Treatment of non-small cell lung cancer with alectinib

Abstract

The present invention relates to a method for treating anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), comprising administering a therapeutically effective dose of alectinib or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, wherein the subject is a resected stage Ib to stage IIIa ALK-positive NSCLC with a tumor of 4 cm or larger.

Description

[Technical Field]

[0001] Field of Invention The present invention relates to a method for treating anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), comprising administering a therapeutically effective dose of alectinib or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, wherein the subject has undergone resection of early-stage ALK-positive NSCLC. [Background technology]

[0002] background Cancer is a leading cause of death worldwide, and non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths.

[0003] Lung cancer survival rates tend to be lower than those of other common cancers due to late diagnosis and limited availability of effective treatments. Approximately 60% of patients diagnosed with NSCLC already have advanced (stage IIIb) or metastatic (stage IV) disease, while about 30% are diagnosed with early-stage disease (stage I or II) and about 10% with stage IIIa. Five-year survival rates for advanced and metastatic disease are very low, ranging from 1% to 5%. For early-stage lung cancer, five-year survival rates are higher, ranging from 14% to 70%, depending on the stage of the disease at diagnosis and available treatment options.

[0004] Approximately half of NSCLC patients experience disease recurrence after surgery despite adjuvant chemotherapy, highlighting the urgent need for new treatments to provide the best possible chance of a cure.

[0005] Approximately 4-5% of NSCLC cases have been shown to have an echinoderm microtubule-associated protein-like 4 (EML4) anaplastic lymphoma kinase (ALK) fusion gene as a result of chromosomal inversions at 2p21 and 2p23. Anaplastic lymphoma kinase is a receptor tyrosine kinase belonging to the insulin receptor family.

[0006] In advanced and metastatic stages, there are currently four approved treatments for ALK-positive NSCLC patients that have been shown to offer clinical benefits and favorable tolerability compared to previously used standard platinum-based chemotherapy.

[0007] Crizotinib was the first ALK inhibitor approved and registered for the treatment of advanced and metastatic ALK-positive NSCLC. Since then, second-generation ALK inhibitors such as alectinib, ceritinib, and brigatinib have been approved for marketing as first-line or second-line treatments for advanced and metastatic ALK-positive NSCLC. Alectinib is described in International Publication No. 2010 / 143664, International Publication No. 2012 / 023597, and International Publication No. 2015 / 163448.

[0008] Despite advances in the treatment of NSCLC, improved treatment methods are still needed, particularly in adjuvant therapy and for early-stage NSCLC. [Overview of the project]

[0009] Summary of the Invention The inventors have found that alectinib adjuvant therapy is remarkably effective in preventing disease relapse in early ALK-positive NSCLC.

[0010] The present invention provides a method for treating anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), comprising administering a therapeutically effective dose of alectinib or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, wherein the subject is a resected stage Ib to stage IIIa ALK-positive NSCLC with a tumor of 4 cm or larger.

[0011] The present invention further provides a method for preventing recurrence of ALK-positive NSCLC in a subject, comprising administering to the subject a therapeutically effective amount of alectinib or a pharmaceutically acceptable salt thereof, wherein the subject has undergone resection of stage Ib ALK-positive NSCLC to stage IIIa ALK-positive NSCLC with a tumor of 4 cm or larger.

[0012] In some embodiments, the subject has undergone resection of stage II to stage IIIA ALK-positive NSCLC.

[0013] In some embodiments, the subject has undergone resection of stage Ib ALK-positive NSCLC to stage IIb ALK-positive NSCLC with a tumor of 4 cm or larger.

[0014] In some embodiments, the subject has undergone resection of stage Ib ALK-positive NSCLC with a tumor of 4 cm or larger.

[0015] In some embodiments, the subject has undergone resection of stage II ALK-positive NSCLC.

[0016] In some embodiments, the subject has undergone resection of stage IIIa ALK-positive NSCLC.

[0017] In some embodiments, the stage of ALK-positive NSCLC is histologically confirmed.

[0018] In some embodiments, the subject does not have metastatic ALK-positive NSCLC.

[0019] In some embodiments, alectinib or a pharmaceutically acceptable salt thereof is administered as adjuvant therapy.

[0020] The subject may have undergone complete resection of ALK-positive NSCLC with negative resection margins. The resection may be by lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy.

[0021] In some embodiments, the subject does not have a mutation that confers resistance to an ALK inhibitor.

[0022] In some embodiments, the subject has not previously been administered an ALK inhibitor. In some embodiments, the subject has not previously received adjuvant radiation therapy.

[0023] Alectinib or a pharmaceutically acceptable salt thereof may be administered orally. Alectinib or a pharmaceutically acceptable salt thereof may be administered twice daily.

[0024] The total daily dose of alectinib or a pharmaceutically acceptable salt thereof may be 600 mg to 1500 mg, preferably 1200 mg, more preferably 600 mg twice daily (BID).

[0025] In some embodiments, alectinib or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition. Preferably, the pharmaceutical composition comprises alectinib hydrochloride. The pharmaceutical composition may comprise lactose monohydrate, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate and carboxymethyl cellulose calcium. The pharmaceutical composition may be formulated as a capsule, preferably a hard capsule. Preferably, the capsule comprises alectinib hydrochloride corresponding to 150 mg of alectinib as the free base. Preferably, the capsule comprises 33.7 mg of lactose monohydrate and 6 mg of sodium lauryl sulfate.

[0026] In some embodiments, the method further comprises administering a therapeutically effective amount of a second therapeutic agent. The second therapeutic agent may be selected from the group consisting of chemotherapeutic agents, hormonal therapeutic agents, immunotherapeutic agents, and molecular targeting agents.

[0027] The present invention also provides alectinib or a pharmaceutically acceptable salt thereof for use in the treatment of ALK-positive NSCLC in subjects, wherein the subjects are resected ALK-positive NSCLC of stage Ib to stage IIIa with tumors of 4 cm or larger.

[0028] The present invention provides alectinib or a pharmaceutically acceptable salt thereof for use in a method for preventing recurrence of ALK-positive NSCLC in a subject, wherein the subject is resected ALK-positive NSCLC of stage Ib to stage IIIa having tumors of 4 cm or larger.

[0029] The present invention provides the use of a therapeutically effective dose of alectinib or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical for use in the treatment of ALK-positive NSCLC in subjects, wherein the subjects are resected stage Ib to stage IIIa ALK-positive NSCLC having tumors of 4 cm or larger. [Brief explanation of the drawing]

[0030] Description of the drawing [Figure 1] Primary endpoint: Kaplan-Meier plot of disease-free survival (DFS) as assessed by the principal investigator in the stage II–IIIA patient population. [Figure 2] Primary endpoint: Kaplan-Meier plot of disease-free survival (DFS) as assessed by the principal investigator in patients intending to receive treatment. [Figure 3] Forest plots for subgroup analysis of DFS in patients with treatment intent. [Figure 4] Exploratory endpoint: Kaplan-Meier plot of CNS disease-free survival in patients intending to receive treatment. [Modes for carrying out the invention]

[0031] Detailed description of the invention alectinib Alectinib is (I) below: It is a tetracyclic compound represented by TIFF2026530006000001.tif55170, The compound has the name 9-ethyl-6,6-dimethyl-8-(4-morpholine-4-ylpiperidine-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (CAS numbers 1256580-46-7 and 1256589-74-8 as hydrochloride salts).

[0032] Alectinib and its salts can be prepared by methods commonly known in the art, for example, by the general methods described in International Publication No. 2010 / 143664 (see in particular Example 366, compound "F6-20"). See also International Publication No. 2012 / 023597 (see in particular Preparation Example 30, compound "F6-20").

[0033] Alectinib is approved for use in the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), as detected in FDA approval trials. This approval is for patients with metastatic lung cancer who have tumors with oncogenic mutations in the ALK gene (also known as ALK-positive) and who have not received prior treatment. The FDA previously approved alectinib as a second-line therapy for ALK-positive NSCLC patients whose tumors have become resistant to crizotinib or who have been unable to continue treatment due to side effects.

[0034] As used herein, alectinib may be used in the form of a free base or in the form of a pharmaceutically acceptable salt.

[0035] Pharmaceutically acceptable salts include appropriate acid additions or their base salts. A review of appropriate medicinal salts can be found in Berge et al., J Pharm Sci, 66, 1-19 (1977). Salts are formed from strong inorganic acids such as mineral acids, such as hydrohalic acids, such as hydrochlorides, hydrobromates and hydroiodic acids, sulfuric acid, sulfuric acid phosphate, bisulfates, hemisulfates, thiocyansates, persulfates and sulfonic acids; strong organic carboxylic acids such as acetic acid, which are unsubstituted or substituted (e.g., by halogens) alkanecarboxylic acids with 1 to 4 carbon atoms; saturated or unsaturated dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or tetraphthalic acid; hydroxycarboxylic acids such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; amino acids such as aspartic acid or glutamic acid; benzoic acid; or organic sulfonic acids, such as (C1-C4)-alkyl- or aryl-sulfonic acids, which are unsubstituted or substituted (e.g., by halogens), such as methane- or p-toluenesulfonic acid.

[0036] Preferred salts include, for example, sulfonates such as hydrochloride, hydrobromide, hydroiodide, phosphate, phosphonate, sulfate, hydrogen sulfate, hemisulfate, methanesulfonate, p-toluenesulfonate, etc.; carboxylates such as acetate, trifluoroacetate, citrate, malate, maleate, tartrate, succinate, salicylate, etc.; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; and ammonium salts such as ammonium salt (NH4 X: X is a monovalent acid group), alkylammonium salt, dialkylammonium salt, trialkylammonium salt, and tetraalkylammonium salt.

[0037] In one preferred embodiment, alectinib is in the form of a hydrochloride salt, more preferably a monohydrochloride salt.

[0038] The present invention also includes a solvate form of alectinib. Preferably, the solvate is a hydrate.

[0039] In one preferred embodiment, alectinib is in the form of a monohydrochloride hydrate, and more preferably a monohydrate.

[0040] Alectinib or its pharmaceutically acceptable salts may be in amorphous or crystalline form.

[0041] The present invention encompasses the use of alectinib in various crystalline forms, polymorphs, and hydrated and anhydrous forms. It is well established in the pharmaceutical industry that chemical compounds can be isolated in any of these forms by slightly altering the method of purifying and / or isolating the compound from the solvent used in the synthesis and preparation of such compounds.

[0042] In one embodiment, alectinib is in an amorphous form. The amorphous monohydrochloride form of alectinib can be prepared according to the teachings in International Publication No. 2016 / 021707.

[0043] In one embodiment, alectinib is in crystalline form, preferably as a monohydrochloride salt. Suitable crystalline forms are known in the art and are taught, for example, in International Publication Nos. 2015 / 163448 and International Publication Nos. 2015 / 163447.

[0044] This invention comprises all enantiomers and tautomers of alectinib and its pharmaceutically acceptable salts. Those skilled in the art will recognize that alectinib has a chiral carbon atom. The corresponding enantiomers and / or tautomers can be isolated / prepared by methods known in the art. The enantiomers are characterized by the absolute configuration of their chiral center and are described by the R- and S-configuration rules by Cahn, Ingold, and Prelog. Such rules are well known in the art (e.g., "Advanced Organic Chemistry", 3). rdSee edition, ed. March, J., John Wiley and Sons, New York, 1985. Compounds containing chiral centers may be used as racemic mixtures, enantiomerically concentrated mixtures, or the racemic mixtures may be separated by known techniques, or the individual enantiomers may be used individually.

[0045] Pharmaceutical composition For use according to the present invention, alectinib or a pharmaceutically acceptable salt thereof is generally formulated with one or more pharmaceutically acceptable carriers, diluents, or excipients. The carrier must be compatible with the other components of the formulation and acceptable in the sense that it is not harmful to its recipient.

[0046] Examples of excipients suitable for various different forms of the pharmaceutical compositions described herein can be found in A. Wade and P.J. Weller, eds., "Handbook of Pharmaceutical Excipients," 2nd edition (1994). Each of the carriers, if more than one is present, must be compatible with the other components of the formulation and acceptable in the sense that it is not harmful to the recipient.

[0047] Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (ARGennaro ed., 1985).

[0048] Examples of suitable carriers include lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, and sorbitol. Examples of suitable diluents include ethanol, glycerol, and water.

[0049] The choice of pharmaceutical carrier, excipient, or diluent may be made in relation to the intended route of administration and standard pharmaceutical practices. The pharmaceutical composition may also contain, as a carrier, excipient, or diluent, or in addition thereto, any suitable binder, lubricant, suspending agent, coating agent, solubilizer, buffer, flavoring agent, surfactant, thickener, preservative (including antioxidant), disintegrant, solubilizer, and substances included for the purpose of isotonicizing the blood and preparation of the intended recipient.

[0050] Preservatives, stabilizers, dyes, and even flavorings may be included in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid, and p-hydroxybenzoic acid esters. Antioxidants and suspending agents may also be used.

[0051] Examples of suitable binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, methylcellulose, povidone (polyvinylpyrrolidone), macrogol, powdered acacia, starch, gelatin, natural sugars such as glucose, anhydrous lactose, liquid lactose, beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, and polyethylene glycol. A preferred binder is hydroxypropylcellulose.

[0052] Examples of suitable lubricants include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, and sodium stearyl fumarate. Magnesium stearate is preferred.

[0053] Examples of suitable stabilizers include para-hydroxybenzoic acids such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; phenols such as benzalkonium chloride, phenol, and cresol; thimerosal, dehydroacetic acid, and sorbic acid.

[0054] Examples of appropriate flavorings include sweeteners, acidulants, and fragrances.

[0055] Examples of suitable disintegrants include sodium starch glycolate, low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium (carmellose calcium), sodium bicarbonate, pregelatinized starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, anhydrous silicic acid, and carmellose.

[0056] Suitable solubilizers include, for example, surfactants, organic polymers, and pH adjusters. Preferred examples include casein, sodium caseinate, skim milk powder, sodium lauryl sulfate (hereinafter also referred to as SLS), sodium dioctyl sulfosuccinate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, sodium lauroyl sarcosinate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, sodium methyl sulfate, sodium ethyl sulfate, sodium butyl sulfate, sodium octyl sulfate, sodium decyl sulfate, and sodium dodecylbenzenesulfonate.

[0057] Suitable solubilizers include surfactants, organic polymers, and pH adjusters.

[0058] Examples of surfactants include ionic surfactants and nonionic surfactants. Ionic surfactants are further classified into anionic surfactants, cationic surfactants, and amphoteric surfactants depending on the charge of the ions they produce. Nonionic surfactants include sugar ester surfactants such as sorbitan fatty acid esters (C12-18), POE sorbitan fatty acid esters (C12-18), and sucrose fatty acid esters; fatty acid ester surfactants such as POE fatty acid esters (C12-18), POE resin acid esters, and POE fatty acid diesters (C12-18); alcohol-based surfactants such as POE alkyl ethers (C12-18); alkylphenol surfactants such as POE alkyl (C8-12) phenyl ether, POE dialkyl (C8-12) phenyl ether, and POE alkyl (C8-12) phenyl ether formalin condensate; and polyoxyethylene-polyoxypropylene block poly Examples include polyoxyethylene-polyoxypropylene block polymer surfactants such as remers and alkyl(C12-18) polyoxyethylene-polyoxypropylene block polymer ethers; alkylamine surfactants such as POE alkylamine (C12-18) and POE fatty acid amide (C12-18); bisphenol surfactants such as POE fatty acid bisphenyl ethers; polycyclic aromatic surfactants such as POA benzylphenyl (or phenylphenyl) ether and POA styrylphenyl (or phenylphenyl) ether; POE ethers and ester-type silicon and fluorine surfactants; and vegetable oil surfactants such as POE castor oil and POE hydrogenated castor oil.

[0059] Examples of anionic surfactants include alkyl sulfates (C12-18, Na, NH4, alkanolamine), POE alkyl ether sulfates (C12-18, Na, NH4, alkanolamine), POE alkylphenyl ether sulfates (C12-18, NH4, alkanolamine, Ca), POE benzyl (or styryl) phenyl (or phenylphenyl) ether sulfates (Na, NH4, alkanolamine), and polyoxyethylene-polyoxypropylene block polymer sulfates (Na, NH4, alkanolamine). Acid surfactants; paraffin (alkane) sulfonate (C12-22, Na, Ca, alkanolamine), AOS (C14-16, Na, alkanolamine), dialkyl sulfosuccinate (C8-12, Na, Ca, Mg), alkylbenzene sulfonate (C12, Na, Ca, Mg, NH4, alkylamine, alkanol, amine, cyclohexylamine), mono or dialkyl (C3-6) naphthalene sulfonate (Na, NH4, alkanolamine, Ca, Mg), naphthalene sulfonate-formaldehyde condensate (Na, NH4 4) Sulfonate surfactants such as alkyl(C8-12) diphenyl ether disulfonate (Na, NH4), lignin sulfonate (Na, Ca), POE alkyl(C8-12) phenyl ether sulfonate (Na), and POE alkyl(C12-18) ether sulfosuccinate half ester (Na); carboxylic acid surfactants such as fatty acid salts (C12-18, Na, K, NH4, alkanolamine), N-methyl fatty acid sarcosinate (C12-18, Na), resinate (Na, K); and POE alkyl(C12-18) Examples of phosphate surfactants include ether phosphates (Na, alkanolamine), POE mono- or dialkyl (C8-12) phenyl ether phosphates (Na, alkanolamine), POE benzylated (or styrylated) phenyl (or phenylphenyl) ether phosphates (Na, alkanolamine), polyoxyethylene-polyoxypropylene block polymers (Na, alkanolamine), phosphatidylcholine-phosphatidylethanolimine (lecithin), and alkyl (C8-12) phosphates.Preferably, examples include monoalkyl sulfates such as sodium lauryl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, and sodium octadecyl sulfate, sodium dioctyl sulfosuccinate, sodium lauroyl sarcosinate, and sodium dodecylbenzenesulfonate.

[0060] Sodium lauryl sulfate is a particularly preferred surfactant. In the present invention, when sodium lauryl sulfate is used, it is more preferable to obtain crystals by crystallization than by spray drying. Known crystalline polymorphs of sodium lauryl sulfate include monohydrate, 1 / 2 hydrate, 1 / 8 hydrate, and non-solvate (Journal of Crystal Growth 263(2004)480-490). Any of the above crystals can be used.

[0061] In one embodiment, alectinib or a pharmaceutically acceptable salt thereof is formulated in accordance with the teachings of International Publication No. 2012 / 023597. For example, in one preferred embodiment, the composition comprises alectinib or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and a solubilizer.

[0062] In another embodiment, alectinib or a pharmaceutically acceptable salt thereof is formulated in accordance with the teachings of International Publication No. 2015 / 163448. For example, in one preferred embodiment, the pharmaceutical composition comprises (i) granules containing alectinib or a pharmaceutically acceptable salt thereof, and (ii) a disintegrant.

[0063] A "disintegrant" is an ingredient that promotes the rapid disintegration of an orally ingested solid dosage form. Appropriate examples are listed above. The disintegrant may be contained in the granules or added to the granules as an external additive. Other additives such as lubricants and fluidizers may be optionally added as external additives or contained in the granules. In one embodiment, granule(i) contains alectinib or a pharmaceutically acceptable salt thereof, a disintegrant, a solubilizer, an excipient and a binder. The granules may further contain one or more additives selected from lubricants, coating agents, stabilizers, flavoring agents and diluents.

[0064] In one preferred embodiment, alectinib or a pharmaceutically acceptable salt thereof is formulated for oral administration, i.e., the composition is an oral formulation.

[0065] In one embodiment, the pharmaceutical composition is formulated as a tablet. A suitable coating agent can then be applied to the tablet to obtain a sugar-coated tablet or a film-coated tablet. Suitable coating agents are well known to those skilled in the art.

[0066] In one preferred embodiment, the pharmaceutical composition comprises alectinib or a pharmaceutically acceptable salt thereof, lactose monohydrate, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate, and carmellose calcium.

[0067] Preferably, the pharmaceutical composition is in the form of a capsule, or more preferably a hard capsule.

[0068] Preferably, the composition is provided in a capsule shell containing hypromellose, carrageenan, potassium chloride, titanium dioxide (E171), corn starch, and carnauba wax.

[0069] The formulation of the present invention preferably contains alectinib or a pharmaceutically acceptable salt thereof in an amount equivalent to, for example, about 20 to about 70% by weight, preferably about 30 to about 60% by weight, and particularly preferably about 35 to about 60% by weight, based on the total amount of the formulation, in terms of free base alectinib.

[0070] More specifically, if the formulation of the present invention is a capsule, alectinib or a pharmaceutically acceptable salt thereof is preferably contained in an amount equivalent to about 20 to about 70% by weight, preferably about 30 to about 60% by weight, and particularly preferably about 35 to about 60% by weight, based on the total amount of components contained in the capsule, in terms of alectinib of free base.

[0071] In a preferred embodiment, the composition is in the form of a unit dosage form containing alectinib or a pharmaceutically acceptable salt thereof in an amount of, for example, 60 mg to 240 mg, preferably 100 mg to 200 mg, and particularly preferably 140 mg to 190 mg per unit dosage form, in terms of free base equivalent to alectinib.

[0072] In one preferred embodiment, the composition is in the form of a unit dosage form containing alectinib hydrochloride equivalent to about 150 mg of alectinib in free base form.

[0073] In one preferred embodiment, the formulation is a dosage form comprising alectinib hydrochloride (equivalent to about 150 mg of alectinib in free base form), lactose (about 33.7 mg as monohydrate), and sodium (about 6 mg as sodium lauryl sulfate).

[0074] The above-mentioned pharmaceutical compositions can be prepared, for example, by mixing, through a process that includes associating the active compound with a support.

[0075] The formulations may, where appropriate, be conveniently provided in individual dosage units, or they may be prepared by any method well known in the pharmaceutical field. All methods involve associating the active compound with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, forming the product into the desired formulation.

[0076] Dosage The composition may be administered orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisionally, intravaginally, intraperitoneally, intravesically, and topically (infusion, powder, ointment, gel, or cream) and by inhalation (oral or nasal spray). Dosage forms include, for example, tablets, capsules, granules, powders, pills, aqueous and non-aqueous oral solutions and suspensions, and parenteral solutions in small containers for unit doses. Dosage forms may be designed to accommodate various methods of administering formulations, including controlled-release formulations delivered subcutaneously.

[0077] The dosage form is preferably oral administration in the form of tablets, capsules, granules, or powder formulations.

[0078] Preferably, the dosage form is a capsule.

[0079] In this invention, "oral preparation" refers to a preparation that can be administered orally. Oral administration refers to swallowing the preparation so that it enters the gastrointestinal tract, and the active ingredient is absorbed mainly through the intestinal tract.

[0080] Specific examples of oral formulations include solid formulations such as tablets, capsules, solutions, powders, lozenges, chewable tablets, granules, gels, films, and sprays, as well as liquid formulations. Examples of liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations can be used as fillers in soft capsules or hard capsules. Generally, carriers used include, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifiers and / or suspending agents. Liquid formulations can also be prepared by dissolving a unit dose of a solid drug, for example, by dissolving a pharmaceutical composition in a package in a carrier such as water.

[0081] The dosage of the active ingredient (the compound represented by formula (I) of the present invention or its salt) varies depending on the symptoms, age, weight, relative health status, other drugs, and method of administration. For example, the general effective dose when administered orally to a patient (warm-blooded animal, especially a human) is preferably 0.001 to 1000 mg per kg of body weight per day, more preferably 0.01 to 300 mg. The daily dose is preferably in the range of 1 to 1500 mg per adult patient of normal weight. In the case of parenteral preparations, the dosage is preferably 0.001 to 1000 mg per kg of body weight per day, more preferably 0.01 to 300 mg. The dose is preferably administered once a day or divided into several doses depending on the symptoms.

[0082] In one embodiment, alectinib or a pharmaceutically acceptable salt thereof is administered twice daily.

[0083] The total daily dose (free base equivalent) of alectinib is preferably 1-1500 mg, 100-1400 mg, 200-1300 mg, 400-1200 mg, 600-1500 mg, 700-1500 mg, 800-1500 mg, 900-1500 mg, 600-1200 mg, 700-1200 mg, 800-1200 mg, 900-1200 mg, or 1000-1200 mg.

[0084] In one embodiment, the total daily dose is 900 mg of alectinib (free base equivalent). Preferably, 450 mg is administered twice daily.

[0085] In one embodiment, the total daily dose is 1200 mg of alectinib (free base equivalent). Preferably, 600 mg is administered twice daily. Preferably, alectinib is administered twice daily as four 150 mg capsules.

[0086] In further embodiments, to mitigate side effects, the alectinib dose of 600 mg BID can be reduced by 150 mg increments to 450 mg BID or 300 mg BID, respectively. Such side effects may include any or a combination thereof: pneumonitis, pneumonia, appendicitis, acute myocardial infarction, nausea, malaise, asthenia, fatigue, tinnitus, vomiting, weight gain, loss of appetite, diarrhea, constipation, headache, cough, rash, anemia, dyspnea, peripheral edema, dysgeusia, increased serum creatinine, neutropenia, decreased neutropenia, decreased white blood cell count, increased serum creatine phosphokinase, increased aspartate aminotransferase, increased alanine aminotransferase, hyperbilirubinemia, COVID-19, myalgia, increased serum alkaline phosphatase, and / or problems related to missing product doses.

[0087] Treatment may continue until completion of the treatment period, recurrence of the disease, unacceptable toxicity, withdrawal of consent, or death. The treatment period may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 17, 19, 20, 21, 22, 23, 24, 36, 48, or 60 months. In one embodiment, the treatment period is 6 months, 12 months, 18 months, or 24 months.

[0088] disease As used herein, the term “tumor” refers to the growth and proliferation of all tumor cells, whether malignant or benign, as well as all precancerous and cancerous cells and tissues. The terms “cancer,” “cancerous,” and “tumor” are not mutually exclusive as used herein.

[0089] The terms "cancer" and "cancerous" refer to or describe a physiological condition in mammals typically characterized by uncontrolled cell proliferation. This definition includes benign and malignant cancers.

[0090] "Early-stage cancer" or "early-stage tumor" refers to cancer that is neither invasive nor metastatic, or cancer classified as stage 0, I, or II.

[0091] Examples of cancer include, but are not limited to, carcinomas, lymphomas, blastomas (including medulloblastoma and retinoblastoma), sarcomas (including liposarcoma and synovial cell sarcoma), neuroendocrine tumors (including carcinoid tumors, gastrinoma, and islet cell carcinoma), mesothelioma, schwannomas (including acoustic neuromas), meningiomas, adenocarcinomas, melanomas, and leukemia or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, and lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastric cancer or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer (including metastatic breast cancer), colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, Merkel cell carcinoma, mycosis fungoides, testicular cancer, esophageal cancer, bile duct tumors, and head and neck cancers and hematological malignancies.

[0092] NSCLC includes squamous cell NSCLC, non-squamous cell NSCLC, adenocarcinoma, and large cell carcinoma.

[0093] In some embodiments, cancer is ALK-positive.

[0094] In a preferred embodiment, the cancer is ALK-positive NSCLC.

[0095] "ALK-positive" or "ALK+" means that the cancer expresses anaplastic lymphoma kinase. In some embodiments, expression is caused by gene rearrangements resulting in the fusion of ALK with other genes, such as EML4, KIF5B, KLC1, TFG, TPR, HIP1, STRN, DCTN1, SQSTM1, NPM1, BCL11A, and BIRC6.

[0096] ALK positivity can be determined at each facility using FDA-approved and CE-marked tests, or through centralized Ventana ALK IHC testing.

[0097] Methods for determining ALK positivity (e.g., reverse transcription PCR) are known. ALK positivity for fusions can be determined in tissue samples using assays such as fluorescence in situ hybridization, IHC, PCR, and sequencing. Tissue sampling is difficult, and the size of tissue biopsy samples from lung cancer patients is very small, making it challenging to test for some important biomarkers. Plasma ALK assays analyzing circulating tumor nucleic acids can enable testing for ALK fusions in more NSCLC patients and can also be used to monitor changes in ALK rearrangement during ALK inhibitor treatment.

[0098] In some embodiments, the Ventana ALK(D5F3)CDx assay (Ventana Medical Systems, Tucson, AZ, USA) is used to determine ALK positivity.

[0099] In some embodiments, the subjects do not exhibit resistance to ALK inhibitors.

[0100] In some embodiments, the subjects do not have mutations that confer resistance to ALK inhibitors.

[0101] In some embodiments, the subjects do not exhibit biomarkers related to resistance to ALK inhibitors.

[0102] Molecular mechanisms of resistance to ALK inhibitors (including mutations and associated biomarkers) may include ALK-independent resistance mechanisms such as secondary mutations in the ALK gene (e.g., gatekeeper mutations), increased copy number of the ALK gene, increased expression of ALK mRNA, and activation of other oncogenic genes and pathways such as EGFR, cKIT, MET, or KRAS.

[0103] Disease Stage The disease staging follows the TNM classification of the 7th edition of the Union Internationale Contre le Cancer (UICC) / American Joint Committee on Cancer (AJCC).

[0104] T-stage classification is determined by the size of the primary tumor in the long axis, or the direct extent of the tumor into adjacent structures such as the mediastinum or chest wall: TX, primary tumor cannot be evaluated, or the tumor is evidenced by the presence of malignant cells in sputum or bronchial lavage fluid, but is not visualized by imaging or bronchoscopy; T0, no evidence of primary tumor; Tis, carcinoma in situ; T1, tumor with a maximum size of 3 cm or less surrounded by the lung or visceral pleura, with no bronchoscopy evidence of invasion proximal to the lobar bronchi (T1a if 2 cm or less, T1b if greater than 2 cm but 3 cm); T2, tumor greater than 3 cm but 7 cm or less, or a tumor having any of the following characteristics: main bronchi more than 2 cm distal to the tracheal bifurcation Tumors that infiltrate the visceral pleura and cause atelectasis or obstructive pneumonia, but whose extent is limited to the hilum and not to the entire lung (T2a if greater than 3 cm but less than or equal to 5 cm, T2b if greater than 5 cm but less than or equal to 7 cm); T3, tumors greater than 7 cm, or tumors that directly infiltrate any of the following: parietal pleura, chest wall (including superior cerebral sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumors within the main bronchus (less than 2 cm from the tracheal bifurcation, but without involvement of the tracheal bifurcation); or associated atelectasis or obstructive pneumonia of the entire lung, or a separate tumor nodule within the same lung lobe; T4, tumors of any size infiltrating any of the mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, tracheal bifurcation, or a separate tumor nodule in a different ipsilateral lobe.

[0105] The N-stage classification indicates the extent of spread to regional lymph nodes: NX, regional lymph node assessment is not possible; N0, no regional lymph node metastasis; N1, metastasis in ipsilateral peribronchial and / or ipsilateral hilar lymph nodes and intrapulmonary lymph nodes, including involvement by direct extension; N2, metastasis in ipsilateral mediastinum and / or tracheal bifurcation lymph nodes; N3: metastasis in contralateral mediastinum, contralateral hilum, ipsilateral or contralateral scalene lymph nodes, or supraclavicular lymph nodes.

[0106] The M-stage classification defines the presence of metastasis beyond the regional lymph nodes: M0: no distant metastasis, M1: distant metastasis present (M1a: separate tumor nodule in the contralateral lung lobe, tumor with pleural nodule, or malignant pleural effusion (or pericardial effusion); M1b: distant metastasis (to extrathoracic organs)).

[0107] Disease staging includes latent carcinoma (TX, N0), stage 0 (Tis, N0), stage Ia (T1, N0), stage Ib (T2a, N0), stage IIa (T2b, N0; T1, N1; T2a, N1), stage IIb (T2b, N1; T3, N0), stage IIIa (T1-2, N2; T3, N1-2; T4, N0-1), stage IIIb (T1-3, N3; T4, N2-3), or stage IV (any T, any N, M1).

[0108] In some embodiments, the subjects are NSCLC of stage Ib (tumor ≥ 4 cm) to stage IIIa with a maximum tumor size of 4 cm or more, which have been completely resected and histologically confirmed.

[0109] In some embodiments, the subjects are NSCLC of stage Ib (tumor ≥ 4 cm) to stage IIb that has been completely resected and histologically confirmed.

[0110] In some embodiments, the subjects are NSCLC of stage Ib (tumor ≥ 4 cm) to stage IIa that has been completely resected and histologically confirmed.

[0111] In some embodiments, the subjects are NSCLC of stage Ib (tumor ≥ 4 cm) that has been completely resected and histologically confirmed.

[0112] In some embodiments, the subjects are those in which stage IIa to stage IIIa NSCLC has been completely resected and histologically confirmed.

[0113] In some embodiments, the subjects have been completely excised and histologically confirmed to have stage IIb to stage IIIa NSCLC.

[0114] In some embodiments, the subject has been completely excised and histologically confirmed to have stage IIIa NSCLC.

[0115] In some embodiments, the subjects have been completely excised and histologically confirmed to have stage II NSCLC.

[0116] In some embodiments, the subject has been completely excised and histologically confirmed to have stage IIa NSCLC.

[0117] In some embodiments, the subjects have been completely excised and histologically confirmed to have stage IIb NSCLC.

[0118] In some embodiments, the subject has a TNM classification of T2-4 N0, T1-4 N1, or T1-3 N2.

[0119] In some embodiments, the subject does not have a TNM classification of N3 or M1.

[0120] In some embodiments, the subjects do not have metastatic or stage IV ALK-positive NSCLC.

[0121] As used herein, "histologically confirmed" means determination by microscopic examination of tissue removed by biopsy or surgical excision.

[0122] As used herein, “excision” refers to the surgical removal of all or part of a tumor. The tumor may be removed along with the surrounding normal, healthy tissue (surgical margin). Preferably, the subject has a negative surgical margin.

[0123] In some embodiments, the resection is performed by lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy. Preferably, the resection is not performed by segmentectomy or partial resection.

[0124] Adjuvant As used herein, “adjuvant” and / or “adjuvant therapy” refer to therapy administered in addition to primary or initial therapy, for example, after tumor resection.

[0125] In some embodiments, the subjects have not previously received adjuvant radiotherapy.

[0126] Preferably, alectinib is administered as adjuvant therapy after complete resection of the tumor.

[0127] In some embodiments, alectinib is administered as adjuvant therapy after tumor resection in ALK+NSCLC patients as detected by FDA-approved trials.

[0128] As used herein, “neoadjuvant” refers to a treatment delivered before the removal of a tumor, for example, to help reduce the size of the tumor.

[0129] Preferably, alectinib is not administered in a neoadjuvant situation. Preferably, the subject has not received alectinib prior to tumor resection.

[0130] In some embodiments, the subjects have not previously received ALK inhibitors.

[0131] In some embodiments, the subject receives radiation therapy before the tumor is removed.

[0132] In some embodiments, the excision is performed one to sixteen weeks before treatment with alectinib, for example, four to twelve weeks, six to ten weeks, four to six weeks, six to eight weeks, or eight to twelve weeks before treatment with alectinib. For example, the excision may be performed one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen weeks before treatment with alectinib.

[0133] Preferably, the excision is performed 4 to 12 weeks before treatment with alectinib.

[0134] Treatment method The present invention provides a method for treating a subject suffering from ALK-positive non-small cell lung cancer, comprising administering a therapeutically effective dose of alectinib to the subject.

[0135] The present invention provides a method for treating or delaying the progression of non-small cell lung cancer in a subject, comprising administering a therapeutically effective dose of alectinib to the subject.

[0136] The present invention provides alectinib or a pharmaceutically acceptable salt thereof for use in the treatment of ALK-positive NSCLC in subjects, wherein the subjects are resected stage Ib to stage IIIa ALK-positive NSCLC with tumors of 4 cm or larger.

[0137] The present invention provides alectinib or a pharmaceutically acceptable salt thereof for use in a method for preventing recurrence of ALK-positive NSCLC in a subject, wherein the subject is resected ALK-positive NSCLC of stage Ib to stage IIIa having tumors of 4 cm or larger.

[0138] In some embodiments, the subjects have ALK-positive NSCLC ranging from stage Ib (tumor ≥ 4 cm) to stage IIIa.

[0139] In some embodiments, alectinib is administered as adjuvant therapy after complete resection of a tumor. In the context of this invention, resection refers to surgery performed prior to alectinib treatment. This invention is not about methods of surgery performed on the human body.

[0140] In some embodiments, alectinib is indicated as adjuvant therapy after tumor resection in adult patients with ALK+NSCLC.

[0141] In some embodiments, alectinib is indicated as adjuvant therapy after tumor resection in adult patients with ALK+NSCLC of stage IB (>4cm) to IIIA.

[0142] In some embodiments, alectinib is indicated as adjuvant therapy after tumor resection in adult patients with stage II–IIIA ALK+NSCLC.

[0143] As used herein, the terms “patient” or “subject” are interchangeable and refer to any single animal, more preferably a mammal (including, for example, dogs, cats, horses, rabbits, zoo animals, cattle, pigs, sheep, and non-human animals such as non-human primates) for which treatment is desired. In certain embodiments, the patient as used herein is human.

[0144] In some embodiments, the patient is non-Asian.

[0145] As used herein, “treatment” refers to a clinical intervention to alter the natural course of the individual being treated, which may be carried out for preventive purposes or in the course of clinicopathology. Desired effects of treatment include preventing the onset or recurrence of disease, reducing symptoms, attenuating any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, improving or alleviating symptoms, and achieving remission or improving prognosis. In some embodiments, the compositions of the present invention are used to delay the onset of disease or to slow the progression of disease.

[0146] "Individual response" or "response" may be assessed using any outcome measure that demonstrates an individual benefit, including, but not limited to, (1) some degree of inhibition of disease progression (e.g., cancer progression), including slowing and complete cessation; (2) reduction of tumor size; (3) inhibition of cancer cell invasion into adjacent peripheral organs and / or tissues (i.e., reduction, slowing, or complete cessation); (4) inhibition of metastasis (i.e., reduction, slowing, or complete cessation); (5) some degree of alleviation of one or more symptoms associated with the disease or disability (e.g., cancer); (6) an increase or extension of the length of survival, including overall survival, progression-free survival, and disease-free survival; and / or (9) a reduction in mortality at a given point in time after treatment.

[0147] The terms "effective response" or "responsiveness" and similar words to a patient's response to treatment with a drug refer to the clinical or therapeutic benefit bestowed upon a patient who is at risk of or has a disease or disorder, such as cancer. In one embodiment, such benefit includes one or more of the following: extension of survival (including overall survival, progression-free survival, and disease-free survival); achieving an objective response (including complete or partial response); or improving the signs or symptoms of cancer.

[0148] "Objective response" refers to measurable responses, including complete response (CR) or partial response (PR). In some embodiments, "objective response rate (ORR)" refers to the sum of the complete response (CR) rate and the partial response (PR) rate.

[0149] "Complete response" or "CR" refers to the disappearance of all signs of cancer (e.g., disappearance of all target lesions) in response to treatment. This does not necessarily mean that the cancer is cured.

[0150] "Sustained response" refers to a sustained effect on reducing tumor growth after discontinuation of treatment. For example, tumor size may remain the same as or be smaller than the size at the start of the administration phase. In some embodiments, the sustained response lasts for at least the duration of treatment, or at least 1.5, 2.0, 2.5, or 3.0 times the length of the treatment period, or longer. As used herein, "reducing or inhibiting cancer recurrence" means reducing or inhibiting the recurrence of a tumor or cancer, or the progression of a tumor or cancer. As disclosed herein, cancer recurrence and / or progression of cancer includes, but is not limited to, cancer metastasis.

[0151] As used herein, “partial response” or “PR” refers to a reduction in the size of one or more tumors or lesions, or the extent of cancer within the body, in response to treatment. For example, in some embodiments, a PR refers to a reduction of at least 30% in the sum of the longest diameters (SLD) of the target lesions, relative to the baseline SLD.

[0152] As used herein, “stable disease” or “SD” refers to a state where, based on the smallest SLD since the start of treatment, there is neither a sufficient reduction in the target lesion to be considered a partial response (PR) nor a sufficient increase to be considered a progressive disease (PD).

[0153] The term "survival period" refers to patients who are still alive and includes overall survival and progression-free survival.

[0154] As used herein, “progression-free survival” (PFS) refers to the length of time during and after treatment in which the treated disease (e.g., cancer) does not worsen. Progression-free survival may include the amount of time a patient experiences a complete or partial response, as well as the amount of time a patient experiences stable disease.

[0155] As used herein, “disease-free survival (DFS)” means the period from randomization to the first confirmed case of disease recurrence or new primary NSCLC, as determined by the principal investigator based on a comprehensive evaluation of imaging data, biopsy results (where clinically available), and clinical findings, or death from any cause, whichever comes first.

[0156] "Extending survival" means an increase in overall survival or progression-free survival in treated patients compared to untreated patients (i.e., patients not treated with medication) and / or patients treated with approved antitumor agents.

[0157] As used herein, “delaying the progression” of a disease means delaying, hindering, slowing, stabilizing, and / or postponing the progression of a disease (such as cancer (e.g., NSCLC, squamous or non-squamous NSCLC)). This delay can be of varying lengths depending on the disease being treated and / or the individual’s medical history. As will be apparent to those skilled in the art, a sufficient or significant delay can effectively include prevention in that the individual does not develop the disease. For example, it can delay the progression of terminal cancer, such as the development of metastases.

[0158] As used herein, “preventive” means reducing the likelihood of disease recurrence compared to treatment with platinum-based chemotherapy.

[0159] A "hazard ratio" is the probability of an event occurring in the treatment group relative to the probability in the control group over a unit of time. Therefore, in this context, the hazard ratio may relate to the probability of a DFS-related event in the alectinib treatment group compared to the chemotherapy treatment group. For example, a hazard ratio of 0.16 means that alectinib reduces the risk of DFS-related events by 84% compared to the chemotherapy (control) group.

[0160] For example, in some embodiments, alectinib administration increases the likelihood of objective response (e.g., CR), extends the patient's PFS, extends the patient's DFS, extends the patient's OS, and / or extends the patient's DOR compared to treatment with platinum-based chemotherapy without alectinib.

[0161] In some embodiments, alectinib increases the likelihood of objective response in subjects compared to treatment with platinum-based chemotherapy without alectinib. In some embodiments, alectinib increases the likelihood of complete response (CR) in subjects compared to treatment with platinum-based chemotherapy without alectinib. In some embodiments, alectinib extends the progression-free survival (PFS) of subjects compared to treatment with platinum-based chemotherapy without alectinib. In some embodiments, alectinib extends the disease-free survival (DFS) of subjects compared to treatment with platinum-based chemotherapy without alectinib. In some embodiments, alectinib extends the overall survival (OS) of subjects compared to treatment with platinum-based chemotherapy without alectinib. In some embodiments, alectinib extends the duration of treatment (DOR) of subjects compared to treatment with platinum-based chemotherapy without alectinib. In some embodiments, alectinib extends the overall response rate (ORR) of subjects compared to treatment with platinum-based chemotherapy without alectinib.

[0162] In some embodiments, the benefits of treatment with alectinib include an increase in overall survival (OS). In some embodiments, the benefits of treatment with alectinib include an increase in disease-free survival (DFS).

[0163] In some embodiments of this disclosure, administration of alectinib to a subject extends the subject's disease-free survival (DFS) compared to administration of platinum-based chemotherapy without alectinib. For example, administration of alectinib to a subject can extend the subject's DFS by approximately 1 to 5 months, 2 to 4 months, 2.1 to 3.9 months, 2.5 to 3.5 months, or 2.8 to 3.4 months compared to administration of platinum-based chemotherapy without alectinib (e.g., approximately 1 month, 1.1 months, 1.2 months, 1.3 months, 1.4 months, 1.5 months, 1.6 months, 1.7 months, 1.8 months, 1.9 months). (1 month, 2 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, or 5 months).

[0164] In some embodiments, alectinib reduces the likelihood of disease recurrence compared to treatment with platinum-based chemotherapy without alectinib. For example, administration of alectinib to a subject reduces the likelihood of disease recurrence by approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, and 100% compared to administration of platinum-based chemotherapy without alectinib. Preferably, administration of alectinib to a subject reduces the likelihood of disease recurrence by approximately 60-90%, for example, 75-85%, compared to administration of platinum-based chemotherapy without alectinib.

[0165] In some embodiments, alectinib has an improved safety profile compared to treatment with platinum-based chemotherapy without alectinib. For example, alectinib may reduce the number of adverse events leading to treatment discontinuation, improve neutrophil and / or white blood cell counts, and / or reduce the incidence of asthenia, nausea, vomiting, loss of appetite, malaise, neutropenia, fatigue, and / or tinnitus compared to treatment with platinum-based chemotherapy.

[0166] In some embodiments, platinum-based chemotherapy comprises a platinum-based chemotherapeutic agent and a nucleoside analog.

[0167] In some embodiments, the platinum-based chemotherapeutic agent is cisplatin, carboplatin, or oxaliplatin.

[0168] In some embodiments, the platinum-based chemotherapeutic agent is cisplatin.

[0169] In some embodiments, the nucleoside analog is gemcitabine.

[0170] In some embodiments, platinum-based chemotherapy includes cisplatin and gemcitabine.

[0171] In some embodiments, platinum-based chemotherapy includes cisplatin and pemetrexed.

[0172] In some embodiments, platinum-based chemotherapy includes cisplatin and vinorelbine.

[0173] In some embodiments, platinum-based chemotherapy is selected from the following: - Day 1: Cisplatin 75 mg / m² 2 +Vinorelbine 25 mg / m² on day 1 and day 8 2 - Day 1: Cisplatin 75 mg / m² 2 +Gemcitabine 1250 mg / m² on days 1 and 8 2 - Day 1: Cisplatin 75 mg / m² 2 +1 day: Pemetrexed 500 mg / m² 2 .

[0174] In some embodiments, four cycles of platinum-based chemotherapy are provided, each cycle lasting 21 days.

[0175] In some cases, the method further includes administering an effective dose of a second therapeutic agent to the patient. In some cases, the second therapeutic agent is selected from a group that includes chemotherapeutic agents, hormone therapies, immunotherapies, molecularly targeted agents, etc.

[0176] Examples of "chemotherapeutic agents" include alkylating agents, platinum preparations, antimetabolites, topoisomerase inhibitors, anticancer antibiotics, and plant-derived anticancer agents. Examples of alkylating agents include nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carboquan, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustine, estramustine sodium phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, pipobromane, etogluside, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribomustine, temozolomide, treosulfan, trophosphamide, dinostatin stimalamer, carboquan, adzelesin, systemustine, and bizelesin. Examples of "platinum preparations" include carboplatin, cisplatin, miboplatin, nedaplatin, and oxaliplatin. Examples of "antimetabolites" include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, enocitabine, cytarabine, cytarabine ocphosphate, ancitabine hydrochloride, 5-FU preparations (fluorouracil, tegafur, UFT, doxifluridine, carmofur, gallocitabine, emitefur, etc.), aminopterin, calcium leucovorin, tabloid, butosin, calcium vorinate, calcium levoforinate, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, pyritrexime, idoxyuridine, mitogwazone, thiazophrine, and ambamustine. Topoisomerase I inhibitors (e.g., irinotecan and topotecan), topoisomerase II inhibitors (e.g., sobuzoxane).Examples of "anticancer antibiotics" include anthracycline anticancer agents (doxorubicin hydrochloride, daunorubicin hydrochloride, acralubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, etc.), actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, neocarutinostatin, mitramycin, sarcomycin, cardinophilin, mitotam, zolubicin hydrochloride, mitoxantrone hydrochloride, and idarubicin hydrochloride. Examples of "plant-derived anticancer agents" include vinca alkaloid anticancer agents (vinblastine sulfate, vincristine sulfate, vindesine sulfate), taxane anticancer agents (paclitaxel, docetaxel, etc.), etoposide, etoposide phosphate, teniposide, and vinorelbine.

[0177] Examples of "hormone therapy agents" include corticosteroids (e.g., dexamethasone, prednisolone, betamethasone, and triamcinolone). Among these, prednisolone is preferred.

[0178] Examples of "immunotherapy agents (BRMs)" include picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, lymphotoxin, BCG vaccine, Corynebacterium parvum, levamisole, polysaccharide potassium, and procodazole.

[0179] "Molecularly targeted drugs" include pharmaceuticals that inhibit the function of cell growth factors and their receptors. Examples of "cell growth factors" include any substance that can promote cell proliferation, such as peptides with a molecular weight of 20,000 or less that exhibit activity at low concentrations by binding to receptors. Specific examples include (1) EGF (epidermal growth factor) or substances with substantially the same activity [e.g., EGF, heregulin (HER2 ligand), etc.], (2) insulin or substances with substantially the same activity [e.g., insulin, IGF (insulin-like growth factor)-1, IGF-2, etc.], (3) FGF (fibroblast growth factor) or substances with substantially the same activity [e.g., acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10, etc.], (4) VEGF (vascular endothelial growth factor), and (5) other cell growth factors [e.g., CSF (colony-stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGFβ (transforming growth factor β), HGF (hepatocyte growth factor), etc.].

[0180] A "cell growth factor receptor" can be any receptor as long as it has the ability to bind to the cell growth factors mentioned above. Specific examples include the EGF receptor, hereglin receptor (HER2), insulin receptor, IGF receptor, FGF receptor-1 or FGF receptor-2, HGF receptor (c-met), VEGF receptor, and SCF receptor (c-kit). Examples of "drugs that inhibit the activity of cell growth factors" include Herceptin (HER2 antibody), Gleevec (c-kit / abl inhibitor), and Iressa (EGF receptor inhibitor).

[0181] Furthermore, even a single formulation can include drugs that inhibit the activity of multiple cell growth factors, or drugs that block the cellular signals produced by cell growth factors.

[0182] In addition to the above-mentioned pharmaceuticals, L-asparaginase, acegraton, procarbazine hydrochloride, protoporphyrin cobalt complex, hematoporphyrin mercury sodium, differentiation inducers (e.g., retinoids, vitamin D, etc.), angiogenesis inhibitors, and alpha-blockers (e.g., tamsulosin hydrochloride, etc.) may also be used. [Examples]

[0183] Examples Clinical trial protocol - trial design Exam Description This randomized, active-controlled, multicenter, open-label Phase III trial is designed to compare alectinib with platinum-based chemotherapy in adjuvant therapy to investigate its efficacy and safety. The primary endpoint of the trial is disease-free survival (DFS), as assessed by the principal investigator, while overall survival (OS) is a secondary endpoint.

[0184] This trial is planned to be conducted at approximately 200 sites in about 30 countries worldwide. Central allocation will be performed via voice response or a web-based interactive response system (IxRS). Allocated patients will be stratified by disease stage (stage Ib [tumor ≥ 4 cm] vs. stage II vs. stage IIIa) and ethnicity (Asian vs. non-Asian). Relevant instructions will be provided to each trial site by the IxRS provider.

[0185] Patients with NSCLC of stage Ib (tumor ≥ 4 cm) to stage IIIa, according to the 7th edition of the Union Internationale Contre le Cancer (UICC) / American Joint Committee on Cancer (AJCC), who have undergone complete resection (negative margins), have histological confirmation, have been confirmed ALK-positive by US Food and Drug Administration (FDA) approved and Conformite Europeenne (CE) marked tests, and who meet all eligibility criteria will be randomized in a 1:1 ratio.

[0186] Staging shall be classified in accordance with the 7th edition of UICC / AJCC, and shall not be performed in accordance with the 8th edition. It has been shown that in the 7th edition classification, stage Ib NSCLC patients with tumors ≥4 cm obtain more limited benefits from adjuvant chemotherapy compared with stage II~IIIa NSCLC patients, and this point is considered in the enrollment cap, stratification, and statistical analysis of the primary endpoint.

[0187] Patients in the test group will receive oral administration of 600 mg alectinib twice daily (BID) with meals for 24 months.

[0188] Patients in the control group will receive one of the protocol-specified platinum-based chemotherapy regimens (including all required pre-medications and permitted concomitant medications) in accordance with local prescribing information. The protocol-specified platinum-based chemotherapy regimens include the following: - 75 mg / m cisplatin on day 1 2 + 25 mg / m vinorelbine on day 1 and day 8 2 - 75 mg / m cisplatin on day 1 2 + 1250 mg / m gemcitabine on day 1 and day 8 2 - 75 mg / m cisplatin on day 1 2 + 500 mg / m pemetrexed on day 1 2

[0189] Four cycles of platinum-based chemotherapy will be administered, and each cycle lasts 21 days. If the cisplatin-based regimen is not tolerated, carboplatin can be administered instead of cisplatin in one of the above combinations.

[0190] Postoperative radiotherapy (PORT) is not permitted as a treatment option. Therefore, stage IIIa N2 NSCLC patients who should receive PORT at the discretion of the principal investigator will be excluded from the trial.

[0191] The investigational drug (alectinib or platinum-based chemotherapy) will be administered until the first occurrence of one of the following: completion of the treatment period (24 months for alectinib and 4 cycles for chemotherapy), disease recurrence, unacceptable toxicity, withdrawal of consent, or death. Patients who complete the investigational treatment regimen or discontinue treatment before disease recurrence (e.g., due to unacceptable toxicity) will continue to be followed until disease recurrence. After disease recurrence, patients will be treated according to local clinical practice at the discretion of the principal investigator. Crossover between the two groups is not permitted in the context of adjuvant therapy.

[0192] The trial will enroll approximately 255 patients during a planned competitive enrollment period of approximately 38 months. Patients inappropriately assigned to the trial will not be replaced. The primary DFS analysis will be performed when approximately 89 DFS events are observed in the stage II–IIIa subgroup. This is expected to occur approximately 60 months after the initial patient was randomized. Data collection will continue for each patient until death or termination of the trial, whichever comes first.

[0193] An independent Data Monitoring Committee (iDMC) will be established to monitor the progress of the trial and ensure that the safety of patients enrolled in the trial is not compromised.

[0194] All assigned patients will undergo regular scheduled visits until the first occurrence of disease recurrence, death, withdrawal from the trial, or termination of the trial. Regular safety assessments will be conducted for both groups during treatment. Safety follow-up visits will be conducted 28 days after the last dose of alectinib or 28 days after the end of the last cycle of platinum-based chemotherapy. For the first 12 weeks (3 months), regular safety assessment visits will be scheduled for both groups at baseline and every 3 weeks (i.e., every chemotherapy cycle). Additional visits will be scheduled for patients in the alectinib group at weeks 2, 4, 8, and 10 to allow for more frequent CPK and liver function assessments. Telephone calls to monitor the safety of patients in the chemotherapy group will be made at the same time points (weeks 2, 4, 8, and 10). From week 12, safety monitoring will continue for patients in the alectinib group every 6 weeks until week 48, and every 12 weeks from week 49 to week 96, until treatment discontinuation. In both groups, scheduled disease assessments will be conducted at baseline, every 12 weeks for the first two years after the start of treatment, every 24 weeks from years 3 to 5, and annually thereafter. These assessments will continue until the first occurrence of disease relapse, death, loss of follow-up, withdrawal of consent, or termination of the study by the sponsor. Unscheduled assessments may be conducted at any time if deemed clinically necessary. Favorable efficacy results obtained in the interim analysis will not affect the timing of disease assessments during the study period.

[0195] Number of patients Approximately 255 patients are expected to be enrolled in this trial at around 200 sites worldwide.

[0196] Target group Selection criteria: Patients must meet the following trial registration criteria: - Signed informed consent document - The person must be 18 years of age or older when signing the informed consent document. - Based on the UICC / AJCC 7th edition, for histologically confirmed NSCLC of stage Ib (tumor ≥ 4cm) to stage IIIa (T2-3 N0, T1-3 N1, T1-3 N2, T4 N0-1), complete resection with negative margins must have been performed 4-12 weeks prior to registration. ○ Permitted types of resection include lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy. ○Resection by segmental resection or partial resection was not permitted. ○ N3 disease is not acceptable. -If mediastinoscopy was not performed preoperatively, it is expected that at least systematic sampling of mediastinal lymph nodes has been carried out. Systematic sampling is defined as the removal of at least one representative lymph node at a specified level. ○Complete mediastinal lymph node dissection (MLND) is preferred. Mediastinal lymph node dissection involves the removal of all lymph nodes at the same level. Patients who have undergone right thoracotomy require sampling or MLND at levels 4 and 7. Patients who have undergone left thoracotomy require sampling or MLND at levels 5 and / or 6 and 7. ○Exceptions are permitted in the following circumstances: ○If a patient has been confirmed to have N2 disease at one level (based on the UICC / AJCC Stage Classification, 7th Edition), it is not necessary to sample at all levels. ○If preoperative staging imaging results (contrast-enhanced computed tomography [CT] and positron emission tomography [PET] scans) do not suggest any disease in the mediastinum, the patient may be considered eligible even if N2 lymph node sampling is not performed at the surgeon's discretion. -ALK-positive disease confirmed by FDA-approved and CE-marked testing. - The patient is able to receive platinum-based chemotherapy regimens in accordance with local package inserts or guidelines. - Eastern Community Oncology Group (ECOG) Performance Status is Grade 0 or - Appropriate hematological function as defined by the following clinical laboratory test results obtained within 3 days prior to the start of the trial treatment: ○ Platelet count ≥ 100 × 10 9 / L ○ANC≧1500 / μL ○Hemoglobin ≥ 9g / dL - Appropriate renal function as defined by the following clinical test results obtained within 3 days prior to the start of the trial treatment: ○Serum creatinine ≤1.5 × upper limit of normal (ULN) and ○Creatinine clearance (CrCl) ≥ 60 mL / min - For women of childbearing potential: You must agree to abstain from sexual intercourse (refrain from heterosexual intercourse) or use a method of contraception with a failure rate of <1% per year during the treatment period and for at least 90 days after the last dose of alectinib or for the period specified in the local package insert or guidelines. A woman is considered capable of becoming pregnant if she is postmenstrual, has not reached a postmenopausal state (absence of menstruation for 12 consecutive months or more without a specified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of the ovaries, fallopian ducts, and / or uterus) or another cause as determined by the principal investigator (e.g., absence of Müllerian ducts). Examples of contraceptive methods with an annual failure rate of <1% include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices (IUDs), and copper-containing IUDs. Hormonal contraceptives need to be supplemented with barrier methods. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the patient's preferred and normal lifestyle. Periodic abstinence (e.g., calendar, ovulation, symptomatic thermometer, or post-ovulation method) and withdrawal (interrupted intercourse) are not acceptable methods of contraception. ○ Women of childbearing potential must have negative serum pregnancy test results prior to randomization (up to 3 days prior) and within 10 days prior to the first dose of the investigational drug. The first dose of the investigational drug (alectinib or chemotherapy) must be administered within 7 days of randomization. - For men: Consent to maintain abstinence (refraining from heterosexual intercourse), use contraception, and refrain from sperm donation, as defined below: ○If a man has a female partner of childbearing age, he must abstain from sexual intercourse or use condoms in addition to an additional method of contraception that results in an annual pregnancy rate of less than 1% for at least 90 days after the last dose of alectinib or for the period specified in the local package insert or guidelines. The man must also refrain from sperm donation during this period. ○If a man has a pregnant female partner, he must abstain from sexual activity or use a condom to avoid exposure to the embryo during the treatment period and for at least 90 days after the last dose of alectinib or for the period specified in the local package insert or guidelines. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the patient's preferred and normal lifestyle. Periodic abstinence (e.g., calendar, ovulation, symptomatic thermometer, or post-ovulation method) and withdrawal (interrupted intercourse) are not acceptable methods of contraception. - Willingness and ability to adhere to scheduled appointments, treatment plans, clinical tests, and other examination procedures.

[0197] Exclusion criteria: Patients who meet any of the following criteria will be excluded from trial enrollment: - Women who are pregnant, breastfeeding, or planning to become pregnant during the study period, within 90 days of the last dose of alectinib, or within the period specified in the local prescribing information or guidelines for chemotherapy. - Prior adjuvant radiotherapy for NSCLC ○Radiation therapy with a neoadjuvant setting is permitted, but it must be completed at least four weeks before the start of the experimental treatment. - Prior exposure to systemic anti-cancer therapy ○ For early-stage malignant tumors with the aim of curative treatment, anticancer therapy is acceptable if the last dose was administered more than 5 years prior to registration. Consultation with the medical monitor is possible. - Prior exposure to ALK inhibitors - Stage IIIa N2 patients who should undergo PORT at the discretion of the principal investigator will be excluded from the study. ○Postoperative radiotherapy is not permitted in this study. - Known hypersensitivity to any component of the investigational drug (alecinib or planned chemotherapy) to which the patient may be randomized. ○This includes, but is not limited to, patients with galactose intolerance, congenital lactase deficiency, or glucose-galactose malabsorption. - Malignant tumors other than NSCLC within the five years prior to registration. However, cured cancers such as basal cell carcinoma of the skin treated curatively, early gastrointestinal (GI) cancer treated by endoscopic resection, cervical intraepithelial neoplasia, intraductal carcinoma of the mammary gland, papillary thyroid carcinoma, or cancers that are judged not to affect the disease-free survival (DFS) or overall survival (OS) of current NSCLC patients are excluded. - Any GI disorder that may affect the absorption of oral medications, such as malabsorption syndrome or post-major bowel resection conditions. - Liver disease characterized by any of the following: ○AST and ALT ≥ 3 × ULN or ○ Other conditions corresponding to decompensated liver disease, such as impaired excretory or synthetic function, coagulation disorders, hepatic encephalopathy, hypoalbuminemia, ascites, bleeding from esophageal varices, etc. or • Active viral, active autoimmune, alcoholic, or other types of acute hepatitis. Active viral hepatitis B is defined as having a positive hepatitis B surface antigen (HBsAg). Patients who have previously been infected with the hepatitis B virus (HBV) or who have recovered from HBV infection (positive for hepatitis B core antibody [HBcAb]-HbcAb but negative for HBsAg) are eligible only if their HBV DNA test is negative. Patients who test positive for hepatitis C virus (HCV) antibodies are only eligible if their PCR test is negative for HCV RNA. - For Japanese patients participating in continuous / intensive pharmacokinetic (PK) sample collection only: They must have received a potent CYP450 3A inhibitor or inducer within 14 days prior to the first dose of the study treatment and within 3 weeks of the start of alectinib administration. - Exclusion criteria based on local package inserts or guidelines regarding chemotherapy - Symptomatic bradycardia patients - Organ transplant history - Known HIV-positive or AIDS-related disease - Clinically significant comorbidities or conditions that the principal investigator believes may interfere with the conduct of this study or the absorption of oral medications, or that may interfere with such treatments, or that pose an unacceptable risk to patients in this study. - Any psychological, familial, sociological, or geographical conditions that may potentially hinder compliance with the trial protocol requirements and / or follow-up procedures; such conditions should be discussed with the patient prior to enrollment in the trial.

[0198] End of exam This trial will be event-driven, with an enrollment period of approximately three years. The number of events required for the primary analysis of the primary endpoint is expected to occur approximately 60 months after the enrollment of the first patient. Patients will be treated until the first completion of treatment (24 months for alectinib and 4 cycles [21-day cycles] of platinum-based chemotherapy), disease relapse, unacceptable toxicity, withdrawal of consent, or death.

[0199] Exam period The final survival follow-up analysis will be conducted approximately five years after the last patient was enrolled. The trial will officially conclude once the final survival follow-up analysis is complete.

[0200] Investigational drug The investigational drugs (IMPs) for this trial are alectinib and platinum-based chemotherapy.

[0201] Test product (investigational drug) Alectinib is provided in capsule form containing the following active ingredient: 9-Ethyl-6,6-dimethyl-8-[4-(morpholine-4-yl)piperidine-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride.

[0202] Each capsule contains alectinib hydrochloride equivalent to 150 mg of alectinib (as free base), along with lactose monohydrate, carboxymethylcellulose calcium, hydroxypropylcellulose, sodium lauryl sulfate (SLS), and magnesium stearate as excipients.

[0203] Alectinib 600 mg (four 150 mg capsules) is administered orally twice daily with meals, in the morning and evening. The first dose of the study drug must be administered as soon as possible after randomization, and within 7 days of randomization. Treatment will continue until completion of the treatment period (24 months), disease recurrence, unacceptable toxicity, withdrawal of consent, or death occurs for the first time.

[0204] If a scheduled dose of alectinib is missed, the missed dose may be taken as a make-up dose, provided that it is not less than six hours before the next scheduled dose. If vomiting occurs after taking alectinib, the patient should take the next dose as usual at the next scheduled dose time. The patient should not take two doses at once to make up for a missed dose.

[0205] The patient records the daily dosage and time in a diary (patient medication diary).

[0206] comparator Four cycles of platinum-based chemotherapy will be provided, each cycle lasting 21 days. The principal investigator may select one of the approved platinum-based chemotherapy regimens, including: - Day 1: Cisplatin 75 mg / m² 2 +Vinorelbine 25 mg / m² on day 1 and day 8 2 - Day 1: Cisplatin 75 mg / m² 2 +Gemcitabine 1250 mg / m² on days 1 and 8 2 - Day 1: Cisplatin 75 mg / m² 2 +1 day: Pemetrexed 500 mg / m² 2

[0207] Taking into account any necessary premedication, the first dose of the investigational drug must be administered as soon as possible after randomization, and within 7 days of randomization. Treatment will continue until completion of the treatment period (4 cycles), disease recurrence, unacceptable toxicity, withdrawal of consent, or death occurs for the first time.

[0208] Regarding the administration of chemotherapy, each facility shall follow standard administration procedures (e.g., order and timing of administration). Patients must receive appropriate premedication, antiemetics, and intravenous fluid replacement for platinum-based therapy, in accordance with local standard treatment and prescribing information.

[0209] Platinum-based chemotherapy cycles may be postponed for safety reasons. However, if the interruption exceeds 21 days (=1 cycle), that cycle will be considered skipped. This does not prevent the principal investigator from completing four cycles.

[0210] The selected cisplatin-based chemotherapy regimen should remain the same throughout all cycles. Carboplatin may be used in patients who experience unacceptable toxicity from cisplatin. The principal investigator must report any switch from a cisplatin-based regimen to a carboplatin-based regimen to the medical monitor.

[0211] statistical methods Main analysis Primary and secondary efficacy analyses will be conducted for all randomized patients (ITT population) and the Stage II–IIIa subgroups. The same analytical methods will be applied to both the ITT population and the Stage II–IIIa subgroups.

[0212] Safety analyses will be conducted for all randomized patients who receive at least one dose of the investigational drug.

[0213] Determination of the number of cases Approximately 255 patients are expected to be randomized to this trial. The number of patients with stage Ib will be limited to 25% to ensure that at least 75% of all randomized patients have disease in stages II–IIIa. The resulting ITT population of all randomized patients will include at least 191 patients in the stage II–IIIa subgroup.

[0214] Registration is expected to occur at a rate of 0.034 patients per facility per month, with approximately 200 facilities participating. Details of the registration are as follows: - Months 1-2: 1 patient per month - Month 3: 2 patients per month - Month 4: 3 patients per month - Months 5-6: 4 patients per month - Months 7-9: 5 patients per month -Months 10-12: 7 patients per month - From the 13th month onward: 8 patients per month

[0215] Based on these assumptions, the registration process is expected to take approximately 38 months to complete.

[0216] The sample size and number of events required to demonstrate efficacy in the primary analysis of DFS, the primary efficacy endpoint, are based on the following assumptions: - The overall two-sided significance level for the Stage II-IIIa subgroup and the ITT group is set at 0.05. -Assuming that the alectinib group improves median disease-free survival (DFS) from 30 months to 55 months compared to the chemotherapy group in the Stage II-IIIa subgroup, the power to detect a hazard ratio (HR) of 0.55 is 80%. -Assuming that in the ITT population, the alectinib group shows an improvement in median disease-free survival (DFS) from 36 months to 62 months compared to the chemotherapy group, the power to detect a hazard ratio (HR) of 0.58 is 80%. - An interim analysis of the DFS will be performed once when approximately 67% of all DFS events have occurred, using the Lan-DeMets approximation for the O'Brien-Fleming boundary.

[0217] Based on these assumptions, the primary DFS analysis will be performed when approximately 89 DFS events have been observed in the Stage II-IIIa subgroup. This is predicted to occur approximately 60 months (5 years) after the initial patients were randomized.

[0218] The focus of this clinical trial is hypothesis testing, aiming to verify whether alectinib demonstrates superiority over chemotherapy in terms of disease-free survival (DFS). To maintain an overall significance level with a two-sided error rate of 0.05, comparisons of DFS between the alectinib group and the chemotherapy group in the stage II-IIIa subgroup and the ITT group will be conducted hierarchically as follows: - Disease-free survival (DFS) in the Stage II–IIIa subgroup will be tested first at an overall two-sided alpha level of 0.05. If the two-sided p-value corresponding to the stratified log-rank test is less than 0.0464 in the primary analysis (to adjust for one interim analysis for efficacy), the null hypothesis will be rejected, and it will be concluded that alectinib extends the duration of DFS compared to chemotherapy in the Stage II–IIIa subgroup. The termination threshold will be adjusted according to the actual number of DFS events. - If alectinib significantly prolongs DFS in the stage II-IIIa subgroup, DFS in the ITT population will be tested at an overall two-sided alpha level of 0.05. If the two-sided p-value corresponding to the stratified log-rank test is less than 0.0463 in the primary analysis (to adjust for one interim analysis for efficacy), the null hypothesis is rejected and it is concluded that alectinib prolongs the duration of DFS compared to chemotherapy in the ITT population. The termination threshold will be adjusted according to the actual number of DFS events.

[0219] If alectinib does not have a significant effect on DFS in the stage II-IIIa subgroup, DFS in the ITT group will not be tested.

[0220] Interim analysis The trial will include one interim efficacy analysis regarding DFS. This interim analysis will be conducted after approximately 67% of events have been observed in the Stage II–IIIa subgroup. Based on the assumptions outlined in the protocol, this corresponds to approximately 59 DFS events in the Stage II–IIIa subgroup. This is predicted to occur approximately 44 months after the initial patients were randomized (i.e., approximately 16 months before the primary analysis), however, the exact timing of this analysis will depend on the actual number of DFS events in the Stage II–IIIa subgroup and not on the number of DFS events observed in the ITT population.

[0221] To control for Type I errors, the stopping boundary in the interim and primary analyses of DFS is calculated using the Lan-DeMets approximation to the O'Brien-Fleming boundary. In the Stage II–IIIa subgroups, the stopping boundary for early rejection of the null hypothesis at the overall two-sided significance level of 5% is HR ≤ 0.52 (p ≤ 0.0118). In the ITT subgroup, the stopping boundary for early rejection of the null hypothesis at the overall two-sided significance level of 5% is HR ≤ 0.55 (p ≤ 0.0121). If the observation rate of DFS events in the ITT subgroup is less than 67% when the number of events required for the interim analysis is reached in the Stage II–IIIa subgroups, the stopping boundary is adjusted according to the actual number of DFS events observed in the ITT subgroup. However, the ITT interim analysis is performed only if the null hypothesis is rejected early in the Stage II–IIIa subgroups.

[0222] An external iDMC will continuously evaluate safety data and review interim analysis data. All summaries and analyses prepared for iDMC review by treatment group will be prepared by an external, independent data coordination center. Members of the iDMC are independent external parties, independent of the trial sponsor, and act in accordance with a charter outlining their roles and responsibilities. The results of these reviews, which may affect the conduct of the trial, will be communicated to the principal investigator in a timely manner for notification to the Institutional Review Board (IRB) / Ethics Committee (EC). A detailed plan is included in the iDMC charter. Even if the interim analysis shows positive efficacy results, the trial methodology and the timing of disease assessment will not be changed.

[0223] Primary efficacy endpoints The primary efficacy objective of this trial is to evaluate the efficacy of alectinib compared to platinum-based chemotherapy, using disease-free survival (DFS) as the criterion. Disease-free survival is defined as the period from randomization to the first confirmed recurrence of the disease or new primary NSCLC, as determined by the principal investigator based on a comprehensive assessment of imaging data, biopsy results (where clinically possible), and clinical findings, or death from any cause, whichever comes first.

[0224] Patients who have not reported experiencing disease relapse, new primary NSCLC, or death will be censored on the date of their last disease assessment. If post-baseline data are unavailable, patients will be censored on the date of randomization.

[0225] To maintain the overall significance level at a two-sided error ratio of 0.05, comparisons of DFS between the alectinib group and the chemotherapy group in the Stage II-IIIa subgroup and the ITT group will be performed hierarchically.

[0226] The null hypothesis (H0) and alternative hypothesis (HA) regarding DFS in the population (stage II-IIIa subgroups and ITT population) can be expressed as follows, based on the DFS survival distribution function (SDF) of the alectinib group and the SDF of the control group, respectively: H0:SDF (Alectinib) = SDF (Chemotherapy) versus H A :SDF (Alectinib) ≠ SDF (Chemotherapy)

[0227] The hazard ratio (HR) in the Stage II–IIIa subgroup is estimated using a stratified Cox regression model with race as the stratification factor, and calculated with a 95% confidence interval. In the ITT population, all stratification factors specified for randomization are used in the stratified Cox regression model. Strata with fewer than 20 patients are pooled for analysis in the stratified Cox regression model. Unstratified HRs are also presented. The median DFS for each treatment group is estimated using the Kaplan-Meier method, and Kaplan-Meier curves are created to visually show the difference between the treatment group and the control group.

[0228] The Brookmeyer-Crowley methodology was used to construct the 95% confidence interval for the median DFS in each treatment group.

[0229] In addition, the impact of loss of follow-up on DFS will be evaluated based on the number of patients who lost follow-up. If more than 5% of patients lost follow-up in terms of DFS in either treatment group, a sensitivity analysis ("worst-case" analysis) will be performed, and patients who lost follow-up will be treated as having relapsed at the time of the final disease evaluation.

[0230] result Compared to platinum-based chemotherapy, alectinib demonstrated a statistically significant and clinically significant improvement in disease-free survival (DFS) as an adjuvant therapy in patients with completely resected anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) of stage IB-IIIA (UICC / AJCC 7th edition).

[0231] A total of 257 patients were enrolled, including 26 stage IB patients, 92 stage II patients, and 139 stage IIIA patients.

[0232] An interim analysis (conducted after 59 events in the Stage II-Stage IIIA subgroup) revealed that treatment with alectinib resulted in a 76% reduction in disease relapse or new primary NSCLC compared to chemotherapy (hazard ratio: 0.24). The results are shown in Table 1 and Figure 1. [Table 1] CI = Confidence Interval NE = Unable to evaluate

[0233] In the treatment-intended population (stage IB [tumor ≥ 4 cm] to stage IIIA), treatment with alectinib resulted in a superior 76% reduction in disease recurrence or new primary NSCLC compared to chemotherapy (hazard ratio 0.24). The results are shown in Table 2 and Figure 2. [Table 2] CI = Confidence Interval NE = Unable to evaluate

[0234] The results were analyzed by subgroups (age, sex, race, ECOG performance status, smoking history, and disease stage). The results are shown in Table 3 and Figure 3. A total of 114 non-Asian patients and 143 Asian patients were enrolled. The results are shown in Table 3 below: [Table 3] CI = Confidence Interval NE = Unable to evaluate

[0235] Alectinib demonstrated outstanding and remarkable results in non-Asian populations, reducing disease relapse or new primary NSCLC by 84% compared to standard platinum-based chemotherapy (hazard ratio: 0.16). In Asian populations, a 64% reduction was achieved (hazard ratio: 0.36).

[0236] CNS-free survival was evaluated in the intention-to-treat population (Table 4 and Figure 4). Treatment with alectinib resulted in a clinically significant prolongation of CNS-free survival compared with chemotherapy (hazard ratio: 0.22).

Table 4

[0237] Compared with chemotherapy, alectinib showed improvements in the number of adverse events leading to treatment discontinuation, neutrophil and leukocyte counts, as well as improvements in asthenia, nausea, vomiting, anorexia, malaise, neutropenia, fatigue and tinnitus.

[0238] This result is surprising and unexpected because alectinib is the first and only ALK inhibitor that has demonstrated a reduction in the risk of disease recurrence or death in patients with treatment-naive ALK-positive NSCLC in Phase III trials. Currently, there are no approved ALK inhibitors for treatment-naive ALK-positive disease for treating cancer before it metastasizes.

[0239] Furthermore, alectinib treatment as described demonstrated improved health-related quality of life compared with chemotherapy. Health-related quality of life is an important clinical consideration for adjuvant treatment in resected ALK+ NSCLC, and was evaluated using SF-36v2, a well-established and validated health status assessment tool. Improvements in both mental and physical health-related quality of life were shown with alectinib treatment.

Claims

1. A method for treating anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), comprising administering a therapeutically effective dose of alectinib or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, wherein the subject is an ALK-positive NSCLC of stage Ib to stage IIIa with a tumor of 4 cm or larger that has been resected.

2. A method for preventing recurrence of ALK-positive NSCLC in a subject, comprising administering a therapeutically effective dose of alectinib or a pharmaceutically acceptable salt thereof to the subject, wherein the subject is ALK-positive NSCLC of stage Ib to stage IIIa with a tumor of 4 cm or larger that has been resected.

3. The method according to claim 1 or claim 2, wherein the subject is an ALK-positive NSCLC of stage II to stage IIIA that has been resected.

4. The method according to claim 1 or claim 2, wherein the subject is an ALK-positive NSCLC of stage Ib to stage IIb having a tumor of 4 cm or larger and has been resected.

5. The method according to claim 1 or claim 2, wherein the subject is a stage Ib ALK-positive NSCLC having a tumor of 4 cm or more that has been resected.

6. The method according to any one of claims 1 to 3, wherein the subject is a stage II ALK-positive NSCLC that has been resected.

7. The method according to any one of claims 1 to 3, wherein the subject is a stage IIIa ALK-positive NSCLC that has been resected.

8. The method according to any one of claims 1 to 7, wherein the stage of ALK-positive NSCLC is histologically confirmed.

9. The method according to any one of claims 1 to 8, wherein the subject does not have metastatic ALK-positive NSCLC.

10. The method according to any one of claims 1 to 9, wherein the alectinib or a pharmaceutically acceptable salt thereof is administered as adjuvant therapy.

11. The method according to any one of claims 1 to 10, wherein the subject is an ALK-positive NSCLC that has been completely resected with negative margins.

12. The method according to any one of claims 1 to 11, wherein the resection is by lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy.

13. The method according to any one of claims 1 to 12, wherein the subject does not have a mutation that confers resistance to an ALK inhibitor.

14. The method according to any one of claims 1 to 13, wherein the subject has not previously received administration of an ALK inhibitor.

15. The method according to any one of claims 1 to 14, wherein the subject has not previously received adjuvant radiotherapy.

16. The method according to any one of claims 1 to 15, wherein the alectinib or a pharmaceutically acceptable salt thereof is administered orally.

17. The method according to any one of claims 1 to 16, wherein the alectinib or a pharmaceutically acceptable salt thereof is administered twice daily.

18. The method according to any one of claims 1 to 17, wherein the total daily dose of alectinib or a pharmaceutically acceptable salt thereof is 600 mg to 1500 mg, preferably 1200 mg, and more preferably 600 mg BID.

19. The method according to any one of claims 1 to 18, wherein the alectinib or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition.

20. The method according to claim 19, wherein the pharmaceutical composition comprises alectinib hydrochloride.

21. The method according to claim 19 or claim 20, wherein the pharmaceutical composition comprises lactose monohydrate, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate, and carboxymethylcellulose calcium.

22. The method according to any one of claims 19 to 21, wherein the pharmaceutical composition is formulated as a capsule, preferably a hard capsule.

23. The method according to claim 22, wherein the capsule contains alectinib hydrochloride equivalent to 150 mg of alectinib as a free base.

24. The method according to claim 22 or claim 23, wherein the capsule contains 33.7 mg of lactose monohydrate and 6 mg of sodium lauryl sulfate.

25. The method according to any one of claims 1 to 24, further comprising administering a therapeutically effective amount of a second therapeutic agent.

26. The method according to claim 25, wherein the second therapeutic agent is selected from the group comprising chemotherapeutic agents, hormone therapy agents, immunotherapy agents, and molecular targeting agents.

27. The method according to any one of claims 1 to 26, wherein the likelihood of recurrence of ALK-positive NSCLC in the subject is reduced compared to treatment with platinum-based chemotherapy.

28. Alectinib or a pharmaceutically acceptable salt thereof for use in a method of treating ALK-positive NSCLC in subjects, wherein the subjects are resected ALK-positive NSCLC of stage Ib to stage IIIa having tumors of 4 cm or larger.

29. Alectinib or a pharmaceutically acceptable salt thereof for use in a method for preventing recurrence of ALK-positive NSCLC in a subject, wherein the subject is ALK-positive NSCLC of stage Ib to stage IIIa with a tumor of 4 cm or larger that has been resected.

30. Alectinib or a pharmaceutically acceptable salt thereof for use according to claim 28 or 29, wherein the alectinib or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition.

31. The subject is alectinib, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 28 to 30, wherein ALK-positive NSCLC of stage II to stage IIIA has been resected.

32. The subject is alectinib, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 28 to 30, for ALK-positive NSCLC of stage Ib to stage IIb having a tumor of 4 cm or larger that has been resected.

33. The subject is alectinib, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 28 to 30, for use in a stage Ib ALK-positive NSCLC having a tumor of 4 cm or larger that has been resected.

34. The subject is alectinib, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 28 to 31, in which stage II ALK-positive NSCLC has been resected.

35. The subject is alectinib, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 28 to 31, wherein stage IIIa ALK-positive NSCLC has been resected.

36. alectinib for use according to any one of claims 28 to 35, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, wherein the stage of ALK-positive NSCLC is histologically confirmed.

37. Alectinib for use according to any one of claims 28 to 36, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, wherein the subject does not have metastatic ALK-positive NSCLC.

38. Alectinib, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 28 to 37, wherein the alectinib or a pharmaceutically acceptable salt thereof is administered as adjuvant therapy.

39. The subject is alectinib, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 28 to 38, wherein ALK-positive NSCLC is completely resected with negative margins.

40. Alectinib for use according to any one of claims 28 to 39, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, wherein the resection is by lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy.

41. Alectinib for use according to any one of claims 28 to 40, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, wherein the subject does not have a mutation that confers resistance to an ALK inhibitor.

42. Alectinib, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 28 to 41, wherein the subject has not previously received administration of an ALK inhibitor.

43. Alectinib, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 28 to 42, wherein the subject has not previously received adjuvant radiotherapy.

44. Alectinib, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 28 to 43, wherein the alectinib, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition is administered orally.

45. Alectinib, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 28 to 44, wherein the alectinib, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition is administered twice daily.

46. Alectinib, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 28 to 45, wherein the total daily dose of alectinib or a pharmaceutically acceptable salt thereof is 600 mg to 1500 mg, preferably 1200 mg, and more preferably 600 mg BID.

47. The pharmaceutical composition for use according to any one of claims 30 to 46, wherein the pharmaceutical composition comprises alectinib hydrochloride.

48. The pharmaceutical composition for use according to any one of claims 30 to 47, wherein the pharmaceutical composition comprises lactose monohydrate, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate, and carboxymethylcellulose calcium.

49. The pharmaceutical composition for use according to any one of claims 30 to 48, wherein the pharmaceutical composition is formulated as a capsule, preferably a hard capsule.

50. The pharmaceutical composition for use according to claim 49, wherein the capsule contains alectinib hydrochloride equivalent to 150 mg of alectinib as a free base.

51. The pharmaceutical composition for use according to claim 49 or claim 50, wherein the capsule comprises 33.7 mg of lactose monohydrate and 6 mg of sodium lauryl sulfate.

52. Alectinib, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 28 to 51, further comprising administering a therapeutically effective amount of a second therapeutic agent.

53. Alectinib for use according to claim 52, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, wherein the second therapeutic agent is selected from the group comprising chemotherapeutic agents, hormone therapy agents, immunotherapy agents, and molecular targeting agents.

54. Alectinib, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 28 to 53, wherein the likelihood of recurrence of ALK-positive NSCLC in the subject is reduced compared to treatment with platinum-based chemotherapy.

55. A method for treating ALK-positive NSCLC in subjects requiring treatment for ALK-positive NSCLC, or for preventing recurrence of ALK-positive NSCLC in subjects requiring prevention of recurrence of ALK-positive NSCLC, The subjects mentioned above are ALK-positive NSCLC of stage Ib to stage IIIa with tumors of 4 cm or larger that have been resected. The method comprises administering to the subject a pharmaceutical composition containing alectinib hydrochloride equivalent to 150 mg of alectinib as a free base, lactose monohydrate, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate, and carboxymethylcellulose calcium. The aforementioned pharmaceutical composition is administered orally twice a day. A method wherein the total daily dose of alectinib corresponds to 1200 mg of alectinib as a free base.

56. A pharmaceutical composition for use in a method for treating ALK-positive NSCLC in a subject or for preventing recurrence of ALK-positive NSCLC in a subject, The subjects mentioned above are ALK-positive NSCLC of stage Ib to stage IIIa with tumors of 4 cm or larger that have been resected. The pharmaceutical composition comprises alectinib hydrochloride equivalent to 150 mg of alectinib as a free base, lactose monohydrate, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate, and carboxymethylcellulose calcium. The aforementioned pharmaceutical composition is administered orally twice a day. A pharmaceutical composition in which the total daily dose of alectinib corresponds to 1200 mg of alectinib as a free base.

57. The use of a therapeutically effective dose of alectinib or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for use in the treatment of ALK-positive NSCLC in subjects, wherein the subjects are ALK-positive NSCLC of stage Ib to stage IIIa with tumors of 4 cm or larger that have been resected.

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