Treatments on the horizon for locally advanced basal cell carcinoma.

Basal cell carcinoma (BCC) is one of the most common human cancers. Most cases of BCC are amenable to surgical and topical treatments with excellent prognosis if diagnosed timely and managed appropriately. However, in a small percentage of cases, it could be locally advanced BBC (laBCC) and not amenable to surgery or radiation, including recurrent, large tumors or tumors that invade deeper tissue. Hedgehog inhibitors (vismodegib and sonidegib) are approved as the first-line treatment of laBCC. PD-1 inhibitor immunotherapy (cemiplimab) is indicated for cases that progressed on or could not tolerate hedgehog inhibitors or when hedgehog inhibitors are contraindicated. Given the modest response and bothersome side effects of some of the agents above, there are reports of novel treatments, and clinical trials are currently evaluating multiple agents.

High response rate with extended dosing of cemiplimab in advanced cutaneous squamous cell carcinoma.

BACKGROUND: Cemiplimab (Libtayo®), a human monoclonal immunoglobulin G4 antibody to the programmed cell death-1 receptor, is approved for the treatment of patients with advanced cutaneous squamous cell carcinoma (CSCC), who are not candidates for curative surgery or curative radiation, using an every-3-weeks (Q3W) dosing interval. Pharmacokinetic modeling indicated that Ctrough of extended intravenous dosing of 600 mg every 4 weeks (Q4W) would be comparable to the approved intravenous dosage of 350 mg Q3W. We examined the efficacy, pharmacokinetics, and safety of cemiplimab dosed Q4W. METHODS: In this open-label, phase II trial (ClinicalTrials.gov identifier NCT02760498), the cohort of patients ≥18 years old with advanced CSCC received cemiplimab 600 mg intravenously Q4W for up to 48 weeks. Tumor measurements were recorded every 8 weeks. The primary endpoint was objective response rate by independent central review. RESULTS: Sixty-three patients with advanced CSCC were treated with cemiplimab. The median duration of follow-up was 22.4 months (range: 1.0-39.8). An objective response was observed in 39 patients (62%; 95% CI: 48.8% to 73.9%), with 22% of patients (n=14) achieving complete response and 40% (n=25) achieving partial response. The most common treatment-emergent adverse events were diarrhea, pruritus, and fatigue. CONCLUSIONS: Extended dosing of cemiplimab 600 mg intravenously Q4W exhibited substantial antitumor activity, rapid and durable responses, and an acceptable safety profile in patients with advanced CSCC. These results confirm that cemiplimab is a highly active therapy for advanced CSCC. Additional data would help ascertain the benefit-risk profile for the 600 mg intravenous dosing regimen compared with the approved regimen.

Concomitant medication use does not appear to alter long-term efficacy of sonidegib for advanced basal cell carcinoma: a post hoc analysis based on the 42-month BOLT study.

BACKGROUND: Sonidegib is approved to treat locally advanced basal cell carcinoma (laBCC) in patients not amenable to surgery or radiation. The BOLT trial demonstrated durable efficacy of sonidegib in laBCC patients over 42 months. BCC is most common in the elderly, who often take chronic medications. OBJECTIVES: We evaluated the efficacy of sonidegib (200 mg daily) in laBCC patients on select concomitant medications. MATERIALS & METHODS: In the Phase II BOLT study, laBCC patients were randomized 1:2 to sonidegib 200 mg:800 mg daily. The primary endpoint was objective response rate (ORR) per central review. Post hoc assessments included ORR and duration of response (DOR) per investigator review for patients on concomitant medications. RESULTS: At 42 months, ORR for laBCC patients taking sonidegib 200 mg daily (n=66) was 71.2% and DOR was 15.7 months according to investigator review. Patients on select concomitant medications (n=37) had an ORR of 73.0%; DOR was not estimable. CONCLUSION: Administration of sonidegib with concomitant medications, excluding strong cytochrome P450 3A4/5 inhibitors/inducers, does not appear to alter its efficacy in laBCC patients.

Inflammation induced by tumor-associated nerves promotes resistance to anti-PD-1 therapy in cancer patients and is targetable by interleukin-6 blockade.

While the nervous system has reciprocal interactions with both cancer and the immune system, little is known about the potential role of tumor associated nerves (TANs) in modulating anti-tumoral immunity. Moreover, while peri-neural invasion is a well establish poor prognostic factor across cancer types, the mechanisms driving this clinical effect remain unknown. Here, we provide clinical and mechniastic association between TANs damage and resistance to anti-PD-1 therapy. Using electron microscopy, electrical conduction studies, and tumor samples of cutaneous squamous cell carcinoma (cSCC) patients, we showed that cancer cells can destroy myelin sheath and induce TANs degeneration. Multi-omics and spatial analyses of tumor samples from cSCC patients who underwent neoadjuvant anti-PD-1 therapy demonstrated that anti-PD-1 non-responders had higher rates of peri-neural invasion, TANs damage and degeneration compared to responders, both at baseline and following neoadjuvant treatment. Tumors from non-responders were also characterized by a sustained signaling of interferon type I (IFN-I) - known to both propagate nerve degeneration and to dampen anti-tumoral immunity. Peri-neural niches of non-responders were characterized by higher immune activity compared to responders, including immune-suppressive activity of M2 macrophages, and T regulatory cells. This tumor promoting inflammation expanded to the rest of the tumor microenvironment in non-responders. Anti-PD-1 efficacy was dampened by inducing nerve damage prior to treatment administration in a murine model. In contrast, anti-PD-1 efficacy was enhanced by denervation and by interleukin-6 blockade. These findings suggested a potential novel anti-PD-1 resistance drived by TANs damage and inflammation. This resistance mechanism is targetable and may have therapeutic implications in other neurotropic cancers with poor response to anti-PD-1 therapy such as pancreatic, prostate, and breast cancers.

Beta-Blocker Use Is Associated With Worse Relapse-Free Survival in Patients With Head and Neck Cancer.

PURPOSE: Although beta-blockers (BBs) have been hypothesized to exert a beneficial effect on cancer survival through inhibition of beta-adrenergic signaling pathways, clinical data on this issue have been inconsistent. We investigated the impact of BBs on survival outcomes and efficacy of immunotherapy in patients with head and neck squamous cell carcinoma (HNSCC), non-small-cell lung cancer (NSCLC), melanoma, or squamous cell carcinoma of the skin (skin SCC), independent of comorbidity status or cancer treatment regimen. METHODS: Patients (N = 4,192) younger than 65 years with HNSCC, NSCLC, melanoma, or skin SCC treated at MD Anderson Cancer Center from 2010 to 2021 were included. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were calculated. Kaplan-Meier and multivariate analyses adjusting for age, sex, TNM staging, comorbidities, and treatment modalities were performed to assess the effect of BBs on survival outcomes. RESULTS: In patients with HNSCC (n = 682), BB use was associated with worse OS and DFS (OS: adjusted hazard ratio [aHR], 1.67; 95% CI, 1.06 to 2.62; P = .027; DFS: aHR, 1.67; 95% CI, 1.06 to 2.63; P = .027), with DSS trending to significance (DSS: aHR, 1.52; 95% CI, 0.96 to 2.41; P = .072). Negative effects of BBs were not observed in the patients with NSCLC (n = 2,037), melanoma (n = 1,331), or skin SCC (n = 123). Furthermore, decreased response to cancer treatment was observed in patients with HNSCC with BB use (aHR, 2.47; 95% CI, 1.14 to 5.38; P = .022). CONCLUSION: The effect of BBs on cancer survival outcomes is heterogeneous and varies according to cancer type and immunotherapy status. In this study, BB intake was associated with worse DSS and DFS in patients with head and neck cancer not treated with immunotherapy, but not in patients with NSCLC or skin cancer.

Non-Melanoma Skin Cancer Detection in the Age of Advanced Technology: A Review.

Skin cancer is the most common cancer diagnosis in the United States, with approximately one in five Americans expected to be diagnosed within their lifetime. Non-melanoma skin cancer is the most prevalent type of skin cancer, and as cases rise globally, physicians need reliable tools for early detection. Artificial intelligence has gained substantial interest as a decision support tool in medicine, particularly in image analysis, where deep learning has proven to be an effective tool. Because specialties such as dermatology rely primarily on visual diagnoses, deep learning could have many diagnostic applications, including the diagnosis of skin cancer. Furthermore, with the advancement of mobile smartphones and their increasingly powerful cameras, deep learning technology could also be utilized in remote skin cancer screening applications. Ultimately, the available data for the detection and diagnosis of skin cancer using deep learning technology are promising, revealing sensitivity and specificity that are not inferior to those of trained dermatologists. Work is still needed to increase the clinical use of AI-based tools, but based on the current data and the attitudes of patients and physicians, deep learning technology could be used effectively as a clinical decision-making tool in collaboration with physicians to improve diagnostic efficiency and accuracy.

Review of the Tumor Microenvironment in Basal and Squamous Cell Carcinoma.

It is widely known that tumor cells of basal and squamous cell carcinoma interact with the cellular and acellular components of the tumor microenvironment to promote tumor growth and progression. While this environment differs for basal and squamous cell carcinoma, the cellular players within both create an immunosuppressed environment by downregulating effector CD4+ and CD8+ T cells and promoting the release of pro-oncogenic Th2 cytokines. Understanding the crosstalk that occurs within the tumor microenvironment has led to the development of immunotherapeutic agents, including vismodegib and cemiplimab to treat BCC and SCC, respectively. However, further investigation of the TME will provide the opportunity to discover novel treatment options.

The Use of a Dehydrated Complete Human Placental Membrane Allograft for Mohs Surgical Defects of the Nose.

BACKGROUND: Repair options for Mohs surgical defects include primary closure, flap or graft, or healing by second intention. These options may not be optimal in all cases. A dehydrated complete human placental membrane (dCHPM) allograft may serve as an alternative repair option. OBJECTIVE: To assess the aesthetic and functional outcomes of an alternative repair technique for Mohs surgical defects of the nose. METHODS: Twenty patients with Mohs surgical defects of the nose repaired with a dCHPM allograft were retrospectively identified. Photographs were used to demonstrate surgical technique and outcomes. Two blinded observers evaluated final outcomes using the Patient and Observer Scar Assessment Scale. RESULTS: Observers rated the scar outcome a combined mean score of 8.4 ± 3.2 (scale 5-50). Patients rated their outcomes a mean of 12.6 ± 7.4 (scale 6-60). The mean "Overall Opinion score" was 2.5 ± 1.8 by patients and 1.9 ± 1.3 by observers (scale 1-10). LIMITATIONS: This was a single institution study with a small sample size. CONCLUSION: Our study demonstrates that dCHPM allografts are a viable alternative repair option for Mohs surgical defects of the nose.

Targeted Therapy and Immunotherapy in Nonmelanoma Skin Cancer.

Advanced nonmelanoma skin cancers (NMSC) are tumors not amenable to surgery and/or radiation. Early systemic treatment attempts with cytotoxic chemotherapy demonstrated low response rates, short durations of response, and high toxicity. Over the last decade, modern therapies for advanced NMSC include targeted therapies and immunotherapies. Hedgehog pathway inhibitors and programmed death-1 inhibitors are available first-line therapies for the treatment of advanced basal cell carcinomas and squamous cell carcinomas, respectively.

Digital photography for the dermatologist.

Dermatology is a specialty reliant on presenting detailed and accurate visual observations. Digital photography is a highly prevalent and accessible technology that can be easily incorporated into a dermatology practice to facilitate documentation and communication of clinical findings. Dermatologists will benefit from being comfortable with digital photography and techniques to improve their photography skills. This review presents the fundamentals of photography and techniques helpful in capturing an adequate image. We explore the application of photography in the setting of microscopy, dermatopathology, dermatoscopy, and Wood's lamp. Lastly, new imaging technologies, such as multispectral and infrared imaging, are discussed.

Advances in Cutaneous Squamous Cell Carcinoma Management.

cSCC is increasing in prevalence due to increased lifespans and improvements in survival for conditions that increase the risk of cSCC. The absolute mortality of cSCC exceeds melanoma in the United States and approaches that of melanoma worldwide. This review presents significant changes in the management of cSCC, focusing on improvements in risk stratification, new treatment options, optimization of existing treatments, and prevention strategies. One major breakthrough in cSCC treatment is the advent of immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1), which have ushered in a renaissance in the treatment of patients with locally advanced and metastatic disease. These agents have offered patients with advanced disease decreased therapeutic toxicity compared to traditional chemotherapy agents, a more durable response after discontinuation, and improved survival. cSCC is an active field of research, and this review will highlight some of the novel and more developed clinical trials that are likely to impact cSCC management in the near future.

Advances in Management and Therapeutics of Cutaneous Basal Cell Carcinoma.

Basal cell carcinoma (BCC), the most common cancer in humans, is a malignant neoplasm of cells derived from the basal layer of the epidermis. Tumor characteristics such as histologic subtype, primary versus recurrent tumor, anatomic location, size, and patient attributes determine the risk level and acceptable treatment options. Surgical options offer histologic confirmation of tumor clearance. Standard excision provides post-treatment histologic assessment, while Mohs micrographic surgery (MMS) provides complete margin assessment intraoperatively. Additional treatment options may be employed in the correct clinical context. Small and low-risk BCCs, broad field cancerization, locally-advanced disease, metastatic disease, cosmetic concerns, or morbidity with surgical approaches raise consideration of other treatment modalities. We review herein a range of treatment approaches and advances in treatments for BCC, including standard excision, MMS, electrodesiccation and curettage, ablative laser treatment, radiation therapy, targeted molecular therapies, topical therapies, field therapies, immunotherapy, and experimental therapies.

PD-1 inhibitors for cutaneous squamous cell carcinoma: A meta-analysis.

PD-1 inhibitors are immunotherapeutic agents used in the treatment of advanced cutaneous squamous cell carcinoma (cSCC). This study aimed to determine the pooled objective response and disease control rates of patients with advanced cSCC treated with PD-1 inhibitors. Pubmed, Cochrane Library and EMBASE databases were searched up to 1 January 2021 to include eligible articles. Objective response rate (ORR) and disease control rate (DCR) were pooled and analysed. Subgroup analysis of the odds ratio (OR) for ORR for patients by PD-L1 tumour proportion score (TPS) was performed. Seven articles including a total of 453 patients were identified and included. Pooled estimate of ORR was 44% (95% CI: 39-49%, I2 = 23.7%) and of DCR was 66% (95% CI: 57-74%, I2 = 68.2%). Pooled odds ratio of ORR for patients by PD-L1 TPS was 2.81 (95% CI: 1.22-6.51, I2 = 0.0%). These results were derived from single-arm studies, some of which were retrospective. No head-to-head trials comparing PD-1 inhibitors have been reported. We present aggregate estimates of ORR and DCR for patients with advanced cSCC treated with PD-1 inhibitors, as well as subgroup analysis for ORR for patients by PD-L1 TPS.

Evidence-Based Consensus Recommendations for the Evolving Treatment of Patients with High-Risk and Advanced Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma is the second most common skin cancer in the United States. Currently, there is no standardized management approach for patients with cutaneous squamous cell carcinoma who develop metastatic or locally advanced disease and are not candidates for curative surgery or curative radiation. To address this issue, the Expert Cutaneous Squamous Cell Carcinoma Leadership program convened an expert steering committee to develop evidence-based consensus recommendations on the basis of a large, structured literature review. Consensus was achieved through modified Delphi methodology. The steering committee included five dermatologists, three medical oncologists, two head and neck surgeons, one radiation oncologist, and a patient advocacy group representative. The steering committee aligned on the following clinical topics: diagnosis and identification of patients considered not candidates for surgery; staging systems and risk stratification in cutaneous squamous cell carcinoma; the role of radiation therapy, surgery, and systemic therapy in the management of advanced disease, with a focus on immunotherapy; referral patterns; survivorship care; and inclusion of the patient's perspective. Consensus was achieved on 34 recommendations addressing 12 key clinical questions. The Expert Cutaneous Squamous Cell Carcinoma Leadership steering committee's evidence-based consensus recommendations may provide healthcare professionals with practically oriented guidance to help optimize outcomes for patients with advanced cutaneous squamous cell carcinoma.

Immunotherapy and Systemic Treatment of Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinomas (cSCC) represent one of the most diagnosed non-melanoma skin cancers and its incidence is increasing globally. Whereas early stage and low risk cSCC is typically treated with surgery, and in some cases other localized therapeutic modalities, locally advanced or metastatic cSCC is a cause of significant morbidity and mortality that requires a different approach to therapy. Therapeutic attempts at treating advanced cSCC include a multi-disciplinary approach with considerations for surgery, radiation, and systemic therapies. In this review, we will discuss the various systemic therapies that have been trialed for advanced cSCC, beginning with the early cytotoxic and platinum-based agents as well as their corresponding limitations. We will then review the targeted approaches using EGFR inhibitors prior to discussing the more recent immunotherapeutics that have shown good tumor responses in this often-lethal disease.

Effects of Sonidegib Following Dose Reduction and Treatment Interruption in Patients with Advanced Basal Cell Carcinoma During 42-Month BOLT Trial.

INTRODUCTION: Sonidegib is a Hedgehog pathway inhibitor approved to treat locally advanced basal cell carcinoma and, depending on regulatory approval, metastatic basal cell carcinoma. Results from the BOLT study demonstrated robust efficacy and continued tolerability through 42 months. This analysis evaluated the impact of sonidegib dose reductions and interruptions in patients with advanced basal cell carcinoma through 42 months. METHODS: BOLT was a randomized, double-blind, multicenter, phase 2 study. Adults with no previous Hedgehog pathway inhibitor therapy were randomized 1:2 to sonidegib 200 or 800 mg once daily. Primary endpoint was objective response rate. Dose modifications were permitted in patients unable to tolerate the dosing schedule or if a treatment-related adverse event was suspected. RESULTS: The incidence of dose interruptions was similar between the 200- and 800-mg groups (68.4% vs 65.3%, respectively). Dose reductions occurred more frequently in patients receiving sonidegib 800 mg (36.7%) than 200 mg (16.5%). Overall response rate for all patients receiving sonidegib 200 mg daily was 48.1% and was similar to those of patients without dose reduction or interruption (48.5%) and patients with at least one dose reduction or interruption (46.2%). CONCLUSION: Dose reductions and interruptions were practical and did not impact the efficacy of sonidegib. In patients with advanced basal cell carcinoma who necessitate long-term treatment, dose interruptions may be beneficial for continued treatment and disease control. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01327053.