22LBA Activity of PD-1 blockade with pembrolizumab as first systemic therapy in patients with advanced Merkel cell carcinoma

Nghiem, P.; Daud, Adil; Friedlander, Philip; Kluger, Harriet M.; Kohrt, Holbrook E.; Kudchadkar, Ragini R.; Lipson, Evan J.; Lundgren, Lisa; Margolin, Kim; Reddy, Sandeep; Shantha, Erica; Sharfman, William H.; Sharon, Eran; Thompson, Julie L.; Topalian, Suzanne L.; Cheever, Mac

doi:10.1016/s0959-8049(15)30074-5

Cited by 22 publications

(16 citation statements)

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“…These responses correlate in part with PD-L1 expression in the tumor cells themselves (39). More recently, a phase I trial of pembrolizumab demonstrated an approximate 80% response rate in patients with MCC, although as of yet, no correlative studies have been reported describing biomarkers that might be predictive of response (14). Only a few studies have explored PD-1 and PD-L1 expression in MCC (40, 41).…”

Section: Discussionmentioning

confidence: 99%

“…MCC develops more frequently in patients with immune dysfunction/suppression than immunocompetent patients (5), and immunosuppressed patients with MCC exhibit reduced survival compared with stage-matched immunocompetent counterparts (6, 7, 13). Immune checkpoint blockade (anti-PD-1) has shown an approximately 80% response rate in phase I trials of MCC (14). Survival in MCC correlates with changes in immune response gene expression signatures as well as the relative density of the associated immune infiltrate (15–17).…”

Section: Introductionmentioning

confidence: 99%

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Density, Distribution, and Composition of Immune Infiltrates Correlate with Survival in Merkel Cell Carcinoma

Feldmeyer

Hudgens

Ray-Lyons

et al. 2016

Clinical Cancer Research

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Purpose Merkel cell carcinoma (MCC) is an aggressive cancer with frequent metastasis and death with few effective therapies. Because programmed death ligand-1 (PD-L1) is frequently expressed in MCC, immune checkpoint blockade has been leveraged as treatment for metastatic disease. There is therefore a critical need to understand the relationships between MCPyV status, immune profiles, and patient outcomes. Experimental Design IHC for CD3, CD8, PD-1, PD-L1, and MCPyV T-antigen (to determine MCPyV status) was performed on 62 primary MCCs with annotated clinical outcomes. Automated image analysis quantified immune cell density (positive cells/mm2) at discrete geographic locations (tumor periphery, center, and hotspot). T-cell receptor sequencing (TCRseq) was performed in a subset of MCCs. Results No histopathologic variable associated with overall survival (OS) or disease-specific survival (DSS), whereas higher CD3+ (P = 0.004) and CD8+ (P = 0.037) T-cell density at the tumor periphery associated with improved OS. Higher CD8+ T-cell density at the tumor periphery associated with improved DSS (P = 0.049). Stratifying MCCs according to MCPyV status, higher CD3+ (P = 0.026) and CD8+ (P = 0.015) T-cell density at the tumor periphery associated with improved OS for MCPyV+ but not MCPyV− MCC. TCRseq revealed clonal overlap among MCPyV+ samples, suggesting an antigen-specific response against a unifying antigen. Conclusions These findings establish the tumor-associated immune infiltrate at the tumor periphery as a robust prognostic indicator in MCC and provide a mechanistic rationale to further examine whether the immune infiltrate at the tumor periphery is relevant as a biomarker for response in ongoing and future checkpoint inhibitor trials in MCC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Density, Distribution, and Composition of Immune Infiltrates Correlate with Survival in Merkel Cell Carcinoma

Feldmeyer

Hudgens

Ray-Lyons

et al. 2016

Clinical Cancer Research

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“…There are already hints that virus-associated cancers respond at high rates to PD1 pathway blockade. Preliminary data show that advanced MCCs, of which approximately 80% are virus associated, have a response rate of higher than 50% to anti-PD1 therapy (pembrolizumab) (meeting abstract) 105 . Substantial response rates among both HBV- and HCV-associated hepatocellular carcinomas to anti-PD1 therapy have also been reported (meeting abstract) 106 .…”

Section: Virus-associated Cancersmentioning

confidence: 99%

Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy

et al. 2016

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With recent approvals for multiple therapeutic antibodies that block cytotoxic T lymphocyte associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) in melanoma, non-small-cell lung cancer and kidney cancer, and additional immune checkpoints being targeted clinically, many questions still remain regarding the optimal use of drugs that block these checkpoint pathways. Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate, highlighted by recent approvals for two PDL1 diagnostic tests. Here, we discuss biomarkers for anti-PD1 therapy based on immunological, genetic and virological criteria. The unique biology of the CTLA4 immune checkpoint, compared with PD1, requires a different approach to biomarker development. Mechanism-based insights from such studies may guide the design of synergistic treatment combinations based on immune checkpoint blockade.

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“…At least one patient with MCC showed a response to pembrolizumab during a phase I trial [53]. A small ongoing phase II trial of pembrolizumab as a first-line treatment for advanced MCC recently reported a 71 % initial response rate among 17 evaluable patients [54••, 55]. It remains to be seen if this response rate will be generalizable and if responses will be durable.…”

Section: Emerging Treatmentsmentioning

confidence: 99%

Merkel Cell Carcinoma Therapeutic Update

Cassler

Merrill

Bichakjian

et al. 2016

Curr. Treat. Options in Oncol.

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Opinion statement Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Early-stage disease can be cured with surgical resection and radiotherapy (RT). Sentinel lymph node biopsy (SLNB) is an important staging tool, as a microscopic MCC is frequently identified. Adjuvant RT to the primary excision site and regional lymph node bed may improve locoregional control. However, newer studies confirm that patients with biopsy-negative sentinel lymph nodes may not benefit from regional RT. Advanced MCC currently lacks a highly effective treatment as responses to chemotherapy are not durable. Recent work suggests that immunotherapy targeting the programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint holds great promise in treating advanced MCC and may provide durable responses in a portion of patients. At the same time, high-throughput sequencing studies have demonstrated significant differences in the mutational profiles of tumors with and without the Merkel cell polyomavirus (MCV). An important secondary endpoint in the ongoing immunotherapy trials for MCC will be determining if there is a response difference between the virus-positive MCC tumors that typically lack a large mutational burden and the virus-negative tumors that have a large number of somatic mutations and predicted tumor neoantigens. Interestingly, sequencing studies have failed to identify a highly recurrent activated driver pathway in the majority of MCC tumors. This may explain why targeted therapies can demonstrate exceptional responses in case reports but fail when treating all comers with MCC. Ultimately, a precision medicine approach may be more appropriate for treating MCC, where identified driver mutations are used to direct targeted therapies. At a minimum, stratifying patients in future clinical trials based on tumor viral status should be considered as virus-negative tumors are more likely to harbor activating driver mutations.

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22LBA Activity of PD-1 blockade with pembrolizumab as first systemic therapy in patients with advanced Merkel cell carcinoma

Cited by 22 publications

References 0 publications

Density, Distribution, and Composition of Immune Infiltrates Correlate with Survival in Merkel Cell Carcinoma

Density, Distribution, and Composition of Immune Infiltrates Correlate with Survival in Merkel Cell Carcinoma

Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy

Merkel Cell Carcinoma Therapeutic Update

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