Treatment of non-small cell lung cancer using afatinib

Abstract

The present invention relates to a method of treating anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), the method comprising administering to a subject in need of such treatment a therapeutically effective amount of afatinib or a pharmaceutically acceptable salt thereof wherein the subject has an ALK-positive NSCLC in the Ib stage to an ALK-positive NSCLC in the IIIa stage of greater than or equal to 4 cm of the resected tumor.

Description

TECHNICAL FIELD

[0001] The present application relates to a method of treating anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC), the method comprising administering to a subject in need of such treatment a therapeutically effective amount of alectinib, or a pharmaceutically acceptable salt thereof, wherein the subject has resected early stage ALK positive NSCLC. BACKGROUND

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

[0003] Due to its late diagnosis and limited availability of effective treatments, survival rates for lung cancer are often lower than for other common cancers. About 60% of patients diagnosed with NSCLC 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% are diagnosed with stage IIIa. The 5-year survival rate for advanced and metastatic disease is very low, reported to range between 1% and 5%. For early stage, the 5-year survival rate is reported to be higher, ranging between 14% and 70%, depending on the extent of the disease at diagnosis and available treatment options.

[0004] Despite adjuvant chemotherapy, about half of patients with NSCLC experience disease recurrence after surgery, thus there is an urgent need for new treatments to provide the best chance of cure.

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

[0006] In advanced and metastatic settings, there are currently four approved treatments for patients with ALK-positive NSCLC that have shown to provide clinical benefit and good tolerability compared to the previously used standard of care, 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 gained marketing authorisation as first- or second-line treatment for advanced and metastatic ALK-positive NSCLC. Alectinib is described in WO 2010 / 143664, WO 2012 / 023597 and WO 2015 / 163448.

[0008] Despite the progress made in the treatment of NSCLC, there is still a search for improved therapies, in particular in the context of adjuvant therapy and early stage NSCLC. SUMMARY

[0009] The present inventors have shown that alectinib adjuvant therapy is surprisingly effective in preventing disease recurrence in early stage ALK-positive NSCLC.

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

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

[0012] In some embodiments, the subject has stage II to stage IIIA ALK-positive NSCLC with resected.

[0013] In some embodiments, the subject has stage Ib ALK-positive NSCLC to stage IIb ALK-positive NSCLC with resected tumor greater than or equal to 4 cm.

[0014] In some embodiments, the subject has stage Ib ALK-positive NSCLC with resected tumor greater than or equal to 4 cm.

[0015] In some embodiments, the subject has resected Stage II ALK-positive NSCLC.

[0016] In some embodiments, the subject has resected Stage IIIa ALK-positive NSCLC.

[0017] In some embodiments, the stage of the 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 can have ALK-positive NSCLC that is completely resected, and negative for margins. Resection can be by lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy.

[0021] In some embodiments, the subject does not comprise a mutation conferring resistance to an ALK inhibitor.

[0022] In some embodiments, the subject has not been previously exposed to an ALK inhibitor. In some embodiments, the subject has not received prior adjuvant radiotherapy.

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

[0024] The total daily dose of alectinib or a pharmaceutically acceptable salt thereof can be between 600 and 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 the form of a pharmaceutical composition. Preferably, the pharmaceutical composition comprises alectinib hydrochloride. The pharmaceutical composition can comprise lactose monohydrate, hydroxypropylcellulose, sodium laurylsulfate, magnesium stearate, and calcium carboxymethylcellulose. The pharmaceutical composition can be formulated into a capsule, preferably a hard capsule. Preferably, the capsule comprises alectinib hydrochloride equivalent to 150 mg of alectinib in the free base form. Preferably, the capsule comprises 33.7 mg lactose monohydrate and 6 mg sodium laurylsulfate.

[0026] In some embodiments, the method further comprises administering a therapeutically effective amount of a second therapeutic agent. The second therapeutic agent can be selected from the group comprising a chemotherapeutic agent, a hormonal therapy agent, an immunotherapeutic agent, a molecularly targeted agent.

[0027] The present invention also provides alectinib or a pharmaceutically acceptable salt thereof for use in treating a subject with ALK-positive NSCLC, wherein the subject has stage Ib to IIIa ALK-positive NSCLC with a resected tumor ≥ 4 cm.

[0028] This invention provides alectinib or a pharmaceutically acceptable salt thereof for use in a method of preventing recurrence of ALK-positive NSCLC in a subject, wherein the subject has stage Ib to IIIa ALK-positive NSCLC with a resected tumor ≥ 4 cm.

[0029] This invention provides the use of a therapeutically effective amount of alectinib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a subject with ALK-positive NSCLC, wherein the subject has stage Ib to stage IIIa ALK-positive NSCLC with a resected tumor ≥ 4 cm. Attached Figure Description

[0030] Figure 1 – Primary endpoint: Kaplan-Meier plot of disease-free survival (DFS) in the investigator-assessed stage II to IIIA population.

[0031] Figure 2 – Primary endpoint: Kaplan-Meier plot of DFS in investigator-assessed intention-to-treat patients.

[0032] Figure 3 – Forest plot of DFS subgroup analysis for patients with intention to receive treatment.

[0033] Figure 4 – Exploratory endpoint: Kaplan-Meier plot of CNS disease-free survival in patients with intention to receive treatment. Detailed Implementation

[0034] Alectinib Alectinib is a tetracyclic compound represented by the following formula (I): , It has the compound name 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carboxynitrile (CAS numbers 1256580-46-7 and 1256589-74-8, for hydrochloride).

[0035] Alectinib and its salts can be produced by methods commonly known in the art, such as the general method described in WO 2010 / 143664 (see in particular Example 366, compound “F6-20”). See also WO 2012 / 023597 (see in particular Production Example 30, compound “F6-20”).

[0036] Alectinib has been approved for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test. This approval covers patients with previously untreated metastatic lung cancer whose tumors have… ALK Oncogenic alterations in the gene (also known as ALK-positive). The FDA has previously approved alectinib as a second-line therapy for patients with ALK-positive NSCLC whose tumors are resistant to crizotinib or who no longer tolerate treatment due to side effects.

[0037] As used in this article, alectinib can be used in the form of a free base, or alternatively in the form of a pharmaceutically acceptable salt.

[0038] Pharmaceutically acceptable salts include their suitable acid addition salts or base salts. A review of suitable pharmaceutical salts can be found in Berge. et al. Found in J Pharm Sci, 66, 1-19 (1977). Salts are formed from acids such as: strong inorganic acids, such as mineral acids, such as hydrohalic acids (such as hydrochlorides, hydrobroms, and hydroiodides), sulfuric acid, phosphate sulfates, hydrogen sulfates, hemisulfates, thiocyanates, persulfates, and sulfonic acids; strong organic carboxylic acids, such as unsubstituted or substituted (e.g., halogenated) alkane carboxylic acids with 1 to 4 carbon atoms, such as acetic acid; saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or tetraphthalic acid; hydroxy carboxylic 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 unsubstituted or substituted (e.g., halogenated) (C1-C4)-alkyl- or aryl-sulfonic acids, such as methanesulfonic acid or p-toluenesulfonic acid.

[0039] Examples of preferred salts include hydrochlorides, hydrobroms, hydroiodates, phosphates, phosphonates, sulfates, hydrogen sulfates, hemisulfates, sulfonates (such as methanesulfonates and p-toluenesulfonates); carboxylates, such as acetates, trifluoroacetates, citrates, malates, maleates, tartrates, succinates, and salicylates; alkali metal salts, such as sodium salts and potassium salts; alkaline earth metal salts, such as magnesium salts and calcium salts; and ammonium salts, such as ammonium salts (NH4X:X is a monovalent acid group), alkylammonium salts, dialkylammonium salts, trialkylammonium salts, and tetraalkylammonium salts.

[0040] In a preferred embodiment, alectinib is in the form of hydrochloride, more preferably in the form of monohydrochloride.

[0041] The present invention also includes a solvate form of alectinib. Preferably, the solvate is a hydrate.

[0042] In one embodiment, alectinib is in the form of a hydrated monohydrochloride, more preferably in the form of a monohydrate.

[0043] Alectinib or its pharmaceutically acceptable salts may be in amorphous or crystalline form.

[0044] This invention covers the use of alectinib in various crystalline, polymorphic, and (anhydrous) hydrated forms. It is well established in the pharmaceutical industry that the chemical compound can be isolated in any of these forms by slightly altering the method of purification and / or separation from the solvent used in the synthesis of such compounds.

[0045] In one embodiment, alectinib is in an amorphous form. The amorphous monohydrochloride form of alectinib can be produced in accordance with the teachings of WO 2016 / 021707.

[0046] In one embodiment, alectinib is in crystalline form, preferably in the form of a monohydrochloride salt. Suitable crystalline forms are known in the art and are taught, for example, in WO 2015 / 163448 and WO 2015 / 163447.

[0047] This invention includes 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 centers and are composed of Cahn, Ingold, and Prelog. R and SSequencing rules are described. Such conventions are well known in the art (see, for example, "Advanced Organic Chemistry", 3rd edition, March, J. ed., John Wiley and Sons, New York, 1985). Compounds containing chiral centers can be used as racemic mixtures, mixtures enriched with enantiomers, or racemic mixtures can be separated using well-known techniques, and individual enantiomers can be used alone.

[0048] Pharmaceutical composition For use according to the invention, alectinib or a pharmaceutically acceptable salt thereof is typically formulated with one or more pharmaceutically acceptable carriers, diluents, or excipients. The carrier must be acceptable in the sense of compatibility with other components of the formulation and harmlessness to its recipient.

[0049] Examples of suitable excipients for the various forms of pharmaceutical compositions described herein can be found in "Handbook of Pharmaceutical Excipients," 2nd edition, (1994), edited by Awade and PJ Weller. A carrier, or if more than one carrier, must be acceptable in the sense of compatibility with the other components of the formulation and harmlessness to the recipient.

[0050] Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical industry and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro, ed. 1985).

[0051] Examples of suitable carriers include lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, and sorbitol. Examples of suitable diluents include ethanol, glycerol, and water.

[0052] The choice of drug carrier, excipient, or diluent can be made based on the intended route of administration and standard pharmaceutical practice. A pharmaceutical composition may contain, as a carrier, excipient, or diluent, or any suitable binder, lubricant, suspending agent, coating agent, solubilizer, buffer, flavoring agent, surfactant, thickener, preservative (including antioxidants), disintegrant, solubilizing agent, and substances included to make the formulation isotonic with the blood of the intended recipient.

[0053] Preservatives, stabilizers, dyes, and even flavoring agents can be provided in pharmaceutical compositions. Examples of preservatives include sodium benzoate, esters of sorbic acid and p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

[0054] Examples of suitable adhesives include hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, polyvinylpyrrolidone, polyethylene glycol (macrogol), powdered gum arabic, starch, gelatin, natural sugars (such as glucose), anhydrous lactose, free-flowing lactose, β-lactose, corn sweeteners, natural and synthetic gums (such as gum arabic, tragacanth, or sodium alginate), and polyethylene glycol. Hydroxypropyl cellulose is a preferred adhesive.

[0055] Examples of suitable lubricants include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, and sodium stearoyl fumarate. Preferably, magnesium stearate may be mentioned.

[0056] Examples of suitable stabilizers include parabens, such as methylparaben and propylparaben; alcohols, such as chlorobutanol, benzyl alcohol and phenylethanol; benzalkonium chloride; phenols, such as phenol and cresol; thimerosal, dehydroacetic acid and sorbic acid.

[0057] Examples of suitable flavoring agents include sweeteners, acidulants, and spices.

[0058] Examples of suitable disintegrants include sodium glycolate starch, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose (calcium carboxymethyl cellulose), sodium bicarbonate, pregelatinized starch, sodium chloride, corn starch, cross-linked sodium carboxymethyl cellulose, crystalline cellulose, silicic anhydride, sodium carboxymethyl cellulose, etc.

[0059] Examples of suitable solvent aids include surfactants, organic polymers, and pH adjusters. Preferred examples include casein, sodium caseinate, skim milk powder, sodium lauryl sulfate (hereinafter also referred to as SLS), dioctyl sodium sulfosuccinate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene 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 dodecylbenzene sulfonate.

[0060] Suitable solubilizers include surfactants, organic polymers, and pH adjusters.

[0061] Examples of surfactants include ionic surfactants and nonionic surfactants. Based on the charge of the ions to be generated, ionic surfactants are further classified into anionic surfactants, cationic surfactants, and amphoteric surfactants. Examples of nonionic surfactants include sugar ester surfactants, such as sorbitol fatty acid esters (C12-18), POE sorbitol fatty acid esters (C12-18), and sucrose fatty acid esters; fatty acid ester surfactants, such as POE fatty acid esters (C12-18), POE resin esters, and POE fatty acid diesters (C12-18); alcohol surfactants, such as POE alkyl ethers (C12-18); alkylphenol surfactants, such as POE alkyl (C8-12) phenyl ethers, POE dialkyl (C8-12) phenyl ethers, and POE alkyl (C8-12) phenyl ether formalin condensates; polyoxyethylene-polyoxypropylene block polymer surfactants, such as polyoxyethylene-polyoxypropylene block polymers and alkyl (C12-18) polyoxyethylene-polyoxypropylene block polymer ethers; and alkylamine surfactants, such as POE alkylamines (C12-18) and POE... Fatty acid amides (C12-18); bisphenol surfactants, such as POE fatty acid diphenyl ether; polycyclic aromatic surfactants, such as POA benzylphenyl (or phenylphenyl) ether and POA styrylphenyl (or phenylphenyl) ether; POE ethers and ester-type silicone and fluorosurfactants; and vegetable oil surfactants, such as POE castor oil and POE hydrogenated castor oil.

[0062] Examples of anionic surfactants include sulfate surfactants such as 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 and polyoxypropylene block polymer sulfates (Na, NH4, alkanolamine); sulfonate surfactants such as paraffin (alkane) sulfonates (C12-22, Na, Ca, alkanolamine), AOS (C14-16, Na, alkanolamine), dialkyl sulfosuccinates (C8-12, Na, Ca, Mg), alkylbenzene sulfonates (C12, Na, Ca, Mg, NH4, alkylamine, alkanol, amine, cyclohexylamine), and mono- or dialkyl (C3-6) surfactants. Naphthalene sulfonates (Na, NH4, alkanolamine, Ca, Mg), naphthalene sulfonate-formalin condensates (Na, NH4), alkyl (C8-12) diphenyl ether disulfonates (Na, NH4), lignin sulfonates (Na, Ca), POE alkyl (C8-12) phenyl ether sulfonates (Na) and POE alkyl (C12-18) ether sulfosuccinate half-esters (Na); carboxylic acid surfactants, such as fatty acid salts (C12-18, Na, K, NH4, alkanolamine), N-methyl-fatty acid sarcosinates (C12-18, Na) and resin salts (Na, K); and phosphate surfactants, such as POE alkyl (C12-18) ether phosphates (Na, alkanolamine), POE mono- or dialkyl (C8-12) phenyl ether phosphates (Na, alkanolamine), POE... Benzylated (or styrenated) phenyl (or phenylphenyl) ether phosphates (Na, alkanolamine), polyoxyethylene-polyoxypropylene block polymers (Na, alkanolamine), phosphatidylcholine-phosphatidylethanolimide (lecithin), and alkyl (C8-12) phosphates. Preferably, references are made to 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 dodecylbenzene sulfonate.

[0063] Sodium lauryl sulfate is a particularly preferred surfactant. In this invention, when using sodium lauryl sulfate, it is more preferable to obtain its crystals by crystallization rather than spray drying. As crystalline polymorphs of sodium lauryl sulfate, monohydrate, half hydrate, eighth hydrate, and nonsolvent are known (Journal of Crystal Growth 263(2004) 480-490). Any crystal can be used.

[0064] In one embodiment, alectinib or a pharmaceutically acceptable salt thereof is formulated according to the teachings of WO 2012 / 023597. For example, in a preferred embodiment, the composition comprises alectinib or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and a solubilizing agent.

[0065] In another embodiment, alectinib or a pharmaceutically acceptable salt thereof is formulated in accordance with the teachings of WO 2015 / 163448. For example, in a preferred embodiment, the pharmaceutical composition comprises (i) particles containing alectinib or a pharmaceutically acceptable salt thereof, and (ii) a disintegrant.

[0066] "Disintegrant" is a component that promotes rapid disintegration of oral solid dosage forms. Suitable examples are as described above. Disintegrants may be contained in the granules or added to the granules as external additives. Other additives, such as lubricants and fluidizing agents, may further optionally be added as external additives or contained in the granules. In one embodiment, the granules (i) contain 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.

[0067] In a preferred embodiment, alectinib or a pharmaceutically acceptable salt thereof is formulated for oral administration, i.e., the composition is an oral formulation.

[0068] In one embodiment, the composition is formulated into tablets. A suitable coating agent may be further applied to the tablets to obtain sugar-coated tablets or film-coated tablets. Suitable coating agents are known to those skilled in the art.

[0069] In a preferred embodiment, the pharmaceutical composition comprises alectinib or a pharmaceutically acceptable salt thereof, lactose monohydrate, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate, and calcium carboxymethyl cellulose.

[0070] Preferably, the pharmaceutical composition is in capsule form, more preferably in hard capsule form.

[0071] Preferably, the composition is provided in a capsule shell comprising hydroxypropyl methylcellulose, carrageenan, potassium chloride, titanium dioxide (E171), corn starch and carnauba wax.

[0072] The formulations of the present invention preferably contain alectinib or a pharmaceutically acceptable salt thereof, in an amount of, for example, about 20 to about 70 wt%, preferably about 30 to about 60 wt%, and particularly preferably about 35 to about 60 wt%, based on the total amount of the formulation and calculated as free base alectinib.

[0073] More specifically, if the formulation of the present invention is a capsule, it contains alectinib or a pharmaceutically acceptable salt thereof in an amount preferably, for example, about 20 to about 70 wt%, preferably about 30 to about 60 wt%, and particularly preferably about 35 to about 60 wt%, based on the total amount of the components to be placed in the capsule, in terms of the free base alectinib.

[0074] 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 to 240 mg, preferably 100 to 200 mg, and particularly preferably 140 to 190 mg, per unit dosage form of free base alectinib.

[0075] In a preferred embodiment, the composition is in the form of a unit dosage form comprising alectinib hydrochloride equivalent to about 150 mg of alectinib in the form of free base.

[0076] In a preferred embodiment, the formulation is a formulation comprising alectinib hydrochloride equivalent to about 150 mg of free base per dosage form, about 33.7 mg of lactose (as a monohydrate), and about 6 mg of sodium (as sodium lauryl sulfate).

[0077] The pharmaceutical composition described above can be prepared by methods including associating the active compound with a carrier (e.g., by mixing).

[0078] Where appropriate, formulations can be conveniently present in discrete dosage units and can be prepared by any method known in the pharmaceutical field. All methods involve the step of associating the active compound with a liquid carrier or a finely chopped solid carrier, or both, and then, if desired, shaping the product into the desired formulation.

[0079] Dose The composition can be administered orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisionally, intravaginally, intraperitoneally, intravesically, and topically (intravenous infusion, powder, ointment, gel, or cream) and by inhalation (oral or nasal spray). Examples of dosage forms include tablets, capsules, granules, powders, pills, aqueous and non-aqueous oral solutions and suspensions, as well as parenteral solutions with unit doses placed in small containers. Dosage forms can be designed to suit various methods of administration, including controlled-release formulations intended for subcutaneous transplantation.

[0080] The dosage form is preferably administered orally as a tablet, capsule, granule or powder formulation.

[0081] Preferably, the dosage form is capsules.

[0082] In this invention, "oral preparation" refers to a preparation that can be administered orally. Oral administration means swallowing the preparation to enter the gastrointestinal tract, and the active ingredient is mainly absorbed through the intestines.

[0083] Specific examples of oral dosage forms include solid dosage forms such as tablets, capsules, solutions, powders, lozenges, chewable tablets, granules, gels, films, and sprays, as well as liquid dosage forms. Examples of liquid dosage forms include suspensions, solutions, syrups, and elixirs. Such dosage forms can be used as fillers in soft or hard capsules. Typically, a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil is used, along with one or more emulsifiers and / or suspending agents. Liquid dosage forms can also be prepared by dissolving a unit dose of a solid pharmaceutical preparation, for example, by dissolving a packaged pharmaceutical composition into a carrier such as water.

[0084] The dosage of the active ingredient (the compound of formula (I) or its salt of the present invention) can vary depending on symptoms, age, weight, relative health condition, other medications, method of administration, etc. For example, the generally effective amount of the active ingredient (the compound of formula (I) or its salt of the present invention) administered orally to a patient (warm-blooded animal, particularly a human) is preferably 0.001 to 1000 mg per body weight (1 kg) per day, and more preferably 0.01 to 300 mg. The daily dose preferably falls within the range of 1 to 1500 mg per adult patient of normal weight. In the case of parenteral administration, the dosage is preferably 0.001 to 1000 mg per body weight (1 kg) per day, and more preferably 0.01 to 300 mg. Ideally, it is administered once daily or divided into several doses according to symptoms.

[0085] In one embodiment, alectinib or a pharmaceutically acceptable salt thereof is administered twice daily.

[0086] The preferred total daily dose of alectinib (free base equivalent) is 1 to 1500 mg, 100 to 1400 mg, 200 to 1300 mg, 400 to 1200 mg, 600 to 1500 mg, 700 to 1500 mg, 800 to 1500 mg, 900 to 1500 mg, 600 to 1200 mg, 700 to 1200 mg, 800 to 1200 mg, 900 to 1200 mg, or 1000 to 1200 mg.

[0087] In one embodiment, the total daily dose is 900 mg alectinib (free base equivalent). Preferably, 450 mg is administered twice daily.

[0088] In one embodiment, the total daily dose is 1200 mg alectinib (free base equivalent). Preferably, 600 mg is administered twice daily. Preferably, alectinib is administered twice daily in the form of four 150 mg capsules.

[0089] In a further embodiment, the alectinib dose of 600 mg BID can be reduced to 450 mg BID or 300 mg BID in 150 mg increments to reduce side effects. Such side effects may include any one or a combination of the following: localized pneumonia, pneumonia, appendicitis, acute myocardial infarction, nausea, weakness, fatigue, tinnitus, vomiting, weight gain, decreased appetite, diarrhea, constipation, headache, cough, rash, anemia, dyspnea, peripheral edema, taste disturbance, increased serum creatinine, neutropenia, decreased neutrophil count, decreased white blood cell count, increased serum creatine phosphokinase, increased aspartate aminotransferase, increased alanine aminotransferase, hyperbilirubinemia, COVID-19, muscle pain, increased blood alkaline phosphatase, and / or product dose omission problems.

[0090] Treatment may continue until the end of the treatment period, disease relapse, 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.

[0091] Disease As used herein, the term “tumor” refers to all proliferative cell growth and proliferation, whether malignant or benign, as well as all precancerous and cancerous cells and tissues. The terms “cancer,” “cancerous,” and “tumor” are not mutually exclusive in this article.

[0092] The terms “cancer” and “cancerous” refer to or describe a physiological condition in mammals that is typically characterized by unregulated cell growth. This definition includes both benign and malignant cancers.

[0093] "Early-stage cancer" or "early-stage tumor" refers to non-invasive or metastatic cancer or cancer classified as stage 0, I, or II.

[0094] Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma (including medulloblastoma and retinoblastoma), sarcoma (including liposarcoma and synovial cell sarcoma), neuroendocrine tumors (including carcinoid tumors, gastrinoma and islet cell carcinoma), mesothelioma, schwannoma (including acoustic neuroma), meningioma, adenocarcinoma, melanoma and leukemia or lymphoid malignancies. More specific examples of this type of cancer include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, and lung squamous cell carcinoma), peritoneal cancer, hepatocellular carcinoma, gastric / stomach cancer (including gastrointestinal cancers), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer (including metastatic breast cancer), colon cancer, rectal cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cell carcinoma, prostate cancer, vulvar cancer, thyroid cancer, hepatocellular carcinoma, anal cancer, penile cancer, Merkel cell carcinoma, mycosis fungoides, testicular cancer, esophageal cancer, biliary tract tumors, and head and neck cancers and hematologic malignancies.

[0095] NSCLC includes squamous NSCLC and non-squamous NSCLC, adenocarcinoma, and large cell carcinoma.

[0096] In some embodiments, the cancer is ALK positive.

[0097] In a preferred embodiment, the cancer is ALK-positive NSCLC.

[0098] "ALK positive" or "ALK" refers to cancer expressing anaplastic lymphoma kinase. In some embodiments, expression is caused by gene rearrangement, which leads to... ALK Other genes (such as EML4 K IF5B , KLC1 , TFG , TPR , HIP1 , STRN , DCTN1 , SQSTM1 , NPM1 , BCL11A and B IRC6 Integration.

[0099] A positive ALK result can be determined through FDA-approved and CE-marked testing or through the central Ventana ALKIHC research center.

[0100] Methods for determining ALK positivity (e.g., reverse transcription-PCR) are known. Assays such as fluorescence in situ hybridization, IHC, PCR, and sequencing can be used to determine ALK positivity in fusions in tissue samples. Testing for several important biomarkers is challenging due to the difficulty of tissue sampling and the very small sample sizes from tissue biopsies of lung cancer patients. Analyzing plasma ALK assays of circulating tumor nucleic acids would enable more patients with NSCLC to be tested for ALK fusions and could also be used to monitor changes in ALK rearrangements during ALK inhibitor therapy.

[0101] In some embodiments, the Ventana ALK (D5F3) CDx assay (Ventana Medical Systems, Tucson, Arizona, USA) is used to determine ALK positivity.

[0102] In some embodiments, subjects did not exhibit resistance to ALK inhibitors.

[0103] In some embodiments, the subject does not contain mutations that confer resistance to ALK inhibitors.

[0104] In some embodiments, subjects did not exhibit biomarkers associated with resistance to ALK inhibitors.

[0105] The molecular mechanisms of resistance to ALK inhibitors (including mutations and related biomarkers) may include: secondary mutations in the ALK gene (e.g., gate gene mutations), increased copy number of the ALK gene, increased expression of ALK mRNA, and ALK-independent resistance mechanisms through activation of other oncogenes and pathways (such as EGFR, cKIT, MET, or KRAS).

[0106] Disease stage Disease staging is based on the TNM classification system of the Union for International Cancer Control (UICC) / American Joint Committee on Cancer (AJCC) 7th edition.

[0107] T staging is determined by the size of the primary tumor along its long axis or the extent to which the tumor extends into adjacent structures (such as the mediastinum or chest wall): TX, primary tumor cannot be assessed, or is confirmed by the presence of malignant cells in sputum or bronchoalveolar lavage fluid, but cannot be observed by imaging or bronchoscopy; T0, no evidence of primary tumor; Tis, In situCancer; T1, tumor with a maximum size of 3 cm or less, surrounded by the lung or visceral pleura, with no bronchoscopic evidence of invasion proximal to the lobar bronchus (T1a if 2 cm or less, T1b if more than 2 cm but less than 3 cm); T2, tumor larger than 3 cm but less than 7 cm or smaller, or a tumor with any of the following characteristics: involvement of the main bronchus, 2 cm or more distal to the carina, invasion of the visceral pleura, accompanied by atelectasis or obstructive pneumonia, extending to the hilar region but not involving the entire lung (T2a if more than 3 cm but less than 5 cm or smaller, T2b if more than 5 cm but less than 7 cm or smaller); T3, tumor larger than 7 cm, or a tumor that directly invades any of the following: parietal pleura, chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or a main bronchus tumor (less than 2 cm distal to the carina). (but not involving the carina); or accompanied by related atelectasis or obstructive pneumonia of the entire lung or a solitary tumor nodule in the same lobe; T4, any size tumor invading any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or a solitary tumor nodule in a different lobe on the same side.

[0108] The N staging describes the extent of spread to regional lymph nodes: NX, regional lymph nodes cannot be assessed; N0, no regional lymph node metastasis; N1, ipsilateral peribronchial and / or ipsilateral hilar lymph node and intrapulmonary lymph node metastasis, including direct extension; N2, ipsilateral mediastinal and / or subcarinal lymph node metastasis; and N3, contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph node metastasis.

[0109] The M staging defines the presence of metastasis outside regional lymph nodes: M0, no distant metastasis; M1, distant metastasis (M1a, solitary tumor nodule in the contralateral lobe, tumor with pleural nodule or malignant pleural (or extracardiac) effusion; M1b, distant metastasis (extrathoracic organs)).

[0110] The disease staging classification includes occult 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).

[0111] In some embodiments, the subject has stage Ib to IIIa NSCLC with a completely resected, histologically confirmed tumor size greater than or equal to 4 cm (tumor ≥ 4 cm).

[0112] In some embodiments, the subject had completely resected, histologically confirmed stage Ib (tumor ≥ 4 cm) to IIb NSCLC.

[0113] In some embodiments, the subject had completely resected, histologically confirmed stage Ib (tumor ≥ 4 cm) to IIa NSCLC.

[0114] In some embodiments, the subject has completely resected, histologically confirmed stage Ib NSCLC (tumor ≥ 4 cm).

[0115] In some embodiments, the subject has completely resected, histologically confirmed stage IIa to IIIa NSCLC.

[0116] In some embodiments, the subject has completely resected, histologically confirmed stage IIb to IIIa NSCLC.

[0117] In some embodiments, the subject has completely resected, histologically confirmed stage IIIa NSCLC.

[0118] In some embodiments, the subject has completely resected, histologically confirmed stage II NSCLC.

[0119] In some embodiments, the subject has completely resected, histologically confirmed stage IIa NSCLC.

[0120] In some embodiments, the subject has completely resected, histologically confirmed stage IIb NSCLC.

[0121] In some embodiments, the subject has a TNM classification of T2-4 N0, T1-4 N1, or T1-3 N2.

[0122] In some embodiments, the subject does not have a TNM classification of N3 or M1.

[0123] In some embodiments, the subject does not have metastatic or stage IV ALK-positive NSCLC.

[0124] As used in this article, "histologically confirmed" means determined by microscopic examination of tissue that has been removed by biopsy or surgical excision.

[0125] As used herein, “resection” refers to the surgical removal of all or part of a tumor. The tumor may be removed along with a certain amount of surrounding normal healthy tissue (surgical margin). Preferably, the subject has negative surgical margins.

[0126] In some embodiments, the resection is performed by lobectomy, sleeve lobectomy, bilateral lobectomy, or pneumonectomy. Preferably, the resection is not performed by segmentectomy or wedge resection.

[0127] Adjuvant As used herein, “adjuvant” and / or “adjuvant therapy” means a therapy given in addition to the primary or initial therapy, such as a therapy given during tumor resection.

[0128] In some embodiments, the subject had not previously received adjuvant radiation therapy.

[0129] Preferably, alectinib is administered as adjuvant therapy after complete tumor resection.

[0130] In some embodiments, alectinib is administered as adjuvant therapy after tumor resection in patients diagnosed with ALK+ NSCLC by an FDA-approved test.

[0131] As used in this article, "neoadjuvant" refers to a treatment delivered before tumor removal to help reduce tumor size.

[0132] Preferably, alectinib is not administered as neoadjuvant therapy. Preferably, alectinib is not administered to the subject prior to tumor resection.

[0133] In some embodiments, the subject had not previously been exposed to ALK inhibitors.

[0134] In some embodiments, the subject has received radiation therapy before the tumor is removed.

[0135] In some embodiments, the resection occurs between 1 and 16 weeks prior to treatment with alectinib, such as between 4 and 12 weeks, 6 and 10 weeks, 4 and 6 weeks, 6 and 8 weeks, or 8 and 12 weeks prior to treatment with alectinib. For example, the resection may occur 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks prior to treatment with alectinib.

[0136] Preferably, the resection occurs between 4 and 12 weeks prior to treatment with alectinib.

[0137] Therapeutic method The present invention provides a method for treating a subject with ALK-positive non-small cell lung cancer, the method comprising administering a therapeutically effective amount of alectinib to the subject.

[0138] 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 amount of alectinib to the subject.

[0139] The present invention provides alectinib or a pharmaceutically acceptable salt thereof for use in treating a subject with ALK-positive NSCLC, wherein the subject has stage Ib to stage IIIa ALK-positive NSCLC with a resected tumor ≥ 4 cm.

[0140] This invention provides alectinib or a pharmaceutically acceptable salt thereof for use in a method of preventing recurrence of ALK-positive NSCLC in a subject, wherein the subject has stage Ib to IIIa ALK-positive NSCLC with a resected tumor ≥ 4 cm.

[0141] In some embodiments, the subject has stage Ib (tumor ≥ 4 cm) to stage IIIa ALK-positive NSCLC.

[0142] In some embodiments, alectinib is administered as adjuvant therapy after complete tumor resection. In the context of this invention, resection refers to surgery performed prior to alectinib treatment. This invention does not relate to methods of performing surgery on the human body.

[0143] In some embodiments, alectinib is indicated as adjuvant therapy in adult patients with ALK+ NSCLC following tumor resection.

[0144] In some embodiments, alectinib is indicated as adjuvant therapy after tumor resection in adult patients with stage IB (>4cm) to IIIA ALK+ NSCLC.

[0145] In some embodiments, alectinib is indicated for adjuvant therapy following tumor resection in adult patients with stage II to IIIA ALK+ NSCLC.

[0146] As used herein, the terms "patient" or "subject" are used interchangeably to refer to any single animal, more preferably a mammal (including non-human animals such as dogs, cats, horses, rabbits, zoo animals, cattle, pigs, sheep, and non-human primates) requiring treatment. In a particular embodiment, the patient herein is a human.

[0147] In some embodiments, the patient is non-Asian.

[0148] As used herein, “treatment” refers to a clinical intervention that attempts to alter the natural processes of the individual being treated, and may be used for prevention or in the course of clinicopathology. The desired effects of treatment include, but are not limited to, preventing the onset or recurrence of disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, improving or alleviating the disease state, and mitigating or improving prognosis. In some embodiments, the compositions of the present invention are used to delay the development of disease or slow its progression.

[0149] "Individual response" or "response" may be assessed using any endpoint that indicates benefit to the individual, including but not limited to (1) inhibiting disease progression (e.g., cancer progression) to some extent, including slowing and completely blocking it; (2) reducing tumor size; (3) inhibiting (i.e., reducing, slowing or completely stopping) cancer cell infiltration into adjacent peripheral organs and / or tissues; (4) inhibiting (i.e., reducing, slowing or completely stopping) metastasis; (5) alleviating one or more symptoms associated with the disease or ailment (e.g., cancer) to some extent; (6) increasing or prolonging the length of survival, including overall survival, progression-free survival and disease-free survival; and / or (9) reducing mortality at a given time point after treatment.

[0150] A patient’s “effective response” to a drug or treatment, or a patient’s “responsiveness” and similar terms, refers to a clinical or therapeutic benefit given to a patient who is at risk of or has a disease or condition such as cancer. In one embodiment, such benefit includes any one or more of the following: prolonged survival (including overall survival, progression-free survival, and disease-free survival); resulting in an objective response (including a complete response or a partial response); or improvement of signs or symptoms of cancer.

[0151] "Objective response" refers to a measurable response, including complete response (CR) or partial response (PR). As used in this article, "objective response rate (ORR)" refers to the sum of the complete response (CR) rate and the partial response (PR) rate.

[0152] "Complete remission" or "CR" means that all signs of cancer have disappeared in response to treatment (e.g., disappearance of all target lesions). This does not always mean that the cancer has been cured.

[0153] "Sustained response" refers to a sustained effect on reducing tumor growth after treatment has ceased. For example, the tumor size may remain the same or smaller compared to its size at the start of the administration phase. In some embodiments, the duration of sustained response is at least the same as the duration of treatment, and is at least 1.5X, 2.0X, 2.5X, or 3.0X longer or longer than the duration of treatment. As used herein, "reducing or inhibiting cancer recurrence" means reducing or inhibiting tumor or cancer recurrence or tumor or cancer progression. As disclosed herein, cancer recurrence and / or cancer progression includes, but is not limited to, cancer metastasis.

[0154] As used herein, "partial response" or "PR" refers to a reduction in the size of one or more tumors or lesions or a reduction in the degree of cancer in vivo in response to treatment. For example, in some embodiments, PR refers to a reduction of at least 30% in the sum of the SLDs of the target lesion relative to the baseline longest diameter (SLD).

[0155] As used in this article, "stable disease" or "SD" refers to the minimum SLD since the start of treatment, where the target lesion has neither shrunk sufficiently to meet PR nor increased sufficiently to meet PD.

[0156] The term "survival" refers to a patient still being alive, and includes overall survival and progression-free survival.

[0157] As used in this article, “progression-free survival” (PFS) refers to the length of time during and after treatment during which the treated disease (e.g., cancer) does not worsen. PFS can include the amount of time a patient experiences a full or partial response, as well as the amount of time a patient experiences stable disease.

[0158] As used in this article, “disease-free survival” (DFS) refers to the time from randomization to the first recorded relapse of disease or new primary NSCLC – determined by the investigator through a comprehensive assessment of imaging data, biopsy results (if clinically feasible), and clinical status – or death from any cause (whichever occurs first).

[0159] "Prolonged survival" refers to an increase in total survival or progression-free survival in treated patients relative to untreated patients (i.e., patients who have not received drug treatment) and / or patients treated with approved antitumor agents.

[0160] As used herein, “delayed progression” of a disease means a delay, impede, slow, postpone, stabilize, and / or postpone the development of a disease (such as cancer, e.g., NSCLC, such as squamous or non-squamous NSCLC)). This delay can have varying lengths of time, depending on medical history and / or the individual to be treated. It will be apparent to those skilled in the art that a sufficient or significant delay can effectively encompass prevention, as the individual will not develop the disease. For example, the development of advanced cancers, such as metastases, may be delayed.

[0161] As used in this article, "prevention" means reducing the likelihood of disease recurrence compared to platinum-based chemotherapy.

[0162] A hazard ratio is the probability of an event occurring in the treatment group relative to the probability in the control group per unit of time. Therefore, in this context, the hazard ratio may be related to the probability of DFS-related events in the alectinib treatment group versus the chemotherapy treatment group. For example, a hazard ratio of 0.16 means that alectinib provides an 84% reduction in the risk of DFS-related events compared to the chemotherapy (control) group.

[0163] For example, in some embodiments, compared with treatment with platinum-based chemotherapy without alectinib, administration of alectinib increases the likelihood of a subject having an objective response (e.g., CR), prolongs the subject's PFS, prolongs the subject's DFS, prolongs the subject's OS, and / or prolongs the subject's DOR.

[0164] In some embodiments, alectinib increases the likelihood of a subject having an objective response compared to treatment with platinum-based chemotherapy without alectinib. In some embodiments, alectinib increases the likelihood of a subject achieving complete remission (CR) compared to treatment with platinum-based chemotherapy without alectinib. In some embodiments, alectinib prolongs progression-free survival (PFS) compared to treatment with platinum-based chemotherapy without alectinib. In some embodiments, alectinib prolongs disease-free survival (DFS) compared to treatment with platinum-based chemotherapy without alectinib. In some embodiments, alectinib prolongs overall survival (OS) compared to treatment with platinum-based chemotherapy without alectinib. In some embodiments, alectinib prolongs disease-free response (DOR) compared to treatment with platinum-based chemotherapy without alectinib. In some embodiments, administration of alectinib to a subject prolongs the objective response rate (ORR) compared to administration of platinum-based chemotherapy without alectinib.

[0165] 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).

[0166] In some embodiments of this disclosure, administration of alectinib to subjects prolonged disease-free survival (DFS) compared to administration of platinum-based chemotherapy in the absence of alectinib. For example, compared to administering platinum-based chemotherapy without alectinib, administering alectinib to subjects can prolong disease-free survival (DFS) by approximately 1 month to approximately 5 months, approximately 2 months to approximately 4 months, approximately 2.1 months to approximately 3.9 months, approximately 2.5 months to approximately 3.5 months, or approximately 2.8 months to approximately 3.4 months (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, 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).

[0167] In some embodiments, administration of alectinib to a subject reduces the likelihood of disease relapse compared to administration of platinum-based chemotherapy without alectinib. For example, administration of alectinib to a subject reduces the likelihood of disease relapse by approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% compared to administration of platinum-based chemotherapy without alectinib. Preferably, administration of alectinib to a subject reduces the likelihood of disease relapse by approximately 60% to 90%, such as 75% to 85%, compared to administration of platinum-based chemotherapy without alectinib.

[0168] In some embodiments, alectinib has improved safety profiles compared to platinum-based chemotherapy without alectinib. For example, compared to treatment with platinum-based chemotherapy, alectinib can reduce the number of adverse events leading to treatment discontinuation, improve neutrophil and / or white blood cell counts, and / or reduce the incidence of weakness, nausea, vomiting, decreased appetite, malaise, neutropenia, fatigue, and / or tinnitus.

[0169] In some embodiments, platinum-based chemotherapy comprises platinum-based chemotherapeutic agents and nucleoside analogs.

[0170] In some embodiments, the platinum-based chemotherapeutic agent is cisplatin, carboplatin, or oxaliplatin.

[0171] In some embodiments, the platinum-based chemotherapy agent is cisplatin.

[0172] In some embodiments, the nucleoside analogue is gemcitabine.

[0173] In some embodiments, platinum-based chemotherapy includes cisplatin and gemcitabine.

[0174] In some embodiments, platinum-based chemotherapy comprises cisplatin and pemetrexed.

[0175] In some embodiments, platinum-based chemotherapy includes cisplatin and vinorelbine.

[0176] In some embodiments, platinum-based chemotherapy is selected from: - Day 1 Cisplatin 75 mg / m 2 Add vinorelbine 25 mg / m² on days 1 and 8. 2 - Day 1 Cisplatin 75 mg / m 2 Add gemcitabine 1250mg / m² on days 1 and 8. 2 - Day 1 Cisplatin 75 mg / m 2 Add pemetrexed 500 mg / m² on day 1. 2 .

[0177] In some embodiments, platinum-based chemotherapy is provided for four cycles, each lasting 21 days.

[0178] In some cases, the method further includes administering an effective amount of a second therapeutic agent to the patient. In some cases, the second therapeutic agent is selected from the group consisting of: chemotherapeutic agents, hormonal agents, immunotherapeutic agents, molecularly targeted agents, etc.

[0179] Examples of "chemotherapy agents" include alkylating agents, platinum preparations, metabolic antagonists, topoisomerase inhibitors, anticancer antibiotics, and plant-derived anticancer agents. Examples of "alkylating agents" include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan, nimustin hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustin, estramustin sodium phosphate, and triethylenetricyanamide. Melamine), carmustine, lomustine, streptozocin, pipobroman, etoglucid, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribomustin, temozolomide, treosulphan, trophosphamide, zinostatin stimalamer, carboquinone, adozelesin, cystemustine, and bizelesin. Examples of "platinum preparations" include carboplatin, cisplatin, miboplatin, nedaplatin, and oxaliplatin.Examples of “metabolic antagonists” include mercaptopurine, 6-mercaptopurine nucleoside, thioinosine, methotrexate, enocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride, and 5-FU-based drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, gallocitabine, and emmitefur). (e.g., aminopterin, calcium leucovorin, tabloid, butocine, leucovorin, levoleucine, cladribine, emetifur, fludarabine, gemcitabine, hydrocycarbamide, pentostatin, piritrexim, idoxuridine, mitoguazone, thiazoplirine, and ambamustine.) Topoisomerase I inhibitors (e.g., irinotecan and topotecan, etc.) and topoisomerase II inhibitors (e.g., sobuzozosen, etc.).Examples of "anticancer antibiotic materials" include anthracycline-based anticancer agents (doxorubicin hydrochloride, daunorubicin hydrochloride, acrarubicin hydrochloride, pirarubicin hydrochloride, and epirubicin hydrochloride, etc.), actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, neocarzinostatin, mithramycin, sarcomycin, carzinophilin, mitotam, zorubicin hydrochloride, mitoxantrone hydrochloride, and idarubicin hydrochloride. Examples of “plant-derived anticancer agents” include vinca alkaloids (vincrine sulfate, vincristine sulfate, and vindesine sulfate), taxanes (paclitaxel and docetaxel, etc.), etoposide, etoposide phosphate, teniposide, and vinorelbine.

[0180] Examples of "hormone therapy agents" include drugs based on adrenocortical hormones (e.g., dexamethasone, prednisolone, betamethasone, and triamcinolone). Among these, prednisolone is preferred.

[0181] Examples of “immunotherapy agents (BRM)” include picibanil, krestin, sisofiran, lentinan, ubenimex, interferon, interleukin, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, lymphotoxin, BCG vaccine, Corynebacterium pumilus, levamisole, polysaccharide K, and procodazole.

[0182] "Molecular targets" include "drugs that inhibit the function of cell proliferation factors and their receptors," etc. Examples of "cell proliferation factors" can be any substance that can promote cell proliferation and include peptides with a molecular weight of 20,000 or less that exhibit their 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, 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), (5) other cell proliferation 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.], etc.

[0183] "Receptors of cell proliferation factors" can be any receptor, as long as it has the ability to bind to the aforementioned cell proliferation factors. Specific examples include EGF receptor, HER2 receptor, 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 proliferation factors" include Herceptin (HER2 antibody), GLEEVEC (c-kit, abl inhibitor), and Iressa (EGF receptor inhibitor).

[0184] Furthermore, this also includes drugs that, even as a single agent, inhibit the activity of multiple cell proliferation factors, or drugs that block cell signals generated by cell proliferation factors.

[0185] In addition to the drugs mentioned above, L-asparaginase, aceglaton, procarbazine hydrochloride, protoporphyrin-cobalt complex, mercury porphyrin-sodium, differentiation promoters (such as retinoids, vitamin D, etc.), angiogenesis inhibitors, and α-blockers (such as tamsulosin hydrochloride, etc.) can also be used.

[0186] Examples Clinical trial protocol - study design Study description This randomized, active-controlled, multicenter, open-label phase III study aims to investigate the efficacy and safety of alectinib compared to platinum-based chemotherapy in adjuvant therapy. The primary endpoint is investigator-assessed disease-free survival (DFS), while overall survival (OS) is a secondary endpoint.

[0187] This study will include approximately 200 centers in about 30 countries worldwide. Central randomization will be conducted via an interactive voice or web-based response system (IxRS). Randomized patients will be stratified according to disease severity (stage Ib [tumor ≥4 cm] vs. stage II vs. stage IIIa) and ethnicity (Asian vs. non-Asian). The IxRS provider will provide relevant instructions to each research center.

[0188] Patients with completely resected (negative margins), histologically confirmed stage Ib (tumor ≥4 cm) to IIIa NSCLC (according to the 7th edition of the Union Internationale Contre le Cancer (UICC) / American Joint Committee on Cancer (AJCC)) and documented ALK-positive disease with a test approved by the US Food and Drug Administration (FDA) and the European Conformité Européenne (CE) mark, and meeting all the necessary eligibility criteria, were randomized 1:1.

[0189] Staging must be performed according to UICC / AJCC version 7, not version 8. Patients with stage Ib NSCLC (classified according to version 7) with tumors ≥4 cm have been shown to derive less benefit from adjuvant chemotherapy than patients with stage II to IIIa NSCLC, and this has been taken into account in the statistical analysis of recruitment caps, stratification, and primary endpoints.

[0190] Patients in the experimental group will receive 600 mg of alectinib orally twice daily (BID) for 24 months with food.

[0191] Patients in the control group will receive one platinum-based chemotherapy regimen (including all necessary preoperative medications and permitted concomitant medications) as specified in the protocol, based on local prescribing information. The platinum-based chemotherapy regimens defined in the protocol include: - Day 1 Cisplatin 75 mg / m 2 Add vinorelbine 25 mg / m² on days 1 and 8. 2 - Day 1 Cisplatin 75 mg / m 2 Add gemcitabine 1250mg / m² on days 1 and 8. 2 - Day 1 Cisplatin 75 mg / m 2 Add pemetrexed 500 mg / m² on day 1 2 Platinum-based chemotherapy will be provided for four cycles, each lasting 21 days. In cases of intolerance to cisplatin-based regimens, carboplatin may be administered instead of cisplatin in one of the above combinations.

[0192] Postoperative radiotherapy (PORT) was not permitted as a treatment option. Therefore, patients with stage IIIa N2 NSCLC whom the researchers believed should receive PORT were excluded from the study.

[0193] Follow-up will continue until the end of treatment (24 months for alectinib and 4 cycles for chemotherapy), disease relapse, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first. Patients who complete the study regimen or discontinue treatment before disease relapse (e.g., due to unacceptable toxicity) will continue to be followed until disease relapse. Upon disease relapse, the investigator will treat the patient as appropriate according to local clinical practice. Cross-treatment between the two groups is not permitted.

[0194] During the planned competitive recruitment period of approximately 38 months, approximately 255 patients will be enrolled in the study. Patients improperly randomized to the study will not be replaced. A primary DFS analysis will be conducted after approximately 89 DFS events have been observed in the stage II to IIIa subgroups. This is expected to occur approximately 60 months after the first patient is randomized. Data collection for each patient will continue until death or the end of the study, whichever occurs first.

[0195] An independent data monitoring committee (iDMC) will be established to monitor the progress of the study and ensure that the safety of patients enrolled in the study is not compromised.

[0196] All randomized patients will receive scheduled, regular follow-up visits until disease relapse, death, withdrawal from the study, or study termination, whichever occurs first. Regular safety assessments will be conducted in both groups during treatment. Safety follow-up visits will be conducted 28 days after the last alectinib dose 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 at baseline and every 3 weeks (i.e., one chemotherapy cycle) for both groups. 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 for safety monitoring will be made to patients in the chemotherapy group at the same time points (weeks 2, 4, 8, and 10). From week 12, safety monitoring of patients in the alectinib group will continue until treatment is discontinued, every 6 weeks until week 48, and every 12 weeks from week 49 to week 96. Scheduled disease assessments will be conducted at baseline in both groups, every 12 weeks for the first two years, every 24 weeks from years 3 to 5, and annually thereafter, until disease relapse, death, loss to follow-up, withdrawal of consent, or termination of the study by the sponsor, whichever occurs first. Unscheduled assessments may be conducted at any time if clinically indicated. Positive efficacy results from interim analyses will not affect the timing of disease assessments during the study period.

[0197] Number of patients It is estimated that approximately 255 patients will be enrolled in this study at around 200 research centers worldwide.

[0198] Target population Inclusion criteria: Patients must meet the following criteria for study entry: - Sign the informed consent form - Must be 18 years of age or older when signing the informed consent form. - Complete resection of histologically confirmed stage Ib (tumor ≥ 4 cm) to IIIa (T2-3 N0, T1-3 N1, T1-3 N2, T4 N0-1) NSCLC (according to UICC / AJCC 7th edition) with negative margins 4 to 12 weeks prior to enrollment. ○ Acceptable resection types include any of the following: lobectomy, sleeve lobectomy, bilateral lobectomy, or pneumonectomy.

[0199] ○ Resection via segmentectomy or wedge resection is not permitted.

[0200] ○ N3 disease is not permitted.

[0201] - If mediastinoscopy was not performed preoperatively, at least mediastinal lymph node sampling is expected. ○ System sampling is defined as removing at least one representative lymph node at a specified level.

[0202] ○ Total mediastinal lymph node dissection (MLND) is preferred. MLND requires the removal of all lymph nodes at the same level.

[0203] For patients who have undergone right thoracotomy, sampling or MLND should be performed at levels 4 and 7; for patients who have undergone left thoracotomy, sampling or MLND should be performed at levels 5 and / or 6 and 7.

[0204] ○ Exceptions will be granted in the following cases: ○ If the patient is already recorded as having a grade 1 N2 disease (according to the UICC / AJCC staging system, version 7), then sampling for all grades is not required.

[0205] ○ If the preoperative staging imaging results (computed tomography [CT] and positron emission tomography [PET] scans) do not indicate evidence of mediastinal disease, the patient may be considered eligible even if N2 lymph node sampling is not performed as decided by the surgeon.

[0206] - ALK-positive disease based on FDA approval and CE marking test records. - Eligible for platinum-based chemotherapy regimens according to local labels or guidelines. - Eastern Cooperative Oncology Group (ECOG) performance status is grade 0, or - Adequate hematological function acquired within 3 days prior to the start of study treatment is defined by the following laboratory test results: ○ Platelet count ≥ 100 x 10⁹ / L ○ ANC ≥ 1500 / μL ○ Hemoglobin ≥ 9 g / dL - Appropriate renal function achieved within 3 days prior to the start of treatment is defined by the following laboratory test results: ○ Serum creatinine ≤ 1.5 x Upper Limit of Normal (ULN), and ○ Creatinine clearance (CrCl) ≥ 60 mL / min - For women of childbearing age: Agree to abstain from sexual intercourse (avoiding heterosexual intercourse) or use a contraceptive method with an annual failure rate of <1% during treatment and for at least 90 days after the last dose of alectinib or according to local labeling or guidelines for chemotherapy. ○ A woman is considered to have reproductive potential if she has not reached postmenopause (absence of menstruation for ≥12 consecutive months without a definite cause other than menopause) and is not permanently infertile due to surgery (i.e., removal of the ovaries, fallopian tubes and / or uterus) or other causes determined by the investigator (e.g., Müllerian duct hypoplasia).

[0207] Examples of contraceptive methods with an annual failure rate of <1% include bilateral tubal ligation, male sterilization, ovulation-suppressing hormonal contraceptives, hormone-releasing intrauterine devices (IUDs), and copper IUDs. Hormonal contraception must be supplemented with barrier methods.

[0208] The reliability of sexual abstinence should be assessed based on the duration of clinical trials and the patient's preferred and habitual lifestyle. Regular abstinence (e.g., calendar-based, ovulation-based, symptom-based, or post-ovulation methods) and withdrawal are unacceptable methods of contraception.

[0209] ○ Women of childbearing age must have a negative serum pregnancy test result before randomization (up to -3 days) and within 10 days after the first dose of the study drug. The first dose of the study drug (alectinib or chemotherapy) must be administered within 7 days after randomization.

[0210] - For men: Agreement to abstain from sexual intercourse (avoiding heterosexual intercourse) or use contraception, and agreement not to donate sperm, as defined below: When with a fertile female partner, the man must abstain from sex or use a condom with an annual failure rate of <1% plus additional contraception for at least 90 days during treatment and after the last dose of alectinib or, according to local labeling or guidelines for chemotherapy. During this same period, the man must avoid donating sperm.

[0211] When with a pregnant female partner, men must abstain from sex or use condoms for at least 90 days during treatment and after the last dose of alectinib or, according to local labeling or guidelines for chemotherapy, to avoid exposing the embryo.

[0212] The reliability of sexual abstinence should be assessed based on the duration of clinical trials and the patient's preferred and habitual lifestyle. Regular abstinence (e.g., calendar-based, ovulation-based, symptom-based, or post-ovulation methods) and withdrawal are unacceptable methods of contraception.

[0213] - Willingness and ability to follow planned visits, treatment plans, laboratory tests, and other research procedures. Exclusion criteria: Patients meeting any of the following criteria will be excluded from the study entry: - Pregnant or breastfeeding, or planning to become pregnant during the study period or within 90 days of the last dose of alectinib or according to local labeling or guidelines for chemotherapy. - Previous adjuvant radiation therapy for NSCLC Radiation therapy is permitted in neoadjuvant therapy and must be completed at least 4 weeks before the start of the study treatment.

[0214] - Previous exposure to systemic anticancer therapy ○ Curative anticancer therapies for early-stage malignant tumors are permitted, provided that the last dose received was administered more than 5 years prior to enrollment. Consult a medical monitor.

[0215] - Previous exposure to ALK inhibitors - Patients with stage IIIa N2 who the researchers believed should receive PORT were excluded from the study. Postoperative radiotherapy is not permitted in this study.

[0216] - Known sensitivity to any component of the investigational drug (alectinib or the 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.

[0217] - Patients must have had a malignant tumor other than NSCLC within the 5 years prior to enrollment, excluding cured basal cell carcinoma of the skin, early gastrointestinal (GI) cancer resected endoscopically, cervical carcinoma in situ, ductal carcinoma in situ, papillary thyroid carcinoma, or any cured cancer not considered to affect current DFS or OS in NSCLC. - Any GI disorder that may affect the absorption of orally administered medications, such as malabsorption syndrome or post-colon resection status. - Liver diseases characterized by any of the following: ○ ALT and AST ≥ 3 x ULN Or ○ Other conditions of liver disease with impaired excretory or synthetic functions, such as coagulopathy, hepatic encephalopathy, hypoalbuminemia, ascites, or esophageal variceal bleeding. or Active viral or active autoimmune, alcoholic or other types of acute hepatitis.

[0218] Active viral hepatitis B is defined as having a positive hepatitis B surface antigen (HBsAg).

[0219] Patients with a history of hepatitis B virus (HBV) infection or regressed HBV infection (HBcAb-HbcAb positive, but HBsAg negative) are eligible only if their HBV DNA test result is negative.

[0220] Patients who test positive for hepatitis C virus (HCV) antibodies are eligible only if their HCV RNA PCR test is negative.

[0221] - Japanese patients only participating in the serial / intensive PK sample collection: those who received a potent / high-potency CYP450 3A inhibitor or inducer within 14 days prior to the first dose of study treatment and during the period from alectinib treatment to week 3. - Any exclusion criteria based on local labeling or guidelines for chemotherapy. - Patients with symptomatic bradycardia - History of organ transplantation - Known HIV positive or AIDS-related illness - Any significant clinical comorbidity or condition that the principal investigator believes may interfere with or treat the study, or may interfere with the absorption of the oral medication, or may pose an unacceptable risk to the patients in this study. - Any psychological, family, social, or geographical conditions that may hinder compliance with study protocol requirements and / or follow-up procedures; these conditions should be discussed with the patient before entering the trial.

[0222] Study end This study is event-driven with a recruitment period of approximately 3 years. The number of events required for the primary analysis of the primary endpoint is expected to occur approximately 60 months after the first patient is enrolled. Patients will be treated until the end of the treatment period (24 months for alectinib and 4 cycles [21-day cycles] for platinum-based chemotherapy), disease relapse, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.

[0223] Study duration The final survival follow-up analysis will be conducted approximately 5 years after the last patient is enrolled. Once the final survival follow-up analysis is completed, the study will officially conclude.

[0224] Study drug The investigational drug (IMP) in this study was alectinib and platinum-based chemotherapy.

[0225] Test product (study drug) Alectinib is available in capsule form containing the following active ingredients: 9-Ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carboxynitrile hydrochloride.

[0226] Each capsule contains alectinib hydrochloride equivalent to 150 mg of alectinib (in its free base form), as well as lactose monohydrate, calcium carboxymethyl cellulose, hydroxypropyl cellulose, sodium lauryl sulfate (SLS), and magnesium stearate as excipients.

[0227] Alectinib 600 mg (four 150 mg capsules) should be taken orally twice daily with food, twice daily. The first dose of the investigational drug should be administered as soon as possible after randomization and no later than 7 days after randomization. Treatment will continue until the end of the treatment period (24 months), disease relapse, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.

[0228] If a patient misses a scheduled dose of alectinib, the missed dose can be made up unless the next dose is due within 6 hours. If vomiting occurs after taking a dose of alectinib, the patient should take the next dose at the scheduled time. Patients should not take two doses simultaneously to make up for a missed dose.

[0229] Patients will record their daily doses and times in a diary (patient dosing diary).

[0230] Comparator Platinum-based chemotherapy will be provided, lasting for four cycles, each lasting 21 days. Investigators can choose one of the permitted platinum-based chemotherapy regimens, including the following: - Day 1 Cisplatin 75 mg / m 2 Add vinorelbine 25 mg / m² on days 1 and 8. 2 - Day 1 Cisplatin 75 mg / m 2 Add gemcitabine 1250mg / m² on days 1 and 8. 2 - Day 1 Cisplatin 75 mg / m 2 Add pemetrexed 500 mg / m² on day 1 2 Considering the required preoperative medication, the first dose of the study drug should be administered as soon as possible after randomization, and no later than 7 days after randomization. Treatment will continue until the end of the treatment period (4 cycles), disease relapse, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.

[0231] Institutions should follow their standard administration protocols (e.g., administration sequence or timing) for chemotherapy. Patients must receive adequate preoperative medication, antiemetics, and IV hydration for platinum-based therapy, in accordance with local standards of care and prescribing information.

[0232] For safety reasons, platinum-based chemotherapy cycles may be delayed; however, if an interruption exceeds 21 days (equivalent to one cycle), that cycle is considered skipped. This does not prevent researchers from completing four cycles.

[0233] The chosen cisplatin-based chemotherapy regimen should be maintained throughout all cycles. For patients experiencing unacceptable toxicity from cisplatin, carboplatin may be used. Investigators should inform the medical monitor when switching from a cisplatin-based regimen to a carboplatin-based regimen.

[0234] Statistical methods Primary analysis Primary and secondary efficacy analyses will be performed on all randomly assigned patients (ITT population) and the stage II to IIIa subgroups. The same analytical methods will be applied to both the ITT population and the stage II to IIIa subgroups.

[0235] Safety analysis will be performed on all randomized patients who received at least one dose of the investigational drug.

[0236] Determination of sample size Approximately 255 patients are expected to be randomized to this study. The number of stage Ib patients will be capped at 25% to ensure that at least 75% of all randomized patients will have stage II to IIIa disease. The resulting ITT population of all randomized patients will include at least 191 patients from the stage II to IIIa subgroup.

[0237] Assuming recruitment proceeds at a rate of 0.034 patients per research center per month, there will be approximately 200 research centers in total. Recruitment details are as follows: - Months 1 to 2: 1 patient per month - Month 3: 2 patients per month - Month 4: 3 patients per month - Months 5 to 6: 4 patients per month - Months 7 to 9: 5 patients per month - Months 10 to 12: 7 patients per month - From cycle 13 onwards: 8 patients per month Based on these assumptions, enrollment will take approximately 38 months to complete.

[0238] In the primary analysis, the sample size and number of events required to demonstrate efficacy with respect to the primary efficacy endpoint DFS are based on the following assumptions: The overall two-sided significance level for the subgroups of stages II to IIIa and the ITT population was 0.05. - With a hazard ratio (HR) of 0.55 based on 80% potency, patients in the stage II to IIIa subgroup receiving alectinib had a median improvement in disease-free survival (DFS) of 30 to 55 months compared to those receiving chemotherapy. - With an HR of 0.58 at 80% potency, this corresponds to a median improvement in DFS of 36 to 62 months in the ITT population compared to patients receiving chemotherapy. - An interim analysis of the DFS was performed when approximately 67% of the total DFS events occurred, using Lan-DeMets with approximate O'Brien-Fleming boundaries. Based on these assumptions, a primary DFS analysis will be conducted after approximately 89 DFS events have been observed in the stage II to IIIa subgroups. This is expected to occur approximately 60 months (5 years) after the first patient is randomized.

[0239] The focus of this clinical trial is hypothesis testing, examining the superiority of alectinib over chemotherapy in terms of disease-free survival (DFS). To control the overall significance level at a two-sided error rate of 0.05, DFS comparisons between the alectinib and chemotherapy groups in the stage II to IIIa subgroups and the ITT population will be conducted at the following levels: Disease-free survival (DFS) in the stage II–IIIa subgroup will initially be tested at a total two-sided α level of 0.05. The null hypothesis will be rejected if the two-sided p-value corresponding to the stratified log-rank test at the primary analysis is less than 0.0464 (to be adjusted for one interim efficacy analysis), and the conclusion will be drawn that alectinib prolonged the duration of DFS relative to chemotherapy in the stage II–IIIa subgroup. The stop boundary will be adjusted based on the actual number of DFS events.

[0240] - If alectinib significantly prolongs DFS in the stage II to IIIa subgroup, DFS in the ITT population will be tested at a total two-sided α level of 0.05. The null hypothesis will be rejected if the two-sided p-value corresponding to the stratified log-rank test at the primary analysis is less than 0.0463 (to be adjusted for one interim efficacy analysis), and the conclusion will be that alectinib prolongs the duration of DFS relative to chemotherapy in the ITT population. The stop boundary will be adjusted based on the actual number of DFS events.

[0241] If alectinib has no significant effect on DFS in the stage II to IIIa subgroups, DFS in the ITT population will not be tested.

[0242] Interim analysis This study plans to conduct one interim efficacy analysis of DFS. The interim analysis will be performed after approximately 67% of events were observed in the stage II–IIIa subgroup. Based on the assumptions described in the protocol, this is associated with approximately 59 DFS events in the stage II–IIIa subgroup. This is expected to occur approximately 44 months after the first patient was randomized (i.e., approximately 16 months prior to the primary analysis), although the exact timing of this analysis will depend on the actual number of DFS events in the stage II–IIIa subgroup, but is independent of the number of DFS events observed in the ITT population.

[0243] To control for Type I errors, the stopping boundaries for the interim and primary analyses of the DFS will be calculated using Lan-DeMets, approximating the O'Brien-Fleming boundaries. In the II–IIIa subgroups, the stopping boundary for early rejection of the null hypothesis is HR ≤ 0.52 (p ≤ 0.0118) for a 5% significance level across the population. In the ITT population, the stopping boundary for early rejection of the null hypothesis is HR ≤ 0.55 (p ≤ 0.0121) for a 5% significance level across the population. If fewer than 67% of the DFS events in the ITT population are observed when the events required for the interim analysis in the II–IIIa subgroups are reached, the stopping boundaries will be adjusted based on the actual number of DFS events observed in the ITT population. However, the ITT interim analysis will only be performed if the null hypothesis for the II–IIIa subgroups is rejected early.

[0244] The external iDMC will continuously evaluate safety data and review data from interim analyses. All summaries and analyses of treatment groups submitted for iDMC review will be prepared by an external independent data coordination center. Members of the iDMC will not be affiliated with the sponsoring organization and will adhere to a charter outlining their roles and responsibilities. Any results from these reviews that affect the progress of the study will be promptly communicated to the investigators and the Institutional Review Board (IRB) / Ethics Committee (EC). A detailed plan will be included in the iDMC charter. Positive efficacy results from interim analyses will not alter the progress of the study or the timing of disease assessment.

[0245] Primary efficacy endpoint The primary efficacy objective of this study was to evaluate the efficacy of alectinib compared to platinum-based chemotherapy on the basis of disease-free survival (DFS). Disease-free survival was defined as the time from randomization to the first recorded disease relapse or new primary NSCLC – determined by the investigator through a comprehensive assessment of imaging data, biopsy results (if clinically feasible), and clinical status – or death from any cause (whichever occurs first).

[0246] Patients who have not reported experiencing disease relapse, new primary NSCLC, or death will be reviewed on the date of their last disease assessment. If no post-baseline data is available, patients will be reviewed on the date of randomization.

[0247] To control the overall significance level at a two-sided error rate of 0.05, the DFS comparison between the alectinib and chemotherapy groups in the stage II to IIIa subgroups and the ITT population will be performed stratified.

[0248] The zero (H0) and alternative (HA) assumptions about DFS in each population (phase II to IIIa subgroups and ITT population) can be expressed by the DFS survival distribution function (SDF) in the alectinib group and the SDF in the control group, respectively: H0: SDF (Alectinib) = SDF (Chemotherapy) Compared to H A SDF (alectinib) ≠ SDF (chemotherapy) HRs for stage II to IIIa subgroups will be estimated using a stratified Cox regression model with ethnicity as the stratification factor, including 95% CI. For the ITT population, all stratification factors specified for randomization will be used in the stratified Cox regression model. Stratifications of fewer than 20 patients will be pooled for analysis in the stratified Cox regression model. Unstratified HRs will also be presented. The Kaplan-Meier method will be used to estimate median DFS for each treatment group, and Kaplan-Meier curves will be constructed to provide a visual representation of the difference between the treatment and control groups.

[0249] The Brookmeyer-Crowley method will be used to construct the 95% CI for median DFS in each treatment group.

[0250] In addition, the impact of loss to follow-up on DFS will be assessed based on the number of patients lost to follow-up. If more than 5% of patients in either treatment group are lost to follow-up for DFS, a sensitivity analysis (“worst-case” analysis) will be performed, in which patients lost to follow-up will be considered as having relapsed disease on the date of the last disease assessment.

[0251] Results Compared with platinum-based chemotherapy, alectinib as adjuvant therapy in patients with completely resected stage IB to IIIA (UICC / AJCC 7th edition) anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) showed statistically and clinically significant improvements in disease-free survival (DFS).

[0252] A total of 257 patients were enrolled, including 26 patients with stage IB, 92 patients with stage II, and 139 patients with stage IIIA.

[0253] Interim analysis (performed after 59 events in the stage II to IIIA subgroups) showed that alectinib treatment reduced disease relapse or new primary NSCLC by 76% compared with chemotherapy (hazard ratio: 0.24). The results are shown in Table 1 and Figure 1.

[0254] Table 1 CI = confidence interval NE = not evaluable In the intention-to-treat population (stage IB [tumor ≥4 cm] to stage IIIA), alectinib treatment significantly reduced disease relapse or new primary NSCLC by 76% compared to chemotherapy (hazard ratio 0.24). Results are shown in Table 2 and Figure 2.

[0255] Table 2 CI = confidence interval NE = not evaluable Results were analyzed by subgroup (age, sex, race, ECOG performance status, tobacco use history, and disease stage). The results are shown in Table 3 and Figure 3. A total of 114 non-Asian and 143 Asian patients were enrolled, and the results are shown in Table 3 below: Table 3 CI = confidence interval NE = not evaluable In non-Asian populations, alectinib remarkably and surprisingly reduced 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).

[0256] CNS disease-free survival was assessed in the intention-to-treat population (Table 4 and Figure 4). Alectinib treatment resulted in a clinically meaningful prolongation of CNS disease-free survival compared to chemotherapy (hazard ratio: 0.22).

[0257] Table 4 CI = confidence interval NE = not evaluable 1 Not formally tested Compared with chemotherapy, alectinib showed improvements in the number of adverse events leading to treatment withdrawal, neutrophil and white blood cell counts, and the incidence of weakness, nausea, vomiting, decreased appetite, malaise, neutropenia, fatigue, and tinnitus.

[0258] The results were surprising and unexpected, as alectinib is the first and only ALK inhibitor to demonstrate in a Phase III trial a reduction in the risk of disease relapse or death in patients with early-stage ALK-positive NSCLC. Currently, there are no approved ALK inhibitors for early-stage ALK-positive disease, intended to treat cancer before it spreads.

[0259] Furthermore, compared to chemotherapy, the described alectinib treatment demonstrated improved health-related quality of life. Health-related quality of life is an important clinical consideration for adjuvant therapy in resected ALK NSCLC and was assessed using SF-36v2 (a well-established and validated health status assessment tool). Alectinib treatment demonstrated improvements in both mental and physical health-related quality of life.

Claims

1. A method for treating anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), the method comprising administering a therapeutically effective amount of alectinib or a pharmaceutically acceptable salt thereof to a subject requiring such treatment, wherein the subject has stage Ib to stage IIIa ALK-positive NSCLC with a resected tumor greater than or equal to 4 cm.

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

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

4. The method according to claim 1 or claim 2, wherein the subject has stage Ib to stage IIb ALK-positive NSCLC with a resected tumor ≥ 4 cm.

5. The method of claim 1 or claim 2, wherein the subject has stage Ib ALK-positive NSCLC with a resected tumor greater than or equal to 4 cm.

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

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

8. The method according to any of the preceding claims, wherein the staging of ALK-positive NSCLC is histologically confirmed.

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

10. The method according to any of the preceding claims, wherein the alectinib or a pharmaceutically acceptable salt thereof is administered as adjunctive therapy.

11. The method according to any of the preceding claims, wherein the subject has completely resected ALK-positive NSCLC with negative surgical margins.

12. The method according to any of the preceding claims, wherein the resection is performed by lobectomy, sleeve lobectomy, bilateral lobectomy or pneumonectomy.

13. The method according to any of the preceding claims, wherein the subject does not contain a mutation conferring resistance to an ALK inhibitor.

14. The method according to any of the preceding claims, wherein the subject has not previously been exposed to an ALK inhibitor.

15. The method according to any of the preceding claims, wherein the subject has not received prior adjuvant radiation therapy.

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

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

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

19. The method according to any of the preceding claims, wherein the alectinib or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition.

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

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

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

23. The method of claim 22, wherein the capsule comprises alectinib hydrochloride equivalent to 150 mg of alectinib in the form of free base.

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

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

26. The method of claim 25, wherein the second therapeutic agent is selected from the group consisting of: chemotherapeutic agents, hormone therapy agents, immunotherapy agents, and molecularly targeted agents.

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

28. Alectinib or a pharmaceutically acceptable salt thereof, used in a method of treating a subject with ALK-positive NSCLC, wherein the subject has stage Ib to stage IIIa ALK-positive NSCLC with a resected tumor ≥ 4 cm.

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

30. The alectinib or a pharmaceutically acceptable salt thereof used according to claim 28 or claim 29, wherein the alectinib or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition.

31. The alectinib, its pharmaceutically acceptable salt, or pharmaceutical composition used according to any one of claims 28 to 30, wherein the subject has resected stage II to IIIA ALK-positive NSCLC.

32. The alectinib, its pharmaceutically acceptable salt, or pharmaceutical composition used according to any one of claims 28 to 30, wherein the subject has stage Ib to IIb ALK-positive NSCLC with a resected tumor ≥ 4 cm.

33. The alectinib, its pharmaceutically acceptable salt, or pharmaceutical composition used according to any one of claims 28 to 30, wherein the subject has stage Ib ALK-positive NSCLC with a resected tumor greater than or equal to 4 cm.

34. The alectinib, its pharmaceutically acceptable salt, or pharmaceutical composition used according to any one of claims 28 to 31, wherein the subject has resected stage II ALK-positive NSCLC.

35. The alectinib, its pharmaceutically acceptable salt, or pharmaceutical composition used according to any one of claims 28 to 31, wherein the subject has resected stage IIIa ALK-positive NSCLC.

36. The alectinib, its pharmaceutically acceptable salt, or pharmaceutical composition used according to any one of claims 28 to 35, wherein the staging of ALK-positive NSCLC is histologically confirmed.

37. The alectinib, its pharmaceutically acceptable salt, or pharmaceutical composition used according to any one of claims 28 to 36, wherein the subject does not have metastatic ALK-positive NSCLC.

38. The alectinib, its pharmaceutically acceptable salt, or pharmaceutical composition used according to any one of claims 28 to 37, wherein the alectinib or its pharmaceutically acceptable salt is administered as adjunctive therapy.

39. The alectinib, its pharmaceutically acceptable salt, or pharmaceutical composition used according to any one of claims 28 to 38, wherein the subject has completely resected ALK-positive NSCLC with negative resection margins.

40. The alectinib, its pharmaceutically acceptable salt, or pharmaceutical composition used according to any one of claims 28 to 39, wherein the resection is performed by lobectomy, sleeve lobectomy, bilateral lobectomy, or pneumonectomy.

41. The alectinib, its pharmaceutically acceptable salt, or pharmaceutical composition used according to any one of claims 28 to 40, wherein the subject does not contain a mutation conferring resistance to an ALK inhibitor.

42. The alectinib, its pharmaceutically acceptable salt, or pharmaceutical composition used according to any one of claims 28 to 41, wherein the subject has not previously been exposed to an ALK inhibitor.

43. The alectinib, its pharmaceutically acceptable salt, or pharmaceutical composition used according to any one of claims 28 to 42, wherein the subject has not received prior adjuvant radiotherapy.

44. The alectinib, its pharmaceutically acceptable salt, or pharmaceutical composition used according to any one of claims 28 to 43, wherein the alectinib, its pharmaceutically acceptable salt, or pharmaceutical composition is administered orally.

45. The alectinib, its pharmaceutically acceptable salt, or pharmaceutical composition used according to any one of claims 28 to 44, wherein the alectinib, its pharmaceutically acceptable salt, or pharmaceutical composition is administered twice daily.

46. ​​The alectinib, its pharmaceutically acceptable salt, or pharmaceutical composition used according to any one of claims 28 to 45, wherein the total daily dose of alectinib or its pharmaceutically acceptable salt is between 600 and 1500 mg, preferably 1200 mg, more preferably 600 mg BID.

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

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

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

50. The pharmaceutical composition of claim 49, wherein the capsule comprises alectinib hydrochloride equivalent to 150 mg of alectinib in the form of free base.

51. The pharmaceutical composition used 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. The alectinib, its pharmaceutically acceptable salt, or pharmaceutical composition used according to any one of claims 28 to 51, further comprising administering a therapeutically effective amount of a second therapeutic agent.

53. The alectinib, its pharmaceutically acceptable salt, or pharmaceutical composition used according to claim 52, wherein the second therapeutic agent is selected from the group consisting of: chemotherapeutic agents, hormonal agents, immunotherapeutic agents, and molecularly targeted agents.

54. Alectinib, its pharmaceutically acceptable salt, or pharmaceutical composition used according to any of the preceding claims, wherein the likelihood of recurrence of ALK-positive NSCLC in the subject is reduced compared with treatment with platinum-based chemotherapy.

55. A method for treating ALK-positive NSCLC in subjects of need or preventing relapse of ALK-positive NSCLC in subjects of need, The subjects mentioned above had stage Ib to IIIa ALK-positive NSCLC with resected tumors 4 cm or larger. The method includes administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising alectinib hydrochloride (equivalent to 150 mg of alectinib in its free base form), lactose monohydrate, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate, and calcium carboxymethyl cellulose. The pharmaceutical composition is administered orally twice daily, and The total daily dose of alectinib is equivalent to 1200 mg of alectinib in the free base form.

56. A pharmaceutical composition used in a method for treating a subject with ALK-positive NSCLC or preventing relapse of ALK-positive NSCLC in a subject. The subjects mentioned above had stage Ib to IIIa ALK-positive NSCLC with resected tumors 4 cm or larger. The pharmaceutical composition comprises alectinib hydrochloride (equivalent to 150 mg of alectinib in its free base form), lactose monohydrate, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate, and calcium carboxymethyl cellulose. The pharmaceutical composition is administered orally twice daily, and The total daily dose of alectinib is equivalent to 1200 mg of alectinib in the free base form.

57. Use of a therapeutically effective amount of alectinib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament used to treat a subject with ALK-positive NSCLC, wherein the subject has stage Ib to stage IIIa ALK-positive NSCLC with a resected tumor greater than or equal to 4 cm.

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