Combination therapy with an anti-her2 antibody-drug conjugate and a bcl-2 inhibitor

Abstract

The present invention is directed to a combination therapy involving an anti-HER2 antibody-drug conjugate and a selective Bcl-2 inhibitor for the treatment of a patient suffering from cancer, particularly, a HER2-expressing cancer.

1 - 50 . (canceled) 
     
     
         51 . A method for the diagnosis of a subject with a HER2-positive tumor as being resistant or susceptible to treatment with an anti-HER2 antibody-drug conjugate, comprising (i) obtaining a tumor sample from said subject, (ii) measuring the expression level of the Bcl-2 gene or its product in said tumor sample relative to a control sample, and (iii) diagnosing said tumor as being resistant to treatment with an anti-HER2 antibody-drug conjugate when the measured expression level of Bcl-2 in said tumor sample is at least 2 fold greater than the expression level in said control sample, or diagnosing said tumor as being susceptible to treatment with an anti-HER2 antibody-drug conjugate when the measured expression level of Bcl-2 in said tumor sample is less than 2 fold greater than the expression level in said control sample. 
     
     
         52 . The method of  claim 51 , wherein said subject is a human patient. 
     
     
         53 . The method of  claim 51 , wherein said control sample is a tumor sample of the same cell type that is not resistant to treatment with said anti-HER2 antibody-drug conjugate. 
     
     
         54 . The method of  claim 51 , wherein the tumor is breast cancer or gastric cancer. 
     
     
         55 . The method of  claim 51 , wherein the tumor sample is a formalin-fixed, paraffin-embedded tumor sample. 
     
     
         56 . The method of  claim 51 , further comprising the step of measuring the expression level of the HER2 gene or its product in said tumor sample. 
     
     
         57 . The method of  claim 51 , further comprising the step of treating said subject with an anti-HER2 antibody-drug conjugate and a selective Bcl-2 inhibitor when the measured expression level of Bcl-2 in said tumor sample is at least 2 fold greater than the expression level in said control sample. 
     
     
         58 . The method of  claim 51 , further comprising the step of treating said patient with an anti-HER2 antibody-drug conjugate when the measured expression level of Bcl-2 in said tumor sample is less than 2 fold greater than the expression level in said control sample. 
     
     
         59 . The method of  claim 51 , wherein the anti-HER2 antibody-drug conjugate is trastuzumab-MCC-DM1. 
     
     
         60 . The method of  claim 51 , wherein the selective Bcl-2 inhibitor is 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide or a pharmaceutically acceptable salt thereof.