PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma

Migden, Michael R.; Rischin, Danny; Schmults, Chrysalyne D.; Guminski, Alexander; Hauschild, Axel; Lewis, Karl D.; Chung, Christine H.; Hernandez‐Aya, Leonel F.; Lim, Annette; Chang, Anne Lynn S.; Rabinowits, Guilherme; Thai, Alesha; Dunn, Lara; Hughes, Brett; Khushalani, Nikhil I.; Modi, Badri; Schadendorf, Dirk; Gao, Bo; Seebach, Frank; Li, Siyu; Li, Jingjin; Mathias, Melissa; Booth, Jocelyn; Mohan, Kosalai Kal; Stankevich, Elizabeth; Babiker, Hani M.; Braña, Irene; Gil-Martín, Marta; Homsi, Jade; Johnson, Melissa L.; Moreno, Víctor; Niu, Jiaxin; Owonikoko, Taofeek K.; Papadopoulos, Kyriakos P.; Yancopouloš, George D.; Lowy, Israel; Fury, Matthew G.

doi:10.1056/nejmoa1805131

Cited by 1,115 publications

(1,100 citation statements)

References 24 publications

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“…In this context, the recent negative results of the randomized multicenter postoperative chemoradiation study in regionally metastatic HNcSCC were disappointing . However, recent studies evaluating immunotherapy demonstrate that cSCC has a high response rate to PD‐1/PD‐L1 blockade, and this treatment option may also be better suited to an aging population than platinum‐based chemotherapy . It is very likely that the next generation of adjuvant trials in HNcSCC will incorporate PD‐1/PD‐L1 immunotherapy in conjunction with adjuvant RT.…”

Section: Discussionmentioning

confidence: 99%

Positive survival trend in metastatic head and neck cutaneous squamous cell carcinoma over four‐decades: Multicenter study

et al. 2019

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Background This study assessed changes over time of survival of head and neck cutaneous squamous cell carcinoma (HNcSCC) with lymph node metastases. Methods A multicenter analysis of 1301 patients with metastatic HNcSCC treated between 1980 and 2017. Differences in disease‐specific survival (DSS) and overall survival (OS) by decade were assessed using multivariate Cox regression. Results Over the study period, we noted an increase in the proportion of patients aged over 80 years (3.9%‐31.7%; P < .001) and immunosuppression (1.9%‐9.9%; P = .03). After adjusting for number and size of metastatic nodes, extranodal extension, perineural invasion, immunosuppression, treatment, and institution, there was a reduction in risk of cancer‐related mortality from 0.47 in 1990‐1999 (P = .04) to 0.30 in 2000‐2009 (P < .001) when compared to 1980‐1989. This remained stable at 0.30 in 2010‐2017 (P = .001). OS remained stable after 1990. Conclusion Despite an aging and more frequently immunosuppressed population, fewer patients are dying from metastatic HNcSCC.

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Section: Discussionmentioning

confidence: 99%

Positive survival trend in metastatic head and neck cutaneous squamous cell carcinoma over four‐decades: Multicenter study

et al. 2019

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“…For metastatic cSCC, immunotherapy is a promising first‐line treatment option. A recent study of PD‐1 blockade with cemiplimab in advanced cSCC reported a response in 47% of the patients . This may be a function of the expression of abundant neoantigens in cSCC.…”

Section: Discussionmentioning

confidence: 99%

Ultraviolet light‐related DNA damage mutation signature distinguishes cutaneous from mucosal or other origin for head and neck squamous cell carcinoma of unknown primary site

et al. 2019

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Background Head and neck squamous cell carcinoma of unknown primary site (HNSCCUP) is a diagnostic challenge. Identification of an ultraviolet (UV) light‐related DNA damage signature using next‐generation sequencing (NGS) can classify the primary site of origin as cutaneous. Methods A 62‐year‐old male was seen with 2 months of left neck swelling. He was a lifetime nonsmoker but had a history of cutaneous squamous cell carcinoma (SCC) of the left helix. He was also found to have left hilar adenopathy. He had a p16‐negative HNSCCUP on fine needle aspiration (FNA) biopsy of the left neck. Results NGS of the FNA specimen revealed a high number of somatic mutations that were mostly C to T transitions, indicating a UV mutation signature and confirming the diagnosis of cutaneous SCC. Conclusions Identification of a UV DNA damage signature with NGS distinguishes HNSCCUP of cutaneous vs mucosal or other squamous cell carcinoma origin.

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“…In immunocompetent individuals, cSCCs express a chemokine profile that facilitates recruitment of immune cells into the TME, but multiple mechanisms within the TME suppress their function including expression of immune checkpoints. Accordingly, half of all patients bearing advanced or recurrent/metastatic cSCCs demonstrate objective responses to PD‐1 mAb treatment . This highly inflamed phenotype is also observed in other SCCs, such as HNSCC where ΔNp63α is frequently overexpressed …”

Section: Cross Talk Between the Nf‐κb And P63 Families Influences Thementioning

confidence: 89%

Intersection of the p63 and NF‐κB pathways in epithelial homeostasis and disease

King

George

Sakakibara

et al. 2019

Molecular Carcinogenesis

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Overexpression of ΔNp63α, a member of the p53/p63/p73 family of transcription factors, is a molecular attribute of human squamous cancers of the head and neck, lung and skin. The TP63 gene plays important roles in epidermal morphogenesis and homeostasis, regulating diverse biological processes including epidermal fate decisions and keratinocyte proliferation and survival. When overexpressed experimentally in primary mouse keratinocytes, ΔNp63α maintains a basal cell phenotype including the loss of normal calcium‐mediated growth arrest, at least in part through the activation and enhanced nuclear accumulation of the c‐rel subunit of NF‐κB (Nuclear Factor‐kappa B). Initially identified for its role in the immune system and hematopoietic cancers, c‐Rel has increasingly been associated with solid tumors and other pathologies. ΔNp63α and c‐Rel have been shown to be associated in the nuclei of ΔNp63α overexpressing human squamous carcinoma cells. Together, these transcription factors cooperate in the transcription of genes regulating intrinsic keratinocyte functions, as well as the elaboration of factors that influence the tumor microenvironment (TME). This review provides an overview of the roles of ΔNp63α and c‐Rel in normal epidermal homeostasis and elaborates on how these pathways may intersect in pathological conditions such as cancer and the associated TME.

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PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma

Cited by 1,115 publications

References 24 publications

Positive survival trend in metastatic head and neck cutaneous squamous cell carcinoma over four‐decades: Multicenter study

Positive survival trend in metastatic head and neck cutaneous squamous cell carcinoma over four‐decades: Multicenter study

Ultraviolet light‐related DNA damage mutation signature distinguishes cutaneous from mucosal or other origin for head and neck squamous cell carcinoma of unknown primary site

Intersection of the p63 and NF‐κB pathways in epithelial homeostasis and disease

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