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Introduction: Cutaneous squamous cell carcinoma (CSCC) is the second most common form of human cancer. Treatment of locally advanced and/or recurrent CSCC is often challenging. A subset of patients are not candidates for curative-intent therapies due to extent of loco-regional disease, refractoriness to prior local therapy, or presence of distant metastasis., Areas Covered: Traditionally, CSCC has been treated with surgery and/or radiotherapy, but in some instances, local therapies can lead to significant functional morbidity or are no longer feasible. Until 2018, systemic therapy options to treat patients with advanced CSCC were limited. Recently, clinical studies have shown activity of Immune Checkpoint Inhibitors (ICI) in patients with advanced CSCC. This article reviews the current systemic therapy options for CSCC with a focus on ICI and emerging promising therapies in the treatment of this challenging disease., Expert Opinion: ICI is currently the most effective and tolerable systemic therapy in the treatment of non-immunosuppressed advanced CSCC and can lead to cure in a subset of patients. Combinatorial therapies to overcome resistance to ICI may further increase the proportion of patients who will benefit from ICI and may help improve the quantity and quality of life of patients affected by this disease.

Introduction: Recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) is associated with dismal prognosis and has limited therapeutic options. PD-1/PD-L1 axis blockade was initially shown to improve outcomes in platinum-refractory HNSCC. More recently, pembrolizumab monotherapy or pembrolizumab combined with chemotherapy resulted in better overall survival than platinum, 5-fluorouracil, and cetuximab (EXTREME regimen) as first-line therapy for R/M HNSCC, establishing a new standard-of-care therapy for this disease., Areas Covered: We review pembrolizumab in the first-line treatment of R/M HNSCC and summarize the impact of PD-L1 expression, tumor and symptom burden, and patient's performance status on treatment decisions. Future perspectives are summarized., Expert Opinion: The standard-of-care first-line therapy for R/M HNSCC is pembrolizumab monotherapy for patients with a PD-L1 combined positive score (CPS)≥1 or pembrolizumab combined with platinum and 5-fluorouracil for patients with any PD-L1 status. Addition of chemotherapy to pembrolizumab increases the response rate but also toxicity and is preferred for patients with good performance status and significant tumor and symptom burden. For patients with a PD-L1 CPS <1, the EXTREME regimen should be considered. New strategies combining pembrolizumab with targeted therapies and immune checkpoints inhibitors are being explored to synergize or overcome resistance to anti-PD-1.