Table 1.
Phase I trial as well as approval stage characteristics of immune checkpoint inhibitors
| Characteristic | Ipilimumab* (36) | Nivolumab (37) | Pembrolizumab (24) | Atezolizumab (25) | Avelumab (38) | Durvalumab (39) | Ipilimumab +Nivolumab (20) |
|---|---|---|---|---|---|---|---|
| Phase I stage | |||||||
| Trial Location | USA | USA | USA | USA, Europe | USA, Europe, Asia | USA, Europe, Asia | USA |
| Number of centers | 2 | 11 | 2 | 20 | 10 | 4 | 4 |
| Tumor types | 1 (non-metastatic melanoma) | 8 solid tumors | All solid tumors | All solid tumors | All solid tumors | All solid tumors | 1 (metastatic melanoma) |
| Trial design (40) | Pre-assigned dose levels | Accelerated titration design transitioned to a 3+3 design | 3+3 design | 3+3 design | 3+3 design | 3+3 design | 3+3 design |
| N patients | 19 | 207 | 30 | 171 | 27 | 27 | 86 |
| N dose levels | 3 | 4 | 3 | 5 | 4 | 6 | 7 |
| Response Criteria | N/A | Recist 1.1(10) | Recist 1.1(10) | Recist 1.1(10) | Recist 1.1(10) | Immune-related | Modified WHO(41) |
| N DLTs | 3 | 0 | 0 | 0 | 1 | 0 | 6 |
| MTD reached | Yes | No | No | No | No | No | Yes |
| Dose recommendation (parameter) | Yes (toxicities) | No clear dose recommended | Yes (lowest dose with efficacy) | Yes (PK) | Yes (PK) | Yes (PK/PD/safety data) | Yes (toxicities) |
| Approval Stage | |||||||
| First FDA approval | Melanoma | Melanoma | Melanoma | Urothelial carcinoma | Merkel cell carcinoma(42) | Urothelial carcinoma | Melanoma |
| Design of first pivotal trial leading to approval | Phase III | Phase III | Phase Ib | Phase II | Phase II | Phase II | Phase III |
| Subsequent approvals | No | 5 (NSCLC, Kidney cancer, Hodgkin Lymphoma, HNSCC, Urothelial) | 5 (NSCLC, HNSCC, Hodgkin Lymphoma, Urothelial, MSI-H cancers) | 1 (NSCLC) | 1 (Urothelial) | No | No |
| Response Criteria Pivotal Trials | Modified WHO(41) | Recist 1.1(10) and International Working Group (Hodgkin)(43) | Recist 1.1(10) and revised response criteria for Lymphomas(43) | Recist 1.1(10) | Recist 1.1(10) | Recist 1.1(10) | Recist 1.1(10) |
| Selection biomarker | No | No | Yes (PDL1 expression is required for NSCLC indication) and MSI-H tested cancers | No | No | No | No |
*
This phase I trial included patients with completely resected melanoma. Hence, response evaluation was not performed
Abbreviations: DLTs: dose limiting toxicities; HNSCCC: head and neck small cell carcinoma; MSI-H: microsatellite instability-high; MTD: maximum tolerated dose; N/A: not applicable; NSCLC: non small cell lung cancer; PD: pharmacodynamics; PK: pharmacokinetics; WHO: world health organization