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Human papillomavirus (HPV) infections underlie a wide spectrum of both benign and malignant epithelial diseases. In this report, we describe the case of a young man who had encephalitis caused by herpes simplex virus during adolescence and currently presented with multiple recurrent skin and mucosal lesions caused by HPV. The patient was found to have a pathogenic germline mutation in the X-linked interleukin-2 receptor subunit gamma gene (IL2RG), which was somatically reverted in T cells but not in natural killer (NK) cells. Allogeneic hematopoietic-cell transplantation led to restoration of NK cytotoxicity, with normalization of the skin microbiome and persistent remission of all HPV-related diseases. NK cytotoxicity appears to play a role in containing HPV colonization and the ensuing HPV-related hyperplastic or dysplastic lesions. (Funded by the National Institutes of Health and the Herbert Irving Comprehensive Cancer Center Flow Cytometry Shared Resources.).

Background Response rates are primary endpoints in many oncology trials; however, correlation with overall survival (OS) is not uniform across cancer types, treatments, or lines of therapy. This study explored the association between objective response (OR) and OS in patients with chemotherapy-refractory metastatic Merkel cell carcinoma who received avelumab (anti-PD-L1). Methods Eighty-eight patients enrolled in JAVELIN Merkel 200 (part A; NCT02155647) received i.v. avelumab 10 mg/kg every 2 weeks until confirmed progression, unacceptable toxicity, or withdrawal. Using conditional landmark analyses, we compared OS in patients with and without confirmed OR (RECIST v1.1). We applied a Cox model that included OR as a time-varying covariate and adjusted for age, visceral disease, and number of previous therapies. Results Twenty-nine patients had confirmed OR; 20 by study week 7 and 7 more between study weeks 7 and 13. Survival probabilities 18 months after treatment initiation were 90% [95% confidence interval (CI) 65.6–97.4] in patients with OR at week 7 and 26.2% (95% CI 15.7–37.8) in patients without OR but who were alive at week 7. Median OS was not reached in patients with OR and was 8.8 months (95% CI 6.4–12.9) in patients without. Similar results were observed for the week 13 landmark. The adjusted Cox model showed OR was associated with a 95% risk reduction of death [hazard ratio 0.052 (95% CI 0.018–0.152)] compared with a nonresponse. Conclusions Patients with OR by 7 or 13 weeks had significantly longer OS than patients without, confirming that early OR is an endpoint of major importance.

Background Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer that has a poor prognosis in patients with advanced disease. Avelumab [anti-programmed death-ligand 1 (PD-L1)] became the first approved treatment for patients with metastatic MCC (mMCC), based on efficacy and safety data observed in the JAVELIN Merkel 200 trial. We report long-term overall survival (OS) data after >5 years of follow-up from the cohort of patients with mMCC whose disease had progressed after one or more prior lines of chemotherapy. Patients and methods In Part A of the single-arm, open-label, phase II JAVELIN Merkel 200 trial, patients with mMCC that had progressed following one or more prior lines of chemotherapy received avelumab 10 mg/kg by intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. In this analysis, long-term OS was analyzed. Results In total, 88 patients were treated with avelumab. At data cut-off (25 September 2020), median follow-up was 65.1 months (range 60.8-74.1 months). One patient (1.1%) remained on treatment, and an additional patient (1.1%) had reinitiated avelumab after previously discontinuing treatment. Median OS was 12.6 months [95% confidence interval (CI) 7.5-17.1 months], with a 5-year OS rate of 26% (95% CI 17% to 36%). In patients with PD-L1+ versus PD-L1− tumors, median OS was 12.9 months (95% CI 8.7-29.6 months) versus 7.3 months (95% CI 3.4-14.0 months), and the 5-year OS rate was 28% (95% CI 17% to 40%) versus 19% (95% CI 5% to 40%), respectively (HR 0.67; 95% CI 0.36-1.25). Conclusion Avelumab monotherapy resulted in meaningful long-term OS in patients with mMCC whose disease had progressed following chemotherapy. These results further support the role of avelumab as a standard of care for patients with mMCC., Highlights • Avelumab led to meaningful long-term OS in patients with previously treated mMCC. • After >5 years of follow-up, median OS was 12.6 months and the 5-year OS rate was 26%. • Longer OS was observed in patients with PD-L1+ versus PD-L1– tumors. • The survival benefit with avelumab greatly exceeds that seen in retrospective analyses of second-line or later chemotherapy. • These results further support the role of avelumab as a standard of care for patients with mMCC.

Inhibitors of the mitogen-activated protein kinase (MAPK) pathway are commonly used in clinical oncology. However, with the exception of BRAF inhibitors (BRAFi), MAPK pathway inhibitors such as epidermal growth factor receptor inhibitors (EGFRi) or MEK inhibitors (MEKi) are associated with dose-limiting papulopustular eruptions. Interestingly, patients treated with a combination of systemic BRAFi and MEKi experience less skin toxicities than patients on monotherapy BRAFi or MEKi. The reduction in cutaneous adverse events with combination therapy is thought to be due to a paradoxical activation of the MAPK pathway by BRAFi in keratinocytes carrying wildtype BRAF. Although treatment options for EGFRi- or MEKi-induced papulopustular eruptions exist, many patients still experience dose reduction, interruption, or discontinuation of EGFRi or MEKi. With the goal of activating MAPK signaling in the skin via BRAFi while minimizing systemic risks, we propose topical BRAFi therapy for the treatment and prevention of papulopustular eruptions due to MAPK pathway inhibitors. If effective, patients will be able to tolerate higher doses of MAPK pathway inhibitors, stay on treatment longer, and achieve better therapeutic outcomes overall.

This population-based cohort study examines associations of voriconazole and other antifungal medications with risk of keratinocyte carcinomas in recipients of lung transplants., Key Points Question What is the association between voriconazole, an antifungal used to treat aspergillosis infections, and the risk of keratinocyte carcinomas among recipients of lung transplants? Findings In a population-based cohort study of 9599 non-Hispanic white recipients of 9793 lung transplants in the United States (2007-2016) with linkage to pharmacy claims, increasing cumulative voriconazole exposure was associated with an increased risk of cutaneous squamous cell carcinoma. Meaning These findings suggest that physicians caring for lung transplant recipients at high risk for aggressive keratinocyte carcinomas should limit voriconazole exposure when possible and encourage skin protection behaviors and more frequent cancer screenings., Importance The antifungal medication voriconazole is used to prevent and treat aspergillosis, a major cause of mortality among recipients of lung transplants (hereinafter referred to as lung recipients). Small studies suggest that voriconazole increases risk of cutaneous squamous cell carcinoma (SCC). Objective To examine associations of voriconazole and other antifungal medications with risk of keratinocyte carcinomas (SCC and cutaneous basal cell carcinoma [BCC]) in lung recipients. Design, Setting, and Participants This population-based cohort study included non-Hispanic white patients (n = 9599) who underwent lung transplant in the United States from January 1, 2007, to December 31, 2016, identified through the national Scientific Registry of Transplant Recipients with data linkable to pharmacy claims. Data were analyzed from March 1, 2018, to February 13, 2019. Exposures Antifungal medication use, including voriconazole, itraconazole, posaconazole, and other antifungals, was ascertained from pharmacy claims and treated as a time-varying exposure (assessed every 30 days). Cumulative antifungal exposure was calculated as the total number of exposed months. Main Outcomes and Measures Primary outcomes were the first SCC or BCC reported to the transplant registry by transplant centers. Follow-up began at transplant and ended at SCC or BCC diagnosis, transplant failure or retransplant, death, loss to follow-up, or December 31, 2016. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (AHRs) for each antifungal medication. Results Among the 9793 lung transplants in 9599 recipients included in the analysis, median age at transplant was 59 (interquartile range [IQR], 48-65) years, 5824 (59.5%) were male, and 5721 (58.4%) reported ever smoking. During a median follow-up of 3.0 (IQR, 1.4-5.0) years after transplant, 1031 SCCs (incidence, 322 per 10 000 person-years) and 347 BCCs (incidence, 101 per 10 000 person-years) were reported. Compared with lung recipients with no observed voriconazole use, those with 1 to 3 months of voriconazole use experienced increased AHR for SCC of 1.09 (95% CI, 0.90-1.31); 4 to 7 months, 1.42 (95% CI, 1.16-1.73); 8 to 15 months, 2.04 (95% CI, 1.67-2.50); and more than 15 months, 3.05 (95% CI, 2.37-3.91). Ever itraconazole exposure was associated with increased SCC risk (AHR, 1.20; 95% CI, 1.00-1.45). For BCC, risk was not associated with voriconazole use but was increased with itraconazole use (AHR, 1.74; 95% CI, 1.27-2.37) or posaconazole use (AHR, 1.55; 95% CI, 1.00-2.41). Conclusions and Relevance In this study, voriconazole use was associated with increased SCC risk among lung recipients, especially after prolonged exposure. Further research evaluating the risk-benefit ratio of shorter courses or alternative medications in transplant recipients at high risk for SCC should be considered.

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer associated with advanced age and immunosuppression. Over the past decade, an association has been discovered between MCC and either integration of the Merkel cell polyomavirus, which likely drives tumorigenesis, or somatic mutations owing to ultraviolet-induced DNA damage. Both virus-positive and virus-negative MCCs are immunogenic, and inhibition of the programmed cell death protein 1 (PD-1)-programmed cell death 1 ligand 1 (PD-L1) immune checkpoint has proved to be highly effective in treating patients with metastatic MCC; however, not all patients have a durable response to immunotherapy. Despite these rapid advances in the understanding and management of patients with MCC, many basic, translational and clinical research questions remain unanswered. In March 2018, an International Workshop on Merkel Cell Carcinoma Research was held at the US National Cancer Institute, at which academic, government and industry experts met to identify the highest-priority research questions. Here, we review the biology and treatment of MCC and report the consensus-based recommendations agreed upon during the workshop.

To describe updates on the pathogenesis, diagnosis, and management of Merkel cell carcinoma (MCC). Sequencing studies revealed that MCCs have either a low mutational burden and integrated Merkel cell polyomavirus (MCPyV), or they have a high number of ultraviolet-associated somatic mutations and no MCPyV. Clinically, prognosis was better for stage III MCC of unknown primary than known primary. Similarly, lack of immunosuppression conferred better prognosis. The immunogenicity of MCC was reflected in high response rates to PD-1/PD-L1 checkpoint inhibitors. MCC is a rare but aggressive neuroendocrine skin cancer associated with advanced age and immunosuppression. Approximately 80% of MCCs are MCPyV driven, whereas MCPyV-negative tumors have mutations in genes such as p53 and RB1. MCC is highly immunogenic, and recently, the anti-PD-L1 antibody avelumab was approved to treat metastatic MCC. Here, we summarized features of the pathogenesis, diagnosis, and management of MCC.

Background Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer associated with poor survival outcomes in patients with distant metastatic disease (mMCC). In an initial analysis from JAVELIN Merkel 200, a phase 2, prospective, open-label, single-arm trial in mMCC, avelumab—a human anti–programmed death-ligand 1 (PD-L1) monoclonal antibody—showed promising efficacy and a safety profile that was generally manageable and tolerable. Here, we report the efficacy of avelumab after ≥1 year of follow-up in patients with distant mMCC that had progressed following prior chemotherapy for metastatic disease. Patients and methods Patients received avelumab 10 mg/kg by 1-h intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was best overall response. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results Patients (N = 88) were followed for a minimum of 12 months. The confirmed objective response rate was 33.0% (95% CI, 23.3%-43.8%; complete response: 11.4%). An estimated 74% of responses lasted ≥1 year, and 72.4% of responses were ongoing at data cutoff. Responses were durable, with the median DOR not yet reached (95% CI, 18.0 months-not estimable), and PFS was prolonged; 1-year PFS and OS rates were 30% (95% CI, 21%-41%) and 52% (95% CI, 41%-62%), respectively. Median OS was 12.9 months (95% CI, 7.5-not estimable). Subgroup analyses suggested a higher probability of response in patients receiving fewer prior lines of systemic therapy, with a lower baseline disease burden, and with PD-L1–positive tumors; however, durable responses occurred irrespective of baseline factors, including tumor Merkel cell polyomavirus status. Conclusions With longer follow-up, avelumab continues to show durable responses and promising survival outcomes in patients with distant mMCC whose disease had progressed after chemotherapy. Trial registration Clinicaltrials.gov identifier: NCT02155647.

The financial cost of cancer treatment in the United States is astronomically high and is expected to rise. The economic burden of cancer care increasingly falls on the patients. Patients thus experience “financial toxicity” of cancer care that can have catastrophic consequences on health and quality of life. Here we examine the results reported by Gilligan et al. in their study of financial toxicity in US cancer patients over 50 years old. This study provided corroborating and compelling data about the financial toxicity experienced by cancer patients. Many questions remain, however, about the consequences of financial toxicity and the full reality of cancer care economics in America.

Background Avelumab is an anti-programmed cell death ligand 1 (PD-L1) antibody approved for treatment of Merkel cell carcinoma (MCC) and locally advanced or metastatic urothelial carcinoma. It shares a similar side effect profile to other immune checkpoint inhibitors, including immune-related adverse reactions in the skin. These adverse skin reactions can present as a morbilliform exanthem, lichenoid dermatitis, vitiligo, autoimmune bullous disorder, among others. Case presentation We describe a patient with advanced MCC successfully treated with avelumab who developed acute onset diffuse lichen planus-like keratoses (LPLK) at sites of existing seborrheic keratoses (SK) and lentigines. Histopathology of an affected SK revealed papillomatous epidermal hyperplasia with lichenoid interface changes, numerous dyskeratotic keratinocytes and intermittent hypergranulosis. The findings resembled lichen planus (LP) arising in an SK. Onset of the skin symptoms corresponded with an inflammatory cancer response (clinical pseudo-progression), and the eruption improved as overall tumor burden decreased. The patient’s pruritus was treated with topical steroids and cyrotherapy for individual symptomatic lesions. Conclusion Diffuse LPLK is a distinct immune-related reaction pattern associated with PD-L1/PD-1 checkpoint blockade. This is an important side effect to be aware of as LPLK frequently mimic keratinocytic neoplasms. Further observation is needed to assess the prevalence and significance of this immune therapy-associated adverse reaction.

Among all tumor types, skin cancers are profoundly sensitive to immunotherapy. Indeed, the recently reported response rates for anti-PD-1 (anti-programmed-death 1) therapy for cutaneous malignant melanomas (MM), Merkel cell carcinomas, basal cell carcinomas, cutaneous squamous cell carcinomas and Kaposi sarcomas are all above 40%. This unique immunogenicity renders skin cancers as a paradigm for tumor–immune interactions and is driven by high mutational burdens, over-expressed tumor antigens and/or viral antigens. However, despite the clear demonstration of immunologic cure of skin cancer in some patients, most tumors develop either early (primary) or late (adaptive) resistance to immunotherapy. Resistance mechanisms are complex, and include contributions of tumor cell-intrinsic, T cell and microenvironment factors that have been recently further elucidated with the advent of single-cell technologies. This review will focus on the exciting progress with immunotherapy for skin cancers to date, and also our current understanding of the mechanisms of resistance to immunotherapy.

9517 Background: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Although MCC is considered chemosensitive, patients typically have limited survival benefit with chemotherapy. Before the approval of immune checkpoint inhibitors, patients with metastatic MCC (mMCC) had a poor prognosis, with a historical 5-year overall survival (OS) rate of approximately 14%. Avelumab (anti–PD-L1) became the first approved treatment for patients with mMCC, based on efficacy and safety data observed in the phase 2 JAVELIN Merkel 200 trial (NCT02155647), in which patients with mMCC received avelumab monotherapy. We report the long-term OS data from the cohort of patients with mMCC whose disease had progressed after ≥1 prior line of chemotherapy. Methods: Eligible patients had histologically confirmed, measurable (per RECIST 1.1) stage IV MCC. Patients received avelumab 10 mg/kg by intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. Long-term OS was analyzed; updated data for other efficacy endpoints, including response and progression-free survival, were not obtained. Results: A total of 88 patients were enrolled and received avelumab treatment. As of September 25, 2020 (data cutoff), median follow-up was 65.1 months (range, 60.8-74.1 months). Median OS was 12.6 months (95% CI, 7.5-17.1 months); the 48- and 60-month OS rates were 30% (95% CI, 20%-40%) and 26% (95% CI, 17%-36%), respectively. At data cutoff, treatment was ongoing in 1 patient (1.1%) and an additional patient (1.1%) had reinitiated avelumab after previously discontinuing treatment. Reasons for treatment discontinuation were disease progression (n = 45 [51.1%]), adverse event (AE; n = 11 [12.5%]), death (n = 10 [11.4%]), withdrawal of consent (n = 9 [10.2%]), loss to follow-up (n = 1 [1.1%]), protocol noncompliance (n = 1 [1.1%]), and other reason (n = 10 [11.4%]). At data cutoff, 19 patients (21.6%) had discontinued treatment but remained in follow-up, and 63 patients (71.6%) had died; causes of death were disease progression (n = 49 [55.7%]), unknown reason (n = 9 [10.2%]), AE not related to study treatment (n = 3 [3.4%]), and other reason (n = 2 [2.3%]). In total, 26 patients (29.5%) received subsequent anticancer therapy; the most common subsequent therapies after trial discontinuation were avelumab (n = 4 [4.5%]), carboplatin and etoposide (n = 4 [4.5%]), and pembrolizumab (n = 4 [4.5%]). Conclusions: Avelumab monotherapy led to meaningful long-term OS in a subset of patients with mMCC whose disease had progressed after chemotherapy. These results further support the role of avelumab as a standard-of-care treatment for patients with mMCC. Clinical trial information: NCT02155647.

Summary Background Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy. Methods In this multicentre, international, prospective, single-group, open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma (aged ≥18 years) were enrolled from 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, haematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary endpoint was confirmed objective response (complete response or partial response) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug (the modified intention-to-treat population). This trial is registered with ClinicalTrials.gov as NCT02155647. Findings Between July 25, 2014, and Sept 3, 2015, 88 patients were enrolled and received at least one dose of avelumab. Patients were followed up for a median of 10·4 months (IQR 8·6–13·1). The proportion of patients who achieved an objective response was 28 (31·8% [95·9% CI 21·9–43·1]) of 88 patients, including eight complete responses and 20 partial responses. Responses were ongoing in 23 (82%) of 28 patients at the time of analysis. Five grade 3 treatment-related adverse events occurred in four (5%) patients: lymphopenia in two patients, blood creatine phosphokinase increase in one patient, aminotransferase increase in one patient, and blood cholesterol increase in one patient; there were no treatment-related grade 4 adverse events or treatment-related deaths. Serious treatment-related adverse events were reported in five patients (6%): enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis (n=1 each). Interpretation Avelumab was associated with durable responses, most of which are still ongoing, and was well tolerated; hence, avelumab represents a new therapeutic option for advanced Merkel cell carcinoma. Funding Merck KGaA, Darmstadt, Germany.

Merkel cell carcinoma is a rare skin cancer associated with Merkel cell polyomavirus in most cases. Prior studies associating Merkel cell carcinoma viral status with prognosis have inconsistent findings. Moshiri et al. used multimodal virus detection to determine that the 81% of patients with virus-positive Merkel cell carcinoma tumors had earlier stage disease and better outcomes relative to virus-negative cases.

Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine skin cancer that is highly immunogenic. Approximately 80% of MCC tumors are virus positive (VP-MCC) and express Merkel cell polyomavirus (MCPyV) T antigens that drive oncogenesis. As VP-MCC have a low mutation burden with few predicted neoantigens, viral oncogenes are thought to be primary targets for anti-cancer immunity. Immune checkpoint inhibitors improve MCC survival, yet not all patients have durable responses. VP-MCC patients who fail checkpoint inhibition or who have immune dysfunction may benefit from adoptive cellular therapy using virus-specific T cells from HLA-matched donors. As the risk of graft versus host disease is low with virus-specific T cells, this approach is being investigated for other viral diseases. We set out to generate MCPyV-specific T cells from healthy donors for potential adoptive immunotherapy. Naïve and memory T cells from donors were magnetically isolated prior to stimulation with autologous monocyte-derived dendritic cells pulsed with 15-mer overlapping peptide libraries of MCPyV T antigens. T cells were serially re-stimulated with peptide-pulsed irradiated, autologous PHA-blasts up to five times. Cultures were maintained in either standard growth cytokines (IL-2, IL-7, and IL-15) or a pro-inflammatory cytokine cocktail. T cell phenotype and reactivity were evaluated by flow cytometry. We found that standard cytokine conditions were unable to promote growth of MCPyV-specific mature T cells. Altering growth conditions to include a cocktail of pro-inflammatory cytokines promoted expansion of polyfunctional Th1 CD4+ T cells specific for MCPyV T antigen peptides. These cells produced TNFα and upregulated the activation markers CD154 and CD137 upon cognate antigen exposure. Cells were generated without bias for particular HLAs. These results suggest that peptide-based expansions may be a suitable platform to generate allogeneic adoptive T cell immunotherapies for patients with VP-MCC. Citation Format: Sarah Davies, John Barrett, Pawel J. Muranski, Isaac Brownell. Generating Merkel cell polyomavirus-specific T cells from healthy donors for adoptive immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2189.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with limited treatment options. Currently two immunotherapies are approved for the treatment of MCC, the PD-L1 inhibitor avelumab and the PD-1 inhibitor pembrolizumab. Unfortunately, these treatments only have durable benefit for less than half of patients that can be treated with immunotherapy. Therefore, new and effective treatments are needed for MCC. To address this, we conducted a high-throughput drug screening of ~4,000 small molecules. Our drug screen identified disulfiram (DSF), an aldehyde dehydrogenase inhibitor used in the treatment of alcoholism, as an agent that selectively reduced MCC cell viability. Recent studies suggest that DSF complexed with copper can have anti-cancer effects. Consistent with this, the addition copper at physiological levels increased the potency of DSF in MCC cells lines. Next, we demonstrated that disulfiram combined with copper synergized with the topoisomerase II inhibitor etoposide, lowering the effective dose of etoposide required to reduce MCC cell viability. Mechanistically, combining DSF, copper and etoposide was cytotoxic but did not induce apoptosis in MCC cell lines. This combination increased the formation of double stranded DNA breaks while disulfiram plus copper induced autophagy, which could mechanistically be an indication of immunogenic cell death signaling. Taken together, our data suggest that disulfiram combined with copper and etoposide could be repurposed for the effective treatment of advanced MCC. One strong advantage of this combination is that all agents can be given orally and at dosages with minimal adverse effects. Citation Format: Natasha Tremayne Hill, Tara Gelb, Dan Urban, Tyler Kellenberger, Matthew Hall, Isaac Brownell. Disulfiram plus copper synergizes with etoposide for the treatment of Merkel cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 575.

BackgroundMerkel cell carcinoma (MCC) is a rare, aggressive skin cancer associated with a high risk of metastasis. In 2017, avelumab (anti–programmed death-ligand 1 (PD-L1)) became the first approved treatment for patients with metastatic MCC (mMCC), based on the occurrence of durable responses in a subset of patients. Here, we report long-term efficacy and safety data and exploratory biomarker analyses in patients with mMCC treated with avelumab.MethodsIn a cohort of this single-arm, phase 2 trial (JAVELIN Merkel 200), patients with mMCC and disease progression after prior chemotherapy received avelumab 10 mg/kg intravenously every 2 weeks. The primary endpoint was confirmed objective response rate (ORR) by independent review per Response Evaluation Criteria in Solid Tumors V.1.1. Other assessments included duration of response, progression-free survival, overall survival (OS), safety and biomarker analyses.ResultsAs of 14 September 2018, 88 patients had been followed up for a median of 40.8 months (range 36.4–49.7 months). The ORR was 33.0% (95% CI 23.3% to 43.8%), including a complete response in 11.4% (10 patients), and the median duration of response was 40.5 months (95% CI 18.0 months to not estimable). As of 2 May 2019 (≥44 months of follow-up), the median OS was 12.6 months (95% CI 7.5 to 17.1 months) and the 42-month OS rate was 31% (95% CI 22% to 41%). Of long-term survivors (OS >36 months) evaluable for PD-L1 expression status (n=22), 81.8% had PD-L1+ tumors. In exploratory biomarker analyses, high tumor mutational burden (≥2 non-synonymous somatic variants per megabase) and high major histocompatibility complex class I expression (30% of tumors with highest expression) were associated with trends for improved ORR and OS. In long-term safety assessments (≥36 months of follow-up), no new or unexpected adverse events were reported, and no treatment-related deaths occurred.ConclusionsAvelumab showed continued durable responses and meaningful long-term survival outcomes in patients with mMCC, reinforcing avelumab as a standard-of-care treatment option for this disease.Trial registration numberNCT02155647

Background The prognosis and treatment options for metastatic Merkel cell carcinoma (MCC) are poor. The immune-privileged status of cancer-testis (CT) antigens imparts tumor specificity, making them ideal candidates for targeted immunotherapy. We investigate the usefulness of the CT antigens SPA17 (sperm protein-17 [SP-17]), IGF2BP3 (insulin-like growth factor-II mRNA-binding protein 3 [IMP-3]), and transmembrane protein with epidermal growth factor (EGF)-like and two follistatin-like domains 1 (TMEFF1) as potential MCC biomarkers and evaluate their possible utility in immunotherapy and molecularly targeted image-guided treatment. Methods The CT antigens SP-17, IMP-3, and TMEFF1 were selected using transcriptome profiling to identify CT antigens expressed in MCC tumors. Antibodies directed against these CT antigens were stained. Twelve normal skin tissue samples were used as a control. The average percentage of positive cells in each tumor was computed. Results Twelve of 14 (86%) MCC cases showed crisp nuclear staining for SP-17, with 2.06% of cells staining positive. IMP-3 showed crisp, perinuclear staining in all 14 MCC cases, with 52.93% MCC cells staining positive. TMEFF1 showed perinuclear staining in all 14 MCC cases, with 96.51% of tumor cells staining positive. Conclusions CT antigens were found to be expressed in both MCC and some control tissues. SP-17 was the most specific yet the least sensitive. IMP-3 and TMEFF1 were both sensitive but not specific. CT antigens may represent valuable treatment targets in MCC.

GATA2 deficiency is a recently described genetic disorder affecting hematopoietic stem cells and is associated with immunodeficiency, hematologic malignancy, and various cutaneous pathologies including cutaneous tumors. To explore the incidence and clinical course of melanoma in patients with germline GATA2 deficiencies, we conducted a retrospective chart review of 71 such patients and identified two with invasive melanoma. One melanoma was diagnosed early because it was associated with pruritus due to a graft-versus-tumor effect following bone marrow transplantation. The other one, a lentigo maligna melanoma, was locally excised but progressed to widespread metastasis and death several years later. Our observations and published studies of melanoma biology suggest an association between decreased GATA2 expression and melanoma progression. These findings suggest that GATA2 deficient patients may have an increased risk of melanoma and should be observed closely for new or changing skin lesions.

// Maria Rita Gaiser 1 , Kenneth Daily 2 , Jochen Hoffmann 1 , Maik Brune 3 , Alexander Enk 1 , Isaac Brownell 2 1 Department of Dermatology, University of Heidelberg, Heidelberg, Germany 2 Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 3 Department of Internal Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany Correspondence to: Maria Rita Gaiser, e-mail: maria-gaiser@gmx.de Keywords: Merkel cell carcinoma, neuron specific enolase, chromogranin A, circulating tumor cells, EpCAM Received: May 13, 2015 Accepted: June 18, 2015 Published: July 02, 2015 ABSTRACT Background: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer. Although used to monitor MCC patients, the clinical utility of neuron-specific enolase (NSE) and chromogranin A (ChrA) blood levels is untested. EpCAM-positive circulating tumor cells (CTC) reflect disease status in several epithelial tumors. Here we investigate the use of NSE and ChrA blood levels and CTC counts as biomarkers for MCC disease behavior. Methods: NSE and ChrA blood levels from 60 patients with MCC were retrospectively analyzed; 30 patients were additionally screened for CTC. Biomarker values were correlated to clinical parameters. Results: Despite routine use by some physicians, NSE and ChrA blood levels did not correlate with progression free survival, disease specific survival, or MCC recurrence. We found CTC in 97% of tested MCC patients. CTC counts were elevated in patients with active disease, suggesting their potential use in monitoring MCC. Conclusion: NSE and ChrA levels were not effective in predicting outcomes or detecting recurrences of MCC. In contrast, CTC counts have potential utility as a biomarker for MCC disease behavior.

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer. Until recently, no durable treatment options were available for patients with advanced disease. As an immunogenic cancer, MCC was hypothesized to be a candidate for PD-L1/PD-1 targeted therapy. On March 23, 2017 the US Food and Drug Administration granted accelerated approval for avelumab, an anti-PD-L1 monoclonal antibody, for the treatment of metastatic MCC on the basis of the JAVELIN Merkel 200 trial. Here we examine the results and implications of this pivotal study, published in Lancet Oncology by Kaufman et al., as well as current developments in the use of immune-checkpoint therapies for treating patients with MCC.

Context: Immune checkpoint inhibitors, including anti–programmed cell death protein 1 (PD-1), anti–programmed cell death protein ligand 1 (PD-L1), and anti–cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) monoclonal antibodies, have been widely used in cancer treatment. They are known to cause immune-related adverse events (irAEs), which resemble autoimmune diseases. Anterior pituitary hypophysitis with secondary hypopituitarism is a frequently reported irAE, especially in patients receiving anti–CTLA4 treatment. In contrast, posterior pituitary involvement, such as central diabetes insipidus (DI), is relatively rare and is unreported in patients undergoing PD-1/PD-L1 blockade. Case Description: We describe a case of a 73-year-old man with Merkel cell carcinoma who received the anti–PD-L1 monoclonal antibody avelumab and achieved partial response. The patient developed nocturia, polydipsia, and polyuria 3 months after starting avelumab. Further laboratory testing revealed central DI. Avelumab was held and he received desmopressin for the management of central DI. Within 6 weeks after discontinuation of avelumab, the patient’s symptoms resolved and he was eventually taken off desmopressin. The patient remained off avelumab and there were no signs or symptoms of DI 2 months after the discontinuation of desmopressin. Conclusion: To our knowledge, this is the first report of central DI associated with anti–PD-L1 immunotherapy. The patient’s endocrinopathy was successfully managed by holding treatment with the immune checkpoint inhibitor. This case highlights the importance of early screening and appropriate management of hormonal irAEs in subjects undergoing treatment with immune checkpoint inhibitors to minimize morbidity and mortality., We report a case of central diabetes insipidus induced by the anti–PD-L1 drug avelumab. The patient was successfully managed by holding the immune checkpoint inhibitor.

Key teaching points •We report a case of a 6-year-old African American boy with X-linked CGD who developed DLE–like skin lesions after starting voriconazole. •Voriconazole is commonly used to treat fungal infections in patients with CGD. •Lupus erythematosus–like skin lesions have been reported in carriers of X-linked CGD and, less commonly, in patients with CGD. •Voriconazole is a significant cause of drug-induced photosensitivity, and may play a role in unmasking an underlying predisposition to lupuslike skin lesions. •Photoprotective measures and routine examinations to monitor for skin toxicity, including skin cancer, are prudent during voriconazole treatment.

Background Idiopathic CD4 Lymphocytopenia (ICL) is a rare immunodeficiency characterized by an absolute CD4+ T count of < 300 cells/µL, in absence of HIV-infection or any other known cause. Patients with ICL have an increased risk of opportunistic infections. The prevalence, natural history, and spectrum of Human Papillomaviruses (HPV) associated diseases in ICL patients are unknown. Methods ICL patients were enrolled in a prospective observational study (N = 90). Demographic, clinical, and immunologic data were analyzed by nonparametric Methods. Immunophenotyping was performed by flow cytometry. Results The median age of ICL patients was 48 years, 47% were women, and 92% were Caucasian. Sixty-five percent of patients had at least one opportunistic infection, with HPV being the most prevalent (34.4%), followed by cryptococcal disease (22%), shingles (15.5%), molluscum contagiosum (8.8%), Histoplasma capsulatum (4.4%), Mycobacterium avium complex (4.4%), and progressive multifocal encephalopathy (2.2%). HPV-related diseases were identified in 18 women and 13 men. ICL patients with HPV disease were younger compared with those without (median age 34 vs. 53.5 years, P < 0.0001). Nine (29%) had anogenital, 9 (29%) had a cutaneous disease (verruca plana, verrucous carcinoma, squamous cell carcinoma) while 13 (42%) had both anogenital and cutaneous disease. Patients with HPV-related disease were also more likely to have history of cryptococcal disease, shingles or molluscum (P = 0.036, P = 0.22 and 0.11, respectively). Thirteen patients had HPV-associated cancers: 7 both mucosal and skin and 3 either skin or mucosal malignancies. Patients with HPV-disease had lower CD4+ T cells (median CD4 70 vs. 114 cells/µL, P = 0.036). No differences were observed in the numbers of CD8+ T cells, B cells, NK cells, and levels of IgG between patients with and without HPV disease. Conclusion HPV-related disease represents the most common opportunistic infection in ICL patients. Patients with ICL and HPV disease are younger, have lower CD4s and high prevalence of HPV-associated malignancies. Therefore, for patients presenting early in life with severe HPV disease further immunological workup should be considered and for patients with ICL excessive screening for HPV-related malignancies should be a priority. Disclosures All Authors: No reported Disclosures.

Background Levamisole is present as a contaminant or additive in most cocaine sold in the United States. Cases of agranulocytosis attributed to levamisole-tainted cocaine have been widely described. A vasculopathic reaction to levamisole has also been reported; however, diagnostic features such as antineutrophil cytoplasmic antibody (ANCA) and additional autoimmune marker positivity are not well recognized. As such, many patients are given a misdiagnosis, prompting aggressive and often unnecessary treatment. Objective We hope to educate practitioners about the clinical and laboratory features of levamisole-induced vasculopathy to ensure accurate diagnosis and management. Methods This was a case series. Results Six patients were admitted with purpuric lesions and vasculitic changes on biopsy specimen; 5 of them were given the diagnosis of and treated for autoimmune conditions before their true diagnosis was revealed. All patients had ANCA positivity, and 4 had additional abnormalities in autoimmune markers. All patients reported recent cocaine abuse, and were ultimately given the diagnosis of levamisole-induced vasculopathy. Limitations This observational study is limited by sample size. Conclusions Patients presenting with purpuric lesions with ANCA positivity should be assessed for cocaine exposure. It is important to recognize that levamisole may not only induce ANCA positivity but also other autoimmune marker abnormalities. Patients can often be treated with less aggressive therapeutic strategies than what is used for primary ANCA-associated vasculitides.

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Early-stage disease can be cured with surgical resection and radiotherapy (RT). Sentinel lymph node biopsy (SLNB) is an important staging tool, as a microscopic MCC is frequently identified. Adjuvant RT to the primary excision site and regional lymph node bed may improve locoregional control. However, newer studies confirm that patients with biopsy-negative sentinel lymph nodes may not benefit from regional RT. Advanced MCC currently lacks a highly effective treatment as responses to chemotherapy are not durable. Recent work suggests that immunotherapy targeting the programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint holds great promise in treating advanced MCC and may provide durable responses in a portion of patients. At the same time, high-throughput sequencing studies have demonstrated significant differences in the mutational profiles of tumors with and without the Merkel cell polyomavirus (MCV). An important secondary endpoint in the ongoing immunotherapy trials for MCC will be determining if there is a response difference between the virus-positive MCC tumors that typically lack a large mutational burden and the virus-negative tumors that have a large number of somatic mutations and predicted tumor neoantigens. Interestingly, sequencing studies have failed to identify a highly recurrent activated driver pathway in the majority of MCC tumors. This may explain why targeted therapies can demonstrate exceptional responses in case reports but fail when treating all comers with MCC. Ultimately, a precision medicine approach may be more appropriate for treating MCC, where identified driver mutations are used to direct targeted therapies. At a minimum, stratifying patients in future clinical trials based on tumor viral status should be considered as virus-negative tumors are more likely to harbor activating driver mutations.

Cutaneous somatosensory nerves function to detect diverse stimuli that act upon the skin. In addition to their established sensory roles, recent studies have suggested that nerves may also modulate skin disorders including atopic dermatitis, psoriasis and cancer. Here, we describe protocols for testing the requirement for nerves in maintaining a cutaneous mechanosensory organ, the touch dome (TD). Specifically, we discuss methods for genetically labeling, harvesting and visualizing TDs by whole-mount staining, and for performing unilateral surgical denervation on mouse dorsal back skin. Together, these approaches can be used to directly compare TD morphology and gene expression in denervated as well as sham-operated skin from the same animal. These methods can also be readily adapted to examine the requirement for nerves in mouse models of skin pathology. Finally, the ability to repeatedly sample the skin provides an opportunity to monitor disease progression at different stages and times after initiation.

9507Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with poor prognosis. Studies of second-line chemotherapy for metastatic MCC (mMCC) have reported median progression-fre...

TPS9605Background: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. MCC with clinically detected lymph node (LN) metastases is associated with high risk of systemic recurrence desp...

192 Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer. Avelumab, a human anti–PD-L1 monoclonal antibody, is FDA and EMA approved for the treatment of metastatic MCC (mMCC). Here, we report efficacy and safety data for avelumab in patients (pts) with mMCC at ≥18-mo of follow-up. Methods: Pts with mMCC and progression on prior chemotherapy received avelumab 10 mg/kg IV Q2W. Objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS) were evaluated by independent review committee (RECIST v1.1) with tumor assessment every 6 wks; overall survival (OS) and adverse events (AEs; NCI CTCAE v4.0) were also evaluated. Results: As of Mar 24, 2017, 88 pts were treated and followed for a median of 23.0 mo (range 18.7–32.0). Median treatment duration was 17 wks (range 2–132; mean 35 wks ±37). Treatment was ongoing in 15 pts (17%); 7 pts (8%) voluntarily discontinued with continuing responses (5 complete responses [CR] and 2 partial responses). Other reasons for discontinuation were disease progression (n = 42; 48%), death (n = 10; 11%), AE (n = 8; 9%), or consent withdrawal/other (n = 6; 7%). Confirmed ORR of 33% (95% CI 23.3–43.8; CR in 11.4%) remained unchanged from previous analysis and median DOR has not been reached (range 2.8–24.9 mo; 95% CI 18.0–not estimable). Responses were ongoing in 20/29 pts (69%), including 5 pts with > 2 y of follow-up. PFS curve showed a plateau with identical 12- and 18-mo rates of 29% (95% CI 19–39). Median OS was 12.6 mo (95% CI 7.5-19.0) and the 12- and 18-mo OS rates were 51% (95% CI 40–61) and 40% (95% CI 29–50), respectively. 66 pts (75%) had a treatment-related (TR)AE, most commonly ( > 10%) fatigue (25%), infusion-related reaction (15%; all grade 1/2), nausea (11%), and diarrhea (11%); 8 (9%) had a grade ≥3 TRAE. 17 pts (19%) had an immune-related AE, which was grade ≥3 in 4 pts (4.5%). No treatment-related deaths occurred. Conclusions: Updated results demonstrate continued durable antitumor activity of avelumab in pts with mMCC, beyond that expected with cytotoxic chemotherapy. The median OS exceeding 1 y and manageable safety profile of avelumab signify a clinically meaningful benefit in pts with mMCC. Clinical trial information: NCT02155647.

Colchicine is a treatment for gout that has been used for more than a millennium. It is the treatment of choice for familial Mediterranean fever and its associated complication, amyloidosis. The 2009 U.S. Food and Drug Administration approval of colchicine as a new drug had research consequences. Recent investigations with large cohorts of patients with gout who have been taking colchicine for years have demonstrated novel applications within oncology, immunology, cardiology and dermatology. Some emerging dermatological uses include the treatment of epidermolysis bullosa acquisita, leucocytoclastic vasculitis, aphthous stomatitis and others. In this work we relate the history and the new horizon of this ancient medicine.

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer with limited treatment options. Approximately 80% of MCC tumors have Merkel cell polyomavirus (MCPyV) DNA integrated into the host genome, and viral oncogenes are thought to drive carcinogenesis. In contrast, MCPyV-negative (MCPyV-) tumors have higher rates of proto-oncogene mutations. Transcriptome differences between MCPyV+ and MCPyV- tumors further suggests divergent underlying pathologies. In order to develop efficacious treatments for MCC and elucidate the pathophysiologies underlying MCPyV+ and MCPyV- MCC, we screened the effects of mechanistically annotated drug libraries on MCC cell viability (CellTiter-Glo). We screened ~4,500 compounds including the NCGC Pharmaceutical Collection of approved and investigational drugs and the oncology-focused MIPE (Mechanism Interrogation PlatE) library against six MCC cell lines (3 MCPyV+ and 3 MCPyV-). We ran follow-up screens on the above cell lines as well as non-MCC control cells to identify agents that specifically reduced viability in MCC. DNA topoisomerase inhibitors, proteasome inhibitors, and PI3K inhibitors potently and efficaciously reduced viability in all MCC cell lines tested. Moreover, using hierarchical clustering we found that viral status impacted pharmacological responses. For example, a subset of HDAC inhibitors were more potent in MCPyV+ than MCPyV- MCC cells. In contrast, a dual RasGAP/ERK inhibitor more potently reduced viability in MCPyV- MCC cells relative to MCPyV+ MCC cells. Together these results identify existing drugs that can be repurposed for treating MCC. Moreover, they help elucidate the distinct pathophysiology driving MCPyV+ and MCPyV- MCC. Citation Format: Tara Gelb, Daniel Urban, Kenneth Daily, Ying Xiao, Min Shen, Matthew Hall, Isaac Brownell. Identification of new treatment options for Merkel cell carcinoma using high throughput chemical screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5116. doi:10.1158/1538-7445.AM2017-5116

Background: Merkel cell carcinoma (MCC), a rare, aggressive skin cancer, is a chemosensitive disease, but responses are seldom durable. Avelumab is a fully human anti-PD-L1 monoclonal antibody. In a phase 2 trial of avelumab in patients with previously treated metastatic MCC (mMCC), the objective response rate (ORR) after ≥6 months of follow-up was 31.8%, including complete response (CR) in 9.1%, the estimated proportion with duration of response (DOR) ≥6 months was 92%, and the 6-month progression-free survival (PFS) rate was 40% (95% CI 29-50) (Kaufman et al., Lancet Oncol 2016). Here we present updated efficacy data with ≥1 year of follow-up in all patients. Methods: Patients with distant mMCC and prior progression on chemotherapy received avelumab 10 mg/kg IV Q2W until confirmed progression, unacceptable toxicity, or withdrawal. Tumors were assessed every 6 weeks (RECIST v1.1 by independent review). ORR, DOR, PFS, and overall survival (OS) were evaluated. Time-to-event endpoints were analyzed using Kaplan-Meier methodology. Safety data were not analyzed for this update. Results: Patients with mMCC (N=88) were treated with avelumab. Median age was 72.5 years (range 33-88), and 53% had visceral disease. As of Sep 3, 2016, median follow-up was 16.4 months (range 12.0-25.3), and treatment was ongoing in 22% (n=19); main reasons for discontinuations were disease progression (n=44; 50%), death (n=7; 8%), adverse event (n=7; 8%), or withdrawal (n=4; 5%). ORR was 33.0% (95% CI 23.3-43.8) with 10 (11.4%) CRs and 19 (21.6%) partial responses, including 1 new CR and 1 patient improving from PR to CR since the 6-month analysis. The 6-month durable response rate was 30.6% (95% CI 20.9-40.3). Median DOR has not been reached (range 2.8-23.3+ months; 95% CI 18.0-not estimable), and responses were ongoing in 21/29 patients (72.4%) at the time of analysis. The estimated proportion of responders with ≥1-year duration of response was 74% (95% CI 53-87). Estimated 1-year PFS rate was 30% (95% CI 21-41) and 1-year OS rate was 52% (95% CI 41-62). Median OS was 12.9 months (95% CI 7.5-not estimable). Conclusion: In longer-term follow-up from this study of avelumab in patients with distant metastatic MCC progressed after chemotherapy, the majority of responses were durable beyond 1 year and 2 new CRs were reported. Maturing PFS and OS data suggest long-term benefit in a proportion of patients. Clinical trial information: NCT02155647. Citation Format: Howard L. Kaufman, Jeffery S. Russell, Omid Hamid, Shailender Bhatia, Patrick Terheyden, Sandra P. D’Angelo, Kent C. Shih, Celeste Lebbé, Michele Milella, Isaac Brownell, Karl D. Lewis, Jochen H. Lorch, Anja von Heydebreck, Lisa Mahnke, Paul Nghiem. Durable responses to avelumab (anti-PD-L1) in patients with Merkel cell carcinoma progressed after chemotherapy: 1-year efficacy update [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT079. doi:10.1158/1538-7445.AM2017-CT079

9530 Background: MCC is a rare, aggressive skin cancer. Avelumab is a fully human anti–PD-L1 antibody. In a phase 2 study in pts with distant mMCC who progressed after prior chemotherapy (JAVELIN Merkel 200; NCT02155647), avelumab showed a manageable safety profile and durable responses, including an objective response rate (ORR) of 31.8%, estimated 6-month durable response rate of 29%, and 6-month overall survival rate of 69%. Here, we report preliminary results from a separate cohort of pts with chemotherapy-naïve mMCC enrolled in the same study. Methods: Eligible pts with mMCC and no prior systemic treatment for metastatic disease received avelumab 10 mg/kg Q2W until confirmed progression, unacceptable toxicity, or withdrawal. Tumors were assessed every 6 weeks (RECIST v1.1). Adverse events (AEs) were assessed by NCI CTCAE v4.0. Results: As of Dec 30, 2016, 29/112 planned pts had been enrolled. Median age was 75.0 years (range 47–87). Median treatment duration was 8.1 weeks (range 2.0–37.9). Of 16 pts with ≥3 months of follow-up, unconfirmed ORR was 68.8% (95% CI 41.3–89.0) with CR in 18.8%; confirmed ORR was 56.3% (95% CI 29.9–80.2; 1 unconfirmed PR with discontinuation). Of 25 pts with ≥6 weeks of follow-up, unconfirmed ORR was 64.0% (95% CI 42.5–82.0). All responses were ongoing at last follow-up, including in 5/5 pts with ≥6 months of follow-up (potential to confirm responses). 20/29 pts (69.0%) had a treatment-related AE (TRAE), including grade 3–4 TRAE in 5 pts (17.2%). TRAEs led to discontinuation in 5 pts (17.2%): 2 pts with infusion-related reaction, and 1 pt each with elevated AST and ALT, cholangitis, and paraneoplastic syndrome. There were no treatment-related deaths. 21/29 pts (72.4%) remain on treatment. Conclusions: In initial results from a cohort of chemotherapy-naïve pts with mMCC, avelumab was associated with early responses and a manageable safety profile, consistent with findings for second-line or later avelumab treatment in a previous cohort. These results suggest that responses mature to become durable and the use of 1L avelumab may increase the probability of response vs later-line treatment. Enrollment and follow-up in this 1L cohort are ongoing. Clinical trial information: NCT02155647.

80 Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer. In a phase 2 trial in previously treated metastatic MCC (mMCC; JAVELIN Merkel 200, NCT02155647), avelumab, a fully human IgG1 anti–PD-L1 antibody, showed durable responses and a manageable safety profile, including confirmed objective response rate (ORR) of 31.8% (95.9% CI 21.9-43.1), 6-mo duration of response (DOR) rate estimate of 92%, and 6-mo progression-free survival (PFS) rate of 40% (95% CI 29-50). We report post-hoc subgroup analyses from this trial. Methods: Pts with mMCC and prior disease progression on chemotherapy received avelumab 10 mg/kg (1h IV) Q2W. Tumors were assessed every 6 wks (RECIST v1.1) by independent review. Kaplan-Meier method was used to estimate 6-mo DOR and PFS rate. Results: 88 pts were treated with avelumab and followed for ≥ 6 mos (data cutoff Mar 3, 2016). Responses occurred in all subgroups analyzed (Table). Trends of higher ORR and 6-mo PFS rates were seen in pts with fewer prior lines, lower disease burden (sum of target lesion diameters), or PD-L1+ tumors. 6-mo response durability was similar across evaluable subgroups. Conclusions: In post-hoc analyses, avelumab showed durable efficacy across subgroups. This trial is enrolling treatment-naive pts with mMCC to receive 1L avelumab. Clinical trial information: NCT02155647. [Table: see text]

Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine neoplasm with a propensity for metastatic spread. When managing MCC, surgical excision is often the initial treatment. As MCC is generally radiosensitive, many institutions include adjuvant radiation therapy (RT) in their standard treatment protocols. In the absence of prospective randomized clinical trials, a number of retrospective reports suggest that adjuvant RT can improve local and regional recurrence rates. Here, we provide an overview of recent studies on the use of RT in MCC treatment and explore the limits of the current knowledge. Ultimately, the benefits and risks associated with using RT in the treatment of MCC remain poorly described and merit more rigorous investigation.

9508Background: Merkel cell carcinoma (MCC) is an aggressive skin cancer associated with Merkel cell polyomavirus. Therapeutic options are limited for metastatic MCC that has progressed after 1st-l...

We report a case of allergic contact dermatitis to WEBCOL(®) alcohol prep pads in a healthy 17-year-old girl who showed no reaction to the individual components of the prep pads upon provocative use testing. Although several case reports have described allergic contact dermatitis to isopropyl alcohol, there have been no reports of allergic contact dermatitis to alcohol prep pads sterilized with gamma irradiation, a common sterilization technique capable of producing volatile products in this type of alcohol prep pad.