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Table 1 Clinical trials of PD-1/PD-L1 inhibitors

From: Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors

Agents Tumors PD-L1 IHC platforms Cells scored by IHC Cutoff Efficacy of agent Clinical trial Ref.
Pembrolizumab Urothelial cancer Dako 22C3 pharmDx Assay Combined score of TC and IC < 1%: 11, 95%CI 4–24% (ORRa) Keynote-052 [30]
1–9% 20, 95%CI 14–28%(ORRa)
≥10% 39, 95% CI 28–50% (ORRa)
Melanoma Dako 22C3 pharmDx Assay Combined score of TC and IC < 1%: 36.4, 95% CI 10.9–69.2% (ORRb) Keynote-041 [116]
≥1% 16.7%, 95% CI 3.6–41.4% (ORRb)
HNSCC Dako 22C3 pharmDx Assay Combined score of TC and IC < 50%: 13, 95%CI 7–20% (ORRb) Keynote-055 [117]
≥50% 27, 95%CI 15–42% (ORRb)
NSCLC Dako 22C3 pharmDx Assay TC < 1% 8.3, 95% CI 0.2–38.5%(ORRa) Keynote-001 [118]
1–49% 17.3, 95% CI 8.2–30.3% (ORRa)
≥50% 51.9, 95% CI 31.9–71.3% (ORRa)
Melanoma Dako 22C3 pharmDx Assay Combined score of TC and IC < 1% 2.8moths, 95% CI 2.7–2.8 months (PFS) 12.6 months, 95% CI 7.0–18.5 months (OS) Keynote-001 [119]
≥1% 5.6 months, 95% CI 4.4–8.1 months (PFS) 29.9 months, 95% CI 24.6-NR months (OS)
Nivolumab Squamous NSCLC Dako 28–8 pharmDx Assay TC < 1% HR of 2 years OS between Nivolumab and Docetaxel HR:0.57, 95%CI 0.38–0.86 Checkmate-017 [120]
≥1% HR:0.75, 95%CI 0.50–1.10
≥5% HR:0.57, 95%CI 0.36–0.92
≥10% HR:0.56, 95%CI 0.33–0.94
≥50% HR:0.63, 95%CI 0.25–1.57
Non-squamous NSCLC Dako 28–8 pharmDx Assay TC < 1% HR of 2 years OS between Nivolumab and Docetaxel HR:0.91, 95%CI 0.67–1.22 Checkmate-057 [120]
≥1% HR:0.62, 95%CI 0.47–0.83
≥5% HR:0.48, 95%CI 0.34–0.68
≥10% HR:0.43, 95%CI 0.30–0.62
≥50% HR:0.38, 95%CI 0.24–0.60
Urothelial cancer Dako 28–8 pharmDx Assay TC < 1% 16.1, 95% CI 10.5–23.1% (ORRa) Checkmate-275 [121]
≥1% 23.8, 95% CI 16.5–32.3% (ORRa)
≥5% 28.4, 95% CI 18.9–39.5% (ORRa)
Urothelial cancer Dako 28–8 pharmDx Assay TC < 1% 26.2%; 95% CI 13.9–42.0%(ORRa)9·9 months, 95% CI 7.0–not estimable (median OS) Checkmate-032 [31]
≥1% 24.0%; 95% CI 9.4–45.1% (ORRa)16.2 months, 95% CI 7.6–NE (median OS)
Renal cell cancer Dako Assayc TC < 1% HR of median OS between Nivolumab and everolimusHR: 0.76; 95% CI 0.60–0.97 Checkmate-025 [122]
≥1% HR: 0.78; 95% CI 0.53–1.16
Squamous NSCLC Dako Assayc TC < 5% Best overall response 14% (PR),20% (SD),49% (PD) Checkmate-063 [123]
≥5% Best overall response 24% (PR),24% (SD),44% (PD)
Renal cell cancer Dako 28–8 pharmDx Assay TC < 5% 18% (ORRa)2.9 months (median PFS) NCT01354431. [124]
≥5% 31% (ORRa)4.9 months (median PFS)
Melanoma Dako Assayc TC < 5% or undefined ORRa: 33.1, 95% CI 25.2–41.7% vs. 15.7%, 95% CI 10.0–23.0% (nivolumab vs. dacarbazine) Checkmate-066 [125]
≥5% ORRa: 52.7, 95% CI 40.8–64.3% vs. 10.8%, 95% CI 4.8–20.2% (nivolumab vs. dacarbazine)
Multiple cancers IHC staining with anti-PD-L1 mAb 5H1 TC < 5% 0% (ORRa) NCT00730639 [126]
≥5% 36% (ORRa)
Atezolizumab NSCLC Ventana SP142 assay TC or IC TC and IC < 1% HR of OS between atezolizumab and docetaxel HR:0.75, 95% CI 0.59–0.96 OAK [127]
TC or IC ≥ 1% HR:0.74, 95% CI 0.58–0.93
Urothelial cancer Ventana SP142 assay IC < 1% 21, 95%CI 9–37% (ORRa) NCT02108652 [128]
1–4% 21, 95%CI 11–35%(ORRa)
≥5% 28, 95%CI 14–47% (ORRa)
Renal cell cancer Ventana SP142 assay IC < 1% 9, 95%CI 1–29% (ORRa)51, 95%CI 27–74% (2-Years OS Rate) NCT01375842 [129]
≥1% 18, 95%CI7–35% (ORRa)65, 95%CI45–86% (2-Years OS Rate)
Multiple cancers Ventana SP142 assay IC < 1% 13%(ORRa), 24-weeks PFS:33.9% NCT01375842 [130]
1–4% 21% (ORRa), 24-weeks PFS:40.9%
5–9% 17% (ORRa), 24-weeks PFS:43.0%
≥10% 46% (ORRa), 24-weeks PFS:60.0%
NSCLC Ventana SP142 assay TC or IC TC and IC < 1% HR of OS between atezolizumab and docetaxel:1.04, 95%CI 0.62–1.75 POPLAR [131]
TC or IC ≥1% HR of OS between atezolizumab and docetaxel: 0.59, 95%CI 0.40–0.85
TC or IC ≥5% HR of OS between atezolizumab and docetaxel: 0.54, 95%CI 0.33–0.89
TC ≥50% or IC ≥10% HR of OS between atezolizumab and docetaxel: 0.49, 95%CI 0.22–1.07
Durvalumab Urothelial cancer Ventana SP263 assay TC or IC TC and IC < 25% 5.1, 95%CI 1.4–12.5%(ORRa) NCT01693562 [132]
TC or IC ≥25% 27.6,95%CI 19.0–37.5%(ORRa)
Avelumab Urothelial cancer Dako assay TC < 5% 4.2% (ORRb)12 months-OS rate: 56.3, 95%CI 33.7–73.9% NCT01772004 [133]
≥5% 53.8% (ORRb)12 months-OS rate: 75.5, 95%CI 41.6–91.4%
  1. Abbreviations: CI confidence interval, HNSCC head and neck squamous cell carcinoma, HR hazard ratio, IC tumor infiltrating immune cell, NE not estimable, ORRa objective response rate, ORRb overall response rate, OS overall survival, mAb monoclonal antibody, PD, progressive disease, PFS progressive-free-survival, PR partially response, SD stably disease, TC tumor cell, Dako Assayc anti-PD-L1 antibody is not given