Method for egfr directed combination treatment of cancer

Abstract

The present invention relates to a method of treating patients suffering from cancers driven by deregulated Human Epidermal Growth Factor Receptor (HER/Human EGFR), wherein an irreversible tyrosine kinase inhibitor (TKI) is administered according to a continuous regimen based on an average daily dose in the range of 10 to 50 mg and the mAB is co-administered according to a dosing regimen ranging from an average weekly iv dose of 50 to 500 mg/m 2 repeated thrice, twice or once a week, once in two weeks, once in three weeks or at least monthly to a patient in need of such treatment.

1 . A method of treating a patient suffering from cancer driven by deregulated Human Epidermal Growth Factor Receptor (HER/Human EGFR), which cancer is selected from the group consisting of head and neck squamous cell carcinoma (HNSCC), malignant glioma, breast cancer, esophageal cancer, gastric cancer, renal cancer, cervical cancer, prostate cancer, ovarian cancer, pancreatic cancer, hepatocellular cancer, and colorectal cancer (CRC), including metastatic forms thereof, and
 wherein: the patient has a tumor expressing mutated forms of the EGFR, and the patient has acquired resistance to tyrosine kinase inhibitor (TKI) treatment,   comprising administering to a patient in need of such treatment a flexible and active regimen for combining an irreversible tyrosine kinase inhibitor (TKI) and a Human EGFR targeted monoclonal antibody (mAB), wherein in this method the TKI is administered according to a continuous regimen based on an average daily dose in the range of 10 to 50 mg and the mAB is co-administered according to a dosing regimen ranging from an average weekly iv dose of 50 to 500 mg/m 2  repeated thrice, twice or once a week, once in two weeks, once in three weeks or at least once monthly,   wherein the method results in overcoming the acquired resistance to tyrosine kinase inhibitor (TKI) treatment.   
     
     
         2 - 7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein the cancer is selected from the group consisting of NSCLC, HNSCC, malignant glioma, breast cancer, esophageal cancer, gastric cancer, renal cancer, cervical cancer, prostate cancer, ovarian cancer, pancreatic cancer, hepatocellular cancer or CRC, including metastatic forms thereof,
 the TKI is selected from the group consisting of HKI-272, BIBW 2992 and PF-00299804, or a pharmaceutically acceptable salt thereof, and is administered according to a continuous regimen based on an average daily dose in the range of 10 to 50 mg,   the mAB is selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab and is co-administered according to a dosing regimen ranging from an average weekly iv dose of 50 to 500 mg/m 2  repeated thrice, twice or once a week, once in two weeks, once in three weeks or at least once monthly to:   a patient with a tumor expressing mutated forms of the EGFR, and with acquired resistance to TKI treatment wherein the method results in overcoming the acquired resistance to tyrosine kinase inhibitor (TKI) treatment.   
     
     
         9 . The method of  claim 1 , wherein the cancer is selected from the group consisting of HNSCC, malignant glioma, breast cancer or CRC, including metastatic forms thereof,
 the TKI is selected from the group consisting of BIBW 2992 and PF-00299804), or a pharmaceutically acceptable salt thereof, and is administered according to a continuous regimen based on an average daily dose in the range of 10 to 50 mg,   the mAB is selected from the group consisting of cetuximab and panitumumab, and is co-administered according to a dosing regimen ranging from an average weekly iv dose of 50 to 500 mg/m 2  repeated twice or once a week or once in two weeks to:   a patient with a tumor harboring EGFR mutations in exons 19 and 21 associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q), and with acquired resistance to TKI treatment wherein the method results in overcoming the acquired resistance to tyrosine kinase inhibitor (TKI) treatment.   
     
     
         10 . The method of  claim 1 , wherein the cancer is HNSCC, including metastatic forms thereof,
 the TKI is selected from the group consisting of BIBW 2992 and PF-00299804, or a pharmaceutically acceptable salt thereof, and is administered according to a continuous regimen based on an average daily dose in the range of 10 to 50 mg,   the mAB is selected from the group consisting of cetuximab and panitumumab, and is co-administered according to a dosing regimen ranging from an average weekly iv dose of 50 to 500 mg/m 2  repeated twice or once a week or once in two weeks to   a patient with acquired resistance to treatment with TKIs, such as gefitinib or erlotinib, afatinib, dacomitinib or others, wherein the method provides to overcome resistance to TKI treatment.   
     
     
         11 . The method of  claim 1 , wherein the cancer is HNSCC or CRC, including metastatic forms thereof,
 the TKI is BIBW 2992, or a pharmaceutical acceptable salt thereof, and is administered according to a continuous regimen based on an average daily dose in the range of 10 to 50 mg,   the mAB is cetuximab and is co-administered according to a dosing regimen ranging from an average weekly iv dose of 50 to 500 mg/m 2  repeated twice or once a week to   (h) a patient with primary or acquired resistance not caused by T790M (T790M−), wherein the method results in overcoming resistance to TKI treatment.   
     
     
         12 . (canceled) 
     
     
         13 . A pharmaceutical kit, comprising a first compartment which comprises an effective amount of a Human EGFR targeted mAB and a second compartment which comprises an effective amount of an irreversible TKI. 
     
     
         14 . The pharmaceutical kit of  claim 13 , wherein the irreversible tyrosine kinase inhibitor (TKI) is selected from the group consisting of EKB-569 (pelitinib), HKI-272 (neratinib), HKI-357, CI-1033, BIBW 2992 and PF-00299804 or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The pharmaceutical kit of  claim 13 , wherein the TKI is selected from the group consisting of 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one, WZ 3146, WZ 4002, and WZ 8040, or a pharmaceutical acceptable salt thereof. 
     
     
         16 . The pharmaceutical kit of  claim 14 , wherein the Human EGFR targeted monoclonal antibody (mAB) is selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, and matuzumab. 
     
     
         17 . The pharmaceutical kit of  claim 14  wherein the Human EGFR targeted monoclonal antibody (mAB) is necitumumab. 
     
     
         18 . The method of  claim 1 , wherein
 (g) the patient has acquired resistance caused by T790M (T790M+), and the method results in overcoming resistance to TKI treatment, or   (h) the patient has acquired resistance not caused by T790M (T790M−), and the method results in overcoming resistance to TKI treatment.   
     
     
         19 . The method of  claim 1 , wherein
 (h) the patient has acquired resistance not caused by T790M (T790M−), and the method results in overcoming resistance to TKI treatment.   
     
     
         20 . The method of  claim 19 , wherein the irreversible tyrosine kinase inhibitor (TKI) is selected from the group consisting of EKB-569 (pelitinib), HKI-272 (neratinib), HKI-357, CI-1033, BIBW 2992 and PF-00299804 or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The method of  claim 19 , wherein the TKI is selected from the group consisting of 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one, WZ 3146, WZ 4002, and WZ 8040, or a pharmaceutical acceptable salt thereof. 
     
     
         22 . The method of  claim 20 , wherein the Human EGFR targeted monoclonal antibody (mAB) is selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab. 
     
     
         23 . The method of  claim 20 , wherein the Human EGFR targeted monoclonal antibody (mAB) is necitumumab. 
     
     
         24 . The method of  claim 8 , wherein the acquired resistance to TKI treatment is acquired resistance of gefitinib, erlotinib, afatinib or dacomitinib treatment. 
     
     
         25 . The method of  claim 9 , wherein the acquired resistance to TKI treatment is acquired resistance of gefitinib, erlotinib, afatinib or dacomitinib treatment. 
     
     
         26 . The method of  claim 11 , wherein the acquired resistance not caused by T790M (T790M−) is caused by a MET oncogene mechanism or mechanism of unknown origin. 
     
     
         27 . The method of  claim 1 , wherein:
 the TKI is selected from the group consisting of EKB-569 (pelitinib), HKI-272 (neratinib), HKI-357, CI-1033, BIBW 2992, PF-00299804, 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one, WZ 3146, WZ 4002 and WZ 8040, or a pharmaceutically acceptable salt thereof, and   the mAB is selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab.