Merkel Cell Carcinoma Patients Research Articles

Different prognosis in cutaneous early-onset and late-onset Merkel cell carcinoma: a population-based retrospective study.

Merkel cell carcinoma (MCC) is a rare and highly aggressive form of skin cancer. However, there is limited research on the clinicopathological features of early-onset MCC (EOMCC) and the differences between EOMCC and late-onset MCC (LOMCC). Our objective was to evaluate the clinicopathological features and cancer-specific survival (CSS) of EOMCC. Our cohort study analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database from January 1, 2018, to December 31, 2020. Data from 1941 patients who were diagnosed with primary cutaneous MCC were included. We then divided the patients with MCC into two groups: those with EOMCC (526 patients) and those with LOMCC (1415 patients). CSS is used as the primary outcome. The EOMCC group exhibited trends toward advanced tumor progression, an expanded surgical scope, increased lymph node retrieval, intensified radiotherapy, greater utilization of systemic therapy, and a better prognosis. Multivariate analysis revealed that LOMCC (HR 3.305 [2.002-5.456], P < 0.001), advanced T stage (HR 1.430 [1.139-1.797], P = 0.002), advanced N stage (HR 1.522 [1.221-1.897], P < 0.001), M1 stage (HR 2.587 [1.480-4.521], P < 0.001), and radiation (HR 0.586 [0.410-0.837], P = 0.003) were significantly associated with CSS. Among these factors, EOMCC/LOMCC was most strongly associated with CSS, indicating that LOMCC is an independent risk factor for CSS. Interestingly, we found that regional EOMCC and localized or in situ LOMCC had almost completely overlapping survival curves (Plog-rank = 0.620). Additionally, we observed that the TNM staging + age model was a more accurate predictor of CSS among MCC patients than using TNM staging alone. We found that EOMCC has distinct clinicopathological features compared to LOMCC. EOMCC is associated with better CSS. The combination of TNM staging and age was more accurate for predicting patient outcomes than TNM staging alone.

The Role of Neoadjuvant Immunotherapy in the Management of Merkel Cell Carcinoma with Clinically Detected Regional Lymph Node Metastasis.

Immunotherapy is emerging as a promising option for certain locally advanced and metastatic cutaneous malignancies. However, the role of neoadjuvant immunotherapy (NIO) in Merkel cell carcinoma (MCC) with clinically detected regional lymph node metastasis (CDRLNM) has not been fully elucidated. For this study, MCC patients with CDRLNM who underwent surgical excision were selected from the National Cancer Database (NCDB). Those who received NIO were propensity-matched with those who did not, and Kaplan-Meier analysis was used to compare overall survival (OS). Of the 1809 selected patients, 356 (19.7%) received NIO followed by wide excision (n = 352, 98.9%) or amputation (n = 4, 1.1%). The rate of complete pathologic response for the primary tumor (ypT0) was 45.2%. Only 223 patents (63.4%) also underwent lymph node dissection (LND). The complete pathologic nodal response (ypN0) rate for these patients was 17.9%. A pathologic complete response of both the primary tumor and the nodal basin (ypT0 ypN0) was seen in 16 of the 223 patients who underwent both primary tumor surgery and LND. Subsequently, 151 pairs were matched between the NIO and no-NIO groups (including only patients with LND). Kaplan-Meier analysis demonstrated a significant OS improvement with NIO (median not reached vs. 35.0 ± 8.0 months; p = 0.025). The 5-year OS was 57% in the NIO group versus 44% in no-NIO group (p = 0.021). The study suggests that NIO in MCC with CDRLNM provides improved OS in addition to promising rates of primary complete response, which could change the profile of surgical resection. This supports ongoing clinical trials exploring the use of NIO in MCC.

The effect of selinexor on prostaglandin synthesis in virus-positive Merkel cell carcinoma cell lines.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with high rates of metastasis and mortality. In vitro studies suggest that selinexor (KPT-330), an inhibitor of exportin 1, may be a targeted therapeutic option for MCC. This selective inhibitor prevents the transport of oncogenic mRNA out of the nucleus. Of note, 80% of MCC tumors are integrated with Merkel cell polyomavirus (MCPyV), and virally encoded tumor-antigens, small T (sT) and large T (LT) mRNAs may require an exportin transporter to relocate to the cytoplasm and modulate host tumor-suppressing pathways. To explore selinexor as a targeted therapy for MCC, we examine its ability to inhibit LT and sT antigen expression in vitro and its impact on the prostaglandin synthesis pathway. Protein expression was determined through immunoblotting and quantified by densitometric analysis. Statistical significance was determined with t-test. Treatment of MCPyV-infected cell lines with selinexor resulted in a significant dose-dependent downregulation of key mediators of the prostaglandin synthesis pathway. Given the role of prostaglandin synthesis pathway in MCC, our findings suggest that selinexor, alone or in combination with immunotherapy, could be a promising treatment for MCPyV-infected MCC patients who are resistant to chemotherapy and immunotherapy.

The prognostic value of the Merkel cell polyomavirus serum antibody test: A dual institutional observational study.

Merkel cell carcinoma (MCC) is an aggressive cancer with often poor outcomes. Limited biomarkers exist for predicting clinical outcomes. The Merkel cell polyomavirus (MCPyV) serum antibody test (AMERK) has shown potential for indicating better recurrence-free survival in a single-institution study. The study aimed to evaluate the link between initial AMERK serostatus and survival. Secondary objectives included examining the relationship between initial AMERK titer levels and tumor burden. A retrospective cohort study across two institutions analyzed patients tested with AMERK within 90 days of MCC diagnosis. Regression models assessed the association of survival outcomes with serostatus, considering various factors. The relationship between AMERK titer and tumor burden indicators was evaluated using ANOVA. Significance testing was exploratory, without a fixed significance level. Of 261 MCC patients tested, 49.4% were initially seropositive (titer ≥75). Multivariable analysis showed that seropositivity improved recurrence, event-free, overall, and MCC-specific survival rates. Strong associations were found between initial AMERK titer and clinical, tumor, and nodal stages, tumor size, and disease extent. Notably, improved survival with seropositivity was observed only in patients with localized disease at initial presentation. Circulating antibodies to MCPyV oncoproteins, as indicated by the AMERK test, are linked with better survival in MCC patients with localized disease at presentation. This could enhance patient risk profiling and treatment personalization. The study's retrospective nature and exploratory analysis are key limitations. Merkel cell carcinoma (MCC) is a potentially aggressive skin cancer, and tools to predict patient outcomes are limited. A blood test called anti-Merkel cell panel (AMERK), which checks for specific antibodies related to this cancer, might give us some clues. In this study, we looked at 261 MCC patients who took the AMERK test within 90 days of diagnosis. We found that patients with an initial positive AMERK result tended to have better outcomes, especially if their cancer was in the early stages. However, it is important to note that this study has limitations, including using retrospective data and exploratory analyses.

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.

Abstract 6107: Survival differences by socioeconomic status in Merkel cell carcinoma: A retrospective analysis using the National Cancer Database

Abstract Introduction: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer whose incidence and survival outcomes demonstrate disparities based on patients’ socioeconomic status (SES). This study aims to evaluate the impact of SES on MCC diagnosis age, comorbidity burden, treatment modalities, and survival outcomes using the National Cancer Database. Methods: We conducted a retrospective analysis of 9742 patients diagnosed with MCC from 2016 to 2020 in the United States. To assess how socioeconomic status influences outcomes, a composite score was created by adding income and education quartile assignments (1, 2, 3, 4), to create new composite SES quartiles of 2-3, 4-5, 6-7, and 8. Patients were stratified into quartiles based on their SES (lowest Q1 to highest Q4). Binomial test was performed for categorical variables and ANOVA was performed for continuous. Survival differences were examined with Cox proportional hazards models and Kaplan-Meier curves. Results: Patients with lower SES presented with MCC at younger ages, with the average age of patients in the lowest SES Q1 being 73.8 years (95% CI 73.15-74.35) and the highest SES Q4 being 75.0 years (95% CI 74.48-75.46). Patients in SES Q1 also had higher Charson-Deyo scores, indicating more comorbidities than patients in SES Q4 (8.41% vs 5.8%, p &amp;lt; 0.001). They were also more likely to have advanced stage 4 MCC (9.67% vs 7.79%, p &amp;lt; 0.01) compared to patients in SES Q4. When treated with surgery, patients in SES Q1 were more likely to be treated with local tumor excision (14.39% vs 10.83%, p &amp;lt; 0.001) whereas patients in SES Q4 were more likely treated with Mohs surgery (5.02% vs 3.56%, p &amp;lt; 0.01). Survival probabilities for patients SES Q1 were worse at 1 year (82.99% vs 85.81%, p&amp;lt;0.001), 3 years (61.18% vs 68.49%, p &amp;lt; 0.001) and 5 years (45.99% vs 55.09%, p &amp;lt; 0.001) compared to patients in SES Q4. Conclusion: This study highlights disparities in age at diagnosis, comorbidities, treatment, and survival outcomes in MCC patients based on SES. Patients in lower SES quartiles are diagnosed younger, bear higher comorbidity burdens, and have worse rates of survival. Citation Format: Rachel C. Chang, Elise K. Brunsgaard, David Reid. Survival differences by socioeconomic status in Merkel cell carcinoma: A retrospective analysis using the National Cancer Database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6107.

Conditional survival analysis and dynamic prediction of long-term survival in Merkel cell carcinoma patients.

Merkel cell carcinoma (MCC) is a rare type of invasive neuroendocrine skin malignancy with high mortality. However, with years of follow-up, what is the actual survival rate and how can we continually assess an individual's prognosis? The purpose of this study was to estimate conditional survival (CS) for MCC patients and establish a novel CS-based nomogram model. This study collected MCC patients from the Surveillance, Epidemiology, and End Results (SEER) database and divided these patients into training and validation groups at the ratio of 7:3. CS refers to the probability of survival for a specific timeframe (y years), based on the patient's survival after the initial diagnosis (x years). Then, we attempted to describe the CS pattern of MCCs. The Least absolute shrinkage and selection operator (LASSO) regression was employed to screen predictive factors. The Multivariate Cox regression analysis was applied to demonstrate these predictors' effect on overall survival and establish a novel CS-based nomogram. A total of 3,843 MCC patients were extracted from the SEER database. Analysis of the CS revealed that the 7-year survival rate of MCC patients progressively increased with each subsequent year of survival. The rates progressed from an initial 41-50%, 61, 70, 78, 85%, and finally to 93%. And the improvement of survival rate was nonlinear. The LASSO regression identified five predictors including patient age, sex, AJCC stage, surgery and radiotherapy as predictors for CS-nomogram development. And this novel survival prediction model was successfully validated with good predictive performance. CS of MCC patients was dynamic and increased with time since the initial diagnosis. Our newly established CS-based nomogram can provide a dynamic estimate of survival, which has implications for follow-up guidelines and survivorship planning, enabling clinicians to guide treatment for these patients better.

Tumor reactive γδ T cells contribute to a complete response to PD-1 blockade in a Merkel cell carcinoma patient

Immunotherapies targeting PD-1/PD-L1 are now widely used in the clinic to treat a variety of malignancies. While most of the research on T cell exhaustion and PD-1 blockade has been focused on conventional αβ T cells, the contribution of innate-like T cells such as γδ T cells to anti-PD-1/PD-L1 mediated therapy is limited. Here we show that tumor reactive γδ T cells respond to PD-1 blockade in a Merkel cell carcinoma (MCC) patient experiencing a complete response to therapy. We find clonally expanded γδ T cells in the blood and tumor after pembrolizumab treatment, and this Vγ2Vδ1 clonotype recognizes Merkel cancer cells in a TCR-dependent manner. Notably, the intra-tumoral γδ T cells in the MCC patient are characterized by higher expression of PD-1 and TIGIT, relative to conventional CD4 and CD8 T cells. Our results demonstrate that innate-like T cells could also contribute to an anti-tumor response after PD-1 blockade.

T antigen-specific CD8+ T cells associate with PD-1 blockade response in virus-positive Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer primarily induced by Merkel cell polyomavirus, which is driven by the expression of the oncogenic T antigens (T-Ags). Blockade of the programmed cell death protein-1 (PD-1) pathway has shown remarkable response rates, but evidence for therapy-associated T-Ag-specific immune response and therapeutic strategies for the nonresponding fraction are both limited. We tracked T-Ag-reactive CD8+ T cells in peripheral blood of 26 MCC patients under anti-PD1 therapy, using DNA-barcoded pMHC multimers, displaying all peptides from the predicted HLA ligandome of the oncoproteins, covering 33 class I haplotypes. We observed a broad T cell recognition of T-Ags, including identification of 20 T-Ag-derived epitopes we believe to be novel. Broadening of the T-Ag recognition profile and increased T cell frequencies during therapy were strongly associated with clinical response and prolonged progression-free survival. T-Ag-specific T cells could be further boosted and expanded directly from peripheral blood using artificial antigen-presenting scaffolds, even in patients with no detectable T-Ag-specific T cells. These T cells provided strong tumor-rejection capacity while retaining a favorable phenotype for adoptive cell transfer. These findings demonstrate that T-Ag-specific T cells are associated with the clinical outcome to PD-1 blockade and that Ag-presenting scaffolds can be used to boost such responses.

Tumor cell-intrinsic PD-1 promotes Merkel cell carcinoma growth by activating downstream mTOR-mitochondrial ROS signaling.

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Inhibitors targeting the programmed cell death 1 (PD-1) immune checkpoint have improved MCC patient outcomes by boosting antitumor T cell immunity. Here, we identify PD-1 as a growth-promoting receptor intrinsic to MCC cells. In human MCC lines and clinical tumors, RT-PCR-based sequencing, immunoblotting, flow cytometry, and immunofluorescence analyses demonstrated PD-1 gene and protein expression by MCC cells. MCC-PD-1 ligation enhanced, and its inhibition or silencing suppressed, in vitro proliferation and in vivo tumor xenograft growth. Consistently, MCC-PD-1 binding to PD-L1 or PD-L2 induced, while antibody-mediated PD-1 blockade inhibited, protumorigenic mTOR signaling, mitochondrial (mt) respiration, and ROS generation. Last, pharmacologic inhibition of mTOR or mtROS reversed MCC-PD-1:PD-L1-dependent proliferation and synergized with PD-1 checkpoint blockade in suppressing tumorigenesis. Our results identify an MCC-PD-1-mTOR-mtROS axis as a tumor growth-accelerating mechanism, the blockade of which might contribute to clinical response in patients with MCC.

Prognosis of Merkel cell carcinoma patients with autoimmune disorders, other types of immune dysfunction, or immunocompetent status: Analysis of 762 patients

Prognosis of Merkel cell carcinoma patients with autoimmune disorders, other types of immune dysfunction, or immunocompetent status: Analysis of 762 patients

Periocular Merkel Cell Carcinoma - an overview of clinical aspects and current therapeutic options

Merkel cell carcinoma (MCC) is a rare but highly aggressive and rapidly expanding malignant skin tumor. It affects the periocular region in approximately 10% of cases. The current treatment recommendation for resectable non-metastatic MCC comprises total surgical excision; however, lymph node or distant metastases are often already present by the time of the diagnosis. Since an immune checkpoint inhibitor therapy with avelumab was first approved for MCC in 2016, there has been considerable improvement in mean survival compared to cytostatic therapy; at the same time, there has been a reduction in serious treatment-associated adverse events. Other immune checkpoint inhibitors are currently still in clinical trials, with very promising initial results. Because of the complexity of the diagnosis, treatment, and prognosis, it is essential that MCC patients receive interdisciplinary care in a specialized center including consultation with a tumor review board.

Enhancing immunogenic responses through CDK4/6 and HIF2α inhibition in Merkel cell carcinoma

Approximately 50% of Merkel cell carcinoma (MCC) patients facing this highly aggressive skin cancer initially respond positively to PD-1-based immunotherapy. Nevertheless, the recurrence of MCC post-immunotherapy emphasizes the pressing need for more effective treatments. Recent research has highlighted Cyclin-dependent kinases 4 and 6 (CDK4/6) as pivotal cell cycle regulators gaining prominence in cancer studies. This study reveals that the CDK4/6 inhibitor, palbociclib can enhance PD-L1 gene transcription and surface expression in MCC cells by activating HIF2α. Inhibiting HIF2α with TC-S7009 effectively counteracts palbociclib-induced PD-L1 transcription and significantly intensifies cell death in MCC. Simultaneously, co-targeting CDK4/6 and HIF2α boosts ROS levels while suppressing SLC7A11, a key regulator of cellular redox balance, promoting ferroptosis- a form of immunogenic cell death linked to iron. Considering the rising importance of immunogenic cell death in immunotherapy, this strategy holds promise for improving future MCC treatments, markedly increasing immunogenic cell death across various MCC cell lines, thus advancing cancer immunotherapy.

Longitudinal multi-functional analysis identified responses of T cells, B cells, and monocytes as hallmarks of immunotherapy tolerance in patients with merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a neuroendocrine carcinoma originating in the skin. Studies are needed to determine the mechanisms of immune escape in patients with MCC, and malignant cell conditions that promote immune evasion. We used Single-cell RNA sequencing (scRNA-seq) to determine cellular features associated with MCC disease trajectory. A longitudinal multi-omics study was performed using scRNA-seq data of peripheral blood harvested from four-time points. Six major cell types and fifteen cell subgroups were identified and confirmed their presence by expression of characteristic markers. The expression patterns and specific changes of different cells at different time points were investigated. Subsequently, bulk RNA data was used to validate key findings. The dynamic characteristics of the cells were identified during the critical period between benign improvement and acquisition of resistance. Combined with the results of the validation cohort, the resistance program expressed in the relapse stage is mainly associated with T cell exhaustion and immune cell crosstalk disorder. Coinciding with immune escape, we also identified a decrease non-classical monocytes and an expansion of classical monocytes with features of high inflammation and immune deficiency. Changes in cellular status, such as depletion of T cells and dysregulation of B cell proliferation and differentiation, may lead to drug resistance in MCC patients. Meanwhile, the widespread decreased antigen presentation ability and immune disorders caused by deletion of MHC class II gene expression should not be ignored.

Merkel cell carcinoma recurrence risk estimation is improved by integrating factors beyond cancer stage: A multivariable model and web-based calculator

Merkel cell carcinoma (MCC) recurs in 40% of patients. In addition to stage, factors known to affect recurrence risk include: sex, immunosuppression, unknown primary status, age, site of primary tumor, and time since diagnosis. Create a multivariable model and web-based calculator to predict MCC recurrence risk more accurately than stage alone. Data from 618 patients in a prospective cohort were used in a competing risk regression model to estimate recurrence risk using stage and other factors. In this multivariable model, the most impactful recurrence risk factors were: American Joint Committee on Cancer stage (P<.001), immunosuppression (hazard ratio 2.05; P<.001), male sex (1.59; P=.003) and unknown primary (0.65; P=.064). Compared to stage alone, the model improved prognostic accuracy (concordance index for 2-year risk, 0.66 vs 0.70; P<.001), and modified estimated recurrence risk by up to 4-fold (18% for low-risk stage IIIA vs 78% for high-risk IIIA over 5years). Lack of an external data set for model validation. As demonstrated by this multivariable model, accurate recurrence risk prediction requires integration of factors beyond stage. An online calculator based on this model (at merkelcell.org/recur) integrates time since diagnosis and provides new data for optimizing surveillance for MCC patients.

Population Pharmacokinetic and Pharmacodynamic Analysis of Navtemadlin in Patients with Relapsed and Refractory (R/R) Myelofibrosis (MF) and Other Myeloid or Solid Tumor Malignancies

Background:Murine double minute 2 (MDM2), a key negative regulator of the tumor suppressor protein p53, is overexpressed in malignancies such as MF and Merkel cell carcinoma (MCC). Navtemadlin is a potent, selective, orally available MDM2 inhibitor that overcomes MDM2 dysregulation by restoring p53 activity and inducing apoptosis of TP53WT tumors. Navtemadlin has been tested in 21- or 28-day treatment cycles, with 5 or 7 consecutive days of dosing per cycle. Navtemadlin elicits plasma concentration-dependent increases in serum macrophage inhibitory cytokine-1 (MIC-1). An increase in MIC-1 relative to baseline MIC-1 serum concentration is a key pharmacodynamic (PD) marker of response to navtemadlin treatment (Zhang et al. Xenobiotica 2022). A population pharmacokinetic (PK) model was developed, based on patients with R/R MF (N=113, NCT03662126); MCC (N=35, NCT03787602); solid tumors and multiple myeloma (ST/MM N=105, Gluck et al. Invest New Drugs 2019); R/R acute myeloid leukemia (AML, N=35, Erba et al. Blood Adv 2019); and healthy volunteers (HV, N=30, Wong et al. Clin Pharmacol Drug Dev 2022).The objectives wereto characterize navtemadlin PK and covariate effects and compare steady-state (SS) PK and PD across cancer types. Methods:A two-compartment PK model with first-order absorption and elimination was estimated using NONMEM ® (first-order conditional estimation with interaction). Four transit compartments captured absorption. Inter-subject variability was modeled as lognormal. A stepwise covariate search used forward addition (p&amp;lt;0.05) followed by backward elimination (p&amp;lt;0.01). Log-transformed SS MIC-1 ratio to baseline (fold ratio) was tested in a fixed-effects linear regression model with respect to SS exposures, with baseline MIC-1 as the covariate. The final population PK and MIC-1 models were evaluated by inspection of parameter tables, by overlaying model predictions with observed data, and by standard residual diagnostics. Results:The PK estimation used 5,282 concentrations from 318 subjects, including 1,415 concentrations in 113 patients with R/R MF. Tumor type affected absorption rate (median, 0.635/hr in MCC; slower vs other types), apparent clearance (median, 8.90 L/hr in MCC; lower vs other types), and apparent central volume (median, 64.4 L in MCC; similar to AML, but lower vs other types) (Table 1). Accordingly, simulated SS area under the curve (AUCss) differed across populations in the order MCC&amp;gt;AML&amp;gt;MF&amp;gt;ST/MM = HV (Figure 1). Covariate analysis indicated median AUC increased with the inflammation marker C-reactive protein, by 21% at 90 th percentile CRP, and with age, by 5% at 90 th percentile age of 75 y, compared to the median, 66 y. Men had 24% lower relative bioavailability than women. Taking navtemadlin with food slowed absorption by 10% but had no impact on AUCss. Other tested covariates, including body weight, creatinine clearance, aspartate transaminase, alanine transaminase, bilirubin, albumin, alpha 1-acid glycoprotein, race, UGT1A1 genotype, recent ruxolitinib treatment in MF, and CYP3A4 inducer/inhibitor concomitant medications, were not significant. Median MIC-1 fold ratio increased with navtemadlin AUCss. Higher baseline MIC-1 resulted in lower SS MIC-1 fold ratio. Median baseline MIC-1 differed by tumor type. In R/R MF, baseline MIC-1 was 2,297 ng/L and SS fold ratio of MIC-1 was 7.79 (N=91). In MCC, baseline MIC-1 was 1,718 ng/L and SS fold ratio of MIC-1 was 16.7 (N=29). In R/R MF, higher baseline spleen volume was also associated with lower SS MIC-1 fold ratio. Exposure-MIC-1 relationships in R/R MF and MCC were generally similar to other tumor types and HV populations (Allard et al. Hemasphere 2019; Zhang et al. Xenobiotica 2022). Conclusions:Tumor type influenced navtemadlin exposure with simulated exposure in R/R MF patients at the selected Phase 3 dose of 240 mg comparable to exposures in MCC patients at 180 mg, the selected Phase 2 dose for that indication. Cancer-associated inflammation and/or treatment history, as well as age and female sex, may increase navtemadlin exposure. The PD marker MIC-1 responds to navtemadlin in a concentration-dependent fashion. The overall SS fold change of MIC-1 PD responses was lower in disease states or subjects with higher baseline MIC-1. These studies demonstrate potent, dose-dependent PK/PD responses following p53 activation with the novel MDM2 inhibitor, navtemadlin, across diverse tumor types.

An Updated Review of the Biomarkers of Response to Immune Checkpoint Inhibitors in Merkel Cell Carcinoma: Merkel Cell Carcinoma and Immunotherapy.

Merkel cell carcinoma (MCC) is primarily a disease of the elderly Caucasian, with most cases occurring in individuals over 50. Immune checkpoint inhibitors (ICI) treatment has shown promising results in MCC patients. Although ~34% of MCC patients are expected to exhibit at least one of the predictive biomarkers (PD-L1, high tumor mutational burden/TMB-H/, and microsatellite instability), their clinical significance in MCC is not fully understood. PD-L1 expression has been variably described in MCC, but its predictive value has not been established yet. Our literature survey indicates conflicting results regarding the predictive value of TMB in ICI therapy for MCC. Avelumab therapy has shown promising results in Merkel cell polyomavirus (MCPyV)-negative MCC patients with TMB-H, while pembrolizumab therapy has shown better response in patients with low TMB. A study evaluating neoadjuvant nivolumab therapy found no significant difference in treatment response between the tumor etiologies and TMB levels. In addition to ICI therapy, other treatments that induce apoptosis, such as milademetan, have demonstrated positive responses in MCPyV-positive MCC, with few somatic mutations and wild-type TP53. This review summarizes current knowledge and discusses emerging and potentially predictive biomarkers for MCC therapy with ICI.

Efficacy of Single-Fraction Postoperative Radiotherapy in Resected, Early-Stage Merkel Cell Carcinoma with High-Risk Features

Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high recurrence risk. Postoperative radiotherapy (PORT) improves the local recurrence rate (LRR) in early-stage MCC with risk factors per NCCN guidelines: primary tumor size > 1cm, head/neck (HN) location, immunosuppression, lymphovascular invasion (LVI), and positive/narrow surgical margins. Conventionally fractionated PORT (C-PORT, ∼50 Gy in 25 fractions) is often recommended for localized MCC with these risk factors; however, some institutions elect observation. Prior studies suggest LRR of ∼20% for stage I/II MCC with high-risk features managed with surgery alone. C-PORT significantly decreases LRR but may cause significant morbidity and financial toxicity. We have previously reported that single fraction (SF)-PORT with 8 Gy achieves high rates of in-field control both in the metastatic and adjuvant settings with minimal morbidity. Here, we present updated long-term outcomes of SF-PORT, offered as an alternative to C-PORT with the hypothesis that it improves LRR relative to observation while minimizing toxicity, for resected stage I/II MCC. A retrospective, single-institution analysis was completed for stage I/II MCC patients receiving SF-PORT following surgical management. The primary objective was estimating the LRR, defined as recurrence within 2 cm of the primary tumor. Patients with resected, stage I/II MCC with at least one high-risk feature were offered C-PORT as standard of care or SF-PORT as an alternative. Forty-six patients (median age: 74.5; range 50-96 years) received SF-PORT to the primary tumor site at a median 44 days after wide local excision (85%), shave/excisional biopsy (13%), or Mohs (2%). Fifty-four percent of patients had 1 high-risk feature, 35% had 2, and 11% had 3 or more. HN (74%) was the most common primary site, 26% of tumors were > 1cm, 26% were LVI+, and 15% of patients were immunosuppressed (pathological margin status was often not available). There were no local recurrences (LRR = 0%) at a median follow-up time of 2.3 years. In-field locoregional control was 96% (44/46 patients) with 2 in-field, regional recurrences observed in draining nodal basins of HN primary lesions. There were 2 out-of-field regional nodal recurrences (1 patient with IMS; neither received elective nodal SFRT). Of 9 patients who received elective nodal SF-PORT, 8 did not have a successful sentinel lymph node biopsy. No MCC-specific deaths were observed. The most common side effect was in-field, grade 1 erythema (13%); no side effects > grade 1 (CTCAE v5) were noted. SF-PORT is associated with a very low LRR which has proven durable with long-term follow-up. The LRR for SF-PORT appears lower than historical controls treated with surgery alone for patients with resected, stage I/II MCC with high-risk features.

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.

43703 Effects of Immunological Therapy on Demographics, Clinical Variables, and Survival in Merkel Cell Carcinoma Patients

43703 Effects of Immunological Therapy on Demographics, Clinical Variables, and Survival in Merkel Cell Carcinoma Patients