Therapeutic and diagnostic methods for cancer

Patent metadata

Field	Value
Publication number	US-11535671-B2
Application number	US-201916655495-A
Country	US
Kind code	B2
Filing date	Oct 17, 2019
Priority date	May 29, 2015
Publication date	Dec 27, 2022
Grant date	Dec 27, 2022

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 expression levels of a biomarker of the invention (e.g., PD-L1 expression levels in tumor-infiltrating immune cells in a tumor sample obtained from the patient) and/or based on the determination of a tumor sample subtype.

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 atezolizumab, wherein a tumor sample obtained from the patient has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise about 5% or more of the tumor sample, and wherein the tumor sample obtained from the patient has been determined to be a The Cancer Genome Atlas (TCGA) luminal cluster II subtype tumor.

2. The method of claim 1 , wherein:
(i) the median overall survival time of a patient administered a therapeutically effective amount of atezolizumab is at least 8 months; or
(ii) the objective response rate of a patient administered a therapeutically effective amount of atezolizumab is at least about 12%.

3. The method of claim 2 , wherein:
(i) the median overall survival time of a patient administered a therapeutically effective amount of atezolizumab is at least about 8.8 months; or
(ii) the objective response rate of a patient administered a therapeutically effective amount of atezolizumab is about 18%.

4. The method of claim 1 , wherein:
(i) the median overall survival time of a patient administered a therapeutically effective amount of atezolizumab is at least 9 months; or
(ii) the objective response rate of a patient administered a therapeutically effective amount of atezolizumab is at least about 14%.

5. The method of claim 4 , wherein the objective response rate of a patient administered a therapeutically effective amount of atezolizumab is about 27%.

6. The method of claim 1 , wherein the tumor sample obtained from the patient has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise about 10% or more of the tumor sample.

7. The method of claim 1 , wherein:
(a) the expression level of at least one of CDKN2A, GATA3, FOXA1, and ERBB2 in the tumor sample obtained from the patient has been determined to be increased relative to a reference level of the at least one gene, and/or
(b) the expression level of at least one of FGFR3, KRT5, KRT14, and EGFR in the tumor sample obtained from the patient has been determined to be decreased relative to a reference level of the at least one gene.

8. The method of claim 7 , wherein:
(a) the expression levels of CDKN2A, GATA3, FOXA1, and ERBB2 in the tumor sample obtained from the patient have been determined to be increased relative to reference levels of the genes, and/or
(b) the expression levels of FGFR3, KRT5, KRT14, and EGFR in the tumor sample obtained from the patient have been determined to be decreased relative to reference levels of the genes.

9. The method of claim 1 , wherein the expression level of miR-99a-5p or miR100-5p in the tumor sample obtained from the patient has been determined to be increased relative to a reference level of the micro RNA (miRNA).

10. The method of claim 9 , wherein the expression levels of miR-99a-5p and miR100-5p in the tumor sample obtained from the patient have been determined to be increased relative to reference levels of the miRNAs.

11. The method of claim 1 , wherein the expression level of at least one of CD8A, GZMA, GZMB, IFNG, CXCL9, CXCL10, PRF1, and TBX21 in the tumor sample obtained from the patient has been determined to be increased relative to a reference level of the at least one gene.

12. The method of claim 11 , wherein the expression levels of at least CXCL9 and CXCL10 in the tumor sample obtained from the patient have been determined to be increased relative to reference levels of the genes.

13. The method of claim 1 , wherein the tumor sample obtained from the patient has been determined to be a luminal cluster II subtype tumor according to expression of the following genes: FGFR3, CDKN2A, KRT5, KRT14, EGFR, GATA3, FOXA1, and ERBB2.

14. The method of claim 1 , further comprising administering to the patient an effective amount of a second therapeutic agent.

15. The method of claim 14 , wherein the second therapeutic agent is selected from the group consisting of a cytotoxic agent, a growth-inhibitory agent, a radiation therapy agent, and an anti-angiogenic agent, or a combination thereof.

16. The method of claim 1 , wherein the bladder cancer is an urothelial bladder cancer.

17. The method of claim 16 , wherein the urothelial bladder cancer is a muscle invasive urothelial bladder cancer.

18. The method of claim 16 , wherein the urothelial bladder cancer is a metastatic urothelial bladder cancer.

19. The method of claim 16 , wherein the urothelial bladder cancer is a locally advanced urothelial bladder cancer.

20. The method of claim 1 , wherein the tumor sample is a formalin-fixed and paraffin-embedded (FFPE) tumor sample, an archival tumor sample, a fresh tumor sample, or a frozen tumor sample.

21. The method of claim 1 , wherein the expression level of PD-L1 is a protein expression level.

22. The method of claim 21 , wherein the protein expression level of PD-L1 is determined using a method selected from immunohistochemistry (IHC), immunofluorescence, flow cytometry, and Western blot.

23. The method of claim 22 , wherein the protein expression level of PD-L1 is determined using IHC and/or wherein the protein expression level of PD-L1 is detected using an anti-PD-L1 antibody.

24. The method of claim 1 , wherein the expression level of PD-L1 is measured using an automated staining instrument.

25. The method of claim 1 , wherein the expression level of PD-L1 is an mRNA expression level.

26. The method of claim 25 , wherein the mRNA expression level of PD-L1 is determined using a method selected from quantitative polymerase chain reaction (qPCR), reverse transcription qPCR (RT-qPCR), RNA sequencing, microarray analysis, in situ hybridization, and serial analysis of gene expression (SAGE).

27. A method for (i) determining whether a patient suffering from a bladder cancer is likely to respond to treatment comprising atezolizumab or (ii) predicting responsiveness of a patient suffering from a bladder cancer to treatment comprising atezolizumab, the method comprising:
determining the expression level of PD-L1 in tumor-infiltrating immune cells in a tumor sample obtained from the patient,
wherein a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise about 5% or more of the tumor sample indicates that the patient is likely to respond to treatment comprising atezolizumab, wherein the tumor sample obtained from the patient has been determined to be a luminal cluster II subtype tumor; and administering to the patient a therapeutically effective amount of atezolizumab.

28. The method of claim 27 , wherein the tumor sample obtained from the patient has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating cells that comprise at least about 10% of the tumor sample.

29. The method of claim 27 , wherein the tumor sample obtained from the patient has been determined to be a luminal cluster II subtype tumor according to expression of the following genes: FGFR3, CDKN2A, KRT5, KRT14, EGFR, GATA3, FOXA1, and ERBB2.

30. The method of claim 27 , wherein the bladder cancer is an urothelial bladder cancer.

31. The method of claim 30 , wherein the urothelial

Assignees

• Genentech Inc

Inventors

• Hegde Priti
• Kowanetz Marcin
• Fine Gregg
• Mariathasan Sanjeev
• Bourgon Richard

Classifications

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• G01N2800/52

  Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis · CPC title

• C07K2319/30

  Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C12Q2600/106

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