Response rate and durability of chemotherapy for metastatic Merkel cell carcinoma among 62 patients.

Iyer, Jayasri G.; Blom, Astrid; Doumani, Ryan; Lewis, Christopher W.; Anderson, Austin; Ma, Congcong; Parvathaneni, Upendra; Bhatia, Shailender; Nghiem, P.

doi:10.1200/jco.2014.32.15_suppl.9091

Cited by 26 publications

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“…Although additional experience with longer follow-up and larger patient cohorts is needed, these early findings compare favorably with results for standard chemotherapy regimens for this tumor, 7,39 for which retrospective studies show a median progression-free survival of approximately 3 months, with progressive disease developing in 90% of patients within 10 months. 6 Pembrolizumab was associated with previously described toxic effects in the relatively elderly patient population included in this study (median age, 68 years); we observed a 15% rate of grade 3 or 4 adverse events that were managed by discontinuation of pembrolizumab and initiation of glucocorticoid treatment as needed, without clear adverse effects on the magnitude or duration of tumor response.…”

Section: Discussionmentioning

confidence: 49%

“…For advanced Merkel-cell carcinoma, cytotoxic chemotherapy offers a median progression- free survival of only 3 months. 6,7 Merkel-cell carcinoma has long been considered to be an immunogenic cancer because it occurs more frequently and has a worse prognosis in immunosuppressed persons than in those with no immune suppression. 8 Two major causative factors have been identified: ultraviolet (UV) light and the Merkel-cell polyomavirus (MCPyV), whose large T antigen is expressed in tumor cells and inactivates p53 and Rb.…”

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confidence: 99%

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PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma

et al. 2016

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BACKGROUND Merkel-cell carcinoma is an aggressive skin cancer that is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus (MCPyV). Advanced Merkel-cell carcinoma often responds to chemotherapy, but responses are transient. Blocking the programmed death 1 (PD-1) immune inhibitory pathway is of interest, because these tumors often express PD-L1, and MCPyV-specific T cells express PD-1. METHODS In this multicenter, phase 2, noncontrolled study, we assigned adults with advanced Merkel-cell carcinoma who had received no previous systemic therapy to receive pembrolizumab (anti–PD-1) at a dose of 2 mg per kilogram of body weight every 3 weeks. The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. Efficacy was correlated with tumor viral status, as assessed by serologic and immunohistochemical testing. RESULTS A total of 26 patients received at least one dose of pembrolizumab. The objective response rate among the 25 patients with at least one evaluation during treatment was 56% (95% confidence interval [CI], 35 to 76); 4 patients had a complete response, and 10 had a partial response. With a median follow-up of 33 weeks (range, 7 to 53), relapses occurred in 2 of the 14 patients who had had a response (14%). The response duration ranged from at least 2.2 months to at least 9.7 months. The rate of progression-free survival at 6 months was 67% (95% CI, 49 to 86). A total of 17 of the 26 patients (65%) had virus-positive tumors. The response rate was 62% among patients with MCPyV-positive tumors (10 of 16 patients) and 44% among those with virus-negative tumors (4 of 9 patients). Drug-related grade 3 or 4 adverse events occurred in 15% of the patients. CONCLUSIONS In this study, first-line therapy with pembrolizumab in patients with advanced Merkel-cell carcinoma was associated with an objective response rate of 56%. Responses were observed in patients with virus-positive tumors and those with virus-negative tumors. (Funded by the National Cancer Institute and Merck; ClinicalTrials.gov number, NCT02267603.)

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Section: Discussionmentioning

confidence: 49%

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confidence: 99%

PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma

et al. 2016

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“…Responses to chemotherapy were rarely durable, even if the metastatic disease burden was small, so early detection of MCC spread did not improve survival. 13 With the advent of immunotherapies and more durable treatment responses, 14,15 early identification of metastases could improve response and survival rates. A comprehensive analysis of metastatic patterns would inform such surveillance practices.…”

Section: Introductionmentioning

confidence: 99%

Patterns of distant metastases in 215 Merkel cell carcinoma patients: Implications for prognosis and surveillance

et al. 2019

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Approximately one‐third of Merkel cell carcinoma (MCC) patients eventually develop distant metastatic disease. Little is known about whether the location of the primary lesion is predictive of initial distant metastatic site, or if survival likelihood differs depending on the metastatic site. Such data could inform imaging/surveillance practices and improve prognostic accuracy. Multivariate and competing‐risk analyses were performed on a cohort of 215 MCC patients with distant metastases, 31% of whom had two or more initial sites of distant metastasis. At time of initial distant metastasis in the 215 patients, metastatic sites (n = 305) included non‐regional lymph nodes (present in 41% of patients), skin/body wall (25%), liver (23%), bone (21%), pancreas (8%), lung (7%), and brain (5%). Among the 194 patients who presented with MCC limited to local or regional sites (stage I‐III) but who ultimately developed distant metastases, distant progression occurred in 49% by 1 year and in 80% by 2 years following initial diagnosis. Primary MCC locations differed in how likely they were to metastasize to specific organs/sites (P < .001). For example, liver metastases were far more likely from a head/neck primary (43% of 58 patients) versus a lower limb primary (5% of 39 patients; P < .0001). Skin‐only distant metastasis was associated with lower MCC‐specific mortality as compared to metastases in multiple organs/sites (HR 2.7; P = .003), in the liver (HR 2.1; P = .05), or in distant lymph nodes (HR 2.0; P = .045). These data reflect outcomes before PD1‐pathway inhibitor availability, which may positively impact survival. In conclusion, primary MCC location is associated with a pattern of distant spread, which may assist in optimizing surveillance. Because it is linked to survival, the site of initial distant metastasis should be considered when assessing prognosis.

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“…It has not been possible to effectively treat advanced disease, leading to a 5-year survival rate of 0–18% for patients with distant metastatic disease and a median survival of only 9.6 months from diagnosis of initial metastasis to death (5–7). Although approximately half of patients initially respond to chemotherapy, responses are not durable, with a median time to progression of only 94 days (8), highlighting the need for improved therapies to treat MCC.…”

Section: Introductionmentioning

confidence: 99%

Tumor-Infiltrating Merkel Cell Polyomavirus-Specific T Cells Are Diverse and Associated with Improved Patient Survival

Miller

Church

Dong

et al. 2017

Cancer Immunology Research

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Tumor-infiltrating CD8+ T cells are associated with improved survival of patients with Merkel cell carcinoma (MCC), an aggressive skin cancer causally linked to Merkel cell polyomavirus (MCPyV). However, CD8+ T-cell infiltration is robust in only 4%–18% of MCC tumors. We characterized the T-cell receptor (TCR) repertoire restricted to one prominent epitope of MCPyV (KLLEIAPNC, “KLL”) and assessed whether TCR diversity, tumor infiltration, or T-cell avidity correlated with clinical outcome. HLA-A*02:01/KLL tetramer+ CD8+ T cells from MCC patient peripheral blood mononuclear cells (PBMC) and tumor-infiltrating lymphocytes (TIL) were isolated via flow cytometry. TCRβ (TRB) sequencing was performed on tetramer+ cells from PBMC or TIL (n = 14) and matched tumors (n = 12). Functional avidity of T-cell clones was determined by IFNγ production. We identified KLL tetramer+ T cells in 14% of PBMC and 21% of TIL from MCC patients. TRB repertoires were diverse (mean of 12 and 29 clonotypes/patient in PBMC and TIL, respectively) and mostly private. An increased fraction of KLL-specific TIL (> 1.9%) was associated with significantly increased MCC-specific survival P = 0.0009). Forty-two distinct KLL-specific TCRα/β pairs were identified. T-cell clones from patients with improved MCC-specific outcomes were more avid (P < 0.05) and recognized an HLA-appropriate MCC cell line. T cells specific for a single MCPyV epitope display marked TCR diversity within and between patients. Intratumoral infiltration by MCPyV-specific T cells was associated with significantly improved MCC-specific survival, suggesting that augmenting the number or avidity of virus-specific T cells may have therapeutic benefit.

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Response rate and durability of chemotherapy for metastatic Merkel cell carcinoma among 62 patients.

Cited by 26 publications

References 0 publications

PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma

PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma

Patterns of distant metastases in 215 Merkel cell carcinoma patients: Implications for prognosis and surveillance

Tumor-Infiltrating Merkel Cell Polyomavirus-Specific T Cells Are Diverse and Associated with Improved Patient Survival

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