Table 5. List of clinical trials that assessed PD-L1 IHC as a biomarker when evaluating targeted therapy agents for PD-L1 positive malignancies.
| Drug | Treatment regimen | Biomarker | Tumor histology | Criteria for biomarker positivity | Percent of tumor samples expressing the biomarker | Outcome | Reference |
|---|---|---|---|---|---|---|---|
| Atezolizumab | Atezolizumab 1200 mg every 3 weeks | PD-L1 IHC | Urothelial carcinoma | PD-L1 IHC scoring: - IC0: <1% immune cells positive - IC1: ≥1% and <5% immune cells positive - IC2/3: ≥5% immune cells positive |
NA | Primary analysis demonstrated significant improvement in objective response rate for each group. Objective response rates: - IC2/3: 27%, 95% CI: 19 to 37, p< 0.0001 - IC1/2/3: 18%, 95% CI: 18 to 34, p= 0.0004 - all patients: 15%, 95% CI: 11 to 20, p= 0.0058 |
[212] |
| Nivolumab | Ipilimumab 3 mg/kg; Nivolumab 1 mg/kg, initial 4 doses once every 3 weeks, then once every 2 weeks. | PD-L1 IHC | Melanoma | - ≥5% tumor cells exhibiting PD-L1 staining of any intensity in ≥100 evaluable tumor cells using an automated IHC assay | - 30% (35 of 118 patients) positive for PD-L1 | Nivolumab plus Ipilimumab: - PD-L1 positive: 14 of 24 patients with complete and partial response, ORR: 58.3% (95% CI: 36.6 to 77.9) - PD-L1 negative: 31 of 56 patients with complete and partial response, ORR: 55.4% (95% CI: 41.5 to 68.7) Ipilimumab monotherapy: - PD-L1 positive: 2 of 11 patients with complete and partial response, ORR: 18.2% (95% CI: 2.3 to 51.8) - PD-L1 negative: 1 of 27 patients with complete and partial response, ORR: 3.7% (95% CI: 0.1 to 19.0) |
[204] |
| Pembrolizumab | Pembrolizumab 10 mg/kg bi-weekly; ipilimumab 3 mg/kg once every 3 weeks for 4 doses | PD-L1 IHC | Advanced melanoma | - ≥1% tumor cells with membranous staining using a standardized IHC assay | 80.5% (671 of 834 patients) positive for PD-L1 | 2 weeks pembrolizumab therapy versus ipilimumab - PD-L1 positive subgroup: PFS: HR= 0.53, 95% CI: 0.41 to 0.67 OS: HR= 0.55, 95% CI: 0.40 to 0.76 - PD-L1 negative subgroup: PFS: HR= 0.67, 95% CI: 0.41 to 1.11 OS: HR= 0.91, 95% CI: 0.49 to 1.69 3 weeks pembrolizumab therapy versus ipilimumab - PD-L1 positive subgroup: PFS: HR= 0.53, 95% CI: 0.40 to 0.66 OS: HR= 0.58, 95% CI: 0.42 to 0.79 - PD-L1 negative subgroup: PFS: HR= 0.76, 95% CI: 0.47 to 1.24 OS: HR= 1.02, 95% CI: 0.56 to 1.85 |
[205] |
| Nivolumab | Concurrent therapy: cohort 1-5 Cohort 1: ipilimumab 3 mg/kg, nivolumab 0.3 mg/kg; Cohort 2a: ipilimumab 1 mg/kg, nivolumab 3 mg/kg; Cohort 3: ipilimumab 3 mg/kg, nivolumab 3 mg/kg; Cohort 4: ipilimumab 3 mg/kg, nivolumab 10 mg/kg; Cohort 5: ipilimumab 10 mg/kg, nivolumab 10 mg/kg Sequential therapy: cohort 6,7 Cohort 6: nivolumab 1 mg/kg; Cohort 7: nivolumab 3 mg/kg |
PD-L1 IHC | Advanced melanoma | - ≥5% tumor cells exhibiting PD-L1 staining of any intensity in ≥100 evaluable tumor cells using a standardized automated IHC assay | - 38% (21 of 56 patients) positive for PD-L1 | ORR in concurrent therapy cohorts: - PD-L1 positive: 46% (6 of 13 patients) - PD-L1 negative: 41% (9 of 22 patients) ORR in sequential therapy cohorts: - PD-L1 positive: 50% (4 of 8 patients) - PD-L1 negative: 8% (1 of 13 patients) |
[216] |
| Nivolumab | Docetaxel 75 mg/m2 once every 3 weeks; nivolumab 3 mg/kg once every 2 weeks | PD-L1 IHC | Squamous-cell NSCLC | - Pre-determined categorization of PD-L1 expression: ≥1%, ≥5% and ≥10% cells exhibiting PD-L1 staining of any intensity in ≥100 evaluable tumor cells using a standardized automated IHC assay (retrospective analysis of pre-treatment specimens) |
- 83% (225 of 272 patients) positive for PD-L1 | HR for OS according to PD-L1 expression level (nivolumab versus docetaxel therapy): (PD-L1 expression: unstratified HR (95%CI)) - <1%: 0.58 (0.37 to 0.92) - ≥1%: 0.69 (0.45 to 1.05) - <5%: 0.70 (0.47 to 1.02) - ≥5%: 0.53 (0.31 to 0.89) - <10%: 0.70 (0.48 to 1.01) - ≥10%: 0.50 (0.28 to 0.89) - Not quantifiable at baseline: 0.39 (0.19 to 0.82) HR for PFS according to PD-L1 expression level (nivolumab versus docetaxel therapy): (PD-L1 expression: unstratified HR (95%CI)) - <1%: 0.66 (0.43 to 1.00) - ≥1%: 0.67 (0.44 to 1.01) - <5%: 0.75 (0.52 to 1.08) - ≥5%: 0.54 (0.32 to 0.90) - <10%: 0.70 (0.49 to 0.99) - ≥10%: 0.58 (0.33 to 1.02) - Not quantifiable at baseline: 0.45 (0.23 to 0.89) * The benefit in survival indices was noted irrespective of PD-L1 expression levels. Therefore, PD-L1 expression was not found to have any predictive or prognostic significance in this study. |
[237] |
| Nivolumab | Docetaxel 75 mg/m2 once every 3 weeks; nivolumab 3 mg/kg once every 2 weeks | PD-L1 IHC | Non-squamous NSCLC | - Pre-determined categorization of PD-L1 expression: ≥1%, ≥5% and ≥10% cells exhibiting PD-L1 staining of any intensity in ≥100 evaluable tumor cells using an automated IHC assay |
- 78% (455 of 582 patients) positive for PD-L1 | Treatment with nivolumab by PD-L1 expression interaction P-value (predictive relationship of PD-L1 level for treatment efficacy with nivolumab): - 1% PD-L1 expression level: OS: p= 0.06; PFS: p= 0.02; ORR: p= 0.002 - 5% PD-L1 expression level: OS: p= < 0.001; PFS: p= < 0.001; ORR: p= 0.002 - 10% PD-L1 expression level: OS: p= < 0.001; PFS: p= < 0.001; ORR: p= 0.002 ORR according to PD-L1 expression for nivolumab therapy: (PD-L1 expression: ORR, CI) - <1%: 9%, 95% CI: 5 to 16 - ≥1%: 31%, 95% CI: 23 to 40 - <5%: 10%, 95% CI: 6 to 17 - ≥5%: 36%, 95% CI: 26 to 46 - <10%: 11%, 95% CI: 6 to 17 - ≥10%: 37%, 95% CI: 27 to 48 ORR according to PD-L1 expression for docetaxel therapy: (PD-L1 expression: ORR, CI) - <1%: 15%, 95% CI: 9 to 23 - ≥1%: 12%, 95% CI: 7 to 19 - <5%: 14%, 95% CI: 9 to 21 - ≥5%: 13%, 95% CI: 7 to 22 - <10%: 14%, 95% CI: 9 to 21 - ≥10%: 13%, 95% CI: 6 to 22 |
[207] |
| Nivolumab | Nivolumab 0.3 / 2 / 10 mg/kg every 3 weeks | PD-L1 IHC | RCC | - ≥5% tumor cells exhibiting PD-L1 staining using a standardized automated IHC assay. Additionally, cut-off value of ≥1% was also evaluated. | - 64% (107 of 168 patients) positive for PD-L1: 78 patients with <5% PD-L1 expression and 29 with ≥5% expression. | <5% PD-L1 expression: - Median PFS: 2.9 months (95% CI: 2.1 to 4.2) - ORR: 18% (14 of 78 patients, 95% CI: 10.2 to 28.3) - Median OS: 18.2 months (95% CI: 12.7 to 26.0) ≥5% PD-L1 expression: - Median PFS: 4.9 months (95% CI: 1.4 to 7.8) - ORR: 31% (9 of 29 patients, 95% CI: 15.3 to 50.8) - Median OS: not reached ≥1% for PD-L1 expression: - ORR, median PFS and median OS were found to be similar when comparing PD-L1 positive versus negative patients (data unavailable). |
[206] |
| Nivolumab | Nivolumab 0.1 / 0.3 / 1 / 3 / 10 mg/kg once every 2 weeks for up to 96 weeks. | PD-L1 IHC | Advanced melanoma | - ≥5% tumor cells exhibiting PD-L1 staining using a standardized automated IHC assay (retrospective analysis) | - 43.90% (18 of 41 patients) positive for PD-L1 | PD-L1 positive patients: - Median OS: not reached - Median PFS: 9.1 months PD-L1 negative patients: - Median OS: 12.5 months - Median PFS: 1.9 months |
[214] |
| Nivolumab | Nivolumab 1 / 3 / 10 mg/kg every 2 weeks (8 weeks cycle) for up to 96 weeks | PD-L1 IHC | Advanced NSCLC | - ≥5% tumor cells exhibiting PD-L1 staining using a standardized automated IHC assay (retrospective analysis) | Not available | PD-L1 positive tumors: - Median OS: 7.8 months (95% CI: 5.6 to 21.7) - Median PFS: 3.6 months (95% CI: 1.8 to 7.5) PD-L1 negative tumors: - Median OS: 10.5 months (95% CI: 5.2 to 21.2) - Median PFS: 1.8 months (95% CI: 1.7 to 2.3) |
[238] |
| Nivolumab | Nivolumab 3 mg/kg once every 2 weeks; docetaxel 75 mg/m2 once every 3 weeks | PD-L1 IHC | Advanced/metastatic squamous cell NSCLC | - No specific cut-off value defined as per study design | - Not applicable | OS HR for nivolumab versus docetaxel therapy, according to PD-L1 expression level: (PD-L1 level: HR (95% CI) - ≥1%: 0.69 (0.45 to 1.05) - <1%: 0.58 (0.37 to 0.92) - ≥5%: 0.53 (0.31 to 0.89) - <5%: 0.70 (0.47 to 1.02) - ≥10%: 0.50 (0.28 to 0.89) - <10%: 0.70 (0.48 to 1.01) The tumor PD-L1 status, however, was not found to be of predictive or prognostic value in this particular study. |
[229] |
| Nivolumab | Nivolumab dose range: 0.1 to 10 mg/kg once every 2 weeks | PD-L1 IHC | NSCLC, melanoma, RCC, colorectal cancer, prostate cancer | - ≥5% tumor cells exhibiting PD-L1 staining using a standardized automated IHC assay | - 45% (17 of 38 patients) with melanoma positive for PD-L1 - 49% (31 of 63 patients) with NSCLC positive for PD-L1 - data presently unavailable for other tumors |
PD-L1 positive melanoma patients: - Median OS: 21.1 months (95%CI: 9.4 to <not reported>) - Median PFS: 9.1 months (95%CI: 1.8 to <not reported>) - ORR: 44% PD-L1 negative melanoma patients: - Median OS: 12.5 months (95%CI: 8.2 to <not reported>) - Median PFS: 2.0 months (95% CI: 1.8 to 9.3) - ORR: 17% Note: Data presently unavailable for other tumors |
[221] |
| Nivolumab | Sequential escalation of nivolumab dosage: 1, 3, 10 mg/kg, in addition to randomly assigned cohorts with doses ranging from 0.1 mg/kg to 10 mg/kg | PD-L1 IHC | Advanced melanoma, NSCLC, RCC, castration resistant prostate cancer, colorectal cancer | - ≥5% tumor cells exhibiting PD-L1 staining, verified by 2 pathologists | - 59.52% (25 of 42 patients) positive for PD-L1: 18 melanoma, 7 colorectal, 5 RCC, 10 NSCLC and 2 prostate cancer patients | Objective response: - PD-L1 positive patients: 36% (9 of 25 patients) - PD-L1 negative patients: 0% (0 of 17 patients) |
[239] |
| Nivolumab | Nivolumab 1 mg/kg, escalated to 3 mg/kg | Three probe FISH assay: PDL2 (PDCD1LG2), PDL1 (CD274), control centromeric probe | Hodgkin’s lymphoma | - Malignant Reed-Sternberg cells identified and analyzed; Classified as follows: - Amplified: target to control probe ratio of 3:1 - Chromosome 9p polysomy: target to control probe ratio of 1:1 and >2 copies of each probe - Relative copy gain: target to control probe ratio > 1:1 and < 3:1 |
- 10 tumor samples available for analysis; All positive for PD-L1/PD-L2 alterations | Primary outcomes (survival indices): - RR: 87%, 95% CI: 66 to 97 - Complete response: 17% (4 patients) - Partial response: 70% (16 patients) - Stable disease: 13% (3 patients) - Polysomy 9p: 8 of 10 samples - PD-L1/PD-L2 gain: 6 of 10 samples - PD-L1/PD-L2 amplification: 4 of 10 samples |
[211] |
| Pembrolizumab | Pembrolizumab 10 mg/kg every 2 weeks | PD-L1 IHC | Recurrent/metastatic SCCHN | - a minimum of 1% tumor cells positive for PD-L1 by IHC | -78% (81 of 104 patients) positive for PD-L1 | -60 patients positive for PD-L1 received treatment. - 17% patients (10 of 60 patients) reported to have grade 3-4 drug related adverse events - Overall response in all patients: 18% (8 of 45 patients), 95% CI: 8 to 32 - Overall response in HPV positive patients (38%, 23 patients): 25% (4 of 16 patients), 95% CI: 7 to 52 - Overall response in HPV negative patients (62%, 37 patients): 14% (4 of 29 patients), 95% CI: 4 to 32 |
KEYNOTE- 012 [210] |
| Pembrolizumab (MK3475) | MK 3475 10 mg/kg every 3 weeks | PD-L1 IHC | NSCLC | - Cut-off value defined by Youden Index from receiver operating characteristics curve, created using irRC assessments | - 29% (9 of 31 patients) with PD-L1 expression score higher than potential cutoff value - 71% (22 of 31 patients) with PD-L1 expression score lower than potential cutoff value |
High PD-L1 expression score group: - ORR (irRC assessment): 67% (6 of 9 patients); 95%CI: 30% to 93% - ORR (RECIST): 57% (4 of 7 patients); 95% CI: 18% to 90% - PFS rate (irRC assessment) at 6 months: 67%, median value not reached; 95% CI: 42 to 100% - OS rate (irRC assessment) at 6 months: 89%, median value not reached; 95% CI: 71% to 100% Low PD-L1 expression score group: |
[219] |
| - According to RECIST criteria: 26% (7 of 27 patients) with high PD-L1 expression and 74% (20 of 27 patients) with low PD-L1 expression | - ORR (irRC assessment): 0% (0 of 22 patients); 95% CI: 0% to 15% - ORR (RECIST): 5% (1 of 20 patients); 95% CI: <not confirmed> - PFS rate (irRC assessment) at 6 months: 11%, median value: 2.1 months; 95% CI: 3% to 40% - OS rate (irRC assessment) at 6 months: 33%, median value: 3.9 months; 95% CI: 18% to 62% |
||||||
| Pembrolizumab (MK3475) | MK 3475 2 mg/kg every 3 weeks or 10 mg/kg every 2 weeks or 10 mg/kg every 3 weeks. | PD-L1 IHC | Melanoma | - ≥1% tumor cells exhibiting PD-L1 staining | - 77% (55 of 71 patients) | PD-L1 positive patients: - ORR: 51%^ - Median PFS: 12 months* - 1 year OS rate: 84%** PD-L1 negative patients: - ORR: 6%^ - PFS: 3 months* - 1 year OS rate: 69%** ^ORR p= 0.0012 (Fischer exact) *PFS HR: 0.31, 95% CI: 0.16 to 0.61, p=0.0004 (log rank) ** p=0.2146 (log rank) |
[218] |
Abbreviations: PD-L1, Programmed death ligand-1; IHC, immunohistochemistry; ORR, overall response rate; PFS, progression free survival; OS, overall survival; HR, hazard ratio; NSCLC, non-small cell carcinoma; CI, confidence interval; RCC, renal cell carcinoma; SCCHN, squamous cell carcinoma of the head and neck; irRC, immune related response criteria.