Table 2.
Clinical trials of investigational agents on acquired resistance
| Mechanism | Target | Mechanism | Drug | Clinical trial No. | Phase | Tumor types | Treatment arms | Status |
|---|---|---|---|---|---|---|---|---|
| INF-γ pathway | STING | STING agonist | E7766 | NCT04144140 | 1 | Solid tumor, lymphoma | E7766 | Recruiting |
| GSK3745417 | NCT03843359 | 1 | Solid tumor | GSK3745417 ± pembrolizumab | Recruiting | |||
| MIW815 | NCT03172936 | 1 | Solid tumor, lymphoma | MIW815 + PDR001 | Active, not recruiting | |||
| SNX281 | NCT04609579 | 1 | Solid tumor, lymphoma | SNX281 ± pembrolizumab | Recruiting | |||
| TAK-676 | NCT04420884 | 1 | Solid tumor | TAK-676 ± pembrolizumab | Recruiting | |||
| JAK | JAK1 inhibitor | AZD4205 | NCT03450330 | 1,2 | NSCLC | AZD4205 + osimertinib | Completed | |
| Itacitinib (INCB039110) | NCT03425006 | 2 | NSCLC | Itacitinib + pembrolizumab | Active, not recruiting | |||
| JAK1/2 inhibitor | Ruxolitinib (INCB018424) | NCT02145637 | 1 | NSCLC | Ruxolitinib + afatinib | Completed | ||
| STAT | STAT3 inhibitor | TTI-101 | NCT03195699 | 1 | Solid tumor | TTI-101 | Recruiting | |
| SHP-1 agonist | SC-43 | NCT04733521 | 1,2 | NSCLC, biliary tract cancer | SC-43 + cisplatin | Not yet recruiting | ||
| Blockade of alternate coinhibitory immune checkpoint receptors | LAG-3 | LAG-3 fusion protein | Eftilagimod alpha (IMP321) | NCT03625323 | 2 | NSCLC, HNSCC | Eftilagimodalpha + pembrolizumab | Recruiting |
| IgG4 mAb | Relatlimab (BMS-986016) | NCT02750514 | 2 | NSCLC | Nivolumab ± relatlimab or ipilimumab or BMS-986205 or dasatinib | Active, not recruiting | ||
| IgG4 mAb | LAG525 | NCT02460224 | 1,2 | Solid tumor | LAG525 ± spartalizumab (PDR001) | Active, not recruiting | ||
| mAb | BI 754111 | NCT03780725 | 1 | NSCLC, HNSCC | BI 754111 + BI 754091 | Completed | ||
| IgG4 mAb | Mavezelimab (MK-4280) | NCT03516981 | 2 | NSCLC | Pembrolizumab + quavonlimab or MK-4280 or lenvatinib | Recruiting | ||
| TIM-3 | Anti-PD-1/TIM-3 bispecific Ab | RO7121661 | NCT03708328 | 1 | Solid tumor | RO7121661 | Recruiting | |
| Anti-TIM-3 mAb | INCAGN02390 | NCT03652077 | 1 | Solid tumor | INCAGN02390 | Active, not recruiting | ||
| Sym023 | NCT03489343 | 1 | Solid tumor, lymphoma | Sym023 | Completed | |||
| LY3321367 | NCT03099109 | 1 | Solid tumor | LY3300054 (anti-PD-L1), LY3321367, LY3300054 + LY3321367 | Active, not recruiting | |||
| Cobolimab (TSR-022) | NCT02817633 | 1 | Solid tumor | Cobolimab ± nivolumab, cobolimab + TSR-042 ± TSR-033 or docetaxel | Recruiting | |||
| Sabatolimab (MBG453) | NCT02608268 | 1,2 | Solid tumor | Sabatolimab ± PDR001 or decitabine | Active, not recruiting | |||
| TIGIT | Anti-TIGIT mAb | Tiragolumab (MTIG7192A/RG-6058) | NCT04294810 | 3 | NSCLC | Atezolizumab ± tiragolumab | Recruiting | |
| NCT04256421 | 3 | SCLC | Atezolizumab + carboplatin + etoposide ± tiragolumab | Recruiting | ||||
| Vibostolimab (MK-7684) | NCT02964013 | 1 | Solid tumor | Vibostolimab ± pembrolizumab ± pemetrexed/carboplatin, vibostolimab + carboplatin + cisplatin + etoposide | Recruiting | |||
| BMS-986207 | NCT02913313 | 1,2 | Solid tumor | BMS-986207 ± nivolumab | Active, not recruiting | |||
| Domvanalimab (AB-154) | NCT04262856 | 2 | NSCLC | Zimberelimab ± dombvanalimab ± etrumadenant | Recruiting | |||
| IBI939 | NCT04672356 | 1 | NSCLC, SCLC | IBI939 + sintilimab | Not yet recruiting | |||
| BTLA | Anti-OX40 mAb | Cudarolimab (IBI101) | NCT03758001 | 1 | Solid tumor | Cudarolimab ± sintilimab | Recruiting | |
| Anti-BTLA mAb | TAB004 | NCT04137900 | 1 | Solid tumor | TAB004 | Recruiting | ||
| VISTA | Anti-VISTA mAb | JNJ-61610588 | NCT02671955 | 1 | Solid tumor | JNJ-61610588 | Terminated | |
| CI-8993 | NCT04475523 | 1 | Solid tumor | CI-8993 | Recruiting | |||
| Small molecule targeting VISTA and PD-L1 | CA-170 | NCT02812875 | 1 | Solid tumor, lymphoma | CA-170 | Completed | ||
| Immune stimulatory agents | OX40 | Hexavalent OX40 agonist Ab | INBRX-106 | NCT04198766 | 1 | Solid tumor | INBRX-106 ± pembrolizumab | Recruiting |
| PD1-Fc-OX40L | SL-279252 | NCT03894618 | 1 | Solid tumor, lymphoma | SL-279252 | Recruiting | ||
| Anti-OX40 agonist mAb | PF-04518600 | NCT02315066 | 1 | Solid cancer | PF-04518600 ± PF-05082566 | Completed | ||
| INCAGN01949 | NCT02923349 | 1,2 | Solid tumor | INCAGN01949 | Completed | |||
| ICOS | Anti-ICOS mAb | GSK3359609 | NCT03693612 | 2 | Solid tumor | GSK3359609 + tremelimumab, docetaxel + paclitaxel + cetuximab | Recruiting | |
| JTX-2011 | NCT02904226 | 1,2 | Solid tumor | JTX-2011 + pembrolizumab or nivolumab or ipilimumab | Completed | |||
| KY1044 | NCT03829501 | 1,2 | Solid tumor | KY1044 ± atezolizumab | Completed | |||
| Tumor microenvironment | CSF1R | MET, CSF1R, SRC kinase inhibitor | TPX-0022 | NCT03993873 | 1 | Solid tumor | TPX-0022 | Recruiting |
| CSF1R mAb | Cabiralizumab (FPA008) | NCT02526017 | 1 | Solid tumor | FPA008 + BMS-936558 | Completed | ||
| TGF-b | TGF-bR inhibitor | Galunisertib (LY2157299) | NCT02423343 | 1,2 | Solid tumor | Galunisertib + nivolumab | Completed | |
| TEW 7197 | NCT02160106 | 1 | Solid tumor | TEW-7197 | Completed | |||
| TGF-b inhibitor | AVID200 | NCT03834662 | 1 | Solid tumor | AVID200 | Active, not recruiting | ||
| Anti-TGF-bmAb | SAR-439459 | NCT04729725 | 1 | Solid tumor | SAR-439459 + cemiplimab | Not yet recruiting | ||
| VEGF | VEGFR TKI inhibitor | Vandetanib (ZD6474) | NCT00418886 | 3 | NSCLC | Vandetanib + pemetrexed | Active, not recruiting | |
| Axitinib (AG-013736) | NCT03472560 | 2 | NSCLC, urothelial cancer | Axitinib + avelumab | Active, not recruiting | |||
| Apatinib (YN968D1) | NCT03389256 | 2 | EGFR T790M-negative NSCLC | Apatinib + EGFR-TKI | Not yet recruiting | |||
| Anti-VEGF mAb | Bevacizumab (L01XC07) | NCT00451906 | 3 | NSCLC | Bevacizumab + first-line chemotherapy | Completed | ||
| IBI305 | NCT03802240 | 3 | Non-squamous NSCLC | Sintilimab ± IBI305 + pemetrexed + cisplatin | Recruiting | |||
| Anti-VEGFR mAb | Ramucirumab (LY3009806) | NCT04340882 | 2 | NSCLC | Ramucirumab + docetaxel + pembrolizumab | Recruiting | ||
| Aurora B/VEGFR/PDGFR/c-Kit/CSF1R inhibitor | Chiauranib (CS2164) | NCT03216343 | 1 | SCLC | Chiauranib | Recruiting | ||
| IL-1b | Anti-IL-1b mAb | Canakinumab (ACZ885) | NCT03626545 | 3 | NSCLC | Canakinumab + docetaxel | Active, not recruiting | |
| IL1RAP Ab | CAN04 | NCT04452214 | 1 | Solid tumor | CAN04 + pembrolizumab | Recruiting | ||
| IL-6 | Anti-IL-6R mAb | Tocilizumab (RO4877533) | NCT04691817 | 1,2 | NSCLC | Tocilizumab + atezolizumab | Not yet recruiting | |
| Anti-IL-6 mAb | Siltuximab (CNTO 328) | NCT00841191 | 1,2 | Solid tumor | Siltuximab | Completed | ||
| IL-8 | Anti-IL-8 mAb | BMS-986253 | NCT04123379 | 2 | NSCLC, HCC | Nivolumab + BMS-813160 or BMS-986253 | Recruiting | |
| Tumor microenvironment | A2AR | A2AR antagonist | PBF-509 | NCT02403193 | 1,2 | NSCLC | PBF-509 + PDR001 | Active, not recruiting |
| Etrumadenant (AB928) | NCT03846310 | 1 | Lung cancer | Etrumadenant + carboplatin + pemetrexed | Recruiting | |||
| CD73 | Small molecule CD73 inhibitor | LY3475070 | NCT04148937 | 1 | Solid tumor | LY3475070 ± pembrolizumab | Recruiting | |
| Anti-CD73 mAb | CPI-006 | NCT03454451 | 1 | Solid cancer, NHL | CPI-006 ± ciforadenant or pembrolizumab | Recruiting | ||
| Oleclumab (MEDI9447) | NCT03381274 | 1,2 | EGFR-mutant NSCLC | MEDI9447 + osimertinib or AZD4635 | Active, not recruiting | |||
| Sym024 | NCT04672434 | 1 | Solid tumor | Sym021 ± Sym024 | Recruiting | |||
| NZV930 | NCT03549000 | 1 | Solid tumor | NZV930 ± PDR001 ± NIR178 | Recruiting | |||
| IDO1 | IDO inhibitor | Indoximod (NLG-8189) | NCT02460367 | 1 | NSCLC | Indoximod + docetaxel + tergenpumatucel-L | Active, not recruiting | |
| B7-H4 | B7-H4 Ab | FPA150 | NCT03514121 | 1 | Solid tumor | FPA150 + pembrolizumab | Active, not recruiting | |
| Epigenetic modulators | Hypomethylating agents | DNMTi | Guadecitabine (SGI-110) | NCT03913455 | 2 | SCLC | Guadecitabine + carboplatin | Active, not recruiting |
| Cytidine nucleoside analogue | CC-486 | NCT02546986 | 2 | NSCLC | Pembrolizumab ± CC-486 | Active, not recruiting | ||
| Deoxycitidine analogue | Aza-TdCyd | NCT03366116 | 1 | Solid tumor | Aza-TdCyd | Recruiting | ||
| HMTi | EZH2 inhibitor | Tazemetostat (EPZ-6438) | NCT01897571 | 1,2 | Solid tumor, B-cell lymphoma | Tazemetostat | Active, not recruiting | |
| HDACi | HDAC inhibitor | ACY-241 | NCT02635061 | 1 | NSCLC | ACY-241 + nivolumab | Active, not recruiting | |
| Mocetinostat (MGCD01013) | NCT02954991 | 2 | NSCLC | Nivolumab + glesatinib or sitravatinib or mocetinostat | Active, not recruiting | |||
| Entinostat (SNDX-275) | NCT01928576 | 2 | NSCLC | Entinostat + azacitidine + nivolumab | Recruiting | |||
| Vorinostat (MK0683) | NCT02638090 | 1,2 | NSCLC | Pembrolizumab ± vorinostat | Recruiting | |||
| Abexinostat (PCI-24781) | NCT03590054 | 1 | Solid tumor | Abexinostat + pembrolizumab | Recruiting | |||
| Adoptive T cell therapy | Genetically modified T cells | NCT02408016 | 1,2 | NSCLC, mesothelioma | Autologous WT1-TCRc4 Gene-transduced CD8-positive Tcm/Tn Lymphocytes | Active, not recruiting | ||
| Genetically modified T cells | NCT02706392 | 1 | ROR1-positive Solid tumor | ROR1 CAR-specific autologous T-Lymphocytes | Recruiting | |||
STING, stimulator of IFN genes; JAK, Janus kinase; NSCLC, non-small cell lung cancer; STAT, signal transducer and activators of transcription; SHP-1, Src-homology2 domain-containing phosphatase-1; LAG-3, lymphocyte-associated gene 3; HNSCC, head and neck squamous cell carcinoma; TIM-3, T-cell immunoglobulin and mucin domain-3; anti-PD-L1, anti-programmed cell death ligand 1; TIGIT, T-cell immunoglobulin and ITIM domain; SCLC, small cell lung cancer; BTLA, B and T-lymphocyte attenuator; VISTA, V-domain immunoglobulin suppressor of T-cell activation; ICOS, inducible T-cell costimulator; CSF1R, colony stimulating factor 1 receptor; TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor; IL, interleukin; Anti-IL-6R-mAb, anti-interleukin-6 receptor monoclonal antibody; TKI, tyrosine kinase inhibitor; EGFR, epidermal growth factor receptor; HCC, hepatocellular carcinoma; A2AR, adenosine A2A receptor; NHL, non-Hodgkin lymphoma; IDO, indoleamine 2,3-dioxygenase; DNMTi, indoleamine 2,3-dioxygenase; HMTi, histone methyltransferase inhibitor; HDACi, histone deacetylase inhibitor; ROR1, tyrosine-protein kinase transmembrane receptor.