Table 8.
Possible predictors to immune checkpoint inhibitor response in locally advanced and metastatic Merkel cell carcinoma.
| Potential Predictor; Assessment | Number of Patients and Type of Malignancy | Treatment | Value as Predictor | Ref. |
|---|---|---|---|---|
| Previous lines of treatment; clinical | 38 advanced MCCs | Pembrolizumab, nivolumab, avelumab, nivolumab + ipilimimab | Negative predictor (p-value = 0.0066) |
Knepper et al., 2019 [17] |
| Unimpaired performance status, absence of immunosuppression; clinical | 41 advanced MCCs | Pembrolizumab, nivolumab, avelumab | Positive predictors | Spassova et al., 2020 [19] |
| Impaired performance status (A), completion of 2 years of treatment(B); clinical | 50 advanced MCCs | Pembrolizumab | A: negative predictor; B: positive predictor |
Nghiem et al., 2021 [84] |
| Absence of immunosuppression, limited number of tumor-involved organ systems; clinical | 114 unresectable MCCs | Pembrolizumab, nivolumab, avelumab | Negative predictors | Spassova et al., 2022 [194] |
| BMI ≥ 30; clinical | 20 advanced MCCs | Avelumab | Positive predictor of longer time to treatment failure (p-value = 0.004) and objective RR (p-value = 0.01) | Badalamenti et al., 2022 [106] |
| MCPyV-specific B-cells and T-cells responses; blood-based | 26 advanced MCCs | Pembrolizumab | Not confirmed as predictor, related to tumor burden | Miller et al., 2018 [195] |
| Reduction of neuron-specific enolase; blood based | 23 advanced MCCs | Immunotherapy | Possible positive predictor | van Veenendaal et al. 2021 [196] |
| PD-L1 expression; immunohistochemical | 88 m-MCCs | Avelumab | Not confirmed as predictor | Kaufman et al., 2018 [99] |
| PD-L1 expression; immunohistochemical | 27 advanced MCCs | Pembrolizumab, nivolumab, avelumab, nivolumab + ipilimimab | Not confirmed as predictor (p-value = 0.606) | Knepper et al., 2019 [17] |
| PD-L1 expression; immunohistochemical | 47 la- MCCs and m-MCCs | Pembrolizumab | Not confirmed as predictor (p-value = 0.68), associated to improved PFS and OS | Nghiem et al., 2019 [18] |
| PD-L1 expression; immunohistochemical | 41 advanced MCCs | Pembrolizumab, nivolumab, avelumab, | Not confirmed as predictor | Spassova et al., 2020 [19] |
| PD-L1 expression; immunohistochemical | 116 m-MCCs | Avelumab | Not confirmed as predictor, responses tended to be higher in PD-L1+ tumors | D’Angelo et al., 2021 [100] |
| PD-1+ cells density; immunohistochemical | 26 advanced MCCs | Pembrolizumab | Positive predictor (p-value = 0.02) | Giraldo et al., 2018 [197] |
| PD-L1+ cells density; immunohistochemical |
26 advanced MCCs | Pembrolizumab | Positive predictor (p-value = 0.03) | Giraldo et al., 2018 [197] |
| PD-1+/PD-L1+ cells proximity; immunohistochemical | 26 advanced MCCs | Pembrolizumab | Positive predictor (p-value = 0.03) | Giraldo et al., 2018 [197] |
| PD-1 expression; immunohistochemical | 27 advanced MCCs | Pembrolizumab, nivolumab, avelumab, nivolumab + ipilimimab | Positive predictor (p-value = 0.00598) | Knepper et al., 2019 [17] |
| TILs with low T-cell clonality and high TCR diversity; immunohistochemical and molecular biology techniques | 41 advanced MCCs | Pembrolizumab, nivolumab, avelumab, | Positive predictor | Spassova et al., 2020 [19] |
| Increased intratumoral CD8+ T-cells; immunohistochemical | 116 m-MCCs | Avelumab | Not confirmed as predictor, responses tended to be higher in tumors rich in CD8+ T-cells | D’Angelo et al., 2021 [100] |
| TILs rich in γδ T cells; flow cytometry from tumor suspension | 39 advanced MCCs | Not specified, not used in all patients | Positive predictor in immunotherapy treated patients (p-value = 0.021) | Gherardin et al., 2021 [198] |
| Effector memory CD4+ and CD8+ T cells co-expressing CD28, HLA-DR and PD-1; blood-based immunophenotype | 27 advanced MCCs | Pembrolizumab | Positive predictor (p-value < 0.05) | Greene et al., 2021 [199] |
| Predominance of CD8+ effector and central memory T-cells (A); T cells in proximity to tumoral cells (B); immunohistochemical | 114 unresectable MCCs | Pembrolizumab, nivolumab, avelumab | Positive predictors ([A] p-value = 0.02; [B] p-value = 0.009) | Spassova et al., 2022 [194] |
| MCPyV positive status; immunohistochemical and molecular biology techniques | 27 advanced MCCs | Pembrolizumab, nivolumab, avelumab, nivolumab + ipilimimab | Not confirmed as predictor (p-value = 0.63) | Knepper et al., 2019 [17] |
| MCPyV positive status; blood-based and immunohistochemical | 47 la-MCCs and m-MCCs | Pembrolizumab | Not confirmed as predictor (p-value = 0.765) | Nghiem et al., 2019 [18] |
| MCPyV positive status; molecular biology techniques | 41 advanced MCCs | Pembrolizumab, nivolumab, avelumab, | Not confirmed as predictor | Spassova et al., 2020 [19] |
| MCPyV positive status; molecular biology techniques | 116 m-MCCs | Avelumab | Not confirmed as predictor, responses tended to be lower in MCPyV + tumors | D’Angelo et al., 2021 [100] |
Note: Abbreviations: la-MCC (locally advanced Merkel cell carcinoma; m-MCC (metastatic Merkel squamous cell carcinoma); PFS (progression-free survival; OS (overall survival); TILs (tumor-infiltrating lymphocytes); TCR (T-cell receptor); MCPyV (Merkel cell polyomavirus).