SKIN January 2021 Volume 5 Issue 1 Copyright 2021 The National Society for Cutaneous Medicine 22 RISING DERM STARS ® ABSTRACTS 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 Nathan Bowers, MD1, Mercedes Porosnicu, MD2 1Department of Dermatology, Wake Forest University School of Medical, Winston-Salem, NC 2Department of Internal Medicine, Section of Hematology & Oncology, Wake Forest University School of Medicine, Winston Salem, NC 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. 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. 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 INTRODUCTION METHODS RESULTS SKIN January 2021 Volume 5 Issue 1 Copyright 2021 The National Society for Cutaneous Medicine 23 Table 1. G A S L/R/M IOD (mo) IOR D Previous PD-L1 TMB Guardant before IO Guardant after IO F1 AE OBS TP53 Other TP53 Other TP53 Other M 73 N L 20 CR On Surg, Adj CRT TPS 60% 61 0 0 Y163N ARID1A ATM G266E R248Q BRIP1, CD22, FANCC, MEN1, NOTCH2 Other primary cSCC x5 RA-PDN 5 mg + MTX F 97 N L 14 CR 3 mo - TPS 60% 11 0 KIT CRCA1 0 KIT BRCA2 E286K CDKN2A, NOTCH2, TERT Hypothyroid Other primary cSCC x3 M 76 N L 14 CR On Surg, Adj RT TPS 30% 19 0 JAK2 0 0 P278S ASXL, CDKN2A, NOTCH1, PIK3CA, TERT Fatigue Mets to right parotid F 81 N L 9 PR On n/a NET S99F Q100 Q16 SS SNV CDKN2A BRCA2 MAP2K1 ND ND NET NET Other primary cSCC x2 M 91 FS M 6 PR On Adj RT NET NET NET NET NET NET NET NET Fatigue M 75 N R 4 PR On None TPS 20% 21 H193L R342 0 ND ND G245N R342 CASP8, MLL2, NOTCH1, RB1 Fatigue F 64 N R 4 PD On Surg, Adj RT CPS 30 8 G266R 0 ND ND G262V FGF12, MDM2, NOTCH1, PIK3CA, PRKCI, SOX2, TERT, TERC M 77 FS R 5 PR On Surg, Adj RT TPS 90% 163 V143M R248W Q136 CCND2 CDKN2A BRCA2 TERT ND ND R248W ALK, BRCA2, CCND1, BARD1, ATR, AXIN1, CDKN2A/B, FGF19, FGF3, FGF4, MYCN, NOTCH1, TERT Lung Nodules M 83 N R 5 PR On Surg TPS 20% 35 0 KRAS ND ND R213Q P278F SS 75- 1G>A ASXL1, CDKN2A, DBMT3A, MLL2, NOTCH1, RB1, TERT, TET2 M 80 N M 4 PD On Surg NET NET 0 NRAS ND ND ND ND M 65 FS L 8 PR On Surg, RT TPS 10% ND T155P PTEN ND ND R342 R213 CDKN2A, HGF, KEAP1, MLL2, MRE11A, SMARCA4, TNFAIP3 G = gender; A = age; L/R/M = loco-regional/recurrent/metastatic; IOD = duration of treatment with immunotherapy; IOR= response obtained with immunotherapy (CR = complete response, PR = partial response, PD = progression of disease); D = duration of response after immunotherapy was stopped; Previous = treatments received before starting immunotherapy; PD-L1 = PD-L1 status measured in all cases with DAKO223 antibodies; TMB = Tumor Mutation Burden measured by Foundation Medicine in tumor tissue; Guardant before/after IO = genomic mutations in blood tested by Guardant 360 platform;F1 = genomic mutation in tumor tested by Foundation; AE = adverse events; Obs = observations; NET = not enough tissue for testing. SKIN January 2021 Volume 5 Issue 1 Copyright 2021 The National Society for Cutaneous Medicine 24 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. 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. Conflict of Interest Disclosures: None Funding: None Corresponding Author: Nathan L. Bowers, MD, PhD Department of Dermatology Wake Forest University School of Medical Winston-Salem, NC Email: nbowers@wakehealth.edu 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. 3. Pickering CR, Zhou JH, Lee JJ, et al. Mutational landscape of aggressive cutaneous squamous cell carcinoma. Clin Cancer Res. 2014;20(24):6582–6592. doi:10.1158/1078- 0432.CCR-14-1768. DISCUSSION