TREATMENT OF NON-SMALL CELL LUNG CANCER WITH ALEKTINIB

Abstract

The present invention relates to a method of treating anaplastic lymphoma kinase (ALK)- positive non-small cell lung cancer (NSCLC), 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 stage Ib ALK-positive NSCLC with a tumour greater or equal to 4cm to stage IIIa ALK-positive NSCLC.

Description

[0001] TREATMENT OF NON SMALL CELL LUNG CANCER WITH ALECTINIB

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a method of treating anaplastic lymphoma kinase (ALUpositive non-small cell lung cancer (NSCLC), 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.

[0004] BACKGROUND

[0005] Cancer is a major cause of death worldwide, with non-small-cell lung cancer (NSCLC) being the leading cause of cancer-related mortality worldwide.

[0006] Survival rates for lung cancer tend to be lower than other common cancers because of its late diagnosis and limited availability of effective treatments. Around 60% of patients diagnosed with NSCLC already have advanced (Stage 11 lb) or metastatic (Stage IV) disease, whereas approximately 30% are diagnosed with early-stage disease (Stage I or II) and approximately 10% with Stage Illa. The 5-year survival rate for advanced and metastatic disease is very poor with the reported range between 1-5%. For early stages, the 5-year survival rates are reported to be higher, ranging between 14-70%, depending on the extent of the disease at diagnosis and available treatment options.

[0007] About half of people with NSCLC experience disease recurrence following surgery, despite adjuvant chemotherapy, therefore new treatments are urgently needed to provide the best chance for cure.

[0008] Approximately 4-5% of NSCLC cases have been shown to harbour the echinoderm microtubule-associated protein-like 4 (EML4) anaplastic lymphoma kinase (ALK) fusion gene a result of a chromosomal inversion at 2p21 and 2p23. Anaplastic Lymphoma Kinase is a receptor tyrosine kinase belonging to an insulin receptor family.

[0009] In the advanced and metastatic setting, there are currently four approved treatments for patients with ALK-positive NSCLC that have been shown to provide clinical benefit and favourable tolerability compared with the previously used standard of care, platinum-based chemotherapy.

[0010] 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 like alectinib, ceritinib, and brigatinib have been granted marketing authorization 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. Despite advancements in the treatment of NSCLC, improved therapies are still being sought, particularly in the adjuvant setting and in respect of early stage NSCLC.

[0011] SUMMARY OF THE INVENTION

[0012] The present inventors have shown that alectinib adjuvant therapy is surprisingly effective at preventing disease recurrence for early-stage ALK-positive NSCLC.

[0013] The invention provides a method of treating anaplastic lymphoma kinase (ALK)-positive nonsmall cell lung cancer (NSCLC), 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 stage lb ALK-positive NSCLC with a tumour greater or equal to 4cm to stage Illa ALK-positive NSCLC.

[0014] The invention further provides a method of preventing ALK-positive NSCLC recurrence in a subject, comprising administering to a subject a therapeutically effective amount of alectinib, or a pharmaceutically acceptable salt thereof, wherein the subject has resected stage lb ALK- positive NSCLC with a tumour greater or equal to 4cm to stage Illa ALK-positive NSCLC.

[0015] In some embodiments, the subject has resected stage II to stage 111 A ALK-positive NSCLC.

[0016] In some embodiments, the subject has resected stage lb ALK-positive NSCLC with a tumour greater or equal to 4cm to stage lib ALK-positive NSCLC.

[0017] In some embodiments, the subject has resected stage lb ALK-positive NSCLC with a tumour greater or equal to 4cm.

[0018] In some embodiments, the subject has resected stage II ALK-positive NSCLC.

[0019] In some embodiments, the subject has resected stage Illa ALK-positive NSCLC.

[0020] In some embodiments, the stage of ALK-positive NSCLC is histologically confirmed.

[0021] In some embodiments, the subject does not have metastatic ALK-positive NSCLC.

[0022] In some embodiments, the alectinib, or pharmaceutically acceptable salt thereof, is administered as adjuvant therapy.

[0023] The subject may have completely resected ALK-positive NSCLC with negative margins. The resection may be by lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy.

[0024] In some embodiments, the subject does not comprise a mutation conferring resistance to ALK inhibitors. In some embodiments, the subject has not had prior exposure to an ALK inhibitor. In some embodiments, the subject has not had prior adjuvant radiotherapy.

[0025] The alectinib, or a pharmaceutically acceptable salt thereof, may be administered orally. The alectinib, or a pharmaceutically acceptable salt thereof, may be administered twice daily.

[0026] The total daily dose of alectinib, or a pharmaceutically acceptable salt thereof, may be between 600 and 1500 mg, preferably 1200 mg, more preferably 600 mg two times per day (BID).

[0027] In some embodiments, the alectinib, or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical composition. Preferably, the pharmaceutical composition comprises alectinib hydrochloride. The pharmaceutical composition may comprise lactose monohydrate, hydroxypropylcellulose, sodium lauryl sulfate, magnesium stearate and carboxymethylcellulose calcium. The pharmaceutical composition may be formulated as a capsule, preferably a hard capsule. Preferably, the capsule comprises alectinib hydrochloride equivalent to 150 mg alectinib as free base. Preferably, the capsule comprises 33.7 mg lactose monohydrate and 6 mg sodium lauryl sulfate.

[0028] In some embodiments, the method further comprises administering a therapeutically effective amount of a second therapeutic agent. The second therapeutic agent may be selected from the group comprising chemotherapeutic agents, hormonal therapeutic agents, immunotherapeutic agents, molecular targeting agents.

[0029] The invention also provides alectinib, or a pharmaceutically acceptable salt thereof, for use in a method of treating ALK-positive NSCLC in a subject, wherein the subject has resected stage lb ALK-positive NSCLC with a tumour greater or equal to 4cm to stage Illa ALK-positive NSCLC.

[0030] The invention provides alectinib, or a pharmaceutically acceptable salt thereof, for use in a method of preventing ALK-positive NSCLC recurrence in a subject, wherein the subject has resected stage lb ALK-positive NSCLC with a tumour greater or equal to 4cm to stage Illa ALK-positive NSCLC.

[0031] The invention provides for use of a therapeutically effective amount of alectinib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating ALK-positive NSCLC in a subject, wherein the subject has resected stage lb ALK- positive NSCLC with a tumour greater or equal to 4cm to stage Illa ALK-positive NSCLC. DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 - Primary Endpoint: Kaplan-Meier plot of Investigator-assessed Disease-Free Survival (DFS) in the stage II to I HA population.

[0033] Figure 2 - Primary Endpoint: Kaplan-Meier Plot of plot of Investigator-assessed DFS in Intent- to-Treat patients.

[0034] Figure 3 - Forest Plot for subgroup analysis of DFS in Intent-to-Treat patients.

[0035] Figure 4 - Exploratory Endpoint: Kaplan-Meier plot of CNS-Disease Free Survival in Intent- to-Treat patients.

[0036] DETAILED DESCRIPTION OF THE INVENTION

[0037] Alectinib

[0038] Alectinib is a tetracyclic compound represented by the following formula (I): having 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-carbonitrile (CAS Nos. 1256580-46-7 and 1256589-74- 8 as hydrochloride).

[0039] Alectinib, and salts thereof, can be produced by methods commonly known in the art, for example, the general methodology 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”).

[0040] Alectinib is approved for use in the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), as detected by an FDA- approved test. The approval covers patients with previously untreated metastatic lung cancer whose tumors have a cancer-causing alteration in the ALK gene (also called ALK positive). FDA previously approved alectinib as second-line therapy for patients with ALK- positive NSCLC whose tumors are resistant to crizotinib or who can no longer tolerate the treatment due to side effects.

[0041] As used herein, alectinib can be used in free base form, or alternatively can be in the form of a pharmaceutically acceptable salt.

[0042] Pharmaceutically acceptable salts include suitable acid addition or base salts thereof. A review of suitable pharmaceutical salts may be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts are formed, for example with strong inorganic acids such as mineral acids, e.g. hydrohalic acids such as hydrochloride, hydrobromide and hydroiodide, sulphuric acid, phosphoric acid sulphate, bisulphate, hemisulphate, thiocyanate, persulphate and sulphonic acids; with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (Ci-C4)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-toluene sulfonic acid.

[0043] Examples of preferred salts include hydrochloride, hydrobromide, hydroiodide, phosphate, phosphonate, sulfate, bisulphate, hemisulphate, sulfonate such as methanesulfonate and p- toluene sulfonate; carboxylate such as an acetate, trifluoroacetate, citrate, malate, maleate, tartrate, succinate and salicylate; alkali metal salts such as a sodium salt, a potassium salt; an alkaline earth metal salt such as a magnesium salt, a calcium salt; and ammonium salts such as an ammonium salt (NH4 X: X is a monovalent acid group), an alkylammonium salt, a dialkylammonium salt, a trialkylammonium salt and a tetraalkylammonium salt.

[0044] In one preferred embodiment, the alectinib is in the form of a hydrochloride salt, more preferably a monohydrochloride salt.

[0045] The present invention also includes solvate forms of alectinib. Preferably the solvate is a hydrate.

[0046] In one embodiment, the alectinib is in the form of a hydrate of a monohydrochloride salt, more preferably, a monohydrate.

[0047] The alectinib, or pharmaceutically acceptable salt thereof, may be in amorphous form or crystalline form. The invention encompasses the use of various crystalline forms, polymorphic forms and (an)hydrous forms of alectinib. It is well established within the pharmaceutical industry that chemical compounds may be isolated in any of such forms by slightly varying the method of purification and or isolation form the solvents used in the synthetic preparation of such compounds.

[0048] In one embodiment, the alectinib is in amorphous form. An amorphous monohydrochloride form of alectinib can be produced in accordance with the teachings of WO 2016 / 021707.

[0049] In one embodiment, the alectinib is in crystalline form, preferably a crystalline 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.

[0050] The invention includes all enantiomers and tautomers of alecitnib and pharmaceutically acceptable salts thereof. The person skilled in the art will recognise that alecitnib possesses a chiral carbon atom. The corresponding enantiomers and / or tautomers may be isolated / prepared by methods known in the art. Enantiomers are characterised by the absolute configuration of their chiral centres and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Such conventions are well known in the art (e.g. see ‘Advanced Organic Chemistry’, 3rdedition, ed. March, J., John Wiley and Sons, New York, 1985). Compounds containing a chiral centre may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.

[0051] Pharmaceutical compositions

[0052] For use according to the present invention, the alectinib, or pharmaceutically acceptable salt thereof, is generally formulated with one or more pharmaceutically acceptable carriers, diluents or excipients therefor. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0053] Examples of suitable excipients for the various different forms of pharmaceutical compositions described herein may be found in the “Handbook of Pharmaceutical Excipients, 2ndEdition, (1994), Edited by A Wade and PJ Weller. The carrier, or, if more than one be present, each of the carriers, must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).

[0054] Examples of suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like. Examples of suitable diluents include ethanol, glycerol and water.

[0055] The choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s), buffer(s), flavouring agent(s), surface active agent(s), thickener(s), preservative(s) (including antioxidants) and the like, disintegrating agents, dissolution aids, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.

[0056] Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may be also used.

[0057] Examples of suitable binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethyl cellulose methylcellulose, povidone (polyvinylpyrrolidone), macrogol, powdered acacia, starch, gelatin, natural sugars such as glucose, anhydrous lactose, freeflow lactose, beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, and polyethylene glycol. A preferred binder is hydroxypropylcellulose.

[0058] Examples of suitable lubricants include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester and sodium stearyl fumarate. Preferably, magnesium stearate may be mentioned.

[0059] Examples of suitable stabilizers include paraoxybenzoates such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride, phenols such as phenol and cresol, thimerosal, dehydroacetic acid and sorbic acid.

[0060] Examples of suitable flavoring agents include a sweetener, an acidulant and a fragrance.

[0061] Examples of suitable disintegrating agents include sodium starch glycolate, low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium (carmellose calcium), sodium hydrogen carbonate, pregelatinized starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride, carmellose, etc.

[0062] Examples of suitable dissolution aids include a surfactant, an organic polymer, and a pH adjusting agent, etc. Preferred examples thereof include casein, sodium caseinate, skimmed milk powder, sodium lauryl sulfate (herein below, also referred to as SLS), dioctyl sodium sulfosuccinate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, sodium lauroylsarcosine, 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.

[0063] Suitable solubilizing agents include surfactants, organic polymers and pH modifiers.

[0064] Examples of surfactants include ionic surfactants and nonionic surfactants. Ionic surfactants are further classified into anionic surfactants, cationic surfactants and amphoteric surfactants depending upon the charge of the ion to be produced. Examples of nonionic surfactants include sugar ester surfactants such as a sorbitan fatty acid ester (C12-18), a POE sorbitan fatty acid ester (C12-18) and sucrose fatty acid ester; fatty acid ester surfactants such as a POE fatty acid ester (C12-18), a POE resin acid ester and a POE fatty acid diester (012-18); alcohol based surfactants such as a POE alkyl ether (012-18); alkyl phenol surfactants such as a POE alkyl (08-12) phenyl ether, a POE dialkyl (08-12) phenyl ether and a POE alkyl (08- 12) phenyl ether formalin condensate; polyoxyethylene-polyoxypropylene block polymer surfactants such as a polyoxyethylene-polyoxypropylene block polymer and an alkyl (012-18) polyoxyethylene-polyoxypropylene block polymer ether; alkylamine surfactants such as a POE alkylamine (012-18) and a POE fatty acid amide (012-18); bisphenol surfactants such as a POE fatty acid bisphenyl ether; polycyclic aromatic surfactants such as a POA benzylphenyl (or phenylphenyl) ether and a POA styrylphenyl (or phenylphenyl) ether; POE ether and ester type silicon and fluorine surfactants; and vegetable oil surfactants such as POE castor oil and POE hydrogenated castor oil.

[0065] Examples of anionic surfactants include sulfate surfactants such as an alkyl sulfate (012-18, Na, NH4, alkanolamine), a POE alkyl ether sulfate (012-18, Na, NH4, alkanolamine), a POE alkyl phenyl ether sulfate (012-18, NH4, alkanolamine, Ca), a POE benzyl (or styryl) phenyl (or phenylphenyl) ether sulfate (Na, NH4, alkanolamine), a polyoxyethylene and a polyoxypropylene block polymer sulfate (Na, NH4, alkanolamine); sulfonate surfactants such as a paraffin (alkane) sulfonate (012-22, Na, Ca, alkanolamine), an AOS (C14-16, Na, alkanolamine), a dialkyl sulfosuccinate (C8-12, Na, Ca, Mg), an alkylbenzene sulfonate (C12, Na, Ca, Mg, NH4, alkylamine, alkanol, amine, cyclohexylamine), a mono or dialkyl (C3-6) naphthalene sulfonate (Na, NH4, alkanolamine, Ca, Mg), a naphthalene sulfonate-formalin condensate (Na, NH4), an alkyl (C8-12) diphenyl ether disulfonate (Na, NH4), a lignin sulfonate (Na, Ca), a POE alkyl (C8-12) phenyl ether sulfonate (Na) and a POE alkyl (C12- 18) ether sulfosuccinic acid half ester (Na); carboxylic acid surfactants such as a fatty acid salt (C12-18, Na, K, NH4, alkanolamine), a N-methyl-fatty acid sarcosinate (C12-18, Na) and a resinate (Na, K); and phosphate surfactants such as a POE alkyl (C12-18) ether phosphate (Na, alkanolamine), a POE mono or dialkyl (C8-12) phenyl ether phosphate (Na, alkanolamine), a POE benzylated (or styrylated) phenyl (or phenylphenyl) ether phosphate (Na, alkanolamine), a polyoxyethylene-polyoxypropylene block polymer (Na, alkanolamine), a phosphatidylcholine-phosphatidyl ethanol imine (lecithin) and an alkyl (C8-12) phosphate. Preferably, e.g., monoalkyl sulfates such as sodium lauryl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate and sodium octadecyl sulfate, dioctylsodium sulfosuccinate, sodium lauroyl sarcosinate and sodium dodecylbenzenesulfonate are mentioned.

[0066] Sodium lauryl sulfate is a particularly preferred surfactant. In the present invention, when sodium lauryl sulfate is used, it is more preferable to obtain a crystal thereof by crystallization rather than spray dry. As a crystal polymorphism of sodium lauryl sulfate, a monohydrate, a 1 / 2 hydrate, a 1 / 8 hydrate and a non-solvate are known (Journal of Crystal Growth 263 (2004) 480-490). Any of the crystals can be used.

[0067] In one embodiment, the alectinib or pharmaceutically acceptable salt thereof is formulated in accordance with the teachings of WO 2012 / 023597. For example, in one preferred embodiment the composition comprises alectinib, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and a dissolution aid.

[0068] In another embodiment, alectininib, or pharmaceutically acceptable salt thereof, is formulated in accordance with the teachings of WO 2015 / 163448. For example, in one preferred embodiment, the pharmaceutical composition comprises (i) a granule containing alectinib, or a pharmaceutically acceptable salt thereof, and (ii) a disintegrating agent.

[0069] The "disintegrating agent" is a component facilitating rapid disintegration of a solid formulation taken orally. Suitable examples are described above. The disintegrating agent can be contained in the granules or added to the granules as an external additive. Other additives such as a lubricant and a fluidizer may be further optionally added as external additives, or contained in the granules. In one embodiment, the granule (i) contains alectinib, or a pharmaceutically acceptable salt thereof, a disintegrating agent, a solubilizing agent, an excipient and a binder. The granule may further contain one or more additives selected from a lubricant, a coating agent, a stabilizer, a flavoring agent and a diluent. In one preferred embodiment, the alectinib, or pharmaceutically acceptable salt thereof, is formulated for oral administration, i.e. the composition is an oral formulation.

[0070] In one embodiment, the composition is formulated as a tablet. An appropriate coating agent can be further applied to tablets to obtain sugar coated tablets or film coated tablets. Suitable coating agents will be familiar to the person skilled in the art.

[0071] In one preferred embodiment, the pharmaceutical composition comprises alectinib, or a pharmaceutically acceptable salt thereof, lactose monohydrate, hydroxypropylcellulose, sodium lauryl sulfate, magnesium stearate and carmellose calcium.

[0072] Preferably the pharmaceutical composition is in the form of a capsule, more preferably a hard capsule.

[0073] Preferably the composition is provided in a capsule shell comprising hypromellose, carrageenan, potassium chloride, titanium dioxide (E171 ), maize starch and carnauba wax.

[0074] The formulation of the present invention preferably contains 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 especially preferably, about 35 to about 60 wt% in terms of free base alectinib based on the total amount of the formulation.

[0075] More specifically, if the formulation of the present invention is a capsule, the alectinib or pharmaceutically acceptable salt thereof is preferably contained in an amount of, for example, about 20 to about 70 wt%, preferably, about 30 to about 60 wt%, and especially preferably, about 35 to about 60 wt% in terms of free base alecinib based on the total amount of the components to be put in a capsule.

[0076] In one preferred embodiment, the composition is in the form of a unit dosage form comprising alectinib or a pharmaceutically acceptable salt thereof in an amount of, for example, 60 to 240 mg, preferably, 100 to 200 mg, and especially preferably, 140 mg to 190 mg in terms of free base alectinib per unit dosage form.

[0077] In one preferred embodiment, the composition is in the form of a unit dosage form comprising alectinib hydrochloride equivalent to about 150 mg alectinib in free base form.

[0078] In one preferred embodiment, the formulation is in a dosage form comprising alectinib hydrochloride equivalent to about 150 mg alectinib in free base form, about 33.7 mg lactose (as monohydrate) and about 6 mg sodium (as sodium lauryl sulfate) per dosage form. The pharmaceutical compositions as described above can be prepared by a process which comprises bringing the active compound into association with the carrier, for example by admixture.

[0079] The formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association an active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0080] Dosage

[0081] The composition may be administered orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically and locally (intravenous drip, powder, ointment, gel or cream) and through inhalation (oral or nose spray). Examples of the dosage form thereof include tablet, capsule, granule, powder, pill, aqueous and nonaqueous oral solution and suspension, and parenteral solution put in small containers for a unit dose. The dosage form may be designed so as to adapt to various methods for administrating a formulation including a controlled release formulation to be subcutaneously grafted.

[0082] The dosage form is preferably oral administration by tablets, capsules, granules or powder formulation.

[0083] Preferably, the dosage form is a capsule.

[0084] In the present invention, the "oral formulation" refers to a formulation that can be orally administered. The oral administration refers to swallowing a formulation so as to enter the gastrointestinal tract and an active ingredient is mainly absorbed through the intestinal tract.

[0085] Specific examples of the oral formulation include solid formulations such as a tablet, a capsule, a solution, a powder, a lozenge, a chewable agent, a granule, a gel, a film agent and a spray and liquid formulations. Examples of the liquid formulation include a suspension, a solution, syrup and an elixir. Such a formulation can be used as filler in soft or hard capsules. Generally, as a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or appropriate oil, and one or more emulsifiers and / or a suspending agent are used. A liquid formulation can be also prepared by dissolving a unit-dose solid medicinal agent, for example, dissolving a pharmaceutical composition in a package into a carrier such as water. The dosage of the active ingredient (a compound represented by formula (I) or a salt thereof of the present invention) may vary depending upon the symptom, age, body weight, relative health condition, other medication, administering method, etc. For example, a generally effective amount of active ingredient (the compound or a salt thereof of the present invention represented by formula (I)) to a patient (a warm-blooded animal, particularly a human) orally administered is preferably 0.001 to 1000 mg and further preferably 0.01 to 300 mg per body weight (1 kg) per day. The dosage thereof used per day preferably falls within the range of 1 to 1500 mg per adult patient having an ordinary body weight. In the case of a parenteral agent, the amount thereof used is preferably 0.001 to 1000 mg and further preferably 0.01 to 300 mg per body weight (1 kg) per day. It is desirable that the amount thereof used is administered once per day or administered depending upon the symptom by dividing the amount used into several portions.

[0086] In one embodiment, the alectinib, or pharmaceutically acceptable salt thereof, is administered twice a day.

[0087] The total daily dose of alectinib (free base equivalent) is preferably from 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, 1000 to 1200 mg.

[0088] In one embodiment, the total daily dose is 900 mg of alectinib (free base equivalent). Preferably, 450 mg is administered twice per day.

[0089] In one embodiment, the total daily dose is 1200 mg of alectinib (free base equivalent). Preferably, 600 mg is administered twice per day. Preferably, the alectinib is administered as four 150 mg capsules twice per day.

[0090] In a further embodiment an alectinib dosage of 600 mg BID can be reduced in 150 mg increments to 450 mg BID or 300 mg BID respectively, in order to mitigate side effects. Such side effects can include any of the following or a combination thereof: pneumonitis, pneumonia, appendicitis, acute myocardial infarction, nausea, malaise, asthenia, fatigue, tinnitus, vomiting, weight increase, decreased appetite, diarrhoea, constipation, headache, cough, rash, anaemia, dyspnoea, oedema peripheral, dysgeusia, blood creatinine increase, neutropenia, neutrophil count decrease, white blood cell count decrease, blood creatine phosphokinase increase, aspartate aminotransferase increase, alanine aminotransferase increase, hyperbilirubinaemia, COVID-19, myalgia, blood alkaline phosphatase increase, and / or product dose omission issue. Treatment may continue until completion of treatment period, disease recurrence, 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 or 12 months or 18 months or 24 months.

[0091] Disease

[0092] The term "tumour" as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms "cancer", "cancerous" and "tumour" are not mutually exclusive as referred to herein.

[0093] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Included in this definition are benign and malignant cancers.

[0094] By "early stage cancer" or "early stage tumor" is meant a cancer that is not invasive or metastatic or is classified as a Stage 0, I, or II cancer.

[0095] 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 cancer), mesothelioma, schwannoma (including acoustic neuroma), meningioma, adenocarcinoma, melanoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small-cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer (including metastatic breast cancer), colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, Merkel cell cancer, mycoses fungoids, testicular cancer, esophageal cancer, tumors of the biliary tract, as well as head and neck cancer and hematological malignancies.

[0096] NSCLC, includes squamous NSCLC and non-squamous NSCLC, adenocarcinoma, and large cell carcinoma.

[0097] In some embodiments, the cancer is ALK-positive.

[0098] In a preferred embodiment, the cancer is ALK-positive NSCLC. By “ALK-positive” or “ALK+” is meant that the cancer expresses anaplastic lymphoma kinase. In some embodiments, expression is caused by gene rearrangements leading to fusion of ALK with other genes, such as EML4, KIF5B, KLC1, TFG, TPR, HIP1, STRN, DCTN1, SQSTM1, NPM1, BCL11A, and BIRC6.

[0099] Determination of ALK positivity may be performed at sites by an FDA-approved and CE- marked test or by central Ventana ALK IHC.

[0100] Methods to determine ALK positivity (e.g., reverse transcription-PCR) are known. ALK positivity for fusions may be determined in tissue samples using assays such as fluorescence in situ hybridization, IHC, PCR, and sequencing. As tissue sampling is difficult and tissue biopsy sample sizes from lung cancer patients are very small, testing of several important biomarkers is challenging. Plasma ALK assays analysing circulating tumor nucleic acids will enable more patients with NSCLC to be tested for ALK fusions and may also be used to monitor changes in ALK rearrangements during ALK inhibitor treatment.

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

[0102] In some embodiments, the subject does not demonstrate resistance to ALK inhibitors.

[0103] In some embodiments, the subject does not comprise a mutation conferring resistance to ALK inhibitors.

[0104] In some embodiments, the subject does not exhibit a biomarker associated with resistance to ALK inhibitors.

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

[0106] Disease stage

[0107] Disease staging is in accordance with the TNM classification system in the Union Internationale Contre le Cancer (UICC) / American Joint Committee on Cancer (AJCC) 7th edition.

[0108] The T staging is determined by the size of primary tumour in long axis, or direct extent of the tumour into adjacent structures such as mediastinum or chest wall: TX, primary tumour cannot be assessed, or tumour proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy; TO, no evidence of primary tumour; Tis, carcinoma in situ, T 1 , tumour 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (T1 a if 2 cm or less, T1 b if more than 2 cm but 3 cm); T2, tumour more than 3 cm but 7 cm or less or tumour with any of the following features: involves main bronchus, 2 cm or more distal to the carina, invades visceral pleura, associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung (T2a if more than 3 cm but 5 cm or less, T2b if more than 5 cm but 7 cm or less); T3, tumour more than 7 cm or one that directly invades any of the following: parietal pleural, chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumour in the main bronchus (less than 2 cm distal to the carina but without involvement of the carina); or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumour nodule(s) in the same lobe; T4, tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, separate tumour nodule(s) in a different ipsilateral lobe.

[0109] The N staging describes the degree of spread to regional lymph nodes: NX, regional lymph nodes cannot be assessed; NO, no regional lymph node metastases; N1 , metastasis in ipsilateral peribronchial and / or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension; N2, metastasis in ipsilateral mediastinal and / or subcarinal lymph node(s); and N3, metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).

[0110] The M staging defines the presence of metastases beyond regional lymph node: MO, no distant metastasis; M1 , distant metastasis (M1a, separate tumor nodule(s) in a contralateral lobe, tumour with pleural nodules or malignant pleural (or pericardial) effusion; M1b, distant metastasis (in extrathoracic organs)).

[0111] Disease stage classifications include occult carcinoma (TX, NO), stage 0 (Tis, NO), stage la (T1 , NO), stage lb (T2a, NO), stage Ila (T2b, NO; T1 , N1 ; T2a, N1), stage lib (T2b, N1 ; T3, NO), stage Illa (T1-2, N2; T3, N1-2; T4, NO-1), stage I lib (T1-3, N3; T4, N2-3), or stage IV (any T, any N, M1).

[0112] In some embodiments, the subject has completely resected, histologically confirmed stage lb with a tumour greater or equal to 4cm in greatest dimension (tumour > 4 cm) to stage Illa NSCLC.

[0113] In some embodiments, the subject has completely resected, histologically confirmed stage lb (tumour > 4 cm) to stage lib NSCLC. In some embodiments, the subject has completely resected, histologically confirmed stage lb (tumour > 4 cm) to stage Ila NSCLC.

[0114] In some embodiments, the subject has completely resected, histologically confirmed stage lb (tumour > 4 cm) NSCLC.

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

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

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

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

[0121] In some embodiments, the subject has a TNM classification of T2-4 NO, 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 herein, “histologically confirmed” refers to determination by microscopic examination of tissue that has been excised by biopsy or surgical resection.

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

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

[0127] Adjuvant

[0128] As used herein, “adjuvant” and / or “adjuvant setting” refers to a therapy given in addition to the primary or initial therapy, for example following resection of a tumour. In some embodiments, the subject has not undergone prior adjuvant radiotherapy. In some embodiments, the subject has not undergone prior adjuvant therapy.

[0129] Preferably, alectinib is administered as adjuvant therapy following complete resection of a tumour.

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

[0131] As used herein, “neo-adjuvant” refers to treatment delivered before resection of tumour, such as to help reduce the size of a tumour.

[0132] Preferably, alectinib is not administered in the neo-adjuvant setting. Preferably, the subject has not been administered alectinib prior to resection of a tumour.

[0133] In some embodiments, the subject has not had prior exposure to ALK inhibitors.

[0134] In some embodiments, the subject has received radiotherapy prior to resection of a tumour.

[0135] In some embodiments, resection occurs between 1 to 16 weeks prior to treatment with alectinib, such as 4 to 12 weeks, 6 to 10 weeks, 4 to 6 weeks, 6 to 8 weeks, or 8 to 12 weeks prior to treatment with alectinib. For example, resection may occur at 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, resection occurs between 4 to 12 weeks prior to treatment with alectinib.

[0137] Method of treatment

[0138] The invention provides a method of treating a subject suffering from ALK-positive non-small cell lung cancer, the method comprising administering to the subject a therapeutically effective amount of alectinib.

[0139] The invention provides methods for treating or delaying progression of non-small cell lung cancer in a subject comprising administering to the subject a therapeutically effective amount of alectinib.

[0140] The invention provides alectinib, or a pharmaceutically acceptable salt thereof, for use in a method of treating ALK-positive NSCLC in a subject, wherein the subject has resected stage lb ALK-positive NSCLC with a tumour greater or equal to 4cm to stage Illa ALK-positive NSCLC.

[0141] The invention provides alectinib, or a pharmaceutically acceptable salt thereof, for use in a method of preventing ALK-positive NSCLC recurrence in a subject, wherein the subject has resected stage lb ALK-positive NSCLC with a tumour greater or equal to 4cm to stage Illa ALK-positive NSCLC.

[0142] In some embodiments, the subject is suffering from stage lb (tumours > 4 cm) to stage Illa, ALK-positive NSCLC.

[0143] In some embodiments, the alectinib is administered as adjuvant therapy following complete resection of tumour. In the context of the present invention, resection refers to a surgery taking place before alectinib treatment. The present invention does not relate to methods of surgery performed on the human body.

[0144] In some embodiments, alectinib is indicated for adjuvant treatment following tumour resection for adult patients with ALK+ NSCLC.

[0145] In some embodiments, alectinib is indicated for adjuvant treatment following tumour resection for adult patients with Stage IB (> 4cm) - 1 HA ALK+ NSCLC.

[0146] In some embodiments, alectinib is indicated for adjuvant treatment following tumour resection for adult patients with Stage ll-IIIA ALK+ NSCLC.

[0147] As used herein, the terms "patient" or "subject" are used interchangeably and refer to any single animal, more preferably a mammal (including such non-human animals as, for example, dogs, cats, horses, rabbits, zoo animals, cows, pigs, sheep, and non-human primates) for which treatment is desired. In particular embodiments, the patient herein is a human.

[0148] In some embodiments, the patient is non-Asian.

[0149] As used herein, "treatment" refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. In some embodiments, compositions of the present invention are used to delay development of a disease or to slow the progression of a disease.

[0150] “Individual response” or “response” can be assessed using any endpoint indicating a benefit to the individual, including, without limitation, (1) inhibition, to some extent, of disease progression (e.g., cancer progression), including slowing down and complete arrest; (2) a reduction in tumor size; (3) inhibition (i.e., reduction, slowing down or complete stopping) of cancer cell infiltration into adjacent peripheral organs and / or tissues; (4) inhibition (i.e. reduction, slowing down or complete stopping) of metatasis; (5) relief, to some extent, of one or more symptoms associated with the disease or disorder (e.g., cancer); (6) increase or extend in the length of survival, including overall survival, progression free survival and disease free survival; and / or (9) decreased mortality at a given point of time following treatment.

[0151] An “effective response” of a patient or a patient’s “responsiveness” to treatment with a medicament and similar wording refers to the clinical or therapeutic benefit imparted to a patient at risk for, or suffering from, a disease or disorder, such as cancer. In one embodiment, such benefit includes any one or more of: extending 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 improving signs or symptoms of cancer.

[0152] An “objective response” refers to a measurable response, including complete response (CR) or partial response (PR). In some embodiments, the “objective response rate (ORR)” refers to the sum of complete response (CR) rate and partial response (PR) rate.

[0153] By “complete response” or “CR” is intended the disappearance of all signs of cancer (e.g., disappearance of all target lesions) in response to treatment. This does not always mean the cancer has been cured.

[0154] “Sustained response” refers to the sustained effect on reducing tumour growth after cessation of a treatment. For example, the tumour size may remain to be the same or smaller as compared to the size at the beginning of the administration phase. In some embodiments, the sustained response has a duration at least the same as the treatment duration, at least 1.5X, 2. OX, 2.5X, or 3. OX length of the treatment duration, or longer. As used herein, “reducing or inhibiting cancer relapse” means to reduce or inhibit tumour or cancer relapse or tumour or cancer progression. As disclosed herein, cancer relapse and / or cancer progression include, without limitation, cancer metastasis.

[0155] As used herein, “partial response” or “PR” refers to a decrease in the size of one or more tumors or lesions, or in the extent of cancer in the body, in response to treatment. For example, in some embodiments, PR refers to at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD.

[0156] As used herein, “stable disease” or “SD” refers to neither sufficient shrinkage of target lesions to qualify for PR, nor sufficient increase to qualify for PD, taking as reference the smallest SLD since the treatment started.

[0157] The term “survival” refers to the patient remaining alive, and includes overall survival as well as progression-free survival. As used herein, "progression-free survival" (PFS) refers to the length of time during and after treatment during which the disease being treated (e.g., cancer) does not get worse. Progression-free survival may include the amount of time patients have experienced a complete response or a partial response, as well as the amount of time patients have experienced stable disease.

[0158] As used herein, “disease-free survival” (DFS) refers to the time from randomization to the first documented recurrence of disease or new primary NSCLC - as determined by the investigator through use of an integrated assessment of radiographic data, biopsy sample results (if clinically feasible), and clinical status - or death from any cause, whichever occurs first.

[0159] By “extending survival” is meant increasing overall or progression-free survival in a treated patient relative to an untreated patient (i.e. relative to a patient not treated with the medicament), and / or relative to a patient treated with an approved anti-tumor agent.

[0160] As used herein, "delaying progression" of a disease means to defer, hinder, slow, retard, stabilize, and / or postpone development of the disease (such as cancer (e.g., NSCLC, such as squamous or non-squamous NSCLC)). This delay can be of varying lengths of time, depending on the history of the disease and / or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late stage cancer, such as development of metastasis, may be delayed.

[0161] As used herein, “preventing” means to reduce the likelihood of disease recurrence as compared to treatment with platinum-based chemotherapy.

[0162] The “hazard ratio” is the probability of an event in a treatment group relative to the control group probability over a unit of time. Thus in the present context, the hazard ratio may relate to the probability of a DFS-related event in the alectinib-treated group versus the chemotherapy-treated group. For example, a hazard ratio of 0.16 means that alectinib provides 84% risk reduction in terms of DFS-related events compared to the chemotherapy- treated (control) group.

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

[0164] In some embodiments, alectinib increases the subject's likelihood of having an objective response as compared to treatment with the platinum-based chemotherapy without alectinib. In some embodiments, alectinib increases the subject's likelihood of having a CR as compared to treatment with the platinum-based chemotherapy without alectinib. In some embodiments, alectinib extends the subject's PFS as compared to treatment with the platinum-based chemotherapy without alectinib. In some embodiments, alectinib extends the subject's DFS as compared to treatment with the platinum-based chemotherapy without alectinib. In some embodiments, alectinib extends the subject's OS as compared to treatment with the platinumbased chemotherapy without alectinib. In some embodiments, alectinib extends the subject's DOR as compared to treatment with the platinum-based chemotherapy without alectinib. In some embodiments, administration of alectinib to the subject extends the subject's ORR as compared to administration of the platinum-based chemotherapy without alectinib.

[0165] In some embodiments, benefit from treatment with alectinib includes an increase in OS. In some embodiments, benefit from treatment with alectinib includes an increase in DFS.

[0166] In some embodiments of the disclosure, administration of alectinib to the subject extends the subject's DFS as compared to administration of the platinum-based chemotherapy without alectinib. For example, administration of alectinib to the subject may extend the subject's DFS by from about 1 month to about 5 months, by from about 2 months to about 4 months, by from about 2.1 months to about 3.9 months, by from about 2.5 months to about 3.5 months, or by from about 2.8 months to about 3.4 months as compared to administration of the platinumbased chemotherapy without alectinib (e.g., by about 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 the subject reduces the subject’s likelihood of disease recurrence as compared to administration of the platinum-based chemotherapy without alectinib. For example, administration of alectinib to the subject reduces the subject’s likelihood of disease recurrence by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 100% as compared to administration of the platinum-based chemotherapy without alectinib. Preferably, administration of alectinib to the subject reduces the subject’s likelihood of disease recurrence by about 60 to 90%, such as 75% to 85% as compared to administration of the platinum-based chemotherapy without alectinib.

[0168] In some embodiments, alectinib has an improved safety profile as compared to the platinumbased chemotherapy without alectinib. For example, alectinib may reduce the number of adverse events leading to withdrawal from treatment, improve neutrophil and / or white blood cell counts, and / or reduce incidence of asthenia, nausea, vomiting, decreased appetite, malaise, neutropenia, fatigue and / or tinnitus relative to treatment with platinum-based chemotherapy.

[0169] In some embodiments, the platinum-based chemotherapy comprises a platinum-based chemotherapeutic agent and a nucleoside analog.

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

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

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

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

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

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

[0176] In some embodiments, the platinum-based chemotherapy is selected from:

[0177] Cisplatin 75 mg / m2on Day 1 plus vinorelbine 25 mg / m2on Days 1 and 8

[0178] Cisplatin 75 mg / m2on Day 1 plus gemcitabine 1250 mg / m2on Days 1 and 8 Cisplatin 75 mg / m2on Day 1 plus pemetrexed 500 mg / m2on Day 1.

[0179] In some embodiments, platinum-based chemotherapy is provided for 4 cycles, with each cycle lasting 21 days.

[0180] In some instances, the method further includes administering to the patient an effective amount of a second therapeutic agent. In some instances, the second therapeutic agent is selected from the group comprising chemotherapeutic agents, hormonal therapeutic agents, immunotherapeutic agents, molecular targeting agents, or the like.

[0181] Examples of the "chemotherapeutic agents" include an alkylating agent, a platinum formulation, a metabolic antagonist, a topoisomerase inhibitor, an anticancer antibiotic substance, and an anticancer agent derived from plant, etc. Examples of the "alkylating agent" include nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan, nimustin hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustin, estramustin sodium phosphate, triethylene melamine, carmustin, lomustin, streptozocin, pipobroman, etoglucid, altretamin, ambamustin, dibrospidium hydrochloride, fotemustin, prednimustin, pumitepa, ribomustin, temozolomid, treosulfan, trophosphamide, zinostatin stimalamer, carboquone, adozelesin, cystemstin, and bizelecin. Examples of the "platinum formulation" include carboplatin, cisplatin, miboplatin, nedaplatin, and oxaliplatin. Examples of the "metabolic antagonist" include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, enocitabin, cytarabin, cytarabin ocfosfate, ancitabin hydrochloride, 5-Fll based pharmaceuticals (for example, fluorouracil, tegafur, UFT, doxifluridin, carmofur, galocitabin, and emitefur, etc.), aminopterin, calcium leucovorin, tabloid, butocin, calcium folinate, calcium levofolinate, cladribin, emitefur, fludarabin, gemcitabin, hydrocycarbamide, pentostatin, piritrexim, idoxuridin, mitoguazon, tiazofurin, and ambamustin. Topoisomerase I inhibitor (for example, irinotecan and topotecan, etc.), topoisomerase II inhibitor (for example, sobuzoxan, etc.). Examples of the "anticancer antiobiotic material" include anthracycline-based anticancer agent (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, mitramycin, sarcomycin, carzinophyllin, mitotam, zorubicin hydrochloride, mitoxantrone hydrochloride, and idarubicin hydrochloride, etc. Examples of the "anticancer agent derived from a plant" include vincalkaloid anticancer agent (vinblatin sulfate, vincristin sulfate, and vindecin sulfate), taxan anticancer agent (paclitaxel and docetaxel, etc), etoposide, etoposide phosphate, teniposide, and vinorelbin.

[0182] Examples of the "hormonal therapeutic agents" include adrenocortical hormone-based pharmaceuticals (for example, dexamethasone, prednisolone, betamethasone, and triamcinolone, etc.). Of these, prednisolone is preferable.

[0183] Examples of the "immunotherapeutic agents (BRM)" include picibanil, krestin, sizofiran, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, lymphotoxin, BCG vaccine, Corynebacterium parvum, levamisole, polysaccharide K, and procodazole.

[0184] The "molecular targeting agents" include a "pharmaceutical which inhibits the function of a cell proliferation factor and its receptor," or the like. Examples of the "cell proliferation factor" can be any substance if only it can promote proliferation of a cell, and the included are a peptide having molecular weight of 20,000 or less which exhibits its activity at low concentration via binding to a receptor. Specific examples thereof include (1) EGF (epidermal growth factor) or a substance which has substantially the same activity [e.g., EGF, heregulin (HER2 ligand) etc.], (2) insulin or a substance which has substantially the same activity [e.g., insulin, IGF (insulin-like growth factor)-"! , IGF-2, etc.], (3) FGF (fibroblast growth factor) or a substance which has 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), TGFp (transforming growth factor P), HGF (hepatocyte growth factor), etc.], etc.

[0185] The "receptor for cell proliferation factor" can be any receptor if only it has an ability of binding to the cell proliferation factor described above. Specific examples thereof include EGF receptor, heregulin receptor (HER2), insulin receptor, IGF receptor, FGF receptor-1 or FGF receptor-2, HGF receptor (c-met), VEGF receptor, and SCF receptor (c-kit). Examples of the "pharmaceuticals which inhibit the activity of cell proliferation factor" include herceptin (HER2 antibody), GLEEVEC (c-kit, abl inhibitor), and Iressa (EGF receptor inhibitor).

[0186] Further, a pharmaceutical which inhibits the activity of a plurality of cell proliferation factors even as a single formulation, or a pharmaceutical which blocks cellular signal produced by cell proliferation factor are also included.

[0187] In addition to the pharmaceuticals described above, L-asparaginase, aceglaton, procarbazine hydrochloride, protoporphyrin ■ cobalt complex, mercury hematoporphyrin ■ sodium, differentiation-promoting agent (e.g. retinoid, vitamin D, etc.), angiogenesis inhibitor, and a- blocker (e.g., tamsulosin hydrochloride, etc.), etc. can be also used.

[0188] EXAMPLES

[0189] Clinical trial protocol - study design

[0190] Description of study

[0191] This randomized, active-controlled, multicenter, open-label, Phase III study is designed to investigate the efficacy and safety of alectinib compared with platinum-based chemotherapy in the adjuvant setting. The primary endpoint of the study is DFS as assessed by investigator, while OS is a secondary endpoint.

[0192] This study will comprise approximately 200 centers in around 30 countries worldwide. Central randomization will be performed via an interactive voice or Web-based response system (IxRS). Randomized patients will be stratified by extent of disease (Stage lb [tumors >4 cm] vs. Stage II vs. Stage Illa) and ethnicity (Asian vs. non-Asian). Relevant instruction will be provided to each study site by the IxRS provider.

[0193] Patients with completely resected (negative margins), histologically-confirmed Stage lb (tumors >4 cm) to Stage Illa NSCLC as per the Union Internationale Contre le Cancer (UICC) / American Joint Committee on Cancer (AJCC) 7th edition with documented ALK- positive disease as assessed by a U.S. Food and Drug Administration (FDA)-approved and Conformite Europeenne (CE)-marked test and meeting all required eligibility criteria, will be randomized in a 1 :1 fashion.

[0194] Staging must occur in accordance with the UICC / AJCC 7th edition and not the 8th edition. Patients with Stage lb NSCLC with tumors >4 cm per the 7th edition classification have been shown to experience more modest benefit from adjuvant chemotherapy treatment than patients with Stage Il-Illa NSCLC, and this has been taken into consideration for recruitment capping, stratification, and statistical analysis of the primary endpoint.

[0195] Patients in the experimental arm will receive alectinib at 600 mg orally twice a day (BID) taken with food for 24 months.

[0196] Patients in the control arm will receive one of the protocol-specified platinum-based chemotherapy regimens (including all required premedications and permitted concomitant medications) according to the local prescribing information. Protocol-defined platinum-based chemotherapy regimens include:

[0197] Cisplatin 75 mg / m2on Day 1 plus vinorelbine 25 mg / m2on Days 1 and 8 Cisplatin 75 mg / m2on Day 1 plus gemcitabine 1250 mg / m2on Days 1 and 8 Cisplatin 75 mg / m2on Day 1 plus pemetrexed 500 mg / m2on Day 1

[0198] Platinum-based chemotherapy will be provided for 4 cycles, with each cycle lasting 21 days. In case of intolerability to a cisplatin-based regimen, carboplatin can be administered instead of cisplatin in one of the above combinations.

[0199] Post-operative radiation therapy (PORT) is not allowed as a treatment option. Therefore, patients with Stage Illa N2 NSCLC who, in the investigator's opinion, should receive PORT, are excluded from the study.

[0200] Study drug (alectinib or platinum-based chemotherapy) will be administered until completion of treatment period (24 months for alectinib and 4 cycles for chemotherapy), recurrence of disease, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first. Patients who complete a study treatment regimen or discontinue treatment prior to disease recurrence (e.g., due to unacceptable toxicity) will continue to be followed until disease recurrence. After disease recurrence, patients will be treated at the discretion of the investigator according to local clinical practice. No crossover in the adjuvant setting will be allowed between the 2 arms.

[0201] Approximately 255 patients will be enrolled into the study over a planned competitive recruitment period of approximately 38 months. Patients inappropriately randomized into the study will not be replaced. The primary DFS analysis will be conducted after approximately 89 DFS events in the Stage Il-Illa subpopulation have been observed. This is expected to occur approximately 60 months after the first patient is randomized. Data collection will continue for each patient until death or study closure, whichever occurs first.

[0202] 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.

[0203] All randomized patients will undergo regular, scheduled visits until disease recurrence, death, withdrawal from the study, or study termination, whichever occurs first. Regular safety assessments will be performed for both arms during treatment. The safety follow-up visit will be performed 28 days after last dose of alectinib or 28 days after the end of the last cycle of platinum-based chemotherapy. For the first 12 weeks (3 months), regular safety assessment visits will be scheduled at baseline and every 3 weeks (i.e., 1 chemotherapy cycle) for both arms. Additional visits will be scheduled for patients in the alectinib arm at Weeks 2, 4, 8, and 10 to allow for more frequent CPK and liver function assessments. Phone calls for safety monitoring of patients in the chemotherapy arm will be performed at the same timepoints (Weeks 2, 4, 8, and 10). From Week 12, patients in the alectinib arm will continue to be monitored for safety until treatment discontinuation every 6 weeks until Week 48 and every 12 weeks from Week 49-96. Scheduled disease assessments will be performed for both arms at baseline, every 12 weeks for the first 2 years, every 24 weeks during Years 3-5, and annually thereafter until disease recurrence, death, loss to follow-up, consent withdrawal, or study termination by the Sponsor, whichever occurs first. If clinically indicated, unscheduled assessments can be performed at any time. Positive efficacy results at an interim analysis will not influence the timing of disease assessments during the study.

[0204] Number of Patients

[0205] Approximately 255 patients are expected to enroll in this study in approximately 200 sites globally.

[0206] Target Population

[0207] Inclusion Criteria:

[0208] Patients must meet the following criteria for study entry:

[0209] Signed Informed Consent Form

[0210] - Age > 18 at time of signing Informed Consent Form Complete resection of histologically-confirmed Stage lb (tumor > 4 cm) to Stage Illa (T2-3 NO, T1-3 N1 , T1-3 N2, T4 NO-1) NSCLC as per UICC / AJCC, 7th edition, with negative margins, at 4-12 weeks before enrolment o Accepted types of resection include any of the following: lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy. o Resection by segmentectomy or wedge resection is not allowed. o N3 disease is not allowed.

[0211] If mediastinoscopy was not performed preoperatively, it is expected that, at a minimum, mediastinal lymph node systematic sampling will have occurred o Systematic sampling is defined as removal of at least 1 representative lymph node at specified levels. o Complete mediastinal lymph node dissection (MLND) is preferred. Mediastinal lymph node dissection entails resection of all lymph nodes at those same levels. o For patients who have undergone a right thoracotomy, sampling or MLND is required at Levels 4 and 7; for those who have undergone a left thoracotomy, sampling or MLND is required at Levels 5 and / or 6 and 7. o Exceptions will be granted for the following situations: o If patients have documented N2 disease in 1 level (per the UICC / AJCC staging system, 7th edition), not all levels need to be sampled. o If the preoperative staging imaging results (contrast computed tomography [CT] and positron emission tomography [PET] scans) do not suggest evidence of disease in the mediastinum, the patient may be considered eligible even if N2 nodal sampling was not performed per surgeon’s decision.

[0212] Documented ALK-positive disease according to an FDA-approved and CE-marked test Eligible to receive a platinum-based chemotherapy regimen according to the local labels or guideline

[0213] Eastern Cooperative Oncology Group (ECOG) Performance Status of Grade 0 or

[0214] - Adequate hematologic function, defined by the following laboratory test results, obtained within 3 days prior to initiation of study treatment: o Platelet count > 100 x 109 / L o ANC > 1500 / pL o Hemoglobin > 9 g / dL

[0215] - Adequate renal function, defined by the following laboratory test results, obtained within 3 days prior to initiation of study treatment: o Serum creatinine < 1 .5 x upper limit of normal (ULN) and o Creatinine clearance (CrCI) > 60 mL / min For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 90 days after the last dose of alectinib or according to local labels or guidelines for chemotherapy o A woman is considered to be of childbearing potential if she is post-menarchal, has not reached a postmenopausal state (> 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e. , removal of ovaries, fallopian tubes, and / or uterus) or another cause as determined by the investigator (e.g., Mullerian agenesis). o Examples of contraceptive methods with a failure rate of < 1 % per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. Hormonal contraceptive methods must be supplemented by a barrier method. o The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. o Women of childbearing potential must have a negative serum pregnancy test result prior to randomization (maximum of -3 days) and within 10 days of the first dose of study drug. First dose of study drug (alectinib or chemotherapy) must be administered within 7 days from randomization.

[0216] For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below: o With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1 % per year during the treatment period and for at least 90 days after the last dose of alectinib or according to local labels or guidelines for chemotherapy. Men must refrain from donating sperm during this same period. o With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 90 days after the last dose of alectinib or according to local labels or guidelines for chemotherapy to avoid exposing the embryo. o The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

[0217] Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures

[0218] Exclusion criteria:

[0219] Patients who meet any of the following criteria will be excluded from study entry:

[0220] Pregnant or breastfeeding, or intending to become pregnant during the study or within 90 days after the last dose of alectinib or according to local labels or guidelines for chemotherapy

[0221] Prior adjuvant radiotherapy for NSCLC o Radiotherapy in the neo-adjuvant setting is allowed and must be completed at least 4 weeks prior to initiation of study treatment.

[0222] Prior exposure to systemic anti-cancer therapy o Anti-cancer therapy for an early stage of malignancy with curative intent, provided that the last dose received was more than 5 years prior to enrolment, may be allowed. The Medical Monitor could be consulted.

[0223] Prior exposure to ALK inhibitors

[0224] Stage Illa N2 patients that, in the investigator's opinion, should receive PORT are excluded from the study o Post-operative radiation therapy is not allowed in the study.

[0225] Known sensitivity to any component of study drug (alectinib or planned chemotherapy) to which the patient may be randomized o This includes, but is not limited to, patients with galactose intolerance, a congenital lactase deficiency, or glucose-galactose malabsorption.

[0226] Malignancies other than NSCLC within 5 years prior to enrolment, except for curatively treated basal cell carcinoma of the skin, early gastrointestinal (Gl) cancer by endoscopic resection, in situ carcinoma of the cervix, ductal carcinoma in situ, papillary thyroid cancer, or any cured cancer that is considered to have no impact on DFS or OS for the current NSCLC

[0227] - Any Gl disorder that may affect absorption of oral medications, such as malabsorption syndrome or status post-major bowel resection

[0228] Liver disease characterized by any of the following: o ALT and AST > 3 x ULN or o Impaired excretory function or synthetic function or other conditions of decompensated liver disease such as coagulopathy, hepatic encephalopathy, hypoalbuminemia, ascites, or bleeding from esophageal varices or

[0229] ■ Active viral or active autoimmune, alcoholic, or other types of acute hepatitis.

[0230] ■ Active viral hepatitis B is defined as having positive hepatitis B surface antigen (HBsAg).

[0231] ■ Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (hepatitis B core antibody [HBcAb] - HbcAb-positive, but negative HBsAg) are eligible only if the HBV DNA test is negative.

[0232] ■ Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA.

[0233] Japanese patients participating in the serial / intensive PK sample collection only: administration of strong / potent CYP450 3A inhibitors or inducers within 14 days prior to the first dose of study treatment and while on treatment with alectinib up to Week 3

[0234] - Any exclusion criteria based on local labels or guidelines for chemotherapy Patients with symptomatic bradycardia

[0235] History of organ transplant

[0236] Known HIV positivity or AIDS-related illness

[0237] - Any clinically significant concomitant disease or condition that could interfere with - or for which the treatment might interfere with - the conduct of the study or the absorption of oral medications or that would pose an unacceptable risk to the patients in this study, in the opinion of the Principal Investigator

[0238] - Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and / or follow-up procedures; those conditions should be discussed with the patient before trial entry.

[0239] End of study

[0240] This study is event-driven with a recruitment period of approximately 3 years. The required number of events for the primary analysis of the primary endpoint is expected to occur approximately 60 months after the first patient has been enrolled. Patients are to be treated until completion of the treatment period (24 months for alectinib and 4 cycles [21 -day cycles] of platinum-based chemotherapy), recurrence of disease, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.

[0241] Length of Study The final survival follow-up analysis will be conducted at approximately 5 years after the last patient is enrolled. The study will formally end once the final survival follow-up analysis has been completed.

[0242] Investigational Medicinal Products

[0243] The investigational medicinal products (IMPs) for this study are alectinib and platinum-based chemotherapies.

[0244] Test Product (Investigational Drug)

[0245] Alectinib comes in a capsule dosage form containing the following active ingredient:

[0246] 9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile hydrochloride.

[0247] Each capsule contains alectinib hydrochloride equivalent to 150 mg alectinib (as free base) along with lactose monohydrate, carboxymethylcellulose calcium, hydroxypropyl cellulose, sodium lauryl sulfate (SLS), and magnesium stearate as excipients.

[0248] Alectinib 600 mg (four 150-mg capsules) should be administered orally BID with food in the morning and evening. First dose of study drug should be administered as soon as possible after randomization and no later than 7 days after randomization. Treatment will continue until completion of treatment period (24 months), disease recurrence, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.

[0249] If a planned dose of alectinib is missed, patients can make up that dose unless the next dose is due within 6 hours. If vomiting occurs after taking a dose of alectinib, patients should take the next dose at the scheduled time. Patients should not take two doses at the same time to make up for a missed dose.

[0250] The patient will record their daily dose and time in a diary (Patient Dosing Diary).

[0251] Comparator

[0252] Platinum-based chemotherapy will be provided for 4 cycles, with each cycle lasting 21 days. Investigators can choose one of the permitted platinum-based chemotherapy regimens, which include the following:

[0253] Cisplatin 75 mg / m2on Day 1 plus vinorelbine 25 mg / m2on Days 1 and 8 Cisplatin 75 mg / m2on Day 1 plus gemcitabine 1250 mg / m2on Days 1 and 8 Cisplatin 75 mg / m2on Day 1 plus pemetrexed 500 mg / m2on Day 1 First dose of study drug should be administered as soon as possible after randomization, taking required premedication into account, and no later than 7 days after randomization. Treatment will continue until completion of treatment period (4 cycles), recurrence of disease, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.

[0254] Institutions should follow their standard administration regiments (e.g., administration sequence or time) for the chemotherapy treatment. Patients must receive adequate premeditations, anti-emetic treatments, and IV hydration for platinum-based treatments according to the local standard of care and prescribing information.

[0255] Platinum-based chemotherapy cycles may be delayed for safety reasons; however, if interrupted for more than 21 days = 1 cycle), the cycle is considered a skipped cycle. This does not prevent investigator from completing 4 cycles.

[0256] The selected cisplatin-based chemotherapy regimen should remain the same for all cycles. For patients who experience unacceptable toxicity with cisplatin, carboplatin can be used. The investigator should inform the Medical Monitor of the switch from a cisplatin-based regimen to a carboplatin-based regimen.

[0257] Statistical Methods

[0258] Primary Analysis

[0259] The primary and secondary efficacy analyses will be performed for all randomized patients (ITT population) and for the Stage Il-Illa subpopulation. The same analysis methods will be applied for both the ITT population and the Stage Il-Illa subpopulation.

[0260] Safety analyses will be performed on all randomized patients who received at least 1 dose of study medication.

[0261] Determination of Sample Size

[0262] Approximately 255 patients are expected to be randomized into the study. The number of Stage lb patients will be capped at 25% to ensure that at least 75% of all randomized patients will have Stage Il-Illa disease. The resulting ITT population of all patients randomized will include a minimum of 191 patients in the Stage Il-Illa subpopulation.

[0263] Recruitment is assumed to happen at a rate of 0.034 patients per site per month, with a total of approximately 200 sites. Detailed recruitment is as follows:

[0264] Months 1-2: 1 patient per month

[0265] Month 3: 2 patients per month

[0266] Month 4: 3 patients per month Months 5-6: 4 patients per month

[0267] Months 7-9: 5 patients per month Months 10-12: 7 patients per month Month 13 onwards: 8 patients per month

[0268] Based on these assumptions, enrolment will take approximately 38 months to complete.

[0269] The sample size and the number of events required to demonstrate efficacy with regard to the primary efficacy endpoint DFS at the primary analysis are based on the following assumptions:

[0270] Overall 2-sided significance level of 0.05 in the Stage Il-Illa subpopulation and the ITT population

[0271] 80% power to detect a hazard ratio (HR) = 0.55, corresponding to an improvement in median DFS from 30-55 months for patients receiving alectinib compared with chemotherapy in the Stage Il-Illa subpopulation

[0272] 80% power to detect an HR = 0.58 corresponding to an improvement in median DFS from 36-62 months for patients receiving alectinib compared with chemotherapy in the ITT population

[0273] One interim analysis for DFS when approximately 67% of the total DFS events have occurred, with use of the Lan-DeMets approximation to the O'Brien-Fleming boundaries

[0274] Based on these assumptions, the primary DFS analysis will be conducted after approximately 89 DFS events in the Stage Il-Illa subpopulation have been observed. This is predicted to occur approximately 60 months (5 years) after the first patient is randomized.

[0275] The focus of this clinical trial is hypothesis testing, testing superiority of alectinib compared with chemotherapy with respect to DFS. To control the overall level of significance at a 2-sided error rate of 0.05, comparisons with respect to DFS between the alectinib and chemotherapy arms within the Stage Il-Illa subpopulation and the ITT population will be conducted hierarchically as follows:

[0276] Disease-free survival (DFS) in the Stage Il-Illa subpopulation will be first tested at an overall 2-sided a-level of 0.05. If the 2-sided p-value corresponding to the stratified logrank test is less than 0.0464 at the primary analysis (in order to adjust for 1 interim analysis for efficacy), the null hypothesis will be rejected, and it will be concluded that alectinib prolongs duration of DFS relative to chemotherapy in the Stage Il-Illa subpopulation. Stopping boundaries will be adjusted depending on the actual number of DFS events. If alectinib significantly prolongs DFS in the Stage Il-Illa subpopulation, then DFS in the ITT population will be tested at an overall 2-sided a-level of 0.05. If the 2-sided p- value corresponding to the stratified log-rank test is less than 0.0463 at the primary analysis (in order to adjust for 1 interim analysis for efficacy), the null hypothesis will be rejected, and it will be concluded that alectinib prolongs duration of DFS relative to chemotherapy in the ITT population. Stopping boundaries will be adjusted depending on the actual number of DFS events.

[0277] If alectinib has no significant effect on DFS in the Stage Il-Illa subpopulation, then DFS in the ITT population will not be tested.

[0278] Interim Analyses

[0279] There is 1 interim analysis for efficacy planned in the study for DFS. The interim analysis will be conducted after approximately 67% of events have been observed in the Stage Il-Illa subpopulation. Based on the assumptions described in the protocol, this relates to approximately 59 DFS events for the Stage Il-Illa subpopulation. This is predicted to occur approximately 44 months after the first patient is randomized (i.e. , approximately 16 months before the primary analysis), although the exact timing of this analysis will depend on the actual number of DFS events in the Stage Il-Illa subpopulation, but irrespective of the number of DFS events observed in the ITT populatin.

[0280] To control the type I error, the stopping boundaries for the DFS interim and primary analyses are to be computed with use of the Lan-DeMets approximation to the O'Brien-Fleming boundaries. In the Stage Il-Illa subpopulation, the stopping boundary for early rejection of the null hypothesis for an overall 2-sided 5% significance level is HR < 0.52 (p < 0.0118). In the ITT population, the stopping boundary for early rejection of the null hypothesis for an overall 2-sided 5% significance level is HR < 0.55 (p < 0.0121). If less than 67% of DFS events in the ITT population have been observed at the time of reaching the required events for the interim analysis in the Stage Il-Illa subpopulation, the stopping boundaries will be adjusted depending on the actual number of DFS events observed in the ITT population. However, the ITT interim analysis would only take place in the case of early rejection of the null hypothesis in the Stage Il-Illa subpopulation.

[0281] An external iDMC will evaluate safety data on an ongoing basis and review the data from the interim analysis. All summaries and analyses by treatment arm for the iDMC's review will be prepared by an external independent data coordinating center. Members of the iDMC will be external to the Sponsor and will follow a charter that outlines their roles and responsibilities. Any outcomes of these reviews that affect study conduct will be communicated in a timely manner to the investigators for notification of the Institutional Review Board (IRB) / Ethics Committee (EC). A detailed plan will be included in the iDMC Charter. Positive efficacy results at the interim analysis will not change the conduct of the study and timing of disease assessments.

[0282] Primary efficacy endpoint

[0283] The primary efficacy objective for this study is to evaluate the efficacy of alectinib compared with platinum-based chemotherapy on the basis of DFS. Disease-free survival is defined as the time from randomization to the first documented recurrence of disease or new primary NSCLC - as determined by the investigator through use of an integrated assessment of radiographic data, biopsy sample results (if clinically feasible), and clinical status - or death from any cause, whichever occurs first.

[0284] Patients who are not reported as experiencing disease recurrence, a new primary NSCLC, or death will be censored at the date of the last disease assessment. If no post-baseline data are available, patients will be censored at the date of randomization.

[0285] To control the overall level of significance at a 2-sided error rate of 0.05, comparisons with respect to DFS between the alectinib and chemotherapy arms within the Stage Il-Illa subpopulation and the ITT population will be conducted hierarchically.

[0286] The null (HO) and alternative (HA) hypotheses regarding DFS in each population (the Stage Il-Illa subpopulation and the ITT population) can be phrased in terms of the DFS survival distribution function (SDF) in the alectinib arm and SDF in the control arm, respectively:

[0287] Ho: SDF (alectinib) = SDF (chemotherapy) versus

[0288] HA: SDF (alectinib) SDF (chemotherapy)

[0289] The HR in the Stage Il-Illa subpopulation will be estimated with use of a stratified Cox regression model with race as stratification factor, including 95% Cis. For the ITT population, all stratification factors specified for randomization will be used for the stratified Cox regression model. Strata with less than 20 patients will be pooled for analysis in the stratified Cox regression model. The unstratified HR will also be presented. Kaplan-Meier methodology will be used to estimate the median DFS for each treatment arm, and the Kaplan-Meier curve will be constructed to provide a visual description of the difference between the treatment and control arms. Brookmeyer-Crowley methodology will be used to construct the 95% Cl for the median DFS for each treatment arm.

[0290] In addition, the impact of loss to follow-up on DFS will be assessed depending on the number of patients who are lost to follow-up. If more than 5% of patients are lost to follow-up for DFS in either treatment arm, a sensitivity analysis ("worst-case" analysis) will be performed in which patients who are lost to follow-up will be considered to have recurrent disease at the date of the last disease assessment.

[0291] Results

[0292] Alectinib, compared with platinum-based chemotherapy, demonstrated a statistically significant and clinically meaningful improvement in DFS 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).

[0293] A total of 257 patients were enrolled, comprising 26 stage IB patients, 92 stage II patients and 139 stage IIIA patients.

[0294] An interim analysis (occurring after 59 events in the stage II to stage IIIA subpopulation) revealed that treatment with alectinib resulted in a 76% reduction in disease recurrence or new primary NSCLC compared to treatment with chemotherapy (hazard ratio: 0.24). The results are show in Table 1 and Figure 1.

[0295] Table 1

[0296] Cl = Confidence Interval

[0297] NE = Not Evaluated

[0298] In the intent-to-treat population (stage IB [tumors >4 cm] to stage IIIA), treatment with alectinib resulted in an excellent 76% reduction in disease recurrence or new primary NSCLC compared to chemotherapy (hazard ratio of 0.24). The results are show in Table 2 and Figure

[0299] 2.

[0300] Table 2

[0301] Cl = Confidence Interval NE = Not Evaluated

[0302] The results were analysed by subgroup (age, sex, race, ECOG performance status, tobacco use history, and disease stage). The results are show 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:

[0303] Table 3

[0304] Cl = Confidence Interval

[0305] NE = Not Evaluated

[0306] Alectinib resulted in an excellent and surprising 84% reduction (hazard ratio: 0.16) in disease recurrence or new primary NSCLC compared to standard platinum-based chemotherapy in the non-Asian population. A 64% reduction (hazard ratio: 0.36) was achieved in the Asian population.

[0307] CNS-disease free survival was assessed in the intent-to-treat population (Table 4 and Figure 4). Treatment with alectinib resulted in a clinically meaningful prolongation of CNS-disease free survival compared to chemotherapy (hazard ratio: 0.22).

[0308] Table 4

[0309] Cl = Confidence Interval

[0310] NE = Not Evaluated1Not formally tested

[0311] Alectinib demonstrated improvements versus chemotherapy in the number of adverse events leading to withdrawal from treatment, neutrophil and white blood cell counts, and incidence of asthenia, nausea, vomiting, decreased appetite, malaise, neutropenia, fatigue and tinnitus.

[0312] The results are surprising and unexpected as alectinib is the first and only ALK inhibitor to demonstrate a reduction in the risk of disease recurrence or death for people with early-stage ALK-positive NSCLC in a Phase III trial. There are currently no approved ALK inhibitors for early-stage ALK-positive disease, to treat cancer before it has spread.

[0313] Furthermore Alectinib treatment as described demonstrated improved Health-related quality of life compared to chemotherapy. Health-related quality of life is an important clinical consideration for adjuvant treatment in resected ALK+ NSCLC and was assessed using SF- 36v2, which is a well-established, validated health status assessment tool. Mental as well as physical Health-related quality of life improvement was shown for Alectinib treatment.

Claims

1. A method for treating or preventing anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), 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 had resection of ALK-positive stage Ib NSCLC with a tumor of at least 4 cm to ALK-positive stage IIIa NSCLC.

2. The method of claim 1, wherein the subject has had resection of ALK-positive stage II to stage IIIa NSCLC.

3. The method of claim 1, wherein the subject has had resection of ALK-positive stage Ib NSCLC with a tumor of at least 4 cm to ALK-positive stage IIb NSCLC.

4. The method of claim 1, wherein the subject has had resection of ALK-positive stage Ib NSCLC with a tumor of at least 4 cm.

5. The method of claim 1, wherein the subject has had resection of ALK-positive stage II NSCLC.

6. The method of claim 1, wherein the subject has had resection of ALK-positive stage IIIa NSCLC.

7. The method of any one of claims 1-6, wherein the subject does not have metastatic ALK-positive NSCLC.

8. The method according to any one of claims 1-7, wherein alectinib or a pharmaceutically acceptable salt thereof is administered as an adjuvant therapy.

9. The method of any one of claims 1-8, wherein the subject has had a complete resection of ALK-positive NSCLC with negative margins, preferably wherein the resection is performed by lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy.

10. The method according to any one of claims 1-9, wherein the subject does not have a mutation that confers resistance to ALK inhibitors.

11. The method of any one of claims 1-10, wherein the subject has not previously been exposed to an ALK inhibitor; and / or wherein the subject has not previously received adjuvant radiation therapy.

12. The method according to any one of claims 1 to 11, wherein alectinib or a pharmaceutically acceptable salt thereof is administered orally, preferably wherein the total daily dose of alectinib or a pharmaceutically acceptable salt thereof is from 600 to 1500 mg, preferably 1200 mg, more preferably 600 mg twice daily.

13. The method according to any one of claims 1-12, wherein alectinib or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition, preferably wherein the pharmaceutical composition comprises alectinib hydrochloride.

14. The method according to claim 13, wherein the pharmaceutical composition comprises lactose monohydrate, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate and calcium carboxymethylcellulose.

15. The method according to claim 13 or 14, wherein the pharmaceutical composition is prepared in the form of a capsule, preferably a hard capsule, more preferably wherein the capsule contains alectinib hydrochloride equivalent to 150 mg of alectinib as a free base.

16. The method of claim 15, wherein the capsule contains 33.7 mg lactose monohydrate and 6 mg sodium lauryl sulfate.

17. The method according to any one of claims 1-16, further comprising administering a therapeutically effective amount of a second therapeutic agent, preferably wherein the second therapeutic agent is selected from the group consisting of chemotherapeutic agents, hormonal therapeutic agents, immunotherapeutic agents, molecularly targeted agents.

18. The method of any one of claims 1-17, wherein the likelihood of recurrence of ALK-positive NSCLC in the subject is reduced compared to treatment with platinum-based chemotherapy.

19. Use of alectinib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of ALK-positive NSCLC in a subject, wherein the subject has had resection of ALK-positive stage Ib NSCLC with a tumor of at least 4 cm prior to ALK-positive stage IIIa NSCLC.

20. The use according to claim 19, wherein alectinib or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition.

21. Use according to claim 19 or 20, wherein the subject has had resection of ALK-positive NSCLC from stage II to stage IIIa.

22. Use according to claim 19 or 20, wherein the subject has had resection of ALK-positive stage Ib NSCLC with a tumor of at least 4 cm to ALK-positive stage IIb NSCLC.

23. Use according to claim 19 or 20, wherein the subject has had resection of ALK-positive stage Ib NSCLC with a tumor of at least 4 cm.

24. Use according to claim 19 or 20, wherein the subject has had resection of ALK-positive stage II NSCLC.

25. Use according to claim 19 or 20, wherein the subject has had resection of ALK-positive stage IIIa NSCLC.

26. The use according to any of paragraphs 19-25, wherein the subject does not have metastatic ALK-positive NSCLC.

27. The use according to any one of claims 19-26, wherein alectinib or a pharmaceutically acceptable salt thereof is administered as adjuvant therapy.

28. The use according to any one of claims 19-27, wherein the subject has had a complete resection of ALK-positive NSCLC with negative margins, wherein the resection is preferably performed by lobectomy, sleeve lobectomy, bilobectomy or pneumonectomy.

29. The use according to any one of paragraphs 19-28, wherein the subject does not have a mutation that confers resistance to ALK inhibitors.

30. The use according to any one of claims 19-29, wherein the subject has not previously been exposed to an ALK inhibitor; and / or wherein the subject has not previously received adjuvant radiation therapy.

31. The use according to any one of claims 19-30, wherein alectinib, a pharmaceutically acceptable salt thereof or a pharmaceutical composition is administered orally, wherein preferably the total daily dose of alectinib or a pharmaceutically acceptable salt thereof is from 600 to 1500 mg, preferably 1200 mg, more preferably 600 mg twice a day.

32. The use according to any one of paragraphs 20-31, wherein the pharmaceutical composition comprises alectinib hydrochloride.

33. The use according to any one of claims 20-32, wherein the pharmaceutical composition comprises lactose monohydrate, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate and calcium carboxymethylcellulose.

34. The use according to any one of claims 20-33, wherein the pharmaceutical composition is prepared in the form of a capsule, preferably a hard capsule, more preferably the capsule contains alectinib hydrochloride equivalent to 150 mg of alectinib as a free base.

35. The use according to claim 34, wherein the capsule contains 33.7 mg of lactose monohydrate and 6 mg of sodium lauryl sulfate.

36. The use according to any one of paragraphs 19-35, further comprising administering a therapeutically effective amount of a second therapeutic agent, wherein preferably the second therapeutic agent is selected from the group consisting of chemotherapeutic agents, hormonal therapeutic agents, immunotherapeutic agents, molecularly targeted agents.

37. The use according to any one of claims 19-36, wherein the likelihood of recurrence of ALK-positive NSCLC in the subject is reduced compared to treatment with platinum-based chemotherapy.

38. A method for treating ALK-positive NSCLC in a subject in need thereof or preventing recurrence of ALK-positive NSCLC in a subject in need thereof, the subject had resection of ALK-positive stage Ib NSCLC with a tumor of at least 4 cm to ALK-positive stage IIIa NSCLC, wherein said method comprises administering to a subject a pharmaceutical composition comprising alectinib hydrochloride equivalent to 150 mg of alectinib as a free base, lactose monohydrate, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate and calcium carboxymethylcellulose, wherein the pharmaceutical composition is administered twice a day by oral administration, and the total daily dose of alectinib is equivalent to 1200 mg of alectinib as the free base.

39. Use of a therapeutically effective amount of alectinib or a pharmaceutically acceptable salt thereof for the treatment of ALK-positive NSCLC in a subject, wherein the subject has had resection of ALK-positive stage Ib NSCLC with a tumor of at least 4 cm prior to ALK-positive stage IIIa NSCLC.