Combination therapy with an anti-axl antibody-drug conjugate

Abstract

The present disclosure relates to combination therapies for the treatment of pathological conditions, such as cancer. In particular, the present disclosure relates to combination therapies comprising treatment with an Antibody Drug Conjugate (ADC) and a secondary agent.

1 . A method for treating cancer in an individual, the method comprising administering to the individual an effective amount of ADCxAXL and a secondary agent. 
     
     
         2 . A first composition comprising ADCxAXL for use in a method of treating cancer in an individual, wherein the treatment comprises administration of the first composition in combination with a second composition comprising a secondary agent. 
     
     
         3 . A first composition comprising a secondary agent for use in a method of treating a disorder in an individual, wherein the treatment comprises administration of the first composition in combination with a second composition comprising ADCxAXL. 
     
     
         4 . Use of ADCxAXL in the manufacture of a medicament for treating cancer in an individual, wherein the medicament comprises ADCxAXL, and wherein the treatment comprises administration of the medicament in combination with a composition comprising a secondary agent. 
     
     
         5 . Use of a secondary agent in the manufacture of a medicament for treating cancer in an individual, wherein the medicament comprises a secondary agent, and wherein the treatment comprises administration of the medicament in combination with a composition comprising ADCxAXL. 
     
     
         6 . A kit comprising:
 a first medicament comprising ADCxAXL;   a second medicament comprising a secondary agent; and, optionally,   a package insert comprising instructions for administration of the first medicament to an individual in combination with the second medicament for the treatment of cancer.   
     
     
         7 . A kit comprising a medicament comprising ADCxAXL and a package insert comprising instructions for administration of the medicament to an individual in combination with a composition comprising a secondary agent for the treatment of cancer. 
     
     
         8 . A kit comprising a medicament comprising a secondary agent and a package insert comprising instructions for administration of the medicament to an individual in combination with a composition comprising ADCxAXL for the treatment of cancer. 
     
     
         9 . A pharmaceutical composition comprising ADCxAXL and a secondary agent. 
     
     
         10 . A method of treating cancer in an individual, the method comprising administering to the individual an effective amount of the composition of  claim 9 . 
     
     
         11 . The composition of  claim 9  for use in a method of treating cancer in an individual. 
     
     
         12 . The use of the composition of  claim 9  in the manufacture of a medicament for treating cancer in an individual. 
     
     
         13 . A kit comprising the composition of  claim 9  and a set of instructions for administration of the medicament to an individual for the treatment of cancer. 
     
     
         14 . The composition, method, use, or kit according to any previous claim, wherein the treatment comprises administering ADCxAXL before the secondary agent, simultaneous with the secondary agent, or after the secondary agent. 
     
     
         15 . The composition, method, use, or kit according to any previous claim, wherein the treatment further comprises administering a chemotherapeutic agent. 
     
     
         16 . The composition, method, use, or kit according to any previous claim, wherein the individual is human. 
     
     
         17 . The composition, method, use, or kit according to any previous claim, wherein the individual has a disorder or has been determined to have cancer. 
     
     
         18 . The composition, method, use, or kit according any previous claim, wherein the individual has, or has been has been determined to have, a cancer characterised by the presence of a neoplasm comprising both AXL+ve and AXL−ve cells. 
     
     
         19 . The composition, method, use, or kit according any previous claim, wherein the individual has, or has been has been determined to have, a cancer characterised by the presence of a neoplasm comprising, or composed of, AXL−ve neoplastic cells. 
     
     
         20 . The composition, method, use, or kit according to any previous claim, wherein the cancer or neoplasm is all or part of a solid tumour. 
     
     
         21 . The composition, method, use, or kit according to any previous claim, wherein the individual has, or has been has been determined to have, a cancer which expresses AXL or AXL+ tumour-associated non-tumour cells, such as AXL+ infiltrating cells. 
     
     
         22 . The composition, method, use, or kit according to  claim 21 , wherein the AXL+ infiltrating cells are dendritic cells, NK cells, or macrophages. 
     
     
         23 . The composition, method, use, or kit according to any preceding claim, wherein the individual has, or has been has been determined to have, a cancer which expresses PD-L1. 
     
     
         24 . The composition, method, use, or kit according to any one of the preceding claims, wherein the treatment:
 a) effectively treats a broader range of disorders,   b) effectively treats resistant, refractory, or relapsed disorders,   c) has an increased response rate, and/or   d) has increased durability;   as compared to treatment with either ADCxAXL or the secondary agent alone.   
     
     
         25 . The composition, method, use, or kit according to any one of the preceding claims, wherein the cancer is selected from the group comprising: breast cancer, lung cancer, gastric cancer, head and neck cancer, colorectal cancer, renal cancer, pancreatic cancer, uterine cancer, hepatic cancer, bladder cancer, endometrial cancer, prostate cancer, non-Hodgkin's lymphoma, NHL, AML), an immune disorder, cardiovascular disorder, thrombosis, diabetes, immune checkpoint disorder, and fibrotic disorder. 
     
     
         26 . A composition, method, use, or kit according to any one of  claims 1  to  25 , wherein the secondary agent is Fludarabine. 
     
     
         27 . A composition, method, use, or kit according to any one of  claims 1  to  25 , wherein the secondary agent is Cytarabine. 
     
     
         28 . A composition, method, use, or kit according to any one of  claims 1  to  25 , wherein the secondary agent is a PD1 antagonist. 
     
     
         29 . A composition, method, use, or kit according to  claim 28 , wherein the PD1 antagonist is selected from pembrolizumab, nivolumab, MEDI0680, PDR001 (spartalizumab), Camrelizumab, AUNP12, Pidilizumab Cemiplimab (REGN-2810), AMP-224, BGB-A317 (Tisleizumab), and BGB-108. 
     
     
         30 . A composition, method, use, or kit according to any one of  claims 1  to  25 , wherein the secondary agent is a PD-L1 antagonist. 
     
     
         31 . A composition, method, use, or kit according to  claim 30 , wherein the PD-L1 antagonist is selected from atezolizumab (Tecentriq), BMS-936559/MDX-1105, durvalumab/MEDI4736, and MSB0010718C (Avelumab). 
     
     
         32 . A composition, method, use, or kit according to any one of  claims 1  to  25 , wherein the secondary agent is a GITR (Glucocorticoid-Induced TNFR-Related protein) agonist. 
     
     
         33 . A composition, method, use, or kit according to  claim 32 , wherein the GITR (Glucocorticoid-Induced TNFR-Related protein) agonist is selected from MEDI1873, TRX518, GWN323, MK-1248, MK 4166, BMS-986156 and INCAGN1876. 
     
     
         34 . A composition, method, use, or kit according to any one of  claims 1  to  25 , wherein the secondary agent is a OX40 agonist. 
     
     
         35 . A composition, method, use, or kit according to  claim 34 , wherein the OX40 agonist is selected from MEDI0562, MEDI6383, MOXR0916, RG7888, OX40mAb24, INCAGN1949, GSK3174998, and PF-04518600. 
     
     
         36 . A composition, method, use, or kit according to any one of  claims 1  to  25 , wherein the secondary agent is a CTLA-4 antagonist. 
     
     
         37 . A composition, method, use, or kit according to  claim 36 , wherein the CTLA-4 antagonist is selected from ipilimumab and Tremelimumab. 
     
     
         38 . A composition, method, use, or kit according to any one of  claims 1  to  25 , wherein the secondary agent is a hypomethylating agent. 
     
     
         39 . A composition, method, use, or kit according to  claim 38 , wherein the hypomethylating agent is azacitidine. 
     
     
         40 . A composition, method, use, or kit according to  claim 38 , wherein the hypomethylating agent is decitabine. 
     
     
         41 . A composition, method, use, or kit according to any one of  claims 1  to  25 , wherein the secondary agent is a PARP inhibitor (PARPi). 
     
     
         42 . A composition, method, use, or kit according to  claim 41 , wherein the PARPi is selected from Olaparib, CEP-9722, BMN-673/talazoparib, Rucaparib, Iniparib/SAR24-550/BSI-201, Veliparib (ABT-888), Niraparib/MK-4827, BGB-290, 3-aminobenzamide, and E7016. 
     
     
         43 . A composition, method, use, or kit according to any one of  claims 1  to  25 , wherein the secondary agent is an agent that upregulates HER2 expression. 
     
     
         44 . A composition, method, use, or kit according to  claim 41 , wherein the agent that upregulates HER2 expression is selected from gemcitabine and tamoxifen. 
     
     
         45 . A composition, method, use, or kit according to any one of  claims 1  to  25 , wherein the secondary agent is an AXL-kinase inhibitor (AXLi). 
     
     
         46 . A composition, method, use, or kit according to  claim 45 , wherein the AXLi is selected from BGB324 (bemcentinib), TP0903, Gilteritinib (ASP2215), Cabozantinib (XL184), SG17079, Merestinib, amuvatinib (MP-470), bosutinib (SKI-606), MGCD265, and foretinib (GSK1363089/XL880). 
     
     
         47 . A composition, method, use, or kit according to any one of  claims 1  to  25 , wherein the secondary agent is a BRAF inhibitor (BRAFi). 
     
     
         48 . A composition, method, use, or kit according to  claim 47 , wherein the BRAFi is selected from vemurafenib, PLX4720, dabrafenib, Sorafenib, Encorafenib, and GDC0879. 
     
     
         49 . A composition, method, use, or kit according to any one of  claims 1  to  25 , wherein the secondary agent is a MEK inhibitor (MEKi). 
     
     
         50 . A composition, method, use, or kit according to  claim 49 , wherein the AXLi is selected from Trametinib, Cobimetinib, Binimetinib, Selumetinib, PD-325901, CI-1040, PD035901, U0126, and TAK-733.