Table 1 Targeted therapies against AXL
From: AXL signaling in cancer: from molecular insights to targeted therapies
Small-molecule AXL TKI | Target(s) | Mechanism(s) | Cancer type | Monotherapy/combination | Clinical trial no./phasea | Statusa | Adverse events | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
Selective AXL Inhibitors | ||||||||||||
Bemcentinib/BGB324/R428 | AXL | Inhibition of Akt and MAPK pathways, upregulate PUMA and downregulate Bcl-2 | NSCLC | + Docetaxel | NCT02922777- I | Completed | Neutropenia, diarrhea, nausea, vomiting, QTc prolongation, transaminase increase, asthenia, and fatigue | |||||
AML or MDS | Monotherapy in AML or MDS/+ cytarabine or decitabine in AML | NCT02488408- Ib/II | Unknown status | |||||||||
NSCLC | + Erlotinib | NCT02424617- I/II | Completed | |||||||||
TNBC or TN-IBC | + Pembrolizumab | NCT03184558- II | Terminated | |||||||||
MDS patients failing standard-of-care therapy | Monotherapy | NCT03824080- II | Completed | |||||||||
Advanced NSCLC | + Pembrolizumab | NCT03184571- II | Completed | |||||||||
Malignant mesothelioma | + Pembrolizumab | NCT03654833- II | Active, not recruiting | |||||||||
Metastatic melanoma | + Pembrolizumab or Dabrafenib/Trametinib | NCT02872259- Ib/II | Completed | |||||||||
Recurrent glioblastoma undergoing surgery | Monotherapy | NCT03965494- I | Terminated | |||||||||
Metastatic pancreatic cancer | + Chemotherapy (nab-paclitaxel/gemcitabine) | NCT03649321- I/II | Terminated | |||||||||
Untreated non-squamous NSCLC | + Pembrolizumab/carboplatin/pemetrexed | NCT05469178- Ib/IIa | Recruiting | |||||||||
TP-0903/Dubermatinib | AXL | Inhibit Aurora B activation to induce G2/M arrest; Induction of apoptosis by suppressing Mcl-1, Bcl-2 and XIAP; upregulation of BIM | Advanced solid tumors | Monotherapy | NCT02729298- I | Completed | Thrombocytopenia, anemia, nausea, syncope, and vomiting | |||||
FLT3 mutated AML | TP-0903 alone/+azacitidine | NCT04518345- Ib/II | Completed | |||||||||
AML | Monotherapy | NCT03013998- Ib/II | Recruiting | |||||||||
Previously treated CLL | Monotherapy/+ ibrutinib | NCT03572634-I/II | Terminated | |||||||||
DS-1205 | AXL | Inhibit GAS6-mediated cell migration | Metastatic or unresectable EGFR-mutant NSCLC | + Gefitinib | Terminated | Combination with gefitinib may induce elevation of liver enzymes, vomiting, diarrhea, and fatigue | ||||||
Metastatic or unresectable EGFR-mutant NSCLC | + Osimertinib | Terminated | ||||||||||
AVB-S6-500/Batiraxcept | AXL decoy receptor | Inhibit GAS6-induced AXL or Src phosphorylation | Platinum-resistant recurrent ovarian cancer | + Pegylated liposomal doxorubicin or paclitaxel | NCT03639246- I | Completed | Avelumab in combination with AVB-S6-500 may result in UTI, hyponatremia, elevated creatinine, anemia, thrombocytopenia, hematuria, anorexia, and sepsis | |||||
Platinum-resistant recurrent ovarian, fallopian tube or primary peritoneal cancer | + Durvalumab (MEDI4736) | NCT04019288- I/II | Active, not recruiting | |||||||||
Platinum-resistant recurrent ovarian cancer | + Paclitaxel vs placebo and paclitaxel | NCT04729608- III | Terminated | |||||||||
Advanced or metastatic ccRCC | AVB-S6-500 alone/+ cabozantinib/+ cabozantinib and nivolumab | NCT04300140- Ib/II | Terminated | |||||||||
Advanced pancreatic adenocarcinoma | + Nab-paclitaxel and gemcitabine | NCT04983407- Ib/II | Terminated | |||||||||
Advanced urothelial carcinoma | + Avelumab | NCT04004442- I | Active, not recruiting | |||||||||
Multitargeted AXL inhibitors | ||||||||||||
BMS777607 | AXL, RON, c-MET, TYRO3, MER | Inhibition of HGF-induced c-MET-phosphorylation and downregulate MEK-ERK and PI3K/Akt pathways | Advanced or metastatic solid tumors | Monotherapy | Completed | Anemia, nausea, Constipation | ||||||
Advanced or metastatic solid tumors | Monotherapy | NCT00605618- I/II | Completed | |||||||||
Cabozantinib/BMS-907351 | AXL, VEGFR2, c-MET, RET, TIE2, c-KIT, Flt3, ROS1 | Decrease AXL phosphorylation and TGF-β-induced E-cadherin expression | NSCLC | With or without erlotinib | NCT00596648- Ib/II | Completed | Fatigue, diarrhea, hypertension, palmar-plantar erythrodysesthesia syndrome, fistula, abdominal and pelvic abscess | |||||
Previously treated metastatic NSCLC | + Erlotinib | NCT01866410- II | Completed | |||||||||
Stage IV NSCLC | Monotherapy/+ erlotinib | NCT01708954- II | Active, not recruiting | |||||||||
KRAS wild-type metastatic colorectal cancer | Monotherapy in MET amplified metastatic colorectal cancer/+ panitumumab | NCT02008383- I | Completed | |||||||||
Locally advanced or metastatic solid tumors | Cabozantinib alone / + atezolizumab | NCT03170960- I/II | Active, not recruiting | |||||||||
Metastatic castration-resistant prostate cancer | + Atezolizumab vs second novel hormonal therapy | NCT04446117- III | Active, not recruiting | |||||||||
Advanced HCC with no previous systemic anticancer therapy | + Atezolizumab vs sorafenib | NCT03755791- III | Active, not recruiting | |||||||||
Metastatic NSCLC previously treated with anti-PD-L1/ PD-1 Antibody and platinum- chemotherapy | + Atezolizumab vs docetaxel monotherapy | NCT04471428- III | Active, not recruiting | |||||||||
Advanced RCC after immune checkpoint inhibitor treatment | + Atezolizumab vs cabozantinib alone | NCT04338269- III | Active, not recruiting | |||||||||
Previously untreated advanced or metastatic RCC | + Nivolumab vs Sunitinib | NCT03141177- III | Active, not recruiting | |||||||||
Non-clear cell RCC | + Nivolumab | NCT03635892- II | Active, not recruiting | |||||||||
Previously untreated advanced or metastatic RCC | + Nivolumab and ipilimumab vs nivolumab and ipilimumab with matched placebo | NCT03937219- III | Active, not recruiting | |||||||||
NSCLC | With or without erlotinib | NCT00596648- Ib/II | Completed | |||||||||
Advanced kidney cancer | Ipilimumab and nivolumab followed by nivolumab alone vs nivolumab with cabozantinib | NCT03793166- III | Active, not recruiting | |||||||||
Recurrent stage IV NSCLC | + Nivolumab or + nivolumab and ipilimumab vs nivolumab alone | NCT03468985- II | Active, not recruiting | |||||||||
Advanced liver cancer | Nivolumab alone/ nivolumab and sorafenib/ nivolumab and ipilimumab/ + nivolumab/ + nivolumab and ipilimumab | NCT01658878-I/II | Active, not recruiting | |||||||||
Radioiodine-refractory differentiated thyroid cancer progressed after prior VEGFR -targeted therapy | Cabozantinib vs placebo | NCT03690388-III | Active, not recruiting | |||||||||
Advanced pancreatic neuroendocrine and carcinoid tumors | Cabozantinib vs Placebo | NCT03375320-III | Active, not recruiting | |||||||||
Hepatocellular carcinoma patients received prior sorafenib | Cabozantinib vs Placebo | NCT01908426- III | Completed | |||||||||
Metastatic RCC | Cabozantinib vs Everolimus | NCT01865747- III | Completed | |||||||||
Bosutinib/SKI-606 | AXL, Src kinase, BCR-ABL | Inhibits autophosphorylation of AXL with downregulation of slug and inhibits PI3K/Akt/mTOR pathways | Recurrent glioblastoma | Monotherapy | NCT01331291- II | Completed | Diarrhea, rash, liver enzyme elevations | |||||
Advanced breast cancer | Monotherapy | NCT00319254- II | Completed | |||||||||
Advanced malignant solid tumors | Monotherapy | NCT01001936- I | Completed | |||||||||
Philadelphia chromosome +ve CML previously treated with one or more TKIs | Monotherapy | NCT02228382- IV | Terminated | |||||||||
CML-CP previously treated with 2 or more TKIs | ABL001 vs Bosutinib | NCT03106779- III | Active, not recruiting | |||||||||
Selected metastatic solid tumors | + Pemetrexed | NCT03023319- I | Completed | |||||||||
HR + HER2- advanced breast cancer refractory to CDK4/ 6 inhibitor | + Palbocicilib and fulvestrant | Active, not recruiting | ||||||||||
Crizotinib/PF-02341066 | AXL, ALK, c-MET, RON | Inhibits phosphorylation of target receptors | ALK+ advanced NSCLC | Brigatinib vs Crizotinib | NCT02737501- III | Completed | Abdominal pain, headache, pain in extremity, nausea, pyrexia | |||||
High-risk uveal melanoma following definitive therapy | Monotherapy | NCT02223819- II | Completed | |||||||||
c-MET +ve gastric adenocarcinoma | Monotherapy | NCT02435108- II | Completed | |||||||||
mCRPC | + Enzalutamide | NCT02207504- I | Completed | |||||||||
Sunitinib/SU11248 | AXL, c-KIT, FLT3, PDGFR, VEGFR2 | Inhibits ligand-mediated VEGFR2, PDGFR-β phosphorylation | Metastatic RCC | Monotherapy | NCT00706706- IV | Completed | Diarrhea, fatigue, hypertension, hematologic adverse events and palmar-plantar erythrodysesthesia syndrome | |||||
Refractory solid tumors | Monotherapy | NCT02691793- IV | Completed | |||||||||
High-risk non-muscle invasive lower urinary tract urothelial carcinoma | Monotherapy | NCT00794950- II | Completed | |||||||||
Advanced cholangiocarcinoma | Monotherapy | NCT01718327- II | Completed | |||||||||
Advanced well-differentiated pancreatic neuroendocrine tumors | Monotherapy | NCT01525550- IV | Completed | |||||||||
Imatinib resistant or intolerant malignant GIST | Monotherapy | NCT00793871- IV | Completed | |||||||||
Locally advanced or recurrent soft tissue sarcoma | Preoperative sunitinib and radiation | NCT01498835- I | Completed | |||||||||
Recurrent ovarian clear cell carcinoma | Monotherapy | NCT01824615- II | Completed | |||||||||
NSCLC patients with brain metastases | Monotherapy | NCT00372775-II | Completed | |||||||||
Metastatic or recurrent thymic carcinoma | Monotherapy | NCT02623127- II | Completed | |||||||||
Sitravatinib/MGCD516 | AXL, c-KIT, VEGFR3 PDGFR, c-MET, RET, MER, FLT3 | Immune-modulation of tumors by reducing immunosuppressive myeloid cells and increase CD4+ & CD+8 T cells | Metastatic, pre-treated TNBC | Monotherapy | NCT04123704- II | Terminated | Diarrhea, fatigue, rash, nausea | |||||
ccRCC | + Nivolumab | NCT03680521- II | Completed | |||||||||
Advanced solid tumor malignancies | Monotherapy | NCT02219711- I/Ib | Completed | |||||||||
Advanced or metastatic kidney cancer progressed on prior VEGF-targeted therapy | + Nivolumab | NCT03015740- I/II | Completed | |||||||||
Locally recurrent or metastatic TNBC | + Tislelizumab/ + tislelizumab and nab-paclitaxel | NCT04734262- II | Active, not recruiting | |||||||||
Advanced solid tumors | + Tislelizumab | NCT03666143- Ib | Completed | |||||||||
NSCLC | + Nivolumab | NCT02954991- II | Terminated | |||||||||
Advanced or metastatic ccRCC or other solid malignancies | + Nivolumab and ipilimumab | NCT04518046- I/Ib | Completed | |||||||||
Advanced or metastatic urothelial carcinoma | + PD-(L)1 checkpoint inhibitors regimens (nivolumab/ pembrolizumab and enfortumab vedotin) | NCT03606174- II | Terminated | |||||||||
Advanced NSCLC | + Nivolumab vs Docetaxel | NCT03906071- III | Active, not recruiting | |||||||||
Unresectable locally advanced or metastatic HCC or GC/GEJC | Monotherapy/ + tislelizumab | NCT03941873- I/II | Completed | |||||||||
Locally advanced or metastatic NSCLC | + Tislelizumab vs Docetaxel | NCT04921358- III | Terminated | |||||||||
Advanced biliary tract cancer | + Tislelizumab | NCT04727996- II | Active, not recruiting | |||||||||
Advanced treatment-naïve PD-L1+ non-squamous NSCLC | + Pembrolizumab | NCT04925986- II | Terminated | |||||||||
Advanced or metastatic malignancies | Monotherapy/ + other anticancer therapies (nivolumab, pembrolizumab, enfortumab vedotin, ipilimumab) | NCT04887870- II/III | Active, not recruiting | |||||||||
S49076 | AXL/MET, c-MET, FGFR1/2/3 | Inhibits Aurora b kinase inhibits phosphorylation of target receptors | Advanced solid tumors | Monotherapy | Completed | Peripheral edema and hypalbuminaemia | ||||||
Recurrent glioblastoma multiforme | + Bevacizumab | ISRCTN11619481- I/II | Completed | |||||||||
ONO-7475 | AXL, MER | – | Acute leukemia or MDS | Monotherapy/ + venetoclax | NCT03176277- I/II | Terminated | – | |||||
PF-07265807 | AXL, MERTK | Enhance dendritic cell activity to prime CD8 + T cells | Metastatic solid tumors | Monotherapy/ + sasanlimab/ + sasanlimab and axitinib | NCT04458259- I | Active, not recruiting | – | |||||
Ningetinib | c-MET, AXL and VEGFR2 | – | Stage IIIB or IV NSCLC patients with EGFR mutation and T790M-negative | + Gefitinib | NCT03758287- I/II | Unknown status | Myocardial enzyme elevation, transaminase elevation, skin rash, diarrhea, hypertension, coagulation abnormalities, and albuminuria | |||||
CB469 | AXL, c-MET | – | NSCLC | + Erlotinib, gefitinib, osimertinib | – | – | ||||||
Foretinib/XL880/GSK1363089 | AXL, c-MET, MERTK, VEGFR1/2/3, TIE2, TYRO3, RON, FLT3, PDGFR-α/ β, c-KIT, ROS1 | Inhibition of inter-receptor tyrosine kinase phosphorylation | Metastatic breast cancer | + Lapatinib | NCT01138384-I/II | Completed | Fatigue, alopecia, diarrhea | |||||
Recurrent/metastatic Triple-negative breast cancer | Monotherapy | NCT01147484-II | Completed | |||||||||
Papillary RCC | Monotherapy | NCT00726323-II | Completed | |||||||||
Metastatic gastric cancer | Monotherapy | NCT00725712-II | Completed | |||||||||
Merestinib/LY2801653 | MERTK, DDR1/2, AXL, MKNK1/2, FLT3, RON, ROS1, TYRO3, c-MET, PDGFR-α, TEK | – | Advanced or metastatic biliary tract cancer | + Cisplatin and gemcitabine | NCT02711553-II | Active, not recruiting | Anemia, thrombocytopenia, leukopenia, neutropenia, nausea, constipation | |||||
NSCLC harboring MET Exon 14 mutations and solid tumors with NTRK rearrangements | Monotherapy | NCT02920996-II | Terminated | |||||||||
Relapsed or refractory AML | + LY2874455 | Completed | ||||||||||
Advanced or metastatic cancer | Monotherapy/ + cisplatin and gemcitabine | Completed | ||||||||||
Advanced cancer | Monotherapy/ + cetuximab in HNSCC/ + cisplatin in cholangiocarcinoma/ + gemcitabine and cisplatin in cholangiocarcinoma/ + ramucirumab in gastric cancer | Completed | ||||||||||
Gilteritinib/ASP2215 | FLT3, AXL, ALK, RET, MERTK | – | FLT3/ITD AML in first complete remission | Gilteritinib vs placebo | NCT02927262-II | Completed | Febrile Neutropenia, anemia, thrombocytopenia, sepsis, pneumonia, diarrhea, fatigue | |||||
Advanced solid tumors | Gilteritinib and 14C-labeled gilteritinib | Completed | ||||||||||
EGFRm+ advanced NSCLC with acquired resistance to an EGFR-TKI | + Erlotinib | NCT02495233-I/II | Terminated | |||||||||
Amuvatinib/MP-470 | AXL-c-KIT, FLT3, c-MET, c-RET, PDGFRs | Suppresses Rad51, which can disrupt DNA repair and make tumor cells more sensitive to radiation | Solid tumors | + paclitaxel and carboplatin/ + carboplatin and etoposide/ + topotecan/ + docetaxel/ + erlotinib | Completed | Fatigue, alopecia, diarrhea, nausea, anorexia, neutropenia, anemia, thrombocytopenia, leukopenia | ||||||
Solid malignancies | Monotherapy | Completed | ||||||||||
Small-cell lung cancer | + Platinum-etoposide chemotherapy | NCT01357395-II | Completed | |||||||||
Unresectable or metastatic solid tumor or lymphoma | Monotherapy | Terminated | ||||||||||
MRX-2843 | MERTK, FLT3, AXL | – | relapsed/refractory AML, ALL, or MPAL | Monotherapy | Recruiting | – | ||||||
Anti-AXL monoclonal antibodies (mAb) and antibody–drug conjugate (ADC) | ||||||||||||
Tilvestamab/ BGB149 | AXL mAb | Directly binds with AXL and prevents GAS6-dependent AXL activation | Relapsed, platinum-resistant, high-grade serous ovarian cancer | Monotherapy | NCT04893551- Ib | Terminated | – | |||||
YW327.6S2 | AXL mAb | Binds to AXL and blocks GAS6 from binding to AXL | In (A549) NSCLC and (MDA-MB-231) breast cancer model | + Erlotinib | – | – | ||||||
CDX-0168 | AXL mAb | Block GAS6-dependent AXL phosphorylation, stimulate ADCC, release pro-inflammatory cytokines, enhance T-cell activation | Human cancer lines and primary human myeloid cells | Monotherapy | – | – | ||||||
Enapotamab Vedotin/ AXL-107-MMAE/ HuMax-AXL-ADC | AXL-ADC | Hinder microtubules and tubulin polymerization to block mitotic spindle assembly and induces cell-cycle arrest | Solid tumors | Monotherapy | NCT02988817- I/II | Completed | Febrile neutropenia, nausea, vomiting, constipation, diarrhea and a rise in γ-glutamyl transferase | |||||
Mipasetamab Uzoptirine/ ADCT-601 | AXL-ADC | DNA interstrand cross-linking by pyrrolobenzodiazepine dimer | Solid tumors | Monotherapy/ + gemcitabine | Recruiting | Palmar-plantar erythrodysesthesia syndrome, anemia, rash maculopapular, and cheilitis and constipation | ||||||
Mecbotamab Vedotin /BA3011/ CAB-AXL-ADC | AXL-ADC | Binding to AXL only under tumor-specific conditions, such as low pH, allows the delivery of a cytotoxic agent directly to the tumor cells | Sarcoma | Mecbotamab vedotin alone / + nivolumab | NCT03425279-I/II | Recruiting | – | |||||
NSCLC | CAB-AXL-ADC alone/ + PD-1 inhibitor | NCT04681131-II | Recruiting | |||||||||
Platinum-resistant high-grade serous ovarian cancer | + Durvalumab | NCT04918186-II | Recruiting | |||||||||
Anti-AXL-CAR therapy | ||||||||||||
CCT301-38 | AXL | Patient’s T cells are engineered to recognize and attack cancer cells with high-AXL expression | Recurrent or refractory stage IV RCC | Monotherapy | NCT03393936-I/II | Unknown status | – | |||||
Relapsed or refractory AXL +ve sarcomas | Monotherapy | Recruiting | ||||||||||
AXL-CAR-T | AXL | – | TNBC | Monotherapy | – | – | ||||||
AXL-CAR.C7R | AXL | – | TNBC | Monotherapy | – | – | ||||||
AXL-CAR-T | AXL | – | Advanced solid tumors | Monotherapy | Recruiting | – | ||||||
AXL-CAR-T | HER2, Mesothelin, Lewis-Y, PSCA, MUC1, GPC3, AXL, EGFR, or B7-H3 | – | Advanced lung or other cancers | Monotherapy | Recruiting | – | ||||||
AXL-CAR-NK | AXL | – | Advanced solid tumors | Monotherapy/ IL7/CCL19 secreting CAR-NK cell therapy/ PD-1/PD-L1/CTLA4-scfv secreting CAR-NK cell therapy/ + Cannabidiol/ + Nicotinamide adenine dinucleotide | NCT05410717-I/II | Recruiting | – | |||||
