Background PD-1 inhibitors were approved for locally advanced and metastatic cutaneous squamous cell carcinoma (CSCC) in 2019.¹ The identification of tumor characteristics that predict potential responders to immune checkpoint inhibitors (ICI) is an area of ongoing research. Here we present a series of consecutive patients with locally advanced, recurrent, or metastatic CSCC treated with PD-1 inhibitors and analyze tumor and blood genomics as well as PD-L1 expression with the aim of correlating with treatment response.

Methods We analyzed cases of CSCC treated with single agent PD-1 inhibitors in the last 2 years at Wake Forest. Demographic and outcome data were collected. Tumor tissue, whenever available, was tested for PD-L1, TMB, MSI, and genetic mutations. Blood was tested for circulating tumor at the beginning of treatment and at the time of maximum response.

Results Fourteen patients with CSCC treated with PD-1 ICI were included in this study. Six had locally advanced disease, seven had recurrent locally advanced disease, and one had metastatic disease. Four patients received treatment for >12 months and all had complete response (CR). Five patients had 6–12 months of treatment and all had near CR (pending imaging studies and ctDNA to confirm). Three patients had <6 months of treatment and had partial response (PR). Two of the patients had progressive disease, although one with possible pseudoprogression based on review of post-treatment surgical pathology specimen. Treatment was well tolerated with no immune related side-effects except one case of grade I hypothyroidism. Eleven patients had sufficient tumor tissue for genomic and PD-L1 testing. Initial blood genomic testing was performed in 12 of 13 patients and in follow up in patients who achieved maximum response. Patients with CR had PD-L1 of at least 30%. The additional tested patients had PD-L1 above 10%. The most frequently mutated gene was TP53 present in tumor in all tested patients and in blood in 6 patients, followed by NOTCH1/2 detected in the tumor of 10 of 11 patients tested. TMB was intermediate/high in tested patients except in the only patient who presented clear tumor progression.

Conclusions Treatment of locally advanced, recurrent, and metastatic CSCC with ICI led to a dramatic change in the management and prognosis of CSCC. Our series of patients with CSCC had a higher than reported rate of response. This corresponded with high TP53 alterations, NOTCH 1/2 alterations, high/intermediate TMB, and high level of expression of PD-L1. PD-L1 rates were higher than previously published.^{1 2}

Ethics Approval The study was approved by Wake Forest University Institution’s Ethics Board, approval number IRB00056249.

References

1. Migden MR, Rischin D, Schmults CD, Guminski A, Hauschild A, Lewis KD, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med. 2018;379:341–51.

2. Garcia-Pedrero JM, Martinez-Camblor P, Diaz-Coto S, et al. Tumor programmed cell death ligand 1 expression correlates with nodal metastasis in patients with cutaneous squamous cell carcinoma of the head and neck. J Am Acad Dermatol 2017;77(3):527–533.