Checkpoint Blockade for Advanced cSCC: Exploring Newer Options

The majority of cutaneous squamous cell carcinomas (cSCC) are treated by surgery or destruction (excision, Mohs micrographic surgery, C&E), although alternative in-office modalities, such as PDT and radiation therapy, are also used.¹ Locally advanced and metastatic cSCC, which represent a small proportion of all cSCC, have presented a treatment challenge. Until recently, little has been available in the way of treatment options. The treatment paradigm for cSCC has evolved significantly with the approval of two immunotherapy medications that block the interaction of PD-1 and PD-L1, which are expressed on the surface of T-cells and tumor cells, respectively. PD-L1 is also found on tumor-infiltrating immune cells. Known as checkpoint inhibitors or checkpoint blockers (CPBs), these systemic treatments offer notable efficacy for many patients with advanced disease.

Advanced cSCC

Cutaneous SCC ranks as the second most common cancer in humans, following BCC. Although many cSCCs will be successfully managed with surgical or destructive modalities, an estimated 3,000 cSCC-associated deaths occur annually in the US. At my community dermatology clinic, we treat advanced cSCC each month with Mohs surgery; as a trial site for cemiplimab, we saw additional cases that were either locally advanced to the point that surgery or radiation was not an option or that had metastasized.

Immunotherapy has emerged as a significant advancement in those cases of cSCC in which surgery or radiation therapy is not appropriate. Immunotherapy causes the body’s immune system to infiltrate and destroy the tumor, rather than using a more blanket approach to cause widespread cell death, as is the case with traditional chemotherapy. Previous systemic therapeutic approaches, such as the use of epidermal growth factor inhibitors, have been shown to provide limited efficacy, in the range of 20 to 30 percent. Efficacy rates with immunotherapy approach 50 percent (See tables).

The two FDA-approved immunotherapy agents are cemiplimab (Libtayo, Regeneron/Sanofi) and pembrolizumab (Keytruda, Merck). Both medications are administered by IV. When receptor interaction is blocked, the T-cells and tumor infiltrating cells see the tumor as foreign and attack it. There are slight differences in the indications for each agent. Although this variation has no practical significance regarding their use, the reported data (See tables, based on Prescribing Information) are not precisely comparable. Cemiplimab is indicated for the treatment of patients with metastatic cSCC or locally advanced cSCC who are not candidates for curative surgery or curative radiation. Pembrolizumab is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma that is not curable by surgery or radiation.

There are concerns about potential adverse effects. Because these agents promote an immune response by blocking the checkpoint between the tumor cell and the T-cell, the immune response can affect almost any organ in the body. Fortunately, most of the side effects that have been seen with the use of these agents are manageable and not severe. The severe adverse effects that can occur require early identification and swift intervention, therefore, physicians must be vigilant in detecting and treating these early. Common symptoms, such as cough (which could possibly signify pneumonitis), diarrhea (which could possibly signify immune mediated colitis), and fatigue (which could possibly signify immune mediated endocrinopathy) should be evaluated and addressed promptly. Guidelines address management of the various adverse events, which are graded by severity.

Other therapeutics used for the treatment of cSCC include cisplatin-based chemotherapy regimens, used for more than 50 years, that borrow from the treatment of head and neck SCC. It should be noted that head and neck SCC is very different in presentation, risk factors, outcome, and treatment from cSCC. Because cisplatin increases the sensitivity to radiation therapy, its use in combination with other chemotherapies has been extensive. Additionally, as mentioned, epidermal growth factor receptor inhibitors have been used. The most well-known of these is likely cetuximab. While these agents have been promising for the treatment of head and neck cancers, regimens based on epidermal growth factor receptor inhibitors have not worked quite as well for cutaneous tumors.

Important Developments

The emergence of checkpoint inhibitors for the treatment of advanced cSCC has expanded treatment options and allows us to serve a wider range of patients. A gap in care remains for cSCC that either does not respond to PD-1 inhibitor therapy or progresses after an initial response. For this reason, new medications designed to enhance the immune response are under development. Once such medication is cavrotolimod (Exicure), also known as AST-008. It is a toll-like receptor 9 agonist and it can induce a potent anti-cancer immune response, especially in combination with CPBs. Early-stage trials show benefit in some cases; further development is proceeding. We will likely see more medications in the future intended to work with checkpoint inhibitors to enhance their response.

1. Work Group; Invited Reviewers, Kim JYS, Kozlow JH, Mittal B, Moyer J, Olenecki T, Rodgers P. Guidelines of care for the management of cutaneous squamous cell carcinoma. J Am Acad Dermatol. 2018 Mar;78(3):560-578.