Targeted Therapies for Periocular Malignancies

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 by Gangadhara Sundar, MD on April 8, 2023.


Targeted therapies are drugs that target specific proteins in the molecular pathway of cancer development and progression. By such targeted action and avoiding effect on all proliferating cells as does systemic chemotherapy, it helps avoid major systemic side effects. They may either be administered alone or in combination with Immunotherapy and /or chemotherapy and radiotherapy.

Several targeted therapeutic agents have been employed in the primary or secondary management of ocular adnexal neoplasms. Common conditions of relevance to the ophthalmologists with established or potential benefits from Targeted Therapy include Basal Cell Carcinoma, Squamous Cell Carcinoma Cutaneous periocular Melanoma, Dermatofibrosarcoma Prouberans, Orbital Meningiomas, Neurofibromatosis and Ocular Adnexal Lymphomas.

Basal Cell Carcinoma (BCC) comprises 80-90% of malignant eyelid tumors. Squamous Cell Carcinoma (SCC) is the second most common cause of malignant eyelid tumors and comprises 5-10% of malignant eyelid tumors.[1]

The standard treatment for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) is surgical excision with occasional use of adjuvant radiotherapy. Surgical excision may include Mohs or local excision with negative margins. When appropriate, Mohs is the preferred management as it offers high cure rates while maximizing conservation of healthy tissue. For many patients, surgical modalities are effective; however, in cases where the tumor is larger, more locally advanced or there is diffuse involvement such as in patients with Basal Cell Nevus Syndrome (Gorlin-Goltz Syndrome), surgical management may not be possible without significant morbidity.[1][2] Additionally, many patients have multiple comorbid conditions and may not be surgical candidates.

The advent of immunotherapy over the last decades has drastically altered oncologic therapies for patients. Through our understanding of the normal immunological pathways, and the ways for which cancer cells have evolved to evade these pathways, therapies have been developed that allow a person's now immune system to target and destroy these cells.[3] These treatment options can target and interfere with cell signaling pathways that have been altered and are allowing for the survival and proliferation of neoplastic cells.

Basal Cell Carcinoma

As aforementioned, BCC is the most common periocular tumor. The most common location is either the upper eyelid or the medial canthal area, followed by the lower eyelid and lateral canthal area. These tumors are locally invasive and rarely metastasize. Therefore, treatment largely hinges on how locally advanced the tumor is on presentation. There are 2 major morphologic subtypes: superficial nodular which tends to to be more common indolent growth and infiltrative/morpheaform which is often more aggressive.

Basal cell nevus syndrome (Gorlin-Goltz Syndrome) is an autosomal dominant condition that affects a younger population with multiple BCCs, dyskeratotic palmar and plantar pitting, and odontogenic keratocysts. In the 1990s, it was discovered that patients with Gorlin-Goltz carry a mutation on chromosome 9q22.3 in the Patched1 (PTCH1 gene). The discovery of this mutation has allowed for better understanding of the pathogenesis of BCCs as mutations in PTCH1 (Ptc) have been implicated in the majority (up to 80-90%) of cases.[4]

The Sonic Hedghog (SHH) pathway plays a crucial role in embryological development, cell cycle regulation and maintenance of progenitor cells in adults. In adults, the pathway is tightly regulated,  and constitutive activation has been associated with the formation of several malignancies. Ptc is a transmembrane protein that is activated by Hedgehog (HH). In the normal (unactivated) status, Ptc blocks SHH signaling by inhibiting the migration of transmembrane protein, Smoothened (SMO).  In the active status, SHH binds to and suppresses PTCH1 which allows for SMO activation. SMO activation leads to the activation of zinc-finger transcription factors known as glioma-associated oncogenes (GLI). The activated GLI transcription factors then promote the transcription of numerous target genes involved in cell proliferation, angiogenesis, stem cell self-renewal and apoptosis. Thus, dysregulated SHH signaling via a germline or somatic mutation leads to constant activation.

Advent of Vismodegib

Vismodegib (Erivedge) was first studied in humans in 2008. It is an orally dosed at 150 mg daily and is a second degeneration cyclopamine that selectively binds SMO. It was and approved by the United States Food and Drug Administration for the treatment of metastatic and locally advanced BCC in January 2012. Prior to FDA approval numerous phase I/II trials were published demonstrating efficacy. A few of those are summarized as follows:

  1. Phase I - Trial of 33 patients with locally advanced or metastatic BCC were enrolled along with 68 patients with a variety of metastatic solid tumors. The overall response rate (partial or complete) was 58%. This included 50% of patients with metastatic BCC and 60% of patients with locally advanced BCC.[5]
  2. Phase II - ERIVANCE - Trial of 104 (February 2009-November 2010) patients, 33 with metastatic BCC. Of the patients with metastatic BCC, 10 (30%) had a response judged by independent reviewer and 15 (45%) had a response as judged by site investigators. Of the 63 patients with locally advanced BCC, 27 (43%) had a response judged by independent reviewer and 38 (60%) has a response as judged by site investigators. This trial was pivotal to FDA approval
  3. Phase II - Trial of 41 patients with Basal Cell Nevus Syndrome were randomly assigned 2:1 to receive vismodegib or placebo. Vismodegib was associated with a decrease in the number of new and existing surgically eligible BCCs. Of note, patients experienced recurrence of BCC after discontinuation at the original sites but the rate of new surgically eligible lesions remained lower in the treated group

The largest study to date (STEVIE), looked at 1215 patients with either locally advanced BCC (n= 1119) or metastatic BCC (n = 96) with vismodegib 150 mg daily for a median duration of 8.6 months. Investigator-assessed Response Rates (RRs) were 69% for patients with locally advanced BCC and 37% for those with metastatic BCC. These numbers were consistent with the investigator-assessed RRs in the ERIVANCE study but higher than the independently-assessed RRs.


Following the development of vismodegib, Sonidegib (Odomzo) emerged as an additional oral therapy. It is structurally distinct from vismodegib but also functions as a SMO inhibitor. The BOLT trial was a multi-center phase II trial that led to its approval and published most of the known safety and efficacy data. In this study, patients were randomized in a 1:2 ratio to receive either 200 mg or 800mg of sonidegib. Objective response rates in the 200 mg group were 42% for locally advanced BCC and 15% for metastatic BCC. In the 800 mg group, the response rate was 38% for locally advanced BCC and 17% for metastatic BCC. This established the standard dose of 200mg as there was no increased efficacy seen with the higher dosing and was associated with a lower side effect profile. At 30 months, objective response rate was sustained at 56% for locally advanced and 7% for metastatic BCC.[4]

Presently, there aren’t head-to-head studies looking at vismodegib versus sonidegib; however, systematic reviews and comparison studies suggest vismodegib may have have increased efficacy in treating metastatic BCC and locally advanced BCC. Further studies are needed to fully explore this.

Side effects of SMO Inhibitors

Side effects from these therapies occur often and are commonly the reason for cessation of treatment. In the ERIVANCE study, frequently reported side effects were muscle spasms (68%), alopecia (63%), dysgeusia (51%), weight loss (46%), fatigue (36%), nausea (29%), anorexia (23%) and diarrhea (22%). In the STEVIE trial, 98% of patients had at least 1 adverse event. The most common side effects were muscle spasms (66%), alopecia (62%), and dysgeusia (55%), weight loss (41%). Sonidegib has a similar side effect profile to vismodegib with the three most common side effects of muscle spasms, alopecia and dysgeusia being see in similar percentages of patients. A small number of patients on 200 mg of sonidegib did have more severe adverse events including hypertension (3%), elevated CK and rhabomyolysis (3-4%) and increased lipases (5%).[6]  As expected, this side effect profile was worsened in the patients receiving 800mg.

In the STEVIE trial, 31% of patients discontinued vismodegib due to adverse events. In the BOLT trial, patients receiving the lower (200 mg) dose, 22% of patients discontinued treatment.[4] Management algorithms have been developed to help prevent complete discontinuation which include symptomatic management and treatment holidays.

Other Applications of SMO Inhibitors:

As aforementioned, a phase II trial that specifically looked at the use of vismodegib in 41 patients with Basal Cell Nevus Syndrome and found Vismodegib was associated with a decrease in the number of new and existing surgically eligible BCCs.

Studies have also looked at using SMO inhibitors as neoadjuvant therapy

Alternative Hedgehog Pathway Inhibitors:

  1. Itraconazole
  2. GLI Inhibitors

Squamous Cell Carcinoma

Squamous cell carcinoma is the second most common malignancy of the periocular skin. In contrast to BCCs, cutaneous SCCs tend to affect the lower eyelid followed by the medial canthus, upper eyelid and lateral canthus respectively.  Also, in contrast to BCCs, these tumors have a higher likelihood of metastasizing both through the lymphatics and blood stream. Not uncommonly, these tumors will spread to the sentinel lymph node/s prior to systemic dissemination. A particularly unique feature of these tumors is their propensity for local perineural invasion and their invasion into the dermis and through various tissue planes.[1]

SCC may arise from precursor lesions such as actinic keratosis or Bowen disease (squamous carcinoma in situ) but can also arise de novo. SCC tends to present as an ulcerated lesion with surrounding erythema an indurated base; however, this can vary. The biggest risk factor for the development of SCC is sun exposure which inactivates TP53 tumor suppressor gene. Additional risk factors include irradiation, immunosuppression, chronic inflammation, and hereditary conditions such as Xeroderma Pigmentosum.

Epithelial Growth Factor Receptor (EGFR), also known as HER-1 or Erb-1, is a transmembrane protein that has an extracellular receptor domain for multiple ligands and an intracellular domain with a tyrosine autophosphorylation site.  Upon binding of either of those domains, EGFR forms either a homodimer with another EGFR or heterodimer with another ErbB family receptor. This can activate multiple pathways. Overactivation of EGFR results in severe epidermal disorganization including reduced apoptosis, increased cellular proliferation and cell migration.[1][7] Squamous cell carcinoma has been shown to have overexpression of EGFR with stronger overexpression directly correlated to disease severity. [7]

Targeted Therapy

Erlotinib (Tarceva): similar to Getitinib, inhibits EGFR through blockage of autophosphorylation via competitive inhibition with ATP. It was first FDA approved in November 2004 for patients with locally advanced or metastatic NSCLC. A phase II trial of 115 patients with recurrent of metastatic SCC of the head and neck demonstrated a median survival of 6 months. Disease stabilization was seen in 44 patients (median of 16 weeks). Erlotinib may also be an option for neoadjuvant or adjuvant therapy. A phase I study that included 15 patients with stage III cutaneous SCC patients who received erlotinib in combination with radiation therapy following surgical resection had a 2-year survival 65% with a recurrence rate of 26.7%.

Gefitinib (Iressa): the first oral EGFR inhibitor shown to selectively inhibit EGFR tyrosine kinase activity via blockage of autophosphorylation. It was first FDA approved in 2003 as monotherapy for non-small cell lung cancer (NSCLC). It has shown in vitro and in vivo reduction in EGFR. For SCC it has been most extensively studied as a neoadjuvant therapy. In one study of 22 patients with locally aggressive or recurrent cutaneous SCC, neoadjuvant use of gefitinib showed an overall response rate of 45%.[7]


EGFR Inhibitors

Cetuximab (Erbitux): a chimeric IgG1 monoclonal antibody that competitively binds EGF. It was FDA approved in March 2006 for locally or regionally advanced head and neck SCC. It is givne as an intravenous infusion at 400 mg/m2 followed by weekly 1-hour infusion at a dose of 250 mg/m2. In a phase II trial of 36 patients with metastatic or unresectable SCC had a mean survival of 8.1 months.[1]

EGFR Inhibitors for Periocular Tumors

Although the use of EGFR inhibitors in periocular tumors is limited, efficacy has been reported. In three patients with locally advanced cutaneous SCC of the periocular skin with orbital extension, two were treated with cetuximab and one was treated with erlotinib with promising results. Studies suggest consideration may be limited for patients with extensive tumor burden, involvement of the orbit or skull base, and or in patients who are otherwise poor surgical candidates.[7]

EGFR Side Effects

The most common side effect is skin toxicity which occurs in 32-78% of patients. Studies have shown that the presence of side effects correlates with a higher response rate.[7] This includes an acne like rash, popular and/or pustular follicular eruption. Interestingly, patients on Gefitinib experience diarrhea more commonly than a skin toxicity.

Importantly, EGFR inhibits have been associated with trichomegaly leading to corneal ulceration and conjunctivitis, and ectropion.

Cutaneous Melanoma

Primary cutaneous melanoma of the eyelid is an uncommon entity, representing approximately 1% of malignant eyelid tumors[1] It most commonly affects the lower eyelid followed by the upper eyelid, lateral canthus and medial canthus respectively. Though there are four sub-types, lentigo maligna melanoma of the most common sub-type seen in the periocular region. Lesions have a heterogeneous presentation but patients with lentigo melanoma typically present with a brown or tan macule with an irregular border.

Malignant melanomas of the eyelid skin typically arise de novo but can develop from pre-cancerous lesions such as lentigo maligna. They can also arise from congenital, melanocytes or dysplastic nevi.[1] The most important risk factor associated with malignant melanoma of the eyelid skin is ultraviolet (UV) exposure.

The mitogen-activated protein kinase (MAPK) pathway is an important pathway is cell proliferation in survival. Upon binding of various ligands to a tyrosine kinase receptor, a downstream cascade involving the activation of RAS proteins, RAF, MAP kinase kinase (MEK) and Extracellular signal-regulated kinase (ERK). This ultimately leads to the expression of genes involved in cell proliferation, differentiation and survival. Constitutive activation of this pathway leads to malignant transformation.

RAF proteins have an important downstream affect on signal transduction, notably in the subtype BRAF. BRAF mutations are seen in as many as 66% of patients with malignant melanoma.[1]


Small molecule that inhibits BRAF V600E mutations. FDA approved in 2011 for the treatment of patients with unresectable or metastatic malignant melanoma. In a phase III trial of 675 patients with unresectable stage III or IV BRAF positive malignant melanoma randomized to either dacarbazine or vemurafenib, overall median survival was 9.6 and 13.2 months respectively.

Resistance is a concern with this therapy leading studies using combination therapy of BRAF and MEK inhibitors. One particular study looked at dabrafenib (selective BRAF inhibitor) and trametinib (selective MEK inhibitor) versus mono therapy with dabrafenib alone and found a median progression-free survival of 9.4 and 5.8 months respectively.[8]

MAPK Side effects

Most notably, cutaneous SCCs were observed in patients on single agent BRAF inhibitors. Despite these, lesions were typically not remarkably aggressive and resolved with cessation of therapy. It is hypothesized that inhibition of BRAF leads to over activation of MEK and the subsequent development of SCCs given the incidence of SCCs were reduced (7% down from 19%) compared to patients receiving monotherapy.[8]

Other Targeted Therapies for cutaneous Melanoma include ipilimumab, Nivolumab, Pembrolizumab[9]

Targeted therapy for Orbital Neoplasms

Orbital Meningioma

Orbital meningiomas may either be Optic Nerve Sheath Meningiomas (ONSM) or Sphenoidal Wing Meningiomas (SWM). The former may either be conservatively managed or with Radiotherapy. However, refractory and recurrent optic nerve sheath meningioma may benefit from targeted therapy. Agents that have been tried and recommended in special situations include Everolimus along with Octreotide, and Sunitinib.

Neurofibromatosis (NF)

These are sporadic or inherited group of tumors that may have devastating visual and disfiguring consequences. Those that are progressive and previously managed by aggressive surgery may be candidates for targeted therapy. Selumetinib, a MEK inhibitor was the first FDA approved agent for pediatric Neurofibromatosis Type I for children older than 2 with inoperative plexiform neurofibromatosis.

Ocular Adnexal Lymphomas (OAL)

Eyelid, conjunctival and Orbital lymphomas are typically managed by local radiation or systemic chemotherapy based on either histological and immunohistochemical characteristics. Immunotherapy with Rituximab for CD 20+ve lesions and Targeted Therapy with Ibrutinib, especially for refractory Mantle Cell Lymphoma may hold promise in the management of these conditions.

Dermatofibrosarcoma Protuberano (DFSP)

These are common dermal yet uncommon orbital neoplasms which are typically surgically managed. However, given their potential malignant potential with systemic spread, targeted therapy with Imatinib, a Tyrosine Kinase Inhibitor (TKI) may be considered.


In summary, targeted therapy with or without immunotherapy may either play a role in the primary and stand alone management of otherwise inoperable periorbital neoplasms or may facilitate surgical resection as a neoadjuvant therapy in these challenging conditions.

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Mehta VJ, Ling J, Sobel RK. Review of Targeted Therapies for Periocular Tumors. Int Ophthalmol Clin. 2017 Winter;57(1):153-168. doi: 10.1097/IIO.0000000000000149. PMID: 27898621.
  2. Yin VT, Pfeiffer ML, Esmaeli B. Targeted therapy for orbital and periocular basal cell carcinoma and squamous cell carcinoma. Ophthalmic Plast Reconstr Surg. 2013 Mar-Apr;29(2):87-92. doi: 10.1097/IOP.0b013e3182831bf3. PMID: 23446297; PMCID: PMC3878052.
  3. Habib LA, Wolkow N, Freitag S, Yoon MK. Advances in Immunotherapy and Periocular Malignancy, Seminars in Ophthalmology, 34:4, 327-333, DOI: 10.1080/08820538.2019.1620813
  4. 4.0 4.1 4.2 Leavitt E, Lask G, Martin S. Sonic Hedgehog Pathway Inhibition in the Treatment of Advanced Basal Cell Carcinoma. Curr Treat Options Oncol. 2019 Nov 26;20(11):84. doi: 10.1007/s11864-019-0683-9. PMID: 31773379.
  5. Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, Solomon JA, Yoo S, Arron ST, Friedlander PA, Marmur E, Rudin CM, Chang AL, Low JA, Mackey HM, Yauch RL, Graham RA, Reddy JC, Hauschild A. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012 Jun 7;366(23):2171-9. doi: 10.1056/NEJMoa1113713. PMID: 22670903; PMCID: PMC5278761.
  6. Kurnia Wijaya J, Djawad K, Wahab S, Nurdin A, Irawan Anwar A. Vismodegib and Sonidegib in Locally Advanced and Metastatic Basal Cell Carcinoma: Update on Hedgehog Pathway Inhibitors. Actas Dermosifiliogr. 2022 May;113(5):443-450. English, Spanish. doi: 10.1016/ Epub 2022 Jan 31. PMID: 35697404.
  7. 7.0 7.1 7.2 7.3 7.4 Yin VT, Merritt H, Esmaeli B. Targeting EGFR and sonic hedgehog pathways for locally advanced eyelid and periocular carcinomas. World J Clin Cases. 2014 Sep 16;2(9):432-8. doi: 10.12998/wjcc.v2.i9.432. PMID: 25232546; PMCID: PMC4163765.    
  8. 8.0 8.1 Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012 Nov 1;367(18):1694-703. doi: 10.1056/NEJMoa1210093. Epub 2012 Sep 29. PMID: 23020132; PMCID: PMC3549295.
  9. Ascierto PA, Borgognoni L, Botti G, Guida M, Marchetti P, Mocellin S, Muto P, Palmieri G, Patuzzo R, Quaglino P, Stanganelli I, Caracò C. New paradigm for stage III melanoma: from surgery to adjuvant treatment. J Transl Med. 2019 Aug 14;17(1):266. doi: 10.1186/s12967-019-2012-2. Erratum in: J Transl Med. 2019 Sep 18;17(1):315. PMID: 31412885; PMCID: PMC6693227.
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