Immunotherapy Surprises in Preoperative Treatment of Squamous Cell Skin Cancer

Skin cancers fall into two groups according to their cells of origin: melanoma (arising from melanocytes, the cells that give skin its colour) and non-melanoma (not melanoma). Around 95% of skin cancers are non-melanoma. The common forms of non-melanoma skin cancer are basal cell cancer and squamous cell cancer, the 2 main types. In descending order of frequency, skin cancers are basal cell cancer, squamous cell cancer and melanoma. Squamous cell skin cancer affects 700 thousand newly diagnosed people annually in the United States alone. Sunlight is the main risk factor for all skin cancers.

Most patients with non-melanoma skin cancer can be treated successfully with surgery. For more advanced tumours, more extensive surgery or radiotherapy is generally sufficient to control regional disease. Metastatic skin cancer, which has spread through the body, is treated according to whether it is basal cell or squamous cell cancer, but options are very limited.

Basal cell skin cancers very rarely metastasise, while about 5% of squamous cell skin cancers spread to regional lymph nodes and distant organs.

A Turning Point in Squamous Cell Skin Cancer Treatment

For stage 2-4 squamous cell skin cancer, neoadjuvant immunotherapy produced a strong pathological complete response rate in a phase II trial. The study was presented at the ESMO 2022 Congress and published simultaneously in NEJM.

Lead author Dr Neil D. Gross and colleagues conducted a pilot study of neoadjuvant cemiplimab immunotherapy. They said the aim was to establish how squamous cell skin cancer cells responded to treatment and to learn more about their biology, but the results were striking. “We were surprised by how well patients responded. More than half had a complete pathological response, and 4 of the 20 patients had a near-complete pathological response.” Gross said.

In this study involving 79 patients at centres in Australia, Germany and the United States, 63% of patients had truly impressive pathological responses. A few even responded so well that they declined surgery.

Dr Gross said, “These results are so dramatic that it is hard to imagine they will not affect how patients in this situation are treated.”

Dramatic Results and an Appealing Option

The 79 patients in the new trial had a median age of 73; 85% were men and 87% were White. Around 91% of tumours were in the head and neck; 6% were stage II, 48% stage III and 46% stage IV. All patients received four doses of 350 mg cemiplimab at 3-week intervals.

After an average follow-up of 9.7 months (range, 1.3-19.6 months), a pathological complete response was achieved in 51% of patients (95% confidence interval, 39%-62%). It had initially been estimated that 25% would achieve a pathological response. A further 13% had a major pathological response (95% CI, 6-22%). 25% did not achieve either a complete or major pathological response, defined as viable tumour cells representing at least 10% of the surgical specimen.

72% of patients experienced an adverse event considered treatment-related by the investigator, most commonly fatigue (28%), maculopapular rash (14%) and diarrhoea (11%). Immune-related adverse events occurred in 15%; 4% experienced a grade 3 immune-related adverse event.

Despite these encouraging results, more research is needed. One key question is the optimal number of preoperative treatments: the pilot used two doses, while the phase II trial used four. Another is whether treatment might spare some patients surgery and radiotherapy. Many important questions about implementation in clinical practice remain unanswered, but I do not think there is any going back. The results are so dramatic that this is a very appealing option for patients and their doctors.