FGFR/PD-1 combination therapy for the treatment of cancer
Provided herein are combination therapies for the treatment of cancer. In particular, the disclosed methods are directed to treatment of cancer in a patient comprising administering an antibody that blocks the interaction between PD-1 and PD-L1 and an FGFR inhibitor, wherein the antibody that blocks the interaction between PD-1 and PD-L1 and the FGFR inhibitor are administered if one or more FGFR variants are present in a biological sample from the patient.
1 . A method of treating cancer in a patient comprising:
administering to the patient a pharmaceutically effective amount of an antibody that blocks the interaction between PD-1 and PD-L1;
monitoring the efficacy of the antibody; and
if the antibody is not efficacious,
evaluating a biological sample from the patient for a presence of one or more FGFR variants, wherein the one or more FGFR variants comprise an FGFR mutation, and wherein the FGFR mutation is FGFR3 G370C; and
administering to the patient a pharmaceutically effective amount of an FGFR inhibitor if the one or more FGFR variants are present in the sample, wherein the FGFR inhibitor is the compound of formula (I):
or a pharmaceutically acceptable salt thereof.
2 . The method of claim 1 , wherein the evaluating step further comprises measuring an expression level of PD-L1 in a biological sample and wherein the second administering step comprises administering the FGFR inhibitor if:
the biological sample has a PD-L1 expression corresponding to an H-score of about 0 to about 99; or
the biological sample has a PD-L1 expression level that is lower than a reference PD-L1 expression level.
3 . The method of claim 1 , wherein the biological sample is blood, lymph fluid, bone marrow, a solid tumor sample, or any combination thereof.
4 . The method of claim 1 , wherein the cancer is lung cancer, bladder cancer, gastric cancer, breast cancer, ovarian cancer, head and neck cancer, esophageal cancer, glioblastoma, or any combination thereof.
5 . The method of claim 4 , wherein the cancer is bladder cancer.
6 . The method of claim 1 , wherein the one or more FGFR variants further comprise an FGFR fusion gene.
7 . The method of claim 1 , wherein the one or more FGFR variants comprise at least one additional FGFR mutation, which is FGFR3 R248C.
8 . The method of claim 1 , wherein the one or more FGFR variants comprise at least one additional FGFR mutation, which is FGFR3 S249C.
9 . The method of claim 1 , wherein the one or more FGFR variants comprise at least one additional FGFR mutation, which is FGFR3 Y373C.
10 . The method of claim 1 , wherein the antibody that blocks an interaction between PD-1 and PD-L1 is an anti-PD-1 antibody, an anti-PD-L1 antibody, or a combination thereof.
11 . The method of claim 2 , wherein the cancer is lung cancer, bladder cancer, gastric cancer, breast cancer, ovarian cancer, head and neck cancer, esophageal cancer, glioblastoma, or any combination thereof.
12 . The method of claim 11 , wherein the cancer is bladder cancer.
13 . The method of claim 2 , wherein the one or more FGFR variants further comprise an FGFR fusion gene.
14 . The method of claim 2 , wherein the one or more FGFR variants comprise at least one additional FGFR mutation, which is FGFR3 R248C.
15 . The method of claim 2 , wherein the one or more FGFR variants comprise at least one additional FGFR mutation, which is FGFR3 S249C.
16 . The method of claim 2 , wherein the one or more FGFR variants comprise at least one additional FGFR mutation, which is FGFR3 Y373C.
17 . The method of claim 2 , wherein the antibody that blocks an interaction between PD-1 and PD-L1 is an anti-PD-1 antibody, an anti-PD-L1 antibody, or a combination thereof.
18 . The method of claim 3 , wherein the cancer is lung cancer, bladder cancer, gastric cancer, breast cancer, ovarian cancer, head and neck cancer, esophageal cancer, glioblastoma, or any combination thereof.
19 . The method of claim 18 , wherein the cancer is bladder cancer.
20 . The method of claim 3 , wherein the one or more FGFR variants further comprise an FGFR fusion gene.
21 . The method of claim 3 , wherein the one or more FGFR variants comprise at least one additional FGFR mutation, which is FGFR3 R248C.
22 . The method of claim 3 , wherein the one or more FGFR variants comprise at least one additional FGFR mutation, which is FGFR3 S249C.
23 . The method of claim 3 , wherein the one or more FGFR variants comprise at least one additional FGFR mutation, which is FGFR3 Y373C.
24 . The method of claim 3 , wherein the antibody that blocks an interaction between PD-1 and PD-L1 is an anti-PD-1 antibody, an anti-PD-L1 antibody, or a combination thereof.
25 . The method of claim 1 , wherein the biological sample:
has a PD-L1 expression corresponding to an H-score of less than 20; or
has a PD-L1 expression level that is lower than a reference PD-L1 expression level.
26 . The method of claim 25 , where the biological sample has a PD-L1 expression corresponding to an H-score of less than 20.
27 . The method of claim 1 , wherein the FGFR inhibitor is the compound of formula (I):
28 . The method of claim 27 , wherein the cancer is lung cancer, bladder cancer, gastric cancer, breast cancer, ovarian cancer, head and neck cancer, esophageal cancer, glioblastoma, or any combination thereof.
29 . The method of claim 28 , wherein the cancer is bladder cancer.
30 . The method of claim 29 , wherein the one or more FGFR variants further comprise an FGFR fusion gene.
31 . The method of claim 29 , wherein the one or more FGFR variants comprise at least one additional FGFR mutation, which is FGFR3 R248C.
32 . The method of claim 29 , wherein the one or more FGFR variants comprise at least one additional FGFR mutation, which is FGFR3 S249C.
33 . The method of claim 29 , wherein the one or more FGFR variants comprise at least one additional FGFR mutation, which is FGFR3 Y373C.
34 . The method of claim 29 , wherein the antibody that blocks an interaction between PD-1 and PD-L1 is an anti-PD-1 antibody, an anti-PD-L1 antibody, or a combination thereof.
35 . The method of claim 29 , wherein the biological sample is a solid tumor sample.
36 . The method of claim 3 , wherein the biological sample is a solid tumor sample.