BackgroundMerkel cell carcinoma (MCC) is an aggressive skin cancer associated with poor survival. Programmed cell death-1 (PD-1) pathway inhibitors have shown high rates of durable tumor regression compared with chemotherapy for MCC. The current study was undertaken to assess baseline and on-treatment factors associated with MCC regression and 3-year survival, and to explore the effects of salvage therapies in patients experiencing initial non-response or tumor progression after response or stable disease following first-line pembrolizumab therapy on Cancer Immunotherapy Trials Network-09/KEYNOTE-017.MethodsIn this multicenter phase II trial, 50 patients with advanced unresectable MCC received pembrolizumab 2 mg/kg every 3 weeks for ≤2 years. Patients were followed for a median of 31.8 months.ResultsOverall response rate to pembrolizumab was 58% (complete response 30%+partial response 28%; 95% CI 43.2 to 71.8). Among 29 responders, the median response duration was not reached (NR) at 3 years (range 1.0+ to 51.8+ months). Median progression-free survival (PFS) was 16.8 months (95% CI 4.6 to 43.4) and the 3-year PFS was 39.1%. Median OS was NR; the 3-year OS was 59.4% for all patients and 89.5% for responders. Baseline Eastern Cooperative Oncology Group performance status of 0, greater per cent tumor reduction, completion of 2 years of treatment and low neutrophil-to-lymphocyte ratio were associated with response and longer survival. Among patients with initial disease progression or those who developed progression after response or stable disease, some had extended survival with subsequent treatments including chemotherapies and immunotherapies.ConclusionsThis study represents the longest available follow-up from any first-line anti-programmed death-(ligand) 1 (anti-PD-(L)1) therapy in MCC, confirming durable PFS and OS in a proportion of patients. After initial tumor progression or relapse following response, some patients receiving salvage therapies survived. Improving the management of anti-PD-(L)1-refractory MCC remains a challenge and a high priority.Trial registration numberNCT02267603.
Summary Background Merkel cell carcinoma (MCC) is an aggressive, high‐grade, cutaneous neuroendocrine tumour (NET). Agents blocking programmed death 1/programmed death ligand 1 have efficacy in metastatic MCC (mMCC), but half of patients do not derive durable benefit. Somatostatin analogues (SSAs) are commonly used to treat low‐ and moderate‐grade NETs that express somatostatin receptors (SSTRs). Objectives To assess SSTR expression and the efficacy of SSAs in mMCC, a high‐grade NET. Methods In this retrospective study of 40 patients with mMCC, SSTR expression was assessed radiologically by somatostatin receptor scintigraphy (SRS; n = 39) and/or immunohistochemically when feasible (n = 9). Nineteen patients (18 had SRS uptake in MCC tumours) were treated with SSA. Disease control was defined as progression‐free survival (PFS) of ≥ 120 days after initiation of SSA. Results Thirty‐three of 39 patients (85%) had some degree (low 52%, moderate 23%, high 10%) of SRS uptake. Of 19 patients treated with SSA, seven had a response‐evaluable target lesion; three of these seven patients (43%) experienced disease control, with a median PFS of 237 days (range 152–358). Twelve of 19 patients did not have a response‐evaluable lesion due to antecedent radiation; five of these 12 (42%) experienced disease control (median PFS of 429 days, range 143–1757). The degree of SSTR expression (determined by SRS and/or immunohistochemistry) did not correlate significantly with the efficacy endpoints. Conclusions In contrast to other high‐grade NETs, mMCC tumours appear frequently to express SSTRs. SSAs can lead to clinically meaningful disease control with minimal side‐effects. Targeting of SSTRs using SSA or other novel approaches should be explored further for mMCC.
Merkel cell carcinoma (MCC) is an aggressive skin cancer associated with a high risk of local recurrence and distant metastasis. Optimal care of this potentially life-threatening cancer is critical but challenging because: physicians are often unfamiliar with its management due to rarity, and MCC management remains controversial, in part because it is rapidly evolving across multiple specialties. While guidelines offer a broad overview of management, they are often not sufficient when making decisions for individual patients. Herein, we present a literature review as well as practical approaches adopted at our institutions for staging, surveillance and therapy of MCC. Each of these areas are discussed in light of how they can be appropriately customized for prevalent but challenging situations. We also provide representative examples of MCC patient scenarios and how they were managed by a multidisciplinary team to identify suitable evidence-based, individualized treatment plans.
9566 Background: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a recurrence rate of 40%. Early detection of recurrence can improve outcomes, and effective surveillance is crucial for management of patients with MCC. While Merkel cell polyomavirus (MCPyV) oncoprotein serology is useful in surveillance for MCPyV-positive MCC tumors, patients with MCPyV-negative tumors have no available blood biomarkers and require frequent imaging. This prospective, multicenter study assessed whether circulating tumor DNA (ctDNA) can assess disease burden and detect recurrence regardless of virus status. Methods: A total of 328 blood samples were collected from 125 patients at various time points with a median follow-up of 6 months (range: 0-21 months) between April 2020 to January 2022. Whole-exome sequencing was performed on tumor tissue and matched normal blood to identify a set of somatic, clonal single nucleotide variants, which were tracked in subsequent blood (plasma) samples using a personalized and multiplex PCR-NGS based ctDNA assay (Signatera). Clinically evident disease was defined as MCC noted either by physical exam or by imaging, and molecular evidence of disease was defined as a positive ctDNA test. Surveillance phase began once there was no clinically evident or molecular evidence of disease. Results: Among 125 patients, 47 (38%) had clinically evident MCC and all were found to be ctDNA-positive at the first time point (sensitivity: 100%; 95% CI: 91-100%). Of the 47, 24 were newly diagnosed with MCC and had a median primary tumor size of 2.2 cm (range 0.5-8.5 cm) and a median ctDNA value of 26 mean tumor molecules (MTM)/mL (range: 0.08-1470 MTM/mL). Primary tumor diameter and ctDNA value were strongly correlated (Spearman’s r = 0.81, p < 0.001). Of the 125 patients, 73 (58%) patients were assessed in the surveillance setting and had a total of 152 plasma samples available for longitudinal ctDNA testing. Over this period, 7 ctDNA tests were positive while 145 were negative. After a positive test, 5/7 developed a clinically evident recurrence (4 within 60 days). Of the remaining 2 without clinical recurrence, one had < 60 days of follow-up at time of data analysis. The estimated risk of recurrence, accounting for incomplete follow-up, was 57% within 60 days of a positive ctDNA test (n = 7 tests). In contrast, after a negative ctDNA test (n = 145 tests), the risk of recurrence was 0% within 60 days and 3% between 60-90 days. Conclusions: To our knowledge, this is the largest study to explore ctDNA testing in MCC patients. This study demonstrates that ctDNA testing can detect MCC recurrence early and is a promising clinical surveillance tool regardless of tumor viral status.
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