic monotherapy, or in combination with other treatments, and the emergence of checkpoint immunotherapy as a neoadjuvant treatment.
text/xml
2160-9381
3703
en
Alexander  Stratigos
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
immunotherapy
Immunotherapy and Its Timing in Advanced Basal Cell Carcinoma Treatment
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Review
2023-10-31
2023-07-20
2023-10-31
2024-01-16
e2023252
Dermatol Pract Concept
For patients with advanced BCC, including locally advanced or metastatic BCC not amenable to curative surgery or radiotherapy, hedgehog pathway inhibitors (HHI) vismodegib and sonidegib are approved as first-line systemic treatment. Results from clinical trials highlight that the overall discontinuation rate of HHI treatment varies from 88% to 92% with vismodegib and is approximately 92% with sonidegib, and half of patients will discontinue HHI after approximately 8 to 12 months. The main factors weighing in on the decision to discontinue HHI, include efficacy (tumor response), adverse events and patient decision. In clinical practice, some of the patients that stop HHI may be re-evaluated if the tumor becomes amenable to surgery, or restart HHI at a later time, while others will need to switch to immunotherapy, depending on the reasons for HHI discontinuation. In this review, we revisit the therapeutic decisions considering a switch from HHI to immunotherapy with anti-PD-1 agent cemiplimab and we highlight the place of cemiplimab in the therapeutic ladder for patients with advanced BCC. We discuss the evidence on the efficacy and safety of anti-PD-1 agents as second-line systemic monotherapy, or in combination with other treatments, and the emergence of checkpoint immunotherapy as a neoadjuvant treatment.
Alexander  Stratigos
2023/10/31
10.5826/dpc.1304a252
e2023252
Department of Dermatology-Venereology, National and Kapodistrian University of Athens, Andreas Sygros Hospital, Athens, Greece
2160-9381
immunotherapy
en
e2023252
Durante G, Comito F, Lambertini M, Broseghini E, Dika E, Ferracin M. Non-coding RNA dysregulation in skin cancers. Essays Biochem. 2021;65(4):641-655.
Immunotherapy and Its Timing in Advanced Basal Cell Carcinoma Treatment
https://dpcj.org/index.php/dpc/article/download/3703/2334
           Immunotherapy and Its Timing in Advanced
               Basal Cell Carcinoma Treatment
                                         Clio Dessinioti1, Alexander J. Stratigos1


1 Skin Cancer and Melanoma Unit, 1st Department of Dermatology-Venereology, National and Kapodistrian University of Athens,
  Andreas Sygros Hospital, Athens, Greece



Key words: basal cell carcinoma, advanced, anti-PD-1, cemiplimab, nivolumab, immunotherapy
Citation: Dessinioti C, Stratigos AJ. Immunotherapy And Its Timing In Advanced Basal Cell Carcinoma Treatment.
Dermatol Pract Concept. 2023;13(4):e2023252. DOI: https://doi.org/10.5826/dpc.1304a252
Accepted: August 9, 2023; Published: October 2023
Copyright: ©2023 Dessinioti 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: Dr Dessinioti has no conflict of interest to declare. Dr. Stratigos reports personal fees and/or research support from
Novartis, Roche, BMS, Abbvie, Sanofi, Regeneron, Genesis Pharma, outside the submitted work.
Authorship: All authors have contributed significantly to this publication.
Corresponding Author: Alexander J Stratigos, Department of Dermato-Oncology, Andreas Sygros Hospital, Athens, Greece.
E-mail: alstrat2@gmail.com




  ABSTRACT             For patients with advanced basal cell carcinoma (BCC), including locally advanced or metastatic
                       BCC not amenable to curative surgery or radiotherapy, hedgehog pathway inhibitors (HHI)
                       ­vismodegib and sonidegib are approved as first-line systemic treatment. Results from clinical trials
                        highlight that the overall discontinuation rate of HHI treatment varies from 88% to 92% with
                        vismodegib and is approximately 92% with sonidegib, and half of patients will discontinue HHI
                        after approximately 8 to 12 months. The main factors weighing in on the decision to discontinue
                        HHI include efficacy (tumor response), adverse events and patient decision. In clinical practice,
                        some of the patients that stop HHI may be re-evaluated if the tumor becomes amenable to surgery,
                        or restart HHI at a later time, while others will need to switch to immunotherapy, depending on the
                        reasons for HHI discontinuation. In this review, we revisit the therapeutic decisions considering a
                        switch from HHI to immunotherapy with anti-PD-1 agent cemiplimab and we highlight the place
                        of cemiplimab in the therapeutic ladder for patients with advanced BCC. We discuss the evidence
                        on the efficacy and safety of anti-PD-1 agents as second-line systemic monotherapy, or in combi-
                        nation with other treatments, and the emergence of checkpoint immunotherapy as a neoadjuvant
                        treatment.




Review | Dermatol Pract Concept. 2023;13(4):e2023252                                                                                          1
Introduction                                                      In another study, among 40 BCCs, 22% had PD-L1 expres-
                                                                  sion on tumor cells, and 82% had PD-L1 expression on
Basal cell carcinoma (BCC) accounts for 75% of all skin           tumor-infiltrating lymphocytes and macrophages [16]. Also,
cancers and is the most common malignant tumor in white           BCC is one of the malignancies with the highest tumor muta-
populations. BCC and cutaneous squamous cell carcinoma            tional burden (TMB), which in turn has been associated with
(cSCC) are referred to as keratinocyte carcinomas (formerly       the presence of tumor neoantigens that may be targeted by
known as nonmelanoma skin cancers) [1].The majority of            immune cells activated with immunotherapy [17].
BCCs is characterized by indolent biological behavior and            Translational research has linked the above mentioned
is cured with surgical excision or topical treatments. How-       genetic and molecular findings in BCC with the development
ever, in some cases, BCC can infiltrate locally into adjacent     of treatments targeting these underlying dysregulations. As
and deeper structures and cause extensive tissue destruction.     a result, our therapeutic options have been enriched with
Metastases are extremely rare (< 0.1%) and may affect the         the Hedgehog pathway inhibitors (HHI) vismodegib and
regional lymph nodes, lung, spine, bone marrow and pelvic         sonidegib, and the anti-PD-1 agent cemiplimab, that have
bones [2].                                                        been regulatory approved for advanced BCC by the Euro-
    Multiple factors are implicated in the development of         pean Medicines Agency (EMA) in Europe. These treatments
sporadic BCC including exposure to ultraviolet radiation          have been a breakthrough for the treatment of patients with
(sun or indoor tanning beds), older age, light skin and hair      advanced BCC as they have replaced conventional systemic
tones, tendency to sunburn, male sex, immunosuppression           chemotherapy, which was previously used for advanced
(solid organ transplantation) and genetic factors [3-6]. Gene     BCC. Platinum-based chemotherapy was studied in a 1978
alterations playing some role in BCC pathogenesis include         phase I-II clinical trial in various solid tumors, that reported
mutations in p53 (17p13), human type II oculo-cutaneous           one complete and one partial response in two patients with
albinism-related gene (OCA2), agouti signaling protein            disseminated BCC [18], however further reports of chemo-
(ASIP), tyrosinase (TYR) and melanocortin 1 receptor gene         therapy for mBCC were generally limited by poor response,
(MC1R, 16q24.3) [1,7,8]. Mutations in the Hedgehog (Hh)           or short duration of response, short overall survival, and
signaling pathway have been detected in practically all BCCs.     lack of serial tumor measurements [19,20].
The Hh signaling pathway is normally required for the hair           In this review, we focus on patients with advanced BCC,
follicle morphogenesis during development and regulation of       including locally advanced and metastatic BCC, not amena-
the hair cycle in adulthood, while its aberrant activation, due   ble to curative surgery or radiotherapy and thus warranting
to mutations in the PTCH1 or SMO genes, leads to BCC              systemic treatment. We highlight the current recommenda-
carcinogenesis [9]. Loss-of-function somatic mutations in         tions for the use of oral Hedgehog inhibitors and intrave-
PTCH1 (9q22.3) and activating mutations in the G-protein          nous anti-PD-1 agents for the treatment of patients with
coupled receptor smoothened (SMO) have been detected in           advanced BCC. We discuss the evidence on the potential
up to approximately 90% and 10% of BCC tumors, respec-            applicability of anti-PD-1 agents as first-line or second-line
tively [10].                                                      systemic monotherapy, or in combination with other treat-
    In addition, cancer immunology via the innate and adap-       ments and the emergence of anti-PD-1 agents as a neoadju-
tive immune system plays a key role in the development of         vant treatment.
keratinocyte carcinomas. The PD-1 pathway is a checkpoint
that plays a central role in the local immunosuppression in       Systemic Treatments for Advanced BCC
the tumor microenvironment [11,12]. PD-L1 is expressed on         Advanced BCC is classified as either locally advanced BCC
tumor and/or immune cells and the programmed cell death           (laBCC) or metastatic BCC (mBCC). Based on the possibility
receptor-1 (PD-1) is expressed on immune cells, including         of treatment with surgery and/or radiotherapy with curative
CD8+ and CD4+ T-cells, B-cells and natural killer cells [11].     definitive intent, the term locally advanced BCC has been
In response to endogenous anti-tumor immunity, cancer cells       used to describe difficult-to-treat or high-risk BCCs in which
express on their surface the programmed cell death ligand-1       current treatment modalities are contraindicated by tumor
(PD-L1), in a process termed adaptive immune resistance           or patient factors [21-23]. Such factors may include tumor
[13]. Blocking the PD-1 pathway is regarded as “common            size and location that may pose technical difficulties of main-
denominator” for cancer therapy [14]. Regarding BCC, the          taining function and aesthetics, large numbers of BCCs, tu-
expression of PD-L1 has been detected in tumors or the            mor subtype, multiple recurrences, and patient comorbidities
tumor microenvironment [15,16]. The percentage of posi-           and frailty [21-23].
tive PD-L1 expression (defined as greater than 5% positive           Systemic treatments for advanced BCC include HHI and
immuno-histochemical staining) was 89.9% in tumor cells           immunotherapy. Systemic therapy is considered for laBCC
and 94.9% in tumor infiltrating lymphocytes of BCCs [15].         and mBCC, when curative surgery and RT are not feasible



2                                                                            Review | Dermatol Pract Concept. 2023;13(4):e2023252
[22,23]. A multidisciplinary board discussion is required to     the primary analysis of the pivotal ERIVANCE BCC trial
determine if BCC is not amenable to curative surgery and/        was 45% for mBCC and 60% for laBCC [31]. The final
or RT and further decide on the type of systemic therapy         39-month update of this trial reported that investigator-
[22,23]. HHI for advanced BCC include vismodegib and son-        assessed ORR was 48.5% for mBCC (all partial responses) and
idegib, which are taken orally. Vismodegib was approved in       60.3% for laBCC. Also, there was stable disease in 42.4% of
2012 by the US FDA and in 2013 by EMA for the treatment          mBCC [29]. At the 39-month study, disease progression was
of adults with symptomatic metastatic BCC or with locally        the reason to discontinue vismodegib in 51.5% of patients
advanced BCC inappropriate for surgery or radiotherapy           with mBCC and in 16.9% of patients with laBCC [29]. Sim-
[24]. Sonidegib was approved in 2015 by the US FDA and           ilar results have been shown with sonidegib [30,32-35]. Sec-
EMA for the treatment of adults with locally advanced BCC        ondary acquired resistance of BCC with a secondary loss of
who are not amenable to curative surgery or radiotherapy         response may occur during HHI treatment and is frequently
[25]. Cemiplimab is a human programmed death receptor            due to mutation of SMO [36,37]. A study of 9 patients with
(PD)-1 monoclonal antibody that belongs to the family of         primary or secondary resistance to vismodegib reported
immune checkpoint inhibitors (ICIs) [26]. Cemiplimab was         absence of response after switch to sonidegib, suggesting a
approved in 2021 by the US FDA and in 2019 by EMA as             class-relating effect [38]. However, the early discontinuation
monotherapy for the treatment of adult patients with meta-       of sonidegib in 4 patients, due to adverse events or patient
static or locally advanced BCC who have progressed on or         decision, may have contributed for not observing a response
are intolerant to a hedgehog pathway inhibitor [27]. It is ad-   [38,39]. Regarding those patients that achieve a complete
ministered by intravenous infusion over 30 minutes and the       response with vismodegib and stop treatment, the median
recommended dosage is 350 mg every 3 weeks until disease         relapse-free survival was 18.4 months or 24 months [40,41].
progression or unacceptable toxicity [27].In the following       Relapse in complete responders is attributed to a persisting,
sections, we will discuss the evidence on the place of cemi-     slow-cycling tumor cell population, induced by vismodegib
plimab immunotherapy in the therapeutic ladder for patients      via a shift in tumor cell identity and activation of the Wnt
with advanced BCC.                                               pathway [42,43]. When BCC relapses in complete respond-
                                                                 ers, re-treatment with vismodegib can be successful (response
Switching From Hedgehog Pathway Inhibitors to                    in 65.7% or 85%) but some patients will not respond again
Anti-PD-1 Immunotherapy for Advanced BCC                         [40,41,44]. These results highlight that non-responding
Hedgehog pathway inhibitors (HHI) vismodegib (150 mg/day)        patients could be considered for switching from HHI to
and sonidegib (200 mg/day) are approved as first-line            ­second-line anti-PD-1 immunotherapy (Figure 1).
systemic treatment for patients with advanced BCC. The              Second, although adverse events are mostly reversible
reported overall discontinuation rate of HHI treatment is        after HHI withdrawal and are usually of mild or moderate
88% to 92% with vismodegib and 92% with sonidegib [28-           severity, they can be considerably distressing to patients and
30]. Median vismodegib treatment duration was 8.6 (range:        are a frequent cause of drug discontinuation [45-47]. Ad-
0-44) months in the STEVIE study and 12.7 (range: 1.1-47.8)      verse events occur in all (100%) patients treated with HHI
months in the ERIVANCE BCC study [28,29]. Median son-            and are class-related, e.g. they are similar for vismodegib and
idegib treatment duration was 11 months [30]. These results      sonidegib [29,31,46,48]. Adverse events more frequently
from clinical trials highlight that half of patients with ad-    observed in clinical trials with HHI include muscle cramps
vanced BCC will discontinue HHI after approximately 8 to         in 49%-71%, alopecia in 55%-66%, dysgeusia in 38% to
12 months. The main factors weighing in on the decision to       71%, weight loss in 16% to 52%, fatigue in 16% to 43%,
discontinue HHI, include efficacy (tumor response), adverse      loss of appetite in 11% to 31% and diarrhea in 8% to 27%
events and patient decision. In clinical practice, some of the   [46]. During HHI treatment, the procedures to assess BCC
patients that discontinue HHI may be re-evaluated for sur-       response and monitor for adverse events, and the manage-
gical excision if the tumor becomes amenable to surgery, or      ment of adverse events, have been reviewed previously and
restart HHI at a later time, while others will need to switch    are outside the scope of this article [46,47,49].
to immunotherapy, depending on the reasons for HHI dis-             The STEVIE study reported long-term safety results
continuation. The results of clinical trials of HHI treatment    among patients with mBCC or laBCC treated with vismo-
in patients with laBCC, that may affect decision to switch       degib for at least 12 months [50]. Among 499 patients, 400
treatment are presented in Table 1. The therapeutic decisions    (80%) discontinued treatment, including 180/499 (36%) due
considering a switch from HHI to cemiplimab are shown in         to adverse events, 14% due to disease progression, and 10%
Figure 1.                                                        due to patient request [50]. Among the 180 patients who dis-
   First, regarding efficacy, the overall response rate (ORR:    continued vismodegib due to adverse events, those were of
complete response or partial response) with vismodegib in        mild severity (grade 1 or 2) in 106 patients (59%), and most



Review | Dermatol Pract Concept. 2023;13(4):e2023252                                                                          3
      Table 1. Summary of results of clinical trials of HHI treatments in patients with advanced BCC,
        that may affect decision to switch to anti-PD-1 immunotherapy: response, rates and reasons
                                             of discontinuation.
                                                 Vismodegib (150 mg/day)                             Sonidegib (200 mg/day)
                                   ERIVANCE study                     STEVIE study                           BOLT study
                                      (39-month                  (median follow-up:                 (30- month and 42-month
                                     update) [29]                   17.9 m) [28]                         update) [30,34]
             Outcome                 N =63 laBCC        N =1119 laBCC        N =1215 total         N =66 laBCC         N =79 total
    Investigator-assessed ORR,         38 (60.3)           738 (68.5)           769 (66.2)       47 (71.2%) [34]            NR
    N (%)
    CR                                     20              360 (33.4)           364 (31.4)             6 (9.1)
    PR                                     18              378 (35.1)           405 (34.9)           41 (62.1)
    SD                                     15              270 (25.1)           309 (26.6)           13 (19.7)
    PD                                     6                 21 (1.9)             30 (2.6)             1 (1.5)
    Median duration of response     26.2 (9.0-37.6)      23 (20.4-26.7)     22.7 (20.3-24.8)       26.1 (central            NR
    in responders, m (95% CI)                                                                      review) 30,34
    Median treatment duration,      12.7 (1.1-47.8)              NR             8.6 (0-44)              NR               11.0 [30]
    m (range)
    Discontinuation, N (%)           64/71 (90.1)                NR              1068 (88)              NR             73 (92.4%)
    Main reason for                                                                                                        [30]
    discontinuation
    Patient decision                     23 (32.4)                               113 (9.3)                                 8 (10.1)
    Adverse event                        17 (23.9)                              349 (28.7)                                23 (29.1)
    Progressive disease                  12 (16.9)                            189 (15.5%)                                 29 (36.7)
    Physician decision                     7 (9.9)                                76 (6.3)                                10 (12.6)
    Death                                  2 (2.8)                                  37 (3)                                  1 (1.3)
    Lost to follow-up                      2 (2.8)                                21 (1.7)                                  2 (2.5)
    Other                                  1 (1.4)                              283 (23.3)

CI = confidence interval; CR = complete response; laBCC = locally advanced BCC; m = months; N = number; NR = not reported;
ORR = objective response rate; PD = progressive disease; PR = partial response; SD = stable disease.




Figure 1. A schematic of therapeutic decisions on switching from hedgehog pathway inhibitors to anti-PD-1 immunotherapy with cemiplimab.
HHI = hedgehog pathway inhibitors; laBCC = locally advanced basal cell carcinoma; mBCC = metastatic basal cell carcinoma;
PD = progressive disease; RFS = relapse-free survival.
a
  results from the final update of the ERIVANCE BCC study [29]
b
  results from STEVIE study [50]
: results from Herms [40]
d
  results from Bassompierre [41]



4                                                                                 Review | Dermatol Pract Concept. 2023;13(4):e2023252
had complete or partial response [50]. The primary analy-        8-18), an objective response (by independent central review)
sis of STEVIE study in 1215 patients with advanced BCC           was observed in 31%, including 6% with complete response
showed similar results, and the leading cause of vismodegib      and 25% with partial response. The response rate was sim-
discontinuation were adverse events (28.7%) [28] (Table 1).      ilar across subgroups regarding age, sex, and intolerance or
In the final update of the ERIVANCE BCC study, overall           progression/lack of response to previous HHI. Cemiplimab
92.3% patients discontinued vismodegib, mainly because           was discontinued in 62% of patients, due to disease progres-
of disease progression (27.9%), patient decision (26%) and       sion (35%), adverse event (16%), or patient decision (6%)
adverse events (21.2%) [29]. In the group of laBCC, 90.1%        [65] (Table 2).
discontinued vismodegib, but the leading cause of discontin-        In this pivotal study, the safety profile of cemiplimab for
uation was patient decision (32.4%), followed by adverse         BCC was consistent with that of other anti-PD-1 agents for
events (23.9%) and disease progression (16.9%) [29]. In the      cutaneous melanoma and cSCC. Treatment-emergent adverse
42-month update of the BOLT study, of those who discon-          events grade 3 or 4 occurred in 48% of patients, including
tinued sonidegib, 29.1% discontinued due to adverse events,      hypertension, colitis, and fatigue. Immune-related adverse
despite the fact that most had only mild (grade 1 or 2) ad-      events (none of grade 4 or 5) occurred in 25% of patients
verse events [30,33] (Table 1).                                  and included hypothyroidism (10%), hyperthyroidism (2%),
   Using HHI as first-line treatment followed by anti-PD-1       thyroiditis (2%), adrenal insufficiency (2%), immune-related
therapy as second-line treatment may increase the tumor          colitis (4%), and hypophysitis, immune-mediated hepatitis
likelihood to respond to anti-PD-1 therapy. The treatment        and maculopapular rash (each in one patient) (Table 2) [65].
with HHI promotes adaptive immune responses, upregulates            The UNICANCER AcSe NIVOLUMAB phase 2 basket
MHC-I expression and increases the intra-tumor infiltration      trial (NCT03012581) evaluated nivolumab in a relatively
with CD4+ and cytotoxic CD8+ T cells [51]. Another study         small number of 32 patients with advanced BCC, including
showed significantly higher PD-L1 immunohistochemical            29 laBCC and 3 mBCC. Patients received nivolumab 240
staining intensity in tumor cells of previous treated BCC        mg by IV infusion every 2 weeks for up to 24 months [67].
versus naïve BCC (32% versus 7%, respectively). Previous         The median follow-up was 17 months (IQR 12-23). In this
treatments included HHI, platinum chemotherapy, gefitinib,       study, the objective response (radiologically) was assessed
topical chemotherapy, surgery, and radiotherapy [15]. The        early at 12 weeks, and was observed in 22%, including 3.1%
evidence on the efficacy and safety of anti-PD-1 immuno-         with complete response and 18.8% with partial response
therapy for advanced BCC is presented in the following           (Table 2). Adverse events occurred in 28% of patients and
sections.                                                        almost half were considered treatment related. Only one re-
                                                                 lated adverse event led to treatment discontinuation. More
Efficacy and Safety of Anti-PD-1 Immunotherapy                   frequent adverse events were diabetes mellitus, colitis, pneu-
as Second-line Systemic Therapy for Advanced                     monitis, myocardial infarction, lymphopenia and bullous
BCC                                                              pemphigoid [67].
The investigation of anti- PD-1 agents for advanced BCC             The above mentioned findings of clinical trials show the
followed the clinical trials and regulatory approval of anti-    efficacy of second-line anti-PD-1 ICI in some patients while
PD-1 immunotherapy for the treatment of other advanced           others will not respond, indicating a considerable group of
skin cancers, including cutaneous melanoma and squamous          patients with primary or secondary resistance to anti-PD-1
cell carcinoma. Anti-PD-1 immunotherapy for advanced             therapy. To overcome these limitations, the use of anti-PD-
BCC was first reported in various case reports treated with      therapies against earlier stages of cancer as neo-adjuvant
cemiplimab, nivolumab, or pembrolizumab, mostly with             treatment has been considered [11].
benefit [52-64].
   Regulatory approvals for BCC indications were based           Is There a Place for Anti-PD-1 Agents as
on a pivotal phase 2 open-label, multicenter, single-arm trial   Neoadjuvant or Adjuvant Treatment for Advanced
that assessed cemiplimab monotherapy in patients with ad-        BCC?
vanced BCC (ClinicalTrials.gov identifier NCT03132636)           The aim of neoadjuvant (presurgical) treatment for ad-
[65,66]. This pivotal trial included 84 patients with laBCC      vanced skin cancer has traditionally been to improve the op-
(group 2) previously treated with HHI, who were not candi-       erability of tumors. Currently there is no treatment approved
dates for further HHI therapy due to progression of disease      for advanced BCC in the neoadjuvant setting. Neoadjuvant
(71%), or no better than stable disease after 9 months of        vismodegib was used in the VISMONEO phase 2 trial in
HHI therapy (8%), or intolerance (38%) [65]. Patients re-        55 patients with locally advanced BCC of the face, and re-
ceived cemiplimab 350 mg by IV infusion every 3 weeks for        sulted in downstaging in surgical resection complexity in 44
up to 93 weeks. At a median follow-up of 15 months (IQR          (80%), of whom 27 had complete response. A recurrence



Review | Dermatol Pract Concept. 2023;13(4):e2023252                                                                         5
         Table 2. Results from clinical trials with anti-PD-1 immunotherapy for advanced BCC.
                                                                         Stratigos, 2021 [65]               Veron, 2022 [67]
 Anti-PD-1 agent                                                              Cemiplimab                       Nivolumab
 N                                                                             84 laBCC                 29 laBCC and 3 mBCC
 Prior systemic treatment
 HHI (vismodegib or sonidegib)                                                    All                              All
 Chemotherapy                                                                     NR                            17 (53%)
 Median FU, m                                                                      15                               17
 ORR (ICR), n (%)                                                              26 (31%)                   At 12 weeks 21.9%
 Complete Response                                                               5 (6%)                        1 (3.1%)
 Partial Response                                                              21 (25%)                        6 (18.8%)
 Stable Disease                                                                41 (49%)                       14 (43.8%)
 Progressive Disease                                                            9 (11%)                       11 (34.3%)
 Not evaluable                                                                  8 (10%)
 Median time to response (IQR), m                                            4.3 (4.2, 7.2)                        5.3
 Disease control rate, n (%)                                                   67 (80%)                        21 (65.7%)
 Duration of response in responders
 Median                                                                      Not reached                         13.8 m
 ≥ 12 months                                                                  11 (46%)
 Estimated duration of response at 12 months (95% CI)                        85% (61-95)
 Estimated 1-year PFS (95%C CI)                                              57% (44-67)
 Estimated 2-year OS (95%C CI)                                               80% (63-90)
 OS, median                                                                  Not reached
 Discontinued                                                                  52 (62%)
 Median treatment duration, w (IQR)                                           47 (27-80)                            32

DDC = durable disease control; HHI = Hedgehog inhibitors vismodegib or sonidegib; ICR = independent central review; IQR = interquartile
range; laBCC = locally advanced basal cell carcinoma; mBCC = metastatic basal cell carcinoma; m = months; N = number of patients; NR =
not reported; OS = overall survival; PFS = progression-free survival; w = weeks.




was noted in 36% at 3-year follow-up [68]. Also, the NCCN            higher adverse events of 12% in the neoadjuvant-adjuvant
guidelines recommend that for patients with high-risk BCC            group and 14% in the adjuvant-only group [70]. The
in whom surgery may cause significant functional damage,             PRADO melanoma trial investigated whether surgery and/or
neoadjuvant vismodegib followed by PDEMA may be con-                 subsequent adjuvant therapy could be omitted in the case of
sidered [22].                                                        a major (complete or near complete) pathological response
     Regarding neoadjuvant immunotherapy, most evidence              (0% or 0% to ≤10% viable tumor cells in surgical speci-
comes from studies in cutaneous melanoma, and there are              men, respectively). In these cases, the landmark two-year
limited studies in keratinocyte cancers, eg cSCC and BCC.            recurrence-free survival and distant-metastasis-free survival
The effects of systemic checkpoint inhibitors in the neoadju-        were 93% and 98% respectively [71].
vant setting for melanoma surpass improved operability as,               In resectable cSCC with primary tumors with diameter of
even more importantly, impact the long-term tumor control            at least 3 cm or with nodal metastasis (stage II, III or IV M0), a
and possibly survival through the induction of a systemic            phase 2 study evaluated neoadjuvant cemiplimab (350 mg every
immune response to cancer cells [11,69]. In resectable ad-           3 weeks for up to 4 doses) followed by surgery in 79 pa-
vanced (stage IIIB-IV) cutaneous melanoma, the combined              tients. A pathological complete response was observed in
neoadjuvant plus adjuvant pembrolizumab regimen (200 mg              40 patients (51%), and a pathological near-complete response
IV every 3 weeks, in 3 doses before surgery and the remain-          in 10 patients (13%). The results on relapse-free survival
ing 15 doses after surgery) was studied in the randomized            have not been reported yet [72]. The NCCN version 1.2023
SWOGS1801 trial compared to standard-care adjuvant                   guidelines recommend that neoadjuvant cemiplimab may be
pembrolizumab (18 doses after lymph-node dissection). The            considered in patients with cSCC with nodal metastasis who
estimated event-free survival was 72% in the neoadjuvant             are considered borderline resectable, unresectable, or for
plus adjuvant group versus 49% in the adjuvant group (HR:            whom surgery may carry a high morbidity [73].
0.58, P = 0.004). There was a similar frequency of grade 3 or



6                                                                                Review | Dermatol Pract Concept. 2023;13(4):e2023252
          Table 3. Clinical trials on neoadjuvant immunotherapy in patients with advanced basal
                                               cell carcinoma.
                        Phase                           Enrollment,
    Study ID           (Status)         Therapy              N                BCC classification               Main outcomes
 NCT05929664              II           Cemiplimab            35         laBCC of the head and neck        Primary: ORR, DCR
 [74]               (active, not                                        requiring greater than 30%        Secondary: SBR, pCR,
                   yet recruiting)                                      auriculectomy, rhinectomy,        mPR, adverse events,
                                                                        upper or lower lip resection,     quality of life
                                                                        orbital exenteration (due to
                                                                        lid or orbital involvement),
                                                                        facial nerve sacrifice or
                                                                        Brigham and Women's stage
                                                                        2b or 3 disease of head and
                                                                        neck
 NCT04323202               I         Pembrolizumab           13         Locoregionally advanced,          Primary: Pathologic
 [75]                (active, not                                       resectable BCC of the head        response assessed by
                     recruiting)                                        and neck                          tumor volume.
                                                                                                          Secondary: Adverse
                                                                                                          events, one-year
                                                                                                          recurrence rates

BCC = basal cell carcinoma; DCR = disease control rate; laBCC = locally advanced basal cell carcinoma; mPR = major pathologic response;
ORR= objective response rate; pCR = pathologic complete response; SBR = surgical/clinical benefit rate.



    For advanced BCC, neoadjuvant anti-PD-1 immuno-                  responses compared to pembrolizumab alone (in 9 patients)
therapy is currently investigated in clinical trials which are       in the proof-of-concept study by Chang et al, for advanced
summarized in Table 3 [74,75]. For laBCC, neoadjuvant                BCC. The ORR at 18 weeks was and 29% for the combina-
nivolumab was used in 2 patients with laBCC as first-line            tion regimen and 44% for the pembrolizumab monotherapy
treatment [76]. Neoadjuvant cemiplimab is investigated in            [82]. A case of laBCC which developed during cemiplimab
patients with advanced BCC requiring greater than 30% au-            therapy for lacSCC, was treated with concomitant sonide-
riculectomy, rhinectomy, upper or lower lip resection, orbital       gib with a clinical response. The combination treatment
exenteration (due to lid or orbital involvement), facial nerve       was well tolerated and the patient received 31 cycles of ce-
sacrifice or Brigham and Women's stage 2b or 3 disease of            miplimab and 10 cycles of sonidegib. The patient died due
head and neck [74].Neoadjuvant pembrolizumab is investi-             to sepsis that was considered unrelated to treatment [80].
gated in patients with resectable high-risk BCC [75]. There          Ongoing clinical trials aim to investigate the combination of
is no recommendation on adjuvant anti-PD-1 treatment for             cemiplimab with pulsed sonidegib therapy, and the combina-
resected advanced BCC outside the context of clinical trials         tion of nivolumab plus relatlimab or ipilimumab for patients
in current guidelines [21,23].                                       with laBCC or mBCC [83,84].
                                                                         The combination of immunotherapeutic agents, such
Have Anti-PD-1 Agents Been Combined With                             as immune checkpoint inhibitors and intralesional onco-
Other Treatments for Advanced BCC?                                   lytic viruses, is studied with the aim to improve the T-cell
Current guidelines recommend cemiplimab as monotherapy               exhaustion, prolong the duration of response and delay
for advanced cSCC and for advanced BCC [22,73,77,78].                resistance, associated with immune checkpoint inhibitor
The need to combine anti-PD-1 with another treatment                 therapy [85,86]. Talimogene laherparepvec was approved
may arise in the case of failure of BCC to respond to                in 2015 as the first engineered oncolytic herpes simplex
anti-PD-1 in some patients, as described in the studies above        virus type 1 (HSV-1) for the treatment of advanced mel-
and in case reports, if new BCCs develop during anti-PD-1            anoma [85,87]. Oncolytic viruses selectively infect and
immunotherapy for other indications or despite response              induce the lysis of cancer cells with subsequent release of
of the index advanced BCC [53,79-81]. In these lines, the            tumor-derived antigens, express immunostimulatory cyto-
combination of anti-PD-1 therapy with HHI, or talimogene             kines and chemokines, such as granulocyte-macrophage
laherparepvec for advanced BCC is currently evaluated in             colony-stimulating factor (GM-CSF) expressed by T-VEC,
clinical trials.                                                     and may trigger a systemic anti-tumor response [85,87].
    The combination of pembrolizumab 200 mg IV ev-                   Intra-tumoural immunotherapy with T-VEC is being stud-
ery 3 weeks with vismodegib (in 7 patients) showed lower             ied in clinical trials, in combination with panitumumab for



Review | Dermatol Pract Concept. 2023;13(4):e2023252                                                                                 7
advanced cSCC, and in combination with nivolumab for              albeit high, median TMB (58 versus 23 mut/MB) and simi-
advanced BCC [88,89].                                             lar median MHC-I expression level on tumor cells (37, IQR
                                                                  21-72 versus 21, IQR 5-62), in responders versus non-re-
Is There Evidence for Anti-PD-1 Agents as                         sponders, respectively. Notably, among some patients with
First-line Systemic Therapy for Advanced BCC?                     high TMB levels who did not have objective response, ma-
The current US NCCN guidelines (version 1.2023) and the           jor histocompatibility complex I (MHC-I) expression was
European guideline update 2023, have issued recommenda-           low or absent [65]. The downregulation of MHC-I has been
tions regarding the place and timing of anti-PD-1 immuno-         implicated in lower antigen modification and presentation,
therapy for advanced BCC [22,23]. The British guidelines          contributing to a possible lower immunogenicity of BCC
(2021) were prepared before the approval of cemiplimab            compared to cSCC [93]. Recently, the dysregulation of reg-
for advanced BCC and do not include a recommendation              ulatory non-coding RNAs, including microRNA (miRNA),
on anti-PD-1 immunotherapy [21]. The NCCN guidelines              has been identified in BCC. Some miRNAs may act as tumor
recommend cemiplimab according to the US FDA approval,            suppressors while others act as oncogenes (oncomiR), and
as a monotherapy for patients with laBCC or mBCC pre-             miRNAs have been associated with specific high-risk BCC
viously treated with an HHI or for whom an HHI is not             subtypes, suggesting a potential prognostic role. In addition,
appropriate [22].                                                 several miRNAs have been shown to affect drug resistance to
    Currently, when a patient is eligible for systemic therapy,   BRAF inhibition in melanoma, underscoring the possibility
including HHI or anti-PD-1 therapy, anti-PD-1 agents are          to add predictive information for response to therapy [94].
recommended as second-line systemic therapy for patients
with advanced BCC previously treated with HHI. The Eu-
                                                                  Conclusions
ropean guideline update 2023 on BCC, recommends that
anti-PD-1 immunotherapy should be offered as second-line          Anti-PD-1 agents offer a therapeutic option in patients with
treatment in patients who progress or have contraindications      advanced BCC not amenable to curative surgery or radio-
to hedgehog inhibitors [23]. In the clinical trials of vismo-     therapy, who have progressed or are intolerant to an HHI.
degib and cemiplimab for laBCC, a similar treatment du-           For laBCC treated with second-line cemiplimab, the possi-
ration was reported with cemiplimab (median 12 months)            bility of a response in approximately one third of patients
and vismodegib (median 12 months)2 the objective response         and of a prolonged duration of response, make anti-PD-1
rate was 31% with cemiplimab and 60% with vismodegib,             immunotherapy an important treatment solution. In addi-
and the median duration of response in responders was not         tion, results from melanoma trials underscore the emergence
reached with cemiplimab and was 26 months with vismode-           of neoadjuvant immunotherapy with anti-PD-1 agents as a
gib [29,65]. However, a direct comparison of these studies        treatment positively affecting the prognostic outcomes in
cannot be made as they included heterogeneous patients; ce-       skin cancer. Treating advanced BCC with immunotherapy
miplimab was used in a highly challenging group of patients       can achieve durable response in some patients, however there
who had progressed or not responded or were intolerant to         is a considerable number of patients who will not respond or
previous HHI treatment.                                           will lose response. The use of biomarkers for Identifying and
    At the moment, there is no validated predictive bio-          treating those patients more likely to respond to anti-PD-1
marker to select those patients with advanced BCC more            therapy is a promising area of active research towards per-
likely to benefit from anti-PD-1 ICI, thus guiding the choice     sonalized treatment.
of anti-PD-1 immunotherapy as first-line therapy for ad-             Clinical and translational research has led to a para-
vanced BCC [26]. PD-L1 positivity by immunohistochem-             digm shift in the treatment of advanced BCC with the ad-
istry has been shown in some advanced BCC tumors, but it          vent of targeted therapies, eg HHI and anti-PD-1 immune
has not been associated with clinical responses to anti-PD-1      checkpoint blockade. However, important treatment gaps
immunotherapy [15,57,65,90]. A high TMB has been con-             still remain on the management of those patients that
sistently reported in advanced BCC [65,91]. Also, a higher        have resistance or unacceptable toxicities with HHI and
TMB has been reported in advanced BCCs with response              ­anti-PD-1 agents. For the challenges that lie ahead, preci-
to anti-PD-1 therapy, however the median TMB in non-              sion medicine and rigorous clinical research aim to provide
responders was 23 mt/Mb, that is above the defined high TMB       further data to guide evidence-based decisions on the opti-
threshold of ≥10 mut/Mb [65,92]. In the pivotal phase 2 clin-     mal timing and combination of treatments for patients with
ical trial of cemiplimab for laBCC, exploratory biomarker         advanced BCC.
data showed similar response to cemiplimab by PD-L1 im-
munohistochemistry status of tumor cells (PD-L1<1%, N
= 35, versus PD-L1 ≥1%, N = 15) [65]. There was similar,



8                                                                            Review | Dermatol Pract Concept. 2023;13(4):e2023252
References                                                                    cell. 2015;27(4):450-461. DOI: 10.1016/j.ccell.2015.03.001.
                                                                              PMID: 25858804. PMCID: PMC4400238.
 1. Dessinioti C, Antoniou C, Katsambas A, Stratigos AJ. Basal cell     15.   Chang J, Zhu GA, Cheung C, Li S, Kim J, Chang AL. Association
    carcinoma: what's new under the sun. Photochem Photobiol.                 Between Programmed Death Ligand 1 Expression in Patients
    2010;86(3):481-491. DOI: 10.1111/j.1751-1097.2010.00735.x.                With Basal Cell Carcinomas and the Number of Treatment Mo-
    PMID: 20550646.                                                           dalities. JAMA Dermatol. 2017;153(4):285-290. DOI: 10.1001
 2. Laga AC, Schaefer IM, Sholl LM, French CA, Hanna J. Metastatic            /jamadermatol.2016.5062. PMID: 28259105.
    Basal Cell Carcinoma. Am J Clin Pathol. 2019;152(6):706-717.        16.   Lipson EJ, Lilo MT, Ogurtsova A, et al. Basal cell carcinoma:
    DOI: 10.1093/ajcp/aqz089. PMID: 31355851. PMCID:                          PD-L1/PD-1 checkpoint expression and tumor regression af-
    PMC6829017.                                                               ter PD-1 blockade. J Immunother Cancer. 2017;5:23. DOI:
 3. Dessinioti C, Tzannis K, Sypsa V, et al. Epidemiologic risk fac-          10.1186/s40425-017-0228-3. PMID: 28344809. PMCID:
    tors of basal cell carcinoma development and age at onset in              PMC5360064.
    a Southern European population from Greece. Exp Dermatol.           17.   Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of
    2011;20(8):622-626. DOI: 10.1111/j.1600-0625.2011.01275.x.                100,000 human cancer genomes reveals the landscape of tu-
    PMID: 21521370.                                                           mor mutational burden. Genome Med. 2017;9(1):34. DOI:
 4. Krakowski AC, Hafeez F, Westheim A, Pan EY, Wilson M. Ad-                 10.1186/s13073-017-0424-2. PMID: 28420421. PMCID:
    vanced basal cell carcinoma: What dermatologists need to know             PMC5395719.
    about diagnosis. J Am Acad Dermatol. 2022;86(6S):S1-S13.            18.   Salem P, Hall SW, Benjamin RS, Murphy WK, ­          Wharton
    DOI: 10.1016/j.jaad.2022.03.023. PMID: 35577405.                          JT, Bodey GP. Clinical phase I-II study of cis-dichloro-­
 5. Dessinioti C, Stratigos AJ. An Epidemiological Update on                  diammineplatinum(II) given by continuous lv infusion. Cancer
    Indoor Tanning and the Risk of Skin Cancers. Curr Oncol.                  Treat Rep. 1978;62(10):1553-1555. PMID: 361227.
    2022;29(11):8886-8903. DOI: 10.3390/curroncol29110699.              19.   Coker DD, Elias EG, Viravathana T, McCrea E, Hafiz M. Che-
    PMID: 36421352. PMCID: PMC9689757.                                        motherapy for metastatic basal cell carcinoma. Arch Dermatol.
 6. Molinaro AM, Ferrucci LM, Cartmel B, et al. Indoor tanning              1983;119(1):44-50. PMID: 6849564.
    and the MC1R genotype: risk prediction for basal cell carci-        20. Moeholt K, Aagaard H, Pfeiffer P, Hansen O. Platinum-based
    noma risk in young people. Am J Epidemiol. 2015;181(11):                cytotoxic therapy in basal cell carcinoma--a review of
    908-916. DOI: 10.1093/aje/kwu356. PMID: 25858289. PM-                   the literature. Acta Oncol. 1996;35(6):677-682. DOI:
    CID: PMC4445390.                                                        10.3109/02841869609083998. PMID: 8938213.
 7. Dessinioti C, Sypsa V, Kypreou K, et al. A case-control study       21. Nasr I, McGrath EJ, Harwood CA, et al. British Association of
    of MC1R variants in Greek patients with basal cell carcinoma:           Dermatologists guidelines for the management of adults with
    increased risk independently of pigmentary characteristics. Exp         basal cell carcinoma 2021. Br J Dermatol. 2021;185(5):899-920.
    Dermatol. 2015;24(6):476-478. DOI: 10.1111/exd.12703.                   DOI: 10.1111/bjd.20524. PMID: 34050920.
    PMID: 25809071.                                                     22. Schmults C, Blitzblau R, Aasi SZ, et al. Basal Cell Skin Cancer.
 8. Tagliabue E, Fargnoli MC, Gandini S, et al. MC1R gene vari-             National Comprehensive Cancer Network (NCCN) Clinical
    ants and non-melanoma skin cancer: a pooled-analysis from               Practice Guidelines in Oncology. 2023; version 1.2023. Avail-
    the M-SKIP project. Br J Cancer. 2015;113(2):354-363.                   able from: https://www.nccn.org/professionals/physician_gls/pdf
    DOI: 10.1038/bjc.2015.231. PMID: 26103569. PMCID:                       /nmsc.pdf, Accessed July 3, 2023.
    PMC4506395.                                                         23. Peris K, Fargnoli MC, Kaufmann R, et al. European
 9. Dessinioti C, Antoniou C, Stratigos AJ. From basal cell carcinoma       consensus-based interdisciplinary guideline for diagnosis and
    morphogenesis to the alopecia induced by hedgehog inhibitors:           treatment of basal cell carcinoma-update 2023. Eur J Cancer.
    connecting the dots. Br J Dermatol. 2017;177(6):1485-1494.              2023;192:113254. DOI: 10.1016/j.ejca.2023.113254. PMID:
    DOI: 10.1111/bjd.15738. PMID: 28626889.                                 37604067.
10. Epstein EH. Basal cell carcinomas: attack of the hedgehog.          24. Erivedge. Summary of product characteristics. Available From:
      Nat Rev Cancer. 2008;8(10):743-754. DOI: 10.1038/nrc2503.             https://www.ema.europa.eu/en/documents/product-information
      PMID: 18813320. PMCID: PMC4457317.                                    /erivedge-epar-product-information_en.pdf, Accessed on July 3,
11.   Topalian SL, Taube JM, Pardoll DM. Neoadjuvant check-                 2023.
      point blockade for cancer immunotherapy. Science.                 25. Odomzo. Summary of product characteristics (SPC). Avail-
      2020;367(6477):eaax0182. DOI: 10.1126/science.aax0182.                able from: https://www.ema.europa.eu/en/documents/product
      PMID: 32001626. PMCID: PMC7789854.                                    -information/odomzo-epar-product-information_en.pdf          As-
12.   Neuner RA, Lee J, Rieger KE, Park C, Colevas AD, Chang ALS.           sessed July 3, 2023.
      Immunotherapy for keratinocyte cancers. Part I: Immune-related    26. Barrios DM, Do MH, Phillips GS, et al. Immune checkpoint
      epidemiology, risk factors, pathogenesis, and immunotherapy           inhibitors to treat cutaneous malignancies. J Am Acad Derma-
      management of keratinocyte cancers. J Am Acad Dermatol.               tol. 2020;83(5):1239-1253. DOI: 10.1016/j.jaad.2020.03.131.
      2023;88(6):1225-1240. DOI: 10.1016/j.jaad.2022.06.1206.               PMID: 32461079. PMCID: PMC7572574.
      PMID: 37268390.                                                   27. European Medicines Agency. Libtayo. Summary of prod-
13.   Pardoll DM. The blockade of immune checkpoints in cancer              uct characteristics. Available from: https://www.ema.europa
      immunotherapy. Nat Rev Cancer. 2012;12(4):252-264. DOI:               .eu/en/documents/product-information/libtayo-epar-product
      10.1038/nrc3239. PMID: 22437870. PMCID: PMC4856023.                   -information_en.pdf, Access date: July 3, 2023.
14.   Topalian SL, Drake CG, Pardoll DM. Immune checkpoint block-       28. Basset-Seguin N, Hauschild A, Kunstfeld R, et al. Vismodegib
      ade: a common denominator approach to cancer therapy. Cancer          in patients with advanced basal cell carcinoma: Primary anal-
                                                                            ysis of STEVIE, an international, open-label trial. Eur J Cancer.



Review | Dermatol Pract Concept. 2023;13(4):e2023252                                                                                       9
      2017;86:334-348. DOI: 10.1016/j.ejca.2017.08.022. PMID:                 of 116 Patients. J Clin Oncol. 2019;37(34):3275-3282. DOI:
      29073584.                                                               10.1200/JCO.18.00794. PMID: 31609670.
29.   Sekulic A, Migden MR, Basset-Seguin N, et al. Long-term safety    41.   Bassompierre A, Dalac S, Dreno B, et al. Efficacy of sonic hedge-
      and efficacy of vismodegib in patients with advanced basal cell         hog inhibitors rechallenge, after initial complete response in re-
      carcinoma: final update of the pivotal ERIVANCE BCC study.              current advanced basal cell carcinoma: a retrospective study from
      BMC Cancer. 2017;17(1):332. DOI: 10.1186/s12885-017                     the CARADERM database. ESMO Open. 2021;6(6):100284.
      -3286-5. PMID: 28511673. PMCID: PMC5433030.                             DOI: 10.1016/j.esmoop.2021.100284. PMID: 34689002.
30.   Dummer R, Guminksi A, Gutzmer R, et al. Long-term effi-                 ­PMCID: PMC8551849.
      cacy and safety of sonidegib in patients with advanced basal      42.    Sanchez-Danes A, Larsimont JC, Liagre M, et al. A slow-cycling
      cell carcinoma: 42-month analysis of the phase II randomized,            LGR5 tumour population mediates basal cell carcinoma relapse
      double-blind BOLT study. Br J Dermatol. 2020;182(6):1369-                after therapy. Nature. 2018;562(7727):434-438. DOI: 10.1038
      1378. DOI: 10.1111/bjd.18552. PMID: 31545507. PMCID:                     /s41586-018-0603-3. PMID: 30297799. PMCID: PMC6295195.
      PMC7318253.                                                       43.    Biehs B, Dijkgraaf GJP, Piskol R, et al. A cell identity switch
31.   Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of              allows residual BCC to survive Hedgehog pathway inhibition.
      vismodegib in advanced basal-cell carcinoma. N Engl J Med.               Nature. 2018;562(7727):429-433. DOI: 10.1038/s41586-018
      2012;366(23):2171-2179. DOI: 10.1056/NEJMoa1113713.                      -0596-y. PMID: 30297801.
      PMID: 22670903. PMCID: PMC5278761.                                44.    Dessinioti C, Plaka M, Dimitrakopoulou A, Stratigos AJ. Com-
32.   Migden MR, Guminski A, Gutzmer R, et al. Treatment with                  plete response is reversible upon vismodegib withdrawal and
      two different doses of sonidegib in patients with locally ad-            re-inducible upon vismodegib rechallenge in a patient with
      vanced or metastatic basal cell carcinoma (BOLT): a multi-               locally advanced basal cell carcinoma. J Eur Acad Dermatol
      centre, randomised, double-blind phase 2 trial. Lancet Oncol.            ­Venereol. 2019;33(5):e187-e188. DOI: 10.1111/jdv.15428.
      2015;16(6):716-728. DOI: 10.1016/S1470-2045(15)70100-2.                   PMID: 30653740.
      PMID: 25981810.                                                   45.     Bower JE, Bak K, Berger A, et al. Screening, assessment, and
33. Dummer R, Guminski A, Gutzmer R, et al. The 12-month anal-                management of fatigue in adult survivors of cancer: an ­American
    ysis from Basal Cell Carcinoma Outcomes with LDE225 Treat-                Society of Clinical oncology clinical practice guideline adap-
    ment (BOLT): A phase II, randomized, double-blind study of                tation. J Clin Oncol. 2014;32(17):1840-1850. DOI: 10.1200
    sonidegib in patients with advanced basal cell carcinoma. J Am            /JCO.2013.53.4495. PMID: 24733803. PMCID: PMC4039870.
    Acad Dermatol. 2016;75(1):113-125 e115. DOI: 10.1016/j              46.   Lacouture ME, Dreno B, Ascierto PA, et al. Characterization and
    .jaad.2016.02.1226. PMID: 27067394.                                       Management of Hedgehog Pathway Inhibitor-Related Adverse
34. Lear JT, Migden MR, Lewis KD, et al. Long-term efficacy                   Events in Patients With Advanced Basal Cell Carcinoma. On-
    and safety of sonidegib in patients with locally advanced and             cologist. 2016;21(10):1218-1229. DOI: 10.1634/theoncologist
    metastatic basal cell carcinoma: 30-month analysis of the                 .2016-0186. Epub 2016 Aug 10. PMID: 27511905. PMCID:
    randomized phase 2 BOLT study. J Eur Acad Dermatol Vene-                  PMC5061532.
    reol. 2018;32(3):372-381. DOI: 10.1111/jdv.14542. PMID:             47.   Fife K, Herd R, Lalondrelle S, et al. Managing adverse events
    28846163. PMCID: PMC5873455.                                              associated with vismodegib in the treatment of basal cell car-
35. Mannino M, Piccerillo A, Fabbrocini G, et al. Clinical character-         cinoma. Future Oncol. 2017;13(2):175-184. DOI: 10.2217/fon
    istics of an Italian patient population with advanced BCC and             -2016-0296. PMID: 27640448.
    real-life evaluation of HHI safety and effectiveness. Dermatol-     48.   Sekulic A, Migden MR, Lewis K, et al. Pivotal ERIVANCE
    ogy. 2023. DOI: 10.1159/000531280. PMID: 37311439.                        basal cell carcinoma (BCC) study: 12-month update of effi-
36. Atwood SX, Sarin KY, Whitson RJ, et al. Smoothened vari-                  cacy and safety of vismodegib in advanced BCC. J Am Acad
    ants explain the majority of drug resistance in basal cell car-           Dermatol. 2015;72(6):1021-1026 e1028. DOI: 10.1016/j
    cinoma. Cancer Cell. 2015;27(3):342-353. DOI: 10.1016/j                   .jaad.2015.03.021. PMID: 25981002.
    .ccell.2015.02.002. PMID: 25759020. PMCID: PMC4357167.              49.   Dessinioti C, Plaka M, Soura E, et al. A Practical Guide for
37. Sharpe HJ, Pau G, Dijkgraaf GJ, et al. Genomic analysis of                the Follow-Up of Patients with Advanced Basal Cell Carci-
    smoothened inhibitor resistance in basal cell carcinoma. Cancer           noma During Treatment with Hedgehog Pathway Inhibitors.
    Cell. 2015;27(3):327-341. DOI: 10.1016/j.ccell.2015.02.001.               ­Oncologist. 2019;24(8):e755-e764. DOI: 10.1634/theoncologist
    PMID: 25759019. PMCID: PMC5675004.                                         .2018-0924. PMID: 31073024. PMCID: PMC6693703.
38. Danial C, Sarin KY, Oro AE, Chang AL. An Investigator-­             50.    Basset-Seguin N, Hauschild A, Grob JJ, et al. Vismodegib
    Initiated Open-Label Trial of Sonidegib in Advanced Basal Cell             in patients with advanced basal cell carcinoma (STEVIE): a
    Carcinoma Patients Resistant to Vismodegib. Clin Cancer Res.               pre-planned interim analysis of an international, open-label
    2016;22(6):1325-1329. DOI: 10.1158/1078-0432.CCR-15                        trial. Lancet Oncol. 2015;16(6):729-736. DOI: 10.1016/S1470
    -1588. PMID: 26546616. PMCID: PMC4794361.                                  -2045(15)70198-1. PMID: 25981813.
39. Doan HQ, Chen L, Nawas Z, Lee HH, Silapunt S, Migden M.             51.    Otsuka A, Dreier J, Cheng PF, et al. Hedgehog pathway inhibi-
    Switching Hedgehog inhibitors and other strategies to address re-          tors promote adaptive immune responses in basal cell carcinoma.
    sistance when treating advanced basal cell carcinoma. Oncotar-             Clin Cancer Res. 2015;21(6):1289-1297. DOI: 10.1158/1078
    get. 2021;12(20):2089-2100. DOI: 10.18632/oncotarget.28080.                -0432.CCR-14-2110. PMID: 25593302.
    PMID: 34611482. PMCID: PMC8487719.                                  52.    Falchook GS, Leidner R, Stankevich E, et al. Responses of met-
40. Herms F, Lambert J, Grob JJ, et al. Follow-Up of Patients With             astatic basal cell and cutaneous squamous cell carcinomas to
    Complete Remission of Locally Advanced Basal Cell Carcinoma                anti-PD1 monoclonal antibody REGN2810. J Immunother
    After Vismodegib Discontinuation: A Multicenter French Study               Cancer. 2016;4:70. DOI: 10.1186/s40425-016-0176-3. PMID:
                                                                               27879972. PMCID: PMC5109769.



10                                                                                    Review | Dermatol Pract Concept. 2023;13(4):e2023252
53. Cohen PR, Kato S, Goodman AM, Ikeda S, Kurzrock R. Ap-                       2021;22(6):848-857. DOI: 10.1016/S1470-2045(21)00126-1.
    pearance of New Cutaneous Superficial Basal Cell Carcinomas                  PMID: 34000246.
    during Successful Nivolumab Treatment of Refractory Meta-              66.   ClinicalTrials.gov. PD-1 in patients with advanced basal cell
    static Disease: Implications for Immunotherapy in Early Versus               carcinoma who experienced progression of disease on hedge-
    Late Disease. Int J Mol Sci. 2017;18(8):1663. DOI: 10.3390                   hog pathway inhibitor therapy, or were intolerant of prior
    /ijms18081663. PMID: 28788102. PMCID: PMC5578053.                            hedgehog pathway inhibitor therapy. 2022; Available from:
54. Borradori L, Sutton B, Shayesteh P, Daniels GA. Rescue therapy               https://clinicaltrials.gov/ct2/show/NCT03132636. Accessed
    with anti-programmed cell death protein 1 inhibitors of ad-                  March 3, 2023.
    vanced cutaneous squamous cell carcinoma and basosquamous              67.   Veron M, Chevret S, Grob JJ, et al. Safety and efficacy of
    carcinoma: preliminary experience in five cases. Br J Derma-                 nivolumab, an anti-PD1 immunotherapy, in patients with ad-
    tol. 2016;175(6):1382-1386. DOI: 10.1111/bjd.14642. PMID:                    vanced basal cell carcinoma, after failure or intolerance to
    27059424.                                                                    sonic Hedgehog inhibitors: UNICANCER AcSe NIVOLUMAB
55. Winkler JK, Schneiderbauer R, Bender C, et al. Anti-programmed               trial. Eur J Cancer. 2022;177:103-111. DOI: 10.1016/j.
    cell death-1 therapy in nonmelanoma skin cancer. Br J Derma-                 ejca.2022.09.013. PMID: 36335780.
    tol. 2017;176(2):498-502. DOI: 10.1111/bjd.14664. PMID:                68.   Bertrand N, Guerreschi P, Basset-Seguin N, et al. Vismodegib in
    27061826.                                                                    neoadjuvant treatment of locally advanced basal cell carcinoma:
56. Lipson EJ, Bagnasco SM, Moore J, Jr., et al. Tumor Regression and            First results of a multicenter, open-label, phase 2 trial (VISMO-
    Allograft Rejection after Administration of Anti-PD-1. N Engl                NEO study): Neoadjuvant Vismodegib in Locally Advanced
    J Med. 2016;374(9):896-898. DOI: 10.1056/NEJMc1509268.                       Basal Cell Carcinoma. EClinicalMedicine. 2021;35:100844.
    PMID: 26962927. PMCID: PMC4850555.                                           DOI: 10.1016/j.eclinm.2021.100844. PMID: 33997740. PM-
57. Cannon JGD, Russell JS, Kim J, Chang ALS. A case of metastatic               CID: PMC8093898.
    basal cell carcinoma treated with continuous PD-1 inhibitor            69.   Garbe C, Dummer R, Amaral T, et al. Neoadjuvant immunother-
    exposure even after subsequent initiation of radiotherapy and                apy for melanoma is now ready for clinical practice. Nat Med.
      surgery. JAAD Case Rep. 2018;4(3):248-250. DOI: 10.1016/j                  2023;29(6):1310-1312. DOI: 10.1038/s41591-023-02336-1.
      .jdcr.2018.01.015. PMID: 29687062. PMCID: PMC5909484.                      PMID: 37193799.
58.   Fischer S, Hasan Ali O, Jochum W, Kluckert T, Flatz L, Siano         70.   Patel SP, Othus M, Chen Y, et al. Neoadjuvant-Adjuvant or
      M. Anti-PD-1 Therapy Leads to Near-Complete Remission                      Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl
      in a Patient with Metastatic Basal Cell Carcinoma. Oncol Res               J Med. 2023;388(9):813-823. DOI: 10.1056/NEJMoa2211437.
      Treat. 2018;41(6):391-394. DOI: 10.1159/000487084. PMID:                   PMID: 36856617. PMCID: PMC10410527.
      29734143.                                                            71.   Reijers ILM, Menzies AM, van Akkooi ACJ, et al. Personalized
59.   Choi FD, Kraus CN, Elsensohn AN, et al. Programmed cell                    response-directed surgery and adjuvant therapy after neoad-
      death 1 protein and programmed death-ligand 1 inhibitors in                juvant ipilimumab and nivolumab in high-risk stage III mela-
      the treatment of nonmelanoma skin cancer: A systematic review.             noma: the PRADO trial. Nat Med. 2022;28(6):1178-1188. DOI:
      J Am Acad Dermatol. 2020;82(2):440-459. DOI: 10.1016/j                     10.1038/s41591-022-01851-x. PMID: 35661157.
      .jaad.2019.05.077. PMID: 31163235.                                   72.   Gross ND, Miller DM, Khushalani NI, et al. Neoadjuvant Cemi-
60.   Dumann K, Artz N, Ziemer M. Complete Remission of Basal                    plimab for Stage II to IV Cutaneous Squamous-Cell Carcinoma.
      Cell Carcinoma Following Treatment With Cemiplimab After 2                 N Engl J Med. 2022;387(17):1557-1568. DOI: 10.1056/NEJ-
      Years. JAMA Dermatol. 2021;157(8):1004-1006. DOI: 10.1001                  Moa2209813. PMID: 36094839. PMCID: PMC9844515.
      /jamadermatol.2021.2206. PMID: 34232273.                             73.   Schmults C, Blitzblau R, Aasi SZ, et al. Squamous cell skin can-
61.   Johansson I, Levin M, Akyurek LM, Olofsson Bagge R, Ny L.                  cer. National Comprehensive Cancer Network (NCCN) Clinical
      PD-1 inhibitor therapy of basal cell carcinoma with pulmo-                 Practice Guidelines in Oncology. 2023; version 1.2023. Avail-
      nary metastasis. J Eur Acad Dermatol Venereol. 2022;36 Suppl               able from: https://www.nccn.org/professionals/physician_gls/
      1:70-73. DOI: 10.1111/jdv.17530. PMID: 34855248.                           pdf/squamous.pdf. Accessed April 21, 2023.
62.   De Giorgi V, Trane L, Savarese I, et al. Lasting response after      74.   Neoadjuvant REGN2810 (Cemiplimab) in Cutaneous Basal
      discontinuation of cemiplimab in a patient with locally ad-                Cell Carcinoma of the Head and Neck. ClinicalTrials.gov ID:
      vanced basal cell carcinoma. Clin Exp Dermatol. 2021;46(8):                NCT05929664. Available from: https://www.clinicaltrials.
      1612-1614. DOI: 10.1111/ced.14804. PMID: 34157152.                         gov/study/NCT05929664?cond=Basal%20Cell%20Carci-
63.   Delaitre L, Martins-Héricher J, Truchot E, et al. Régression de            noma&term=neoadjuvant&rank=4 . Accessed on July 11, 2023.
      carcinomes basocellulaire et épidermoïde cutanés sous pem-           75.   A Phase 1B, Single Arm Study of Neoadjuvant-Adjuvant Pem-
      brolizumab [Regression of cutaneous basal cell and squamous                brolizumab in Resectable Advanced Basal Cell Carcinoma
      cell carcinoma under pembrolizumab]. Ann Dermatol Venereol.                of the Head and Neck to Assess for Pathologic Responses
      2020;147(4):279-284. DOI: 10.1016/j.annder.2019.10.031.                    in the Tumor Microenvironment. ClinicalTrial.gov ID:
      PMID: 31879092.                                                            NCT04323202. Available From: https://www.clinicaltrials
64.   Ikeda S, Goodman AM, Cohen PR, et al. Metastatic basal cell                .gov/study/NCT04323202?cond=Basal%20Cell%20Carcinoma
      carcinoma with amplification of PD-L1: exceptional response                &term=neoadjuvant&rank=6 . Accessed on July 11, 2023.
      to anti-PD1 therapy. NPJ Genom Med. 2016;1:16037-. DOI:              76.   Ligtenberg KG, Hu JK, Damsky W, et al. Neoadjuvant
      10.1038/npjgenmed.2016.37. PMID: 27942391. PMCID:                          anti-programmed cell death 1 therapy for locally advanced basal
      PMC5142752.                                                                cell carcinoma in treatment-naive patients: A case series. JAAD
65.   Stratigos AJ, Sekulic A, Peris K, et al. Cemiplimab in locally ad-         Case Rep. 2020;6(7):628-633. DOI: 10.1016/j.jdcr.2020.05.010.
      vanced basal cell carcinoma after hedgehog inhibitor therapy: an           PMID: 32613057. PMCID: PMC7317689.
      open-label, multi-centre, single-arm, phase 2 trial. Lancet Oncol.



Review | Dermatol Pract Concept. 2023;13(4):e2023252                                                                                          11
 77.       Stratigos AJ, Garbe C, Dessinioti C, et al. European interdis-   86. Ribas A, Dummer R, Puzanov I, et al. Oncolytic Virother-
      ciplinary guideline on invasive squamous cell carcinoma of the            apy P ­romotes Intratumoral T Cell Infiltration and Improves
      skin: Part 2. Treatment. Eur J Cancer. 2020;128:83-102. DOI:              Anti-PD-1 Immunotherapy. Cell. 2017;170(6):1109-1119 e1110.
      10.1016/j.ejca.2020.01.008. PMID: 32113942.                               DOI: 10.1016/j.cell.2017.08.027. PMID: 28886381. PMCID:
78. Keohane SG, Botting J, Budny PG, et al. British Association                 PMC8034392.
      of Dermatologists guidelines for the management of people             87. Liu BL, Robinson M, Han ZQ, et al. ICP34.5 deleted herpes
      with cutaneous squamous cell carcinoma 2020. Br J Derma-                  simplex virus with enhanced oncolytic, immune stimulating, and
      tol. 2021;184(3):401-414. DOI: 10.1111/bjd.19621. PMID:                   anti-tumour properties. Gene Ther. 2003;10(4):292-303. DOI:
      33150585.                                                                 10.1038/sj.gt.3301885. PMID: 12595888.
79. Weis J, Grote C, Weichenthal M, Hauschild A. Complete response          88. A Phase 1 Study of Talimogene Laherparepvec and Panitumumab
     of advanced cutaneous squamous cell and basal cell carcinomas              in Patients With Locally Advanced Squamous Cell Carcinoma
     with sequential cemiplimab and sonidegib therapy. J Eur Acad               of the Skin (SCCS). ClinicalTrials.gov ID NCT04163952. Avail-
     Dermatol Venereol. 2022;36 Suppl 1:66-69. DOI: 10.1111/                    able from: https://www.clinicaltrials.gov/study/NCT04163952?
     jdv.17403. PMID: 34855253.                                                 cond=Squamous%20Cell%20Carcinoma%20of%20the
80. Colombo E, Gurizzan C, Ottini A, et al. The association of ce-              %20Skin&term=talimogene&rank=1 . Accessed on July 20, 2023.
     miplimab plus sonidegib for synchronous cutaneous squa-                89. A Phase II Study of Talimogene Laherparepvec Followed by Tal-
     mous cell carcinoma and basal cell carcinoma of the head and               imogene Laherparepvec + Nivolumab in Refractory T Cell and
     neck: Two case reports. Front Oncol. 2023;13:1111146. DOI:                 NK Cell Lymphomas, Cutaneous Squamous Cell Carcinoma,
     10.3389/fonc.2023.1111146. PMID: 36925925. PMCID:                          Merkel Cell Carcinoma, and Other Rare Skin Tumors. Clini-
     PMC10013465.                                                               calTrials.gov ID: NCT02978625. Available from: https://www
81. Sabbatino F, Marra A, Liguori L, et al. Resistance to                       .clinicaltrials.gov/study/NCT02978625?cond=NCT02978625
     anti-PD-1-based immunotherapy in basal cell carcinoma: a                   &rank=1 . Accessed on July 10, 2023.
     case report and review of the literature. J Immunother Can-            90. Gompertz-Mattar M, Perales J, Sahu A, et al. Differential expres-
        cer. 2018;6(1):126. DOI: 10.1186/s40425-018-0439-2. PMID:                 sion of programmed cell death ligand 1 (PD-L1) and inflamma-
        30458852. PMCID: PMC6247622.                                              tory cells in basal cell carcinoma subtypes. Arch Dermatol Res.
82.   Chang ALS, Tran DC, Cannon JGD, et al. Pembrolizumab                        2022;314(8):777-786. DOI: 10.1007/s00403-021-02289-w.
       for advanced basal cell carcinoma: An investigator-initiated,              PMID: 34647186.
       proof-of-concept study. J Am Acad Dermatol. 2019;80(2):              91.   Goodman AM, Kato S, Cohen PR, et al. Genomic landscape of
       564-566. DOI: 10.1016/j.jaad.2018.08.017. PMID: 30145186.                  advanced basal cell carcinoma: Implications for precision treat-
       ­PMCID: PMC6839543.                                                        ment with targeted and immune therapies. Oncoimmunology.
83.   A Prospective, Open, Single-arm, Single Center, Phase II Trial to           2018;7(3):e1404217. DOI: 10.1080/2162402X.2017.1404217.
        Assess the Efficacy of Anti-PD1 Antibody in Combination With              PMID: 29399405. PMCID: PMC5790366.
        Pulsed Hedgehog Inhibitor in Advanced Basal Cell Carcinoma.         92.   Yamakawa K, Ogata D, Hiki K, et al. Metastatic basal cell car-
      ClinicalTrials.gov ID: NCT04679480.Availabe from: https://www               cinoma with a high tumor mutational burden that achieved
      .clinicaltrials.gov/study/NCT04679480?cond=basal%20cell                     complete response with pembrolizumab. Int J Dermatol.
      %20carcinoma&intr=cemiplimab&rank=4 .Accessed on July                       2023;62(2):e79-e80. DOI: 10.1111/ijd.16245. PMID: 35553058.
      16, 2023.                                                             93.   Hall ET, Fernandez-Lopez E, Silk AW, Dummer R, Bhatia S.
84.   Nivolumab Alone or Plus Relatlimab or Ipilimumab for Pa-                    Immunologic Characteristics of Nonmelanoma Skin Cancers:
      tients With Locally-Advanced Unresectable or Metastatic Basal               Implications for Immunotherapy. Am Soc Clin Oncol Educ
      Cell Carcinoma. ClinicalTrials.gov ID: NCT03521830. Avail-                  Book. 2020;40:1-10. DOI: 10.1200/EDBK_278953. PMID:
      able from: https://www.clinicaltrials.gov/study/NCT03521830?                32207669.
      cond=basal%20cell%20carcinoma&intr=nivolumab&rank=1.                  94.   Durante G, Comito F, Lambertini M, Broseghini E, Dika E,
      Accessed on July 16, 2023.                                                  Ferracin M. Non-coding RNA dysregulation in skin can-
                                                                                  ­
85.   Ziogas DC, Martinos A, Petsiou DP, Anastasopoulou A, Gogas                  cers. Essays Biochem. 2021;65(4):641-655. DOI: 10.1042
      H. Beyond Immunotherapy: Seizing the Momentum of On-                        /EBC20200048. PMID: 34414406.
      colytic Viruses in the Ideal Platform of Skin Cancers. Cancers
      (Basel). 2022;14(12). DOI: 10.3390/cancers14122873. PMID:
      35740539. PMCID: PMC9221332.




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