TABRECTA 200mg tablets medication leaflet

Tabrecta 150 mg film-coated tablets

Tabrecta 200 mg film-coated tablets

Tabrecta 150 mg film-coated tablets

Each film-coated tablet contains capmatinib dihydrochloride monohydrate equivalent to 150 mgcapmatinib.

Tabrecta 200 mg film-coated tablets

Each film-coated tablet contains capmatinib dihydrochloride monohydrate equivalent to 200 mgcapmatinib.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Tabrecta 150 mg film-coated tablets

Pale orange brown, ovaloid, curved film-coated tablet with bevelled edges, unscored, debossed with“DU” on one side and “NVR” on the other side. Approximate size: 18.3 mm (length) x 7.3 mm(width).

Tabrecta 200 mg film-coated tablets

Yellow, ovaloid, curved film-coated tablet with bevelled edges, unscored, debossed with “LO” on oneside and “NVR” on the other side. Approximate size: 20.3 mm (length) x 8.1 mm (width).

Tabrecta as monotherapy is indicated for the treatment of adult patients with advanced non-small celllung cancer (NSCLC) harbouring alterations leading to mesenchymal-epithelial transition factor geneexon 14 (METex14) skipping, who require systemic therapy following prior treatment withimmunotherapy and/or platinum-based chemotherapy.

Treatment with Tabrecta should be initiated by a physician experienced in the use of anticancertherapies.

Patients have to be selected for treatment with Tabrecta based on the presence of genetic alterationsleading to a METex14 skipping mutation in tumour tissue or plasma specimens using a validated test.

If a genetic alteration is not detected in a plasma specimen, tumour tissue should be tested (seesections 4.4 and 5.1).

The recommended dose of Tabrecta is 400 mg orally twice daily with or without food.

Treatment should be continued based on individual safety and tolerability and as long as the patient isderiving clinical benefit from therapy.

If a dose of Tabrecta is missed or vomiting occurs, the patient should not make up for the dose, buttake the next dose at the scheduled time.

The recommended dose reduction schedule for the management of adverse reactions based onindividual safety and tolerability is listed in Table 1.

Table 1 Tabrecta dose reduction schedule

Dose level Dose and schedule Number and strength of tablets

Starting dose 400 mg twice daily Two 200 mg tablets/twice daily

First dose reduction 300 mg twice daily Two 150 mg tablets/twice daily

Second dose reduction 200 mg twice daily One 200 mg tablet/twice daily

Doses of Tabrecta below 200 mg twice daily have not been investigated in clinical studies.

Recommendations for dose modifications of Tabrecta for adverse reactions are provided in Table 2.

Table 2 Tabrecta dose modifications for the management of adverse reactions

Adverse reaction Severity Dose modification

Interstitial lung disease Any grade Permanently discontinue(ILD)/pneumonitis treatment-related Tabrecta.

Isolated ALT and/or AST elevations Grade 3 (>5.0 to Temporarily withhold Tabrectafrom baseline, without concurrent ≤20.0 x ULN) until recovery to baselinetotal bilirubin increase ALT/AST grade.

If recovered to baseline within7 days, then resume Tabrecta atthe same dose, otherwiseresume Tabrecta at a reduceddose as per Table 1.

Grade 4 (>20.0 x ULN) Permanently discontinue

Tabrecta.

Combined elevations in ALT and/or If patient develops ALT Permanently discontinue

AST with concurrent total bilirubin and/or AST >3 x ULN Tabrecta.

increase, in the absence of cholestasis along with total bilirubinor haemolysis >2 x ULN, irrespectiveof baseline grade

Isolated total bilirubin elevation from Grade 2 (>1.5 to Temporarily withhold Tabrectabaseline, without concurrent ALT ≤3.0 x ULN) until recovery to baselineand/or AST increase bilirubin grade.

If recovered to baseline within7 days, then resume Tabrecta atthe same dose, otherwiseresume Tabrecta at a reduceddose as per Table 1.

Grade 3 (>3.0 to Temporarily withhold Tabrecta≤10.0 x ULN) until recovery to baselinebilirubin grade.

If recovered to baseline within7 days, then resume Tabrecta ata reduced dose as per Table 1,otherwise permanentlydiscontinue Tabrecta.

Grade 4 (>10.0 x ULN) Permanently discontinue

Tabrecta.

Serum creatinine increased Grade 2 (>1.5 to Temporarily withhold Tabrecta≤3.0 x ULN) until recovery to baseline serumcreatinine grade.

If recovered to baseline, thenresume Tabrecta at the samedose level.

Grade 3 (>3.0 to Temporarily withhold Tabrecta≤6.0 x ULN) until recovery to baseline serumcreatinine grade.

If recovered to baseline, thenresume Tabrecta at a reduceddose as per Table 1.

Grade 4 (>6.0 x ULN) Permanently discontinue

Tabrecta.

Vomiting Grade 2 Temporarily withhold Tabrectauntil resolved to grade ≤1.

If resolved to grade ≤1 thenresume Tabrecta the same doselevel.

Grade 3 Temporarily withhold Tabrectauntil resolved to grade ≤2.

If resolved to grade ≤2 thenresume Tabrecta at a reduceddose as per Table 1.

Grade 4 Temporarily withhold Tabrectauntil resolved to grade ≤2.

If resolved to grade ≤2 thenresume Tabrecta at a reduceddose as per Table 1.

Other adverse reactions Grade 2 Maintain dose level. Ifintolerable, considertemporarily withholding

Tabrecta until resolved, thenresume Tabrecta at a reduceddose as per Table 1.

Grade 3 Temporarily withhold Tabrectauntil resolved, then resume

Tabrecta at a reduced dose asper Table 1.

Grade 4 Permanently discontinue

Tabrecta.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limitof normal.

Grading according to CTCAE Version 4.03 (CTCAE = Common Terminology Criteria for Adverse

Events).

Baseline = at the time of treatment initiation.

No dose adjustment is necessary in patients 65 years of age or older (see section 5.2).

Caution should be exercised in patients with severe renal impairment as Tabrecta has not been studiedin these patients. No dose adjustment is necessary in patients with mild or moderate renal impairment(see section 5.2).

No dose adjustment is necessary in patients with mild, moderate or severe hepatic impairment (seesection 5.2).

The safety and efficacy of Tabrecta in children aged 0 to 18 years have not been established. No dataare available.

Tabrecta should be taken orally twice daily with or without food. Patients with swallowing difficultiesare recommended to take Tabrecta with food. The tablets should be swallowed whole to ensure thatthe full dose is administered.

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

Assessment of METex14 skipping alterations status

When detecting the presence of alterations leading to METex14 skipping using tissue-based orplasma-based specimens, it is important that a well-validated and robust test is chosen to avoid falsenegative or false positive results. For the characteristics of tests used in clinical studies see section 5.1.

ILD/pneumonitis, which can be fatal, has occurred in patients treated with Tabrecta (see section 4.8).

Prompt investigation should be performed in any patient with new or worsening of pulmonarysymptoms indicative of ILD/pneumonitis (e.g. dyspnoea, cough, fever). Tabrecta should beimmediately withheld in patients with suspected ILD/pneumonitis and permanently discontinued if noother potential causes of ILD/pneumonitis are identified (see section 4.2).

Transaminase elevations have occurred in patients treated with Tabrecta (see section 4.8). Liverfunction tests (including ALT, AST and total bilirubin) should be performed prior to the start oftreatment, every 2 weeks during the first 3 months of treatment, then once a month or as clinicallyindicated, with more frequent testing in patients who develop transaminase or bilirubin elevations.

Based on the severity of the adverse reaction, temporarily withhold, dose reduce, or permanentlydiscontinue Tabrecta (see section 4.2).

Elevations of pancreatic enzymes

Elevations in amylase and lipase levels have occurred in patients treated with Tabrecta (seesection 4.8). Amylase and lipase should be monitored at baseline and regularly during treatment with

Tabrecta. Based on the severity of the adverse reaction, temporarily withhold, dose reduce, orpermanently discontinue Tabrecta (see section 4.2).

Embryo-foetal toxicity

Based on findings from animal studies and its mechanism of action, Tabrecta can cause foetal harmwhen administered to a pregnant woman due to its foetotoxicity and teratogenicity (see section 4.6).

Pregnant women and women of childbearing potential should be advised of the potential risk to afoetus if Tabrecta is used during pregnancy or if the patient becomes pregnant while taking Tabrecta.

Sexually active women of childbearing potential should use effective contraception during treatmentwith Tabrecta and for at least 7 days after the last dose. The pregnancy status of women ofchildbearing potential should be verified prior to starting treatment with Tabrecta.

Male patients with sexual partners who are pregnant, possibly pregnant, or who could becomepregnant should use condoms during treatment with Tabrecta and for at least 7 days after the last dose.

Risk of photosensitivity

Based on findings from animal studies, there is a potential risk of photosensitivity reactions with

Tabrecta (see section 5.3). In Study GEOMETRY mono-1, it was recommended that patients limitdirect ultraviolet exposure during treatment with Tabrecta and adopt the following protectivemeasures: use of sunscreen on exposed parts of the body, wearing of protective clothing andsunglasses. These measures should be continued for at least 7 days after the last dose.

Interaction with other medicinal products

There is a potential for drug-drug interactions with Tabrecta as victim or perpetrator (see section 4.5).

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

Capmatinib undergoes metabolism through CYP3A4 enzyme and aldehyde oxidase. The risk of adrug-drug interaction via aldehyde oxidase has not been evaluated as there are no confirmed clinicallyrelevant inhibitors.

Effect of other medicinal products on Tabrecta

Strong CYP3A inhibitors

In healthy subjects, co-administration of a single 200 mg capmatinib dose with the strong CYP3Ainhibitor itraconazole (200 mg once daily for 10 days) increased capmatinib AUCinf by 42% with nochange in capmatinib Cmax compared to administration of capmatinib alone. Patients should be closelymonitored for adverse reactions during co-administration of Tabrecta with strong CYP3A inhibitors,including but not limited to, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir,nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, andvoriconazole.

Strong CYP3A inducers

In healthy subjects, co-administration of a single 400 mg capmatinib dose with the strong CYP3Ainducer rifampicin (600 mg once daily for 9 days) decreased capmatinib AUCinf by 67% and decreased

Cmax by 56% compared to administration of capmatinib alone. Decreases in capmatinib exposure maydecrease Tabrecta anti-tumour activity. Co-administration of Tabrecta with strong CYP3A inducers,including but not limited to, carbamazepine, phenobarbital, phenytoin, rifampicin and St. John’s wort(Hypericum perforatum), should be avoided. An alternative medicinal product with no or minimalpotential to induce CYP3A should be considered.

Moderate CYP3A inducers

Simulations using physiologically-based pharmacokinetic (PBPK) models predicted thatco-administration of a 400 mg capmatinib dose with the moderate CYP3A inducer efavirenz (600 mgdaily for 20 days) would result in a 44% decrease in capmatinib AUC0-12h and 34% decrease in Cmax atsteady-state compared to administration of capmatinib alone. Decreases in capmatinib exposure maydecrease Tabrecta anti-tumour activity. Caution should be exercised during co-administration of

Tabrecta with moderate CYP3A inducers.

Agents that raise gastric pH

Capmatinib demonstrates pH-dependent solubility and becomes poorly soluble as pH increases invitro. In healthy subjects, co-administration of a single 600 mg capmatinib dose with the proton pumpinhibitor rabeprazole (20 mg once daily for 4 days) decreased capmatinib AUCinf by 25% anddecreased Cmax by 38% compared to administration of capmatinib alone. Clinically relevant drug-druginteractions between capmatinib and gastric-acid-reducing agents are unlikely to occur asco-administration of rabeprazole had no clinically meaningful effect on exposure of capmatinib.

Effect of Tabrecta on other medicinal products

Substrates of CYP enyzmes

Moderate inhibition of CYP1A2 was observed when capmatinib was co-administered with thesensitive CYP1A2 substrate caffeine. Co-administration of capmatinib (400 mg twice daily) withcaffeine increased caffeine AUCinf by 134%. If capmatinib is co-administered with narrow therapeuticindex CYP1A2 substrates, such as theophylline and tizanidine, dose reduction of the co-administeredmedicinal product may be required.

Clinically relevant drug-drug interactions between capmatinib and CYP3A substrates are unlikely tooccur as co-administration of capmatinib had no clinically meaningful effect on exposure ofmidazolam (a CYP3A substrate).

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrates

In cancer patients, co-administration of digoxin (P-gp substrate) with multiple doses of capmatinib(400 mg twice daily) increased digoxin AUCinf by 47% and increased Cmax by 74% compared toadministration of digoxin alone. In cancer patients, co-administration of rosuvastatin (BCRP substrate)with multiple doses of capmatinib (400 mg twice daily) increased rosuvastatin AUCinf by 108% andincreased Cmax by 204% compared to administration of rosuvastatin alone. Co-administration of

Tabrecta with a P-gp or BCRP substrate may increase the incidence and severity of adverse reactionsof these substrates. Caution should be exercised during co-administration of Tabrecta with P-gp(digoxin, dabigatran etexilate, colchicine, sitagliptin, saxagliptin and posaconazole) or BCRP(methotrexate, rosuvastatin, pravastatin, mitoxantrone and sulphasalazine) substrates. If capmatinib isco-administered with narrow therapeutic index P-gp or BCRP substrates, dose reduction of theco-administered medicinal product may be required.

Sexually-active women of childbearing potential should use effective contraception (methods thatresult in less than 1% pregnancy rates) during treatment with Tabrecta and for at least 7 days after thelast dose.

Male patients with sexual partners who are pregnant, possibly pregnant, or who could becomepregnant should use condoms during treatment with Tabrecta and for at least 7 days after the last dose.

There are no data from the use of capmatinib in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3). Based on findings from animal studies and its mechanism ofaction, capmatinib is suspected to cause congenital malformations when administered duringpregnancy. Tabrecta should not be used during pregnancy unless the clinical condition of the womanrequires treatment with capmatinib.

The pregnancy status of women of childbearing potential should be verified prior to starting treatmentwith Tabrecta.

It is unknown whether capmatinib or its metabolites are excreted in human milk after administration of

Tabrecta. There is insufficient information on the excretion of capmatinib or its metabolites in animalmilk. A risk to the breast-fed infant cannot be excluded. Because of the potential for serious adversereactions in breast-fed infants, breast-feeding should be discontinued during treatment with Tabrectaand for at least 7 days after the last dose.

No human fertility data on capmatinib are available. Fertility studies with capmatinib were notconducted in animals.

Tabrecta has no or negligible influence on the ability to drive and use machines.

The most common adverse reactions are peripheral oedema (67.5%), nausea (44.4%), fatigue (34.4%),blood creatinine increased (33.8%), vomiting (25.0%), dyspnoea (22.5%), decreased appetite (21.3%)and back pain (20.6%). The most common grade 3 or 4 adverse reactions are peripheral oedema(14.4%), lipase increased (9.4%), ALT increased (8.1%), fatigue (8.1%), dyspnoea (6.9%) andamylase increased (5.6%).

Serious adverse reactions were reported in 35 of 160 patients (21.9%) who received Tabrecta. Seriousadverse reactions in >2% of patients included dyspnoea (5.6%), ILD/pneumonitis (5.0%), cellulitis(3.1%) and peripheral oedema (2.5%).

Dose interruptions were reported in 81 of 160 patients (50.6%). Adverse reactions requiring doseinterruption included peripheral oedema (15.0%), blood creatinine increased (11.3%), lipase increased(8.1%), nausea (8.1%), ALT increased (6.3%), fatigue (5.6%), amylase increased (5.0%), vomiting(5.0%), dyspnoea (3.8%), blood bilirubin increased (3.1%) and AST increased (3.1%).

Dose reductions were reported in 49 of 160 patients (30.6%). Adverse reactions requiring dosereductions included peripheral oedema (16.3%), ALT increased (5.0%), blood creatinine increased(3.8%), fatigue (3.1%) and nausea (2.5%).

Permanent discontinuation was reported in 19 of 160 patients (11.9%). The most frequent adversereactions leading to permanent discontinuation of Tabrecta were ILD/pneumonitis (3.8%), peripheraloedema (2.5%), ALT increased (1.3%), AST increased (1.3%), blood bilirubin increased (1.3%),blood creatinine increased (1.3%), lipase increased (1.3%), amylase increased (0.6%), fatigue (0.6%)and urticaria (0.6%).

The safety of Tabrecta was evaluated in patients with locally-advanced or metastatic NSCLC in apivotal, global, prospective, multi-cohort, non-randomised, open-label Phase II study (GEOMETRYmono-1) across all cohorts (N=373), regardless of prior treatment or MET dysregulation (mutationand/or amplification) status. The frequencies of adverse reactions are based on all-cause adverse eventfrequencies identified in 160 patients with METex14 skipping mutations exposed to capmatinib at therecommended dose, whereas frequencies for changes in laboratory parameters are based on worseningfrom baseline shifts by at least 1 grade (grading according to CTCAE version 4.03). The safety profilefor all GEOMETRY mono-1 patients (N=373) and for patients with METex14 skipping mutations(N=160) is comparable. The median duration of exposure to capmatinib across MET-mutated cohortswas 34.9 weeks (range: 0.4 to 195.7 weeks). Among patients who received capmatinib, 55.0% wereexposed for at least 6 months and 36.3% were exposed for at least one year.

Adverse reactions from clinical studies (Table 3) are listed by MedDRA system organ class. Withineach system organ class, the adverse reactions are ranked by frequency, with the most frequentreactions first. In addition, the corresponding frequency category for each adverse reaction is based onthe following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to<1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). Within each frequency grouping,adverse reactions are presented in the order of decreasing seriousness.

Table 3 Adverse reactions in patients (N=160) harbouring METex14 skipping mutations instudy GEOMETRY mono-1 (Data cut-off: 30-Aug-2021)

Adverse reaction All grades All grades Grade 3/4

Frequency category % %

Cellulitis Common 4.4 2.5*

Decreased appetite Very common 21.3 1.3*

Respiratory, thoracic, and mediastinal disorders

Dyspnoea Very common 22.5 6.9*

Cough Very common 17.5 0.6*

ILD/pneumonitis1 Common 7.5 4.4*

Vomiting Very common 25.0 0.6*

Nausea Very common 44.4 0.6*

Diarrhoea Very common 15.6 -

Constipation Very common 13.1 1.3*

Hypersensitivity† Uncommon 0.3 0.3

Pruritus Very common 10.6 0.6*

Rash2 Common 9.4 -

Urticaria Common 2.5 0.6*

Oedema peripheral3 Very common 67.5 14.4*

Pyrexia Very common 10.6 1.3*

Fatigue4 Very common 34.4 8.1*

Back pain Very common 20.6 1.3*

Weight decreased Very common 12.5 -

Non-cardiac chest pain5 Common 9.4 1.3*

Albumin decreased Very common 78.3 1.9*

Creatinine increased Very common 74.5 0.6*

Alanine aminotransferase increased Very common 45.9 11.5

Amylase increased Very common 37.2 7.1

Lipase increased Very common 33.3 11.5

Aspartate aminotransferase increased Very common 33.8 5.7

Phosphate decreased Very common 30.1 4.5

Sodium decreased Very common 22.3 4.5

Bilirubin increased Common 8.3 0.6*1 ILD/pneumonitis includes preferred terms (PTs) of ILD, pneumonitis and organisingpneumonia.

2 Rash includes PTs of rash, rash maculopapular and rash vesicular.

3 Oedema peripheral includes PTs of oedema peripheral and peripheral swelling.

4 Fatigue includes PTs of fatigue and asthenia.

5 Non-cardiac chest pain includes PTs of chest discomfort, musculoskeletal chest pain andnon-cardiac chest pain.

* No grade 4 adverse reactions reported in GEOMETRY mono-1 patients with METex14skipping mutations.

† Hypersensitivity has been observed in solid tumour patients treated with Tabrectamonotherapy (N=580). Hypersensitivity has also been observed in the post-marketing settingand in expanded access programmes with Tabrecta.

Cases of acute kidney injury (n=1), renal failure (n=4) and acute pancreatitis (n=1) were reported in

GEOMETRY mono-1 MET-amplified patients.

Any grade ILD/pneumonitis was reported in 12 of 160 patients (7.5%). Grade 3 ILD/pneumonitis wasreported in 7 patients (4.4%), with one fatal event of treatment-related pneumonitis (0.6%) and onefatal event of organising pneumonia (0.6%). ILD/pneumonitis occurred in 6 of 63 patients (9.5%) witha history of prior radiotherapy and 6 of 97 patients (6.2%) who did not receive prior radiotherapy. Sixpatients (3.8%) discontinued Tabrecta due to ILD/pneumonitis. ILD/pneumonitis mostly occurredwithin approximately the first 3 months of treatment. The median time-to-onset of grade 3 or higher

ILD/pneumonitis was 7.0 weeks (range: 0.7 to 88.4 weeks).

Any grade ALT/AST elevations were reported in 24 of 160 patients (15.0%). Grade 3 or 4 ALT/ASTelevations were observed in 13 of 160 patients (8.1%) treated with Tabrecta. Two patients (1.3%)discontinued Tabrecta due to ALT/AST elevations. ALT/AST elevations mostly occurred withinapproximately the first 3 months of treatment. The median time-to-onset of grade 3 or higher

ALT/AST elevations was 6.4 weeks (range: 2.1 to 17.9 weeks).

Elevations of pancreatic enzymes

Any grade amylase/lipase elevations were reported in 27 of 160 patients (16.9%). Grade 3 or 4amylase/lipase elevations were reported in 18 of 160 patients (11.3%) treated with Tabrecta. Threepatients (1.9%) discontinued Tabrecta due to amylase/lipase elevations. The median time to onset ofgrade 3 or higher amylase/lipase elevations was 10.1 weeks (range: 2.3 to 68.0 weeks).

Peripheral oedema

Any grade peripheral oedema was reported in 108 of 160 patients (67.5%). This adverse reactionincludes the PTs of peripheral oedema, which was the most frequent at 65.0% and peripheral swellingwhich occurred in 4.4% of patients. Grade 3 or 4 peripheral oedema was reported in 23 of 160 patients(14.4%) treated with Tabrecta. Four patients (2.5%) discontinued Tabrecta due to peripheral oedema.

The median time to onset of grade 3 or higher peripheral oedema was 24.3 weeks (range: 1.4 to86.9 weeks).

Of the 160 patients with METex14 skipping mutations in the GEOMETRY mono-1 study whoreceived 400 mg capmatinib twice daily, 85% were 65 years or older, and 4.4% were 85 years orolder. The occurrence of grade ≥3 events increased with age. Treatment-related serious events weremore frequent in patients aged ≥65 to <75 years (22%) and those aged ≥85 years (28.6%) whencompared to those patients aged ≥75 to <85 years (8.5%) and patients younger than 65 years (8.3%),although this comparison is limited by the small sample size in patients aged ≥85 years.

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 limited experience with overdose in clinical studies with Tabrecta. Patients should be closelymonitored for signs or symptoms of adverse reactions, and general supportive measures andsymptomatic treatment should be initiated in cases of suspected overdose.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EX17.

Capmatinib is an inhibitor of the MET receptor tyrosine kinase. Capmatinib inhibits METphosphorylation (both autophosphorylation and phosphorylation triggered by the ligand hepatocytegrowth factor [HGF]), MET-mediated phosphorylation of downstream signalling proteins, as well asproliferation and survival of MET-dependent cancer cells.

Capmatinib did not prolong the QT interval to any clinically relevant extent following administrationof Tabrecta at the recommended dose.

Detection of METex14 skipping status

In GEOMETRY mono-1, MET exon 14 skipping mutations were determined using a qualitative real-time PCR test (RT-PCR) designed to detect exon 14-deleted MET mRNA derived fromformalin-fixed, paraffin-embedded human tissue. The test is indicated as an aid in selecting non-smallcell lung cancer (NSCLC) patients whose tumours carry a MET mutation that causes in-frame deletionof the entire exon 14 (141 bases) in mRNA for treatment with capmatinib.

The efficacy of capmatinib for the treatment of patients with locally advanced or metastatic NSCLCwith a MET exon 14 (METex14) skipping mutation was studied in a prospective, multi-cohort,non-randomised, open-label Phase II Study GEOMETRY mono-1. Patients (N=373) were enrolledinto study cohorts based on their prior treatment and MET dysregulation (mutation and/oramplification) status. Patients with a METex14 skipping mutation (N=160) were enrolled into the

MET-mutated cohorts regardless of MET amplification. The demonstrated efficacy of capmatinib isbased on Cohorts 4 and 6 which enrolled 100 previously-treated patients.

In the MET-mutated cohorts, eligible NSCLC patients were required to have Epidermal Growth Factor

Receptor (EGFR) wild-type (for exon 19 deletions and exon 21 L858R substitution mutations) and

Anaplastic Lymphoma Kinase (ALK) negative status, and a METex14 skipping mutation with at leastone measurable lesion as defined by Response Evaluation Criteria in Solid Tumours (RECIST)version 1.1, along with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1.

Patients with symptomatic central nervous system (CNS) metastases who were neurologically unstableor required increasing doses of steroids within the prior 2 weeks to manage CNS symptoms, patientswith clinically significant uncontrolled cardiac disease, or patients pre-treated with any MET or HGFinhibitor were not eligible for the study.

In the MET-mutated cohorts, a total of 100 adult previously-treated patients with locally advanced ormetastatic NSCLC with a METex14 skipping mutation were enrolled and treated with Tabrecta. Thepatients had been treated with 1 or 2 prior lines of systemic therapy for advanced disease, except for3 patients (3.0%) who had received 3 prior lines before receiving capmatinib. The median duration ofexposure to capmatinib was 27.9 weeks.

Patients continued treatment until documented disease progression, intolerance to therapy, or theinvestigator determined that the patient was no longer experiencing clinical benefit.

The demographic characteristics of the previously-treated patients were 56% female, median age70 years (range: 49 to 90 years), 29% aged 75 years of age or older, 73% white, 24% Asian, 1.0%black, 59% never smoked, 37% were former smokers, 78% had adenocarcinoma, 26% had ECOG PS0, 73% had ECOG PS 1, and 17% had CNS metastases. The majority of patients (62%) had stage IVdisease. Ninety-one percent of patients had prior chemotherapy, 86% had prior platinum-basedchemotherapy, 32% had prior immunotherapy, and 16% had received 2 prior systemic therapies.

The primary endpoint of the study was overall response rate (ORR) as determined by a Blinded

Independent Review Committee (BIRC) according to RECIST 1.1. The key secondary endpoint wasduration of response (DOR) by BIRC.

Efficacy results from Study GEOMETRY mono-1 for previously-treated NSCLC patients with a

METex14 skipping mutation are summarised in Table 4.

Table 4 Efficacy results by BIRC in previously-treated NSCLC patients with a METex14skipping mutation who received Tabrecta in GEOMETRY mono-1 (data cut-off: 30-

Aug-2021)

Overall previously Cohort 4 (2/3L) Cohort 6 (2L)

Efficacy parameters treated population N=69 N=31(N=100)

Overall response ratea 44.0% (34.1, 54.3) 40.6% (28.9, 51.6% (33.1, 69.8)(95% CI)b 53.1)

Complete response (CR), n 1 (1.0) 1 (1.4) 0 (0.0)(%)

Partial response (PR), n (%) 43 (43.0) 27 (39.1) 16 (51.6)

Duration of responsea

Number of responders, n 44 28 16

Median, months (95% CI)c 9.72 (5.62, 12.98) 9.72 (5.55, 12.98) 9.05 (4.17, NE)

Abbreviations: CI, confidence interval; NE, not estimable.

ORR: CR+PR.a Determined by RECIST v1.1.b Clopper and Pearson exact binomial 95% CI.c Based on Kaplan-Meier estimate.

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

Tabrecta in all subsets of the paediatric population in the treatment of lung malignant neoplasm (seesection 4.2 for information on paediatric use).

Capmatinib exhibited dose-proportional increases in systemic exposure (AUCinf and Cmax) across thedose range tested (200 to 400 mg twice daily). Steady-state is expected to be achieved afterapproximately 3 days after oral dosing of capmatinib 400 mg twice daily, with a geometric meanaccumulation ratio of 1.39 (coefficient of variation (CV): 42.9%). Inter-individual variability of Cmaxand AUCtau was estimated to be 38% and 40%, respectively.

In humans, absorption is rapid after oral administration of capmatinib. Under fasted conditions, peakplasma levels of capmatinib (Cmax) were reached approximately 1 to 2 hours (Tmax) after an oral400 mg dose of capmatinib tablets in cancer patients. Under fed conditions, Tmax is approximately4-6 hours. The absorption of capmatinib tablets after oral administration is estimated to be greater than70%.

Food does not alter capmatinib bioavailability to a clinically meaningful extent. Tabrecta can beadministered with or without food (see section 4.2).

When capmatinib was administered with food in healthy subjects, oral administration of a single600 mg dose with a high-fat meal increased capmatinib AUCinf by 46% and no change in Cmaxcompared to when capmatinib was administered under fasted conditions. A low-fat meal in healthysubjects had no clinically meaningful effect on capmatinib exposure.

When capmatinib was administered at 400 mg twice daily in cancer patients, exposure (AUC0-12h) wassimilar after administration of capmatinib with food and under fasted conditions.

Capmatinib is 96% bound to human plasma proteins, independent of concentration. The apparentmean volume of distribution at steady-state (Vss/F) is 164 litres in cancer patients.

The blood-to-plasma ratio was 1.5 (concentration range of 10 to 1000 ng/ml), but decreased at higherconcentrations to 0.9 (concentration 10000 ng/ml), indicating a saturation of distribution into redblood cells.

Capmatinib crosses the blood-brain barrier (see section 5.3).

In vitro and in vivo studies indicated that capmatinib is cleared mainly through metabolism driven bycytochrome P450 (CYP) 3A4 (40-50%) and aldehyde oxidase (40%). The biotransformation ofcapmatinib occurs essentially by Phase I metabolic reactions including C-hydroxylation, lactamformation, N-oxidation, N-dealkylation, carboxylic acid formation, and combinations thereof. Phase IIreactions involve glucuronidation of oxygenated metabolites. The most abundant radioactivecomponent in plasma is unchanged capmatinib (42.9% of radioactivity AUC0-12h). The majorcirculating metabolite, M16 (CMN288), is pharmacologically inactive and accounts for 21.5% of theradioactivity in plasma AUC0-12h.

The effective elimination half-life (calculated based on geometric mean accumulation ratio) ofcapmatinib is 6.54 hours. The geometric mean steady-state apparent oral clearance (CLss/F) ofcapmatinib was 19.8 litres/hour.

Capmatinib is eliminated mainly through metabolism, and subsequent faecal excretion. Following asingle oral administration of [14C]-capmatinib capsule to healthy subjects, 78% of the totalradioactivity was recovered in the faeces and 22% in the urine. Excretion of unchanged capmatinib inurine is negligible.

No overall differences in the safety or effectiveness were observed between patients aged 65 and75 years or older and younger patients.

Effect of age, gender, race and body weight

Population pharmacokinetic analysis showed that there is no clinically relevant effect of age, gender,race, or body weight on the systemic exposure of capmatinib.

Based on a population pharmacokinetic analysis that included 207 patients with normal renal function(creatinine clearance [CLcr] ≥90 ml/min), 200 patients with mild renal impairment (CLcr 60 to89 ml/min), and 94 patients with moderate renal impairment (CLcr 30 to 59 ml/min), mild or moderaterenal impairment had no clinically significant effect on the exposure of capmatinib. Tabrecta has notbeen studied in patients with severe renal impairment (CLcr 15 to 29 ml/min) (see section 4.2).

A study was conducted in non-cancer subjects with various degrees of hepatic impairment based on

Child-Pugh classification using a 200 mg single-dose of capmatinib. The geometric mean systemicexposure (AUCinf) of capmatinib was decreased by approximately 23% and 9% in subjects with mild(N=6) and moderate (N=8) hepatic impairment, respectively, and increased by approximately 24% insubjects with severe (N=6) hepatic impairment compared to subjects with normal (N=9) hepaticfunction. Mild, moderate or severe hepatic impairment had no clinically significant effect on theexposure of capmatinib.

Capmatinib exposure-response relationships and the time course of the pharmacodynamic response areunknown.

In vitro evaluation of medicinal product interaction potential

Interactions between enzymes and Tabrecta

In vitro studies showed that capmatinib is an inhibitor of CYP2C8, CYP2C9 and CYP2C19.

Capmatinib also showed weak induction of CYP2B6 and CYP2C9 in cultured human hepatocytes.

Simulations using PBPK models predicted that capmatinib given at a dose of 400 mg twice daily isunlikely to cause clinically relevant interaction via CYP2B6, CYP2C8, CYP2C9 or CYP2C19.

Interactions between transporters and Tabrecta

Based on in vitro data, capmatinib is a P-gp substrate, but not a BCRP or multidrugresistance-associated (MRP2) substrate. Capmatinib is not a substrate of transporters involved inactive hepatic uptake in primary human hepatocytes.

Based on in vitro data, capmatinib and its major metabolite CMN288 showed reversible inhibition ofrenal transporters MATE1 and MATE2K. Capmatinib may inhibit MATE1 and MATE2K at clinicallyrelevant concentrations.

Based on in vitro data, capmatinib showed reversible inhibition of hepatic uptake transporters

OATP1B1, OATP1B3, and OCT1. However, capmatinib is not expected to cause clinically relevantinhibition of OATP1B1, OATP1B3, and OCT1 uptake transporters based on the concentrationachieved at the therapeutic dose. Capmatinib is not an inhibitor of renal transporters OAT1 or OAT3.

Capmatinib is not a MRP2 inhibitor in vitro.

Repeated-dose toxicity

Signs indicative of CNS toxicity (such as tremors and/or convulsions), and histopathological findingsof white matter vacuolation in the thalamus/caudate/putamen regions of the midbrain were observed inrats at doses ≥2.9 exposure multiples of the human clinical exposure based on AUC at the 400 mgtwice daily dose. No signs of CNS toxicity or brain abnormalities were observed in cynomolgusmonkey studies. The relevance of the CNS findings in rats to humans is unknown.

Capmatinib crossed the blood-brain barrier in rats with a brain-to-blood exposure (AUCinf) ratio ofapproximately 9%.

A reversible, minimal-to-mild subcapsular neutrophilic infiltration associated with single cell necrosiswas seen in the liver of male monkeys treated for 13 weeks at dose levels of ≥4.7 exposure multiplesof the human clinical exposure based on AUC at the 400 mg twice daily dose.

Capmatinib is not genotoxic based on a standard battery of in vitro and in vivo tests.

In embryo-foetal development studies in rats and rabbits, capmatinib was teratogenic and foetotoxic atdose levels not eliciting maternal toxicity. In rats, decreased foetal weight and increased incidence oflitters and foetuses with limb malformations were observed at the maternal exposure of ≥0.89exposure multiples of the anticipated clinical exposure (based on the AUC). In rabbits, limb, lung andtongue malformations were seen at the maternal exposure of ≥0.025 exposure multiples of theanticipated clinical exposure.

In vitro and in vivo photosensitisation assays with capmatinib suggested that capmatinib has thepotential for photosensitisation.

Cellulose microcrystalline

Mannitol

Crospovidone

Povidone

Magnesium stearate

Silica colloidal anhydrous

Sodium laurilsulfate

Tabrecta 150 mg film-coated tablets

Hypromellose

Titanium dioxide (E171)

Macrogol

Talc

Iron oxide, yellow (E172)

Iron oxide, red (E172)

Iron oxide, black (E172)

Tabrecta 200 mg film-coated tablets

Hypromellose

Titanium dioxide (E171)

Macrogol

Talc

Iron oxide, yellow (E172)

Not applicable.

3 years.

This medicinal product does not require any special temperature storage conditions.

Store in the original package in order to protect from moisture.

PCTFE/PVC (polychlorotrifluoroethylene/polyvinyl chloride) blisters backed with an aluminiumlidding foil.

Packs containing 60 or 120 film-coated tablets.

Not all pack sizes may be marketed.

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

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/22/1650/001-004

20 June 2022

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

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