Advanced Merkel Cell Carcinoma Research Articles

Development of a Multiplex Immunofluorescence Assay for Tumor Microenvironment Studies of Human and Murine Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma. Checkpoint inhibitor immunotherapy plays an essential role in management of advanced MCC; however, predictors of immunotherapy response remain poorly defined. Syngeneic mouse models suitable for testing novel immunotherapy and combination therapy approaches are likely to soon become available and will require assays for evaluating the tumor microenvironment (TME). Multiplex immunofluorescence (mIF) is a powerful approach to characterize the TME for understanding immunotherapy responses and immune surveillance. In this methods article, we provide detailed instructions on assay development for mIF, using as examples two new mIF panels for TME investigations of human and murine MCC tumors. Specifically, we demonstrate panels that allow simultaneous visualization of the Merkel cell master transcription factor SOX2 for tumor cell identification, alongside T-cells markers (CD3, CD8, and FOXP3), macrophage markers (F4/80 for mouse, CD163 for human), together with the checkpoint marker PD-L1 for human tumors, and the myeloid derived suppressor cell marker Arg1 for mouse tumors. We provide detailed protocols for investigators to incorporate these mIF panels into their investigations of human and murine MCC. We also provide fundamental guidance for mIF assay development that will be broadly useful for investigators who are considering modifying the panels presented here, or developing their own mIF panels.

Lack of Clinically Significant Relationships of Age or Body Mass Index with Merkel Cell Carcinoma Immunotherapy Outcomes.

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with a high risk of metastasis. The development of anti-PD-1/PD-L1 immunotherapy has improved outcomes for advanced MCC, yet about 50% of such patients do not achieve durable responses. This study analyzed the effects of age and body mass index (BMI) on immunotherapy response in 183 advanced MCC patients from a single-center longitudinal database. Using Fine-Gray or Cox regression models, treatment response, progression-free survival (PFS), MCC-specific survival, and overall survival (OS) were evaluated. Age showed a significant non-linear relationship with treatment response (p = 0.04), with patients much older or younger than 70 years less likely to respond. However, age was not significantly associated with PFS (p = 0.21), MCC-specific survival (p = 0.72), or OS (p = 0.36). Similarly, BMI was not significantly correlated with treatment response (p = 0.41), PFS (p = 0.52), MCC-specific survival (p = 0.78), or OS (p = 0.71). Unlike previous studies suggesting that obesity and advanced age improve outcomes in other cancers, these associations were not observed in MCC. These findings suggest that age and BMI should not influence eligibility for immunotherapy in MCC patients, emphasizing the importance of unbiased patient selection for this treatment.

Quality of life and patient-reported toxicities in patients with advanced Merkel cell carcinoma treated with combined nivolumab and ipilimumab with or without stereotactic body radiation therapy.

Merkel cell carcinoma is a rare skin cancer associated with poor survival. Based on a previous Phase II trial of adults with advanced Merkel cell carcinoma by Kim and colleagues (2022), there is now a strong rationale for combination therapy (i.e., nivolumab and ipilimumab) to become a treatment option for patients with advanced Merkel cell carcinoma. The goal of this paper was to report on the secondary outcome of quality of life (QOL) among patients on this trial. Patients receiving combined nivolumab and ipilimumab, with or without stereotactic body radiation therapy (SBRT), completed the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 prior to starting treatment and every 2 weeks thereafter. Changes in QOL during treatment and post-treatment were evaluated using piecewise random-effects mixed models. Exploratory analyses compared changes in QOL between study arms. The original trial was registered with ClinicalTrials.gov (NCT03071406). Study participants (n = 50) reported no changes in overall QOL (ps > 0.05), but emotional functioning improved during treatment (p = 0.01). Cognitive and social functioning worsened post-treatment (ps < 0.01). In general, patients treated with combination therapy only (n = 25) reported no change in QOL over time, whereas patients also treated with SBRT (n = 25) consistently demonstrated worsening QOL post-treatment. QOL is generally preserved in patients treated with combination therapy, but the addition of SBRT may worsen QOL. Combined with clinical efficacy data published previously, results support the use of combination therapy with nivolumab and ipilimumab as a treatment option for patients with advanced Merkel cell carcinoma.

Therapeutic Approaches for Non-Melanoma Skin Cancer: Standard of Care and Emerging Modalities.

Skin cancer encompasses a range of cutaneous malignancies, with non-melanoma skin cancers (NMSCs) being the most common neoplasm worldwide. Skin exposure is the leading risk factor for initiating NMSC. Ultraviolet (UV) light induces various genomic aberrations in both tumor-promoting and tumor-suppressing genes in epidermal cells. In conjunction with interactions with a changed stromal microenvironment and local immune suppression, these aberrations contribute to the occurrence and expansion of cancerous lesions. Surgical excision is still the most common treatment for these lesions; however, locally advanced or metastatic disease significantly increases the chances of morbidity or death. In recent years, numerous pharmacological targets were found through extensive research on the pathogenic mechanisms of NMSCs, leading to the development of novel treatments including Hedgehog pathway inhibitors for advanced and metastatic basal cell carcinoma (BCC) and PD-1/PD-L1 inhibitors for locally advanced cutaneous squamous cell carcinoma (cSCC) and Merkel cell carcinoma (MCC). Despite the efficacy of these new drugs, drug resistance and tolerability issues often arise with long-term treatment. Ongoing studies aim to identify alternative strategies with reduced adverse effects and increased tolerability. This review summarizes the current and emerging therapies used to treat NMSC.

Durability of immune checkpoint inhibitor (ICI) response following treatment discontinuation in advanced merkel cell carcinoma (MCC).

9596 Background: Advanced MCC has a high response rate to ICI therapy, but the durability of responses once treatment is discontinued remains unclear. We therefore reviewed the long-term outcomes of advanced MCC patients at our institution who discontinued ICI treatment after achieving favorable initial response. Methods: In an IRB-approved single institution retrospective review of advanced MCC patients, we analyzed all patients who received at least one dose of anti-PD(L)1 monotherapy for unresectable or metastatic disease, achieved stable disease (SD) or better, and discontinued treatment for a reason other than disease progression. Duration of response and outcomes of subsequent therapy were assessed. Results: Of 195 advanced MCC patients treated with ICI, we identified 45 who met study criteria. Of these, 21 (47%) had a complete response (CR) to initial ICI treatment, 23 (51%) a partial response (PR) and 1 (2%) SD. Twenty-five (56%) patients discontinued ICI electively and 20 (44%) discontinued due to toxicity. In total, 21 of the 45 patients (47%) experienced disease progression at a median of 11.2 months (range 2.1-22.7 months) from ICI cessation. The median follow-up after ICI discontinuation for patients who have not experienced progression is 22.8 months (5.8-82.0 months). There was a lower rate of progression in patients who achieved CR vs. non-CR (24% vs 67%, p=0.006) and a trend towards a lower rate in those who discontinued electively vs. due to toxicity (36% vs 60%, p=0.14). For patients in whom the molecular subtype was known, there was a higher risk for progression in patients with viral MCC (12 of 16, 75%) compared to UV-associated MCC (4 of 13, 31%, p=0.02). Fifteen of the 21 patients (71%) who experienced progression were rechallenged with ICI therapy, including both single agent (12 patients, 57%) and combination (3, 14%) therapy. The remaining patients received locally-directed therapy only (3, 14%), chemotherapy (1, 5%), declined further treatment (1, 5%), or transferred care and were lost to follow up (1, 5%). Eleven of 15 ICI-retreated patients (73%) achieved an objective response to rechallenge, including all 3 patients who received combination therapy with ipilimumab+nivolumab. Twelve of the 45 patients have expired; 6 due to progressive MCC and remaining 6 known or suspected from unrelated causes. Conclusions: Patients with advanced MCC have a substantial risk of disease progression following treatment discontinuation despite initial favorable ICI response, 47% in our series with a median time to event of 11.2 months, particularly in those that achieve less than a complete response. In the setting of disease progression post-ICI discontinuation, most patients maintain sensitivity to retreatment with the same drug class. Virus-positive MCC may be a risk factor for post-discontinuation relapse, which should be validated in future studies.

Phase 1b trial of IFx-Hu2.0, a novel in situ cancer vaccine, in checkpoint inhibitor-resistant Merkel cell carcinoma (MCC) and cutaneous squamous cell carcinoma (cSCC).

9592 Background: MCC and cSCC have limited treatment options when refractory to immune checkpoint inhibitor (ICI) therapy. IFx-Hu2.0 (IFx) is a plasmid DNA encoding for an immunogenic bacterial protein, Emm55, formulated with a transfection agent for direct intra-tumoral (IT) injection. In this Phase 1b study, we evaluated the safety and efficacy of different schedules of IT IFx in patients (pts) with advanced MCC or cSCC. Methods: In the first trial stage (n=9), IT IFx was administered in up to 3 lesions on 3 schedules following a 3+3 exposure escalation schema; weekly x 1, 2, or 3. In the second trial expansion stage (n=11), IT IFx was administered weekly x 3. The primary objective of the study was to establish safety and feasibility of repeated IT administrations of the investigational agent. ≥80% completion of planned study therapy was predefined as a successful feasibility outcome. Given the proposed potential for immune priming effects of IFx, we performed an unplanned exploratory analysis of post-protocol treatment efficacy to evaluate response to ICI rechallenge. Results: We treated 22 pts (MCC, 13; cSCC, 9). All pts had received prior anti-PD(L)1 based treatment with disease progression being the reason for ICI discontinuation in all patients but one. Two pts did not complete planned study therapy due to rapid clinical progression and were replaced but included in the safety analysis. IT IFx was well tolerated at all dose schedules evaluated with 1 high-grade toxicity deemed possibly treatment related (G3 hepatitis in a patient recently treated with ICI). The study therefore met predefined study endpoints for safety and efficacy. After protocol specified IT therapy, 11 MCC pts and 6 cSCC pts were treated with anti-PD(L)1 based therapy as the immediate post-protocol treatment. Five of 9 (56%) evaluable MCC patients and 1 of 7 (14%) cSCC patients experienced an objective response to this ICI rechallenge, with duration of response ongoing in 4 patients (6+, 19+, 21+, 23+ months) and the two other responses lasting 23 and 33 months. The two remaining MCC patients were not evaluable for response from IO rechallenge due to radiation administered to the only measurable disease site(s), but both remain progression free at 11+ and 13+ months with previously progressive disease. Conclusions: IT IFx-Hu2.0 is safe and feasible to administer at weekly dosing repeated up to 3 weeks. An unplanned exploratory analysis revealed frequent (56%) and durable responses in advanced MCC to ICI re-challenge despite prior resistance to this class of drug, suggesting that IFx induced an immune priming effect. Preliminary biomarker analyses to investigate this phenomenon are ongoing and will be presented. Clinical trial information: NCT04160065 .

Merkel Cell Carcinoma: Integrating Epidemiology, Immunology, and Therapeutic Updates.

Merkel cell carcinoma (MCC) is a rare skin cancer characterized by neuroendocrine differentiation. Its carcinogenesis is based either on the integration of the Merkel cell polyomavirus or on ultraviolet (UV) mutagenesis, both of which lead to high immunogenicity either through the expression of viral proteins or neoantigens. Despite this immunogenicity resulting from viral or UV-associated carcinogenesis, it exhibits highly aggressive behavior. However, owing to the rarity of MCC and the lack of epidemiologic registries with detailed clinical data, there is some uncertainty regarding the spontaneous course of the disease. Historically, advanced MCC patients were treated with conventional cytotoxic chemotherapy yielding a median response duration of only 3 months. Starting in 2017, four programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors-avelumab, pembrolizumab, nivolumab (utilized in both neoadjuvant and adjuvant settings), and retifanlimab-have demonstrated efficacy in treating patients with disseminated MCC on the basis of prospective clinical trials. However, generating clinical evidence for rare cancers, such as MCC, is challenging owing to difficulties in conducting large-scale trials, resulting in small sample sizes and therefore lacking statistical power. Thus, to comprehensively understand the available clinical evidence on various immunotherapy approaches for MCC, we also delve into the epidemiology and immune biology of this cancer. Nevertheless, while randomized studies directly comparing immune checkpoint inhibitors and chemotherapy in MCC are lacking, immunotherapy shows response rates comparable to those previously reported with chemotherapy but with more enduring responses. Notably, adjuvant nivolumab has proven superiority to the standard-of-care therapy (observation) in the adjuvant setting.

First-line Immunotherapy for Metastatic Merkel Cell Carcinoma: Analysis of Real-world Survival Data and Practice Patterns.

Immune checkpoint inhibitors are a promising new therapy for advanced Merkel Cell Carcinoma (MCC). We investigated real-world utilization and survival outcomes of first-line immunotherapies in a contemporary cohort. Using the National Cancer Database (NCDB), we identified 759 patients with MCC between 2015 and 2020 with stage IV disease and known status of first-line systemic therapy. Univariable and multivariable analyses were used to determine predictors of immunotherapy usage. Overall survival (OS) was compared for patients receiving immunotherapy, chemotherapy, or no systemic therapies. We identified 759 patients meeting our inclusion criteria: 329 patients received immunotherapy, 161 received chemotherapy, and 269 received no systemic therapy. Adjusting for demographic, clinical, and facility factors, high facility volume significantly predicted first-line immunotherapy use (OR 1.99; P =0.017). Median OS was 16.2, 12.3, and 8.7 months, among patients who received immunotherapy, chemotherapy, or no systemic therapy, respectively ( P <0.001). On Cox multivariable survival analysis, first-line immunotherapy treatment (HR=0.79, P =0.041) and treatment at high-volume centers (HR=0.58, P =0.004) were associated with improved OS. Consistent with clinical trial results, first-line immunotherapy associated with improvement in median overall survival for patients with stage IV MCC, significantly outperforming chemotherapy in this real-world cohort. Treatment at high-volume centers associated with first-line immunotherapy utilization suggesting that familiarity with this rare disease is important to achieving optimal outcomes for metastatic MCC.

NCCN Guidelines® Insights: Merkel Cell Carcinoma, Version 1.2024.

The NCCN Guidelines for Merkel Cell Carcinoma (MCC) provide recommendations for diagnostic workup, clinical stage, and treatment options for patients. The panel meets annually to discuss updates to the guidelines based on comments from expert review from panel members, institutional review, as well as submissions from within NCCN and external organizations. These NCCN Guidelines Insights focus on the introduction of a new page for locally advanced disease in the setting of clinical node negative status, entitled "Clinical N0 Disease, Locally Advanced MCC." This new algorithm page addresses locally advanced disease, and the panel clarifies the meaning behind the term "nonsurgical" by further defining locally advanced disease. In addition, the guideline includes the management of in-transit disease and updates to the systemic therapy options.

Abstract C034: First in Human phase 1/2a trial of a macrocyclic ATR inhibitor (ATRN-119) in patients with advanced solid tumors

Abstract Background: ATRN-119 is an oral and highly selective nanomolar inhibitor of Ataxia Telangiectasia and Rad3- related (ATR) kinase, an enzyme that is activated by replication stress and DNA damage and prevents the collapse of DNA replication forks into double strand breaks. ATRN-119 is being studied in advanced solid tumors with dysregulated components of the DNA damage response (DDR) based on the hypothesis that these tumors will be more susceptible to ATR inhibition. Single agent ATRN-119 demonstrates increased cytotoxicity in vitro against a broad spectrum of human colon, breast, pancreatic, sarcoma, ovarian and prostate cancer cell lines that harbor genomic alterations of DDR genes. In vivo, ATRN-119 has demonstrated tumor growth inhibition in human castration-resistant prostate cancer and human colon cancer cell line-derived xenografts (CDX) mice models, and in BRCA mutant high grade serous ovarian cancer patient derived xenografts (PDXs). Trial design: This is a first-in-human Phase 1/2a open-label study (NCT04905914) to evaluate safety, tolerability, pharmacokinetics (PK), and preliminary e!cacy of oral daily ATRN-119 in subjects with advanced solid tumors, conducted in 2 parts. Part 1 consists of a 3+3 dose escalation design at up to 6 dose levels to evaluate the tolerability, PK, dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of repeated daily doses of ATRN-119. Enrollment in Part 1 is ongoing. Subjects must be ≥12 years old with advanced solid tumor, have documented DDR mutations, or advanced Merkel cell carcinoma, must have failed at least one prior standard treatment, have ECOG performance status of 0 or 1, with a life expectancy &amp;gt; 3 months. Primary objective is safety/tolerability and secondary objective is efficacy. After determination of the MTD or maximum feasible dose (MFD) in Part 1, Part 2 will enroll up to 30 additional subjects. The trial is currently recruiting across 4 locations in the United States. Clinical trial identification: ClinicalTrials.gov Identifier: NCT04905914 Citation Format: Fiona Simpkins, Reva Schneider, Amit Mahipal, Patricia LoRusso, Crystal Miller, Eric Brown, Mike Carleton, Joachim Gullbo, Nadeem Q Mirza. First in Human phase 1/2a trial of a macrocyclic ATR inhibitor (ATRN-119) in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C034.

EPH80 Survival and Best Recorded Response (BRR) in Patients With Advanced Merkel Cell Carcinoma (MCC): Analysis of a Prospective German MCC Registry Study (MCC TRIM) of the German Dermatologic Cooperative Oncology Group

EPH80 Survival and Best Recorded Response (BRR) in Patients With Advanced Merkel Cell Carcinoma (MCC): Analysis of a Prospective German MCC Registry Study (MCC TRIM) of the German Dermatologic Cooperative Oncology Group

Avelumab for Advanced Merkel Cell Carcinoma: Global Real-World Data on Patient Response and Survival.

Avelumab is a programmed cell death-ligand 1 (PD-L1) inhibitor approved by the Food and Drug Administration for advanced Merkel cell carcinoma (MCC). Studies conducted in real-world settings have shed light on its effectiveness and safety in clinical settings. Real-world studies on avelumab for MCC from North and South America, Europe, and Asia have been presented in this review. Most studies are on patients over age 70 and have a male-predominant sex ratio. Overall response rates range from 29.1% to 72.1%, (disease control rate: 60.0-72.7%; complete response rate: 15.8%-37.2%; partial rate: 18.2-42.1%; stable disease: 7.1-30.9%; progressive disease: 7.1-40.0%) and median progression free survival ranges from 8.1 to 24.1 months depending on the population studied. Immunosuppressed patients appear to benefit from avelumab as well, with response rates equivalent to the general population. Patients receiving avelumab as a first-line agent tend to have better outcomes than those using it as a second-line therapy. Fatigue, infusion-related reactions, and dyspnea were some of the most common adverse events identified in real-world studies. Autoimmune hepatitis and thyroiditis were also observed. The use of avelumab as a safe and effective treatment option for advanced MCC is supported by real-world data, although additional study is required to assess long-term efficacy and safety outcomes.

1145P Clinical characteristics and survival of patients with advanced Merkel cell carcinoma (MCC) treated with avelumab: Analysis of a prospective German MCC registry (MCC TRIM)

1145P Clinical characteristics and survival of patients with advanced Merkel cell carcinoma (MCC) treated with avelumab: Analysis of a prospective German MCC registry (MCC TRIM)

1147P First-line treatment (tx) patterns and overall survival (OS) of patients (pts) with advanced Merkel cell carcinoma (aMCC) in England from 2013-2022: Results of a nationwide observational cohort study

1147P First-line treatment (tx) patterns and overall survival (OS) of patients (pts) with advanced Merkel cell carcinoma (aMCC) in England from 2013-2022: Results of a nationwide observational cohort study

1146P Updated results from POD1UM-201: A phase II study of retifanlimab in patients with advanced or metastatic Merkel cell carcinoma (MCC)

1146P Updated results from POD1UM-201: A phase II study of retifanlimab in patients with advanced or metastatic Merkel cell carcinoma (MCC)

Retifanlimab: a breakthrough for the management of Merkel cell carcinoma

Merkel cell carcinoma (MCC) is a rare, highly metastatic cutaneous neuroendocrine cancer originating from specialized Merkel cells, which are responsible for touch sensation in the skin. It is characterized by a firm, rapidly expanding nodule on sun-exposed skin areas, especially the head and neck. It has a high mortality rate, with reported overall survival rates ranging from 14% for distant disease to 51% for local disease. In March 2023, retifanlimab (Zynyz) received accelerated U.S. Food and Drug Administration (FDA) approval for treating adults with metastatic or recurrent locally advanced MCC. This drug offers a first-line response against MCC by improving the body’s immune response against cancer cells. This article aims to provide updated guidelines on the properties, dosing, and mechanism of action while discussing its use for the management of adults.

Sustained complete response to chemotherapy in a patient with advanced merkel cell carcinoma: A case report

Merkel cell carcinoma (MCC) is a rare neuroendocrine skin cancer. Over the last decade immune checkpoint inhibitors (ICIs) replaced chemotherapy as the recommended first-line therapy option. Across nonrandomized studies chemotherapy showed an overall response rate (ORR) ranged from 50% to 60%, a complete response (CR) rate from 3% to 30% and a progression free survival (PFS) of 3-4 months. We report a clinical case regarding a 72-year-old woman with MCC with right gluteus cutaneous lesion and inguinal and iliac lymph-adenopathies at diagnosis. The initial treatment was based on systemic chemotherapy with carboplatin + etoposide followed by lymphadenectomy. A pancreatic recurrence occurred after thirteen months, histologically confirmed. Systemic chemotherapy with the same regimen yielded a CR without a further progression for the subsequent eight years. The patient died due to nononcological causes, MCC-free, 11 years after the diagnosis.

Extended duration of treatment using reduced-frequency dosing of anti-PD-1 therapy in patients with advanced melanoma and Merkel cell carcinoma.

Optimal duration of treatment (DoT) with immune checkpoint inhibitors (ICI) in metastatic cancers remains unclear. Many patients, especially those without radiologic complete remission, develop progressive disease after ICI discontinuation. Extending DoT with ICI may potentially improve efficacy outcomes but presents major logistical and cost challenges with standard frequency dosing (SFD). Receptor occupancy data supports reduced frequency dosing (RFD) of anti-PD-1 antibodies, which may represent a more practical and economically viable option to extend DoT. We conducted a retrospective study of patients with metastatic melanoma and Merkel cell carcinoma (MCC), who received ICI at RFD administered every 3months, after initial disease control at SFD. We evaluated efficacy, safety, and cost-savings of the RFD approach in this cohort. Between 2014 and 2021, 23 patients with advanced melanoma (N = 18) or MCC (N = 5) received anti-PD-1 therapy at RFD. Median DoT was 1.1years at SFD and 1.2years at RFD. The 3year PFS after start of RFD was 73% in melanoma and 100% in MCC patients, which compare favorably to historical control rates. In the subset of 15 patients who received at least 2years of therapy, total savings amounted to $1.1 million in drug costs and 384h saved despite the extended DoT (median 3.4years), as compared to the calculated cost of 2years at SFD. ICI administration at RFD can allow extension of treatment duration, while preserving efficacy and reducing logistical and financial burden. RFD approach deserves further exploration in prospective clinical trials.

Successful rechallenge with avelumab in a patient with advanced Merkel cell carcinoma who presented pembrolizumab‐induced myositis

AbstractMerkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer, associated with high mortality. Immune checkpoint inhibitors (ICIs) have demonstrated long‐lasting efficiency for treating advanced MCC. Despite a good safety profile, ICI remain associated with non‐negligible risk of immune‐related adverse events (irAEs), which may require treatment discontinuation if they are severe. We report the case of a long‐lasting complete response to Avelumab after rechallenge in a patient with a metastatic MCC who became resistant to this anti‐Programmed cell Death Ligand 1 (anti‐PD‐L1) treatment and who presented severe neuromuscular toxicity during anti‐PD‐1 treatment with Pembrolizumab, without recurrence of the irAE. The potential specificity of therapeutic properties and irAEs of each ICI supports a personalized management of antitumoral immunogenic response and its adverse effects.

Adjuvant immunotherapy with nivolumab versus observation in completely resected Merkel cell carcinoma (ADMEC-O): disease-free survival results from a randomised, open-label, phase 2 trial

Merkel cell carcinoma (MCC) is an immunogenic but aggressive skin cancer. Even after complete resection and radiation, relapse rates are high. PD-1 and PD-L1 checkpoint inhibitors showed clinical benefit in advanced MCC. We aimed to assess efficacy and safety of adjuvant immune checkpoint inhibition in completely resected MCC (ie, a setting without an established systemic standard-of-care treatment). In this multicentre phase 2 trial, patients (any stage, Eastern Cooperative Oncology Group performance status 0-1) at 20 academic medical centres in Germany and the Netherlands with completely resected MCC lesions were randomly assigned 2:1 to receive nivolumab 480 mg every 4 weeks for 1 year, or observation, stratified by stage (American Joint Committee on Cancer stages 1-2 vs stages 3-4), age (<65 vs ≥65 years), and sex. Landmark disease-free survival (DFS) at 12 and 24 months was the primary endpoint, assessed in the intention-to-treat populations. Overall survival and safety were secondary endpoints. This planned interim analysis was triggered when the last-patient-in was followed up for more than 1 year. This study is registered with ClinicalTrials.gov (NCT02196961) and with the EU Clinical Trials Register (2013-000043-78). Between Oct 1, 2014, and Aug 31, 2020, 179 patients were enrolled (116 [65%] stage 3-4, 122 [68%] ≥65 years, 111 [62%] male). Stratification factors (stage, age, sex) were balanced across the nivolumab (n=118) and internal control group (observation, n=61); adjuvant radiotherapy was more common in the control group. At a median follow-up of 24·3 months (IQR 19·2-33·4), median DFS was not reached (between-groups hazard ratio 0·58, 95% CI 0·30-1·12); DFS rates in the nivolumab group were 85% at 12 months and 84% at 24 months, and in the observation group were 77% at 12 months and 73% at 24 months. Overall survival results were not yet mature. Grade 3-4 adverse events occurred in 48 [42%] of 115 patients who received at least one dose of nivolumab and seven [11%] of 61 patients in the observation group. No treatment-related deaths were reported. Adjuvant therapy with nivolumab resulted in an absolute risk reduction of 9% (1-year DFS) and 10% (2-year DFS). The present interim analysis of ADMEC-O might suggest clinical use of nivolumab in this area of unmet medical need. However, overall survival events rates, with ten events in the active treatment group and six events in the half-the-size observation group, are not mature enough to draw conclusions. The explorative data of our trial support the continuation of ongoing, randomised trials in this area. ADMEC-O suggests that adjuvant immunotherapy is clinically feasible in this area of unmet medical need. Bristol Myers Squibb.