PD-1 inhibitors (cemiplimab, pembrolizumab) as first-line systemic therapy
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Most cutaneous squamous cell carcinomas (SCCs) are cured with a single procedure. A small number grow deep, invade nerves, keep coming back, or spread to lymph nodes or distant organs. When surgery and radiationcan no longer clear the disease, treatment shifts to medication that works throughout the body.
Foradvanced SCC, that first medication is almost always immunotherapy with a PD-1 inhibitor. This article explains why SCC responds so well to this approach, how the drugs work in plain language, what the trials showed for cemiplimab and pembrolizumab, who is eligible, the special problem for transplant recipients, and what treatment and monitoring involve.
The immune system keeps its T cells from attacking the body's own tissue using "checkpoint" switches. One switch is a protein called PD-1. Many cancers press that switch to hide from the immune system.
A PD-1 inhibitor — also called a checkpoint inhibitor — is an antibody given by vein that blocks the PD-1 switch, so T cells can recognize the tumor and attack it. It does not poison cancer cells the way chemotherapy does; it takes a brake off the immune system.
Cutaneous SCC is an unusually good target for this. Because it is driven by years of ultraviolet damage, it carries one of the highest tumor mutational burdens of any cancer — a huge number of DNA changes. Those changes make the tumor look "foreign," so once the brake is released the immune system has many abnormal features to recognize. That biology is why response rates in SCC are higher than in most other solid tumors treated with these drugs.
Two PD-1 inhibitors are approved by the U.S. Food and Drug Administration for advanced cutaneous SCC. They have not been compared head-to-head; the choice usually comes down to physician experience, scheduling, and insurance coverage.
Approved in 2018 as the first drug specifically for advanced cutaneous SCC, based on the phase 2 EMPOWER-CSCC-1 trial (also called Study 1540) in patients with metastatic or locally advanced disease not curable by surgery or radiation.
Across the trial's groups, roughly 45–50% of patients had an objective response (significant tumor shrinkage), and a subset had complete disappearance of the tumor. In extended follow-up, the median duration of response had not been reached — meaning the typical response was still ongoing past several years — and estimated survival at two years was around 70%.
Approved for recurrent or metastatic cutaneous SCC in 2020 and expanded in 2021 to include locally advanced disease, based on the phase 2 KEYNOTE-629 trial.
Objective responses occurred in about 35% of patients with recurrent or metastatic disease and about 50% of patients with locally advanced disease. As with cemiplimab, responses tended to be durable, frequently lasting well over a year.
The headline for both drugs is the same: a minority-to-half of patients get a major response, but those responses are unusually long-lasting compared with older chemotherapy, and a meaningful number of tumors clear entirely.
PD-1 immunotherapy is the first-line systemic treatment for advanced cutaneous SCC. It is generally offered when:
Immunotherapy is also being studied before surgery, to shrink a borderline tumor so a smaller operation is possible — covered in neoadjuvant immunotherapy before surgery. A history of controlled autoimmune disease (such as psoriasis or well-managed thyroid disease) does not automatically rule it out, but calls for a careful discussion.
The same checkpoints that a PD-1 inhibitor blocks are also what keep a transplant recipient's immune system from attacking the donated organ. Releasing that brake to fight the cancer can cause the immune system to reject the transplant.
In published series of solid-organ transplant recipients treated with checkpoint inhibitors for skin cancer, roughly 40% experienced allograft rejection, and in many of those cases the organ was permanently lost. For a kidney recipient that can mean a return to dialysis; for a liver, heart, or lung recipient it can be life-threatening.
This does not make immunotherapy impossible, but it makes it a shared decision between the oncology and transplant teams, sometimes with adjusted anti-rejection medication or preventive steroids. Non-immunotherapy options — such as cetuximab or platinum chemotherapy — are often weighed first. This is covered in depth in advanced SCC in transplant recipients and immunosuppressed patients.
Some tumors never respond, and some respond and then start growing again months or years later. Options at that point depend on the situation and may include:
Managing the side effects of these drugs is its own topic — see how the side effects of immunotherapy are managed.
Immunotherapy has changed the outlook for advanced cutaneous squamous cell carcinoma. Because the cancer is so heavily mutated by sun damage, PD-1 inhibitors — cemiplimab and pembrolizumab — produce responses in a large share of patients, and those responses often last for years. They are now the first systemic treatment for locally advanced or metastatic disease that surgery and radiation cannot cure.
The main cautions are the immune-related side effects these drugs can cause and the serious risk of transplant rejection in organ recipients. Both are reasons to have this treatment guided by a medical oncologist who manages advanced skin cancer regularly.
Disclaimer: This article is for educational purposes only and not a substitute for professional medical advice. Always consult a qualified dermatologist or oncologist about your personal diagnosis and treatment plan.
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