Alunbrig 90 mg and 180 mg film-coated tablets starter pack

Alunbrig is indicated as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (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 of anticancer 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 demonstrated proficiency in the specific technology being utilised.

Posology

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

If Alunbrig is interrupted for 14 days or longer for reasons other than adverse reactions, treatment should 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 be administered and the next dose should be taken at the scheduled time.

Treatment should continue as long as clinical benefit is observed.

Dose adjustments

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

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 are summarised in Table 2.

Table 2: Recommended Alunbrig dose modifications for adverse reactions

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

Special populations

Elderly

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

Hepatic impairment

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

Renal impairment

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 once daily for the first 7 days, then 90 mg once daily is recommended for patients with severe renal impairment (eGFR < 30 mL/min) (see section 5.2). Patients with severe renal impairment should be closely 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).

Paediatric population

The safety and efficacy of Alunbrig in patients less than 18 years of age have not been established. No data are available.

Method of administration

Alunbrig is for oral use. The tablets should be swallowed whole and with water. Alunbrig may be taken 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 features consistent 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 1-2 pulmonary adverse reactions resolved with interruption of treatment or dose modification. Increased age 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 worsening respiratory 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., pulmonary embolism, tumour progression, and infectious pneumonia). The dose should be modified accordingly (see section 4.2).

Hypertension

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

Blood pressure should be monitored regularly during treatment with Alunbrig. Hypertension should be treated according to standard guidelines to control blood pressure. Heart rate should be monitored more frequently in patients if concomitant use of a medicinal product known to cause bradycardia cannot be avoided. For severe hypertension (≥ Grade 3), Alunbrig should be withheld until hypertension has recovered to Grade 1 or to baseline. The dose should be modified accordingly (see section 4.2).

Bradycardia

Bradycardia has occurred in patients treated with Alunbrig (see section 4.8). Caution should be exercised 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 concomitant medicinal products known to cause bradycardia should be evaluated. Upon recovery, the dose should be modified accordingly (see section 4.2). In case of life-threatening bradycardia, if no contributing concomitant medication is identified or in case of recurrence, treatment with Alunbrig should be discontinued (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 visual symptoms, 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 be advised to report any unexplained muscle pain, tenderness, or weakness. CPK levels should be monitored regularly during Alunbrig treatment. Based on the severity of the CPK elevation, and if associated with muscle pain or weakness, treatment with Alunbrig should be withheld, and the dose modified 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 the severity of the laboratory abnormalities, treatment with Alunbrig should be withheld, and the dose modified accordingly (see section 4.2).

Hepatotoxicity

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

Hyperglycaemia

Elevations of serum glucose have occurred in patients treated with Alunbrig. Fasting serum glucose should be assessed prior to initiation of Alunbrig and monitored periodically thereafter. Antihyperglycaemic treatment should be initiated or optimised as needed. If adequate hyperglycaemic control cannot be achieved with optimal medical management, Alunbrig should be withheld until adequate hyperglycaemic control is achieved; upon recovery reducing the dose as described in Table 1 may be considered or Alunbrig may be permanently discontinued.

Drug-drug interactions

The concomitant use of Alunbrig with strong CYP3A inhibitors should be avoided. If concomitant use of strong CYP3A inhibitors cannot be avoided, the dose of Alunbrig should be reduced from 180 mg to 90 mg, or from 90 mg to 60 mg. After discontinuation of a strong CYP3A inhibitor, Alunbrig should 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 (see section 4.5). 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 the initiation 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.

Photosensitivity and photodermatosis

Photosensitivity to sunlight has occurred in patients treated with Alunbrig (see section 4.8). Patients should be advised to avoid prolonged sun exposure while taking Alunbrig, and for at least 5 days after discontinuation of treatment. When outdoors, patients should be advised to wear a hat and protective clothing, and to use a broad-spectrum Ultraviolet A (UVA)/ Ultraviolet B (UVB) sunscreen and lip balm (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 modified accordingly (see section 4.2).

Fertility

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

Lactose

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

Sodium

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

CYP3A inhibitors

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, with a single 90 mg brigatinib dose increased brigatinib C_max by 21%, AUC_0-INF by 101% (2-fold), and AUC_0-120 by 82% (< 2-fold), relative to a 90 mg brigatinib dose administered alone. The concomitant use 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. If concomitant use of strong CYP3A inhibitors cannot be avoided, the dose of Alunbrig should be reduced by approximately 50% (i.e. from 180 mg to 90 mg, or from 90 mg to 60 mg). After discontinuation of a strong CYP3A inhibitor, Alunbrig should be resumed at the dose that was tolerated prior to the initiation of the strong CYP3A inhibitor.

Moderate CYP3A inhibitors (e.g., diltiazem and verapamil) may increase the AUC of brigatinib by approximately 40% based on simulations from a physiologically-based pharmacokinetic model. No dose adjustment is required for Alunbrig in combination with moderate CYP3A inhibitors. Patients should be closely monitored when Alunbrig is coadministered with moderate CYP3A inhibitors.

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

CYP2C8 inhibitors

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 C_max by 41%, AUC_0-INF by 12%, and AUC_0-120 by 15%, relative to a 90 mg brigatinib dose administered alone. The effect of gemfibrozil on the pharmacokinetics of brigatinib is not clinically meaningful and the underlying mechanism for the decreased exposure of brigatinib is unknown. No dose adjustment is required during coadministration with 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 is not expected to result in a clinically meaningful change in the systemic exposure of brigatinib. No dose adjustment is required for Alunbrig during coadministration with P-gp and BCRP inhibitors.

Agents that may decrease brigatinib plasma concentrations

CYP3A inducers

In healthy subjects, coadministration of multiple 600 mg daily doses of rifampicin, a strong CYP3A inducer, with a single 180 mg brigatinib dose decreased brigatinib C_max by 60%, AUC_0-INF by 80% (5-fold), and AUC_0-120 by 80% (5-fold), relative to a 180 mg brigatinib dose administered alone. The concomitant 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 on simulations 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 the initiation 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

CYP3A substrates

In vitro studies in hepatocytes have shown that brigatinib is an inducer of CYP3A4. In patients with cancer, coadministration of multiple 180 mg daily doses of Alunbrig with a single 3 mg oral dose of midazolam, a sensitive CYP3A substrate, decreased midazolam C_max by 16%, AUC_0-INF by 26%, and AUC_0-last by 30%, relative to a 3 mg oral dose of midazolam administered alone. Brigatinib reduces plasma concentrations of coadministered medicinal products that are predominantly metabolised by CYP3A. Therefore, coadministration of Alunbrig with CYP3A substrates with a narrow therapeutic index (e.g., alfentanil, fentanyl, quinidine, cyclosporine, sirolimus, tacrolimus) should be avoided as their effectiveness may be reduced.

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

Transporter substrates

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

Women of childbearing potential/Contraception in males and females

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

Pregnancy

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

Breast-feeding

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

Fertility

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

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

Summary of the safety profile

The most common adverse reactions (≥ 25%) reported in patients treated with Alunbrig at the recommended 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, and vomiting.

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

Tabulated list of adverse reactions

The data described below reflect exposure to Alunbrig at the recommended dosing regimen in three clinical trials: a Phase 3 trial (ALTA 1L) in patients with advanced ALK-positive NSCLC previously not treated with an ALK-inhibitor (N = 136), a Phase 2 trial (ALTA) in patients treated with Alunbrig with ALK-positive NSCLC who previously progressed on crizotinib (N = 110), and a phase 1/2 dose escalation/expansion trial in patients with advanced malignancies (N = 28). Across these studies, the median duration of exposure in patients receiving Alunbrig at the recommended dosing regimen was 21.8 months.

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

Description of selected adverse reactions

Pulmonary adverse reactions

In ALTA 1L, 2.9% of patients experienced any Grade ILD/pneumonitis early in treatment (within 8 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 fatal pneumonia. Following Grade 1-2 pulmonary adverse reactions, treatment with Alunbrig was either interrupted and then restarted or the dose was reduced. Early pulmonary adverse reactions also occurred 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 (see sections 4.2 and 4.4).

Elderly

Early pulmonary adverse reaction was reported in 10.1% of patients ≥ 65 years of age compared with 3.1% of patients < 65 years of age.

Hypertension

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 mg regimen. Mean systolic and diastolic blood pressure, in all patients, increased over time (see sections 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 mg regimen. (see sections 4.2 and 4.4).

Visual disturbance

Visual disturbance adverse reactions were reported in 14% of patients treated with Alunbrig at the 180 mg regimen. Of these, three Grade 3 adverse reactions (1.1%) including macular oedema and cataract were reported.

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

Peripheral neuropathy

Peripheral neuropathy adverse reactions were reported in 20% of patients treated at the 180 mg regimen. 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 maximum duration 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 at the 180 mg regimen. The incidence of Grade 3-4 elevations of CPK was 18%. The median time to onset for CPK elevations was 28 days.

Dose reduction for CPK elevation occurred in 10% of patients at the 180 mg regimen (see sections 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 and lipase were 7.7% and 15%, respectively. The median time to onset for amylase elevations and lipase elevations was 16 days and 29 days, respectively.

Dose reduction for elevation of lipase and amylase occurred in 4.7% and 2.9% of patients, respectively at 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 AST were 4.7% and 3.6%, respectively.

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

Hyperglycaemia

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

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 at different dosing regimens, showed that photosensitivity and photodermatosis was reported in 5.8% of patients and Grade 3-4 occurred in 0.7% of patients. Dose reduction occurred in 0.4% of patients (see sections 4.2 and 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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

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

Mechanism of action

Brigatinib is a tyrosine kinase inhibitor that targets ALK, c-ros oncogene 1 (ROS1), and insulin-like growth 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 vivo assays.

Brigatinib inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice. Brigatinib inhibited the in vitro and in vivo viability of cells expressing mutant forms of EML4-ALK associated with resistance to ALK inhibitors, including G1202R and L1196M.

Cardiac electrophysiology

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

Clinical efficacy and safety

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 previously received an ALK-targeted therapy. Eligibility criteria permitted enrolment of patients with a documented ALK rearrangement based on a local standard of care testing and an ECOG Performance status of 0-2. Patients were allowed to have up to 1 prior regimen of chemotherapy in the locally advanced or metastatic setting. Neurologically stable patients with treated or untreated central nervous system (CNS) metastases, including leptomeningeal metastases, were eligible. Patients with a history of 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 at 90 mg once daily (N = 137) or crizotinib 250 mg orally twice daily (N = 138). Randomisation was stratified by brain metastases (present, absent) and prior chemotherapy use for locally advanced or metastatic disease (yes, no).

Patients in the crizotinib arm who experienced disease progression were offered crossover to receive treatment with Alunbrig. Among all 121 patients who were randomised to the crizotinib arm and discontinued 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 crizotinib arm received subsequent Alunbrig treatment, including 65 (54%) patients who crossed over in the study.

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 response rate (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 overall survival.

Baseline demographics and disease characteristics in ALTA 1L were median age 59 years old (range 27 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% CNS metastases at baseline, 14% prior radiotherapy to the brain, and 27% prior chemotherapy. Sites of extra-thoracic metastases include brain (30% of patients), bone (31% of patients), and liver (20% of patients). 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 median follow-up duration of 24.9 months in the Alunbrig arm. The median PFS by BIRC in the ITT population 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 January 2021 performed at a median follow-up duration of 40.4 months in the Alunbrig arm are presented below.

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 brain metastases and patients with measurable brain metastases (≥ 10 mm in longest diameter) at baseline are summarised in Table 5.

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 had progressed on crizotinib. Eligibility criteria permitted enrolment of patients with a documented ALK rearrangement 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 they were neurologically stable and did not require an increasing dose of corticosteroids. Patients with a history 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 other response/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 outcome measures included confirmed ORR as evaluated by an Independent Review Committee (IRC); time to response; progression free survival (PFS); duration of response (DOR); overall survival; and intracranial 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 and 57% 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 of extra-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) curve for investigator-assessed PFS is shown in Figure 2

Table 6: Efficacy results in ALTA (ITT population)

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 treatment arm (ALTA)

Abbreviations: ITT = Intent-to-treat

Note: Progression-Free survival was defined as time from initiation of treatment until the date at which disease progression was 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 ALTA with 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

% 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, or unequivocal 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 mg arm (N=74).

Study 101

In a separate dose finding study, 25 patients with ALK-positive NSCLC that progressed on crizotinib were administered Alunbrig at 180 mg once daily with 7-day lead-in at 90 mg once daily regimen. Of these, 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-month probability of overall survival was 84.0% (95% CI: 62.8, 93.7).

Paediatric population

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 cell carcinoma) (see section 4.2 for information on paediatric use).

Absorption

In Study 101, following administration of a single oral dose of brigatinib (30-240 mg) in patients, the median time to peak concentration (T_max) was 1-4 hours postdose. After a single dose and at steady state, systemic exposure was dose proportional over the dose range of 60-240 mg once daily. Modest accumulation was observed upon repeated dosing (geometric mean accumulation ratio: 1.9 to 2.4). The geometric mean steady state C_max of brigatinib at doses of 90 mg and 180 mg once daily was 552 and 1,452 ng/mL, respectively, and the corresponding AUC_0-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 C_max by 13% with no effect on AUC. Brigatinib can be administered with or without food.

Distribution

Brigatinib was moderately bound (91%) to human plasma proteins and binding was not concentration-dependent. The blood-to-plasma concentration ratio is 0.69. In patients given brigatinib 180 mg once daily, the geometric mean apparent volume of distribution (V_z/F) of brigatinib at steady state was 307 L, indicating moderate distribution into tissues.

Biotransformation

In vitro studies demonstrated that brigatinib is primarily metabolised by CYP2C8 and CYP3A4, and to a 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 urine and faeces combined, 48%, 27%, and 9.1% of the radioactive dose was excreted as unchanged brigatinib, 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.

Elimination

In patients given brigatinib 180 mg once daily, the geometric mean apparent oral clearance (CL/F) of brigatinib 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 single 180 mg oral dose of [¹⁴C]brigatinib, 65% of the administered dose was recovered in faeces and 25% of the administered dose was recovered in urine. Unchanged brigatinib represented 41% and 86% of the total radioactivity in faeces and urine, respectively, the remainder being metabolites.

Specific populations

Hepatic impairment

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 hepatic impairment (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 function and patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Unbound AUC_0-INF was 37% higher in patients with severe hepatic impairment (Child-Pugh class C) as compared to healthy subjects with normal hepatic function (see section 4.2).

Renal impairment

The pharmacokinetics of brigatinib is similar in patients with normal renal function and in patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min) based on the results of population pharmacokinetic analyses. In a pharmacokinetic study, unbound AUC_0-INF was 94% higher in patients with severe renal impairment (eGFR < 30 mL/min, N = 6) as compared to patients with normal renal function (eGFR ≥ 90 mL/min, N = 8) (see section 4.2).

Race and gender

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

Age, body weight, and albumin concentrations

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

Safety pharmacology studies with brigatinib identified potential for pulmonary effects (altered respiration rate; 1-2 times the human C_max), cardiovascular effects (altered heart rate and blood pressure; at 0.5 times the human C_max), and renal effects (reduced renal function; at 1-2.5 times the human C_max), 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 possible relevance 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 recovery period; 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 monkeys at ≥ 0.2 times the human AUC; however, these were minimal and similar to those reported as background findings in naive monkeys, and there was no clinical evidence of respiratory distress in these monkeys.

Carcinogenicity studies have not been performed with brigatinib.

Brigatinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) or the mammalian cell chromosomal aberration assays, but slightly increased the number of micronuclei in a rat bone marrow micronucleus test. The mechanism of micronucleus induction was abnormal chromosome segregation (aneugenicity) and not a clastogenic effect on chromosomes. This effect was observed at approximately 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. In rats, findings included lower weight of testes, seminal vesicles and prostate gland, and testicular tubular 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 male reproductive organs in rats and monkeys occurred at exposures ≥ 0.2-times the AUC observed in patients at the 180 mg once daily dose. No apparent adverse effects on female reproductive organs were observed in general toxicology studies in rats and monkeys.

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

Tablet core

Lactose monohydrate

Microcrystalline cellulose

Sodium starch glycolate (type A)

Silica colloidal hydrophobic

Magnesium stearate

Tablet coating

Talc

Macrogol

Polyvinyl alcohol

Titanium dioxide

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

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 tablets

1 clear thermoformable poly-chloro-tri-fluoro-ethylene (PCTFE) blister with heat sealable paper-laminated foil lidding in a carton, containing 7 film-coated tablets.

• Alunbrig 180 mg film-coated tablets

3 clear thermoformable poly-chloro-tri-fluoro-ethylene (PCTFE) blisters with heat sealable paper-laminated foil lidding in a carton, containing 21 film-coated tablets.

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 local requirements