CANCER TREATMENT USING COMBINATION OF NEUTROPHIL MODULATOR WITH MODULATOR OF IMMUNE CHECKPOINT
The present disclosure provides methods of treating a cancer in a subject. The method includes a step of measuring a base level of a biomarker selected from a group consisting of hepatocyte growth factor, absolute neutrophil count, c-Met+ neutrophils and neutrophil to lymphocyte ratio (NLR) in the subject. The method also includes the steps of determining that the base level of said biomarker is equal or more than a threshold value or determining the change in the said biomarker upon administration of an immune checkpoint modulator is equal or more than a threshold value; and administering to the subject a combination of c-Met inhibitor and a modulator of an immune checkpoint.
1 - 26 . (canceled)
27 . A method of treating a subject having a cancer, the method comprising:
(A) administering to the subject a c-Met inhibitor which comprises a compound of the following formula
wherein:
R 1 and R 2 are independently hydrogen or halogen;
X and X 1 are independently hydrogen or halogen;
A and G are independently CH or N, or CH=G is replaced with a sulfur atom;
E is N;
J is CH, S or NH;
M is N or C;
Ar is aryl or heteroaryl, optionally substituted with 1-3 substituents independent selected from: C 1-6 alkyl, C 1-6 alkoxyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-7 cycloalkyl, halogen, cyano, amino, —CONR 4 R 5 , —NHCOR 6 , —SO 2 NR 7 R 8 , C 1-6 alkoxyl-, C 1-6 alkyl-, amino-C 1-6 alkyl-, heterocyclyl and heterocyclyl-C 1-6 alkyl-, or two connected substituents together with the atoms to which they are attached form a 4-6 membered lactam fused with the aryl or heteroaryl;
R 3 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, halogen, amino, or —CONH—C 1-6 alkyl-heterocyclyl;
R 4 and R 5 are independently hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, heterocyclyl-C 1-6 alkyl, or R 4 and R 5 together with the N to which they are attaches form a heterocyclyl;
R 6 is C 1-6 alkyl or C 3-7 cycloalkyl; and
R 7 and R 8 are independently hydrogen or C 1-6 alkyl;
(B) administering to the subject an anti-PD-1 antibody or an anti-PD-L1 antibody.
28 . The method of claim 27 , wherein the c-Met inhibitor is selected from the group consisting of:
29 . The method of claim 27 , wherein the c-Met inhibitor is APL-101, which has the following formula:
30 . The method of claim 27 , wherein the anti-PD-1 antibody is selected from the group consisting of those disclosed in WO2016/014688.
31 . The method of claim 27 , wherein the anti-PD-1 antibody is APL-501, GB226, or genolimzumab.
32 . The method of claim 27 , wherein the anti-PD-L1 antibody is selected from the group consisting of those disclosed in WO2016/022630.
33 . The method of claim 27 , wherein the anti-PD-L1 antibody is APL-502 or TQB2450.
34 . The method of claim 27 , wherein the cancer is selected from the groups consisting of a lung cancer, a melanoma, a renal cancer, a liver cancer, a myeloma, a prostate cancer, a breast cancer, a colorectal cancer, a pancreatic cancer, a thyroid cancer, a hematological cancer, a leukemia and a non-Hodgkin's lymphoma.
35 . The method of claim 27 , wherein the cancer is a non-small cell lung cancer (NSCLC), renal cell carcinoma or hepatocellular carcinoma.