1. Background
Periorbital skin malignancies encompass a wide range of neoplastic conditions that pose unique challenges due to the anatomical and functional complexity of the periocular region. Basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and sebaceous gland carcinoma (SGC) are the most prevalent types of non-melanocytic malignancies in this area [ 1 , 2 ]. Among these, BCC is the most common, representing approximately 90% of periocular malignancies, followed by SCC ( Figure 1 ). These cancers typically present a significant risk for local invasion, given the thin nature of the periorbital skin and proximity to critical structures like the eyelid and orbit, which can lead to significant functional impairment and disfigurement. Traditional treatment approaches, primarily surgical, often lead to significant functional and cosmetic impairments [ 1 , 2 ]. The advent of targeted therapy has revolutionized the management of these malignancies by offering more precise and less invasive treatment options [ 2 ]. Targeted therapies, including monoclonal antibodies, small molecule inhibitors, and immunotherapies, specifically attack cancer cells while sparing healthy tissues, thereby reducing side effects and improving outcomes [ 2 , 3 , 4 , 5 , 6 , 7 ]. In particular, targeted therapies are being explored for periocular malignancies to minimize surgical morbidity, especially in cases in which traditional surgery could compromise vision or cause significant aesthetic damage. The relevance of these therapies is underscored by their growing application in cases in which either surgery is not feasible, or there is a need to reduce tumor burden prior to surgical intervention [ 4 , 5 ].
This review focuses specifically on non-melanocytic malignancies because, while melanoma is a significant concern in periocular oncology, it has been extensively studied in the context of targeted therapies. Numerous reviews and studies have already explored the role of targeted drug delivery in melanoma treatment, including the use of BRAF and MEK inhibitors, and immunotherapies such as checkpoint inhibitors [ 6 ]. In contrast, there is a relative lack of research addressing the application of targeted therapies in non-melanocytic periocular malignancies, where a clear gap exists in research and clinical guidance. Our aim is to fill this gap by providing a comprehensive analysis of the current and emerging targeted drug delivery strategies for non-melanocytic skin cancers in the periocular region [ 7 , 8 , 9 ].
This review aims to provide a comprehensive overview of targeted drug delivery in the treatment of periorbital skin malignancies. It will explore the various types of targeted therapies currently available, discuss their mechanisms of action, and assess their clinical efficacy. Additionally, this review will address the management of side effects associated with these therapies and consider emerging trends and future directions in the field.
2. Methodology
This review conducted a comprehensive literature search using PubMed and Reference Citation Analysis (RCA) to gather relevant data on targeted drug delivery in periorbital non-melanocytic skin malignancies. PubMed, managed by the National Library of Medicine, was chosen for its extensive collection of peer-reviewed biomedical research. The search strategy employed keywords and medical subject headings (MeSH) including “periorbital malignancies”, “non-melanocytic skin cancers”, “targeted drug delivery”, “basal cell carcinoma”, “squamous cell carcinoma”, “nanoparticles”, “immunotherapy”, “biodegradable polymers”, and “monoclonal antibodies”. Boolean operators (AND, OR, NOT) were used to refine and ensure the relevance of the search results.
The search focused on English-language articles published up to 2024 to maintain accessibility and relevance to contemporary clinical practices. Titles and abstracts were manually screened, and full texts of pertinent articles were reviewed to extract key information on drug delivery mechanisms, clinical outcomes, advances in nanotechnology, and challenges in targeted therapies for periorbital skin malignancies.
To ensure thoroughness, manual searches of reference lists from included studies and citation tracking were performed to identify additional relevant studies. Articles were selected based on their contribution to the understanding of targeted drug delivery systems, therapeutic efficacy, safety profiles, and recent advancements. This methodology aimed to provide a comprehensive overview of the role and progress of targeted drug delivery in treating periorbital non-melanocytic skin malignancies, with a focus on improving precision, reducing side effects, and optimizing clinical outcomes.
3. Classification
Non-melanocytic periorbital skin malignancies are classified based on their cellular origin and histopathological characteristics. Basal cell carcinoma (BCC) is the most common periorbital skin malignancy [ 2 , 3 , 4 , 5 ]. It includes subtypes such as nodular, superficial, morpheaform (sclerosing), and pigmented. BCC is known for its slow growth and low metastatic risk, although it can cause significant local tissue destruction if untreated. Squamous cell carcinoma (SCC) is more aggressive than BCC, with a higher propensity for local invasion and metastasis. It often arises from precancerous lesions like actinic keratosis [ 2 , 3 , 4 , 6 , 8 ]. SCC subtypes include keratoacanthoma, intraepidermal (Bowen’s disease), and invasive SCC [ 9 , 10 ]. Sebaceous gland carcinoma is a rare but highly aggressive malignancy, typically originating in the eyelid’s meibomian glands. It presents a high risk of recurrence and metastasis, leading to significant morbidity [ 9 ]. Subtypes include papillary, nodular, and pagetoid forms. Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine tumor that metastasizes early, often resulting in a poor prognosis [ 11 , 12 , 13 ]. It is characterized by rapid growth. Other rare non-melanocytic malignancies, such as dermatofibrosarcoma protuberans (DFSP) and microcystic adnexal carcinoma (MAC), also occur in the periorbital region, although they are less common [ 11 , 12 ]. Various non-melanocytic skin cancer characteristcs are summarized in Table 1 .
4. Mechanisms of Targeted Drug Delivery
Targeted therapy in oncology represents a therapeutic approach that uses drugs designed to target specific molecules involved in the growth, progression, and spread of cancer cells. Unlike traditional chemotherapy, which attacks all rapidly dividing cells, targeted therapy focuses on specific molecular targets, with the goal of reducing side effects and improving treatment efficacy [ 1 , 2 , 3 , 4 ]. Targeted therapy acts on specific proteins, receptors, or other molecules that regulate cancer cell growth and survival. Patients often undergo genetic or molecular testing to identify mutations or abnormal expressions of proteins that may be targeted by available drugs [ 2 ]. This approach allows treatment to be tailored to the molecular characteristics of the individual patient’s tumor.
These therapies have a variety of strengths, such as increased specificity, reduced side effects, and possible efficacy in tumors resistant to conventional therapies. This treatment modality is the subject of numerous clinical and nonclinical studies aimed at bringing continuous updates in their application and improvements in their limitations [ 3 , 6 ].
Several types of molecular target therapy have been developed in the field of oncology. They can be divided, according to the molecular characteristics of the agents used, into monoclonal antibodies, small molecules, and gene therapy [ 1 ]. In recent years, new findings in targeted therapy have been used in targeted drug delivery. The latter is an advanced strategy that aims to deliver drugs specifically into diseased cells or target tissues, minimizing exposure to healthy tissues and reducing side effects [ 4 ]. In this regard, nanoparticle-based therapies are becoming increasingly important. While much of the literature on these therapies focuses on broader areas, such as head and neck malignancies, there is a growing need to extend these findings specifically to periorbital malignancies.
5. Monoclonal Antibodies
Monoclonal antibodies (mAbs) are defined as antigen-specific antibodies produced in the laboratory by genetic engineering and cell immunology techniques [ 1 ]. They are divided into four categories, according to the nature of the chains that they are made from, as murine, chimeric, humanized and human mAbs [ 5 ]. According to the category they belong to, the names of these drugs end in -omab, -ximab, -zumab, and -umab [ 5 ]. Furthermore, the inclusion of -ci(r)-, li(m)-, or t(u)- indicates that they target the circulatory or immune system or tumor cells, respectively. Moreover, based on the number and characteristics of their ligands, mAbs can be divided into unconjugated mAbs [ 6 ], conjugated mAbs [ 7 ], and bispecific mAbs [ 8 ]. In the first case, they function by themselves, and in the second case, they are linked to another agent (for example, a chemotherapy or radiotherapy agent), and the bispecific mAbs are linked to another mAb [ 5 ].
5.1. Mechanisms of Action
Unconjugated mAbs have the ability to bind to specific cell surface antigens. In oncology, they exert their function by following various possible mechanisms: binding to an antigen of a tumor cell, agonizing T-response-mediated cells or recognizing the immune system’s antigens [ 9 ].
Regarding the mAbs of the first group, they can act by following a direct or indirect mechanism. In the indirect mechanism, the binding to the tumor cell generates the attack on the latter by innate immune system. Destruction of the cell in this case can occur by complement-dependent cytotoxicity (CMC) [ 10 ], antibody-dependent cell-mediated cytotoxicity (ADCC) [ 11 , 12 ] or antibody-dependent cellular phagocytosis (ADCP) [ 13 ]. In these cases, tumor killing is performed by the recall of complement, natural killer cells, and macrophages, respectively.
In cases in which mAbs act following a direct mechanism, they bind a cell membrane antigen, frequently a receptor, leading to interference with the intracellular signal transduction related to it. Therefore, they may lead to the apoptosis of the tumor cell or disrupt an important pathway in tumorigenesis, or in the ablation of important elements of the tumor microenvironment (TME) [ 1 ]. The main targets of this group of mAbs are the epidermal growth factor receptor (EGFR) pathway, Human Epidermal Growth Factor Receptor 2 (HER2/neu), and Vascular Endothelial Growth Factor (VEGF) [ 5 ].
The mAbs that agonize the T-cell-mediated response act by recognizing some members of the tumor necrosis factor receptor (TNFR) family, like CD40, OX40, 4-1BB, and GITR [ 14 ]. These differ from the mAbs belonging to the third group, which bind to specific molecules of immune system cells by removing the blockage exerted by cancer cells on them. The mAbs of the third group therefore bind to so-called immuno-checkpoint inhibitors (ICIs), and will be addressed later in this study [ 9 ]. However, it is necessary to specify that a single monoclonal antibody can activate multiple mechanisms simultaneously. This is the case with trastuzumab, which can both inhibit HER2 and determine ADCC [ 15 ]. Conjugated mAbs are bound to a chemotherapeutic drug or radioactive isotope, and bind specifically to tumor cells to release the toxic load directly into the tumor [ 7 ]. Bispecific mAbs are designed to recognize two different antigens, allowing for greater specificity or facilitating the recruitment of immune cells, such as T lymphocytes, against the tumor [ 8 ].
5.2. Applications in Periorbital Skin Malignancies
In the context of periocular skin tumors, the most commonly used mAbs are intracellular pathway inhibitors and ICIs. EGFR-inhibitors have been used in the treatment of cutaneous squamous cell carcinoma (SCC).
EGFR, also known as Her1 or Erbb1, is a tyrosine kinase receptor, which, upon binding to its ligands (epidermal growth factor [EGF] and transforming growth factor-α (TGF-α)) dimerizes and autophosphorylates, leading to the stimulation of cell proliferation, reduction in apoptosis, and blockage of cell differentiation [ 16 ]. In particular, this dimerization leads to the activation of multiple possible pathways including RAS/RAF/MEK/MAPK, PI3K/AKT, and STAT [ 17 ]. The resultant effect of EGFR activation in both normal and malignant human skin is severe epidermal disorganization and invasion. Inhibitors of the EGFR pathway can act on the receptor (mAbs) or on some intracellular signal elements (small molecules).
Squamous Cell Carcinoma
The development of SCC appears to involve the alteration of several intracellular pathways, including tp53, ras, p16/CDKN2A, and EGFR [ 18 ]. This results in over-expressions in the cutaneous SCC of the head–neck area, and some studies have proposed EGFR overexpression as an independent predictor of metastasis and correlated it with tumor aggressiveness [ 19 ]. Cetuximab is a chimeric monoclonal IgG1 antibody, which acts by the competitive inhibition of EGFR. It was used in a phase II study of metastatic or inoperable whole-body cutaneous SCC with a dosage of 400 mg/m 2 for induction and a maintenance dose of 250 mg/m 2 . That study reported the achievement of disease control in 69% of the patients [ 20 ] and a disease control rate (DCR) at week 6 of 69%. Moreover, cetuximab has been used for the treatment of locally advanced SCC (laSCC) and metastatic cutaneous SCC (mSCC) of the head and neck alone [ 21 ] and in combination with radiotherapy, platinum, or placitaxel [ 22 , 23 , 24 , 25 ]. Currently, National Comprehensive Cancer Network (NCCN) guidelines contemplate the use of cetuximab in cases of laSCC in combination with radiotherapy (RT) [ 26 ], or alone when ICIs are contraindicated or have already failed [ 27 ]. This choice stems from the fact that cetuximab has been shown to have a response rate of 28%, a progression-free survival (PFS) of about 4 months, and an overall survival (OS) of about 1 year. These results are significantly lower than those of ICIs, which therefore tend to be preferred over EGFR inhibitors in the management of this malignancy [ 28 ]. The literature offers no further important clinical trials concerning the use of EGFR mAb-inhibitors periocularly [ 29 ], and in fact, there are no trials underway for its use as neoadjuvant therapy [ 30 ].
Despite promising results, cetuximab therapy has several limitations that should be further investigated. Indeed, the rates of relapse and therapeutic failure are likely to be due to early resistance mechanisms developed by the tumor [ 31 ]. Among these, the most relevant are increased ligand production, upregulation of EGFR expression, mutations in KRAS, BRAF, NRAS, and PIK3CA genes, and the expression of the EGFR truncation [ 31 ].
Panitimumab is a humanized EGFR-inhibitor mAb, and its use in laSCC and mSCC has also been investigated [ 32 ]. In a phase II trial conducted on 16 patients, however, it did not return results as encouraging as those of cetuximab. In fact, an overall response rate of 31%, an overall survival of 11 months, and a median PFS of 8 months were reported. The median duration of overall response was 6 months [ 33 ].
6. Immunotherapy with Checkpoint Inhibitors
ICIs represent a class of mAbs currently used for the immunotherapy treatment of various cancers [ 34 ]. It is known that cancer cells develop several mechanisms to ensure their own proliferation, and one of the most important of these is the evasion of immune-surveillance systems [ 35 ]. Under physiological conditions, cells of the immune system use fundamental signaling pathways in order to maintain immunotolerance, and the molecules involved are therefore named immune checkpoints [ 35 ]. In order to avoid attack by the immune system, tumor cells express molecules capable of stimulating these pathways by ensuring their own growth [ 36 ]. Consequently, ICIs interfere with this mechanism, increase immunosurveillance, and impair tumor cell survival.
The main targets of ICIs are expressed by cytotoxic T cells. They are as follows: cytotoxic T-lymphocyte-associated molecule-4 (CTLA-4) [ 35 ], programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1) [ 37 ].
6.1. Mechanisms of Action
Concerning PD-1 and PDL-1, the first is a receptor present on cytotoxic T cells and the second is its ligand, expressed, in this case, by tumor cells. Their interaction mediates tumor immunoresistance, leading to a series of cellular events, the most important of which are exhaustion of the cytotoxic T cell response and, in addition, the selection of Treg cells able to increase immunosuppression in the TME [ 38 , 39 ]. From a molecular point of view, the interaction between PD-1 and its ligand would appear to result in the phosphorylation of the Lck protein, which recruits the tyrosine phosphatase Shp2, which in turn inactivates TCR and CD28. Their inactivation inhibits the proper functioning of cytotoxic T cells and the related immune system co-stimulation signals [ 40 , 41 ]. Activation of CTLA-4 suppresses the T cell response in the early stages of T cell differentiation and plays a role in T reg cell activation [ 42 ].
PD-1, PDL-1, and CTLA-4 inhibitors, therefore, have been shown to lead to the restoration of the normal antitumoral response. They have been used, especially anti-PD-1 and anti-PDL-1, in a variety of tumors, leading to disease control or disease improvement [ 43 ].
6.2. Applications in Skin Malignancies
Inhibitors of PD-1 and PDL-1 are the most widely used ICIs in the context of periocular skin tumors.
6.2.1. Squamous Cell Carcinoma
Cemiplimab and pembrolizumab are anti-PD-1 drugs, which represent one of the systemic therapies currently used in the management of SCC ( Figure 2 ). In this tumor, systemic therapy is used in the case of primary and recurrent locally advanced disease in non-surgical candidates, in patients with regional resected high-risk disease, in patients with unresectable, inoperable or incompletely resected disease, and in patients with regional recurrence or distant metastatic disease [ 27 ]. Based on evidence from some important clinical trials, the NCCN guidelines recommend cemiplimab and pembrolizumab in laSCC and mSCC not amenable to surgery and RT, and for use individually. In contrast, chemotherapy and EGFR inhibitors can be combined with RT [ 27 ].
There are several data supporting anti-PD-1 in SCC. First, patients treated with ICIs, compared with those treated with other systemic therapies, presented better survival ( P = 0.034) [ 44 ]. This finding could be explained by the high tumor mutation burden that characterizes SCC, which would make it more susceptible to immunotherapy than systemic chemotherapy or targeted therapies [ 44 ]. The main adverse events are diarrhoea, fatigue, nausea, constipation, and rash, and a small number of patients discontinue therapy because of side effects. In trials performed on cemiplimab, the most encouraging data were the achievement of a response rate of 54%, complete response (CR) of 13%, and partial response (PR) of 41% [ 45 ]. For pembrolizumab, however, the KEYNOTE-629 study reported an objective response rate (ORR) of 50%, CR of 16.7%, and PR of 33.3% [ 46 ]. A possible, but not yet fully defined, indication could be the use of anti-PD-1 as neoadjuvant therapy. This application would be particularly important in the setting of periocular tumors to arrive at a more conservative approach. Cemiplimab, used as neoadjuvant, brought a CR of 51% and a major pathologic response of 13% [ 47 ]. Pembrolizumab, however, has been less studied in this setting. In small studies conducted on periocular SCC, cemiplimab has led to some encouraging results. In a case series of seven patients with a periorbital SCC, all had a clinically and/or radiologically measurable response as a result of being treated with an anti-PD-1 [ 48 ]. There are other case series, in which cemiplimab prevented exenteration in 9/11 [ 49 ] and 13/13 [ 50 ] patients, respectively. In conclusion, a much larger case history is needed on the use of anti-PD-1 treatments as drugs that can lead to tumor downstaging in a neoadjuvant setting.
6.2.2. Merkel Cell Carcinoma
Merkel cell carcinoma (MCC) is a highly immunogenic tumor in both the polyomavirus-related and unrelated forms [ 51 ]. For this reason, immunoresistance is one of the basic tenets of tumor progression, and as a result, immunotherapy has been shown to be extremely effective in its management [ 52 ]. Currently, NCCN guidelines recommend the use of ICIs in disseminated MCC as first-line therapy [ 51 ], and they are the standard of care even for the treatment of recurrent or inoperable MCC [ 30 ]. The currently approved drugs are anti-PDL-1 (avelumab) and anti-PD-1 (pembrolizumab, retifanlimab, and nivolumab) [ 53 ]. Figure 2 presents the specific mechanism of action. It would seem that these drugs, in fact, have a response rate comparable to that of chemotherapy (32–64%), with a longer duration of response (DOR) [ 51 ]. The use of avelumab is supported by the JAVELIN Merkel 200 trial, in which 116 patients participated and an ORR of 39.7%, a durable response rate (DRR) of 30.2%, and a median overall survival (OS) of 20.3 months were reported [ 54 ]. There were also 88 patients treated with as a second-line therapy (after chemotherapy) for whom data up to 49 [ 55 ] and 60 months [ 56 ] were recorded. The median OS was 12.6 months, and the median OS rates were 31% at 42 months and 28% after 5 years, respectively. The evidence on pembrolizumab came from a phase II study of 50 patients with advanced unresectable MCC that reported an overall response rate of 58% in all the patients and 89.5% for the patients with responsive disease, a 3-year OS of 58.4%, a median PFS of 16.8 months, and a PFS of 39.1% [ 57 ]. In the PODIUM-201 study, retifanlimab in 87 patients with advanced (aMCC) or metastatic MCC (mMCC) resulted in an ORR of 46.2% ( n = 30, 8 CR (12.3%); 22 PR (33.8%)) and a disease control rate (DCR) of 53.8% ( n = 35) [ 58 ]. The efficacy of nivolumab has been proven in various settings. One study evaluated the response of 50 patients with aMCC to therapy with nivolumab alone ( n = 25) or in combination with ipiliumumab (anti-CTLA-4) ( n = 25). The difference in ORR in the two groups (72% and 52%, respectively) was not significant [ 59 ]. Nivolumab also demonstrated efficacy in a neoadjuvant setting in the CHECKMATE 358 trial. In this phase I/II trial, nivolumab was administered one month before surgery to 36 patients, with a pathologic complete response (pCR) of 47.2%, while 54.5% of the patients had tumor reductions of 30% [ 60 ].
The use of ICIs as neoadjuvant treatments could be particularly valuable in the setting of periocular surgery. However, sufficient data on post-surgical outcomes are not yet available. Therefore, neoadjuvant treatment in surgery for MCC (especially periocular) should be discussed with a multidisciplinary team; if the recommendation from the assessment is to opt for this treatment, ICIs, particularly nivolumab, should be preferred over chemotherapy [ 30 ]. Concerning the safety of these drugs, avelumab has also been shown to achieve encouraging results in the immunocompromised patient [ 61 ]. Avelumab, pembrolizumab, and nivolumab showed treatment-related adverse events (AEs) occurring in 68% to 77% of patients, and grade 3 or 4 AEs occurring in 5% to 21%. Immune-related AEs were seen in less than 20% of patients receiving avelumab, and they were all grade 1 or 2 [ 53 ]. Finally, the use of ICIs as adjuvant therapy is currently being studied, but for the time being, the use of chemotherapy or radiotherapy is still preferred in this setting [ 52 ].
6.2.3. Basal Cell Carcinoma
ICIs are used as second-line therapy in locally advanced (laBCC) or metastatic BCC (mBC) in patients already treated with HH inhibitors or in whom the latter are contraindicated [ 62 ]. Specifically, cemiplimab was investigated with this indication in a study of 84 patients. They were followed with a median follow-up of 15 months, presenting an ORR of 31%. Among these patients, 48% reported grade 3–4 adverse events (AEs) [ 63 ].
7. Small Molecule Inhibitors
Small molecules are low-molecular-weight molecules (<900 Da) that can penetrate the cell and bind to specific proteins. Thus, they can enhance or inhibit certain cellular pathways, including those implicated in tumorigenesis. There are currently 89 small molecules approved in the US and China in the oncological field [ 16 ]. Depending on the target protein, they can act on kinases [ 64 ], proteasome, and poly ADPribose polymerase (PARP). By acting on these proteins, they disrupt the signaling pathways involved in carcinogenesis, while in other cases, they promote the apoptosis of tumor cells [ 1 ].
7.1. Mechanisms of Action
Kinase inhibitors are among the most widely used small molecules in cancer therapy. These enzymes allow the transfer of a group from ATP to a recipient protein. Based on their substrates, protein kinases are classified into tyrosine kinases (receptor-related or not), serine/threonine kinases, and tyrosine-kinase-like enzymes [ 16 ]. Proteasomes are multicatalytic enzyme complexes involved in the destruction of misfolded proteins, toxic agents, and other cell-damaging elements. Their inhibition leads to dysfunction and subsequent cancer cell death [ 65 ]. PARPs represent a group of post-translational acting enzymes that intervene in various elements of cellular functioning. Most studied has been their role in DNA repair. In this case, the inhibition of the target protein leads to tumor cell death [ 66 ]. In addition, there are small molecules directed against proteins implicated in cellular pathways specific to certain tumor types. This is the case of the inhibitors of B-cell lymphoma 2 (BCL-2) family of proteins and the Hedgehog (HH) pathway [ 16 ].
7.2. Applications in Periorbital Skin Malignancies
Regarding periorbital skin malignancies, they are used in the treatment of Sonidegib (HH-inhibitors) and SCC (EGFR-inhibitors) [ 30 ].
7.2.1. Basal Cell Carcinoma
The onset of BCC has been associated with the altered expression of several genes, including the gene for melanocortin 1 receptor (mc1r), oculocutaneous albinism type 2 gene (OCA2), p53, agouti signaling protein (ASIP), and tyrosinase (TYR) [ 29 , 67 ], but the most relevant is the inappropriate activation of the Hedgehog (HH) signaling pathway, which is also present in Gorlin Goltz syndrome or multiple basal cell nevus syndrome. Under normal conditions, Patched-1 (PTCH1), a transmembrane protein, inhibits the smoothened protein (SMO), which, when activated, leads to the activation of the transcription factor Gli and its entry into the nucleus. This event results in the expression of genes involved in the stimulation of cell division. The loss of function of PTCH1, or an increase in the function of the remaining elements of the signaling pathway, therefore favors BCC tumorigenesis. Vismodegib and sonidegib are HH-pathway inhibitors (HPIs) that act by binding the SMO and blocking the entire cellular cascade downstream of that protein. Their use was authorized in 2012 and 2015, respectively, for the treatment of laBCC not eligible for surgery or radiotherapy and mBCC [ 29 , 62 ]. Vismodegib is administered at an oral dosage of 150 mg/day and its long-term efficacy and safety have been reported in several studies. Among these, the ERIVANCE trial [ 68 ] and the STEVIE trial [ 69 ] should be mentioned. ERIVANCE was a phase II study that evaluated the response to vismodegib in 63 patients with laBCC and 33 patients with mBCC who reported an ORR of 43% and 30%, respectively, in the primary analysis (performed 9 months after the completion of accrual). The long-term update, performed at 39 months, demonstrated ORR values of 60.3% (laBCC) and 48.5% (mBCC), as well as the durability of response, efficacy against aggressive subtypes, and manageable long-term safety of vismodegib in patients with advanced BCC [ 68 ]. In the phase II STEVIE trial, a response rate of 68.5% was observed in 1119 patients with laBCC, and a rate of 36.9% was found in 96 patients with mBCC. The trial also confirmed the data on the safety profile and tolerability of the drug [ 69 ].
Concerning periocular BCCs, vismodegib could also play a role as neoadjuvant therapy in order to bring about a reduction in tumor size, which would avoid exenteration or surgery that result in the impairment of visual function or in disfiguring outcomes. Several trials have been conducted to support this indication, including VISMONEO [ 70 ], VISORB [ 71 ], and some previous minor studies [ 72 , 73 , 74 ]. VISMONEO is a phase II trial aimed at evaluating the ability of vismodegib to reduce the size of the facial BCC in order to opt for less invasive surgery. In total, 55 patients with a facial laBCC, including 19 with a periocular malignancy, were enrolled, and the results were evaluated after 6 months of treatment. Within this population, downstaging was documented in 44% of the cases with a tumor size reduction of 66% and a 70.9% ORR. Moreover, a complete response was registered in 27 patients [ 70 ].
In the VISORB trial, 34 patients with periocular laBCC treated with vismodegib for 12 months were examined. Complete response (CR) was reported in 56%, partial response (PR) in 29%, and disease stability (SD) in 26%. In addition, visual function was assessed before and after treatment or surgery following the Visual Assessment Weighted Score (VAWS), and it was found that the patients improved or remained stable in this respect as well. Finally, of the patients who underwent surgery, 67% achieved radicalization [ 71 ], and in those with residual disease, an additional SMO mutation was found [ 75 ].
Previous smaller studies conducted by Gill et al. [ 73 ], Demirci et al. [ 72 ], and Ozgur et al. [ 74 ] reported similar results about the efficacy of vismodegib in the management of periocular and orbital-invading laBCC.
Furthermore, a trial is currently underway on the 12-week use of vismodegib in patients with a BCC >2 cm [ 29 ]. Despite the numerous advantages described, vismodegib is not free of adverse events (AE), which, in some cases have affected the continuity of treatment, namely muscle spasms, alopecia, taste loss, weight loss, decreased appetite, fatigue, nausea, and diarrhoea [ 32 , 62 ].
In conclusion, vismodegib has returned significant results regarding its use as neoadjuvant therapy in laBCC. Such use is particularly important for the management of orbit-invading or periocular BCC, where downstaging of the tumor results in less invasive surgery, which significantly affects the patient’s quality of life [ 76 ]. However, several aspects remain to be clarified. Firstly, the duration and treatment regime should be defined, with the possibility of introducing a discontinuous regimen in order to limit the AEs. There is also a need for more long-term follow-up data in order to increase knowledge about the possibility of relapse and resistance and the tolerability of the drug.
Concerning sonidegib, it was studied in the phase II BOLT study. In this study, 230 patients with laBCC and mBCC were observed for 42 months on either a 200 mg or an 800 mg treatment. The data showed ORR values of 56% and 46% in patients with laBCC with a dosage of 200 mg and 800 mg, respectively. The ORR values for mBCC, on the other hand, were 8% and 17%. Furthermore, the disease control rate (DCR) was greater than 80% in all the treated subgroups [ 77 ].
These results argue for a possible use of sonidegib for the long-term management of laBCC. Again, most of the patients experienced the side effects already mentioned for vismodegib and, in addition, an increase in creatine kinase [ 78 ].
7.2.2. Squamous Cell Carcinoma
In cutaneous SCC, small molecules that inhibit EGFR-activated intracellular signaling (which, we note, is overexpressed in this type of cancer) could be used. To date, some studies have been conducted on the use of two tyrosine kinase inhibitors already used in non-small cell lung carcinoma (NSCLC), namely gefitinib and erlotinib. They act by blocking the autophosphorylation of EGFR and all carcinogenic cellular events related to the latter [ 16 ]. Figure 3 presents the specific mechanism of action.
A phase II study of gefitinib as neoadjuvant therapy was conducted in 22 patients with histologically aggressive or recurrent SCC who may or may not have been candidates for surgery. The patients received gefitinib therapy at a dosage of 250 mg/day, and then, depending on response, they were given radiotherapy (preceded or not preceded by surgery) and another 12 months of gefitinib [ 21 , 78 , 79 ]. The overall response rate to induction therapy was 45.5% Of the four patients with a clinical CR who underwent surgery after induction therapy, three had no residual tumor. In total, 13 of 22 evaluable patients (59.1%) experienced grade 2 toxicities, and the most common side effects were nausea, diarrhoea, fatigue, and acneiform rash [ 78 ]. No trials have been performed on the use of erlotinib in SCC. However, there are some cases in the literature in which it has been effectively used in laSCC and mSCC [ 21 , 79 ].
In conclusion, based on in vitro studies on and results obtained from the management of other cancers, EGFR inhibitors could lead to promising results for the management of cutaneous laSCC and mSCC. However, larger trials should be performed to obtain more data on ORR, DOR, toxicity, and long-term safety. Figure 4 tries to simplify the actual targeted therapy approach to periocular non-melanocytic skin cancers.
8. Other Targeted Therapies
8.1. Gene Therapy
Gene therapy provides for the insertion of genetic material (DNA or RNA) inside cancer cells via a vector, leading to the activation or silencing of certain genes. The ultimate goal of this procedure in oncology is cancer cell death or inhibition of disease progression [ 80 ].
The gene therapy strategies with application in oncology are oncogene activation inhibition, tumor suppressor gene activation, immunotherapy, suicide gene therapy, and anti-angiogenic gene therapy [ 81 ].
The inhibition of an oncogene occurs through the insertion into the cell of an antisense oligonucleotide, which can anneal to cDNA or RNA targets. This results in blocking the transcription of that gene and all elements related to its expression [ 82 ].
Usually, these are genes that regulate the cell cycle. Potential targets may be some genes important for tumor cells or for TME, such as, for example EGF, platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), transforming growth factor beta (TGF-β), TGF-α, and VEGF [ 82 ].
The activation of tumor suppressor genes (including the Rb gene, the p53 gene, CDK-inhibitors, and BRCA-1/2) allows the expression of the genes involved in cell cycle regulation and apoptosis [ 81 ]. For example, gendicine, a recombinant human p53 adenovirus, consists of an adenoviral gene delivery system that is able to insert the p53 gene into cancer cells, thereby stimulating cell death [ 83 ].
The application of gene therapy in immunotherapy has been the most thoroughly explored approach until now. It is based on the concept of enhancing the immune-mediated T cell response against tumor cells. To this end, gene therapy allows the development of molecules that are highly specialized in the recognition of tumor antigens, and the most widely used and promising molecules are chimeric antigen receptor (CAR)-T molecules [ 84 ]. In CAR-T cell therapy, T lymphocytes from the affected patient are harvested, and a CAR encoding transgene is inserted into them [ 85 ]. The clonal expansion of ultra specialized T cells is then stimulated and reinfused into the patient. This technique is currently used in the management of certain lymphomas and leukemias, and in multiple myeloma [ 81 , 86 ].
Regarding antiangiogenic gene therapy, it aims to inhibit tumor neovascularization. An example is the use of a lentivirus gene capable of leading to the production of an anti-VEGF mAb (bevacizumab) in HEK-293 cells [ 87 ]. This strategy would achieve a high concentration of bevacizumab and improve its efficacy [ 81 ].
In suicide gene therapy, a cytotoxic element is introduced in the form of a prodrug, along with genes encoding enzymes to activate it. In this therapeutic strategy, mesenchymal stem cells could be used as vectors, taking into account their marked ability to migrate into the TME [ 88 ]. Currently, the possibility of using the combination of Herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GC, cytosine deaminase/5-fluorocytosine, cytochrome P450/cyclophosphamide, and carboxypeptidase/4-[2-chloroethyl 2-mesyloxyetel-0-amino] benzoyl-l-glutamic acid) is being explored.
8.2. Nanoparticle-Based Delivery Systems
Nanoparticles include liposomes, polymeric nanoparticles, metal oxide nanoparticles, silicon dioxide nanoparticles, and magnetic nanoparticles (MNPs) [ 89 ].
In recent years, several innovative strategies have been introduced in the field of cancer therapies, with a focus on increasingly specific and personalized therapy [ 1 ]. Nanoparticles represent an effective way to improve the outcomes of drugs available to date, as they can act on their toxicity and selectivity and enhance their mechanisms of efficacy [ 90 ]. Nanoparticles fulfil their function in four configurations: association with anticancer agents (nanoparticle-based delivery agents), allowing the combination of multiple anticancer agents (nanoparticle-based codelivery of drugs and genes), allowing the drug to which they are bound to respond to certain chemical/physical stimuli inside or outside the body (stimuli-responsive drug delivery), and association with molecules that recognize certain tumor antigens (nanoparticle-based receptor-targeted delivery) [ 91 ].
The nanoparticle-based delivery systems used to date have an active and a passive targeting strategy [ 92 ]. Passive targeting corresponds to all the properties of the drug that allow optimization of the drug in reaching tumor cells based on its structural characteristics [ 93 ]. Nanocarriers reach the tumor site as a result of enhanced permeability and retention phenomena, known as the EPR effect [ 94 ]. Nanoparticles are extremely important in this mechanism because their insertion can change various aspects of drug function. They in fact intervene in pharmacokinetics by increasing drug availability and improve the ability of the drug to diffuse into the TME, thereby increasing uptake by tumor cells and beneficial effects and reducing side effects.
Active targeting makes it possible to reach tumor cells by recognizing and attacking specific antigens [ 92 ].
Nanoparticles improve controlled drug delivery and release. They can protect drugs from premature degradation in the body by increasing their stability and circulation times [ 95 ].
Alternatively, nanoparticles can be designed to release the drug in response to specific stimuli [ 89 ] in the TME, such as acidic pH, the presence of particular enzymes, or even external stimuli, such as heat, light [ 96 ], or magnetic fields [ 97 , 98 ]. In addition, nanoparticles are also able to lead to the sensitization of tumor cells. This principle is applied in photothermal and photodynamic therapy [ 99 ] and enhanced radiotherapy. Lastly, they can be used as vectors for gene therapy or immune stimulators in immunotherapy [ 100 ].
While nanoparticles have been extensively studied in various cancers, their specific application in periorbital malignancies is still in its early stages. Recent studies, however, have begun to explore the potential of nanoparticle-based therapies in this unique anatomical region. For example, polymeric nanoparticles loaded with chemotherapeutic agents have shown promising results in in vitro models of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), which are the most common non-melanocytic malignancies of the periorbital region [ 97 , 98 , 99 , 100 ].
9. Side Effects of Targeted Therapies
9.1. Ocular and Periocular Side Effects
Targeted therapies, while offering precise treatment options, can also lead to a range of ocular and periocular side effects. These side effects may include conditions such as conjunctivitis, dry eye syndrome, and eyelid inflammation [ 89 ]. More severe effects, such as uveitis, keratitis, or optic neuropathy, can also occur, potentially impacting vision and requiring prompt intervention. Hypertrichosis and periocular edema are common and can be particularly distressing for patients due to their impact on appearance. The management of these side effects is crucial to maintaining patients’ quality of life and ensuring continued adherence to treatment regimens [ 22 , 28 , 91 , 92 , 93 ].
9.2. Management of Side Effects
The management of ocular and periocular side effects from targeted therapies requires a multidisciplinary approach, often involving collaboration between oncologists and ophthalmologists. Early identification and intervention are key to preventing long-term complications [ 67 , 79 , 86 ]. Treatment strategies may include the use of lubricating eye drops for dry eye syndrome, corticosteroids for inflammation, and antibiotics for secondary infections. In cases of more severe side effects, such as uveitis or optic neuropathy, discontinuation or adjustment of the targeted therapy may be necessary, along with the introduction of immunosuppressive agents [ 2 , 24 , 86 ]. Regular monitoring and patient education on recognizing early symptoms are essential to minimizing the impact of these side effects and maintaining adherence to the prescribed cancer treatment.
10. Conclusions
In summary, targeted drug delivery represents a significant advancement in the treatment of periorbital skin malignancies, offering the potential for more precise and effective therapies with reduced side effects compared to traditional treatments. By focusing on specific molecular targets, these therapies can improve outcomes and provide new options for patients with malignancies resistant to conventional methods. However, the management of ocular and periocular side effects remains a critical aspect of treatment, requiring vigilant monitoring and a collaborative approach to ensure patient well-being and treatment adherence. As research continues to evolve, the integration of targeted therapies into clinical practice holds promise for further enhancing treatment efficacy and patient quality of life in the realm of periorbital skin malignancies.
Acknowledgments
Figure 2 , Figure 3 and Figure 4 were created by A.S. through Biorender ( https://www.biorender.com ).
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Author Contributions
Conceptualization, A.S., B.T. and M.Z.; methodology, A.S., B.T., P.L.S. and F.D. software, B.T.; validation, A.S., B.T. and P.L.S.; formal analysis, A.S. and B.T.; investigation, M.Z.; resources, A.S., C.F., P.C.P., A.A. and C.G.; data curation, A.S. and B.T.; writing—original draft preparation, A.S. and B.T.; writing—review and editing, A.S., B.T. and P.L.S.; visualization, C.F., P.C.P., A.A. and C.G.; supervision, C.F., P.C.P. and F.D.; project administration, M.Z., C.F. and P.C.P.; funding acquisition, M.Z., A.A. and C.G. All authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
The authors declare no conflicts of interest.
References
1. Lee Y.T. Tan Y.J. Oon C.E. Molecular targeted therapy: Treating cancer with specificity Eur. J. Pharmacol. 2018 834 188 196 10.1016/j.ejphar.2018.07.034 30031797
2. Wahida A. Buschhorn L. Fröhling S. Jost P.J. Schneeweiss A. Lichter P. Kurzrock R. The coming decade in precision oncology: Six riddles Nat. Rev. Cancer 2023 23 43 54 10.1038/s41568-022-00529-3 36434139
3. Sarmento-Ribeiro A.B. Scorilas A. Gonçalves A.C. Efferth T. Trougakos I.P. The emergence of drug resistance to targeted cancer therapies: Clinical evidence Drug Resist. Updates 2019 47 100646 10.1016/j.drup.2019.100646 31733611
4. Ashique S. Sandhu N.K. Chawla V. Chawla P.A. Targeted Drug Delivery: Trends and Perspectives Curr. Drug Deliv. 2021 18 1435 1455 10.2174/1567201818666210609161301 34151759
5. Bayer V. An Overview of Monoclonal Antibodies Semin. Oncol. Nurs. 2019 35 150927 10.1016/j.soncn.2019.08.006 31488319
6. Tsao L.-C. Force J. Hartman Z.C. Mechanisms of Therapeutic Antitumor Monoclonal Antibodies Cancer Res. 2021 81 4641 4651 10.1158/0008-5472.CAN-21-1109 34145037 PMC8448950
7. Thomas A. Teicher B.A. Hassan R. Antibody–drug conjugates for cancer therapy Lancet Oncol. 2016 17 e254 e262 10.1016/S1470-2045(16)30030-4 27299281 PMC6601617
8. Thakur A. Huang M. Lum L.G. Bispecific antibody based therapeutics: Strengths and challenges Blood Rev. 2018 32 339 347 10.1016/j.blre.2018.02.004 29482895
9. Delgado M. Garcia-Sanz J.A. Therapeutic Monoclonal Antibodies against Cancer: Present and Future Cells 2023 12 2837 10.3390/cells12242837 38132155 PMC10741644
10. Stasiłojć G. Österborg A. Blom A.M. Okrój M. New perspectives on complement mediated immunotherapy Cancer Treat. Rev. 2016 45 68 75 10.1016/j.ctrv.2016.02.009 26994325
11. Pereira N.A. Chan K.F. Lin P.C. Song Z. The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity mAbs 2018 10 693 711 10.1080/19420862.2018.1466767 29733746 PMC6150623
12. Chin D.S. Lim C.S.Y. Nordin F. Arifin N. Jun T.G. Antibody-Dependent Cell-Mediated Cytotoxicity Through Natural Killer (NK) Cells: Unlocking NK Cells for Future Immunotherapy Curr. Pharm. Biotechnol. 2021 23 552 578 10.2174/1389201022666210820093608 34414871
13. Cao X. Chen J. Li B. Dang J. Zhang W. Zhong X. Wang C. Raoof M. Sun Z. Yu J. Promoting antibody-dependent cellular phagocytosis for effective macrophage-based cancer immunotherapy Sci. Adv. 2022 8 eabl9171 10.1126/sciadv.abl9171 35302839 PMC8932662
14. Pourakbari R. Hajizadeh F. Parhizkar F. Aghebati-Maleki A. Mansouri S. Aghebati-Maleki L. Co-Stimulatory Agonists: An Insight into the Immunotherapy of Cancer EXCLI J. 2021 20 1055 1085 10.17179/excli2021-3522 34267616 PMC8278219
15. Liu X. Lu Y. Huang J. Xing Y. Dai H. Zhu L. Li S. Feng J. Zhou B. Li J. CD16+ fibroblasts foster a trastuzumab-refractory microenvironment that is reversed by VAV2 inhibition Cancer Cell 2022 40 1341 1357.e13 10.1016/j.ccell.2022.10.015 36379207
16. Zhong L. Li Y. Xiong L. Wang W. Wu M. Yuan T. Yang W. Tian C. Miao Z. Wang T. Small molecules in targeted cancer therapy: Advances, challenges, and future perspectives Signal Transduct. Target. Ther. 2021 6 201 10.1038/s41392-021-00572-w 34054126 PMC8165101
17. Yin V.T. Targeting EGFR and sonic hedgehog pathways for locally advanced eyelid and periocular carcinomas World J. Clin. Cases 2014 2 432 438 10.12998/wjcc.v2.i9.432 25232546 PMC4163765
18. Lee N.G. Kim L.A. Freitag S.K. The Role of Genetics in the Pathogenesis of Periocular Cutaneous Neoplasms: Implications for Targeted Therapy Semin. Ophthalmol. 2013 28 267 274 10.3109/08820538.2013.825278 24138034 PMC4342750
19. Uribe P. Gonzalez S. Epidermal growth factor receptor (EGFR) and squamous cell carcinoma of the skin: Molecular bases for EGFR-targeted therapy Pathol. Res. Pract. 2011 207 337 342 10.1016/j.prp.2011.03.002 21531084
20. Maubec E. Petrow P. Scheer-Senyarich I. Duvillard P. Lacroix L. Gelly J. Certain A. Duval X. Crickx B. Buffard V. Phase II Study of Cetuximab as First-Line Single-Drug Therapy in Patients with Unresectable Squamous Cell Carcinoma of the Skin J. Clin. Oncol. 2011 29 3419 3426 10.1200/JCO.2010.34.1735 21810686
21. El-Sawy T. Sabichi A.L. Myers J.N. Kies M.S. William W.N. Glisson B.S. Lippman S. Esmaeli B. Epidermal Growth Factor Receptor Inhibitors for Treatment of Orbital Squamous Cell Carcinoma Arch. Ophthalmol. 2012 130 1608 1611 10.1001/archophthalmol.2012.2515 23229707
22. Hitt R. Irigoyen A. Cortes-Funes H. Grau J.J. García-Sáenz J.A. Cruz-Hernandez J.J. Phase II study of the combination of cetuximab and weekly paclitaxel in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of head and neck Ann. Oncol. 2012 23 1016 1022 10.1093/annonc/mdr367 21865152
23. de Mello R.A. Gerós S. Alves M.P. Moreira F. Avezedo I. Dinis J. Cetuximab Plus Platinum-Based Chemotherapy in Head and Neck Squamous Cell Carcinoma: A Retrospective Study in a Single Comprehensive European Cancer Institution PLoS ONE 2014 9 e86697 10.1371/journal.pone.0086697 24516537 PMC3916324
24. Tsuchida E. Results of radiotherapy plus Cetuximab for squamous cell carcinoma of the head and neck Jpn. J. Clin. Radiol. 2015 60 1681 1687
25. Tahara M. Kiyota N. Yokota T. Hasegawa Y. Muro K. Takahashi S. Onoe T. Homma A. Taguchi J. Suzuki M. Phase II trial of combination treatment with paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (CSPOR-HN02) Ann. Oncol. 2018 29 1004 1009 10.1093/annonc/mdy040 29408977
26. Wollina U. Tchernev G. Lotti T. Chimeric Monoclonal Antibody Cetuximab Targeting Epidermal Growth Factor-Receptor in Advanced Non-Melanoma Skin Cancer Open Access Maced. J. Med. Sci. 2018 6 152 155 10.3889/oamjms.2018.022 29484016 PMC5816291
27. Howell J.Y. Ramsey M.L. Squamous Cell Skin Cancer StatPearls [lntermet] StatPearls Publishing Treasure Island, FL, USA 2023 Available online: https://pubmed.ncbi.nlm.nih.gov/28722968/ (accessed on 1 September 2024)
28. Jiang R. Fritz M. Que S.K.T. Cutaneous Squamous Cell Carcinoma: An Updated Review Cancers 2024 16 1800 10.3390/cancers16101800 38791879 PMC11119634
29. Ju S. Rokohl A.C. Guo Y. Yao K. Fan W. Heindl L.M. Personalized treatment concepts in extraocular cancer Adv. Ophthalmol. Pract. Res. 2024 4 69 77 10.1016/j.aopr.2024.02.003 38590555 PMC10999489
30. Trotier D.C. Huang L. van Landingham S.W. Burr A.R. Ma V.T. Review of recent advances in managing periocular skin malignancies Front. Oncol. 2024 14 1275930 10.3389/fonc.2024.1275930 38500654 PMC10944901
31. Patel B. Saba N.F. Current Aspects and Future Considerations of EGFR Inhibition in Locally Advanced and Recurrent Metastatic Squamous Cell Carcinoma of the Head and Neck Cancers 2021 13 3545 10.3390/cancers13143545 34298761 PMC8306284
32. Allen R.C. Molecularly targeted agents in oculoplastic surgery Curr. Opin. Ophthalmol. 2017 28 485 492 10.1097/ICU.0000000000000403 28598870
33. Foote M.C. McGrath M. Guminski A. Hughes B.G.M. Meakin J. Thomson D. Zarate D. Simpson F. Porceddu S.V. Phase II study of single-agent panitumumab in patients with incurable cutaneous squamous cell carcinoma Ann. Oncol. 2014 25 2047 2052 10.1093/annonc/mdu368 25091317
34. Kimiz-Gebologlu I. Gulce-Iz S. Biray-Avci C. Monoclonal antibodies in cancer immunotherapy Mol. Biol. Rep. 2018 45 2935 2940 10.1007/s11033-018-4427-x 30311129
35. Pardoll D.M. The blockade of immune checkpoints in cancer immunotherapy Nat. Rev. Cancer 2012 12 252 264 10.1038/nrc3239 22437870 PMC4856023
36. Zhang Y. Zhang Z. The history and advances in cancer immunotherapy: Understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications Cell. Mol. Immunol. 2020 17 807 821 10.1038/s41423-020-0488-6 32612154 PMC7395159
37. Lin X. Lu X. Luo G. Xiang H. Progress in PD-1/PD-L1 pathway inhibitors: From biomacromolecules to small molecules Eur. J. Med. Chem. 2020 186 111876 10.1016/j.ejmech.2019.111876 31761384
38. Alsaab H.O. Sau S. Alzhrani R. Tatiparti K. Bhise K. Kashaw S.K. Iyer A.K. PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome Front. Pharmacol. 2017 8 561 10.3389/fphar.2017.00561 28878676 PMC5572324
39. Ai L. Xu A. Xu J. Roles of PD-1/PD-L1 Pathway: Signaling, Cancer, and Beyond Adv. Exp. Med. Biol. 2020 1248 33 59 10.1007/978-981-15-3266-5_3 32185706
40. Hui E. Cheung J. Zhu J. Su X. Taylor M.J. Wallweber H.A. Sasmal D.K. Huang J. Kim J.M. Mellman I. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition Science 2017 355 1428 1433 10.1126/science.aaf1292 28280247 PMC6286077
41. Kamphorst A.O. Wieland A. Nasti T. Yang S. Zhang R. Barber D.L. Konieczny B.T. Daugherty C.Z. Koenig L. Yu K. Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent Science 2017 355 1423 1427 10.1126/science.aaf0683 28280249 PMC5595217
42. Boutros C. Tarhini A. Routier E. Lambotte O. Ladurie F.L. Carbonnel F. Izzeddine H. Marabelle A. Champiat S. Berdelou A. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination Nat. Rev. Clin. Oncol. 2016 13 473 486 10.1038/nrclinonc.2016.58 27141885
43. Tang Q. Chen Y. Li X. Long S. Shi Y. Yu Y. Wu W. Han L. Wang S. The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers Front. Immunol. 2022 13 964442 10.3389/fimmu.2022.964442 36177034 PMC9513184
44. Amaral T. Osewold M. Presser D. Meiwes A. Garbe C. Leiter U. Advanced cutaneous squamous cell carcinoma: Real world data of patient profiles and treatment patterns J. Eur. Acad. Dermatol. Venereol. 2019 33 44 51 10.1111/jdv.15845 31658392
45. Migden M.R. Rischin D. Schmults C.D. Guminski A. Hauschild A. Lewis K.D. Chung C.H. Hernandez-Aya L.F. Lim A.M. Chang A.L.S. PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma N. Engl. J. Med. 2018 379 341 351 10.1056/NEJMoa1805131 29863979
46. Hughes B. Munoz-Couselo E. Mortier L. Bratland Å. Gutzmer R. Roshdy O. Mendoza R.G. Schachter J. Arance A. Grange F. Pembrolizumab for locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma (KEYNOTE-629 study): An open-label, nonrandomized, multicenter, phase II trial Ann. Oncol. 2021 32 1276 1285 10.1016/j.annonc.2021.07.008 34293460
47. Gross N.D. Miller D.M. Khushalani N.I. Divi V. Ruiz E.S. Lipson E.J. Meier F. Su Y.B. Swiecicki P.L. Atlas J. Neoadjuvant Cemiplimab for Stage II to IV Cutaneous Squamous-Cell Carcinoma N. Engl. J. Med. 2022 387 1557 1568 10.1056/NEJMoa2209813 36094839 PMC9844515
48. Goldfarb J.A. Ferrarotto R. Gross N. Goepfert R. Debnam J.M. Gunn B. Nagarajan P. Esmaeli B. Immune checkpoint inhibitors for treatment of periorbital squamous cell carcinoma Br. J. Ophthalmol. 2023 107 320 323 10.1136/bjophthalmol-2021-319417 34625433
49. Steren B.B. Burtness B. Bhatia A.M. Demirci H. Shinder R. Yoo D. Tse B. Pointdujour-Lim R. Cemiplimab for Orbital Squamous Cell Carcinoma in 11 Cases Ophthalmic Plast. Reconstr. Surg. 2022 38 496 502 10.1097/IOP.0000000000002190 35502804
50. Tiosano A. Ben-Ishai M. Cnaany Y. Markel G. Kurman N. Popovtzer A. Bar Sela G. Ben Simon G. Gershoni A. Yassur I. Primary cemiplimab treatment for orbital squamous cell carcinoma is effective and may alleviate the need for orbital exenteration Eye 2023 37 2482 2487 10.1038/s41433-022-02358-y 36690728 PMC10397183
51. Becker J.C. Stang A. DeCaprio J.A. Cerroni L. Lebbé C. Veness M. Nghiem P. Merkel cell carcinoma Nat. Rev. Dis. Primers 2017 3 17077 10.1038/nrdp.2017.77 29072302 PMC6054450
52. Hernandez L.E. Mohsin N. Yaghi M. Frech F.S. Dreyfuss I. Nouri K. Merkel cell carcinoma: An updated review of pathogenesis, diagnosis, and treatment options Dermatol. Ther. 2022 35 e15292 10.1111/dth.15292 35560755
53. Thakker S. Venna S. Belzberg M. Jang S. DeSimone J. Al-Mondhiry J. Merkel cell carcinoma J. Am. Acad. Dermatol. 2024 91 598 605 10.1016/j.jaad.2024.04.039 38685409
54. D’Angelo S.P. Lebbé C. Mortier L. Brohl A.S. Fazio N. Grob J.-J. Prinzi N. Hanna G.J. Hassel J.C. Kiecker F. First-line avelumab in a cohort of 116 patients with metastatic Merkel cell carcinoma (JAVELIN Merkel 200): Primary and biomarker analyses of a phase II study J. Immunother. Cancer 2021 9 e002646 10.1136/jitc-2021-002646 34301810 PMC8311489
55. D’Angelo S.P. Bhatia S. Brohl A.S. Hamid O. Mehnert J.M. Terheyden P. Shih K.C. Brownell I. Lebbé C. Lewis K.D. Avelumab in patients with previously treated metastatic Merkel cell carcinoma: Long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial J. Immunother. Cancer 2020 8 e000674 10.1136/jitc-2020-000674 32414862 PMC7239697
56. D’Angelo S. Bhatia S. Brohl A. Hamid O. Mehnert J. Terheyden P. Shih K. Brownell I. Lebbé C. Lewis K. Avelumab in patients with previously treated metastatic Merkel cell carcinoma (JAVELIN Merkel 200): Updated overall survival data after >5 years of follow-up ESMO Open 2021 6 100290 10.1016/j.esmoop.2021.100290 34715570 PMC8564559
57. Nghiem P. Bhatia S. Lipson E.J. Sharfman W.H. Kudchadkar R.R. Brohl A.S. Friedlander P.A. Daud A. Kluger H.M. Reddy S.A. Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma J. Immunother. Cancer 2021 9 e002478 10.1136/jitc-2021-002478 33879601 PMC8061836
58. Vinohrady K. Tumori I. Etico C. Etico C. Devices M. Review W.I. Abstracts 545 MCC 2021 9 574 575
59. Bhatia S. Topalian S.L. Sharfman W.H. Meyer T. Lao C.D. Fariñas-Madrid L. Devriese L.A. Aljumaily R. Ferris R.L. Honma Y. Non-comparative, open-label, international, multicenter phase I/II study of nivolumab (NIVO) ± ipilimumab (IPI) in patients (pts) with recurrent/metastatic merkel cell carcinoma (MCC) (CheckMate 358) J. Clin. Oncol. 2023 41 (Suppl. S47) 9506 10.1200/JCO.2023.41.16_suppl.9506
60. Topalian S.L. Bhatia S. Amin A. Kudchadkar R.R. Sharfman W.H. Lebbé C. Delord J.-P. Dunn L.A. Shinohara M.M. Kulikauskas R. Neoadjuvant Nivolumab for Patients with Resectable Merkel Cell Carcinoma in the CheckMate 358 Trial J. Clin. Oncol. 2020 38 2476 2487 10.1200/JCO.20.00201 32324435 PMC7392746
61. Averbuch I. Stoff R. Miodovnik M. Fennig S. Bar-Sela G. Yakobson A. Daliot J. Asher N. Fenig E. Avelumab for the treatment of locally advanced or metastatic Merkel cell carcinoma—A multicenter real-world experience in Israel Cancer Med. 2023 12 12065 12070 10.1002/cam4.5890 37012213 PMC10278518
62. Network NCC NCCN Clinical Practice Guidelines in Oncology: Basal Cell Skin Cancer NCCN Evid Blocks Plymouth Meeting, PA, USA 2019 Volume 1 1 10
63. Moujaess E. Merhy R. Kattan J. Sarkis A.-S. Tomb R. Immune Checkpoint Inhibitors for Advanced or Metastatic Basal Cell Carcinoma: How much Evidence do we Need? Immunotherapy 2021 13 1293 1304 10.2217/imt-2021-0089 34463126
64. Roskoski R. Properties of FDA-approved small molecule protein kinase inhibitors: A 2023 update Pharmacol. Res. 2023 187 106552 10.1016/j.phrs.2022.106552 36403719
65. Fricker L.D. Proteasome Inhibitor Drugs Annu. Rev. Pharmacol. Toxicol. 2020 60 457 476 10.1146/annurev-pharmtox-010919-023603 31479618
66. Profiling B.P. Small—Molecule Inhibitors of PARPs: From Tools for Investigating ADP—Ribosylation to Therapeutics Act. Based Protein Profiling 2018 420 211 231 10.1007/82_2018_137 PMC11793873 30242511
67. Montagna E. Lopes O.S. Molecular basis of basal cell carcinoma An. Bras. Dermatol. 2017 92 517 520 10.1590/abd1806-4841.20176544 28954101 PMC5595599
68. Sekulic A. Migden M.R. Basset-Seguin N. Garbe C. Gesierich A. Lao C.D. Miller C. Mortier L. Murrell D.F. Hamid O. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: Final update of the pivotal ERIVANCE BCC study BMC Cancer 2017 17 332 10.1186/s12885-017-3286-5 28511673 PMC5433030
69. Basset-Séguin N. Hauschild A. Kunstfeld R. Grob J. Dréno B. Mortier L. Ascierto P. Licitra L. Dutriaux C. Thomas L. Vismodegib in patients with advanced basal cell carcinoma: Primary analysis of STEVIE, an international, open-label trial Eur. J. Cancer 2017 86 334 348 10.1016/j.ejca.2017.08.022 29073584
70. Bertrand N. Guerreschi P. Basset-Seguin N. Saiag P. Dupuy A. Dalac-Rat S. Dziwniel V. Depoortère C. Duhamel A. Mortier L. Vismodegib in neoadjuvant treatment of locally advanced basal cell carcinoma: First results of a multicenter, open-label, phase 2 trial (VISMONEO study): Neoadjuvant Vismodegib in Locally Advanced Basal Cell Carcinoma eClinicalMedicine 2021 35 100844 10.1016/j.eclinm.2021.100844 33997740 PMC8093898
71. Kahana A. Unsworth S.P. Andrews C.A. Chan M.P. Bresler S.C. Bichakjian C.K. Durham A.B. Demirci H. Elner V.M. Nelson C.C. Vismodegib for Preservation of Visual Function in Patients with Advanced Periocular Basal Cell Carcinoma: The VISORB Trial Oncololgy 2021 26 e1240 e1249 10.1002/onco.13820 PMC8265335 33988881
72. Demirci H. Worden F. Nelson C.C. Elner V.M.M. Kahana A.M. Efficacy of Vismodegib (Erivedge) for Basal Cell Carcinoma Involving the Orbit and Periocular Area Ophthalmic Plast. Reconstr. Surg. 2015 31 463 466 10.1097/IOP.0000000000000388 25675162 PMC4564370
73. Gill H.S. Moscato E.E. Chang A.L.S. Soon S. Silkiss R.Z. Vismodegib for Periocular and Orbital Basal Cell Carcinoma JAMA Ophthalmol. 2013 131 1591 1594 10.1001/jamaophthalmol.2013.5018 24136169
74. Ozgur O.K. Yin V. Chou E. Ball S. Kies M. William W.N. Migden M. Thuro B.A. Esmaeli B. Hedgehog Pathway Inhibition for Locally Advanced Periocular Basal Cell Carcinoma and Basal Cell Nevus Syndrome Am. J. Ophthalmol. 2015 160 220 227.e2 10.1016/j.ajo.2015.04.040 25935097
75. Unsworth S.P. Tingle C.F. Heisel C.J. Eton E.A. Andrews C.A. Chan M.P. Bresler S.C. Kahana A. Analysis of residual disease in periocular basal cell carcinoma following hedgehog pathway inhibition: Follow up to the VISORB trial PLoS ONE 2022 17 e0265212 10.1371/journal.pone.0265212 36455049 PMC9714843
76. Gershoni A. Tiosano A. Ben Ishai M. Barayev E. Ben Simon G.J. Yassur I. Vismodegib improves quality of life in patients with periocular locally advanced basal cell carcinoma: Subgroup analysis, STEVIE trial Eye 2022 36 407 413 10.1038/s41433-021-01493-2 33692538 PMC8807711
77. Dummer R. Guminksi A. Gutzmer R. Lear J. Lewis K. Chang A. Combemale P. Dirix L. Kaatz M. Kudchadkar R. Long-term efficacy and safety of sonidegib in patients with advanced basal cell carcinoma: 42-month analysis of the phase II randomized, double-blind BOLT study Br. J. Dermatol. 2020 182 1369 1378 10.1111/bjd.18552 31545507 PMC7318253
78. Lewis C.M. Glisson B.S. Feng L. Wan F. Tang X. Wistuba I.I. El-Naggar A.K. Rosenthal D.I. Chambers M.S. Lustig R.A. A Phase II Study of Gefitinib for Aggressive Cutaneous Squamous Cell Carcinoma of the Head and Neck Clin. Cancer Res. 2012 18 1435 1446 10.1158/1078-0432.CCR-11-1951 22261807 PMC6167936
79. Engelhardt C. Curiel-Lewandrowski C. Warneke J. Cranmer L. Metastatic cutaneous squamous cell carcinoma responding to erlotinib therapy J. Am. Acad. Dermatol. 2011 65 237 238 10.1016/j.jaad.2009.12.042 21679836
80. Bulaklak K. Gersbach C.A. The once and future gene therapy Nat. Commun. 2020 11 5820 10.1038/s41467-020-19505-2 33199717 PMC7670458
81. Cesur-Ergün B. Demir-Dora D. Gene therapy in cancer J. Gene Med. 2023 25 e3550 10.1002/jgm.3550 37354071
82. LE B.T. Raguraman P.R. Kosbar T.R. Fletcher S. Wilton S.D. Veedu R.N. Antisense Oligonucleotides Targeting Angiogenic Factors as Potential Cancer Therapeutics Mol. Ther. Nucleic Acids 2019 14 142 157 10.1016/j.omtn.2018.11.007 30594893 PMC6307321
83. Patil S.D. Rhodes D.G. Burgess D.J. DNA-based therapeutics and DNA delivery systems: A comprehensive review AAPS J. 2005 7 E61 E77 10.1208/aapsj070109 16146351 PMC2751499
84. Abou-El-Enein M. Elsallab M. Feldman S.A. Fesnak A.D. Heslop H.E. Marks P. Till B.G. Bauer G. Savoldo B. Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy Blood Cancer Discov. 2021 2 408 422 10.1158/2643-3230.BCD-21-0084 34568831 PMC8462122
85. Ma C.-C. Wang Z.-L. Xu T. He Z.-Y. Wei Y.-Q. The approved gene therapy drugs worldwide: From 1998 to 2019 Biotechnol. Adv. 2020 40 107502 10.1016/j.biotechadv.2019.107502 31887345
86. Jommi C. Bramanti S. Pani M. Ghirardini A. Santoro A. CAR T-Cell Therapies in Italy: Patient Access Barriers and Recommendations for Health System Solutions Front. Pharmacol. 2022 13 915342 10.3389/fphar.2022.915342 35837293 PMC9275825
87. Fallah A. Heidari H.R. Bradaran B. Sisakht M.M. Zeinali S. Molavi O. A gene-based anti-angiogenesis therapy as a novel strategy for cancer treatment Life Sci. 2019 239 117018 10.1016/j.lfs.2019.117018 31678280
88. Shah K. Mesenchymal stem cells engineered for cancer therapy Adv. Drug Deliv. Rev. 2012 64 739 748 10.1016/j.addr.2011.06.010 21740940 PMC3395998
89. Sun L. Liu H. Ye Y. Lei Y. Islam R. Tan S. Tong R. Miao Y.-B. Cai L. Smart nanoparticles for cancer therapy Signal Transduct. Target. Ther. 2023 8 418 10.1038/s41392-023-01642-x 37919282 PMC10622502
90. Sun T. Zhang Y.S. Pang B. Hyun D.C. Yang M. Xia Y. Engineered Nanoparticles for Drug Delivery in Cancer Therapy Angew. Chem. Int. Ed. 2014 53 12320 12364 10.1002/anie.201403036 25294565
91. Amreddy N. Babu A. Muralidharan R. Panneerselvam J. Srivastava A. Ahmed R. Mehta M. Munshi A. Ramesh R. Recent Advances in Nanoparticle-Based Cancer Drug and Gene Delivery 1st ed. Elsevier Inc. Amsterdam, The Netherlands 2017 10.1016/bs.acr.2017.11.003 PMC6550462 29405974
92. Alavi M. Hamidi M. Passive and active targeting in cancer therapy by liposomes and lipid nanoparticles Drug Metab. Pers. Ther. 2019 34 20180032 10.1515/dmpt-2018-0032 30707682
93. Li J. Wang Q. Xia G. Adilijiang N. Li Y. Hou Z. Fan Z. Li J. Recent Advances in Targeted Drug Delivery Strategy for Enhancing Oncotherapy Pharmaceutics 2023 15 2233 10.3390/pharmaceutics15092233 37765202 PMC10534854
94. Shi Y. van der Meel R. Chen X. Lammers T. The EPR effect and beyond: Strategies to improve tumor targeting and cancer nanomedicine treatment efficacy Theranostics 2020 10 7921 7924 10.7150/thno.49577 32685029 PMC7359085
95. Liu Y. Yang G. Jin S. Xu L. Zhao C. Development of High-Drug-Loading Nanoparticles Chempluschem 2020 85 2143 2157 10.1002/cplu.202000496 32864902
96. Akasov R. Khaydukov E.V. Yamada M. Zvyagin A.V. Leelahavanichkul A. Leanse L.G. Dai T. Prow T. Nanoparticle enhanced blue light therapy Adv. Drug Deliv. Rev. 2022 184 114198 10.1016/j.addr.2022.114198 35301045
97. Kang T. Li F. Baik S. Shao W. Ling D. Hyeon T. Surface design of magnetic nanoparticles for stimuli-responsive cancer imaging and therapy Biomaterials 2017 136 98 114 10.1016/j.biomaterials.2017.05.013 28525855
98. Yoon H.-M. Kang M.-S. Choi G.-E. Kim Y.-J. Bae C.-H. Yu Y.-B. Jeong Y.-I. Stimuli-Responsive Drug Delivery of Doxorubicin Using Magnetic Nanoparticle Conjugated Poly(ethylene glycol)- g -Chitosan Copolymer Int. J. Mol. Sci. 2021 22 13169 10.3390/ijms222313169 34884973 PMC8658650
99. Hou Y. Yang X. Liu R. Zhao D. Guo C. Zhu A. Wen M. Liu Z. Qu G. Meng H. Pathological Mechanism of Photodynamic Therapy and Photothermal Therapy Based on Nanoparticles Int. J. Nanomed. 2020 15 6827 6838 10.2147/IJN.S269321 PMC7501968 32982235
100. Zaimy M.A. Saffarzadeh N. Mohammadi A. Pourghadamyari H. Izadi P. Sarli A. Moghaddam L.K. Paschepari S.R. Azizi H. Torkamandi S. New methods in the diagnosis of cancer and gene therapy of cancer based on nanoparticles Cancer Gene Ther. 2017 24 233 243 10.1038/cgt.2017.16 28574057