From: Immunotherapies targeting stimulatory pathways and beyond
Category | Target | Drug | Trial | Phase | Type of tumor | Clinical efficacy | Safety | Comments |
---|---|---|---|---|---|---|---|---|
T cell co-stimulatory targets | CD27 | Varlilumab | NCT01460134 | I | Advanced solid malignancies | N = 25 ORR 4% and DCR 36% with 1 PR and 8 SD | No DLTs reported | Used as monotherapy |
NCT02335918 | I/II | Advanced solid malignancies | N = 90 ORR 8% and DCR 37% with 7 PR and 26 SD | 5 serious AEs: acute kidney injury, mixed motor neuropathy, pneumonitis, small bowel obstruction, and acute hepatitis | Used with nivolumab | |||
CD70 | ARGX-110 | NCT01813539 | I/II | Advanced, CD70 positive solid or hematologic malignancies | N = 26 DCR 54%, 14 SD with a mean duration of 3.7 months | No DLTs reported | Used as monotherapy | |
CD40/ CD40L | SEA-CD40 | NCT02376699 | I | Advanced solid malignancies | N = 34 ORR 3% and DCR 32% with 1 PR and 10 SD | 5 cases of DLTs, all infusion-related reactions Serious AEs included dyspnea (27%), and headache (27%) | Used as monotherapy | |
CP-870,893 | NCT01103635 | I | Metastatic melanoma | N = 22 ORR 27%, DCR 59% with 2 CR, 4 PR, and 7 SD Median PFS was 3.2 months | 2 cases DLTs (immune colitis) Serious AEs: one grade 3 CRS | Used with tremelimumab | ||
JNJ-64457107 (JNJ-107) | NCT02829099 | I | Advanced solid malignancies | N = 95 ORR 1%, DCR 25% with 1 PR and 23 SD | 2 cases of DLTs: 1 grade 3 headache and 1 grade 3 elevation of transaminases with grade 2 hyperbilirubinemia | Used as monotherapy | ||
APX005M | NCT03123783 | I/II | Advanced melanoma and immunotherapy-naïve NSCLC | Phase I: N = 9 ORR 22%, DCR 67% with 2 PR, 4 SD, 3 PD Phase II: N = 10 ORR 20%, DCR 40% with 2 PR, 2 SD, 6 PD | No DLTs reported | Used with nivolumab | ||
NCT02706353 | I/II | Metastatic melanoma | – | – | Ongoing | |||
4-1BB/ 4-1BBL | Utomilumab (PF05082566) | NCT02179918 | I | Advanced solid malignancies | N = 23 ORR 26%, DCR 70% with 2 CR, 4 PR, 10 SD | No DLTs reported | Used with pembrolizumab | |
ADG106 | NCT03802955 | I | Advanced solid malignancies or relapsed and refractory NHL | N = 14 ORR 0%, DCR 57% with 8 SD | No DLTs reported | Used as monotherapy | ||
OX40/ OX40L | MEDI0562 | NCT02705482 | I | Advanced solid malignancies | Durvalumab cohort: N = 26 ORR 12%, DCR 46% with 3 PR, 9 SD Tremelimumab cohort: N = 31 ORR 0%, DCR 29% with 9 SD | 5 cases of DLTs (2 with durvalumab and 3 with tremelimumab), no specifics provided 2 grade 5 AEs related to MEDI0562: renal failure (durvalumab cohort) and multiorgan failure (tremelimumab cohort) | Used with durvalumab or tremelimumab | |
GSK3174998 (GSK998) | NCT02528357 | I | Advanced solid malignancies | N = 138 ORR 7%, DCR 14% with 2 CR, 8 PR, 10 SD | 2 DLTs in the combination group: 1 grade 3 pleural effusion and 1 grade 1 myocarditis | Used as monotherapy or with pembrolizumab | ||
ATOR-1015 | NCT03782467 | I | Advanced solid malignancies | No specifics provided. 9/14 patients have discontinued therapy: clinical deterioration (n = 6), death from disease (n = 2), or PD (n = 1) | No DLTs reported | Used as monotherapy | ||
mRNA-2416 | NCT03323398 | I | Advanced solid or hematologic malignancies | Monotherapy: N = 39 ORR 0%, DCR of 15% with 6 SD lasting ≥ 14 weeks | No DLTs reported | Used as monotherapy or with durvalumab | ||
GITR/ GITRL | MK-1248 | NCT02553499 | I | Advanced solid malignancies | Monotherapy: N = 20 ORR 0% and DCR 15% with 3 SD Combination: N = 17 ORR 18% and DCR 47% with 1 CR, 2 PR, 3 SD | No DLTs reported | Used as monotherapy or with pembrolizumab | |
AMG 228 | NCT02437916 | I | Advanced solid malignancies | N = 27 ORR 0%, DCR 23% with 7 SD and 20 PD | No DLTs reported 1 grade 5 pneumonitis | Used as monotherapy | ||
BMS-986156 | NCT02598960 | I/II | Advanced solid malignancies | Monotherapy: N = 34 ORR 0%, DCR 32% with 11 SD, 18 PD, 5 non-evaluable disease Combination: N = 258 ORR 7%, DCR 41% with 2 CR, 19 PR, 84 SD, 117 PD, 18 non-evaluable disease | 1 DLT: Grade 4 CK elevation | Used as monotherapy or with nivolumab | ||
Other Direct Immune Stimulatory Targets | LXR | RGX-104 | NCT02922764 | I | Advanced solid or hematologic malignancies | Monotherapy: N = 12 DCR 42% with 5 confirmed SD,        1 presumptive PR Combination: N = 11 ORR 22%, DCR 66% with 2 CR, 4 SD | Neutropenia was a DLT reported only in the combination cohort No additional details provided | Used as monotherapy or with docetaxel |
IL-2/ IL-2R | RO6874281 | NCT02627274 | I | Advancedsolid malignancies | No specifics are provided. Long-lasting responses in 3/35 patients | No DLTs reported | Used as monotherapy | |
hu14.18-IL2 | NCT00590824 | II | Resectable stage III or IV melanoma | No details are provided on responses for 18 patients (n = 11 neoadjuvant, and n = 7 adjuvant) 6 patients had a median RFS of 5.7 months, a 24-month RFS rate 39% and a 24-month OS of 65% | 6 toxicities leading to dose-adjustments: hypotension (n = 3), syncope (n = 1), elevated transaminases (n = 2), and elevated serum creatinine (n = 1) | Used as monotherapy | ||
ALKS 4230 | NCT02799095 | I/II | Advanced solid malignancies | Monotherapy: N = 14 ORR 0%, DCR 57% with 8 SD Combination: N = 11 ORR 9%, DCR 73% with 1 PR,7 SD | No DLTs reported | Used as monotherapy and with pembrolizumab | ||
Bempegaldesleukin (NKTR-214 – BEMPEG) | NCT02983045 | I/II | Advanced solid malignancies | N = 23 ORR 48%, DCR 70% with 4 CR, 7 PR, 5 SD | No DLTs reported 9% stopped therapy from AEs | Used with nivolumab | ||
Previously untreated stage IV melanoma patients | N = 38 ORR 53% with 13 CR and 7 PR Median duration of response was not reached | No DLTs reported 10% stopped therapy from AEs | ||||||
IRX-2 | NCT03758781 | I | Advanced solid tumors | – | – | Ongoing | ||
IL-15 | ALT-803 | NCT02523469 | I | Stage III or IV NSCLC | N = 21 ORR 29%, DCR 76% with 6 PR, 10 SD Median PFS: 9.4 months Median OS: 17.4 months | No DLTs reported | Used with nivolumab | |
NCT01885897 | I/II | Relapsed hematologic malignancies after allogenic bone marrow transplant | N = 33 ORR 6%, DCR 15%, with 1 CR (lasted 7 months), 1 PR (lasted 5 months), 3 SD (lasted ≥ 2 months) | No DLTs reported | Used as monotherapy | |||
n-803 | NCT03381586 | I | Healthy volunteers | – | No DLTs reported | Used as monotherapy | ||
rhIL-15 | NCT03388632 | I | Advanced solid malignancies | – | – | Ongoing | ||
A3R | Namodenoson (CF102) | NCT02128958 | II | Advanced, refractory HCC and Child–Pugh class B | N = 34 ORR 9% with 3 OR. No specifics about the type of responses are available OS 4.1 months | No grade 4–5 AEs | Used as monotherapy | |
CD11b | GB1275 | NCT04060342 | I/II | Advanced solid malignancies | N = 22 DCR 32% with 7 SD (4 monotherapy and 3 combination cohort) | No DLTs reported | Used as monotherapy or with pembrolizumab or nab-paclitaxel and gemcitabine | |
STING | MIW815 (ADU-S100) | NCT03172936 | I | Advanced solid malignancies and lymphomas | No specifics are provided regarding responses At time of cut-off, 74% of patients (n = 49) were unenrolled: PD (n = 28), physician decision (n = 18), AEs (n = 2), or death (n = 1) | No DLTs reported | Used in combination with spartalizumab | |
SB 11,285 | NCT04096638 | I | Advanced solid malignancies | – | – | Ongoing | ||
TLR-2 | Tomaralimab (OPN-305) | NCT02363491 | I/II | Heavily pretreated patients with low and intermediate risk MDS | N = 22 ORR 50%, DCR 73% with 6 CR, 5 PR, 5 SD | No DLTs No additional toxicity data was provided | Used as monotherapy | |
TLR-4 | G100 | NCT02180698 | I | Unresectable or metastatic soft tissue sarcomas | N = 14 ORR 14%, DCR 100% with 1 CR, 1 PR, 11 SD | There were no grade 3–5 AEs reported No additional safety data was provided | Intratumoral monotherapy | |
TLR-7 | NJH395 | NCT03696771 | I | Non-breast HER2 + advanced malignancies | N = 18 ORR 0%, DCR 50% with no CR or PR, 9 SD | 5 DLTs: 3 increased liver enzymes, 1 aseptic meningitis, and 1 meningism | Used as monotherapy | |
TLR-8 | Motolimod (VTX-2337) | NCT02124850 | I | Previously untreated stage II, III, and IV HNSCC | No clinical efficacy reported | No DLTs reported | Used with cetuximab | |
NCT01836029 | II | Recurrent/ metastatic HNSCC | Motolimod: N = 100 ORR 40%, DCR 62% with 2 CR, 36 PR, 22 SD. Median PFS 6.1 months and median OS 13.5 months Placebo: N = 95 ORR 34%, DCR 58% with 5 CR, 27 PR, and 23 SD. PFS 5.9 months, OS 11.3 | Serious AEs: vomiting (6%), pneumonia (6%), and dehydration (6%) | Combined with platinum therapy, fluorouracil, and cetuximab | |||
TLR-7 and 8 | MEDI9197 | NCT02556463 | I | Advanced solid malignancies | MEDI9197 monotherapy: N =35 ORR 0%, DCR 29% with 0 CR, 0 PR, and 10 SD MEDI9197 with durvalumab: N = 17 ORR 0%, DCR 18% with 0 CR, 0 PR, 3 SD | Monotherapy: 2 DLTs from CRS Combination: 1 DLT from hemorrhagic shock from a ruptured liver metastasis | Intratumoral use with or without durvalumab and/or radiation therapy | |
NKTR-262 | NCT03435640 | I | Advanced solid malignancies | N = 17 ORR not provided, DCR 41%. Unknown specific number of CR, PR, SD At least 2 PRs mentioned | 1 DLT: transaminitis | Used with bempegaldesleukin | ||
TLR-9 | Tilsotolimod (IMO-2125) | NCT03052205 | I | Advanced solid malignancies | N = 51 ORR 0%, DCR 29% with 15 SD | No DLTs reported | Used as intratumoral monotherapy | |
NCT02644967 | I/II | |||||||
Lefitolimod (MGN1703) | NCT02200081 | II | Extensive-stage SCLC | N = 59 ORR 12%, DCR 51%, 0 CR, 7 PR2, SD 23 | No grade 5 AEs 5 with grade 4 neutropenia | Maintenance monotherapy | ||
NCT02668770 | I | Advanced solid malignancies | – | – | Ongoing | |||
Cavrotolimod (AST-008) | NCT03684785 | I/II | Advanced solid malignancies | – | – | Ongoing | ||
SMAC/ IAP | Birinapant | NCT02587962 | I/II | Advanced solid malignancies | N = 18 ORR 11% DCR 22% with 2 PR, 2 SD | 1 DLT: grade 3 elevation of transaminases | Used with pembrolizumab | |
Indirect Immune activators | CXCL12 | NOX-A12 | NCT03168139 | I/II | Metastatic pancreatic and MSS CRC | N = 20 ORR 0%, DCR 25% with 5 SD Median PFS: 1.87 months OS: 42% at 6 months and 22% at 12 months | No specifics provided but attributed to pembrolizumab | Used as monotherapy and with pembrolizumab |
CXCR4 | Balixafortide | NCT01837095 | I | Metastatic, HER-2 negative, CXCR4 positive BC | N = 56 ORR 30%, median duration of 3.2 months Clinical benefit rate 44%, median duration 6.9 months DCR 76% There were 16 PR, 25 SD (8 of which lasted > 6 months) | No DLTs reported Serious AEs in 38%: febrile neutropenia (9%), urinary tract infection (5%), and pneumonia (4%) | Used with eribulin | |
PI3K | IPI-549 | NCT02637531 | I | Advanced solid malignancies | N = 30 ORR 7% with 2 PR at 8 weeks | 2 DLTs: one grade 3 rash and one grade 3 transaminitis | Used with nivolumab | |
SAR260301 | NCT01673737 | I | Advanced solid malignancies | N = 19 ORR 0%, DCR 26% with 5 SD | 2 DLTs: one grade 3 pneumonitis and one grade 3 GGT elevation | Used as monotherapy | ||
SYK/ FLT3 | TAK-659 | NCT02834247 | I | Advanced solid malignancies | N = 19 ORR 5%, DCR 63% with 1 PR and 11 PD | 3 DLTs: one grade 3 fever, one myocarditis and one left ventricular dysfunction (both thought to be due to nivolumab) | Used with nivolumab | |
MNK 1/2 | Tomivosertib (eFT508) | NCT03616834 | II | Advanced solid malignancies | N = 39 ORR 5%, DCR 46% with 3 PR and 15 SD 7 NSCLC patients had DFP of ≥ 24 weeks | 7 DLTs: hypersensitivity, hepatic toxicity, and constipation 4 grade 5 AEs but none were attributed to tomivesertib | Used with other ICIs | |
HDAC | Vorinostat | NCT02619253 | I | Advanced, refractory urothelial, renal, and prostate carcinoma | N = 37 ORR 0%, DCR 5% with 2 PR PFS: 2.8 months (PD-1/PD-L1 naïve urothelial and RCC), 5.2 months (PD-1/PD-L1 resistant patients), and 3.5 months (prostate cancer patients) | No DLTs reported | Used with pembrolizumab | |
KA2507 | NCT03008018 | I | Advanced solid malignancies | N = 20 ORR 0%, DCR 35% with 7 SD | No DLTs reported | Used as monotherapy | ||
HSP90 | Onalespib | NCT02503709 | I | Advanced solid malignancies | N = 21 ORR 5%, DCR 48% with 1 PR that lasted > 10 months, 9 SD | 2 DLTs: grade 3 troponin elevation and mucositis | Used with a cyclin-dependent kinase inhibitor (AT7519M) | |
WEE-1 | Adavosertib | NCT02617277 | I | Advanced solid malignancies | N = 54 ORR 4%, DCR 36% with 2 PR and 17 SD | 3 DLTs: nausea (n = 2) and diarrhea (n = 1) | Used with durvalumab |