Cutaneous squamous cell carcinoma (cSCC) is the second most common non melanoma skin cancer after basal cell carcinoma. Its incidence rate has been increasing by 2-7% each year over the last 30 years. In most patients, tumors develop on the skin of the head and neck – areas exposed to sunlight, which is one of the most important extrinsic factors in the development of the disease. There are also other extrinsic factors that are potentially related to the cSCC development, for example, industrial carcinogens such as tar or fuel oil.
Intrinsic factors associated with cSCC include age, fair skin, as well as some other skin conditions like hidradenitis suppurativa, scars or chronic wounds,which have greater photosensitivity, making genes in the skin more susceptible to mutation. cSCC rarely occurs in people under 45 years of age, but its incidence dramatically increases with age. It is also very prevalent in immunosuppressed patients, who also experience higher rates of recurrence.
In its early minimally invasive phase, cSCC may be difficult to distinguish from other less aggressive skin conditions. Therefore, it is particularly important that at diagnosis all risk factors for recurrence (i.e., location, size of the tumor, history of other skin conditions, etc.) and whether metastasis has occurred are assessed to identify the most suitable treatment options.
The primary treatment goal is complete surgical removal of the tumor, after which more than 95% of patients with cSCC have excellent outcomes. Although surgery is the most frequent and successful treatment option, in some cases patient preferences and other factors may lead to radiation therapy. Approximately 5% of patients with cSCC develop locally advanced or metastatic disease when tissues and organs underlying the original tumor are invaded by the tumor cells, or the tumor metastasizes to other organs. These forms of cSCC have a poor prognosis and very low survival rates. For these patients, systemic therapy is required.
Prior to the emergence of therapies against the anti-programmed cell death receptor 1 protein (PD-1) or programmed death-ligand 1 (PD-L1) antibodies(anti-PD-(L)1 antibodies), other systemic treatments were palliative and had only short-lived effects. Recent scientific data suggest the C5a involvement with tumor formation and progression. Expression of the receptors for C5a (C5aR) is increased in many epithelial tumors, including cSCC. C5a is expressed at high levels in the tumor environment and may directly promote tumor growth and, through several mechanisms, metastasis. PD-1 is overexpressed by human cSCC and plays an integral role in suppressing the immune response, thereby preventing immune-mediated killing of cancer cells.
Cemiplimab and pembrolizumab are FDA-approved anti-PD-(L)1 antibodies for the treatment of locally advanced or metastatic cSCC that is not curable by surgery or radiation. There are no other treatment options for patients with PD-(L)1-resistant or refractory cSCC. A combination of an anti-C5a therapy with PD-1 checkpoint inhibition could reverse resistance to PD-1 or PD-L1 inhibitor therapy.
An open-label, multicenter Phase II study evaluating vilobelimab alone and in combination with pembrolizumab in patients with PD-1 or PD-L1 inhibitor resistant/refractory locally advanced or metastatic cSCC is currently enrolling patients.
