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.

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.

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.

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.

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.

Treatment of advanced cutaneous squamous cell carcinoma: a Mohs surgery and dermatologic oncology perspective.

Locally advanced or metastatic cutaneous squamous cell carcinoma no longer amenable to surgical resection or primary radiation therapy requires an alternative approach to treatment. Until 2018, management consisted of limited systemic chemotherapies, which carried marginal clinical benefit. The introduction of immunotherapy with anti-PD-1 antibodies resulted in alternative treatment options for advanced cutaneous squamous cell carcinoma with substantial antitumor activity, durable response and acceptable safety profile. The field of immunotherapeutics continues to expand with adjuvant, neoadjuvant and intralesional studies currently in progress. Herein, the authors discuss their approach for the treatment of advanced cutaneous squamous cell carcinoma from the perspective of a Mohs surgeon and a dermatologic oncologist.

Elective neck dissection versus observation in patients with head and neck cutaneous squamous cell carcinoma.

BACKGROUND: The survival benefit of elective neck dissection (END) for patients with cutaneous squamous cell carcinoma (cSCC) of the head and neck and no evidence of regional metastasis (cN0) has never been reported. The aim of this study was to determine the effect of END on patient survival. METHODS: The authors included patients with head and neck cSCC who had undergone primary surgery from 1995 to 2017. The primary end point was survival, and the secondary end points were the incidence of occult regional disease and regional disease control. To assess the impact of END on survival, the authors used multivariable Cox proportional hazards models with propensity score and matching techniques for internal validation. RESULTS: A total of 1111 patients presented with no evidence of nodal disease; 173 had END, and 938 were observed. Adjuvant radiotherapy to the neck was administered to 101 patients (9%). END resulted in a 5-year overall survival rate of 52%, whereas the rate was 63% in the observation group (P = .003 [log-rank]). The 5-year disease-free survival rate for patients undergoing END was similar to that for the observation group (73% vs 75%; P = .429). A multivariate regression model showed that the performance of END was not associated with improved rates of overall, disease-specific, or disease-free survival; similarly, among patients with advanced disease (T3-4), those who underwent END did not have improved survival rates. CONCLUSIONS: Among patients with cSCC of the head and neck, observation of the neck nodes resulted in noninferior survival rates in comparison with END at the time of primary surgery. Further studies are required to elucidate the role of END in patients with advanced disease.

Integrated analysis of a phase 2 study of cemiplimab in advanced cutaneous squamous cell carcinoma: extended follow-up of outcomes and quality of life analysis.

BACKGROUND: To provide pooled longer term data from three groups of a phase 2 study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC), and to determine duration of response (DOR) and impact on quality of life (QoL). METHODS: Patients received cemiplimab 3 mg/kg every 2 weeks (group 1, metastatic CSCC [mCSCC], n=59; group 2, locally advanced CSCC, n=78) or cemiplimab 350 mg every 3 weeks (group 3, mCSCC, n=56). Primary endpoint was objective response rate (ORR) per independent central review (ICR). QoL was repeatedly measured at day 1 of each treatment cycle (groups 1 and 2: 8 weeks; group 3: 9 weeks). RESULTS: Median duration of follow-up was 15.7 months. Overall, ORR per ICR was 46.1% (95% CI: 38.9% to 53.4%). Complete response (CR) rates were 20.3%, 12.8%, and 16.1% for groups 1, 2, and 3, respectively. Median time to CR was 11.2 months. Among patients with partial response or CR, the estimated proportion of patients with ongoing response at 12 months from the first objective response was 87.8% (95% CI: 78.5% to 93.3%), with median DOR not reached. Kaplan-Meier estimated probability of overall survival (OS) was 73.3% (95% CI: 66.1% to 79.2%) at 24 months, with median OS not reached. Global Health Status (GHS)/QoL improvements were observed as early as cycle 2 and were significantly improved and durable until last assessment. Kaplan-Meier estimate of median time to first clinically meaningful improvement for pain was 2.1 (95% CI: 2.0 to 3.7) months and was significantly improved in responders versus non-responders (p<0.0001). CONCLUSIONS: This is the largest (n=193) clinical dataset for a programmed cell death-1 inhibitor against advanced CSCC, confirming the sustained substantial clinical activity of cemiplimab in these patients, including new findings of improved CR rates over time, increasing DOR, and durable pain control and GHS/QoL improvement. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02760498), https://clinicaltrialsgov/ct2/show/NCT02760498.

Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial.

BACKGROUND: Before February, 2021, there was no standard treatment regimen for locally advanced basal cell carcinoma after first-line hedgehog inhibitor (HHI) therapy. Cemiplimab, a PD-1 antibody, is approved for treatment of advanced cutaneous squamous cell carcinoma and has shown clinical activity as monotherapy in first-line non-small-cell lung cancer. Here, we present the primary analysis data of cemiplimab in patients with locally advanced basal cell carcinoma after HHI therapy. METHODS: We did an open-label, multicentre, single-arm, phase 2 trial across 38 outpatient clinics, primarily at academic medical centres, in Canada, Europe, and the USA. Eligible patients (aged ≥18 years and with an Eastern Cooperative Oncology Group performance status of 0 or 1) with a histologically confirmed diagnosis of metastatic basal cell carcinoma (group 1) or locally advanced basal cell carcinoma (group 2) who had progressed on or were intolerant to previous HHI therapy were enrolled. Patients were not candidates for further HHI therapy due to progression of disease on or intolerance to previous HHI therapy or having no better than stable disease after 9 months on HHI therapy. Patients received cemiplimab 350 mg intravenously every 3 weeks for up to 93 weeks or until progression or unacceptable toxicity. The primary endpoint was objective response by independent central review. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. The primary analysis is reported only for group 2; group 1 data have not reached maturity and will be reported when the timepoint, according to the statistical analysis plan, has been reached. This study is registered with ClinicalTrials.gov, NCT03132636, and is no longer recruiting new participants. FINDINGS: Between Nov 16, 2017, and Jan 7, 2019, 84 patients were enrolled and treated with cemiplimab. At data cutoff on Feb 17, 2020, median duration of follow-up was 15 months (IQR 8-18). An objective response per independent central review was observed in 26 (31%; 95% CI 21-42) of 84 patients, including two partial responses that emerged at tumour assessments before the data cutoff and were confirmed by tumour assessments done subsequent to the data cutoff. The best overall response was five (6%) patients with a complete response and 21 (25%) with a partial response. Grade 3-4 treatment-emergent adverse events occurred in 40 (48%) of 84 patients; the most common were hypertension (four [5%] of 84 patients) and colitis (four [5%]). Serious treatment-emergent adverse events occurred in 29 (35%) of 84 patients. There were no treatment-related deaths. INTERPRETATION: Cemiplimab exhibited clinically meaningful antitumour activity and an acceptable safety profile in patients with locally advanced basal cell carcinoma after HHI therapy. FUNDING: Regeneron Pharmaceuticals and Sanofi.

Fixed Dose of Cemiplimab in Patients with Advanced Malignancies Based on Population Pharmacokinetic Analysis.

INTRODUCTION: This study outlined cemiplimab intravenous (IV) dosing strategy to move from body weight (BW)-based 3 mg/kg every-2-week (Q2W) dosing in first-in-human study (study 1423; NCT02383212) to fixed 350 mg every-3-week (Q3W) dosing, utilizing population pharmacokinetics (PopPK) modeling and simulations, and supported by a limited dataset from a phase 2 study (study 1540; NCT02760498). METHODS: Cemiplimab concentration data from a total of 505 patients were pooled from study 1423 in advanced malignancies and study 1540 in advanced cutaneous squamous cell carcinoma (CSCC). All patients received weight-based cemiplimab dose (1, 3, 10 mg/kg Q2W or 3 mg/kg Q3W) except 4% who received 200 mg Q2W. A linear two-compartment PopPK model incorporating covariates that improved goodness-of-fit statistics was developed to compare cemiplimab exposure at 350 mg Q3W versus 3 mg/kg Q2W. Upon availability, observed cemiplimab concentration at 350 mg Q3W in study 1540 was then compared with the simulated values. RESULTS: Post hoc estimates of cemiplimab exposure and variability (505 patients; weight range 30.9-156 kg; median 76.1 kg) at steady state were found to be similar at 350 mg Q3W and 3 mg/kg Q2W. Effect of BW on cemiplimab exposure was described by exposure versus BW plots and at extreme BW. Overlay of individual observed cemiplimab concentrations in 51 patients with metastatic CSCC on simulated concentration-time profiles in 2000 patients at 350 mg Q3W confirmed cemiplimab exposure similarity and demonstrated the robustness of dose optimization based on PopPK modeling and simulations. CONCLUSIONS: Cemiplimab 350 mg Q3W is being further investigated in multiple indications.