Uses for and article of manufacture including her2 dimerization inhibitor pertuzumab

Abstract

The present application describes uses for Pertuzumab, a first-in-class HER2 dimerization inhibitor. In particular, the application describes methods for extending progression free survival in a HER2-positive breast cancer patient population; combining two HER2 antibodies to treat HER2-positive cancer without increasing cardiac toxicity; and treating HER2-positive cancer by co-administering a mixture of Pertuzumab and Trastuzumab from the same intravenous bag.

What is claimed is: 
     
         1 . A method for extending progression free survival in a HER2-positive breast cancer patient population by 6 months or more comprising administering Pertuzumab, Trastuzumab and chemotherapy to the patients in the population. 
     
     
         2 . The method of  claim 1  which results in an objective response rate of 80% or more in the patients in the population. 
     
     
         3 . The method of  claim 1  wherein the chemotherapy comprises taxane. 
     
     
         4 . The method of  claim 3  wherein the taxane is Docetaxel. 
     
     
         5 . The method of  claim 1  wherein the breast cancer is metastatic or locally recurrent, unresectable breast cancer, or de novo Stage IV disease. 
     
     
         6 . The method of  claim 1  wherein the patients in the population have not received previous treatment or have relapsed after adjuvant therapy. 
     
     
         7 . The method of  claim 1  wherein the HER2-positive breast cancer is defined as immunohistochemistry (IHC) 3+ and/or fluorescence in situ hybridization (FISH) amplification ratio≧2.0. 
     
     
         8 . The method of  claim 1  wherein the patients in the population have a left ventricular ejection fraction (LVEF) of ≧50% at baseline. 
     
     
         9 . The method of  claim 1  wherein the patients in the population have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. 
     
     
         10 . A method of combining two HER2 antibodies to treat HER2-positive cancer without increasing cardiac toxicity in a HER2-positive cancer patient population, comprising administering Pertuzumab, Trastuzumab, and chemotherapy to the patients in the population. 
     
     
         11 . The method of  claim 10  wherein cardiac toxicity in the patient population is monitored for incidence of symptomatic left ventricular systolic dysfunction (LVSD) or congestive heart failure (CHF), or decrease in left ventricular ejection fraction (LVEF). 
     
     
         12 . The method of  claim 10  wherein the HER2-positive cancer is breast cancer. 
     
     
         13 . The method of  claim 10  wherein the breast cancer is metastatic or locally recurrent, unresectable breast cancer, or de novo Stage IV disease. 
     
     
         14 . An article of manufacture comprising a vial with Pertuzumab therein and a package insert, wherein the package insert provides the safety data in Table 3 or Table 4. 
     
     
         15 . The article of manufacture of  claim 14  wherein the package insert provides the efficacy data in Table 2, Table 5,  FIG. 8 , or  FIG. 10 . 
     
     
         16 . The article of manufacture of  claim 14  wherein the vial is a single-dose vial containing about 420 mg of Pertuzumab. 
     
     
         17 . A method for making an article of manufacture comprising packaging together a vial with Pertuzumab therein and a package insert, wherein the package insert provides the safety data in Table 3 or Table 4. 
     
     
         18 . A method of ensuring safe and effective use of Pertuzumab comprising packaging together a vial with Pertuzumab therein and a package insert, wherein the package insert provides the safety data in Table 3 or Table 4 and the efficacy data in Table 2, Table 5,  FIG. 8 , or  FIG. 10 . 
     
     
         19 . A method of treating early-stage HER2-positive breast cancer comprising administering Pertuzumab, Trastuzumab, and chemotherapy to a patient with the breast cancer, wherein the chemotherapy comprises anthracycline-based chemotherapy, or carboplatin-based chemotherapy. 
     
     
         20 . The method of  claim 19  wherein chemotherapy comprises anthracycline-based chemotherapy which comprises 5-FU, epirubicin, and cyclophosphamide (FEC). 
     
     
         21 . The method of  claim 20  wherein the Pertuzmab is administered concurrently with the anthracycline-based chemotherapy. 
     
     
         22 . The method of  claim 19  wherein the chemotherapy comprises carboplatin-based chemotherapy which comprises Docetaxel and Carboplatin. 
     
     
         23 . The method of  claim 22  wherein the Pertuzmab is administered concurrently with the carboplatin-based chemotherapy. 
     
     
         24 . The method of  claim 19  wherein Pertuzumab administration does not increase cardiac toxicity relative to the treatment without Pertuzumab. 
     
     
         25 . The method of  claim 19  which comprises neoadjuvant or adjuvant therapy. 
     
     
         26 . A method of treating HER2-positive cancer in a patient comprising co-administering a mixture of Pertuzumab and Trastuzumab from the same intravenous bag to the patient. 
     
     
         27 . The method of  claim 26  which further comprises administering chemotherapy to the patient. 
     
     
         28 . An intravenous (IV) bag containing a stable mixture of Pertuzumab and Trastuzumab suitable for administration to a cancer patient. 
     
     
         29 . The IV bag of  claim 28  wherein the mixture is in saline solution. 
     
     
         30 . The IV bag of  claim 29  wherein the saline solution comprises about 0.9% NaCl or about 0.45% NaCl. 
     
     
         31 . The IV bag of  claim 28  which is a 250 mL 0.9% saline polyolefin or polyvinyl chloride infusion bag. 
     
     
         32 . The IV bag of  claim 28  which contains a mixture of about 420 mg or about 840 mg of Pertuzumab and from about 200 mg to about 1000 mg of Trastuzumab. 
     
     
         33 . The IV bag of  claim 28  wherein the mixture is stable for up to 24 hours at 5° C. or 30° C. 
     
     
         34 . The IV bag of  claim 28  wherein stability has been evaluated by an assay selected from the group consisting of: color, appearance and clarity (CAC), concentration and turbidity analysis, particulate analysis, size exclusion chromatography (SEC), ion-exchange chromatography (IEC), capillary zone electrophoresis (CZE), image capillary isoelectric focusing (iCIEF), and potency assay. 
     
     
         35 . A method of treating HER2-positive gastric cancer in a human subject comprising administering Pertuzumab, Trastuzumab, and chemotherapy to the subject with HER2-positive gastric cancer. 
     
     
         36 . The method of  claim 35  wherein the gastric cancer comprises non-resectable locally advanced gastric cancer, or metastatic gastric cancer, or advanced, post-operatively recurrent gastric cancer, which may not be amenable to curative therapy by known methods, or adenocarcinoma of the stomach or gastroesophageal junction. 
     
     
         37 . The method of  claim 35  wherein the patient has not received prior anti-cancer treatment for metastatic gastric cancer, has an Eastern Cooperative Oncology Group Performance Status Scale (ECOG PS) of 0-1, or has a HER2-positive status of IHC 3+ or IHC2+/ISH+. 
     
     
         38 . The method of  claim 35  wherein the chemotherapy comprises platin (cisplatin) and/or fluoropyrimidine (capecitabine or 5-fluorouracil (5-FU)). 
     
     
         39 . The method of  claim 38  wherein Pertuzumab, Trastuzumab, cisplatin, and capecitabine or 5-FU are administered. 
     
     
         40 . The method of  claim 35  wherein Pertuzumab is administered at a dose of 840 mg in all treatment cycles. 
     
     
         41 . The method of  claim 35  which improves overall survival (OS) relative to a patient treated with Trastuzumab and the chemotherapy only, or improves progression free survival (PFS) or response rate (RR) relative to treatment with Trastuzumab and chemotherapy only. 
     
     
         42 . A method of treating gastric cancer in a human subject comprising administering Pertuzumab to the subject with gastric cancer, wherein Pertuzumab is administered at a dose of 840 mg in all treatment cycles. 
     
     
         43 . The method of  claim 42  wherein Pertuzumab is administered at the dose of 840 mg for six treatment cycles. 
     
     
         44 . The method of  claim 42  which maintains Pertuzumab trough levels above about 20 μg/mL in the subject. 
     
     
         45 . The method of  claim 42  further comprising administering Trastuzumab and chemotherapy to the subject. 
     
     
         46 . A method of treating HER2-positive non-resectable or metastatic adenocarcinoma of the stomach or gastroesophageal junction in a human patient who did not receive prior chemotherapy for metastatic disease, except prior adjuvant or neoadjuvant therapy completed more than six months before the current treatment, comprising administering Pertuzumab, Trastuzumab, cisplatin, and capecitabine or fluorouracil (5-FU) to the patient in an amount to improve progression free survival (PFS) and/or overall survival (OS), wherein the patient has an Eastern Cooperative Oncology Group Performance Status Scale (ECOG PS) of 0-1. 
     
     
         47 . A method of improving progression free survival (PFS) in a human patient with HER2-positive non-resectable or metastatic adenocarcinoma of the stomach or gastroesophageal junction comprising administering Pertuzumab to the patient in combination with Trastuzumab and chemotherapy. 
     
     
         48 . A method of treating HER2-positive breast cancer in a patient comprising administering Pertuzumab, Trastuzumab and vinorelbine to the patient. 
     
     
         49 . The method of  claim 48  wherein the Pertuzumab and Trastuzumab are co-administered to the patient from a single intravenous bag. 
     
     
         50 . The method of  claim 48  wherein the breast cancer is metastatic or locally advanced. 
     
     
         51 . The method of  claim 48  wherein the patient has not previously received systemic non-hormonal anticancer therapy in the metastatic setting. 
     
     
         52 . A method of treating HER2-positive breast cancer in a patient comprising administering Pertuzumab, Trastuzumab, and aromatase inhibitor to the patient. 
     
     
         53 . The method of  claim 52  wherein the aromatase inhibitor is anastrazole or letrozole. 
     
     
         54 . The method of  claim 52  wherein the breast cancer is hormone receptor-positive advanced breast cancer. 
     
     
         55 . The method of  claim 54  wherein the hormone receptor is estrogen receptor (ER) and/or progesterone receptor (PgR). 
     
     
         56 . The method of  claim 52  wherein the patient has not previously received systemic nonhormonal anticancer therapy in the metastatic setting. 
     
     
         57 . The method of  claim 52  wherein the patient receives induction chemotherapy. 
     
     
         58 . The method of  claim 57  wherein the induction chemotherapy comprises a taxane. 
     
     
         59 . The method of  claim 17  wherein the package insert further comprises the warning box in Example 4. 
     
     
         60 . A method of treating a cancer patient comprising administering to the patient an initial dose of 840 mg of Pertuzumab followed every 3 weeks thereafter by a dose of 420 mg of Pertuzumab, and further comprising re-administering an 840 mg dose of Pertuzumab to the patient if the time between two sequential 420 mg doses is 6 weeks or more. 
     
     
         61 . The method of  claim 60  further comprising administering 420 mg of Pertuzumab every 3 weeks after the re-administered 840 mg dose. 
     
     
         62 . The method of  claim 60  wherein the cancer patient has HER2-positive breast cancer. 
     
     
         63 . The method of  claim 1  which which reduces the risk of death by about 34% or more relative to a patient treated with Trastuzumab and the chemotherapy. 
     
     
         64 . The method of  claim 17  wherein the package insert further provides the Overall Survival (OS) efficacy data in Example 9 or Table 14. 
     
     
         65 . A method for treating HER2-positive metastatic or locally recurrent breast cancer in a patient comprising administering Pertuzumab, Trastuzumab and taxoid to the patient, wherein the patient has been previously treated with a Trastuzumab and/or lapatinib as adjuvant or neoadjuvant therapy. 
     
     
         66 . The method of  claim 65  wherein the taxoid is Docetaxel, Paclitaxel, or nab-paclitaxel. 
     
     
         67 . The method of  claim 65  wherein the taxoid is Paclitaxel or nab-paclitaxel. 
     
     
         68 . The method of  claim 65  wherein the patient has been previously treated with Trastuzumab as neoadjuvant therapy.