Advanced Merkel Cell Carcinoma Research Articles

Adjuvant Radiation in Locally Advanced Merkel Cell Carcinoma Reduces Regional and Distant Relapse and Improves Disease-Specific Survival

Adjuvant Radiation in Locally Advanced Merkel Cell Carcinoma Reduces Regional and Distant Relapse and Improves Disease-Specific Survival

Real-world clinical outcomes in avelumab-treated patients (pts) in the United States (U.S.) from SPEAR-Merkel: Study informing treatment pathway decisions in Merkel cell carcinoma (MCC).

269 Background: MCC is a rare, aggressive disease associated with poor prognosis. Avelumab, a fully human anti–PD-L1 monoclonal antibody, was the first immune checkpoint inhibitor approved by the FDA for the treatment of metastatic MCC (mMCC). In the JAVELIN Merkel 200 trial (Clinical trial information: NCT02155647), avelumab resulted in durable responses and a high objective response rate (ORR) in pts with mMCC. This retrospective descriptive study assessed real-world clinical outcomes in avelumab-treated pts with locally advanced MCC (laMCC) and mMCC in a US community oncology setting. Methods: This study included data on avelumab-treated laMCC and mMCC pts from 1/1/17 to 3/31/19 within The US Oncology Network. Study data were captured through 9/30/19 using structured fields and chart review of iKnowMed electronic healthcare records. Real-world ORR was assessed. Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Results: 33 pts initiated treatment with avelumab (laMCC n = 11; mMCC n = 22) and were followed up for a median of 10.9 months (range, 0.5-27.2 months). Median age was 77 years (range, 44-90+ years), 78.8% of pts were male, and the majority (84.8%) of pts were treated in the first-line setting. During treatment, 27.2% of pts had emergency department visits and 39.4% were hospitalized; 1% and 23.1%, respectively, were treatment related. Clinical outcomes are reported in the table. Conclusions: This is the first study to examine pts with laMCC treated with avelumab in a real-world setting. Although the sample population is small, results suggest the clinical benefits in the real world in pts with mMCC treated with avelumab are consistent with benefits reported in the JAVELIN Merkel 200 trial. [Table: see text]

Positron Emission Tomography in Merkel Cell Carcinoma.

Simple SummaryThere is currently no consensus on a widely accepted algorithm for imaging Merkel cell carcinoma (MCC) patients. Baseline, tomographic imaging is not generally recommended in early-stage disease, but its value in locally advanced and/or distant metastatic MCC has been well established. In this context, the hybrid imaging modality positron emission tomography/computed tomography (PET/CT) is increasingly applied in the workup of metastatic or unresectable MCC, providing essential information for staging, restaging, and treatment monitoring of the disease. Although the role of PET/CT in the management of loco-regional MCC is still limited and less well-defined, current evidence suggests its important contribution also in cases of localized MCC. Herein, we provide a structured literature review summarizing the most important studies on the role of PET or PET/CT with different radiopharmaceuticals in the clinical care of MCC.Merkel cell carcinoma (MCC) is a rare neuroendocrine skin malignancy usually arising as a nonspecific nodule on sun-exposed areas of the head and neck. Given the poor prognosis of this aggressive tumor, assessment of disease burden in pre- and post-treatment care may ensure an optimal management with significant implications for patient surveillance and prognosis. Although imaging has established its role in locally advanced or distant metastatic MCC, a standard imaging algorithm is yet to be determined and respective recommendations are mainly based on melanoma. Positron emission tomography/computed tomography (PET/CT) is increasingly evolving as a valuable imaging tool in metastatic or unresectable MCC, mostly utilizing the glucose analogue 18F-fluorodeoxyglucose (18F-FDG) as a radiotracer. Despite being inferior in detecting the disease in its early stages compared to the “gold standard” of sentinel lymph node biopsy, recent evidence suggests an important role for 18F-FDG PET/CT in the routine workup of localized MCC. Moreover, 68Ga-labeled somatostatin analogues have been employed as PET tracers in the field of MCC with promising, yet comparable to 18F-FDG, results. This article provides a structured literature review of the most important studies investigating the role of PET or PET/CT in the clinical practice of MCC.

Retrospective Multicenter Analysis of the Outcome of a Re-Induction with Immune Checkpoint Inhibitors in Advanced Merkel Cell Carcinoma

Significant progress has been made in the treatment of advanced Merkel cell carcinoma (MCC) by establishing immune checkpoint inhibitors (ICI). Tumor progression, durable response, or adverse events may lead to ICI discontinuation in MCC patients. If in these patients tumor progression occurs, the question remains if re-induction with ICI achieves renewed tumor response. This retrospective multicenter study evaluated patients in with re-induction of anti-PD-1/anti-PD-L1 therapy for advanced MCC. Clinical data were extracted at treatment initiation, tumor response, treatment cessation, and subsequent tumor response to re-induction. Eight patients from seven centers (mean age 67.8 years) were included. The median duration of initial therapy with anti-PD-1/anti-PD-L1 was 9.6 months (2–21 months). Two patients achieved complete response (CR), four patients partial response (PR), one patient stable disease (SD), while in one patient progressive disease (PD) occurred as best overall response (BOR) to ICI. Reason for discontinuation of ICI was PD in three patients and severe adverse events in five patients. Following a median anti-PD-1/anti-PD-L1 therapy-free interval of 9.5 months (3–18 months), re-induction with ICI therapy was initiated. Five of eight patients (62.5%) achieved an objective response upon re-induction, while in three patients, no response could be observed. Notably, adverse events, which had led to the discontinuation of the first ICI treatment line, were not observed upon re-induction. The initial response to immune checkpoint inhibitors seems to be an important marker for successful re-induction. Interestingly, adverse events leading to treatment discontinuation were not observed during re-induction.

1090P Real-world (RW) clinical outcomes in patients (pts) with locally advanced (LA) or metastatic Merkel cell carcinoma (mMCC) treated in United States (US) oncology clinical practices: Results from SPEAR-Merkel

1090P Real-world (RW) clinical outcomes in patients (pts) with locally advanced (LA) or metastatic Merkel cell carcinoma (mMCC) treated in United States (US) oncology clinical practices: Results from SPEAR-Merkel

1182P Baseline neutrophil-lymphocyte ratio and its variations after adjuvant radiotherapy predict clinical survival outcomes in locally advanced Merkel cell carcinoma (MCC)

High baseline neutrophil-lymphocyte ratio (NLR) ≥ 3.5 was shown to be a negative prognostic factor in several solid cancers including MCC. The present study explores the prognostic and predictive role of basal NLR and its variations after adjuvant radiotherapy (RT) in stage II-III MCC patients (pts). We retrospectively identified 95 stage II-III MCC pts referred to our Institution from 2004 to 2019. All pts had Eastern Cooperative Oncology Group Performance Status 0 or 1 and were negative for active infections and autoimmune disease. No pts received concomitant immunosuppressive/immunostimulating drugs. We collected NLR values at the following timepoints: baseline at diagnosis, within one month before RT start and within one month after RT completion. Hazard ratios (HRs) were calculated using Cox’s proportional hazards regression model. Overall DFS and OS were 17,9 and 42.1 months (mos) respectively. All pts underwent radical surgery, followed by RT treatment (28.5%, 27 pts) or follow up (FU) alone (71,5%, 68 pts). Median FU was 42.6 (4.6 - 235.5) mos. Baseline NLR was significantly associated with DFS (HR 1.71 95%CI 1.43-2.05, p<0.001) and OS (HR 1.40 95%CI 1.11-1.77 p=0.004). In 11 out 27 (40.7%) pts who underwent RT, a decrease of post-RT NRL values was observed in comparison to pre-RT NLR values. There was a trend towards worse mDFS in pts whose NLR increased after RT compared to those whose NLR decreased after RT (mPFS 13.1 vs 52 mos, 95%CI 0.86- 8.62; HR 2.73; p= 0.087). In the multivariate model, older age and baseline NLR were both strongly associated with worse DFS (HR_NLR 1.63; 95%CI 1.34-1.99 p<0.001) and OS (HR_NLR 1.44; 95%CI 1.10-1.90 p=0.008). Despite being a retrospective study design, RT seems to be able to modulate the frequencies of peripheral immune subsets and correlates with the shift to a more favorable peripheral immune profile. Further studies are needed to determine the role of NLR as potential prognostic and predictive biomarkers to consider when selecting MCC pts for adjuvant treatment.

Avelumab for advanced Merkel cell carcinoma in the Netherlands: a real-world cohort

BackgroundMerkel cell carcinoma (MCC) is associated with high recurrence rates and poor survival when metastatic disease is present. The immune checkpoint inhibitor avelumab has shown high response rates (RRs) and...

Sites of distant metastasis in Merkel cell carcinoma differ by primary tumor site and are of prognostic significance: A population-based study in the Surveillance, Epidemiology, and End Results database from 2010 to 2016

Sites of distant metastasis in Merkel cell carcinoma differ by primary tumor site and are of prognostic significance: A population-based study in the Surveillance, Epidemiology, and End Results database from 2010 to 2016

Avelumab for the treatment of patients with Merkel cell carcinoma

Merkel cell carcinoma is a rare and aggressive skin tumor that is difficult to treat even at early stages. Treatment approaches for advanced disease are limited and standard chemotherapy provides short-lived disease control in half of patients without significant impact on the overall survival. The new immunotherapy with anti-PD-1/PD-L1 inhibitors allows to improve clinical outcomes of this disease. Avelumab is a fully human IgG1 monoclonal anti- PD-L1 antibody that blocks the interaction between programmed cell death ligand 1 (PD-L1) on tumor cells and programmed cell death-1 receptor (PD-1) on T cells, thereby elimination immunosuppression in the tumor microenvironment. Avelumab provides disease control in 43,2% of the patients with metastatic/locally advanced unresectable Merkel cell carcinoma for the second and subsequent lines treatment with the objective response rate (ORR) 33%. The response was ongoing for ≥ 6 months in 86% of patient with median duration of response 40,5 months. Responses occurred irrespectively of PD-L1 expression and presence of polyomavirus in tumor cells (MCPyV), 3-year overall survival rate reached 32%. Avelumab is more effective for the first line of treatment, providing the disease control in 78,6% the patients with ORR 71,5% lasting for ≥ 6 months. Treatment is well tolerated for the first, second and subsequent lines, demonstrating the adequate safety profile. The most common adverse events were fatigue, diarrhea and nausea. There were 7 patients in Russia treated with avelumab for metastatic/locally advanced unresectable Merkel cell carcinoma.

Current concepts and approaches to merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive and rare cutaneous cancer of the mechanoreceptor unit of the skin with a neuroendocrine origin. MCC incidence has been on the rise over the past two decades. Risk factors include old age, chronic UV exposure, and immunosuppression. Although MCC is a cutaneous malignancy that is often misdiagnosed as a benign nodule at the time of diagnosis, it has an aggressive disease course due to its high recurrence and metastatic potential. The PD-1/PD-L1 checkpoint blockade has recently shown promising results in the management of advanced MCC. Avelumab and pembrolizumab are considered the new standard of care for metastatic MCC. Despite advances in the field, studies are needed to elucidate the role of immunotherapy for patients who are resistant to treatment. Most ongoing clinical trials aim to assess the efficacy of checkpoint inhibitor combination therapies. This article reviews the most current literature on the surgical and medical management of MCC.

Advanced Merkel cell carcinoma-A focus on medical drug therapy.

Merkel cell carcinoma (MCC) is a rare but aggressive non-melanoma skin cancer with significant morbidity and mortality. Treatment of choice for primary and locoregional MCC is complete surgical removal with sentinel lymphonodectomy and postsurgical radiotherapy of tumor basin and locoregional lymph nodes. In nonresectable and advanced tumors, drug therapy is indicated. While cytotoxic chemotherapy has resulted in higher response rates, overall survival remained nearly unaffected. With a better insight into tumor development and biology, new treatment s became available. Immune checkpoint inhibitors result in durable responses with a better safety profile that classical combined chemotherapy. Combinations of immune checkpoint inhibitors with and without radiotherapy help to overcome acquired drug-resistance. New compounds for vaccination and oral use are on the horizon. Despite all progress, treatment of MCC remains a challenge that needs close interdisciplinary teamwork.

865 Immunotherapy in advanced Merkel cell carcinoma: Frequent responses but a potentially concerning recurrence rate after therapy discontinuation

865 Immunotherapy in advanced Merkel cell carcinoma: Frequent responses but a potentially concerning recurrence rate after therapy discontinuation

906 Early effector T-cell densities predict response in patients with advanced Merkel cell carcinoma treated with anti-PD-1

Background: We previously nominated PD-1+ cell densities in pre-treatment tumor specimens as a potential biomarker for response to pembrolizumab (anti-PD-1) in patients with advanced Merkel cell carcinoma (MCC). Here, we used multiplex immunofluorescence (mIF) in a separate cohort of MCC patients treated with anti-PD-1 to determine which immune cell subset(s) contribute PD-1 to the tumor microenvironment (TME). We also characterized PD-1 expression intensity on lymphocytes, as an indication of their functional state, and tested for an association with anti-PD-1 response. Methods: We performed mIF staining on pre-treatment formalin-fixed paraffin embedded tumor specimens from 23 unique patients. The mIF panel included PD-1, CD4, CD8, CD20, FoxP3, and CD56 (tumor marker). The density of each cell type and intensity of PD-1 expression (PD-1lovs. PD-1hi) were determined and correlated with response assessments by RECIST1.1. Results: Total PD-1 cell densities were higher in responders vs. non-responders, supporting our original findings. Additionally, median CD4, CD8 and CD20 cell densities were increased in those who responded to therapy. While CD8+ cells are often cited as contributing the majority of PD-1 to the TME, we found an equal proportion was contributed by CD4+ cells. Approximately 4% of the CD8+PD-1+ cells also expressed FoxP3. Of the immune cell phenotypes tested, CD8+FoxP3+PD-1lodensities showed the strongest association with response to anti-PD-1 (p=0.01, Mann-Whitney U test). Conclusions: The next generation of tissue-based biomarkers for predicting response to immunotherapy are likely to utilize multiplex IF/IHC technologies, which can quantify complex cell phenotypes in situ. Here, we highlight CD8+FoxP3+PD-1loas a key cell type associated with anti-PD-1 response. Representing early, tumor-specific effector T-cells with strong proliferative potential and IFN-gamma secretion, CD8+FoxP3+ cells warrant additional exploration as a predictive biomarker.

Inhibition of PI3K by copanlisib exerts potent antitumor effects on Merkel cell carcinoma cell lines and mouse xenografts

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer with steadily increasing incidence and poor prognosis. Despite recent success with immunotherapy, 50% of patients still succumb to their diseases. To date, there is no Food and Drug Administration-approved targeted therapy for advanced MCC. Aberrant activation of phosphatidylinositide-3-kinase (PI3K)/AKT/mTOR pathway is frequently detected in MCC, making it an attractive therapeutic target. We previously found PI3K pathway activation in human MCC cell lines and tumors and demonstrated complete clinical response in a Stage IV MCC patient treated with PI3K inhibitor idelalisib. Here, we found that both PI3K-α and -δ isoforms are abundantly expressed in our MCC cell lines and clinical samples; we therefore examined antitumor efficacy across a panel of five PI3K inhibitors with distinctive isoform-specificities, including idelalisib (PI3K-δ), copanlisib (PI3K-α/δ), duvelisib (PI3K-γ/δ), alpelisib (PI3K-α), and AZD8186 (PI3K-β/δ). Of these, copanlisib exerts the most potent antitumor effects, markedly inhibiting cell proliferation, survival, and tumor growth by suppressing PI3K/mTOR/Akt activities in mouse models generated from MCC cell xenografts and patient-derived tumor xenografts. These results provide compelling preclinical evidence for application of copanlisib in advanced MCC with aberrant PI3K activation for which immunotherapy is insufficient, or patients who are unsuitable for immunotherapy.

Aggressive Behaviour of Merkel Cell Carcinoma in a Kidney Transplant Patient Receiving Tacrolimus Treatment – Is There an Alternative in Immune Checkpoint Inhibitor Treatment?

Background: Merkel cell carcinoma (MCC) is a rare skin neoplasm first described by Toker in 1972. The tumor usually presents in the sixth to seventh decade of life as a solitary reddish-brown to violaceous subcutaneous nodule on the head, neck, or the extremities. It is seen at an earlier age only in immunocompromised patients like transplant patients in immunosuppressive therapy. Thus, cancer has now become the second cause of death among transplant patients. The tumor growth is rapid in MCC patients, and for metastatic disease, no substantial benefit is obtained by chemotherapy. A new drug has recently become available, an immune checkpoint inhibitor (CPI), avelumab, that is able to delay disease progression significantly. However, there are no current guidelines for the use of immune checkpoint inhibitors in transplant patients. Case Presentation: We describe the case of a 55-year-old kidney transplant patient on immunosuppressive therapy with tacrolimus with an early occurrence of a Merkel cell carcinoma whose aggressive behaviour could not be hampered by Avelumab, due to fear of allograft rejection. Conclusion: CPI therapy is potentially lifesaving in advanced MCC. Further studies are urgently needed to test its benefit in this rapidly expanding field of post-transplant malignancies where there are only a few and less effective therapeutic options.

Effectiveness of PD1-inhibitors in advanced Merkel cell carcinoma: Real life data in a Swedish cohort.

e22063 Background: Merkel Cell Carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer that affects the elderly. Most cases are associated with the Merkel cell polyomavirus. It has previously been shown in clinical trials that MCC respond to immunotherapy with PD1 and PDL1-inhibition. PD1-inhibitiors have been used to treat MCC at Karolinska University Hospital in Sweden since 2016. The aim of this study is to describe the PD1-MCC-cohort at Karolinska. Methods: Patients with inoperable MCC that were treated with PD1-inhibitor at the oncology dept between August 2016 and February 2020 at Karolinska were included in the study, and response data was assessed retrospectively. Response was assessed clinically and through CT-scans. Results: Among 12 treated pts, median age was 75 yrs, 8 male and 4 female, 10 were treatment naive, 2 with prior chemotherapy. 10 pts received pembrolizumab and 2 pts nivolumab. No pts discontinued treatment due to side-effects. Comorbidities seen in the cohort were amongst others Atrial fibrillation (4 pts), Systemic Lupus Erythematosus (1), Hypertension (6), COPD (1), Aortic stenosis (2) and congestive heart failure (1). Follow-up time was median 10 months (range 2-43). First evaluation varied between 2-4 months with the majority at ~3 months. At first evaluation ORR was 75% and PFS and OS was 75% and 100% respectively. At 10 months, PFS and OS rates were 58% and 67% respectively. At study end mean PFS was 15,4 months and mean OS 17,8 months. 6 pts (50%) were still in response. Conclusions: PD1-inhibitors in clinical use in this cohort induced rapid and durable tumor responses in patients with advanced MCC, and the treatment was well tolerated. Our conclusion is that a PD1-inhibitor is a feasible and effective treatment for advanced Merkel Cell Carcinoma in the clinical setting.

Real-world clinical outcomes in avelumab-treated patients (pts) in the United States (U.S.) from SPEAR-Merkel –Study informing treatment Pathway dEcisions in Merkel cell cARcinoma (MCC).

e22029 Background: MCC is a rare, aggressive disease associated with poor prognosis. Avelumab, a fully human anti–PD-L1 monoclonal antibody, was the first immune checkpoint inhibitor approved by the FDA for the treatment of metastatic MCC (mMCC). In the JAVELIN Merkel 200 trial (Clinical trial information: NCT02155647), avelumab resulted in durable responses and a high objective response rate (ORR) in pts with mMCC. This retrospective descriptive study assessed real-world clinical outcomes in avelumab-treated pts with locally advanced MCC (laMCC) and mMCC in a US community oncology setting. Methods: This study included data on avelumab-treated laMCC and mMCC pts from 1/1/17 to 3/31/19 within The US Oncology Network. Study data were captured through 9/30/19 using structured fields and chart review of iKnowMed electronic healthcare records. Real-world ORR was assessed. Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Results: 33 pts initiated treatment with avelumab (laMCC n = 11; mMCC n = 22) and were followed up for a median of 10.9 months (range, 0.5-27.2 months). Median age was 77 years (range, 44-90+ years), 78.8% of pts were male, and the majority (84.8%) of pts were treated in the first-line setting. During treatment, 27.2% of pts had emergency department visits and 39.4% were hospitalized; 1% and 23.1%, respectively, were treatment related. Clinical outcomes are reported in the table. Conclusions: This is the first study to examine pts with laMCC treated with avelumab in a real-world setting. Although the sample population is small, results suggest the clinical benefits in the real world in pts with mMCC treated with avelumab are consistent with benefits reported in the JAVELIN Merkel 200 trial. Clinical trial information: NCT02155647 . [Table: see text]

Treatment of primary Merkel cell carcinoma: Radiotherapy can be an effective, less morbid alternative to surgery

The standard treatment approach for localised Merkel cell carcinoma (MCC) is wide surgical excision followed by adjuvant radiotherapy. However extensive surgery for locally advanced MCC may cause morbidity and disfigurement, compromise function and delay adjuvant therapy. Since MCC is a highly radiosensitive tumour, an alternative treatment option for advanced MCCs, especially those in anatomically challenging locations, is radiotherapy. Complete and durable control is achieved in up to 90% of cases if the definitive treatment of primary MCC is with radiotherapy. It is generally less morbid than surgery and can produce excellent cosmetic and functional outcomes.

FDA Accelerated Approval of Pembrolizumab for Recurrent Locally Advanced or Metastatic Merkel Cell Carcinoma.

On December 19, 2018, the Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA, Merck & Co. Inc., Whitehouse Station, NJ) for adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). Approval was based on Cancer Immunotherapy Trials Network protocol 9, also known as KEYNOTE-017 (NCT02267603), a multicenter, nonrandomized, open-label trial that enrolled 50 patients with recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for their advanced disease. The major efficacy outcome measures were overall response rate (ORR) and response duration assessed by blinded independent central review per RECIST 1.1. The ORR was 56% (95% confidence interval: 41, 70) with a complete response rate of 24%. The median response duration was not reached. Among the 28 patients with responses, 96% had response durations of greater than 6 months and 54% had response durations of greater than 12 months. The most common adverse reactions of pembrolizumab reported in at least 20% of patients who received pembrolizumab as a single agent were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. IMPLICATIONS FOR PRACTICE: This report presents key information on the basis for the Food and Drug Administration's accelerated approval of pembrolizumab for the treatment of recurrent locally advanced or metastatic Merkel cell carcinoma, including efficacy and safety information. This approval provides patients and physicians with an additional treatment option for this aggressive and life-threatening carcinoma.

Landscape of current and future therapies of Merkel cell carcinoma.

Merkel cell carcinoma is rare and aggressive skin cancer, which occurrence is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus. In recent years, significant progress in understanding the mechanism of Merkel cell carcinoma pathogenesis has been observed. This neoplasm often expresses PD-L1, and MCPyV-specific T cells can express PD-1 thus PD-1/PD-L1 checkpoint therapies seem to be remarkably interesting treatment options. Many clinical trials are currently being conducted to confirm their effectiveness and safety for this group of patients. However, only about half of advanced Merkel cell carcinoma patients could achieve remission or disease stabilization through PD-1/PD-L1 checkpoint therapies thus innovative treatments are still needed. In this article, we have presented current and future directions in the development of Merkel cell carcinoma therapy.