Background
Target | Agent | Mechanism of action | Indications | Advantages | Limitations | |
---|---|---|---|---|---|---|
FDA-approved immune checkpoint inhibitors | CTLA-4 | Ipilimumab | Inhibits CTLA-4 and allows T cell activation | CRC (in combination with nivolumab), HCC (in combination with nivolumab), melanoma (alone or in combination with nivolumab), mesothelioma (in combination with nivolumab), NSCLC (in combination with nivolumab), RCC (in combination with nivolumab) | Often better tolerated than chemotherapy - Used in a variety of solid and hematologic malignancies - Durable responses Potential for “cure” even in metastatic disease FDA-approved - Biomarkers available to predict response to therapy | Only a small proportion of patients benefit - Limited in cancers with “cold” TMEs - Autoimmune-like toxicities: - Cytopenias - Diarrhea/colitis - Fatigue - Hepatitis - Hypophysitis - Hypothyroidism - Myocarditis - Nephritis - Pneumonitis - Rash/pruritus - Uveitis |
PD-1 | Cemiplimab | Inhibits PD-1 and allows T cell activation | BCC, CSCC, NSCLC | |||
Nivolumab | Inhibits PD-1 and allows T cell activation | CRC (alone or in combination with ipilimumab), esophageal SCC, HCC (alone or in combination with ipilimumab), HL, HNSCC, melanoma (alone or in combination with ipilimumab), mesothelioma (in combination with ipilimumab), NSCLC (alone or in combination with ipilimumab), RCC (alone or in combination with ipilimumab), urothelial carcinoma | ||||
Pembrolizumab | Inhibits PD-1 and allows T cell activation | BC, cervical cancer, CRC, CSCC, endometrial carcinoma, esophageal carcinoma, gastric carcinoma, HCC, HL, HNSCC, melanoma, mesothelioma, MCC, MSI-High/MMR-deficient/TMB-high cancers, NSCLC, large B cell lymphoma, RCC, SCLC, urothelial carcinoma | ||||
PD-L1 | Atezolizumab | Inhibits PD-L1 and allows T cell activation | BC, HCC, melanoma, NSCLC, SCLC, urothelial carcinoma | |||
Avelumab | Inhibits PD-L1 and allows T cell activation | MCC, RCC, urothelial carcinoma | ||||
Durvalumab | Inhibits PD-L1 and allows T cell activation | NSCLC, SCLC, urothelial carcinoma | ||||
New immune checkpoint inhibitors and other inhibitory targets | LAG-3 (CD223) | LAG525 (IMP701), REGN3767 (R3767), BI 754,091, tebotelimab (MGD013), eftilagimod alpha (IMP321), FS118 | Inhibit LAG-3 and allow T cell activation | NA | Often better tolerated than chemotherapy - Can be used to enhance response to other ICIs - Responses seen in therapy refractory disease - Some may work in “cold” TMEs - Novel biomarkers available to further personalize treatment | Clinical outcomes not available for some agents - May not be potent enough to be used as monotherapy - Best combination strategies and indications are unclear - Use with other ICIs may increase toxicities - Toxicities may be similar to those found with the use of existing ICIs: - Cytopenias - Fatigue - Rash/pruritus - Diarrhea/colitis - Hepatitis - Pneumonitis - Unique toxicities and areas of concern: - Antigen sink (CD47) - Increased risk of infections - Hemolytic anemia (CD47) - Infertility (LIF) - Myositis - Neurotoxicity (SEMA4D) - On-target, off-tumor toxicities - Poor wound healing |
TIM-3 | MBG453, Sym023, TSR-022 | Inhibit TIM-3 and allow T cell activation | ||||
B7-H3, B7-H4 | MGC018, FPA150 | Inhibit B7-H3 or B7-H4 and allow T cell activation | ||||
A2aR | EOS100850, AB928 | Inhibits A2aR and allow T cell and APC activation | ||||
CD73 | CPI-006 | Inhibit CD73 and allow T cell and APC activation | ||||
NKG2A | Monalizumab | Inhibits NKG2A and allows T cell activation | ||||
PVRIG/PVRL2 | COM701 | Inhibits PVRIG and allows T cell activation | ||||
CEACAM1 | CM24 | Inhibits CEACAM1 and allows T and NK cells activation | ||||
CEACAM 5/6 | NEO-201 | Inhibits CEACAM5 and 6 which allows T cell activation while interfering with tumor cell growth | ||||
FAK | Defactinib | Inhibits FAK and interferes with tumor growth | ||||
CCL2/CCR2 | PF-04136309 | Inhibits CCR-2 and allows T cell recruitment and activation | ||||
LIF | MSC-1 | Inhibits LIF and allows T cell and APC activation while interfering with cancer growth | ||||
CD47/SIRPα | Hu5F9-G4 (5F9), ALX148, TTI-662, RRx-001 | Inhibits CD47 or SIRPα and allows T cell and APC activation | ||||
CSF-1 (M-CSF)/CSF-1R | Lacnotuzumab (MCS110), LY3022855, SNDX-6352, emactuzumab (RG7155), pexidartinib (PLX3397) | Inhibits CSF-1 and allows APC activation | ||||
IL-1 and IL-1R3 (IL-1RAP) | CAN04, Canakinumab (ACZ885) | Inhibits IL-3 or IL-1RAP and allows T cell and APC activation | ||||
IL-8 | BMS-986253 | Inhibits IL-8 and decreases immunosuppressive TME while interfering with tumor growth | ||||
SEMA4D | Pepinemab (VX15/2503) | Inhibits SEMA4D and decreases immunosuppressive TME while interfering with tumor growth | ||||
Ang-2 | Trebananib | Inhibits Ang-2 and allows APC activation while interfering with cancer growth | ||||
CLEVER-1 | FP-1305 | Inhibits CLEVER-1 and allows APC activation | ||||
Axl | Enapotamab vedotin (EnaV) | Inhibits Axl and allows APC activation while interfering with cancer growth | ||||
Phosphatidylserine | Bavituximab | Inhibits phosphatidylserine and allows T cell and APC activation while interfering with cancer growth |
Category | Target | Drug | Trial | Phase | Type of tumor | Clinical efficacy | Safety | Comments |
---|---|---|---|---|---|---|---|---|
Inhibitory immune checkpoint targets | LAG-3 (CD223) | LAG525 (IMP701) | NCT02460224 | I/II | Advanced malignancies | 11/121 patients in the combination group achieved PR 1 patient had a CR | DLTs occurred in 4/121 patients included grade 3 and 4 pneumonitis, acute kidney injury, and autoimmune hepatitis | With or without spartalizumab |
NCT03365791 | II | Solid or hematologic malignances | DCR for neuroendocrine tumors (86%), diffuse large B cell lymphoma (43%), and small cell lung cancer (27%) | 11/72 patients had grade 3 or 4 AEs including dyspnea, fatigue, and poor appetite | In combination with spartalizumab | |||
REGN3767 (R3767) | NCT03005782 | I | Solid or hematologic malignances | Monotherapy group: ORR 0% and DCR 48% with 12 SD Combination group: ORR 5% and DCR was 31% with 2 PR and 11 SD 2/12 PR and 6 SD in the group crossed over from monotherapy to the combination | 1/67 DLT in the combination group (G4 CK elevation + G3 myasthenic syndrome + G1 elevation of troponin | Alone or in combination with cemiplimab | ||
BI 754,091 | NCT03156114, NCT03433898, NCT03780725 | I | Advanced or metastatic solid tumors | Not reported | 21/321 DLTs, particularly infusion-related reactions (n = 6). Serious AEs: 77/321 (27%): pleural effusion (n = 6), deep venous thrombosis (n = 4), cardiac tamponade (n = 1), and acute kidney injury (n = 1) | Used in combination with anti-PD-1 therapy | ||
NCT03697304 | II | |||||||
Tebotelimab (MGD013) | NCT03219268 | I | Advanced or metastatic solid or hematologic malignancies | Dose escalation (n = 29): ORR 10% and DCR 55% with 3 confirmed PR, 1 unconfirmed PR, and 13 SD Expansion cohort (n = 41): ORR 7%, DCR 59% with 3 PR, and 21 SD | 2/207 DLTs: immune-mediated hepatitis and increased lipase | Alone or in combination with margetuximab (for patients who had expression of HER2 on their tumors) | ||
Eftilagimod alpha (IMP321) | NCT02676869 | I | Advanced melanoma | 1/18 CR | No DLTs reported | Used with pembrolizumab | ||
NCT03252938 | I | Advanced solid tumors | ORR 17% and DCR 33% with 1/6 PR, 1/6 SD, and 4/6 PD | No DLTs reported | Used with avelumab | |||
NCT03625323 | II | Advanced or metastatic NSCLC and HNSCC | ORR 47% and DCR 82% with 8/17 PR and 6/17 SD | Most common toxicities included cough (31%), fatigue (19%), and diarrhea (15%) | Used with pembrolizumab | |||
FS118 | NCT03440437 | I | Advanced solid tumors | Ongoing | ||||
TIM-3 | MBG453 | NCT02608268 | I/II | Advanced solid tumors | ORR in the monotherapy group was 0% and DCR was 29% with 25/87 SD ORR in the combination group was 5% and DCR was 44% with 4/86 PR and 34/86 SD | One DLT in combination cohort (grade 4 MG) 11% developed grade 3 or 4 AEs in the combination cohort | Combined with spartalizumab | |
Sym023 | NCT03489343 | I | Advanced solid tumors and lymphomas | – | – | No results available | ||
TSR-022 | NCT02817633 | I | Advanced solid tumors | – | – | Ongoing | ||
B7-H3 and B7-H4 | MGC018 | NCT03729596 | I/II | Advanced solid tumors | ORR 0% and DCR 15% with 3/20 SD | 1 DLT: grade 4 neutropenia 3 serious AEs: pneumonitis, gastroenteritis, stasis dermatitis | Used as monotherapy | |
FPA150 | NCT03514121 | I | B7-H4 positive solid malignancies | ORR 3% and DCR 38% with 1/29 PR and 10/29 SD | No DLTs or grade 4/5 toxicities were reported | Used as monotherapy | ||
A2aR | EOS100850 | NCT02740985 | I | Advanced solid tumors | ORR 0% and a DCR of 29% with 6/21 SD | No DLTs and no grade 3 or 4 AEs | Used as monotherapy. First in human | |
AB928 | NCT03719326 NCT03720678 NCT03629756 | I | Advanced solid tumors | ORR 4% and DCR of 27% with 1/26 PR and 6/26 SD | 1 DLT: grade 1 rash 6 patients with grade 3 or 4 AEs: fatigue, nausea, and cytopenias | Used in combination with standard chemotherapy or anti-PD-1 therapy | ||
CD73 | CPI-006 | NCT03454451 | I | Advanced solid tumors | 1 patient (monotherapy) with metastatic CRPC: substantial reduction in the size of a target lesion after only 5 cycles, sustained at the time of cutoff | No DLTs reported | Used as monotherapy or in combination with an anti-A2aR agent (CPI-444) | |
NKG2A | Monalizumab | NCT03088059 | II | Platinum-resistant, recurrent or metastatic, HNSCC | PFS: 7.4 weeks Median OS: 27.7 weeks ORR 0%, DCR 22% with 6/27 SD | No DLTs reported | Used as monotherapy | |
NCT02643550 | II | Platinum-resistant, recurrent or metastatic, HNSCC | ORR 20% DCR 58% with 8/40 PR 15/40 SD | No DLTs reported | Used in combination with cetuximab | |||
PVRIG/ PVRL2 | COM701 | NCT03667716 | I | Advanced Solid tumors | DCR 57% (16/28 patients) No CRs 1/16 PR in the monotherapy group 1/12 unconfirmed PR in the combination group | No DLTs reported | Used as monotherapy and in combination with nivolumab | |
Inhibitory targets beyond immune checkpoints | CEACAM1 | CM24 | NCT02346955 | I | Advanced or recurrent solid tumors | ORR of 0% and a DCR of 30% with 8/27 SD Median OS 4 months (lower dose), and 6 months (higher dose) | No DLTs 4 individuals with grade 3–4 GGT elevation | Used as monotherapy |
CEACAM 5/6 | NEO-201 | NCT03476681 | I | Advanced solid tumors | ORR 0% and DCR 33% with radiological SD in 3/9 patients | No DLTs reported | Used as monotherapy | |
FAK | Defactinib | NCT02546531 | I | Advanced pancreatic adenocarcinoma | Escalation cohort (n = 8): ORR 13% and DCR 50% with 1 PR, 3 SD, and 4 PD Expansion cohort (= 20): ORR 5% and DCR 60% with 1 PR, 11 SD, 7 PD and 1 non-evaluable response | No DLTs were seen Most common grade 1 and 2 AEs included fatigue, anorexia, nausea, and vomiting | Used in combination with pembrolizumab and gemcitabine | |
CCL2/ CCR2 | PF-04136309 | NCT02732938 | I | Metastatic pancreatic adenocarcinoma | ORR 23.8%, DCR 38% with 0/21 CR, 5/21 confirmed PR, 1/21 unconfirmed PR, and 3/21 SD | DLTs: dysesthesia, hypokalemia, and hypoxia 24% pulmonary toxicities including 3 patients with grade 3 pneumonitis, 1 grade 4 hypoxia, and 1 grade 5 pneumonia | Used in combination with nab-paclitaxel and gemcitabine | |
LIF | MSC-1 | NCT03490669 | I | Advanced solid tumors | DCR 22% with 9/41 SD lasting > 16 weeks | No DLTs reported | Used as monotherapy | |
CD47/ SIRP | Hu5F9-G4 (5F9) | NCT02216409 | I | Advanced Solid tumors | ORR ~ 5% DCR 19% with 2/43 PR (ovarian and fallopian tube cancers) and 6/43 SD (CRC) | AEs occurred with higher doses. These included constitutional symptoms (50%), headache (34%), anemia (39%), and lymphopenia (28%) | Used as monotherapy | |
NCT02953509 | I/II | Relapsed and refractory NHL | CRR 21% ORR 49% with 16/75 CR and 21/75 PR | DLTs 4% (no specifics provided) | Combined with rituximab | |||
ALX148 | NCT03013218 | I | Advanced solid tumors or refractory NHL | ICI-naïve HNSCC: ORR 40% (4/10), median PFS 4.6 months, and median OS not reached after 14 months of follow-up Non-ICI-naïve HNSCC: ORR 0%, median PFS 2 months, median OS 7.4 months ALX148 + trastuzumab in gastric/gastroesophageal cancers (n = 20): ORR 20%, median PFS 2.2 months, and median OS 8.1 months Monotherapy (n = 25): DCR 16% with 4/25 SD | 2 DLTs: neutropenia with infection and thrombocytopenia with a significant bleed 1 grade 5 (fatal) toxicity under investigation Most AEs (66%) were low grade | Used in monotherapy agent or with pembrolizumab, trastuzumab, rituximab, ramucirumab, 5FU, paclitaxel, or cisplatin | ||
TTI-662 | NCT03530683 | I | Relapsed or refractory lymphomas | 1 patient (DLBCL) with 5 prior lines of therapy achieved a PR by week 8 and a CR by week 36 | No DLTs | Used as monotherapy | ||
RRx-001 | NCT02518958 | I | Advanced solid malignancies or lymphomas | ORR 25%, DCR 67% with 3/12 PR, 5/12 SD, and 3/12 PD | No DLTs reported 1 patient discontinued therapy due to pneumonitis | Used in combination with nivolumab | ||
CSF-1 (M-CSF)/ CSF-1R | Lacnotuzumab (MCS110) | NCT02807844 | I/II | Advanced malignancies | DCR 27% 3/48 had pancreatic cancer: 1 PR, and 2 SD lasting > 300 days | No DLTs reported | Used in conjunction with spartalizumab | |
LY3022855 | NCT02265536 | I | Metastatic BC and metastatic CRPC | BC (n = 22): DCR 23% with 5/22 SD. 2 of these had a response that lasted > 9 months CRPC (n = 7): ORR 0% and DCR 43% with 3/7 SD lasting up to 4 months | No DLTs reported | Used as monotherapy | ||
SNDX-6352 | NCT03238027 | I | Advanced solid tumors | DCR 13% with 4/32 SD that lasted > 4 months | 2 DLTs, one grade 3 fatigue and one grade 3 pneumonitis | Used as monotherapy and in combination with durvalumab | ||
Emactuzumab (RG7155) | NCT01494688 | I | Advanced solid tumors | Monotherapy (n = 99): ORR 0% and DCR 13% with 13/99 SD Combination (n = 54): ORR 7% DCR 50% with 4/54 PR 23/54 SD | No DLTs in the monotherapy, 2 DLTs in the combination: one grade 4 hypokalemia and one grade 3 hemorrhagic enterocolitis One grade 5 AE: bowel perforation | Used as monotherapy or in combination with paclitaxel | ||
Pexidartinib (PLX3397) | NCT01525602 | I | Advanced solid tumors | ORR 16%, DCR 50%, PD rate 45% with 1/38 CR, 5/38 PR, 13/38 SD, and 17/38 PD | 2 DLTs: one grade 3 atrial fibrillation and one grade 3 hypophosphatemia | Used in combination with paclitaxel | ||
NCT02777710 | I | Advanced or metastatic pancreatic adenocarcinoma or CRC | ORR 0% and DCR 21% with 4/19 SD | 2 DLTs: both transaminase elevation, one with hyperbilirubinemia | Used with durvalumab | |||
NCT02734433 | I | Asian patients with symptomatic, advanced solid malignancies | DCR 67% with 1/11 PR and 4/11 SD | 5 patients experienced at least one grade 3 or 4 AE: elevated transaminases and anemia | Monotherapy | |||
IL-1 and IL-1R3 (IL-1RAP) | CAN04 | NCT03267316 | I | Advanced or metastatic NSCLC, CRC, BC, or pancreatic adenocarcinoma | DCR 45% with 9/22 SD including 2 whose response lasted > 4 months | No DLTs or grade 4–5 AEs reported | Used as monotherapy | |
Canakinumab (ACZ885) | NCT03968419 | II | Early-stage NSCLC | – | – | Ongoing | ||
IL-8 | BMS-986253 | NCT02536469 | I | Advanced solid tumors | ORR 0% and DCR 73% with 11/15 SD and 4/15 PD | No DLTs reported | Used as monotherapy | |
NCT03400332 | I/II | Advanced solid tumors | – | – | Ongoing | |||
SEMA4D | Pepinemab (VX15/2503) | NCT03268057 | I/II | Advanced-stage NSCLC | Immunotherapy-naïve (n = 21): ORR 24% and DCR 81% with 5/21 PR and 12/21 SD Immunotherapy-refractory (n = 29): ORR was 7% and DCR was 59% with 2 patients achieving PR and 15 SD | No DLTs reported | Used in combination with avelumab | |
Ang-2 | Trebananib | NCT03239145 | I | Advanced solid tumors | DCR 33% and ORR 7% with 1/15 PR and 4/15 SD Median time to progression: 2.6 months OS: 11.4 months | No DLTs and no grade 3 or 4 AEs | Used in combination with pembrolizumab | |
CLEVER-1 | FP-1305 | NCT03733990 | I/II | Advanced solid tumors | ORR 3% and DCR 27% with 2/30 PR, 6/30 SD, and 22/30 PD | No DLTs reported | Used as monotherapy | |
Axl | Enapotamab vedotin (EnaV) | NCT02988817 | I | Advanced solid tumors | ORR 6%, DCR 55% with 3/47 PR and 26/47 SD | 6 DLTs: constipation, vomiting, GGT elevation, febrile neutropenia, and diarrhea | First-in-human clinical trial. Used as monotherapy | |
Phosphatidylserine | Bavituximab | NCT01264705 | II | Advanced, unresectable HCC | ORR 5%, DCR 58% with 2/38 PR and 20/38 SD | No DLTs or grade 4–5 AEs reported | Used in combination with sorafenib |