WO2016164217A1 - Therapeutic combinations for treating cancer - Google Patents
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- WO2016164217A1 WO2016164217A1 PCT/US2016/024839 US2016024839W WO2016164217A1 WO 2016164217 A1 WO2016164217 A1 WO 2016164217A1 US 2016024839 W US2016024839 W US 2016024839W WO 2016164217 A1 WO2016164217 A1 WO 2016164217A1
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- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
Definitions
- the present invention relates to combination treatment methods for treating cancer, particularly non-small cell lung cancer (NSCLC). More specifically, the invention relates to methods of treating or managing cancer, particularly NSCLC, in a subject, comprising administering an irreversible mutant epidermal growth factor receptor (EGFR) inhibitor compound in combination with one or more other therapies, particularly
- NSCLC non-small cell lung cancer
- EGFR epidermal growth factor receptor
- the present invention relates to pharmaceutical compositions and methods comprising said irreversible mutant EGFR inhibitor compounds for treating cancer in combination with one or more other therapies, such as Radiotherapy, administered simultaneously, separately, or sequentially.
- lung cancer remains the most common cancer worldwide with approximately 1.35 million new cases annually and non- small cell lung cancer (NSCLC) accounting for almost 85% of all lung cancers (Herbst RS et al., N Engl J Med. 2008; 359: 1367-80). Additionally, lung cancer continues to be the most common cause of cancer-related deaths worldwide with a 5-year survival rate of less than 10% in patients with advanced disease.
- NSCLC non- small cell lung cancer
- EGFR epidermal growth factor receptor
- TKIs first-generation reversible EGFR tyrosine kinase inhibitors
- Toxicity associated with both erlotinib and gefitinib includes skin rash and diarrhea related to inhibition of wild-type EGFR (WT EGFR) in skin and intestine, respectively (Herbst et al, Clin Lung Cancer. 2003; 4:366- 9).
- T790M mediates resistance to first-generation EGFR inhibitors by acting as a "gatekeeper" mutation, inducing steric hindrance in the ATP binding pocket and preventing inhibitor binding (Pao et al, PLoS Med. 2005;2:e73; Kwak et al, Proc Natl Acad Sci U S A.
- CO- 1686 is a potent, small- molecule, irreversible tyrosine kinase inhibitor (TKI) that selectively targets the common EGFR mutations (L858R, dell9, T790M) and has minimal inhibitory activity towards WT EGFR (Walter, A. et al., Cancer Discovery. 2013;3: 1404-15). Oral administration of CO- 1686 leads to tumor regressions in cell-based and patient- derived xenograft models as well as a transgenic mouse model expressing mutant forms of EGFR.
- TKI irreversible tyrosine kinase inhibitor
- CO-1686 is currently being evaluated in several ongoing clinical studies, including: 1) Study to Evaluate Safety, Pharmacokinetics, and Efficacy of Rociletinib (CO- 1686) in Previously Treated Mutant EGFR in NSCLC Patients (NCT01526928), 2) TIGER- 1: Safety and Efficacy Study of Rociletinib (CO-1686) or Erlotinib in Patients With Mutant EGFR NSCLC Who Have Not Had Any Previous EGFR Directed Therapy (NCT02186301), 3) TIGER-2: A Phase 2, Open-label, Multicenter, Safety and Efficacy Study of Oral CO-1686 as 2nd Line EGFR-directed TKI in Patients With Mutant EGFR NSCLC (NCT02147990), and 4) TIGER- 3: Open Label, Multicenter Study of Rociletinib (CO-1686) Mono Therapy Versus Single-agent Cytotoxic Chemotherapy in Patients With Mutant EGFR NSCLC Who Have Failed
- the initial area of clinical study for CO-1686 is the treatment of patients with mutant EGFR NSCLC who have received prior EGFR-directed therapy. Expansion of CO- 1686 into the front-line setting of mutant EGFR NSCLC patients is currently ongoing considering the equivalent potency observed between erlotinib and CO-1686 in biochemical, cellular, and in vivo xenograft studies using NSCLC cell lines and models with an EGFR activating mutation.
- Toxicity associated with erlotinib and gefitinib includes skin rash and diarrhea related to inhibition of WT EGFR in skin and intestine, respectively (Herbst RS et al., N Engl J Med. 2008;359: 1367-80).
- Use of a WT EGFR sparing, mutant selective inhibitor such as CO-1686 has the potential for preventing some of these side-effects observed with first- generation EGFR inhibitors and therefore improving patient quality-of-life.
- CO- 1686 has shown a manageable safety profile and it is notable that adverse events (AEs) typical of WT EGFR inhibition (rash and chronic diarrhea) have typically not been observed at doses up to 2000 mg daily (Soria et al., presented at EORTC-NCI-AACR, November 18- 21, 2014, Barcelona, Spain).
- AEs adverse events
- BM brain metastases
- EGFR inhibitors can enhance the anti-tumor activity of radiotherapy (RT) through multiple mechanisms (Chinnaiyan et al. Cancer Res. 2005; 65(8):3328-35; Mehta, Front Oncol. 2012 Apr 10;2:31; Sato et al. Anticancer Res. 2012; 32(11):4877-81).
- RT radiotherapy
- the combination of erlotinib and RT in vitro reduced the number of cells in S-phase and enhanced the induction of apoptosis in NSCLC and SCC (squamous cell carcinoma) cell lines.
- erlotinib and RT increased tumor growth inhibition as compared to either monotherapy in NSCLC and SCC xenograft models.
- WBRT may disrupt the blood brain barrier (BBB), allowing for greater penetration of erlotinib into the brain (Rubin et al. Disruption of the blood-brain barrier as the primary effect of CNS irradiation. Radiother Oncol 1994; 31(1): 51-60).
- BBB blood brain barrier
- the rate of rash was higher in the WBRT and erlotinib combination group as compared to the WBRT and placebo combination group.
- 40 unselected NSCLC patients were treated with erlotinib monotherapy (150 mg daily) for one week, then concurrently with WBRT, followed by erlotinib maintenance (Welsh et al. J Clin Oncol. 2013; 31(7):895-902).
- the overall response rate was 86% with a median survival time of 11.8 months.
- Ionizing radiation results in skin injury (radiation dermatitis) in 95% of patients receiving radiation therapy for cancer, resulting from the activation of numerous cytokines and chemokines produced from immune cells in the dermis and epidermis (Ryan et al. J Invest Dermatol. 2012; 132(3 Pt 2):985-93).
- the present invention is directed to the combination of WT sparing EGFR inhibitors and RT that provide better therapeutic profiles than current single agent therapies or other combination therapies utilizing EGFR inhibitors.
- combination therapies of an irreversible mutant EGFR inhibitor compound with one or more other therapies, particularly radiotherapy, that have at least an additive potency or at least an additive therapeutic effect.
- the invention is directed to combination therapies where the therapeutic efficacy is greater than additive, e.g., a synergistic efficacy exists between an irreversible mutant EGFR inhibitor compound and one or more other therapies, particularly radiotherapy.
- such combination therapies also reduce or avoid unwanted or adverse effects.
- the combination therapies of the invention provide an improved overall therapy relative to the administration of the therapeutic agents by themselves.
- doses of existing therapeutic agents can be reduced or administered less frequently in using the combination therapies of the invention, thereby increasing patient compliance, improving therapy and reducing unwanted or adverse effects.
- this invention is directed to combination therapies designed to treat or manage cancer, particularly NSCLC, in a subject, wherein the combination therapies comprise administering an irreversible mutant EGFR inhibitor to the subject in need thereof in combination with one or more other therapies, particularly radiotherapy.
- this invention is directed to methods of treating or managing cancer, particularly NSCLC, in a subject, comprising administering a therapeutically effective amount of an irreversible mutant EGFR inhibitor in combination with the administration of therapeutically effective amount of one or more other therapies, particularly radiotherapy.
- the present invention provides methods for treating cancer, particularly NSCLC, in a subject comprising administering an Mutant EGFR inhibitor compound that covalently modifies Cysteine 797 in EGFR, wherein said compound exhibits at least 2-fold greater inhibition of a drug resistant Mutant EGFR relative to wild type EGFR, and an additional therapy, particularly radiotherapy.
- the present invention provides methods for treating drug resistant cancer, particularly NSCLC, in a subject comprising administering an Mutant EGFR inhibitor compound that covalently modifies Cysteine 797 in EGFR, wherein said compound exhibits at least 2-fold greater inhibition of a drug resistant Mutant EGFR relative to wild type EGFR, and an additional therapy, particularly radiotherapy.
- Radiotherapy treatment using high-energy radiation to kill cancer cells such as x- rays, gamma rays, and charged particles.
- Radiotherapy includes, but is not limited to, external-beam radiation therapy (IMRT, IGRT, Tomotherapy, stereotactic radiosurgery, stereotactic body radiation therapy, and proton therapy), internal radiation therapy (brachytherapy), and systemic radiation therapy such as radioactive iodine or radioactive substance bound to an antibody or protein.
- IMRT external-beam radiation therapy
- IGRT Tomotherapy
- stereotactic radiosurgery stereotactic body radiation therapy
- proton therapy proton therapy
- brachytherapy internal radiation therapy
- systemic radiation therapy such as radioactive iodine or radioactive substance bound to an antibody or protein.
- the present invention provides methods for treating cancer, particularly NSCLC, comprising irreversible mutant EGFR inhibitor compounds in combination with one or more other therapies, particularly radiotherapy, administered simultaneously, separately, or sequentially.
- the present invention provides pharmaceutical compositions of compounds or pharmaceutically acceptable salts of one or more compounds described herein and a pharmaceutically acceptable carrier or excipient.
- FIGURE 1 Impact of CO- 1686, afatinib, and RT as single agents and in combination with radiation on body weight in the NCI-H1975 xenograft model.
- Mice were implanted with NCI-H1975 (L858R/T790M EGFR) cells by subcutaneous injection, and then treated with afatinib (20 mg/kg daily), CO- 1686 (50 mg/kg twice daily), and radiation (2 Gy on a 5-days on, 2-day off cycle) as single agents or in combinations.
- irreversible mutant EGFR inhibitor or “covalent mutant EGFR inhibitor” refers to a third generation EGFR inhibitor that covalently binds to a mutant form of epidermal growth factor receptor (EGFR).
- an irreversible mutant EGFR inhibitor covalently binds to cysteine 797 of mutant EGFR and exhibits at least 2-fold greater inhibition of a drug-resistant mutant EGFR relative to wild type EGFR.
- Irreversible mutant EGFR inhibitors include, but are not limited to, CO- 1686, WZ4002, AZD9291, CNX2006, ASP8273, EGF816, HM61713, TAS-2913, AZ5104 and others. Structures of a few exemplary irreversible mutant EGFR inhibitors are shown in Table 1.
- Radiotherapy refers to any treatment using high-energy radiation to kill cancer cells such as x-rays, gamma rays, and charged particles.
- Radiotherapy includes, but is not limited to, external-beam radiation therapy (IMRT, IGRT, Tomotherapy, stereotactic radiosurgery, stereotactic body radiation therapy, and proton therapy), internal radiation therapy (brachytherapy), and systemic radiation therapy such as radioactive iodine or radioactive substance bound to an antibody or protein.
- Radiotherapy may be used to treat localized solid tumors cancers of the skin, tongue, larynx, brain, breast, lung or uterine cervix. It can also be used to treat leukemia and lymphoma, i.e., cancers of the blood-forming cells and lymphatic system, respectively.
- Whole brain radiation therapy is radiation given to the whole brain, usually over a period of weeks.
- non-small cell lung cancer or “NSCLC” refers to any type of epithelial lung cancer other than small cell lung cancer (SCLC).
- kinase inhibitor refers to any type of enzyme inhibitor that specifically blocks the action of one or more kinases responsible for cancer, particularly NSCLC.
- a kinase inhibitor of the present invention refers to a small molecule, a protein/peptide or an antibody.
- the quantity and/or magnitude of the symptoms in the treated subject is at least 10% lower than, at least 25% lower than, at least 50% lower than, at least 75% lower than, and/or at least 90% lower than the quantity and/or magnitude of the symptoms in the untreated subject.
- inhibitory compound refers to any compound capable of interacting with (i.e., for example, attaching, binding etc.) to a binding partner under conditions such that the binding partner becomes unresponsive to its natural ligands.
- Inhibitory compounds may include, but are not limited to, small organic molecules, antibodies, and proteins/peptides.
- inhibitor or "covalent inhibitor” as used herein, refers to an inhibitor that covalently modifies an enzyme, and inhibition therefore cannot be reversed.
- drug refers to any pharmacologically active substance capable of being administered which achieves a desired effect.
- Drugs or compounds can be synthetic or naturally occurring, non-peptide, proteins or peptides, oligonucleotides or nucleotides, polysaccharides or sugars.
- administered refers to any method of providing a composition to a patient such that the composition has its intended effect on the patient.
- An exemplary method of administering is by a direct mechanism such as, local tissue administration (i.e., for example, extravascular placement), oral ingestion, transdermal patch, topical, inhalation, suppository etc.
- a therapeutically effective amount refers to that amount of therapeutic agent sufficient to destroy, modify, control or remove cancer tissue.
- a therapeutically effective amount may refer to the amount of therapeutic agent sufficient to delay or minimize the spread of cancer.
- a therapeutically effective amount may also refer to the amount of therapeutic agent that provides a therapeutic benefit in the treatment or management of cancer.
- a therapeutically effective amount with respect to an irreversible mutant EGFR inhibitor of the combination therapies of the invention means that amount of an irreversible mutant EGFR inhibitor in combination with one or more other therapies, particularly an Radiotherapy that provides a therapeutic benefit in the treatment or management of cancer, particularly NSCLC, including amelioration of symptoms associate with cancer, such as NSCLC.
- the term can encompass an amount that improves overall therapy, reduces or avoids unwanted effects, or enhances the therapeutic efficacy of or synergizes with one or more other therapies, such as Radiotherapy, utilized in combination therapies of the invention.
- the "therapeutically effective amount” may vary depending, for example, on the kinase inhibitors selected, the stage of the cancer, the age, weight and/or health of the patient and the judgment of the prescribing physician. An appropriate amount in any given instance may be readily ascertained by those skilled in the art or capable of determination by routine experimentation .
- a combination therapy of the invention refers to the beneficial effects that a patient derives from a combination therapy of the invention, which does not result in a cure of cancer, such as NSCLC.
- a combination therapy of the invention "manages” cancer, particularly NSCLC, so as to prevent the progression or worsening of the cancer.
- the terms “treat”, “treating”, and “treatment” refer to the eradication, removal, modification or control of cancer, particularly NSCLC, that results from the combination therapy of the invention. In certain embodiments, such terms refer to minimizing or delaying of the spread of cancer, particularly NSCLC.
- combination therapy or “combination treatment” refers to methods of treating cancer, particularly NSCLC, in a subject comprising an irreversible mutant EGFR inhibitor compound with one or more other therapies, particularly
- Radiotherapy encompass administering an irreversible mutant EGFR inhibitor and one or more other therapies simultaneously, separately or sequentially.
- patient is a human or animal and need not be hospitalized.
- out-patients persons in nursing homes are "patients.”
- a patient may comprise any age of a human or non-human animal and therefore includes both adult and juveniles (i.e., children). It is not intended that the term "patient” connote a need for medical treatment, therefore, a patient may voluntarily or involuntarily be part of
- subject refers to a vertebrate, preferably a mammal, more preferably a primate, still more preferably a human. Mammals include, without limitation, humans, primates, wild animals, feral animals, farm animals, sports animals, and pets.
- pharmaceutically or “pharmacologically acceptable”, as used herein, refer to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human.
- pharmaceutically acceptable carrier includes any and all solvents, or a dispersion medium including, but not limited to, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils, coatings, isotonic and absorption delaying agents, liposome, commercially available cleansers, and the like. Supplementary bioactive ingredients also can be incorporated into such carriers.
- salts refers to any salt that complexes with identified compounds contained herein.
- examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as, but not limited to, acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic, acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and
- Salt compounds can also be administered as pharmaceutically acceptable quaternary salts known by a person skilled in the art, which specifically include the quaternary ammonium salts of the formula— NR,R',R"+Z -, wherein R, R', R" is independently hydrogen, alkyl, or benzyl, and Z is a counter ion, including, but not limited to, chloride, bromide, iodide, alkoxide, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate).
- quaternary salts known by a person skilled in the art, which specifically include the quaternary ammonium salts of the formula— NR,R',R"+Z -, where
- Salt compounds can also be administered as pharmaceutically acceptable pyridine cation salts having a substituted or unsubstituted partial formula: wherein Z is a counter ion, including, but not limited to, chloride, bromide, iodide, alkoxide, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate).
- Z is a counter ion, including, but not limited to, chloride, bromide, iodide, alkoxide, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fum
- prodrug refers to a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of the invention.
- Prodrugs may only become active upon some reaction under biological conditions, but they may have activity in their unreacted forms.
- Examples of prodrugs contemplated herein include, without limitation, analogs or derivatives of compounds of the invention, and/or their salts when salt formation is possible, but in particular, derivatives of zinc binding thiol moiety.
- prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties, (e.g., propionic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl- lower alkyl esters (e.g., benzyl ester), heteroaryl esters (nicotinate ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower- alkyl amides, di-lower alkyl esters
- Prodrugs and their uses are well known in the art (see, e.g., Berge et al. 1977). Prodrugs can typically be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (Manfred E. Wolff ed.1995) and (Rautio, 2008).
- the term "activity” refers to the activation, production, expression, synthesis, intercellular effect, and/or pathological or aberrant effect of the referenced molecule, either inside and/or outside of a cell.
- the terms “comprises,” “comprising,” “includes,” “including,” “contains,” “containing,” and any variations thereof, are intended to cover a non-exclusive inclusion, such that a process, method, product-by-process, or composition of matter that comprises, includes, or contains an element or list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, product-by-process, or composition of matter.
- cancer can be a metastatic cancer.
- additional cancers related to the methods described herein include, but are not limited to, breast, ovarian, pancreatic, sarcoma, prostate cancer, colon cancer (such as a colon carcinoma, including small intestine cancer), glioma, leukemia, liver cancer, melanoma (e.g., metastatic malignant melanoma), acute myeloid leukemia, kidney cancer, bladder cancer, renal cancer (e.g., renal cell carcinoma), glioblastoma, brain tumors, chronic or acute leukemias including acute lymphocytic leukemia (ALL), adult T-cell leukemia (T-ALL), chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphomas (e.g., Hodgkin's and non-Hodgkin's lymphoma, lymphomas (e.g., Hodgkin's and non-Hodgkin's lymphoma,
- methods described herein can be useful for treating a combination of two or more types of cancer. In some aspects the methods are useful to treat individual patients diagnosed with cancer.
- the present invention provides pharmaceutical compositions comprising at least one pharmaceutically-acceptable carrier, in addition to one or more compounds described herein.
- the composition can take any suitable form for the desired route of administration. Where the composition is to be administered orally, any suitable orally deliverable dosage form can be used, including without limitation tablets, capsules (solid or liquid filled), powders, granules, syrups and other liquids, elixirs, inhalants, troches, lozenges, and solutions. Injectable compositions or i.v. infusions are also provided in the form of solutions, suspensions, and emulsions.
- the administration of an irreversible mutant epidermal growth factor receptor (EGFR) inhibitor compound may be prior to, immediately prior to, during, immediately subsequent to or subsequent to the administration of radiotherapy.
- EGFR epidermal growth factor receptor
- Radiation may be selected from any type suitable for treating cancer. Radiation may come from a machine outside the body (external radiation), may be placed inside the body (internal radiation), or may use unsealed radioactive materials that go throughout the body (systemic radiation therapy). The type of radiation to be given depends on the type of cancer, its location, how far into the body the radiation will need to penetrate, the patient's general health and medical history, whether the patient will have other types of cancer treatment, and other factors. In certain embodiments, radiation is delivered in more than one manner, e. g., internal radiation and external radiation.
- Radiotherapy can be administered in any therapeutically effective dose.
- the cumulative dose is less than 90 Gy, such as less than 80 Gy, such as less than 70 Gy, such as less than 60 Gy, such as less than 50 Gy, such as less than 40 Gy, such as less than 30 Gy, such as less than 20 Gy.
- the cumulative dose is between about 10 to 100 Gy, such as about 20 to 80 Gy, such as about 30 to 70 Gy, such as about 40 to 60 Gy.
- the irradiation dose is selected from 5-25 Gy, such as from 10-20 Gy.
- the total dosage of radiotherapy may be fractionated into several smaller doses delivered over a period of time to allow normal cells time to recover, to allow tumor cells that were in a relatively radio-resistant phase of the cell cycle during one treatment to cycle into a sensitive phase of the cycle before the next fraction is given, or to allow hypoxic tumor cells to reoxygenate between fractions, improving the tumor cell kill.
- the summed value of individual fractionized dose should add up to about the total dose of radiation therapy prescribed.
- Fractionated doses of radiotherapy may be administered at intervals.
- the fractionized doses are administered over a period of minutes, hours, or weeks such as 1 to 26 weeks, such as from about 1 to 15 weeks, such as from 2 to 12 weeks.
- the fractionized doses are administered over a period less than about 15 weeks, such as less than about 14 weeks such as less than about 13 weeks, such as less than about 12 weeks, such as less than about 11 weeks, such as about less than about 10 weeks, such as less than about 9 weeks, such as less than about 8 weeks, such as less than about 7 weeks, such as less than about 6 weeks, such as less than about 5 weeks, such as less than about 4 weeks.
- the cumulative external irradiation is a therapeutically effective amount of radiation for killing cells.
- Example 1 Tolerability and efficacy of CO- 1686, afatinib, and RT in the NCI- HI 975 xenograft model
- NCI-H1975 human NSCLC adenocarcinoma cells were obtained from the American Type Culture Center (Manassas, VA), and were grown in RPMI 1640 (Life Technologies; Carlsbad, CA) supplemented with 10% FBS (HyClone; South Logan, UT), 2mM L-glutamine, and 1% Penicillin- Streptomycin (Mediatech; Corning, NY) at 37°C in a humidified 5% C0 2 incubator. Cells were harvested and resuspended in PBS at a
- External X-ray beam radiation therapy was performed using a Faxitron CP- 160 cabinet irradiator, and given daily for 5 days with 2 days off except for the treatment group afatinib plus radiation which received radiation for 5 days with 9 days off due to toxicity.
- Afatinib was administered intraperitoneally daily for twenty-one days at a dosage of 20 mg/kg.
- CO-1686 was administered orally twice daily for twenty-one days at a dosage of 50 mg/kg.
- Animals treated with localized radiation received a 2 gray (Gy) dose for five consecutive days followed by a two day dosing holiday. This schedule was repeated for three cycles.
- the radiation regimen was also combined with the afatinib and CO- 1686 regimens described previously.
- a vehicle treated group served as the control group for efficacy analysis.
- Tumors were measured twice per week until the study was ended on Day 60. Each mouse was euthanized when its tumor reached the endpoint volume of 1500 mm 3 or on the final day, whichever came first. The time-to-endpoint (TTE) was calculated for each mouse. The primary treatment outcome was determined from an analysis of percent tumor growth delay (%TGD), defined as the percent increase in median TTE of treated versus control mice, with differences between two groups deemed significant at P ⁇ 0.05 using logrank survival analysis. Short-term efficacy was determined from an analysis of tumor growth inhibition (TGI) on Days 12 and 22.
- TGI tumor growth inhibition
- TGI was defined as the percent difference between the median tumor volumes (MTVs) of treated and control mice, with results analyzed for statistical significance at P ⁇ 0.05 using the Mann-Whitney U-test. A treatment that produced at least 60% TGI was considered potentially therapeutically active. Animals were also monitored for partial regression (PR) and complete regression (CR) responses. Treatment tolerability was assessed by frequent observation for clinical signs of treatment-related (TR) side effects and by body weight (BW) measurements.
- MTVs median tumor volumes
- the median TTE for vehicle-treated controls was 13.8 days, establishing a maximum possible TGD of 46.2 days (335%) for the 60-day study.
- the MTV for all animals in the vehicle group was 1183 mm 3 , with a range of 446 to 1800 mm 3 .
- the Day 22 MTV of three remaining animals was 1352 mm 3 , with a range of 221 to 1800 mm 3 .
- the CO- 1686 monotherapy produced a significant survival difference versus controls (P ⁇ 0.01, logrank) with seven PRs. Additionally, an analysis of TGI at Day 12 and at Day 22 found a significant effect on tumor growth versus controls (P ⁇ 0.01, Mann- Whitney test). [0074] The afatinib monotherapy regimen produced a significant survival difference versus controls (P ⁇ 0.001, logrank) with four PRs. An analysis of TGI at Day 12 found a significant effect on tumor growth versus controls (P ⁇ 0.001, Mann- Whitney test).
- the CO- 1686 / radiation combination therapy produced a significant survival difference versus controls (P ⁇ 0.001, logrank) with all ten animals being classified as PRs.
- the combination therapy also produced a significant survival difference to both
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Abstract
The present invention relates to combination treatment methods for treating cancer, particularly non-small cell lung cancer (NSCLC). More specifically, the invention relates to methods of treating or managing cancer, particularly NSCLC, in a subject, comprising administering an irreversible mutant EGFR inhibitor compound in combination with one or more other therapies, particularly radiotherapy.
Description
THERAPEUTIC COMBINATIONS FOR TREATING CANCER
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Application Serial No. 62/145,055 filed April 9, 2015, entitled "Therapeutic Combinations for Treating Cancer", the contents of which are herein incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to combination treatment methods for treating cancer, particularly non-small cell lung cancer (NSCLC). More specifically, the invention relates to methods of treating or managing cancer, particularly NSCLC, in a subject, comprising administering an irreversible mutant epidermal growth factor receptor (EGFR) inhibitor compound in combination with one or more other therapies, particularly
Radiotherapy.
[0003] The present invention relates to pharmaceutical compositions and methods comprising said irreversible mutant EGFR inhibitor compounds for treating cancer in combination with one or more other therapies, such as Radiotherapy, administered simultaneously, separately, or sequentially.
BACKGROUND
[0004] Despite years of research and prevention strategies, lung cancer remains the most common cancer worldwide with approximately 1.35 million new cases annually and non- small cell lung cancer (NSCLC) accounting for almost 85% of all lung cancers (Herbst RS et al., N Engl J Med. 2008; 359: 1367-80). Additionally, lung cancer continues to be the most common cause of cancer-related deaths worldwide with a 5-year survival rate of less than 10% in patients with advanced disease.
[0005] Activating mutations in the epidermal growth factor receptor (EGFR) are key drivers of NSCLC malignancy in 10-15% of patients of European descent and approximately 30% of patients of East Asian descent (Rosell et al., N Engl J Med. 2009; 361:958-67). Patients with the most common EGFR mutations (exon 21 L858R and deletions in exon 19) typically have good responses to therapy with first-generation reversible EGFR tyrosine
kinase inhibitors (TKIs), such as erlotinib or gefitinib (Mok et al, N Engl J Med. 2009;
361:947-57; Fukuoka et al, J Clin Oncol. 2011; 29:2866-74). Toxicity associated with both erlotinib and gefitinib includes skin rash and diarrhea related to inhibition of wild-type EGFR (WT EGFR) in skin and intestine, respectively (Herbst et al, Clin Lung Cancer. 2003; 4:366- 9).
[0006] Despite the impressive initial response to treatment, disease progression generally occurs after 9 to 14 months of erlotinib or gefitinib therapy, driven in approximately 60% of cases by a second site EGFR point mutation that results in the substitution of threonine with methionine at amino acid position 790 (T790M; Sequist et al., Sci Transl Med.
201 l;3:75ra26; Pao et al, PLoS Med. 2005; 2:e73; Sharma et al, Nat Rev Cancer.
2007;7: 169-81; Yu HA et al, Clin Cancer Res. 2013; 19:2240-7). Research suggests that T790M mediates resistance to first-generation EGFR inhibitors by acting as a "gatekeeper" mutation, inducing steric hindrance in the ATP binding pocket and preventing inhibitor binding (Pao et al, PLoS Med. 2005;2:e73; Kwak et al, Proc Natl Acad Sci U S A.
2005;102:7665-70; Kobayashi et al, N Engl J Med. 2005;352:786-92). Additional work has indicated that T790M increases the affinity of EGFR for ATP, therefore out-competing ATP- competitive TKIs and restoring enzymatic activity in their presence (Yun et al, Proc Natl Acad Sci U S A. 2008;105:2070-5).
[0007] Patients with mutant EGFR NSCLC who have failed treatment with first generation EGFR inhibitors and have acquired resistance through the T790M mutation have few treatment options. Currently, there are no targeted therapies for these patients, who are usually treated with cytotoxic chemotherapy that has limited efficacy, but significant toxicity, in the second- or third-line setting. Although second generation irreversible HER-family TKIs, including dacomitinib (PF299804) and afatinib (BIBW2992), are able to inhibit T790M-mutant EGFR in vitro in biochemical and cell-based assays, in clinical trials these agents have not been shown to induce compelling responses in patients that have failed first- generation TKIs (Miller et al, Lancet Oncol. 2012; 13:528-38). Due to the potent inhibition of WT EGFR and its associated toxicities, these agents cannot reach exposures in the clinic required to inhibit T790M in tumor tissue.
[0008] To circumvent this problem, third generation irreversible mutant EGFR inhibitors were developed. A covalent inhibitor that inhibits mutant EGFR, including T790M, more potently than the WT receptor, termed WZ4002, was described (Zhou et al, Nature.
2009;462: 1070-4), but did not progress into human trials. CO- 1686 is a potent, small- molecule, irreversible tyrosine kinase inhibitor (TKI) that selectively targets the common
EGFR mutations (L858R, dell9, T790M) and has minimal inhibitory activity towards WT EGFR (Walter, A. et al., Cancer Discovery. 2013;3: 1404-15). Oral administration of CO- 1686 leads to tumor regressions in cell-based and patient- derived xenograft models as well as a transgenic mouse model expressing mutant forms of EGFR.
[0009] CO-1686 is currently being evaluated in several ongoing clinical studies, including: 1) Study to Evaluate Safety, Pharmacokinetics, and Efficacy of Rociletinib (CO- 1686) in Previously Treated Mutant EGFR in NSCLC Patients (NCT01526928), 2) TIGER- 1: Safety and Efficacy Study of Rociletinib (CO-1686) or Erlotinib in Patients With Mutant EGFR NSCLC Who Have Not Had Any Previous EGFR Directed Therapy (NCT02186301), 3) TIGER-2: A Phase 2, Open-label, Multicenter, Safety and Efficacy Study of Oral CO-1686 as 2nd Line EGFR-directed TKI in Patients With Mutant EGFR NSCLC (NCT02147990), and 4) TIGER- 3: Open Label, Multicenter Study of Rociletinib (CO-1686) Mono Therapy Versus Single-agent Cytotoxic Chemotherapy in Patients With Mutant EGFR NSCLC Who Have Failed at Least One Previous EGFR-Directed TKI and Platinum-doublet Chemotherapy (NCT02322281).
[0010] The initial area of clinical study for CO-1686 is the treatment of patients with mutant EGFR NSCLC who have received prior EGFR-directed therapy. Expansion of CO- 1686 into the front-line setting of mutant EGFR NSCLC patients is currently ongoing considering the equivalent potency observed between erlotinib and CO-1686 in biochemical, cellular, and in vivo xenograft studies using NSCLC cell lines and models with an EGFR activating mutation. Interim data from a Phase 1/2 Study demonstrated that heavily-pretreated patients with T790M+ NSCLC receiving rociletinib (500 or 625 mg BID) had a 67% objective response rate (Soria et al., Interim phase 2 results with the irreversible, mutant selective, EGFR inhibitor rociletinib (CO-1686); presented at EORTC-NCI-AACR,
November 18-21, 2014, Barcelona, Spain).
[0011] Toxicity associated with erlotinib and gefitinib includes skin rash and diarrhea related to inhibition of WT EGFR in skin and intestine, respectively (Herbst RS et al., N Engl J Med. 2008;359: 1367-80). Use of a WT EGFR sparing, mutant selective inhibitor such as CO-1686 has the potential for preventing some of these side-effects observed with first- generation EGFR inhibitors and therefore improving patient quality-of-life. To date, CO- 1686 has shown a manageable safety profile and it is notable that adverse events (AEs) typical of WT EGFR inhibition (rash and chronic diarrhea) have typically not been observed at doses up to 2000 mg daily (Soria et al., presented at EORTC-NCI-AACR, November 18- 21, 2014, Barcelona, Spain).
[0012] Approximately 30 - 50% of patients with NSCLC will develop brain metastases (BM) during the course of the disease (Yamanaka. Medical management of brain metastases from lung cancer (Review) Oncol Rep. 2009; 22: 1269-1276.), and similar rates of BM have been reported for patients with advanced mutant EGFR NSCLC (Rangachari Lung Cancer 2015). Whole brain radiotherapy (WBRT) is commonly used to treat BM, and associated with a poor prognosis and median survival of 4 - 6 months (Gaspar et al. The role of whole brain radiation therapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol. 2010; 96: 17-32).
[0013] The role of EGFR inhibitors in treating BM in patients has not been conclusively established. Drug transporters such as P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) often limit TKIs from entering the brain, thus one of the main challenges in effectively treating BM with these therapeutics is to achieve drug concentrations in the brain sufficient for clinical activity. Administration of erlotinib at the approved daily dose of 150 mg results in cerebrospinal fluid levels approximately 5% of the steady-state level achieved in plasma (Togashi et al. J Thorac Oncol. 2010; 5: 950-955; Deng et al. Mol Clin Oncol. 2014 Jan; 2(1): 116-120). There is evidence from several clinical trials to suggest that EGFR inhibitors are active in BM in patients with mutant EGFR NSCLC (Porta et al. Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation. Eur Respir J 2011; 37:624-31; Park et al. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation, Lung Cancer. 2012; 77(3):556-60).
[0014] Preclinical data suggests that EGFR inhibitors can enhance the anti-tumor activity of radiotherapy (RT) through multiple mechanisms (Chinnaiyan et al. Cancer Res. 2005; 65(8):3328-35; Mehta, Front Oncol. 2012 Apr 10;2:31; Sato et al. Anticancer Res. 2012; 32(11):4877-81). For example, the combination of erlotinib and RT in vitro reduced the number of cells in S-phase and enhanced the induction of apoptosis in NSCLC and SCC (squamous cell carcinoma) cell lines. In vivo, the combination of erlotinib and RT increased tumor growth inhibition as compared to either monotherapy in NSCLC and SCC xenograft models. In addition, WBRT may disrupt the blood brain barrier (BBB), allowing for greater penetration of erlotinib into the brain (Rubin et al. Disruption of the blood-brain barrier as the primary effect of CNS irradiation. Radiother Oncol 1994; 31(1): 51-60).
[0015] Erlotinib and concurrent WBRT have been evaluated in several clinical trials. In a randomized Phase 2 clinical trial comparing placebo (n = 40) or erlotinib (100 mg daily, n = 40) given concurrently with WBRT followed by placebo or erlotinib (150 mg daily)
maintenance, respectively, the combination of erlotinib and WBRT failed to show a benefit in neurological progression free survival and overall survival (Lee et al. J Natl Cancer Inst. 2014 Jul 16; 106(7)). Notably, only 1/35 patients in the erlotinib and WBRT cohort had an activating mutation in EGFR. As expected, the rate of rash was higher in the WBRT and erlotinib combination group as compared to the WBRT and placebo combination group. In a single arm Phase 2 trial, 40 unselected NSCLC patients were treated with erlotinib monotherapy (150 mg daily) for one week, then concurrently with WBRT, followed by erlotinib maintenance (Welsh et al. J Clin Oncol. 2013; 31(7):895-902). The most common toxicity (n = 27, 67.5%) was acneiform rash associated with WT EGFR inhibition. The overall response rate was 86% with a median survival time of 11.8 months. Surprisingly, 50% of the patients had activating mutations in EGFR, a much higher percentage than what would be expected in this patient population. The median survival was 9.3 months for those with WT EGFR and 19.1 months for those with EGFR mutations. These results should be interpreted cautiously given the small sample size, lack of randomization, and potential bias in the population. Larger prospective randomized clinical trials are required to establish the role of EGFR TKIs, alone or in combination with WBRT, to prevent or treat BMs.
[0016] Targeted genetic ablation of EGFR in the epidermis resulted in skin lesions similar to those observed in humans from WT EGFR inhibition by EGFR inhibitors
(Lichtenberger et al. Sci Transl Med. 2013 Aug 21;5(199): 199ral l l; Mascia et al. Sci Transl Med. 2013 Aug 21;5(199): 199ral l0). These lesions were accompanied with chemokine driven skin inflammation and the early infiltration of macrophages, and mast cells, and later infiltration of eosinophils, T cells, and neutrophils. These data highlight the importance of WT EGFR in maintaining skin immune homeostasis.
[0017] Ionizing radiation results in skin injury (radiation dermatitis) in 95% of patients receiving radiation therapy for cancer, resulting from the activation of numerous cytokines and chemokines produced from immune cells in the dermis and epidermis (Ryan et al. J Invest Dermatol. 2012; 132(3 Pt 2):985-93).
SUMMARY
[0018] The present invention is directed to the combination of WT sparing EGFR inhibitors and RT that provide better therapeutic profiles than current single agent therapies or other combination therapies utilizing EGFR inhibitors. Encompassed by the invention are combination therapies, of an irreversible mutant EGFR inhibitor compound with one or more
other therapies, particularly radiotherapy, that have at least an additive potency or at least an additive therapeutic effect. Preferably, the invention is directed to combination therapies where the therapeutic efficacy is greater than additive, e.g., a synergistic efficacy exists between an irreversible mutant EGFR inhibitor compound and one or more other therapies, particularly radiotherapy. Preferably, such combination therapies also reduce or avoid unwanted or adverse effects.
[0019] In certain embodiments, the combination therapies of the invention provide an improved overall therapy relative to the administration of the therapeutic agents by themselves. In certain embodiments, doses of existing therapeutic agents can be reduced or administered less frequently in using the combination therapies of the invention, thereby increasing patient compliance, improving therapy and reducing unwanted or adverse effects.
[0020] Accordingly, this invention is directed to combination therapies designed to treat or manage cancer, particularly NSCLC, in a subject, wherein the combination therapies comprise administering an irreversible mutant EGFR inhibitor to the subject in need thereof in combination with one or more other therapies, particularly radiotherapy. In particular, this invention is directed to methods of treating or managing cancer, particularly NSCLC, in a subject, comprising administering a therapeutically effective amount of an irreversible mutant EGFR inhibitor in combination with the administration of therapeutically effective amount of one or more other therapies, particularly radiotherapy.
[0021] In one embodiment, the present invention provides methods for treating cancer, particularly NSCLC, in a subject comprising administering an Mutant EGFR inhibitor compound that covalently modifies Cysteine 797 in EGFR, wherein said compound exhibits at least 2-fold greater inhibition of a drug resistant Mutant EGFR relative to wild type EGFR, and an additional therapy, particularly radiotherapy.
[0022] In one embodiment, the present invention provides methods for treating drug resistant cancer, particularly NSCLC, in a subject comprising administering an Mutant EGFR inhibitor compound that covalently modifies Cysteine 797 in EGFR, wherein said compound exhibits at least 2-fold greater inhibition of a drug resistant Mutant EGFR relative to wild type EGFR, and an additional therapy, particularly radiotherapy.
[0023] Radiotherapy treatment using high-energy radiation to kill cancer cells such as x- rays, gamma rays, and charged particles. Radiotherapy includes, but is not limited to, external-beam radiation therapy (IMRT, IGRT, Tomotherapy, stereotactic radiosurgery, stereotactic body radiation therapy, and proton therapy), internal radiation therapy
(brachytherapy), and systemic radiation therapy such as radioactive iodine or radioactive substance bound to an antibody or protein.
[0024] In one embodiment, the present invention provides methods for treating cancer, particularly NSCLC, comprising irreversible mutant EGFR inhibitor compounds in combination with one or more other therapies, particularly radiotherapy, administered simultaneously, separately, or sequentially.
[0025] In one embodiment, the present invention provides pharmaceutical compositions of compounds or pharmaceutically acceptable salts of one or more compounds described herein and a pharmaceutically acceptable carrier or excipient.
BRIEF DESCRIPTION OF THE FIGURES
[0026] FIGURE 1: Impact of CO- 1686, afatinib, and RT as single agents and in combination with radiation on body weight in the NCI-H1975 xenograft model. Mice were implanted with NCI-H1975 (L858R/T790M EGFR) cells by subcutaneous injection, and then treated with afatinib (20 mg/kg daily), CO- 1686 (50 mg/kg twice daily), and radiation (2 Gy on a 5-days on, 2-day off cycle) as single agents or in combinations. Values represent percentage body weight change from baseline (n = 9 - 10 per group).
[0027] FIGURE 2: Antitumor activity of CO- 1686 and afatinib and RT as single agents and in combination with radiation on tumor growth in the NCI-H1975 xenograft model. Mice were implanted with NCI-H1975 cells by subcutaneous injection, and then treated afatinib (20 mg/kg daily), CO-1686 (50 mg/kg twice daily), and radiation (2 Gy on a 5-days on, 2-day off cycle) as single agents or in combinations. Values represent mean tumor volume in mm3 (n = 9 - 10 per group).
DETAILED DESCRIPTION
[0028] The following description is merely exemplary in nature and is not intended to limit the present disclosure, application, or uses.
[0029] Various embodiments of the disclosure could also include permutations of the various elements recited in the claims as if each dependent claim was a multiple dependent claim incorporating the limitations of each of the preceding dependent claims as well as the independent claims. Such permutations are expressly within the scope of this disclosure.
[0030] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art(s) to which this
invention belongs. Although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods, devices and materials are now described.
[0031] As used herein, "irreversible mutant EGFR inhibitor" or "covalent mutant EGFR inhibitor" refers to a third generation EGFR inhibitor that covalently binds to a mutant form of epidermal growth factor receptor (EGFR). In some embodiments, an irreversible mutant EGFR inhibitor covalently binds to cysteine 797 of mutant EGFR and exhibits at least 2-fold greater inhibition of a drug-resistant mutant EGFR relative to wild type EGFR. Irreversible mutant EGFR inhibitors include, but are not limited to, CO- 1686, WZ4002, AZD9291, CNX2006, ASP8273, EGF816, HM61713, TAS-2913, AZ5104 and others. Structures of a few exemplary irreversible mutant EGFR inhibitors are shown in Table 1.
[0032] As used herein, "radiotherapy" refers to any treatment using high-energy radiation to kill cancer cells such as x-rays, gamma rays, and charged particles. Radiotherapy includes, but is not limited to, external-beam radiation therapy (IMRT, IGRT, Tomotherapy, stereotactic radiosurgery, stereotactic body radiation therapy, and proton therapy), internal radiation therapy (brachytherapy), and systemic radiation therapy such as radioactive iodine or radioactive substance bound to an antibody or protein. Radiotherapy may be used to treat localized solid tumors cancers of the skin, tongue, larynx, brain, breast, lung or uterine cervix. It can also be used to treat leukemia and lymphoma, i.e., cancers of the blood-forming cells and lymphatic system, respectively. Whole brain radiation therapy (WBRT) is radiation given to the whole brain, usually over a period of weeks.
[0033] As used herein, the term "non-small cell lung cancer" or "NSCLC" refers to any type of epithelial lung cancer other than small cell lung cancer (SCLC).
[0034] As used herein, the term "kinase inhibitor" refers to any type of enzyme inhibitor that specifically blocks the action of one or more kinases responsible for cancer, particularly NSCLC. In certain embodiments, a kinase inhibitor of the present invention refers to a small molecule, a protein/peptide or an antibody.
[0035] The terms "reduce," "inhibit," "diminish," "suppress," "decrease," "prevent" and grammatical equivalents (including "lower," "smaller," etc.) when in reference to the expression of any symptom in an untreated subject relative to a treated subject, mean that the quantity and/or magnitude of the symptoms in the treated subject is lower than in the untreated subject by any amount that is recognized as clinically relevant by any medically trained personnel. In one embodiment, the quantity and/or magnitude of the symptoms in the treated subject is at least 10% lower than, at least 25% lower than, at least 50% lower than, at
least 75% lower than, and/or at least 90% lower than the quantity and/or magnitude of the symptoms in the untreated subject.
[0036] The term "inhibitory compound" as used herein, refers to any compound capable of interacting with (i.e., for example, attaching, binding etc.) to a binding partner under conditions such that the binding partner becomes unresponsive to its natural ligands.
Inhibitory compounds may include, but are not limited to, small organic molecules, antibodies, and proteins/peptides.
[0037] The term "irreversible inhibitor" or "covalent inhibitor" as used herein, refers to an inhibitor that covalently modifies an enzyme, and inhibition therefore cannot be reversed.
[0038] The term "drug" or "compound" as used herein, refers to any pharmacologically active substance capable of being administered which achieves a desired effect. Drugs or compounds can be synthetic or naturally occurring, non-peptide, proteins or peptides, oligonucleotides or nucleotides, polysaccharides or sugars.
[0039] The term "administered" or "administering", as used herein, refers to any method of providing a composition to a patient such that the composition has its intended effect on the patient. An exemplary method of administering is by a direct mechanism such as, local tissue administration (i.e., for example, extravascular placement), oral ingestion, transdermal patch, topical, inhalation, suppository etc.
[0040] The term "therapeutically effective amount" refers to that amount of therapeutic agent sufficient to destroy, modify, control or remove cancer tissue. A therapeutically effective amount may refer to the amount of therapeutic agent sufficient to delay or minimize the spread of cancer. A therapeutically effective amount may also refer to the amount of therapeutic agent that provides a therapeutic benefit in the treatment or management of cancer. Further, a therapeutically effective amount with respect to an irreversible mutant EGFR inhibitor of the combination therapies of the invention means that amount of an irreversible mutant EGFR inhibitor in combination with one or more other therapies, particularly an Radiotherapy that provides a therapeutic benefit in the treatment or management of cancer, particularly NSCLC, including amelioration of symptoms associate with cancer, such as NSCLC. Used in connection with an amount of irreversible mutant EGFR inhibitor, the term can encompass an amount that improves overall therapy, reduces or avoids unwanted effects, or enhances the therapeutic efficacy of or synergizes with one or more other therapies, such as Radiotherapy, utilized in combination therapies of the invention. The "therapeutically effective amount" may vary depending, for example, on the kinase inhibitors selected, the stage of the cancer, the age, weight and/or health of the patient
and the judgment of the prescribing physician. An appropriate amount in any given instance may be readily ascertained by those skilled in the art or capable of determination by routine experimentation .
[0041] As used herein, the terms "manage", "managing", and "management" refer to the beneficial effects that a patient derives from a combination therapy of the invention, which does not result in a cure of cancer, such as NSCLC. In certain embodiments, a combination therapy of the invention "manages" cancer, particularly NSCLC, so as to prevent the progression or worsening of the cancer.
[0042] As used herein, the terms "treat", "treating", and "treatment refer to the eradication, removal, modification or control of cancer, particularly NSCLC, that results from the combination therapy of the invention. In certain embodiments, such terms refer to minimizing or delaying of the spread of cancer, particularly NSCLC.
[0043] As used herein, the term "combination therapy" or "combination treatment" refers to methods of treating cancer, particularly NSCLC, in a subject comprising an irreversible mutant EGFR inhibitor compound with one or more other therapies, particularly
Radiotherapy. As used herein, these terms encompass administering an irreversible mutant EGFR inhibitor and one or more other therapies simultaneously, separately or sequentially.
[0044] The term "patient", as used herein, is a human or animal and need not be hospitalized. For example, out-patients, persons in nursing homes are "patients." A patient may comprise any age of a human or non-human animal and therefore includes both adult and juveniles (i.e., children). It is not intended that the term "patient" connote a need for medical treatment, therefore, a patient may voluntarily or involuntarily be part of
experimentation whether clinical or in support of basic science studies.
[0045] The term "subject" as used herein refers to a vertebrate, preferably a mammal, more preferably a primate, still more preferably a human. Mammals include, without limitation, humans, primates, wild animals, feral animals, farm animals, sports animals, and pets.
[0046] The term "pharmaceutically" or "pharmacologically acceptable", as used herein, refer to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human.
[0047] The term, "pharmaceutically acceptable carrier", as used herein, includes any and all solvents, or a dispersion medium including, but not limited to, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils, coatings, isotonic and absorption delaying agents,
liposome, commercially available cleansers, and the like. Supplementary bioactive ingredients also can be incorporated into such carriers.
[0048] The term "salts", as used herein, refers to any salt that complexes with identified compounds contained herein. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as, but not limited to, acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic, acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and
polygalacturonic acid. Salt compounds can also be administered as pharmaceutically acceptable quaternary salts known by a person skilled in the art, which specifically include the quaternary ammonium salts of the formula— NR,R',R"+Z -, wherein R, R', R" is independently hydrogen, alkyl, or benzyl, and Z is a counter ion, including, but not limited to, chloride, bromide, iodide, alkoxide, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate). Salt compounds can also be administered as pharmaceutically acceptable pyridine cation salts having a substituted or unsubstituted partial formula: wherein Z is a counter ion, including, but not limited to, chloride, bromide, iodide, alkoxide, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate).
[0049] The term "prodrug" refers to a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of the invention. Prodrugs may only become active upon some reaction under biological conditions, but they may have activity in their unreacted forms. Examples of prodrugs contemplated herein include, without limitation, analogs or derivatives of compounds of the invention, and/or their salts when salt formation is possible, but in particular, derivatives of zinc binding thiol moiety. Examples of prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties, (e.g., propionic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl- lower alkyl esters (e.g., benzyl ester), heteroaryl esters (nicotinate ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower-
alkyl amides, di-lower alkyl amides, and hydroxy amides. Naturally occurring amino acid esters or their enantiomers, dipeptide esters, phosphate esters, methoxyphosphate esters, disulfides and disulfide dimers. Prodrugs and their uses are well known in the art (see, e.g., Berge et al. 1977). Prodrugs can typically be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (Manfred E. Wolff ed.1995) and (Rautio, 2008).
[0050] As used in this disclosure, including the appended claims, the singular forms "a," "an," and "the" include plural references, unless the content clearly dictates otherwise, and are used interchangeably with "at least one" and "one or more."
[0051] Unless otherwise indicated, all numbers expressing quantities of ingredients, dimensions reaction conditions and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about".
[0052] As used herein, the term "activity" refers to the activation, production, expression, synthesis, intercellular effect, and/or pathological or aberrant effect of the referenced molecule, either inside and/or outside of a cell.
[0053] As used herein, the terms "comprises," "comprising," "includes," "including," "contains," "containing," and any variations thereof, are intended to cover a non-exclusive inclusion, such that a process, method, product-by-process, or composition of matter that comprises, includes, or contains an element or list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, product-by-process, or composition of matter.
[0054] In this application and the claims, the use of the singular includes the plural unless specifically stated otherwise. In addition, use of "or" means "and/or" unless stated otherwise. Moreover, the use of the term "including", as well as other forms, such as "includes" and "included", is not limiting. Also, terms such as "element" or "component" encompass both elements and components comprising one unit and elements and components that comprise more than one unit unless specifically stated otherwise.
[0055] Methods described herein can be extended to a variety of cancers, particularly NSCLC. In some instances, cancer can be a metastatic cancer. Examples of additional cancers related to the methods described herein include, but are not limited to, breast, ovarian, pancreatic, sarcoma, prostate cancer, colon cancer (such as a colon carcinoma, including small intestine cancer), glioma, leukemia, liver cancer, melanoma (e.g., metastatic malignant melanoma), acute myeloid leukemia, kidney cancer, bladder cancer, renal cancer (e.g., renal cell carcinoma), glioblastoma, brain tumors, chronic or acute leukemias including
acute lymphocytic leukemia (ALL), adult T-cell leukemia (T-ALL), chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphomas (e.g., Hodgkin's and non-Hodgkin's lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma, Burkitt's lymphoma, anaplastic large-cell lymphomas (ALCL), cutaneous T-cell lymphomas, nodular small cleaved-cell lymphomas, peripheral T-cell lymphomas, Lennert's lymphomas, immunoblastic lymphomas, T-cell leukemia/lymphomas (ATLL), entroblastic/centrocytic (cb/cc) follicular lymphomas cancers, diffuse large cell lymphomas of B lineage, angioimmunoblastic lymphadenopathy (AILD)-like T cell lymphoma and HIV associated body cavity based lymphomas), embryonal carcinomas, undifferentiated carcinomas of the rhino-pharynx (e.g., Schmincke's tumor), Castleman's disease, Kaposi's Sarcoma, multiple myeloma, Waldenstrom's macroglobulinemia and other B-cell
lymphomas, nasopharangeal carcinomas, bone cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, solid tumors of childhood, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, epidermoid cancer, squamous cell cancer, or
environmentally induced cancers including those induced by asbestos, e.g., mesothelioma. In another embodiment, methods described herein can be useful for treating a combination of two or more types of cancer. In some aspects the methods are useful to treat individual patients diagnosed with cancer.
[0056] The present invention provides pharmaceutical compositions comprising at least one pharmaceutically-acceptable carrier, in addition to one or more compounds described herein. The composition can take any suitable form for the desired route of administration. Where the composition is to be administered orally, any suitable orally deliverable dosage form can be used, including without limitation tablets, capsules (solid or liquid filled), powders, granules, syrups and other liquids, elixirs, inhalants, troches, lozenges, and solutions. Injectable compositions or i.v. infusions are also provided in the form of solutions, suspensions, and emulsions.
[0057] The administration of an irreversible mutant epidermal growth factor receptor (EGFR) inhibitor compound may be prior to, immediately prior to, during, immediately subsequent to or subsequent to the administration of radiotherapy.
[0058] Radiation may be selected from any type suitable for treating cancer. Radiation may come from a machine outside the body (external radiation), may be placed inside the body (internal radiation), or may use unsealed radioactive materials that go throughout the body (systemic radiation therapy). The type of radiation to be given depends on the type of cancer, its location, how far into the body the radiation will need to penetrate, the patient's general health and medical history, whether the patient will have other types of cancer treatment, and other factors. In certain embodiments, radiation is delivered in more than one manner, e. g., internal radiation and external radiation.
[0059] Radiotherapy can be administered in any therapeutically effective dose. In some embodiments, the cumulative dose is less than 90 Gy, such as less than 80 Gy, such as less than 70 Gy, such as less than 60 Gy, such as less than 50 Gy, such as less than 40 Gy, such as less than 30 Gy, such as less than 20 Gy. In some embodiments, the cumulative dose is between about 10 to 100 Gy, such as about 20 to 80 Gy, such as about 30 to 70 Gy, such as about 40 to 60 Gy. In certain embodiments, the irradiation dose is selected from 5-25 Gy, such as from 10-20 Gy.
[0060] The total dosage of radiotherapy may be fractionated into several smaller doses delivered over a period of time to allow normal cells time to recover, to allow tumor cells that were in a relatively radio-resistant phase of the cell cycle during one treatment to cycle into a sensitive phase of the cycle before the next fraction is given, or to allow hypoxic tumor cells to reoxygenate between fractions, improving the tumor cell kill. The summed value of individual fractionized dose should add up to about the total dose of radiation therapy prescribed.
[0061] Fractionated doses of radiotherapy may be administered at intervals. In certain embodiments, the fractionized doses are administered over a period of minutes, hours, or weeks such as 1 to 26 weeks, such as from about 1 to 15 weeks, such as from 2 to 12 weeks. In certain embodiments, the fractionized doses are administered over a period less than about 15 weeks, such as less than about 14 weeks such as less than about 13 weeks, such as less than about 12 weeks, such as less than about 11 weeks, such as about less than about 10 weeks, such as less than about 9 weeks, such as less than about 8 weeks, such as less than about 7 weeks, such as less than about 6 weeks, such as less than about 5 weeks, such as less
than about 4 weeks. In certain embodiments, the cumulative external irradiation is a therapeutically effective amount of radiation for killing cells.
EMBODIMENTS OF THE INVENTION
[0062] Specific embodiments of the invention are described in the following sections. EXAMPLES
[0063] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention.
[0064] Example 1 Tolerability and efficacy of CO- 1686, afatinib, and RT in the NCI- HI 975 xenograft model
[0065] NCI-H1975 human NSCLC adenocarcinoma cells were obtained from the American Type Culture Center (Manassas, VA), and were grown in RPMI 1640 (Life Technologies; Carlsbad, CA) supplemented with 10% FBS (HyClone; South Logan, UT), 2mM L-glutamine, and 1% Penicillin- Streptomycin (Mediatech; Corning, NY) at 37°C in a humidified 5% C02 incubator. Cells were harvested and resuspended in PBS at a
concentration of 5 x 107 cells/mL. Xenografts were initiated by subcutaneously implanting 1 x 107 cells in 50% Matrigel (0.2 mL suspension) into the right flank of each test animal. Eleven days later mice bearing established xenograft tumors were sorted into six groups (n = 10/group) and dosing was initiated.
[0066] External X-ray beam radiation therapy was performed using a Faxitron CP- 160 cabinet irradiator, and given daily for 5 days with 2 days off except for the treatment group afatinib plus radiation which received radiation for 5 days with 9 days off due to toxicity.
[0067] Tumors were measured using calipers twice per week, while body weights were observed daily for the first 5 days and then twice per week. Limited body weight loss was observed with CO- 1686 and radiotherapy combination therapy (Fig. 1). The combination of CO- 1686 and radiotherapy is more potent on tumor growth inhibition than afatinib or radiotherapy alone, or the combination thereof (Fig. 2).
[0068] Treatment began on Day 1 in six groups of mice (n = 10) with established subcutaneous H1975 tumors (196 - 256 mm3). Afatinib was administered intraperitoneally daily for twenty-one days at a dosage of 20 mg/kg. CO-1686 was administered orally twice daily for twenty-one days at a dosage of 50 mg/kg. Animals treated with localized radiation received a 2 gray (Gy) dose for five consecutive days followed by a two day dosing holiday. This schedule was repeated for three cycles. The radiation regimen was also combined with
the afatinib and CO- 1686 regimens described previously. A vehicle treated group served as the control group for efficacy analysis.
[0069] Tumors were measured twice per week until the study was ended on Day 60. Each mouse was euthanized when its tumor reached the endpoint volume of 1500 mm3 or on the final day, whichever came first. The time-to-endpoint (TTE) was calculated for each mouse. The primary treatment outcome was determined from an analysis of percent tumor growth delay (%TGD), defined as the percent increase in median TTE of treated versus control mice, with differences between two groups deemed significant at P < 0.05 using logrank survival analysis. Short-term efficacy was determined from an analysis of tumor growth inhibition (TGI) on Days 12 and 22. TGI was defined as the percent difference between the median tumor volumes (MTVs) of treated and control mice, with results analyzed for statistical significance at P < 0.05 using the Mann-Whitney U-test. A treatment that produced at least 60% TGI was considered potentially therapeutically active. Animals were also monitored for partial regression (PR) and complete regression (CR) responses. Treatment tolerability was assessed by frequent observation for clinical signs of treatment-related (TR) side effects and by body weight (BW) measurements.
[0070] All regimens were acceptably tolerated except for the afatinib / radiation combination therapy which experienced two treatment-related deaths and a 17.2% group mean BW loss by Day 8. All dosing for that group was stopped on Day 6. Once the remaining animals recovered their body weight, dosing resumed on Day 13 at a lowered afatinib dose of 10 mg/kg and one additional cycle (starting on Day 14) of five daily localized radiation doses at 2 Gy.
[0071] The median TTE for vehicle-treated controls was 13.8 days, establishing a maximum possible TGD of 46.2 days (335%) for the 60-day study. Nine of ten tumors in vehicle treated control animals reached the tumor volume endpoint size of 1500 mm3 with one PR.
[0072] On Day 12, the MTV for all animals in the vehicle group was 1183 mm3, with a range of 446 to 1800 mm3. The Day 22 MTV of three remaining animals was 1352 mm3, with a range of 221 to 1800 mm3.
[0073] The CO- 1686 monotherapy produced a significant survival difference versus controls (P < 0.01, logrank) with seven PRs. Additionally, an analysis of TGI at Day 12 and at Day 22 found a significant effect on tumor growth versus controls (P < 0.01, Mann- Whitney test).
[0074] The afatinib monotherapy regimen produced a significant survival difference versus controls (P < 0.001, logrank) with four PRs. An analysis of TGI at Day 12 found a significant effect on tumor growth versus controls (P < 0.001, Mann- Whitney test).
However, by Day 22 the difference in TGI compared to the remaining control animals was not significant (P > 0.05, Mann- Whitney test).
[0075] Radiation as a monotherapy produced a significant survival difference versus controls (P < 0.01, logrank) with one PR. An analysis of TGI at Day 12 found a significant effect on tumor growth versus controls (P < 0.001, Mann- Whitney test). However, by Day 22 the difference in TGI compared to the remaining control animals was not significant (P > 0.05, Mann-Whitney test).
[0076] The CO- 1686 / radiation combination therapy produced a significant survival difference versus controls (P < 0.001, logrank) with all ten animals being classified as PRs. The combination therapy also produced a significant survival difference to both
corresponding monotherapies (P < 0.05, logrank) A separate analysis of TGI at Day 12 and at Day 22 also found a significant effect on tumor growth versus controls (P < 0.01, Mann- Whitney test).
[0077] The afatinib / radiation combination regimen exceeded the acceptable levels of toxicity and could not be evaluated for survival analysis. A separate analysis of tumor growth inhibition at Day 12 on the surviving animals did find a significant effect on tumor growth versus controls (P < 0.01, Mann- Whitney test). However, by Day 22, the amount of TGI was no longer significant when compared to the remaining control animals (P > 0.05, Mann- Whitney test).
[0078] In summary, all therapies were active against NCI-H1975 human NSCLC xenografts in female athymic nude mice. However, the afatinib and radiation combination therapy used in this study exceeded acceptable levels of toxicity and was not evaluable for survival. All other therapies were well tolerated. The combination therapy of CO- 1686 and radiation exhibited a significant increase in survival when compared to control animals and both corresponding monotherapies and produced more PRs than any other treatment group.
[0079] The description of the present invention has been presented for purposes of illustration and description, but is not intended to be exhaustive or limiting of the invention to the form disclosed. The scope of the present invention is limited only by the scope of the following claims. Many modifications and variations will be apparent to those of ordinary skill in the art. The embodiment described and shown in the figures was chosen and described in order to best explain the principles of the invention, the practical application, and
to enable others of ordinary skill in the art to understand the invention for various
embodiments with various modifications as are suited to the particular use contemplated.
[0080] While the invention has been particularly shown and described with reference to a number of embodiments, it would be understood by those skilled in the art that changes in the form and details may be made to the various embodiments disclosed herein without departing from the spirit and scope of the invention and that the various embodiments disclosed herein are not intended to act as limitations on the scope of the claims. All references cited herein are incorporated in their entirety by reference.
TABLE 1 - Examples of irreversible EGFR inhibitors
Claims
1. A method for treating cancer having mutant epidermal growth factor receptor (EGFR) in a subject comprising administering an irreversible mutant EGFR inhibitor and radiotherapy.
2. The method of claim 1, wherein the irreversible mutant EGFR inhibitor covalently binds to cysteine 797 of mutant EGFR and exhibits at least 2-fold greater inhibition of a drug-resistant mutant EGFR relative to wild type EGFR.
3. The method of claim 1, wherein said cancer is non-small cell lung cancer (NSCLC).
4. The method of claim 1, wherein the irreversible mutant EGFR inhibitor is selected from the group consisting of CO-1686, WZ4002, AZD9291, CNX2006, ASP8273, EGF816, HM61713, TAS-2913, and AZ5104.
5. The method of claim 1, wherein in the irreversible mutant EGFR inhibitor is
rociletinib (CO-1686).
6. The method of claim 1, wherein the radiotherapy is selected from the group consisting of external-beam radiation therapy including intensity-modulated radiation therapy (EVIRT), image-guided radiation therapy (IGRT), tomotherapy, stereotactic radiosurgery, stereotactic body radiation therapy, photon beam, electron beam and proton therapy; internal radiation therapy (brachytherapy); and systemic radiation therapy such as radioactive iodine or radioactive substance bound to an antibody or protein.
7. The method of claim 2, wherein the drug-resistant mutant is selected from the group consisting of L858R/T790M EGFR and Exon-19 Deletion/T790M.
8. The method of claim 2, wherein the drug resistant mutant is selected from the group consisting of T790M, L858R, G719S, G719C, G719A, L861Q, a small in-frame deletion in exon 19, and an insertion in exon 20.
9. The method of claim 3, wherein said subject has relapsed NSCLC.
10. The method of claim 9, wherein the subject was previously treated with a first EGFR inhibitor.
11. The method of claim 10, wherein said first EGFR inhibitor was selected from the group consisting of erlotinib, gefitinib, afatinib, dacomitinib, cetuximab,
panitumumab, CO-1686, WZ4002, AZD9291, CNX2006, ASP8273, EGF816, HM61713, TAS-2913, and AZ5104.
12. The method of claim 1, wherein the irreversible mutant EGFR inhibitor and
radiotherapy are administered concurrently, separately, or sequentially.
13. The method of claim 1, wherein the radiotherapy comprises whole brain radiotherapy.
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US10513509B2 (en) | 2016-05-26 | 2019-12-24 | Recurium Ip Holdings, Llc | EGFR inhibitor compounds |
US11098030B2 (en) | 2016-05-26 | 2021-08-24 | Recurium Ip Holdings, Llc | EGFR inhibitor compounds |
WO2018234556A1 (en) * | 2017-06-23 | 2018-12-27 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for preventing or treating cancer resistance to egfr inhibition |
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