Where Do Chemotherapy and EGFR-Targeted Therapy Fit?

Introduction

For most people with locally advanced or metastatic cutaneous squamous cell carcinoma (SCC), the first medication offered today isPD-1 immunotherapy— cemiplimab or pembrolizumab. But immunotherapy isn't right for everyone, and it doesn't work for everyone it's given to. Before checkpoint inhibitors existed, and still today for a meaningful subset of patients, two older classes of drugs do the work instead: EGFR-targeted therapy (mainly cetuximab) and platinum-based chemotherapy.

This page explains how each of these approaches works, how well they perform compared with immunotherapy, and — most importantly — who actually ends up needing them: largely organ transplant recipients, other immunosuppressed patients, and people whose disease has already progressed through immunotherapy.

Platinum-Based Chemotherapy

Traditional chemotherapy — most often cisplatin or carboplatin, sometimes combined with a second drug such as doxorubicin, 5-fluorouracil, or a taxane — was for decades the main systemic option for advanced cutaneous SCC. It works by damaging the DNA of rapidly dividing cells throughout the body, which includes cancer cells but also normal tissues like bone marrow, hair follicles, and the lining of the gut.

One of the foundational studies, evaluating cisplatin-based chemotherapy in 28 patients with advanced basal cell and squamous cell skin cancers (used alone or before surgery or radiation), reported an overall response rate of 68%, including complete remission in 28% of patients. More recent single-arm and retrospective series in cutaneous SCC specifically have shown similarly meaningful, though not universal, response rates.

Chemotherapy's side effects — nausea, fatigue, low blood counts with infection risk, hair loss, and nerve or kidney effects depending on the regimen — are generally more burdensome than those of immunotherapy or cetuximab, especially in older patients or those with other health problems. This is one reason it has moved to a later-line or specific-situation role rather than remaining first choice.

Who Actually Ends Up on These Treatments

In current practice, cetuximab and chemotherapy are most often used for:

• •Organ transplant recipients and other immunosuppressed patients. Because checkpoint inhibitors can trigger transplant rejection or dangerous flares of autoimmune disease, many transplant teams and oncologists start with cetuximab or chemotherapy instead, especially early on — see advanced SCC in transplant and immunosuppressed patients.
• •Disease that has progressed on immunotherapy. When a PD-1 inhibitor stops controlling the cancer, cetuximab or chemotherapy is a standard next line of systemic treatment.
• •An active autoimmune condition that makes immunotherapy's risk of a serious flare too high.
• •Combined with radiation. Cetuximab is sometimes given alongside radiation for locally advanced, unresectable tumors to try to improve local control, drawing on experience from head and neck squamous cell cancer.

The decision is individualized and made by a medical oncologist experienced in skin cancer, weighing the tumor's behavior, the patient's overall health and organ function, and whichever of these factors apply.

Conclusion

Cetuximab and platinum-based chemotherapy were the backbone of systemic treatment for advanced cutaneous SCC before immunotherapy arrived, and they still have a real role today — most often for organ transplant recipients and other immunosuppressed patients, for people whose disease has progressed after immunotherapy, or when an active autoimmune condition rules out a checkpoint inhibitor.

They are generally less effective and less durable than PD-1 immunotherapy, but they remain a genuine, well-studied option, and for some patients they are the safer starting point. The right choice depends on your specific tumor, your immune status, and your overall health — a conversation best had with a medical oncologist experienced in advanced skin cancer.