RU2804713C2 - Treatment regimen for breast cancer using neratinib - Google Patents

Abstract

FIELD: oncology.

SUBSTANCE: extended treatment regimen for HER-2/neu overexpressing/amplifying cancer including a course of treatment with neratinib in patients with HER-2/neu overexpressing/amplifying cancer after completion of surgical treatment and adjuvant therapy is described. The neratinib regimen may be extended for periods ranging from twelve months to five years.

EFFECT: proposed scheme provides a reduction in the risk of recurrence of the disease.

10 cl

Description

BACKGROUND ART

Breast cancer is the most commonly diagnosed malignancy in women and the leading cause of cancer-related death among women worldwide. The overall incidence of breast cancer is estimated to reach 5 million women in the next ten years [Parkin, DM and Fernandez LM, Use of statistics to assess the global burden of breast cancer. Breast Journal . 2006; (12, Suppl 1):S70-80; World Health Statistics. 2008, World Health Organization.] In 2007, breast cancer caused approximately 540,000 deaths worldwide [World Health Organization Fact Sheet No. 297. 2008; available on the WHO website.]

The erbB (erythroblastic leukemia virus oncogene homologues) TKI (tyrosine kinase inhibitor) family consists of 4 members: erbB-1 (EGFR (epidermal growth factor receptor)), erbB-2 (HER-2, neu), erbB-3 (HER-3 ) and erbB-4 (HER-4). The erbB family of receptors is involved in cell proliferation, tumorigenesis and metastasis and is aberrantly expressed in many tumor types. HER2-positive breast cancers, that is, breast cancers that test positive for a protein called human EGFR associated with overexpression of the Erb-2 protein or amplification of the erbB-2 gene in breast cancers, are associated with more aggressive clinical course of the disease and a less favorable prognosis [Slamon D, Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987(235):177-182].

Trastuzumab, a humanized monoclonal antibody that selectively binds to the human erbB-2 receptor, improves the prognosis of women with erbB-2-positive breast cancer. In patients with metastatic breast cancer overexpressing erbB-2, trastuzumab in combination with chemotherapy improves tumor regression, prolongs time to tumor progression, and increases median survival compared with chemotherapy alone, leading to its approval as a first-line treatment for metastatic disease. . [Ligibel JA and Winer EP, Trastuzumab/chemotherapy combinations in metastatic breast cancer. Seminars in Oncology. 2002; 29(3 Suppl 11): 38-43]. Herceptin (trastuzumab) [Package insert, Genentech (2008)]. Trastuzumab has also been approved for use in the adjuvant setting in combination with other drugs for the treatment of erbB-2-overexpressing metastatic breast cancer with or without lymph node involvement (estrogen receptor negative (ER negative)/progesterone receptor negative (PgR negative). -negative)). Thus, trastuzumab is used as part of a treatment regimen consisting of (a) doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel, (b) a regimen with docetaxel and carboplatin, and (c) as monotherapy after combination anthracycline therapy.

Currently, the standard treatment after diagnosis of HER-positive breast cancer is surgery followed by adjuvant therapy for a year. Standard adjuvant therapy is some combination of chemotherapy, radiation therapy, hormone therapy for ER/PR-positive disease, and trastuzumab. Despite adjuvant therapy, patients with early stage breast cancer remain at risk of relapse. Published reports of trastuzumab treatment have demonstrated disease-free survival rates ranging from 80.6% [Smith I, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomized controlled trial. Lancet. 2007; 369:29-36] at three years to 85.9%-82% at four years [Perez EA, et al., Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patients with HER2-positive breast cancer. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings. 2007; 25(18S): 512 and Slamon D, et al. , Phase III trial comparing AC-T with AC-TH and with TCH in the adjuvant treatment of HER2 positive early breast cancer patients: second interim efficacy analysis. Presentation by Slamon D. SABCC 2006].

The use of HKI-272 (neratinib) for the treatment of tumors has been described [US Patent No. 6,288,082]. Neratinib is a potent irreversible inhibitor of all erbBs. Neratinib is an orally administered small molecule that inhibits erbB-1, erbB-2 and erbB-4 at the level of intracellular tyrosine kinase domains, which is different from the mechanism of action of trastuzumab. Neratinib reduces erbB-1 and erbB-2 autophosphorylation, subsequent signal transduction, and growth of erbB-1- and erbB-2-dependent cell lines. Preclinical data suggest that neratinib will have antitumor activity in cancer cell lines expressing erbB-1 and/or erbB 2, with a cellular mean inhibitory concentration (IC ₅₀ ) of less than 100 nM [Rabindran SK, et al. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Research . 2004;64(11):3958-65].

There is a need for drugs and treatment regimens that improve patient survival and/or drugs and treatment regimens that reduce breast cancer recurrence after completion of primary treatment and adjuvant therapy.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a treatment regimen for a HER-2/neu overexpressing/amplifying tumor, comprising administering a course of treatment with neratinib as a continuation of adjuvant trastuzumab therapy in patients with HER-2/neu overexpressing/amplifying cancer, e.g., neratinib is administered after completion of surgery. treatment and standard adjuvant therapy.

In another aspect, the invention provides a method or regimen for reducing the recurrence rate of HER-2/neu overexpression/amplification breast cancer in patients compared to patients receiving primary treatment and adjuvant trastuzumab alone. The method involves administering neratinib to specified patients after primary treatment and standard adjuvant therapy with trastuzumab. In one embodiment, the method is also used after completion of one or more conventional neoadjuvant therapy or standard adjuvant therapy.

In yet another aspect, the invention provides a regimen for increasing invasive disease-free survival by treating patients with cancer with neratinib after completion of primary treatment and standard adjuvant therapy with trastuzumab. In one embodiment, treatment with neratinib is initiated between two weeks and forty-eight months after surgery and standard adjuvant trastuzumab therapy.

Other aspects and advantages of the invention will be apparent from the following detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the invention provides an extended treatment regimen for adjuvant therapy of HER-2/neu overexpressing/amplifying cancer, comprising administering a course of treatment with neratinib to patients with HER-2/neu overexpressing/amplifying cancer. This extended adjuvant therapy includes initiation of treatment with neratinib after completion of adjuvant therapy with trastuzumab. This extended adjuvant therapy is used to provide prolonged invasive disease-free survival (IDFS) or disease-free survival for ductal carcinoma in situ (DFS-DCIS) and/or increased overall survival, time to systemic relapse, and systemic recurrence-free survival.

When used here, invasive disease-free survival (IDFS) is defined as the time from the date of randomization to the date of the IDFS event, including invasive ipsilateral breast tumor recurrence, local/regional invasive recurrence, systemic recurrence, death from any cause, invasive contralateral breast cancer and other primary invasive cancer (not breast cancer). DFS-DCIS is defined as the time from randomization to the first occurrence of any IDFS event or ductal carcinoma in situ . Systemic relapse-free survival (DDFS) is the time from randomization to first systemic relapse or death from any cause. Time to systemic recurrence (TTDR) is defined as the time from randomization to the date of first systemic tumor recurrence, excluding local/regional recurrences and other breast cancers or cancers other than breast cancer, and considering deaths before systemic breast cancer recurrence glands as phenomena that exclude the possibility of determining the time before systemic relapse (“censoring events”).

Thus, extended adjuvant therapy according to the invention using neratinib increases disease-free survival by reducing the risk of relapse or death. In one embodiment, extended adjuvant therapy with neratinib reduces the risk, that is, the risk rate, of cancer recurrence or death by 30% or 20% compared with that typically observed after treatment with trastuzumab.

In another embodiment, with the extended neratinib treatment regimen described herein, less than 15%, less than 10%, and/or less than 5% of patients receiving primary treatment and adjuvant therapy have cancer three years after initiation of treatment. In yet another embodiment, with the extended neratinib treatment regimen described herein, less than 20%, less than 15%, and/or less than 5% of patients receiving primary treatment and adjuvant therapy have cancer five years after initiation of treatment.

As used herein, neratinib refers to the HKI-272 compound having the following basic structure:

,

in its free base form. Optionally, a pharmaceutically acceptable salt or hydrate thereof may be used. The basic structure presented above is a specific HKI-272 compound called HKI-272 or neratinib, which has the chemical name [(2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl )methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide].

Another compound, HKI-272, may be used in place of neratinib, although this is currently less preferred. In one embodiment, "HKI-272 compound" refers to a compound derived from the basic structure of neratinib shown above. Suitable derivatives may include, for example, an ester, an ether or a carbamate. Such an HKI-272 compound may have the structure:

,

Where:

R ¹ represents halogen;

R ² represents pyridinyl, thiophenyl, pyrimidinyl, thiazolyl or phenyl, where R ² is optionally substituted with up to three substituents;

R ³ represents O or S;

R ⁴ represents CH ₃ or CH ₂ CH ₂ OCH ₃ ;

R ⁵ represents CH ₃ or CH ₂ CH ₃ ; And

n represents 0 or 1.

As used herein, the term "halogen" refers to Cl, Br, I and F.

Also included are pharmaceutically acceptable salts, hydrates and prodrugs of neratinib and/or other HKI compounds described herein. "Pharmaceutically acceptable salts and esters" refer to salts and esters that are pharmaceutically acceptable and have the desired pharmacological properties. Such salts include, for example, salts that can be formed where acidic protons present in the compounds are able to react with inorganic or organic bases. Suitable inorganic salts include, for example, those formed by alkali metals or alkaline earth metals, eg sodium, potassium, magnesium, calcium, aluminum. Suitable organic salts also include, for example, those formed by organic bases such as amine bases, for example ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like, and bases that can form N-tetraalkylammonium salts such as N -tetrabutylammonium salts. Pharmaceutically acceptable salts may also include acid addition salts formed by reacting basic moieties such as amines in the parent compound with inorganic acids (eg, hydrochloric acid, hydrobromic acid) and organic acids (eg, acetic acid, citric acid, maleic acid, propionic acid). , lactic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric acids and alkane and arenesulfonic acids, such as methanesulfonic acid and benzenesulfonic acid, naphthalene sulfonic acid, toluenesulfonic acid, camphorsulfonic acid). Other suitable examples of pharmaceutically acceptable salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, hydrogen phosphate, isonicotinate, lactate, salicylate, hydrogen citrate, tartrate, oleate, tannate, pantothenate, hydrogen tartrate , ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate, pamoate (i.e., 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)), and fatty acid salts such as caproate, laurate, myristate, palmitate, stearate, oleate, linoleate and linolenate.

Pharmaceutically acceptable esters include esters formed by carboxy groups, sulfonyloxy groups and phosphonoxy groups present in the compounds of the invention, for example, esters with straight chain alkyls having 1-6 carbon atoms or branched chain alkyl groups containing 1-6 carbon atoms, including methyl, ethyl, propyl, butyl, 2-methylpropyl and 1,1-dimethylethyl ethers, cycloalkyl ethers, alkylaryl ethers, benzyl ethers and the like. When two acidic groups are present, the pharmaceutically acceptable salt or ester may be an acidic salt or ester or a non-acidic salt or ester; and similarly, when more than two acid groups are present, some or all of such groups may be involved in the formation of the salt or ester. The compounds used herein may be present in free base form or in salt and/or ester form, and the reference to such compounds is intended to include both the parent compound (in free base form) and its pharmaceutically acceptable salts or esters. Also, one or more than one compound used herein may be present in more than one stereoisomeric form, and reference to such compounds is intended to include all individual stereoisomers and all mixtures (racemic or non-racemic) of such stereoisomers.

The preparation of the HKI-272 compounds, of which neratinib is a variant, is described in detail in US Patent Application Publication No. 2005/0059678, incorporated herein by reference. See also US Patent No. 6288082, US Patent No. 6002008, US Patent No. 6297258, and US Patent Application Publication No. 2007/0104721, incorporated herein by reference. The methods described in these documents can also be used to prepare neratinib and/or other HKI-272 and substituted 3-quinoline compounds used herein and are incorporated herein by reference. In addition to the methods described in these documents, International Patent Application Publications No. WO-96/33978 and WO-96/33980, incorporated herein by reference, describe methods useful for preparing these HKI-272 compounds. While these methods describe the preparation of certain quinazolines, they are also applicable to the preparation of the corresponding substituted 3-cyanoquinolines and are incorporated herein by reference.

The term “treating” or “treating” refers to the administration of neratinib to a subject to prevent, or delay, alleviate, or stop, or suppress the development of symptoms or conditions associated with tumors.

Trastuzumab and methods for preparing it and making compositions therefrom have been described. See, for example, US Patent No. 6821515, US Patent No. 6399063 and US Patent No. 6387371. Trastuzumab is commercially available from Genentech under the name Herceptin. As used herein, the term “trastuzumab” includes trastuzumab and altered forms and derivatives of trastuzumab. The term "trastuzumab" includes agents that target the same Her-2 receptor epitope that trastuzumab targets. This epitope is known from HS Cho et al ., Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab, Nature 421 (2003), pp. 756–760.

As used herein, tumors with amplification/overexpression of erB-2 (used interchangeably with Her-2 and neu) include certain types of breast cancer and other tumors, which may include ovarian, bladder, gastric, pancreatic, colorectal, prostate cancer gland and lung, including non-small cell lung cancer. Other tumors that express or overexpress ErbB1 include a variety of human solid tumors, including non-small cell lung cancer (NSCL), prostate cancer, breast cancer, colorectal cancer, and ovarian cancer. Methods for examining samples to determine the presence of erb-1 and/or erB-2/Her-2 overexpression in a tumor are known to those skilled in the art.

Primary treatment and adjuvant antitumor therapy

As defined herein, primary treatment is the initial treatment given to a patient after diagnosis of a tumor, such as a HER-2/neu overexpression/amplification tumor. Primary treatment is also called radical local treatment. Primary treatment for HER-2/neu overexpression/amplification tumors includes surgery (in the case of breast cancer, this may include lumpectomy, modified radical mastectomy, mastectomy) and/or radiation therapy, alone or in combination. Adjuvant therapy refers to treatment usually given after initial or primary treatment to increase the likelihood of cure. Currently, standard adjuvant therapy for HER-2/neu overexpressing/amplifying tumors includes, for example, chemotherapy and/or antibody therapy. Typically, if one or more of these adjuvant therapies are given before primary treatment (eg, surgery), it is called neoadjuvant therapy. In the following parts of the description, the term “neoadjuvant/adjuvant” is used as a shorthand to refer to both neoadjuvant and standard adjuvant therapy. It is possible to administer one or more types of adjuvant therapy simultaneously.

In one embodiment, the patient may already have received chemotherapy, including the use of a treatment regimen using an anthracycline or taxane, or any treatment regimen using cyclophosphamide, methotrexate and 5-fluorouracil. Such chemotherapy may include one or more of an anthracycline such as doxorubicin, cyclophosphamide, paclitaxel, docetaxel and carboplatin. Another suitable neoadjuvant/adjuvant therapy is combination anthracycline therapy. Other neoadjuvant/adjuvant therapies include, but are not limited to, lapatinib [lapatinib ditosylate, Tykerb, TYKERB®], pertuzumab [Roche, Genentech], bevacizumab [Avastin, Avastin®, Genentech], trastuzumab-DM-1 [Genentech]. The choice of neoadjuvant or adjuvant therapy is not a limitation of the present invention. Extended adjuvant therapy according to the invention begins after completion of treatment with trastuzumab. Trastuzumab is usually given after completion of chemotherapy or concurrently with chemotherapy as maintenance therapy. For trastuzumab, single doses and multiple doses are suggested. In one embodiment, a single loading dose of trastuzumab in the range of approximately 4-5 mg/kg is administered by intravenous infusion over 90 minutes on day 1, followed by approximately 2 mg/kg per week starting on day 8. Usually 1 cycle is 3 weeks. Breaks between cycles can range from 1 to 2-3 weeks. In another embodiment, trastuzumab is administered on an every 3 week dosing schedule using 8 mg/kg as a loading dose and 6 mg/kg as a maintenance dose. Trastuzumab can also be administered at a dose of 6 mg/kg once every 3-4 weeks. Other trastuzumab regimens may be developed and used.

In one embodiment, the patient may have already received the primary treatment, and also, in addition to neoadjuvant/adjuvant trastuzumab therapy, other neoadjuvant/adjuvant therapy. In one embodiment, one or more adjuvant therapies may be continued after completion of trastuzumab treatment during extended adjuvant therapy. Accordingly, neither primary treatment nor neoadjuvant/adjuvant therapy includes treatment with neratinib prior to initiation of the extended neratinib treatment regimen of the invention.

Extended treatment regimen for neratinib according to the invention

In one embodiment, the extended neratinib treatment regimen described herein is initiated approximately one year, approximately two years, or approximately three years after the start of primary treatment. An extended adjuvant neratinib regimen is initiated after completion of neoadjuvant/adjuvant trastuzumab therapy.

The extended treatment regimen described herein can be initiated after completion of at least one administration of trastuzumab, a cycle of neoadjuvant/adjuvant trastuzumab therapy lasting at least 3 weeks, at least three cycles of neoadjuvant/adjuvant trastuzumab therapy lasting at least 3 weeks, at least four months, at least six months, at least eight months, or at least one year of neoadjuvant/adjuvant trastuzumab therapy. In one embodiment, the extended neratinib treatment regimen is initiated at least about two weeks, at least about one month, at least about six months, at least about nine months, or about one to four years after completion of trastuzumab treatment.

As described here, an extended neratinib regimen is used to reduce the recurrence rate of HER-2/neu overexpression/amplification breast cancer in patients. This frequency can be measured at a time point of six months, one year, three years, or five years after the start of treatment. The treatment regimen includes administration of neratinib to these patients after primary treatment and neoadjuvant/adjuvant therapy. In another embodiment, an extended neratinib regimen is used to increase invasive disease-free survival, DFS-DCIS, systemic relapse-free survival, and/or time to systemic relapse in patients with cancer.

This extended adjuvant therapy of the invention may include only a single dose of neratinib after completion of treatment with trastuzumab. However, in another embodiment, the extended neratinib treatment regimen is administered over a period of one month, two months, at least six months, at least one year, at least 18 months, or for longer periods as needed or desired. . In another embodiment, patients receive treatment with neratinib for a period of from about 8 months to about 5 years, from about 12 months (one year) to about three years, or for longer or shorter periods as determined by a medical professional.

As used herein, the term "administration" with respect to the administration of neratinib means either the direct administration of a compound or composition, or the administration of a prodrug, derivative or analogue from which an effective amount of the neratinib compound is formed in the body.

As used herein and except where otherwise noted, the terms "individual", "subject" and "patient" are used interchangeably and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, non-human primates and humans. Preferably, the term "individual", "subject" or "patient" refers to a person. In most embodiments, the subjects or patients are in need of therapeutic treatment. Accordingly, the term “subject” or “patient” as used herein means any mammalian patient or mammalian subject to whom the claimed treatment regimen may be administered.

As used herein, the term "effective amount" or "pharmaceutically effective amount" when administered to a subject to treat a tumor means an amount sufficient to inhibit, slow, reduce or eliminate lesions or tumor growth in the subject, or to inhibit, slow or reduce the progression of a disease and/ or improving a subject's progression-free survival rate.

Neratinib (or the selected HKI-272 compound) can be administered, for example, orally, in a dosage range of about 0.01 to 100 mg/kg. In one embodiment, neratinib is administered in a dosage range of about 0.1 to about 90 mg/kg. In another embodiment, neratinib is administered in a dosage range of about 1 to about 80 mg/kg. In another embodiment, neratinib is administered in a dosage range of about 10 to about 70 mg/kg. In yet another embodiment, neratinib is administered in a dosage range of about 15 to about 60 mg/kg. In yet another embodiment, neratinib is administered in a dosage range of about 20 to about 240 mg per day, at least about 40 mg, at least about 120 mg, or at least about 160 mg on the days of the cycle on which it is administered. One skilled in the art can easily conduct empirical activity studies to determine the biological activity of a compound in biological assays and thus determine what dose to administer when administering the compound by another route of administration.

In one embodiment, the oral dose of neratinib is at least about 700 mg per week. In another embodiment, the oral dose of neratinib is from about 800 mg per week to at least about 1700 mg per week. In another embodiment, the oral dose of neratinib is from about 840 mg per week to about 1680 mg per week. In another embodiment, the oral dose of neratinib is from about 900 mg per week to about 1600 mg per week. In another embodiment, the oral dose of neratinib is from about 1000 mg per week to about 1500 mg per week. In yet another embodiment, the oral dose of neratinib is from about 1100 mg per week to about 1400 mg per week. In yet another embodiment, the oral dose of neratinib is from about 1200 mg per week to about 1300 mg per week. The exact dosage will be determined by the attending physician based on experience with the individual subject being treated. Other treatment regimens and options are predictable and determined under the guidance of a physician.

For neratinib, it is desirable that the compound be presented in unit dose form. Neratinib can be administered in a dose range of approximately 0.01 to 100 mg/kg or in a dose range of 0.1 to 10 mg/kg. In one embodiment, neratinib is administered orally 1-6 times daily, more commonly 1-4 times daily. Suitable unit dosage forms include tablets, capsules and powders in sachets or vials. Such unit dosage forms may contain 0.1 to 300 mg of neratinib, 2 to 100 mg, 120 mg to 300 mg per day, or 240 mg per day. Alternatively, neratinib may be administered by another suitable route of administration, for example intravenous. In another embodiment, neratinib is administered once a week. In certain situations, administration of neratinib may be delayed or discontinued for a short period (eg, 1, 2, or three weeks) during the course of treatment. Such delay or cessation may occur once or several times during the course of treatment. An effective amount will be known to one skilled in the art; it will also depend on the form of the connection. One skilled in the art can easily conduct empirical activity studies to determine the biological activity of a compound in biological assays and thereby determine the dosage to administer.

In one embodiment, suitable examples of pharmaceutical carriers used herein include, but are not limited to, excipients, diluents, fillers, disintegrants, lubricants and other agents that may function as a carrier. The term "pharmaceutically acceptable excipient" means an excipient useful in the manufacture of a pharmaceutical composition that is generally safe, non-toxic and desirable, and includes excipients acceptable for veterinary use as well as for human pharmaceutical use. Such excipients may be solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous. Pharmaceutical compositions are prepared according to acceptable pharmaceutical methods, such as those described in Remingtons Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985). Pharmaceutically acceptable carriers are those that are compatible with the other ingredients of the composition and are biologically acceptable. Suitable pharmaceutically acceptable excipients or carriers for a composition in tablet or caplet form include, for example, inert excipients such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating agents and disintegrants such as corn starch or alginic acid; binding agents such as gelatin or starch; lubricants such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl 4-hydroxybenzoate; and antioxidants such as ascorbic acid. Compositions in tablet or caplet form may be uncoated or coated, either to modify their breakdown and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve their stability and/or appearance, using conventional coating agents. and methods well known in the art.

In one embodiment, the invention provides an extended treatment regimen for HER-2/neu overexpression/amplification of cancer, comprising administering an extended course of treatment with neratinib to patients with HER-2/neu overexpression/amplification of cancer. Such extended treatment includes initiation of treatment with neratinib after completion of surgery and/or adjuvant therapy. This extended treatment is used to provide increased invasive disease-free survival and/or increased overall survival, time to systemic relapse, and systemic relapse-free survival.

As described herein, the extended neratinib treatment regimen is initiated at least one, at least two, or at least three years after the start of initial treatment. In one embodiment, treatment with neratinib is initiated at least about 2 weeks to about four years after completion of primary treatment and standard neoadjuvant/adjuvant therapy.

In one embodiment, the selected concomitant treatment may be used in combination with an extended neratinib treatment regimen. For example, patients may additionally receive concomitant treatment with bisphosphonates to treat osteopenia or osteoporosis. In another embodiment, patients may additionally receive concomitant endocrine therapy. It is possible that such concomitant treatment may not constitute adjuvant therapy, but rather represent treatment for other conditions or symptoms that may be present in the patient.

Pharmaceutical packaging/kits

The invention includes a product or pharmaceutical package comprising a course of anticancer treatment for one mammalian individual, including one or more than one container containing one, one to four or more units of neratinib and optionally one, one to four or more units of another active agent.

In another embodiment, pharmaceutical packages include a course of anticancer treatment for one mammalian individual, including a container containing a unit dosage form of rapamycin, a container containing a unit of neratinib, and optionally a container of another active agent.

In some embodiments, the compositions of the invention are presented in packages in a form ready for administration. In other embodiments, the compositions of the invention are presented in concentrated form in packages, optionally with a diluent necessary to prepare the final solution for administration. In other embodiments, the product contains a compound useful in the invention in solid form and, optionally, a separate container with a suitable solvent or carrier for the compound useful in the invention.

In other embodiments, the above packages/kits include other components, for example, instructions for diluting, mixing and/or administering the product, other containers, syringes, needles, and so on. Other such package/kit components will be apparent to one skilled in the art.

The following examples show the use of the combinations according to the invention. It should be understood that, for reasons known to those skilled in the art, changes or modifications may be made, for example, in the manufacture of components, routes of administration and dosages.

EXAMPLES

Neratinib as monotherapy was studied in a phase 2 study in subjects with metastatic erbB-2-positive breast cancer. Sixty-six subjects with prior trastuzumab treatment were included in group A; 70 subjects without any prior exposure to trastuzumab were included in arm B. Objective response rate and median progression-free survival were used as measures of antitumor activity.

Preliminary data based on independent radiographic assessment showed that among subjects previously treated with trastuzumab, the overall response rate (ORR) was 26% (CI 95%) and median progression-free survival (PFS) was 23 weeks (CI 95). %). For patients without prior exposure to trastuzumab, the ORR was 57% (CI 95%) and median PFS was 40 weeks (95% CI). Antitumor activity in arm A provides a rationale for investigating neratinib as monotherapy in subjects refractory to trastuzumab.

In group A, the average duration of trastuzumab use was 60 weeks. Twenty-eight (28%) subjects received trastuzumab as adjuvant or neoadjuvant therapy. The majority (48%) of subjects received one course of trastuzumab treatment for metastatic disease, and approximately 43% of patients received a second or third course of trastuzumab treatment for metastatic disease. Subjects in Group A had also previously received extensive treatment with cytotoxic agents, with 53% of subjects having received 2-3 prior courses of treatment and another 27% having received more than 3 prior courses of treatment with cytotoxic agents. Taken together, these prior treatment data characterize the study population of Group A as having been repeatedly treated previously and likely to be treatment refractory. As such, the ORR of 26% in the treatment-refractory population suggests that neratinib is likely a highly active agent against erbB-2-positive breast cancer.

The main adverse event associated with neratinib was diarrhea, which was generally well managed with medication, discontinuation of treatment, or dose changes. Other common adverse events are nausea, vomiting, fatigue and anorexia.

Example 1

A randomized, double-blind, placebo-controlled, phase 3 trial compared neratinib with placebo after treatment with trastuzumab in women with early-stage breast cancer with HER-2/neu overexpression/amplification. Subjects must complete prior adjuvant trastuzumab therapy. If the subject has received trastuzumab for less than 12 months, the subject must have received at least 8 prior doses, and it must be noted that the subject is either ineligible to receive further adjuvant trastuzumab therapy or cannot receive further adjuvant trastuzumab therapy. After completing a course of prior adjuvant therapy, including treatment with trastuzumab for at least 8 and preferably 12 months, subjects are eligible for treatment using the treatment regimen described here. The last dose of trastuzumab should be administered at least 2 weeks and no more than 4 years before randomization. Randomization was performed according to the following stratification factors: ER- and/or PgR-positive or ER- and PgR-negative; lymph node involvement (0, 1-3, 4 or more); the diagnosis is less than or more than 3 years old; administration of trastuzumab sequentially or simultaneously with chemotherapy.

Eligible patients are randomly assigned in a 1:1 ratio to one of the following two groups: neratinib, 240 mg daily for 1 year; or placebo, daily for 1 year. After discontinuation of study treatment, subjects will continue to be monitored for disease relapse and survival until a predetermined number of invasive disease-free survival (IDFS) events are achieved and for overall survival until the end of the study. The primary efficacy endpoint of IDFS and secondary time-to-event endpoints will be analyzed using the stratified log-rank test. The hazard ratio and corresponding 95% confidence interval will be obtained from a stratified Cox proportional hazards regression model [DR Cox, 1972, “Regression Models and Life Tables (with Discussion)”, Journal of the Royal Statistical Society, Series B 34:187-220] . Mean time-to-event values and associated 95% confidence intervals will be estimated using the Kaplan-Meier method [Kaplan, EL and Meier, Paul. "Nonparametric estimation from incomplete observations." J. Am. Stat. Assoc. 53, 457-481 (1958)]. The primary efficacy analysis will be conducted in the intention-to-treat population, defined as all subjects randomized. Adverse events and serious adverse events will be summarized by treatment arm for the safety population, defined as all subjects who received neratinib or placebo. The incidence of grade 3 or higher diarrhea will also be summed and differences between treatment groups will be analyzed using the Mantel-Haenszel test [Mantel N & Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J. Nat. Cancer Inst. 22 :719-48, 1959].

All publications cited herein are incorporated herein by reference. While the invention has been described with reference to specific embodiments, it should be understood that modifications may be made without departing from the spirit of the invention. Such modifications are intended to be within the scope of the appended claims.

Claims (12)

1. The use of neratinib or a pharmaceutically acceptable salt thereof in a method of treating breast cancer with overexpression/amplification of HER-2/neu in an extended adjuvant regimen of neratinib, where the method includes the use of an extended regimen of adjuvant therapy with neratinib in a patient having breast cancer with overexpression/amplification HER-2/neu amplification, wherein the extended adjuvant neratinib regimen is initiated at least 2 weeks, at least one month, at least six months, or at least nine months after completion of adjuvant trastuzumab therapy, and wherein the extended adjuvant neratinib regimen is administered for a period of at least six months, at least 12 months, at least 18 months, 8 months to 5 years, or 12 months to approximately three years. 2. Use according to claim 1, where an extended regimen of adjuvant therapy with neratinib reduces the incidence of relapse of breast cancer with overexpression/amplification of HER-2/neu in the patient. 3. The use of claim 1 or 2, wherein the extended adjuvant neratinib regimen improves invasive disease-free survival (IDFS), disease-free survival in ductal carcinoma in situ (DFS-DCIS), disease-free survival (DDFS), and /or the patient's time to systemic relapse (TTDR). 4. Application according to any one of paragraphs. 1-3, wherein neratinib or a pharmaceutically acceptable salt thereof is presented in unit dosage form. 5. Use according to claim 4, where the unit dosage form contains from 0.1 to 300 mg or from 2 to 100 mg of neratinib or a pharmaceutically acceptable salt thereof. 6. Use according to claim 4 or 5, where the standard dosage form is a tablet, capsule and powder in sachets or bottles. 7. Application according to any one of paragraphs. 4-6, wherein neratinib or a pharmaceutically acceptable salt thereof is administered orally 1-6 times daily. 8. Use according to claim 7, wherein neratinib or a pharmaceutically acceptable salt thereof is administered orally 1-4 times a day. 9. Application according to any one of paragraphs. 4-8, wherein neratinib or a pharmaceutically acceptable salt thereof is administered at a dose of 120 to 300 mg per day or 240 mg per day. 10. Application according to any one of paragraphs. 1-9, wherein the pharmaceutically acceptable salt is a sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, hydrogen phosphate, isonicotinate, lactate, salicylate, hydrogen citrate, tartrate, oleate, tannate, pantothenate, hydrogen tartrate salt , ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, 1,1'-methylene-bis-(2-hydroxy-3-naphthoate ), caproate, laurate, myristate, palmitate, stearate, oleate, linoleate and linolenate.