Tabrecta, as monotherapy, is indicated for the treatment of adult patients with unresectable locally advanced or metastatic non-small cell lung cancer (NSCLC) with a MET exon 14 skipping mutation.

Treatment with Tabrecta should be initated by a physician experienced in the use of anticancer therapies. Patients should be selected for treatment with Tabrecta based on the presence of genetic alterations leading 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 if feasible (see sections 4.4 and 5.1). Posology 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 is deriving clinical benefit from therapy. If a dose of Tabrecta is missed or vomiting occurs, the patient should not make up for the dose, but take the next dose at the scheduled time. Dose modifications The recommended dose reduction schedule for the management of adverse reactions based on individual 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 Tabrecta should be permanently discontinued in patients unable to tolerate 200 mg orally twice daily. 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 (ILD)/pneumonitis Any grade treatment-related Permanently discontinue Tabrecta. Grade 3 (>5.0 to =20.0 x ULN) Temporarily withhold Tabrecta until recovery to baseline ALT/AST grade. If recovered to baseline within 7 days, then resume Tabrecta at the same dose, otherwise resume Tabrecta at a reduced dose as per Table 1. Isolated ALT and/or AST elevations from baseline, without concurrent total bilirubin increase Grade 4 (>20.0 x ULN) Permanently discontinue Tabrecta. Combined elevations in ALT and/or AST with concurrent total bilirubin increase, in the absence of cholestasis or haemolysis If patient develops ALT and/or AST >3 x ULN along with total bilirubin >2 x ULN, irrespective of baseline grade Permanently discontinue Tabrecta. Grade 2 (>1.5 to =3.0 x ULN) Temporarily withhold Tabrecta until recovery to baseline bilirubin grade. If recovered to baseline within 7 days, then resume Tabrecta at the same dose, otherwise resume Tabrecta at a reduced dose as per Table 1. Grade 3 (>3.0 to =10.0 x ULN) Temporarily withhold Tabrecta until recovery to baseline bilirubin grade. If recovered to baseline within 7 days, then resume Tabrecta at a reduced dose as per Table 1, otherwise permanently discontinue Tabrecta. Isolated total bilirubin elevation from baseline, without concurrent ALT and/or AST increase Grade 4 (>10.0 x ULN) Permanently discontinue Tabrecta. Adverse reaction Severity Dose modification Grade 2 Maintain dose level. If intolerable, consider temporarily withholding Tabrecta until resolved, then resume Tabrecta at a reduced dose as per Table 1. Grade 3 Temporarily withhold Tabrecta until resolved, then resume Tabrecta at a reduced dose as per Table 1. Other adverse reactions Grade 4 Permanently discontinue Tabrecta. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ILD, interstitial lung disease ; ULN, upper limit of normal. Grading according to CTCAE Version 4.03 (CTCAE = Common Terminology Criteria for Adverse Events). Baseline = at the time of treatment initiation. Special populations Elderly No dose adjustment is necessary in patients 65 years of age or older (see section 5.2). Renal impairment Caution should be exercised in patients with severe renal impairment as Tabrecta has not been studied in these patients. No dose adjustment is necessary in patients with mild or moderate renal impairment (see section 5.2). Hepatic impairment No dose adjustment is necessary in patients with mild, moderate or severe hepatic impairment (see section 5.2). Paediatric population The safety and efficacy of Tabrecta in children aged 0 to 18 years have not been established. No data are available. Method of administration Tabrecta should be taken orally with or without food. The tablets should be swallowed whole with a glass of water and should not be broken, crushed or chewed to ensure that the 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 or plasma-based specimens, it is important that a well-validated and robust test is chosen to avoid false negative or false positive results. For the characteristics of tests used in clinical studies see section 5.1. Interstitial lung disease (ILD)/pneumonitis 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 pulmonary symptoms indicative of ILD/pneumonitis (e.g. dyspnoea, cough, fever). Tabrecta should be immediately withheld in patients with suspected ILD/pneumonitis and permanently discontinued if no other potential causes of ILD/pneumonitis are identified (see section 4.2). Hepatic effects Transaminase elevations have occurred in patients treated with Tabrecta (see section 4.8). Liver function tests (including ALT, AST and total bilirubin) should be performed prior to the start of treatment, every 2 weeks during the first 3 months of treatment, then once a month or as clinically indicated, 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 permanently discontinue Tabrecta (see section 4.2). Elevations of pancreatic enzymes Elevations in amylase and lipase levels have occurred in patients treated with Tabrecta (see section 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, or permanently discontinue Tabrecta (see section 4.2). Hypersensitivity reactions No cases of serious hypersensitivity were reported in patients treated with Tabrecta in Study GEOMETRY mono-1. In other clinical studies, cases of serious hypersensitivity were reported in patients treated with Tabrecta (see section 4.8). Clinical symptoms included pyrexia, chills, pruritus, rash, blood pressure decreased, nausea and vomiting. Based on the severity of the adverse drug reaction, temporarily withhold or permanently discontinue Tabrecta. Embryo-foetal toxicity Based on findings from animal studies and its mechanism of action, Tabrecta can cause foetal harm when 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 a foetus 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 treatment with Tabrecta and for at least 7 days after the last dose. The pregnancy status of women of childbearing potential should be verified prior to starting treatment with Tabrecta. Male patients with sexual partners who are pregnant, possibly pregnant, or who could become pregnant should use condoms during treatment with Tabrecta and for at least 7 days after the last dose (see section 4.6). 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 limit direct ultraviolet exposure during treatment with Tabrecta and adopt the following protective measures: use of sunscreen on exposed parts of the body, wearing of protective clothing and sunglasses. These measures should be continued for at least 7 days after the last dose. Excipients 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 a drug-drug

Women of childbearing potential/Contraception in males and females Sexually-active women of childbearing potential should use effective contraception (methods that result in less than 1% pregnancy rates) during treatment with Tabrecta and for at least 7 days after the last dose. Male patients with sexual partners who are pregnant, possibly pregnant, or who could become pregnant should use condoms during treatment with Tabrecta and for at least 7 days after the last dose. Pregnancy There are no data from the use of capmatinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Based on findings from animal studies and its mechanism of action, capmatinib is suspected to cause congenital malformations when administered during pregnancy. Tabrecta should not be used during pregnancy unless the clinical condition of the woman requires treatment with capmatinib. The pregnancy status of women of childbearing potential should be verified prior to starting treatment with Tabrecta. Breast-feeding 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 animal milk. A risk to the breast-fed infant cannot be excluded. Because of the potential for serious adverse reactions in breast-fed infants, breast-feeding should be discontinued during treatment with Tabrecta and for at least 7 days after the last dose. Fertility No human fertility data on capmatinib are available. Fertility studies with capmatinib were not conducted in animals.

Tabrecta may have minor influence on the ability to drive and use machines. During treatment with Tabrecta, fatigue and asthenia have been reported.

Summary of the safety profile The safety of Tabrecta was evaluated in patients with locally advanced or metastatic NSCLC in the pivotal, global, prospective, multi-cohort, non-randomized, open-label Phase II Study A2201 (GEOMETRY mono-1) across all cohorts (N = 373), regardless of prior treatment or MET dysregulation (mutation and/or amplification) status. The median duration of exposure to Tabrecta across all cohorts was 17.9 weeks (range: 0.4 to 281.0 weeks). Among patients who received Tabrecta, 36.7% were exposed for at least 6 months and 21.7% were exposed for at least one year. The frequencies of adverse reactions are based on all-cause adverse event frequencies identified in 373 patients exposed to capmatinib at the recommended dose. The most common adverse drug reactions (ADRs) reported with an incidence of =20% (all Grades) in patients who received Tabrecta were peripheral oedema (56.8%), nausea (45.6%), fatigue (34.0%), vomiting (28.4%), blood creatinine increased (27.1%), dyspnoea (24.9%), and decreased appetite (21.4%). The most common Grade 3 or 4 ADRs reported with an incidence of =5% in patients who received Tabrecta were peripheral oedema (10.5%), fatigue (8.0), dyspnoea (7.0%), ALT increased (7.0%), and lipase increased (6.7%). Serious adverse events (AEs) regardless of causality were reported in 198 patients (53.1%) who received Tabrecta. Serious AEs regardless of causality in > 2% of patients included dyspnoea (6.7%), pneumonia (5.9%), pleural effusion (4.3%), general physical health deterioration (2.9%) and vomiting (2.4%). Fourteen patients (3.8%) died while on treatment with Tabrecta due to causes other than the underlying malignancy. One of these deaths was confirmed as treatment-related: pneumonitis. Dose interruptions due to an adverse event regardless of causality were reported in 211 patients (56.6%) who received Tabrecta. Adverse events regardless of causality requiring dose interruption in > 2% of patients who received Tabrecta included peripheral oedema (11.0%), blood creatinine increased (8.3%), nausea (6.2%), lipase increased (5.6%), vomiting (5.6%), ALT increased (4.8%), dyspnoea (4.6%), pneumonia (4.3%), amylase increased (3.8%), AST increased (3.2%), asthenia (2.4%) and blood bilirubin increased (2.1%). Dose reductions due to an adverse event regardless of causality were reported in 98 patients (26.3%) who received Tabrecta. Adverse events regardless of causality requiring dose reductions in > 2% of patients who received Tabrecta included peripheral oedema (9.1%), ALT increased (3.2%) and blood creatinine increased (2.1%). Permanent discontinuation of Tabrecta due to an AE regardless of causality was reported in 65 patients (17.4%). The most frequent AEs (=0.5%) leading to permanent discontinuation of Tabrecta were peripheral oedema (2.1%), pneumonitis (1.6%), fatigue (1.3%), ALT increased (0.8%), AST increased (0.8%), blood creatinine increased (0.8%), nausea (0.8%), pneumonia (0.8%), vomiting (0.8%), blood bilirubin increased (0.5%), breast cancer (0.5%), cardiac failure (0.5%), general physical health deterioration (0.5%), ILD (0.5%), lipase increased (0.5%), organising pneumonia (0.5%) and pleural effusion (0.5%). Tabulated list of adverse reactions Adverse reactions from clinical studies (Table 3) are listed by MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each adverse reaction is based on the 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 drug reactions in patients (N = 373) who received Tabrecta in Study A2201 (GEOMETRY mono-1) (Data cut-off: 30-Aug-2021) Adverse reaction All grades Frequency category All grades % Grade 3/4 % Infections and infestations Cellulitis Common 2.9 1.1* Metabolism and nutrition disorders Decreased appetite Very common 21.4 1.1* Respiratory, thoracic, and mediastinal disorders Dyspnoea Very common 24.9 7.0 Cough Very common 16.6 0.5* ILD/pneumonitis Common 4.6 1.9* Gastrointestinal disorders Nausea Very common 45.6 2.4* Vomiting Very common 28.6 2.4* Constipation Very common 18.8 0.8* Diarrhoea Very common 18.5 0.5* Acute pancreatitis Uncommon 0.3 0.3* Skin and subcutaneous tissue disorders Pruritus1 Common 9.7 0.3* Rash2 Common 8.6 0.5* Urticaria Common 1.3 0.5* Renal and urinary disorders Acute kidney injury3 Common 3.8 0.8* General disorders and administration site conditions Oedema peripheral4 Very common 56.8 10.5* Fatigue5 Very common 34 8.0* Back pain Very common 16.9 0.8* Non-cardiac chest pain6 Very common 14.2 1.9* Pyrexia7 Very common 14.2 0.8* Weight decreased Common 11.0 0.5* Investigations† Albumin decreased Very common 72.0 1.9* Creatinine increased Very common 65.0 0.5* Alanine aminotransferase increased Very common 39.1 9.4 Amylase increased Very common 33.6 4.7 Lipase increased Very common 28.7 9.2 Aspartate aminotransferase increased Very common 27.5 5.8 Phosphate decreased Very common 25.9 4.4 Sodium decreased Very common 23.6 6.0 Bilirubin increased Common 8.0 1.1* 1 Pruritus includes preferred terms (PTs) of pruritus and pruritus allergic. 2 Rash includes PTs of rash, rash macular, rash maculopapular, rash erythematous and rash vesicular. 3 Acute kidney injury includes PTs of acute kidney injury and renal failure. 4 Oedema peripheral includes PTs of peripheral swelling, oedema peripheral, and fluid overload. 5 Fatigue includes PTs of fatigue and asthenia. 6 Non-cardiac chest pain includes PTs of chest discomfort, musculoskeletal chest pain, non-cardiac chest pain and chest pain. 7 Pyrexia includes PTs of pyrexia and body temperature increased. * No grade 4 adverse reactions reported in Study A2201 (GEOMETRY mono-1). † Grading according to CTCAE Version 4.03. Frequency is based on worsening from baseline laboratory values. Adverse drug reactions from clinical studies and post-marketing experience Hypersensitivity has been observed in other clinical studies (frequency category: Uncommon), post-marketing experience and expanded access programs with Tabrecta (see section 4.4) Description of selected adverse reactions ILD/pneumonitis Any Grade ILD/pneumonitis was reported in 17 of 373 patients (4.6%) treated with Tabrecta in Study A2201 (GEOMETRY mono-1). Grade 3 ILD/pneumonitis was reported in 7 patients (1.9%), with a fatal event of pneumonitis reported in 1 patient (0.3%). ILD/pneumonitis occurred in 9 of 173 patients (5.2%) with a history of prior radiotherapy and 8 of 200 patients (4.0%) who did not receive prior radiotherapy. Eight patients (2.1%) discontinued Tabrecta due to ILD/pneumonitis. ILD/pneumonitis mostly occurred within approximately the first 3 months of treatment. The median time-to-onset of Grade 3 or higher ILD/pneumonitis was 7.9 weeks (range: 0.7 to 88.4 weeks). Hepatic effects Any Grade ALT/AST elevations were reported in 55 of 373 patients (14.7%) treated with Tabrecta in Study A2201 (GEOMETRY mono-1). Grade 3 or 4 ALT/AST elevations were observed in 26 of 373 patients (7.0%) treated with Tabrecta. Three patients (0.8%) discontinued Tabrecta due to ALT/AST elevations. ALT/AST elevations mostly occurred within approximately the first 3 months of treatment. The median time-to-onset of Grade 3 or higher ALT/AST elevations was 7.6 weeks (range: 2.1 to 201.6 weeks). Elevations of pancreatic enzymes Any Grade amylase/lipase elevations were reported in 52 of 373 patients (13.9%) treated with Tabrecta in Study A2201 (GEOMETRY mono 1). Grade 3 or 4 amylase/lipase elevations were reported in 32 of 373 patients (8.6%) treated with Tabrecta. Three patients (0.8%) discontinued Tabrecta due to amylase/lipase elevations. The median time to onset of Grade 3 or higher amylase/lipase elevations was 8.5 weeks (range: 0.1 to 135.0 weeks). 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 limited experience with in clinical studies with Tabrecta. Patients should be closely monitored for signs or symptoms of adverse reactions, and general supportive measures and symptomatic treatment should be initiated in cases of suspected .

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EX17. Mechanism of action Capmatinib is an inhibitor of the MET receptor tyrosine kinase. Capmatinib inhibits MET phosphorylation (both autophosphorylation and phosphorylation triggered by the ligand hepatocyte growth factor [HGF]), MET-mediated phosphorylation of downstream signaling proteins, as well as proliferation and survival of MET- dependent cancer cells Pharmacodynamic effects Cardiac electrophysiology Capmatinib did not prolong the QT interval to any clinically relevant extent following administration of Tabrecta at the recommended dose. Detection of METex14 skipping status In GEOMETRY mono-1, MET exon 14 skipping mutations were determined using a qualitative realtime PCR test (RT-PCR) designed to detect exon 14-deleted MET mRNA derived from formalin-fixed, paraffin-embedded human tissue. The test is indicated as an aid in selecting non-small cell lung cancer (NSCLC) patients whose tumours carry a MET mutation that causes in-frame deletion of the entire exon 14 (141 bases) in mRNA for treatment with capmatinib. Clinical efficacy and safety The efficacy of Tabrecta for the treatment of patients with locally advanced or metastatic NSCLC with a MET exon 14 skipping mutation was studied in a prospective, multi-cohort, non-randomized, open-label Phase II GEOMETRY mono- 1 (Study A2201). Patients (N = 373) were enrolled into study cohorts based on their prior treatment and MET dysregulation (mutation and/or amplification) status, of whom 160 had MET exon 14 skipping mutation regardless of MET amplification. The MET-mutated cohorts consisted of 60 treatment-naïve patients (Cohorts 5b and 7) and 100 previously-treated patients (Cohorts 4 and 6). The efficacy data for treatment-naïve and previously-treated patients were analyzed independently. 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 MET-exon 14 skipping mutation with at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (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 unstable or required increasing doses of steroids within the prior 2 weeks to manage CNS symptoms, patients with clinically significant uncontrolled cardiac disease, or patients pre-treated with any MET or HGF inhibitor were not eligible for the study. Patients continued treatment until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. The demographic characteristics of the MET-mutated study population were 61% female, median age 71 years (range: 48 to 90 years), 85% aged 65 years or older, 77% white, 19% Asian, 1.3% black, 61% never smoked, 83% had adenocarcinoma, 25% had ECOG PS 0, 74% had ECOG PS 1, and 16% had CNS metastases. In the previously-treated cohorts (Cohorts 4 and 6) (N=100), 91% had received prior chemotherapy, 86% had prior platinum-based chemotherapy, 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 was duration of response (DOR) by BIRC. Efficacy results from GEOMETRY mono-1 for both treatment-naïve and previously- treated MET-mutated NSCLC patients are summarized in Tables 4 and 5. Table 4 Efficacy results by BIRC in treatment-naïve NSCLC patients with a METex14 skipping mutation who received Tabrecta in GEOMETRY mono-1 (data cut-off: 30-Aug-2021) Efficacy parameters Overall treatment-naïve population (N=60) Cohort 5b N=28 Cohort 7 N=32 Overall response ratea (95% CI)b 68.3% (55.0, 79.7) 67.9% (47.6, 84.1) 68.8% (50.0, 83.9) Complete response (CR), n (%) 3 (5.0) 2 (7.1) 1 (3.1) Partial response (PR), n (%) 38 (63.3) 17 (60.7) 21 (65.6) Duration of responsea Number of responders, n 41 19 22 Median, months (95% CI)c Patients with DOR =6 months Patients with DOR =12 months 16.59 (8.41, 22.11) 70.7% 48.8% 12.58 (5.55, NE) 68.4% 47.4% 16.59 (8.34, NE) 72.7% 50.0% Disease Control Ratea (95% CI)b 98.3 (91.1, 100.0) 96.4% (81.7,99.9) 100.0% (89.1, 100.0) Progression-Free Survivala Number of events, n (%) 37 (61.7) 18 (64.3) 19 (59.4) Progressive Disease, n (%) 30 (50.0) 15 (53.6) 15 (46.9) Deaths, n (%) 7 (11.7) 3 (10.7) 4 (12.5) Median, months (95% CI)c 12.45 (8.31, 17.97) 12.42 (8.21, 23.39) 12.45 (6.87, 20.50) Overall Survival Number of events, n (%) 30 (50.0) 17 (60.7) 13 (40.6) Median, months (95% CI)c 25.49 (15.24, NE) 20.76 (12.42, NE) NE (12.85, 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. Table 5 Efficacy results by BIRC in previously-treated NSCLC patients with a METex14 skipping mutation who received Tabrecta in GEOMETRY mono-1 (data cut-off: 30-Aug-2021) Efficacy parameters Overall previously-treated population (N=100) Cohort 4 (2/3L) N=69 Cohort 6 (2L) N=31 Overall response ratea (95% CI)b 44.0% (34.1, 54.3) 40.6% (28.9, 53.1) 51.6% (33.1, 69.8) 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 Patients with DOR =6 months Patients with DOR =12 months 9.72 (5.62, 12.98) 63.6% 36.4% 9.72 (5.55, 12.98) 64.3% 32.1% 9.05 (4.17, NE) 62.5% 43.8% Disease Control Ratea (95% CI)b 82.0% (73.1, 89.0) 78.3% (66.7, 87.3) 90.3% (74.2, 98.0) Progression-Free Survivala Number of events, n (%) 83 (83.0) 60 (87.0) 23 (74.2) Progressive Disease, n (%) 75 (75.0) 54 (78.3) 21 (67.7) Deaths, n (%) 8 (8.0) 6 (8.7) 2 (6.5) Median, months (95% CI)c 5.49 (4.17, 8.11) 5.42 (4.17, 6.97) 6.93 (4.17, 13.34) Overall Survival Number of events, n (%) 70 (70.0) 53 (76.8) 17 (54.8) Median, months (95% CI)c 14.85 (11.63, 23.82) 13.57 (8.61, 22.24) 24.28 (13.54, 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. Paediatric population The licensing authority 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 (see section 4.2 for information on paediatric use).

Capmatinib exhibited dose-proportional increases in systemic exposure (AUCinf and Cmax) across the dose range tested (200 to 400 mg twice daily). Steady-state is expected to be achieved after approximately 3 days after oral dosing of capmatinib 400 mg twice daily, with a geometric mean accumulation ratio of 1.39 (coefficient of variation (CV): 42.9%). Inter-individual variability of Cmax and AUCtau was estimated to be 38% and 40%, respectively. Absorption In humans, absorption is rapid after oral administration of capmatinib. Under fasted conditions, peak plasma levels of capmatinib (Cmax) were reached approximately 1 to 2 hours (Tmax) after an oral 400 mg dose of capmatinib tablets in cancer patients. Under fed conditions, Tmax is approximately 4-6 hours. The absorption of capmatinib tablets after oral administration is estimated to be greater than 70%. Food effect Food does not alter capmatinib bioavailability to a clinically meaningful extent. Tabrecta can be administered with or without food (see section 4.2). When capmatinib was administered with food in healthy subjects, oral administration of a single 600 mg dose with a high-fat meal increased capmatinib AUCinf by 46% and no change in Cmax compared to when capmatinib was administered under fasted conditions. A low-fat meal in healthy subjects had no clinically meaningful effect on capmatinib exposure. When capmatinib was administered at 400 mg twice daily in cancer patients, exposure (AUC0-12h) was similar after administration of capmatinib with food and under fasted conditions. Distribution Capmatinib is 96% bound to human plasma proteins, independent of concentration. The apparent mean 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 higher concentrations to 0.9 (concentration 10000 ng/ml), indicating a saturation of distribution into red blood cells. Capmatinib crosses the blood-brain barrier (see section 5.3). Biotransformation In vitro and in vivo studies indicated that capmatinib is cleared mainly through metabolism driven by cytochrome P450 (CYP) 3A4 (40-50%) and aldehyde oxidase (40%). The biotransformation of capmatinib occurs essentially by Phase I metabolic reactions including C-hydroxylation, lactam formation, N-oxidation, N-dealkylation, carboxylic acid formation, and combinations thereof. Phase II reactions involve glucuronidation of oxygenated metabolites. The most abundant radioactive component in plasma is unchanged capmatinib (42.9% of radioactivity AUC0-12h). The major circulating metabolite, M16 (CMN288), is pharmacologically inactive and accounts for 21.5% of the radioactivity in plasma AUC0-12h. Elimination The effective elimination half-life (calculated based on geometric mean accumulation ratio) of capmatinib is 6.54 hours. The geometric mean steady-state apparent oral clearance (CLss/F) of capmatinib was 19.8 litres/hour. Capmatinib is eliminated mainly through metabolism, and subsequent faecal excretion. Following a single oral administration of [14C]-capmatinib capsule to healthy subjects, 78% of the total radioactivity was recovered in the faeces and 22% in the urine. Excretion of unchanged capmatinib in urine is negligible. Special populations Elderly No overall differences in the safety or effectiveness were observed between patients aged 65 and 75 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. Renal impairment 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 to 89 ml/min), and 94 patients with moderate renal impairment (CLcr 30 to 59 ml/min), mild or moderate renal impairment had no clinically significant effect on the exposure of capmatinib. Tabrecta has not been studied in patients with severe renal impairment (CLcr 15 to 29 ml/min) (see section 4.2). Hepatic impairment 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 systemic exposure (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% in subjects with severe (N=6) hepatic impairment compared to subjects with normal (N=9) hepatic function. Cmax was decreased by approximately 28% and 17% in subjects with mild and moderate hepatic impairment, respectively, compared to subjects with normal hepatic function, while Cmax was similar (increased by 2%) in subjects with severe hepatic impairment compared to subjects with normal hepatic function. Mild, moderate or severe hepatic impairment had no clinically significant effect on the exposure of capmatinib. Pharmacokinetic/pharmacodynamic relationship Capmatinib exposure-response relationships and the time course of the pharmacodynamic response are unknown. In vitro evaluation of medicinal product

Repeated-dose toxicity Repeat-dose toxicity studies conducted in rats and cynomolgus monkeys revealed the following target organs or systems: pancreas, brain/central nervous system (CNS), liver, and potentially the kidney. Reversible findings in the pancreas were observed in rats and monkeys in 28-day and 13-week studies, including pancreatic acinar cell vacuolation and/or apoptosis without inflammation, occasionally accompanied by increased amylase or lipase. In rats, the doses of 60 mg/kg/day or higher in males and 30 mg/kg/day or higher in females showed reversible low-grade pancreatic changes in 28-day and/or 13-week studies. In monkeys, pancreatic findings included reversible low-grade acinar cell apoptosis in all groups with higher serum amylase at the high dose of 150 mg/kg/day in the 28-day study, and increases in amylase and lipase in a small number of animals at 75 mg/kg/day in the 13-week study. Signs indicative of CNS toxicity (such as tremors and/or convulsions), and histopathological findings of white matter vacuolation in the thalamus were observed in rats at a dose of 60 mg/kg/day for females and 120 mg/kg/day for males in a 28- day toxicity study (at doses = 2.2 times the human exposure based on AUC at the 400 mg twice daily clinical dose). Additionally, results from a 13-week rat toxicity study reproduced the CNS effects and histopathological findings in the brain, and also demonstrated that the CNS effects and brain lesions were reversible. No signs of CNS toxicity or brain abnormalities were observed in cynomolgus monkey studies. Slight changes in serum liver enzymes (ALT, AST, and/or SDH) were observed in several different studies in rats and monkeys. These changes were restricted to highly variable, minimal-to-mild elevations lacking a clear dose response. These liver enzyme elevations were mostly observed in the absence of any histological correlate within the liver, with the exception of a 13-week monkey study, which showed a reversible, minimal-to-mild subcapsular neutrophilic infiltration associated with single cell necrosis in males at 75 mg/kg/day. Histopathologic changes were observed in the kidneys in a 28-day monkey study where mild-to-moderate deposits of amphophilic, crystalline-like material surrounded by multinucleated giant cells within the renal interstitium and/or tubular lumen were present at a dose of 75 mg/kg/day and higher. However, in a 13-week monkey study, renal precipitates or kidney toxicity was not observed at any doses tested (up to 75 mg/kg/day). Follow-up investigations on the identity of the crystalline-like material indicated that the material is not capmatinib or its metabolites, but rather calcium phosphate precipitates. No effects on male and female reproductive organs occurred in general toxicology studies conducted in rats and monkeys at doses resulting in exposures of up to approximately 3.6 times the human exposure based on AUC at the 400 mg twice daily clinical dose. Safety pharmacology Safety pharmacology studies with capmatinib indicated no significant effects on CNS and respiratory functions in rats, and no effects on cardiovascular function in monkeys. Capmatinib inhibited hERG potassium current by 50% at 18.7 microM. Carcinogenicity and mutagenicity Carcinogenicity studies with capmatinib have not been conducted. Capmatinib was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) and did not cause chromosomal aberrations in the in vitro chromosome aberration assay in human peripheral blood lymphocytes. Capmatinib was not clastogenic in the in vivo bone marrow micronucleus test in rats. Photosensitivity In vitro and in vivo photosensitization assays with capmatinib suggested that capmatinib has the potential for photosensitization. The no-observed-adverse-effect- level (NOAEL) for in vivo photosensitization was 30 mg/kg/day (Cmax of 14,000 ng/mL), about 2.9 times the human Cmax at the 400 mg twice daily clinical dose. Reproductive toxicity In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of capmatinib up to 30 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis. At 30 mg/kg/day in rats and 60 mg/kg/day in rabbits, the maternal systemic exposure (AUC) was approximately 1.4 and 1.5 times, respectively, the exposure in humans at the MRHD of 400 mg twice daily. In rats, maternal toxicity (reduced body weight gain and food consumption) was observed at the dose of 30 mg/kg/day. Fetal effects included reduced fetal weights, irregular/incomplete ossification, and increased incidences of fetal malformations (e.g. abnormal flexure/inward malrotation of hindpaws/forepaws, thinness of forelimbs, lack of/reduced flexion at the humerus/ulna joints, narrowed or small tongue) at doses of =10 mg/kg/day (with maternal systemic exposure at 0.56 times the exposure in humans at the MRHD of 400 mg twice daily). In rabbits, no maternal effects were detected at doses up to 60 mg/kg/day. Fetal effects included small lung lobe at =5 mg/kg/day (with systemic exposure at 0.016 times the exposure in humans at the MRHD of 400 mg twice daily), and reduced fetal weights, irregular/incomplete ossification and increased incidences of fetal malformations (e.g. abnormal flexure/malrotation of hindpaws/forepaws, thinness of forelimbs/hindlimbs, lack of/reduced flexion at the humerus/ulna joints, small lung lobes, narrowed or small tongue) at the dose of 60 mg/kg/day (with systemic exposure at 1.5 times the exposure in humans at the MRHD of 400 mg twice daily).

Tablet core Microcrystalline cellulose Mannitol Crospovidone Povidone Magnesium stearate Colloidal anhydrous silica Sodium laurilsulfate Film-coating 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 aluminium lidding 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 local requirements.

Feb. 16, 2026

spc-doc_PLGB 00101-1218.pdf

Bulk SPC upload Feb2026