ALUNBRIG 180mg tablets medication leaflet

Alunbrig 30 mg film-coated tablets

Alunbrig 90 mg film-coated tablets

Alunbrig 180 mg film-coated tablets

Alunbrig 30 mg film-coated tablets

Each film-coated tablet contains 30 mg of brigatinib.

Each film-coated tablet contains 56 mg of lactose monohydrate.

Alunbrig 90 mg film-coated tablets

Each film-coated tablet contains 90 mg of brigatinib.

Each film-coated tablet contains 168 mg of lactose monohydrate.

Alunbrig 180 mg film-coated tablets

Each film-coated tablet contains 180 mg of brigatinib.

Each film-coated tablet contains 336 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Alunbrig 30 mg film-coated tablets

Round, white to off-white film-coated tablet of approximately 7 mm in diameter with debossed “U3”on one side and plain on the other side.

Alunbrig 90 mg film-coated tablets

Oval, white to off-white film-coated tablet of approximately 15 mm in length with debossed “U7” onone side and plain on the other side.

Alunbrig 180 mg film-coated tablets

Oval, white to off-white film-coated tablet of approximately 19 mm in length with debossed “U13” onone side and plain on the other side.

Alunbrig is indicated as monotherapy for the treatment of adult patients with anaplastic lymphomakinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously not treated with an

ALK inhibitor.

Alunbrig is indicated as monotherapy for the treatment of adult patients with ALK-positive advanced

NSCLC previously treated with crizotinib.

Treatment with Alunbrig should be initiated and supervised by a physician experienced in the use ofanticancer medicinal products.

ALK-positive NSCLC status should be known prior to initiation of Alunbrig therapy. A validated

ALK assay is necessary for the selection of ALK-positive NSCLC patients (see section 5.1).

Assessment for ALK-positive NSCLC should be performed by laboratories with demonstratedproficiency in the specific technology being utilised.

The recommended starting dose of Alunbrig is 90 mg once daily for the first 7 days, then 180 mg oncedaily.

If Alunbrig is interrupted for 14 days or longer for reasons other than adverse reactions, treatmentshould be resumed at 90 mg once daily for 7 days before increasing to the previously tolerated dose.

If a dose is missed or vomiting occurs after taking a dose, an additional dose should not beadministered and the next dose should be taken at the scheduled time.

Treatment should continue as long as clinical benefit is observed.

Dosing interruption and/or dose reduction may be required based on individual safety and tolerability.

Alunbrig dose reduction levels are summarised in Table 1.

Table 1: Recommended Alunbrig dose reduction levels

Dose Dose reduction levels

First Second Third90 mg once daily reduce to 60 mg once permanently not applicable(first 7 days) daily discontinue180 mg once daily reduce to 120 mg once reduce to 90 mg once reduce to 60 mg oncedaily daily daily

Alunbrig should be permanently discontinued if patient is unable to tolerate the 60 mg once daily dose.

Recommendations for dose modifications of Alunbrig for the management of adverse reactions aresummarised in Table 2.

Table 2: Recommended Alunbrig dose modifications for adverse reactions

Adverse reaction Severity* Dose modification

Interstitial lung Grade 1 * If event occurs during the first 7 days of treatment,disease Alunbrig should be withheld until recovery to(ILD)/pneumonitis baseline, then resumed at same dose level and notescalated to 180 mg once daily.

* If ILD/pneumonitis occurs after the first 7 days oftreatment, Alunbrig should be withheld untilrecovery to baseline, then resumed at same doselevel.

* If ILD/pneumonitis recurs, Alunbrig should bepermanently discontinued.

Grade 2 * If ILD/pneumonitis occurs during the first 7 daysof treatment, Alunbrig should be withheld untilrecovery to baseline, then resumed at next lowerdose level as described in Table 1 and notescalated to 180 mg once daily.

* If ILD/pneumonitis occurs after the first 7 days oftreatment, Alunbrig should be withheld untilrecovery to baseline. Alunbrig should be resumedat next lower dose level as described in Table 1.

* If ILD/pneumonitis recurs, Alunbrig should bepermanently discontinued.

Grade 3 or 4 * Alunbrig should be permanently discontinued.

Hypertension Grade 3 hypertension * Alunbrig should be withheld until hypertension(SBP ≥ 160 mmHg or has recovered to Grade ≤ 1 (SBP < 140 mmHg and

DBP ≥ 100 mmHg, DBP < 90 mmHg), then resumed at same dose.medical intervention * If Grade 3 hypertension recurs, Alunbrig should beindicated, more than withheld until hypertension has recovered toone anti-hypertensive Grade ≤ 1 then resumed at the next lower dosemedicinal product, or level per Table 1 or permanently discontinued.more intensivetherapy thanpreviously usedindicated)

Grade 4 hypertension * Alunbrig should be withheld until hypertension(life threatening has recovered to Grade ≤ 1 (SBP < 140 mmHgconsequences, urgent and DBP < 90 mmHg), then resumed at the nextintervention lower dose level per Table 1 or permanentlyindicated) discontinued.

* If Grade 4 hypertension recurs, Alunbrig shouldbe permanently discontinued.

Adverse reaction Severity* Dose modification

Bradycardia (heart Symptomatic * Alunbrig should be withheld until recovery torate less than bradycardia asymptomatic bradycardia or to a resting heart60 bpm) rate of 60 bpm or above.

* If a concomitant medicinal product known tocause bradycardia is identified and discontinued,or its dose is adjusted, Alunbrig should beresumed at same dose upon recovery toasymptomatic bradycardia or to a resting heartrate of 60 bpm or above.

* If no concomitant medicinal product known tocause bradycardia is identified, or if contributingconcomitant medicinal products are notdiscontinued or dose modified, Alunbrig shouldbe resumed at the next lower dose level per

Table 1 upon recovery to asymptomaticbradycardia or to a resting heart rate of 60 bpm orabove.

Bradycardia with * If contributing concomitant medicinal product islife-threatening identified and discontinued, or its dose is adjusted,consequences, urgent Alunbrig should be resumed at the next lowerintervention indicated dose level per Table 1 upon recovery toasymptomatic bradycardia or to a resting heartrate of 60 bpm or above, with frequent monitoringas clinically indicated.

* Alunbrig should be permanently discontinued ifno contributing concomitant medicinal product isidentified.

* Alunbrig should be permanently discontinued incase of recurrence.

Elevation of CPK Grade 3 or 4 elevation * Alunbrig should be withheld until recovery toof CPK Grade ≤ 1 (≤ 2.5 × ULN) elevation of CPK or to(> 5.0 × ULN) with baseline, then resumed at the same dose.

Grade ≥ 2 muscle pain * If Grade 3 or 4 elevation of CPK recurs withor weakness Grade ≥ 2 muscle pain or weakness, Alunbrigshould be withheld until recovery to

Grade ≤ 1 (≤ 2.5 × ULN) elevation of CPK or tobaseline, then resumed at the next lower doselevel per Table 1.

Elevation of lipase Grade 3 elevation of * Alunbrig should be withheld until recovery toor amylase lipase or amylase Grade ≤ 1 (≤ 1.5 × ULN) or to baseline, then(> 2.0 × ULN) resumed at same dose.

* If Grade 3 elevation of lipase or amylase recurs,

Alunbrig should be withheld until recovery to

Grade ≤ 1 (≤ 1.5 × ULN) or to baseline, thenresumed at the next lower dose level per Table 1.

Grade 4 elevation of * Alunbrig should be withheld until recovery tolipase or amylase Grade ≤ 1 (≤ 1.5 × ULN), then resumed at the(> 5.0 x ULN) next lower dose level per Table 1.

Adverse reaction Severity* Dose modification

Hepatotoxicity Grade ≥ 3 elevation * Alunbrig should be withheld until recovery to(> 5.0 × ULN) of baseline or less than or equal to 3 × ULN, theneither alanine resumed at next lower dose per Table 1.aminotransferase(ALT) or aspartateaminotransferase(AST) with bilirubin≤ 2 × ULN

Grade ≥ 2 elevation * Alunbrig should be permanently discontinued.(> 3 × ULN) of ALTor AST withconcurrent totalbilirubinelevation > 2 × ULNin the absence ofcholestasis orhaemolysis

Hyperglycaemia For Grade 3 (greater * If adequate hyperglycaemic control cannot bethan 250 mg/dL or achieved with optimal medical management,13.9 mmol/L) or Alunbrig should be withheld until adequategreater hyperglycaemic control is achieved. Uponrecovery, Alunbrig may either be resumed at thenext lower dose per Table 1 or permanentlydiscontinued.

Visual disturbance Grade 2 or 3 * Alunbrig should be withheld until recovery to

Grade 1 or baseline, then resumed at the nextlower dose level per Table 1.

Grade 4 * Alunbrig should be permanently discontinued.

Other adverse Grade 3 * Alunbrig should be withheld until recovery toreactions baseline, then resumed at the same dose level.

* If the Grade 3 event recurs, Alunbrig should bewithheld until recovery to baseline, then resumedat the next lower dose level as per Table 1 orpermanently discontinued.

Grade 4 * Alunbrig should be withheld until recovery tobaseline, then resumed at the next lower doselevel as per Table 1.

* If the Grade 4 event recurs, Alunbrig should bewithheld until recovery to baseline, then resumedat the next lower dose level as per Table 1 orpermanently discontinued.

bpm = beats per minute; CPK = Creatine Phosphokinase; DBP = diastolic blood pressure; SBP = systolic blood pressure;

ULN = upper limit of normal

*Graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI CTCAE v4).

The limited data on the safety and efficacy of Alunbrig in patients aged 65 years and older suggest thata dose adjustment is not required in elderly patients (see section 4.8). There are no available data onpatients over 85 years of age.

No dose adjustment of Alunbrig is required for patients with mild hepatic impairment (Child-Pughclass A) or moderate hepatic impairment (Child-Pugh class B). A reduced starting dose of 60 mg oncedaily for the first 7 days, then 120 mg once daily is recommended for patients with severe hepaticimpairment (Child-Pugh class C) (see section 5.2).

No dose adjustment of Alunbrig is required for patients with mild or moderate renal impairment(estimated glomerular filtration rate (eGFR) ≥ 30 mL/min). A reduced starting dose of 60 mg oncedaily for the first 7 days, then 90 mg once daily is recommended for patients with severe renalimpairment (eGFR < 30 mL/min) (see section 5.2). Patients with severe renal impairment should beclosely monitored for new or worsening respiratory symptoms that may indicate ILD/pneumonitis(e.g., dyspnoea, cough, etc.) particularly in the first week (see section 4.4).

The safety and efficacy of Alunbrig in patients less than 18 years of age have not been established. Nodata are available.

Alunbrig is for oral use. The tablets should be swallowed whole and with water. Alunbrig may betaken with or without food.

Grapefruit or grapefruit juice may increase plasma concentrations of brigatinib and should be avoided(see section 4.5).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Pulmonary adverse reactions

Severe, life-threatening, and fatal pulmonary adverse reactions, including those with featuresconsistent with ILD/pneumonitis, can occur in patients treated with Alunbrig (see section 4.8).

Most pulmonary adverse reactions were observed within the first 7 days of treatment. Grade 1-2pulmonary adverse reactions resolved with interruption of treatment or dose modification. Increasedage and shorter interval (less than 7 days) between the last dose of crizotinib and the first dose of

Alunbrig were independently associated with an increased rate of these pulmonary adverse reactions.

These factors should be considered when initiating treatment with Alunbrig. Patients with a history of

ILD or drug-induced pneumonitis were excluded from the pivotal trials.

Some patients experienced pneumonitis later in treatment with Alunbrig.

Patients should be monitored for new or worsening respiratory symptoms (e.g., dyspnoea, cough, etc.),particularly in the first week of treatment. Evidence of pneumonitis in any patient with worseningrespiratory symptoms should be promptly investigated. If pneumonitis is suspected, the dose of

Alunbrig should be withheld, and the patient evaluated for other causes of symptoms (e.g., pulmonaryembolism, tumour progression, and infectious pneumonia). The dose should be modified accordingly(see section 4.2).

Hypertension has occurred in patients treated with Alunbrig (see section 4.8).

Blood pressure should be monitored regularly during treatment with Alunbrig. Hypertension should betreated according to standard guidelines to control blood pressure. Heart rate should be monitoredmore frequently in patients if concomitant use of a medicinal product known to cause bradycardiacannot be avoided. For severe hypertension (≥ Grade 3), Alunbrig should be withheld untilhypertension has recovered to Grade 1 or to baseline. The dose should be modified accordingly (seesection 4.2).

Bradycardia

Bradycardia has occurred in patients treated with Alunbrig (see section 4.8). Caution should beexercised when administering Alunbrig in combination with other agents known to cause bradycardia.

Heart rate and blood pressure should be monitored regularly.

If symptomatic bradycardia occurs, treatment with Alunbrig should be withheld and concomitantmedicinal products known to cause bradycardia should be evaluated. Upon recovery, the dose shouldbe modified accordingly (see section 4.2). In case of life-threatening bradycardia, if no contributingconcomitant medication is identified or in case of recurrence, treatment with Alunbrig should bediscontinued (see section 4.2).

Visual disturbance

Visual disturbance adverse reactions have occurred in patients treated with Alunbrig (see section 4.8).

Patients should be advised to report any visual symptoms. For new or worsening severe visualsymptoms, an ophthalmologic evaluation and dose reduction should be considered (see section 4.2).

Creatine phosphokinase (CPK) elevation

Elevations of CPK have occurred in patients treated with Alunbrig (see section 4.8). Patients should beadvised to report any unexplained muscle pain, tenderness, or weakness. CPK levels should bemonitored regularly during Alunbrig treatment. Based on the severity of the CPK elevation, and ifassociated with muscle pain or weakness, treatment with Alunbrig should be withheld, and the dosemodified accordingly (see section 4.2).

Elevations of pancreatic enzymes

Elevations of amylase and lipase have occurred in patients treated with Alunbrig (see section 4.8).

Lipase and amylase should be monitored regularly during treatment with Alunbrig. Based on theseverity of the laboratory abnormalities, treatment with Alunbrig should be withheld, and the dosemodified accordingly (see section 4.2).

Elevations of hepatic enzymes (aspartate aminotransferase, alanine aminotransferase) and bilirubinhave occurred in patients treated with Alunbrig (see section 4.8). Liver function, including AST, ALTand total bilirubin should be assessed prior to the initiation of Alunbrig and then every 2 weeks duringthe first 3 months of treatment. Thereafter, monitoring should be performed periodically. Based on theseverity of the laboratory abnormalities, treatment should be withheld, and the dose modifiedaccordingly (see section 4.2).

Elevations of serum glucose have occurred in patients treated with Alunbrig. Fasting serum glucoseshould be assessed prior to initiation of Alunbrig and monitored periodically thereafter.

Antihyperglycaemic treatment should be initiated or optimised as needed. If adequate hyperglycaemiccontrol cannot be achieved with optimal medical management, Alunbrig should be withheld untiladequate hyperglycaemic control is achieved; upon recovery reducing the dose as described in Table 1may be considered or Alunbrig may be permanently discontinued.

The concomitant use of Alunbrig with strong CYP3A inhibitors should be avoided. If concomitant useof strong CYP3A inhibitors cannot be avoided, the dose of Alunbrig should be reduced from 180 mgto 90 mg, or from 90 mg to 60 mg. After discontinuation of a strong CYP3A inhibitor, Alunbrigshould be resumed at the dose that was tolerated prior to the initiation of the strong CYP3A inhibitor.

The concomitant use of Alunbrig with strong and moderate CYP3A inducers should be avoided (seesection 4.5). If concomitant use of moderate CYP3A inducers cannot be avoided, the dose of Alunbrigmay be increased in 30 mg increments after 7 days of treatment with the current Alunbrig dose astolerated, up to a maximum of twice the Alunbrig dose that was tolerated prior to the initiation of themoderate CYP3A inducer. After discontinuation of a moderate CYP3A inducer, Alunbrig should beresumed at the dose that was tolerated prior to the initiation of the moderate CYP3A inducer.

Photosensitivity and photodermatosis

Photosensitivity to sunlight has occurred in patients treated with Alunbrig (see section 4.8). Patientsshould be advised to avoid prolonged sun exposure while taking Alunbrig, and for at least 5 days afterdiscontinuation of treatment. When outdoors, patients should be advised to wear a hat and protectiveclothing, and to use a broad-spectrum Ultraviolet A (UVA)/ Ultraviolet B (UVB) sunscreen and lipbalm (SPF ≥ 30) to help protect against potential sunburn. For severe photosensitivity reactions(≥ Grade 3), Alunbrig should be withheld until recovery to baseline. The dose should be modifiedaccordingly (see section 4.2).

Women of childbearing potential should be advised to use effective non-hormonal contraceptionduring treatment with Alunbrig and for at least 4 months following the final dose. Men with femalepartners of childbearing potential should be advised to use effective contraception during treatmentand for at least 3 months after the last dose of Alunbrig (see section 4.6).

Alunbrig contains lactose monohydrate. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinalproduct.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Agents that may increase brigatinib plasma concentrations

In vitro studies demonstrated that brigatinib is a substrate of CYP3A4/5. In healthy subjects,coadministration of multiple 200 mg twice daily doses of itraconazole, a strong CYP3A inhibitor, witha single 90 mg brigatinib dose increased brigatinib Cmax by 21%, AUC0-INF by 101% (2-fold), and

AUC0-120 by 82% (< 2-fold), relative to a 90 mg brigatinib dose administered alone. The concomitantuse of strong CYP3A inhibitors with Alunbrig, including but not limited to certain antivirals (e.g.,indinavir, nelfinavir, ritonavir, saquinavir), macrolide antibiotics (e.g., clarithromycin, telithromycin,troleandomycin), antifungals (e.g., ketoconazole, voriconazole), and nefazodone should be avoided. Ifconcomitant use of strong CYP3A inhibitors cannot be avoided, the dose of Alunbrig should bereduced by approximately 50% (i.e. from 180 mg to 90 mg, or from 90 mg to 60 mg). Afterdiscontinuation of a strong CYP3A inhibitor, Alunbrig should be resumed at the dose that wastolerated prior to the initiation of the strong CYP3A inhibitor.

Moderate CYP3A inhibitors (e.g., diltiazem and verapamil) may increase the AUC of brigatinib byapproximately 40% based on simulations from a physiologically-based pharmacokinetic model. Nodose adjustment is required for Alunbrig in combination with moderate CYP3A inhibitors. Patientsshould be closely monitored when Alunbrig is coadministered with moderate CYP3A inhibitors.

Grapefruit or grapefruit juice may also increase plasma concentrations of brigatinib and should beavoided (see section 4.2).

In vitro studies demonstrated that brigatinib is a substrate of CYP2C8. In healthy subjects,coadministration of multiple 600 mg twice daily doses of gemfibrozil, a strong CYP2C8 inhibitor,with a single 90 mg brigatinib dose reduced brigatinib Cmax by 41%, AUC0-INF by 12%, and AUC0-120by 15%, relative to a 90 mg brigatinib dose administered alone. The effect of gemfibrozil on thepharmacokinetics of brigatinib is not clinically meaningful and the underlying mechanism for thedecreased exposure of brigatinib is unknown. No dose adjustment is required during coadministrationwith strong CYP2C8 inhibitors.

P-gp and BCRP inhibitors

Brigatinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro.

Given that brigatinib exhibits high solubility and high permeability, inhibition of P-gp and BCRP isnot expected to result in a clinically meaningful change in the systemic exposure of brigatinib. Nodose adjustment is required for Alunbrig during coadministration with P-gp and BCRP inhibitors.

Agents that may decrease brigatinib plasma concentrations

In healthy subjects, coadministration of multiple 600 mg daily doses of rifampicin, a strong CYP3Ainducer, with a single 180 mg brigatinib dose decreased brigatinib Cmax by 60%, AUC0-INF by 80%(5-fold), and AUC0-120 by 80% (5-fold), relative to a 180 mg brigatinib dose administered alone. Theconcomitant use of strong CYP3A inducers with Alunbrig, including but not limited to rifampicin,carbamazepine, phenytoin, rifabutin, phenobarbital, and St. John’s wort should be avoided.

Moderate CYP3A inducers may decrease the AUC of brigatinib by approximately 50% based onsimulations from a physiologically-based pharmacokinetic model. The concomitant use of moderate

CYP3A inducers with Alunbrig, including but not limited to efavirenz, modafinil, bosentan, etravirine,and nafcillin should be avoided. If concomitant use of moderate CYP3A inducers cannot be avoided,the dose of Alunbrig may be increased in 30 mg increments after 7 days of treatment with the current

Alunbrig dose as tolerated, up to a maximum of twice the Alunbrig dose that was tolerated prior to theinitiation of the moderate CYP3A inducer. After discontinuation of a moderate CYP3A inducer,

Alunbrig should be resumed at the dose that was tolerated prior to the initiation of the moderate

CYP3A inducer.

Agents that may have their plasma concentrations altered by brigatinib

In vitro studies in hepatocytes have shown that brigatinib is an inducer of CYP3A4. In patients withcancer, coadministration of multiple 180 mg daily doses of Alunbrig with a single 3 mg oral dose ofmidazolam, a sensitive CYP3A substrate, decreased midazolam Cmax by 16%, AUC0-INF by 26%, and

AUC0-last by 30%, relative to a 3 mg oral dose of midazolam administered alone. Brigatinib reducesplasma concentrations of coadministered medicinal products that are predominantly metabolised by

CYP3A. Therefore, coadministration of Alunbrig with CYP3A substrates with a narrow therapeuticindex (e.g., alfentanil, fentanyl, quinidine, cyclosporine, sirolimus, tacrolimus) should be avoided astheir effectiveness may be reduced.

Alunbrig may also induce other enzymes and transporters (e.g., CYP2C, P-gp) via the samemechanisms responsible for induction of CYP3A (e.g., pregnane X receptor activation).

Coadministration of brigatinib with substrates of P-gp (e.g., digoxin, dabigatran, colchicine,pravastatin), BCRP (e.g., methotrexate, rosuvastatin, sulfasalazine), organic cation transporter1 (OCT1), multidrug and toxin extrusion protein 1 (MATE1), and 2K (MATE2K) may increase theirplasma concentrations. Patients should be closely monitored when Alunbrig is coadministered withsubstrates of these transporters with a narrow therapeutic index (e.g., digoxin, dabigatran,methotrexate).

Women of childbearing age being treated with Alunbrig should be advised not to become pregnant andmen being treated with Alunbrig should be advised not to father a child during treatment. Women ofreproductive potential should be advised to use effective non-hormonal contraception during treatmentwith Alunbrig and for at least 4 months following the final dose. Men with female partners ofreproductive potential should be advised to use effective contraception during treatment and for atleast 3 months after the last dose of Alunbrig.

Alunbrig may cause foetal harm when administered to a pregnant woman. Studies in animals haveshown reproductive toxicity (see section 5.3). There are no clinical data on the use of Alunbrig inpregnant women. Alunbrig should not be used during pregnancy unless the clinical condition of themother requires treatment. If Alunbrig is used during pregnancy, or if the patient becomes pregnantwhile taking this medicinal product, the patient should be apprised of the potential hazard to a foetus.

It is unknown whether Alunbrig is excreted in human milk. Available data cannot exclude potentialexcretion in human milk. Breast-feeding should be stopped during treatment with Alunbrig.

No human data on the effect of Alunbrig on fertility are available. Based on repeat-dose toxicitystudies in male animals, Alunbrig may cause reduced fertility in males (see section 5.3). The clinicalrelevance of these findings to human fertility is unknown.

Alunbrig has minor influence on the ability to drive and use machines. However, caution should beexercised when driving or operating machines as patients may experience visual disturbance,dizziness, or fatigue while taking Alunbrig.

The most common adverse reactions (≥ 25%) reported in patients treated with Alunbrig at therecommended dosing regimen were increased AST, increased CPK, hyperglycaemia, increased lipase,hyperinsulinaemia, diarrhoea, increased ALT, increased amylase, anaemia, nausea, fatigue,hypophosphataemia, decreased lymphocyte count, cough, increased alkaline phosphatase, rash,increased APTT, myalgia, headache, hypertension, decreased white blood cell count, dyspnoea, andvomiting.

The most common serious adverse reactions (≥ 2%) reported in patients treated with Alunbrig at therecommended dosing regimen other than events related to neoplasm progression were pneumonia,pneumonitis, dyspnoea and pyrexia.

The data described below reflect exposure to Alunbrig at the recommended dosing regimen in threeclinical trials: a Phase 3 trial (ALTA 1L) in patients with advanced ALK-positive NSCLC previouslynot treated with an ALK-inhibitor (N = 136), a Phase 2 trial (ALTA) in patients treated with Alunbrigwith ALK-positive NSCLC who previously progressed on crizotinib (N = 110), and a phase 1/2 doseescalation/expansion trial in patients with advanced malignancies (N = 28). Across these studies, themedian duration of exposure in patients receiving Alunbrig at the recommended dosing regimen was21.8 months.

Adverse reactions reported are presented in Table 3 and are listed by system organ class, preferredterm and frequency. Frequency categories are very common (≥ 1/10), common (≥ 1/100 to < 1/10) anduncommon (≥ 1/1 000 to < 1/100). Within each frequency grouping, undesirable effects are presentedin order of frequency.

Table 3: Adverse reactions reported in patients treated with Alunbrig (per Common

Terminology Criteria for Adverse Events (CTCAE) version 4.03) at the 180 mg regimen(N = 274)

System organ Frequency Adverse reactions† Adverse reactionsclass category all grades Grade 3-4

Infections and Very Pneumoniaa,binfestations common Upper respiratory tract infection

Common Pneumoniaa

Blood and Very Anaemia Lymphocyte count decreasedlymphatic common Lymphocyte count decreasedsystem APTT increaseddisorders White blood cell countdecreased

Neutrophil count decreased

Common Decreased platelet count APTT increased

Uncommon Neutrophil count decreased

Metabolism Very Hyperglycaemiaand nutrition common Hyperinsulinaemiacdisorders Hypophosphataemia

Hypomagnesaemia

Hypercalcaemia

Hyponatraemia

Decreased appetite

Common Hypophosphataemia

Hyponatraemia

Decreased appetite

Psychiatric Common Insomniadisorders

Nervous system Very Headacheddisorders common Peripheral neuropathye

Dizziness

Common Memory impairment Headached

Dysgeusia Peripheral neuropathye

Uncommon Dizziness

Eye disorders Very Visual disturbancefcommon

Common Visual disturbancef

Cardiac Common Bradycardiag Electrocardiogram QTdisorders Electrocardiogram QT prolongedprolonged

Tachycardiah

Palpitations

Uncommon Bradycardiag

Vascular Very Hypertensioni Hypertensionidisorders common

Respiratory, Very Coughthoracic and common Dyspnoeajmediastinal Common Pneumonitisk Pneumonitiskdisorders Dyspnoeaj

System organ Frequency Adverse reactions† Adverse reactionsclass category all grades Grade 3-4

Gastrointestinal Very Lipase increased Lipase increaseddisorders common Diarrhoea

Amylase increased

Nausea

Abdominal painl

Stomatitism

Common Dry mouth Amylase increased

Dyspepsia Nausea

Flatulence Abdominal painl

Uncommon Pancreatitis Vomiting

Stomatitism

Dyspepsia

Hepatobiliary Very AST increaseddisorders common ALT increased

Alkaline phosphatase increased

Common Blood lactate dehydrogenase ALT increasedincreased AST increased

Hyperbilirubinaemia Alkaline phosphatase increased

Uncommon Hyperbilirubinaemia

Skin and Very Rashnsubcutaneous common Pruritusotissue disorders Common Dry skin Rashn

Photosensitivity reactionp Photosensitivity reactionp

Uncommon Dry skin

Prurituso

Musculoskeleta Very Blood CPK increased Blood CPK increasedl and common Myalgiaqconnective Arthralgiatissue disorders Common Musculoskeletal chest pain

Pain in extremity

Musculoskeletal stiffness

Uncommon Pain in extremity

Musculoskeletal chest pain

Myalgiaq

Renal and Very Blood creatinine increasedurinary commondisorders

General Very Fatiguerdisorders and common Oedemasadministration Pyrexiasite conditions Common Non-cardiac chest pain Fatiguer

Chest discomfort

Uncommon Pyrexia

Oedemas

Non-cardiac chest pain

System organ Frequency Adverse reactions† Adverse reactionsclass category all grades Grade 3-4

Investigations Common Blood cholesterol increasedt

Weight decreased

Uncommon Weight decreased† The frequencies for ADR terms associated with chemistry and haematology laboratory changes were determined basedon the frequency of abnormal laboratory shifts from baseline.a Includes atypical pneumonia, pneumonia, pneumonia aspiration, pneumonia cryptococcal, lower respiratory tractinfection, lower respiratory tract infection viral, lung infectionb Includes Grade 5 eventsc Grade not applicabled Includes headache, sinus headache, head discomfort, migraine, tension headachee Includes paraesthesia, peripheral sensory neuropathy, dysaesthesia, hyperaesthesia, hypoaesthesia, neuralgia, neuropathyperipheral, neurotoxicity, peripheral motor neuropathy, polyneuropathy, burning sensation, post herpetic neuralgiaf Includes altered visual depth perception, cataract, colour blindness acquired, diplopia, glaucoma, intraocular pressureincreased, macular oedema, photophobia, photopsia, retinal oedema, vision blurred, visual acuity reduced, visual fielddefect, visual impairment, vitreous detachment, vitreous floaters, amaurosis fugaxg Includes bradycardia, sinus bradycardiah Includes sinus tachycardia, tachycardia, atrial tachycardia, heart rate increasedi Includes blood pressure increased, diastolic hypertension, hypertension, systolic hypertensionj Includes dyspnoea, dyspnoea exertionalk Includes interstitial lung disease, pneumonitisl Includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper,epigastric discomfortm Includes aphthous stomatitis, stomatitis, aphthous ulcer, mouth ulceration, oral mucosal blisteringn Includes dermatitis acneiform, erythema, exfoliative rash, rash, rash erythematous, rash macular, rash maculo-papular,rash papular, rash pruritic, rash pustular, dermatitis, dermatitis allergic, dermatitis contact, generalised erythema, rashfollicular, urticaria, drug eruption, toxic skin eruptiono Includes pruritus, pruritus allergic, pruritus generalised, pruritus genital, vulvovaginal pruritusp Includes photosensitivity reaction, polymorphic light eruption, solar dermatitisq Includes musculoskeletal pain, myalgia, muscle spasms, muscle tightness, muscle twitching, musculoskeletal discomfortr Includes asthenia, fatigues Includes eyelid oedema, face oedema, oedema peripheral, periorbital oedema, swelling face, generalised oedema,peripheral swelling, angioedema, lip swelling, periorbital swelling, skin swelling, swelling of eyelidt Includes blood cholesterol increased, hypercholesterolemia

Pulmonary adverse reactions

In ALTA 1L, 2.9% of patients experienced any Grade ILD/pneumonitis early in treatment (within8 days), with Grade 3-4 ILD/pneumonitis in 2.2% of patients. There were no fatal ILD/pneumonitis.

Additionally, 3.7% of patients experienced pneumonitis later in treatment.

In ALTA, 6.4% of patients experienced pulmonary adverse reactions of any grade, including

ILD/pneumonitis, pneumonia and dyspnoea, early in treatment (within 9 days, median onset: 2 days);2.7% of patients had Grade 3-4 pulmonary adverse reactions and 1 patient (0.5%) had fatalpneumonia. Following Grade 1-2 pulmonary adverse reactions, treatment with Alunbrig was eitherinterrupted and then restarted or the dose was reduced. Early pulmonary adverse reactions alsooccurred in a dose escalation study in patients (N = 137) (Study 101) including three fatal cases(hypoxia, acute respiratory distress syndrome and pneumonia). Additionally, 2.3% of patients in

ALTA experienced pneumonitis later in treatment, with 2 patients having Grade 3 pneumonitis (seesections 4.2 and 4.4).

Early pulmonary adverse reaction was reported in 10.1% of patients ≥ 65 years of age compared with3.1% of patients < 65 years of age.

Hypertension was reported in 30% of patients treated with Alunbrig at the 180 mg regimen with 11%having Grade 3 hypertension. Dose reduction for hypertension occurred in 1.5% at the 180 mgregimen. Mean systolic and diastolic blood pressure, in all patients, increased over time (seesections 4.2 and 4.4).

Bradycardia

Bradycardia was reported in 8.4% of patients treated with Alunbrig at the 180 mg regimen.

Heart rates of less than 50 beats per minute (bpm) were reported in 8.4% of patients at the 180 mgregimen. (see sections 4.2 and 4.4).

Visual disturbance

Visual disturbance adverse reactions were reported in 14% of patients treated with Alunbrig at the180 mg regimen. Of these, three Grade 3 adverse reactions (1.1%) including macular oedema andcataract were reported.

Dose reduction for visual disturbance occurred in two patients (0.7%) at the 180 mg regimen (seesections 4.2 and 4.4).

Peripheral neuropathy adverse reactions were reported in 20% of patients treated at the 180 mgregimen. Thirty-three percent of patients had resolution of all peripheral neuropathy adverse reactions.

The median duration of peripheral neuropathy adverse reactions was 6.6 months, with a maximumduration of 28.9 months.

Creatine phosphokinase (CPK) elevation

In ALTA 1L and ALTA, elevations of CPK were reported in 64% of patients treated with Alunbrig atthe 180 mg regimen. The incidence of Grade 3-4 elevations of CPK was 18%. The median time toonset for CPK elevations was 28 days.

Dose reduction for CPK elevation occurred in 10% of patients at the 180 mg regimen (seesections 4.2 and 4.4).

Elevations of pancreatic enzymes

Elevations of amylase and lipase were reported in 47% and 54% of patients treated with Alunbrig,respectively at the 180 mg regimen. For elevations to Grade 3 and 4, the incidences for amylase andlipase were 7.7% and 15%, respectively. The median time to onset for amylase elevations and lipaseelevations was 16 days and 29 days, respectively.

Dose reduction for elevation of lipase and amylase occurred in 4.7% and 2.9% of patients, respectivelyat the 180 mg regimen (see sections 4.2 and 4.4).

Elevation of hepatic enzymes

Elevations of ALT and AST were reported in 49% and 68% of patients treated with Alunbrig,respectively at the 180 mg regimen. For elevations to Grade 3 and 4, the incidences for ALT and ASTwere 4.7% and 3.6%, respectively.

Dose reduction for elevation of ALT and AST occurred in 0.7% and 1.1% of patients, respectively atthe 180 mg regimen (see sections 4.2 and 4.4).

Sixty one percent of patients experienced hyperglycaemia. Grade 3 hyperglycemia occurred in 6.6% ofpatients.

No patients had dose reductions due to hyperglycaemia.

Photosensitivity and photodermatosis

A pooled analysis from seven clinical trials with data from 804 patients, treated with Alunbrig atdifferent dosing regimens, showed that photosensitivity and photodermatosis was reported in 5.8% ofpatients and Grade 3-4 occurred in 0.7% of patients. Dose reduction occurred in 0.4% of patients (seesections 4.2 and 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific antidote for overdose with Alunbrig. In the event of an overdose, the patientshould be monitored for adverse reactions (see section 4.8) and appropriate supportive care should beprovided.

Pharmacotherapeutic group: antineoplastic agent, protein kinase inhibitors, ATC code: L01ED04

Brigatinib is a tyrosine kinase inhibitor that targets ALK, c-ros oncogene 1 (ROS1), and insulin-likegrowth factor 1 receptor (IGF-1R). Brigatinib inhibited autophosphorylation of ALK and

ALK-mediated phosphorylation of the downstream signalling protein STAT3 in in vitro and in vivoassays.

Brigatinib inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALKfusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLCxenograft growth in mice. Brigatinib inhibited the in vitro and in vivo viability of cells expressingmutant forms of EML4-ALK associated with resistance to ALK inhibitors, including G1202R and

L1196M.

In Study 101, the QT interval prolongation potential of Alunbrig was assessed in 123 patients withadvanced malignancies following once daily brigatinib doses of 30 mg to 240 mg. The maximummean QTcF (corrected QT by the Fridericia method) change from baseline was less than 10 msec. Anexposure-QT analysis suggested no concentration-dependent QTc interval prolongation.

ALTA 1L

The safety and efficacy of Alunbrig was evaluated in a randomised (1:1), open-label, multicentre trial(ALTA 1L) in 275 adult patients with advanced ALK-positive NSCLC who had not previouslyreceived an ALK-targeted therapy. Eligibility criteria permitted enrolment of patients with adocumented ALK rearrangement based on a local standard of care testing and an ECOG Performancestatus of 0-2. Patients were allowed to have up to 1 prior regimen of chemotherapy in the locallyadvanced or metastatic setting. Neurologically stable patients with treated or untreated central nervoussystem (CNS) metastases, including leptomeningeal metastases, were eligible. Patients with a historyof pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis were excluded.

Patients were randomised in a 1:1 ratio to receive Alunbrig 180 mg once daily with a 7-day lead-in at90 mg once daily (N = 137) or crizotinib 250 mg orally twice daily (N = 138). Randomisation wasstratified by brain metastases (present, absent) and prior chemotherapy use for locally advanced ormetastatic disease (yes, no).

Patients in the crizotinib arm who experienced disease progression were offered crossover to receivetreatment with Alunbrig. Among all 121 patients who were randomised to the crizotinib arm anddiscontinued study treatment by the time of the final analysis, 99 (82%) patients received subsequent

ALK tyrosine kinase inhibitors (TKIs). Eighty (66%) patients who were randomised to the crizotinibarm received subsequent Alunbrig treatment, including 65 (54%) patients who crossed over in thestudy.

The major outcome measure was progression-free survival (PFS) according to Response Evaluation

Criteria in Solid Tumours (RECIST v1.1) as evaluated by a Blinded Independent Review Committee(BIRC). Additional outcome measures as evaluated by the BIRC include confirmed objective responserate (ORR), duration of response (DOR), time to response, disease control rate (DCR), intracranial

ORR, intracranial PFS, and intracranial DOR. Investigator-assessed outcomes include PFS and overallsurvival.

Baseline demographics and disease characteristics in ALTA 1L were median age 59 years old (range27 to 89; 32% 65 and over), 59% White and 39% Asian, 55% female, 39% ECOG PS 0, and 56%

ECOG PS 1, 58% never smokers, 93% Stage IV disease, 96% adenocarcinoma histology, 30% CNSmetastases at baseline, 14% prior radiotherapy to the brain, and 27% prior chemotherapy. Sites ofextra-thoracic metastases include brain (30% of patients), bone (31% of patients), and liver (20% ofpatients). The median relative dose intensity was 97% for Alunbrig and 99% for crizotinib.

At the primary analysis performed at a median follow-up duration of 11 months in the Alunbrig arm,the ALTA 1L study met its primary endpoint demonstrating a statistically significant improvement in

PFS by BIRC.

A protocol-specified interim analysis with cut-off date of 28 June 2019 was performed at a medianfollow-up duration of 24.9 months in the Alunbrig arm. The median PFS by BIRC in the ITTpopulation was 24 months in the Alunbrig arm and 11 months in the crizotinib arm (HR = 0.49 [95%

CI (0.35, 0.68)], p < 0.0001).

The results from the protocol-specified final analysis with last patient last contact date of 29 January2021 performed at a median follow-up duration of 40.4 months in the Alunbrig arm are presentedbelow.

Table 4: Efficacy results in ALTA IL (ITT population)

Efficacy parameters Alunbrig Crizotinib

N = 137 N = 138

Median duration of follow-up (months)a 40.4 15.2(range: 0.0-52.4) (range: 0.1-51.7)

Primary efficacy parameters

PFS (BIRC)

Number of patients with events, n (%) 73 (53.3%) 93 (67.4%)

Progressive disease, n (%) 66 (48.2%)b 88 (63.8%)c

Death, n (%) 7 (5.1%) 5 (3.6%)

Median (in months) (95% CI) 24.0 (18.5, 43.2) 11.1 (9.1, 13.0)

Hazard ratio (95% CI) 0.48 (0.35, 0.66)

Log-rank p-valued < 0.0001

Secondary efficacy parameters

Confirmed objective response rate (BIRC)

Responders, n (%) 102 (74.5%) 86 (62.3%)(95% CI) (66.3, 81.5) (53.7, 70.4)p-valued,e 0.0330

Complete response, % 24.1% 13.0%

Partial response, % 50.4% 49.3%

Duration of confirmed response (BIRC)

Median (months) (95% CI) 33.2 (22.1, NE) 13.8 (10.4, 22.1)

Overall survivalf

Number of events, n (%) 41 (29.9%) 51 (37.0%)

Median (in months) (95% CI) NE (NE, NE) NE (NE, NE)

Hazard ratio (95% CI) 0.81 (0.53, 1.22)

Log-rank p-valued 0.3311

Overall survival at 36 months 70.7% 67.5%

BIRC = Blinded Independent Review Committee; NE = Not Estimable; CI = Confidence Interval

Results in this table are based on final efficacy analysis with last patient last contact date of 29 January 2021.a duration of follow up for the whole studyb includes 3 patients with palliative radiotherapy to the brainc includes 9 patients with palliative radiotherapy to the braind Stratified by presence of iCNS metastases at baseline and prior chemotherapy for locally advanced or metastatic disease forlog-rank test and Cochran Mantel-Haenszel test, respectivelye From a Cochran Mantel-Haenszel testf Patients in the crizotinib arm who experienced disease progression were offered crossover to receive treatment with Alunbrig.

Figure 1: Kaplan-Meier plot of progression-free survival by BIRC in ALTA 1L

Results in this figure are based on final efficacy analysis with last patient last contact date of 29 January 2021.

BIRC assessment of intracranial efficacy according to RECIST v1.1 in patients with any brainmetastases and patients with measurable brain metastases (≥ 10 mm in longest diameter) at baselineare summarised in Table 5.

Table 5: BIRC-assessed intracranial efficacy in patients in ALTA 1L

Patients with measurable brain metastases atbaseline

Efficacy parameters Alunbrig Crizotinib

N = 18 N = 23

Confirmed intracranial objective response rate

Responders, n (%) 14 (77.8%) 6 (26.1%)(95% CI) (52.4, 93.6) (10.2, 48.4)p-valuea,b 0.0014

Complete response % 27.8% 0.0%

Partial response % 50.0% 26.1%

Duration of confirmed intracranial responsec

Median (months) (95% CI) 27.9 (5.7, NE) 9.2 (3.9, NE)

Patients with any brain metastases at baseline

Alunbrig Crizotinib

N = 47 N = 49

Confirmed intracranial objective response rate

Responders, n (%) 31 (66.0%) 7 (14.3%)(95% CI) (50.7, 79.1) (5.9, 27.2)p-valuea,b < 0.0001

Complete response (%) 44.7% 2.0%

Partial response (%) 21.3% 12.2%

Duration of confirmed intracranial responsec

Median (months) (95% CI) 27.1 (16.9, 42.8) 9.2 (3.9, NE)

Intracranial PFSd

Number of patients with events, n (%) 27 (57.4%) 35 (71.4%)

Progressive disease, n (%) 27 (57.4%)e 32 (65.3%)f

Death, n (%) 0 (0.0%) 3 (6.1%)

Median (in months) (95% CI) 24.0 (12.9, 30.8) 5.5 (3.7, 7.5)

Hazard ratio (95% CI) 0.29 (0.17, 0.51)

Log-rank p-valuea < 0.0001

CI = Confidence Interval; NE = Not Estimable

Results in this table are based on final efficacy analysis with last patient last contact date of 29 January 2021.a Stratified by presence prior chemotherapy for locally advanced or metastatic disease for log-rank test and Cochran

Mantel-Haenszel test, respectivelybFrom a Cochran Mantel-Haenszel testc measured from date of first confirmed intracranial response until date of intracranial disease progression (new intracraniallesions, intracranial target lesion diameter growth ≥ 20% from nadir, or unequivocal progression of intracranial nontargetlesions) or death or censoringd measured from date of randomisation until date of intracranial disease progression (new intracranial lesions, intracranialtarget lesion diameter growth ≥ 20% from nadir, or unequivocal progression of intracranial nontarget lesions) or death orcensoring.e includes 1 patient with palliative radiotherapy to the brainf includes 3 patients with palliative radiotherapy to the brain

ALTA

The safety and efficacy of Alunbrig was evaluated in a randomised (1:1), open-label, multicenter trial(ALTA) in 222 adult patients with locally advanced or metastatic ALK-positive NSCLC who hadprogressed on crizotinib. Eligibility criteria permitted enrolment of patients with a documented ALKrearrangement based on a validated test, ECOG Performance Status of 0-2, and prior chemotherapy.

Additionally, patients with central nervous system (CNS) metastases were included, provided theywere neurologically stable and did not require an increasing dose of corticosteroids. Patients with ahistory of pulmonary interstitial disease or drug-related pneumonitis were excluded.

Patients were randomised in a 1:1 ratio to receive Alunbrig either 90 mg once daily (90 mg regimen,

N = 112) or 180 mg once daily with 7-day lead-in at 90 mg once daily (180 mg regimen, N = 110).

The median duration of follow-up was 22.9 months. Randomisation was stratified by brain metastases(present, absent) and best prior response to crizotinib therapy (complete or partial response, any otherresponse/unknown).

The major outcome measure was confirmed objective response rate (ORR) according to Response

Evaluation Criteria in Solid Tumours (RECIST v1.1) as evaluated by investigator. Additional outcomemeasures included confirmed ORR as evaluated by an Independent Review Committee (IRC); time toresponse; progression free survival (PFS); duration of response (DOR); overall survival; andintracranial ORR and intracranial DOR as evaluated by an IRC.

Baseline demographics and disease characteristics in ALTA were median age 54 years old(range 18 to 82; 23% 65 and over), 67% White and 31% Asian, 57% female, 36% ECOG PS 0 and57% ECOG PS 1, 7% ECOG PS2, 60% never smoker, 35% former smoker, 5% current smoker,98% Stage IV, 97% adenocarcinoma, and 74% prior chemotherapy. The most common sites ofextra-thoracic metastasis included 69% brain (of whom 62% had received prior radiation to the brain),39% bone, and 26% liver.

Efficacy results from ALTA analysis are summarised in Table 6. and the Kaplan-Meier (KM) curvefor investigator-assessed PFS is shown in Figure 2

Table 6: Efficacy results in ALTA (ITT population)

Efficacy parameter Investigator assessment IRC assessment90 mg 180 mg 90 mg 180 mgregimen* regimen† regimen* regimen†

N = 112 N = 110 N = 112 N = 110

Objective response rate(%) 46% 56% 51% 56%

CI‡ (35, 57) (45, 67) (41, 61) (47, 66)

Time to response

Median (months) 1.8 1.9 1.8 1.9

Duration of response

Median (months) 12.0 13.8 16.4 15.795% CI (9.2,17.7) (10.2,19.3) (7.4, 24.9) (12.8, 21.8)

Progression-free survival

Median (months) 9.2 15.6 9.2 16.795% CI (7.4, 11.1) (11.1, 21) (7.4, 12.8) (11.6, 21.4)

Overall survival

Median (months) 29.5 34.1 NA NA95% CI (18.2, NE) (27.7, NE) NA NA12-month survival 70.3% 80.1% NA NAprobability (%)

CI = Confidence Interval; NE = Not Estimable; NA = Not Applicable

*90 mg once daily regimen†180 mg once daily with 7-day lead-in at 90 mg once daily‡Confidence Interval for investigator assessed ORR is 97.5% and for IRC assessed ORR is 95%

Figure 2: Investigator-assessed systemic progression-free survival: ITT population by treatmentarm (ALTA)

Abbreviations: ITT = Intent-to-treat

Note: Progression-Free survival was defined as time from initiation of treatment until the date at which disease progressionwas first evident or death, whichever comes first.

*90 mg once daily regimen†180 mg once daily with 7-day lead-in at 90 mg once daily

IRC assessments of intracranial ORR and duration of intracranial response in patients from ALTAwith measurable brain metastases (≥ 10 mm in longest diameter) at baseline are summarised in

Table 7.

Table 7 Intracranial efficacy in patients with measurable brain metastases at baseline in ALTA

Patients with measurable

IRC-assessed efficacy parameter brain metastases at baseline90 mg regimen* 180 mg regimen†(N = 26) (N = 18)

Intracranial objective response rate(%) 50% 67%95% CI (30, 70) (41, 87)

Intracranial disease control rate(%) 85% 83%95% CI (65, 96) (59, 96)

Duration of intracranial response‡,

Median (months) 9.4 16.695% CI (3.7, 24.9) (3.7, NE)% CI = Confidence Interval; NE = Not Estimable

*90 mg once daily regimen†180 mg once daily with 7-day lead-in at 90 mg once daily‡Events include intracranial disease progression (new lesions, intracranial target lesion diameter growth ≥ 20% from nadir, orunequivocal progression of intracranial non-target lesions) or death.

In patients with any brain metastases at baseline, intracranial disease control rate was 77.8%(95% CI 67.2-86.3) in the 90 mg arm (N = 81) and 85.1% (95% CI 75-92.3) in the 180 mgarm (N = 74).

Study 101

In a separate dose finding study, 25 patients with ALK-positive NSCLC that progressed on crizotinibwere administered Alunbrig at 180 mg once daily with 7-day lead-in at 90 mg once daily regimen. Ofthese, 19 patients had an investigator-assessed confirmed objective response (76%; 95% CI: 55, 91)and the KM estimate median duration of response among the 19 responders was 26.1 months(95% CI: 7.9, 26.1). The KM median PFS was 16.3 months (95% CI: 9.2, NE) and the 12-monthprobability of overall survival was 84.0% (95% CI: 62.8, 93.7).

The European Medicines Agency has waived the obligation to submit the results of studies with

Alunbrig in all subsets of the paediatric population in lung carcinoma (small cell and non-small cellcarcinoma) (see section 4.2 for information on paediatric use).

In Study 101, following administration of a single oral dose of brigatinib (30-240 mg) in patients, themedian time to peak concentration (Tmax) was 1-4 hours postdose. After a single dose and at steadystate, systemic exposure was dose proportional over the dose range of 60-240 mg once daily. Modestaccumulation was observed upon repeated dosing (geometric mean accumulation ratio: 1.9 to 2.4).

The geometric mean steady state Cmax of brigatinib at doses of 90 mg and 180 mg once daily was552 and 1,452 ng/mL, respectively, and the corresponding AUC0-τ was 8,165 and 20,276 h∙ng/mL,respectively. Brigatinib is a substrate of the transporter proteins P-gp and BCRP.

In healthy subjects, compared to overnight fasting, a high fat meal reduced brigatinib Cmax by 13%with no effect on AUC. Brigatinib can be administered with or without food.

Brigatinib was moderately bound (91%) to human plasma proteins and binding was notconcentration-dependent. The blood-to-plasma concentration ratio is 0.69. In patients given brigatinib180 mg once daily, the geometric mean apparent volume of distribution (Vz/F) of brigatinib at steadystate was 307 L, indicating moderate distribution into tissues.

In vitro studies demonstrated that brigatinib is primarily metabolised by CYP2C8 and CYP3A4, and toa much lesser extent by CYP3A5.

Following oral administration of a single 180 mg dose of [14C]brigatinib to healthy subjects,

N-demethylation and cysteine conjugation were the two major metabolic clearance pathways. In urineand faeces combined, 48%, 27%, and 9.1% of the radioactive dose was excreted as unchangedbrigatinib, N-desmethyl brigatinib (AP26123), and brigatinib cysteine conjugate, respectively.

Unchanged brigatinib was the major circulating radioactive component (92%) along with AP26123(3.5%), the primary metabolite also observed in vitro. In patients, at steady state, the plasma AUC of

AP26123 was < 10% of brigatinib exposure. In in vitro kinase and cellular assays, the metabolite,

AP26123, inhibited ALK with approximately 3-fold lower potency than brigatinib.

In patients given brigatinib 180 mg once daily, the geometric mean apparent oral clearance (CL/F) ofbrigatinib at steady state was 8.9 L/h and the median plasma elimination half-life was 24 h.

The primary route of excretion of brigatinib is in faeces. In six healthy male subjects given a single180 mg oral dose of [14C]brigatinib, 65% of the administered dose was recovered in faeces and 25% ofthe administered dose was recovered in urine. Unchanged brigatinib represented 41% and 86% of thetotal radioactivity in faeces and urine, respectively, the remainder being metabolites.

The pharmacokinetics of brigatinib was characterised in healthy subjects with normal hepatic function(N = 9), and patients with mild hepatic impairment (Child-Pugh class A, N = 6), moderate hepaticimpairment (Child-Pugh class B, N = 6), or severe hepatic impairment (Child-Pugh class C, N = 6).

The pharmacokinetics of brigatinib was similar between healthy subjects with normal hepatic functionand patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.

Unbound AUC0-INF was 37% higher in patients with severe hepatic impairment (Child-Pugh class C) ascompared to healthy subjects with normal hepatic function (see section 4.2).

The pharmacokinetics of brigatinib is similar in patients with normal renal function and in patientswith mild or moderate renal impairment (eGFR ≥ 30 mL/min) based on the results of populationpharmacokinetic analyses. In a pharmacokinetic study, unbound AUC0-INF was 94% higher in patientswith severe renal impairment (eGFR < 30 mL/min, N = 6) as compared to patients with normal renalfunction (eGFR ≥ 90 mL/min, N = 8) (see section 4.2).

Population pharmacokinetic analyses showed that race and gender had no impact on thepharmacokinetics of brigatinib.

Age, body weight, and albumin concentrations

The population pharmacokinetic analyses showed that body weight, age, and albumin concentrationhad no clinically relevant impact on the pharmacokinetics of brigatinib.

Safety pharmacology studies with brigatinib identified potential for pulmonary effects (alteredrespiration rate; 1-2 times the human Cmax), cardiovascular effects (altered heart rate and bloodpressure; at 0.5 times the human Cmax), and renal effects (reduced renal function; at 1-2.5 times thehuman Cmax), but did not indicate any potential for QT prolongation or neurofunctional effects.

Adverse reactions seen in animals at exposure levels similar to clinical exposure levels with possiblerelevance to clinical use were as follows: gastrointestinal system, bone marrow, eyes, testes, liver,kidney, bone, and heart. These effects were generally reversible during the non-dosing recoveryperiod; however, effects in the eyes and testes were notable exceptions due to lack of recovery.

In repeated dose toxicity studies, lung changes (foamy alveolar macrophages) were noted in monkeysat ≥ 0.2 times the human AUC; however, these were minimal and similar to those reported asbackground findings in naive monkeys, and there was no clinical evidence of respiratory distress inthese monkeys.

Carcinogenicity studies have not been performed with brigatinib.

Brigatinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) or the mammalian cellchromosomal aberration assays, but slightly increased the number of micronuclei in a rat bone marrowmicronucleus test. The mechanism of micronucleus induction was abnormal chromosome segregation(aneugenicity) and not a clastogenic effect on chromosomes. This effect was observed atapproximately five fold the human exposure at the 180 mg once daily dose.

Brigatinib may impair male fertility. Testicular toxicity was observed in repeat-dose animal studies. Inrats, findings included lower weight of testes, seminal vesicles and prostate gland, and testiculartubular degeneration; these effects were not reversible during the recovery period. In monkeys,findings included reduced size of testes along with microscopic evidence of hypospermatogenesis;these effects were reversible during the recovery period. Overall, these effects on the malereproductive organs in rats and monkeys occurred at exposures ≥ 0.2-times the AUC observed inpatients at the 180 mg once daily dose. No apparent adverse effects on female reproductive organswere observed in general toxicology studies in rats and monkeys.

In an embryo-foetal development study in which pregnant rats were administered daily doses ofbrigatinib during organogenesis; dose-related skeletal anomalies were observed at doses as low asapproximately 0.7-times the human exposure by AUC at the 180 mg once daily dose. Findingsincluded embryo-lethality, reduced foetal growth, and skeletal variations.

Lactose monohydrate

Microcrystalline cellulose

Sodium starch glycolate (type A)

Silica colloidal hydrophobic

Magnesium stearate

Talc

Macrogol

Polyvinyl alcohol

Titanium dioxide

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

Alunbrig 30 mg film-coated tablets

Round wide mouth high density polyethylene (HDPE) bottles with two-piece polypropylene childresistant screw cap closures with foil induction seal liner, containing either 60 or 120 film-coatedtablets, together with one HDPE canister containing a molecular sieve desiccant.

Clear thermoformable poly-chloro-tri-fluoro-ethylene (PCTFE) blister with heat sealablepaper-laminated foil lidding in a carton, containing either 28, 56 or 112 film-coated tablets.

Alunbrig 90 mg film-coated tablets

Round wide mouth high density polyethylene (HDPE) bottles with two-piece polypropylene childresistant screw cap with foil induction seal liner closures, containing either 7 or 30 film-coated tablets,together with one HDPE canister containing a molecular sieve desiccant.

Clear thermoformable poly-chloro-tri-fluoro-ethylene (PCTFE) blister with heat sealablepaper-laminated foil lidding in a carton, containing either 7 or 28 film-coated tablets.

Alunbrig 180 mg film-coated tablets

Round wide mouth high density polyethylene (HDPE) bottles with two-piece polypropylene childresistant screw cap with foil induction seal liner closures, containing 30 film-coated tablets, togetherwith one HDPE canister containing a molecular sieve desiccant.

Clear thermoformable poly-chloro-tri-fluoro-ethylene (PCTFE) blister with heat sealablepaper-laminated foil lidding in a carton, containing 28 film-coated tablets.

Treatment initiation pack Alunbrig 90 mg and 180 mg film-coated tablets

Each pack consists of an outer carton with two inner cartons containing:

* Alunbrig 90 mg film-coated tablets1 clear thermoformable poly-chloro-tri-fluoro-ethylene (PCTFE) blister with heat sealablepaper-laminated foil lidding in a carton, containing 7 film-coated tablets.

* Alunbrig 180 mg film-coated tablets3 clear thermoformable poly-chloro-tri-fluoro-ethylene (PCTFE) blisters with heat sealablepaper-laminated foil lidding in a carton, containing 21 film-coated tablets.

Not all pack sizes may be marketed.

Patients should be advised to keep the desiccant canister in the bottle and not to swallow it.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements

Takeda Pharma A/S

Delta Park 452665 Vallensbaek Strand

Denmark

Alunbrig 30 mg film-coated tablets

EU/1/18/1264/001 60 tablets in bottle

EU/1/18/1264/002 120 tablets in bottle

EU/1/18/1264/011 28 tablets in carton

EU/1/18/1264/003 56 tablets in carton

EU/1/18/1264/004 112 tablets in carton

Alunbrig 90 mg film-coated tablets

EU/1/18/1264/005 7 tablets in bottle

EU/1/18/1264/006 30 tablets in bottle

EU/1/18/1264/007 7 tablets in carton

EU/1/18/1264/008 28 tablets in carton

Alunbrig 180 mg film-coated tablets

EU/1/18/1264/009 30 tablets in bottle

EU/1/18/1264/010 28 tablets in carton

Alunbrig treatment initiation pack

EU/1/18/1264/012 7 x 90 mg + 21 x 180 mg tablets in carton

Date of first authorisation: 22 November 2018

Date of latest renewal: 24 July 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.