Therapeutic and diagnostic methods for cancer

Patent metadata

Field	Value
Publication number	US-2022153861-A1
Application number	US-202217590918-A
Country	US
Kind code	A1
Filing date	Feb 2, 2022
Priority date	Feb 29, 2016
Publication date	May 19, 2022
Grant date	—

Abstract

The present invention provides therapeutic and diagnostic methods and compositions for cancer, for example, bladder cancer. The invention provides methods of treating bladder cancer, methods of determining whether a patient suffering from bladder cancer is likely to respond to treatment comprising a PD-L1 axis binding antagonist, methods of predicting responsiveness of a patient suffering from bladder cancer to treatment comprising a PD-L1 axis binding antagonist, and methods of selecting a therapy for a patient suffering from bladder cancer, based on somatic mutation levels of genes of the invention (e.g., somatic mutation levels in a tumor sample obtained from the patient).

First claim

What is claimed is:

1 . A method of treating a patient suffering from a bladder cancer, the method comprising administering to the patient a therapeutically effective amount of a PD-L1 axis binding antagonist, wherein a tumor sample obtained from the patient has been determined to have an increased level of somatic mutation in at least one gene set forth in Table 1 relative to a reference level of somatic mutation in the at least one gene set forth in Table 1.

2 . The method of claim 1 , wherein the tumor sample obtained from the patient has been determined to have increased levels of somatic mutations in at least one-third of the genes set forth in Table 1 relative to reference levels of somatic mutations in the at least one-third of the genes set forth in Table 1.

3 . The method of claim 2 , wherein the tumor sample obtained from the patient has been determined to have increased levels of somatic mutations in at least one-half of the genes set forth in Table 1 relative to reference levels of somatic mutations in the at least one-half of the genes set forth in Table 1.

4 . The method of claim 3 , wherein the tumor sample obtained from the patient has been determined to have increased levels of somatic mutations in at least two-thirds of the genes set forth in Table 1 relative to reference levels of somatic mutations in the at least two-thirds of the genes set forth in Table 1.

5 . The method of claim 4 , wherein the tumor sample obtained from the patient has been determined to have increased levels of somatic mutations in at least three-fourths of the genes set forth in Table 1 relative to reference levels of somatic mutations in the at least three-fourths of the genes set forth in Table 1.

6 . The method of claim 5 , wherein the tumor sample obtained from the patient has been determined to have increased levels of somatic mutations in the genes set forth in Table 1 relative to reference levels of somatic mutations in the genes set forth in Table 1.

7 . The method of any one of claims 1 - 6 , wherein the somatic mutations are substitutions, deletions, and/or insertions.

8 . The method of any one of claims 1 - 6 , wherein the somatic mutations of the at least one gene set forth in Table 1 are protein-altering somatic mutations.

9 . The method of claim 7 or 8 , wherein the substitutions, deletions, and/or insertions are in coding regions.

10 . The method of any one of claims 7 - 9 , wherein the deletions and/or insertions are indels.

11 . The method of any one of claims 1 - 10 , wherein the tumor sample obtained from the patient has a whole-genome mutation load that is higher than a reference level whole-genome mutation load.

12 . The method of claim 11 , wherein the median whole-genome mutation load is at least about 10 mutations per megabase (Mb).

13 . A method for determining whether a patient suffering from a bladder cancer is likely to respond to treatment comprising a PD-L1 axis binding antagonist, the method comprising:
determining the level of somatic mutation in at least one gene set forth in Table 1 from a tumor sample obtained from the patient, and comparing the level of somatic mutation in the at least one gene set forth in Table 1 to a reference level of somatic mutation in the at least one gene set forth in Table 1, wherein an increased level of somatic mutation in the at least one gene set forth in Table 1 relative to the reference level indicates that the patient is likely to respond to treatment comprising a PD-L1 axis binding antagonist.

14 . A method for predicting responsiveness of a patient suffering from a bladder cancer to treatment comprising a PD-L1 axis binding antagonist, the method comprising:
determining the level of somatic mutation in at least one gene set forth in Table 1 from a tumor sample obtained from the patient, and comparing the level of somatic mutation in the at least one gene set forth in Table 1 to a reference level of somatic mutation in the at least one gene set forth in Table 1, wherein an increased level of somatic mutation in the at least one gene set forth in Table 1 relative to the reference level indicates that the patient is likely to respond to treatment comprising a PD-L1 axis binding antagonist.

15 . A method for selecting a therapy for a patient suffering from a bladder cancer, the method comprising:
determining the level of somatic mutation in at least one gene set forth in Table 1 from a tumor sample obtained from the patient, and selecting a therapy comprising a PD-L1 axis binding antagonist for the patient based on an increased level of somatic mutation in the at least one gene set forth in Table 1 relative to the reference level of somatic mutation in the at least one gene set forth in Table 1.

16 . The method of any one of claims 13 - 15 , further comprising administering to the patient a therapeutically effective amount of a PD-L1 axis binding antagonist based on the increased level of somatic mutation in at least one gene set forth in Table 1 relative to a reference level of somatic mutation in the at least one gene set forth in Table 1 in the tumor sample.

17 . The method of any one of claims 1 - 16 , wherein the PD-L1 axis binding antagonist is selected from the group consisting of a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist.

18 . The method of claim 17 , wherein the PD-L1 axis binding antagonist is a PD-L1 binding antagonist.

19 . The method of claim 18 , wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners.

20 . The method of claim 19 , wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1.

21 . The method of claim 19 , wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to B7-1.

22 . The method of any one of claims 19 - 21 , wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to both PD-1 and B7-1.

23 . The method of any one of claims 18 - 22 , wherein the PD-L1 binding antagonist is an antibody.

24 . The method of claim 23 , wherein the antibody is selected from the group consisting of atezolizumab (MPDL3280A), YW243.55.S70, MDX-1105, MED14736 (durvalumab), and MSB0010718C (avelumab).

25 . The method of claim 23 , wherein the antibody comprises a heavy chain comprising HVR-H1 sequence of SEQ ID NO:19, HVR-H2 sequence of SEQ ID NO:20, and HVR-H3 sequence of SEQ ID NO:21; and a light chain comprising HVR-L1 sequence of SEQ ID NO:22, HVR-L2 sequence of SEQ ID NO:23, and HVR-L3 sequence of SEQ ID NO:24.

26 . The method of claim 23 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:26 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:4.

27 . The method of claim 17 , wherein the PD-L1 axis binding antagonist is a PD-1 binding antagonist.

28 . The method of claim 27 , wherein the PD-1 binding antagonist inhibits the binding of PD-1 to one or more of its ligand binding partners.

29 . The method of claim 28 , wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PD-Li.

30 . The method of claim 28 , wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L2.

31 . The method of any one of claims 28 - 30 , wherein the

Assignees

• Genentech Inc
• Found Medicine Inc

Inventors

• Bourgon Richard
• Fabrizio David
• Fine Gregg
• Frampton Garrett M
• Hegde Priti
• Mariathasan Sanjeev
• Stephens Philip J
• Sun James Xin
• Yelensky Roman

Classifications

• Y02A90/10

  Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation · CPC title

• G16H50/30

  for calculating health indices; for individual health risk assessment · CPC title

• G16H20/10

  relating to drugs or medications, e.g. for ensuring correct administration to patients · CPC title

• C12Q2600/156

  Polymorphic or mutational markers · CPC title

• C12Q2600/106

  Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism · CPC title