Increased PD-L1 Tumor Expression Correlates with High Rate of Response to PD-1 Inhibitors in Patients with Unresectable, Recurrent, and Metastatic Cutaneous Squamous Cell Carcinoma

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Nathan Bowers
Mercedes Porosnicu


Squamous Cell Carcinoma, PD-L1, PD-1 Inhibitor


Background: PD-1 inhibitors were approved for locally advanced and metastatic cutaneous squamous cell carcinoma (CSCC) in 2019 with ORR of 47% and CR of 4%. 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 unresectable, recurrent, or metastatic CSCC treated with PD-1 inhibitors and analyze tumor and blood genomics as well as PD-L1 expression with the aim to correlate with treatment response.

Methods:  We analyzed all cases of CSCC treated with single agent PD-1 inhibitors in the last 2 years at Wake Forest Comprehensive Cancer Center. Demographic and outcome data was collected. Tumors tested for genomics and PD-L1 expression in all cases with available tissue. PD-L1 tumor expression was tested by IHC utilizing DAKO 22C3 pharmDx antibodies.  Tumor genomic studies including TMB and MSI were performed by Foundation Medicine platform. Blood was tested for circulating tumor DNA by Guardant 360 platform, at the beginning of treatment and in follow up at the time of maximum response.  Response was assessed by RECIST 1.1 Criteria.

Results (Table 1):
Eleven patients with CSCC treated with PD-1 ICI were included in this study. Five patients had locally advanced disease, five patients had recurrent locally advanced disease, and three patients had metastatic disease. Three patients received treatment for at least 12 months and all have CR to date. Two patients have been on treatment for 6 months, and they have excellent PR with possible CR per imaging studies. Of the six patients who have been on treatment for less than 6 months, one patient has excellent PR with negative PET, three patients have very good clinical response with imaging studies pending, one patient has questionable response, and one patient only recently started treatment. Treatment is well tolerated with no treatment discontinuation. Immune-related complications are rare consisting of only one patient developing hypothyroidism during treatment. Eight patients had sufficient tumor tissue for genomic and PD-L1 testing. Initial blood genomic testing was performed in 10 of 11 patients and in follow up in all three patients who achieved maximum response. Patients with CR had PD-L1 of at least 30%. The additional tested patients have PD-L1 above 10%.  The most frequently mutated tDNA gene was TP53 and the second most frequently mutated gene was the NOTCH1/2. TMB was intermediate or high in all tested patients.

Discussion:  Treatment of locally advanced unresectable, recurrent, and metastatic CSCC with ICI has led to a dramatic change in the management and prognosis of CSCC. Our series of patients with CSCC has a higher than reported rate of response and especially complete response. This corresponds with high TP53 alterations (100% of patients), NOTCH 1/2 alterations (90 % of patients) and high level of expression of PD-L1 (90% patients). Interestingly, PD-L1 rates were higher than previously published.


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