Capmatinib

Capmatinib is an inhibitor of the MET receptor tyrosine kinase. In some lung cancers, mutations that cause skipping of MET exon 14 remove a regulatory part of the receptor, so the mutant MET is less able to switch itself off and its downstream signalling is pathologically increased. Capmatinib blocks this signalling.

Mechanism of Action

• MET inhibition: capmatinib inhibits MET phosphorylation, both autophosphorylation and phosphorylation triggered by its ligand, hepatocyte growth factor (HGF), as well as MET-mediated phosphorylation of downstream signalling proteins.
• Effect on cancer cells: it reduces the proliferation and survival of MET-dependent cancer cells. DrugBank notes that it acts on both wild-type and mutant MET.
• Cardiac electrophysiology: capmatinib did not prolong the QT interval to a clinically relevant extent at the recommended dose.

Pharmacokinetics

• Absorption: rapid and estimated at more than 70%. Peak levels occur 1 to 2 hours after a dose when fasting (4 to 6 hours when fed). Exposure rises in proportion to dose between 200 and 400 mg twice daily, and steady state is reached after about 3 days (accumulation ratio 1.39). A high-fat meal raised the AUC by 46% with no change in Cmax, and a low-fat meal had no meaningful effect; in patients on 400 mg twice daily, exposure was similar fed or fasted.
• Distribution: 96% bound to plasma proteins, independent of concentration; apparent volume of distribution at steady state 164 L. Capmatinib crosses the blood–brain barrier.
• Metabolism: cleared mainly by CYP3A4 (40–50%) and aldehyde oxidase (about 40%), through phase I reactions and glucuronidation of oxygenated metabolites. Unchanged capmatinib is the main plasma component; the major metabolite, M16 (CMN288), is pharmacologically inactive.
• Elimination: effective half-life 6.54 hours; apparent oral clearance at steady state 19.8 L/h. After a radiolabelled dose, 78% of the radioactivity was recovered in faeces and 22% in urine, with negligible unchanged capmatinib in urine.
• Special populations: age, sex, race and body weight have no clinically relevant effect on exposure. Mild or moderate renal impairment has no clinically significant effect (severe impairment has not been studied). Mild, moderate or severe hepatic impairment had no clinically significant effect on exposure (AUC about 23% lower, 9% lower and 24% higher respectively).

• Non-small cell lung cancer with METex14 skipping: as monotherapy in adults with advanced NSCLC harbouring alterations leading to mesenchymal-epithelial transition factor gene exon 14 (METex14) skipping, who require systemic therapy following prior treatment with immunotherapy and/or platinum-based chemotherapy.
• Patient selection: the alteration must be shown in tumour tissue or plasma with a validated test. If it is not detected in plasma, tumour tissue should be tested.

• Hypersensitivity to capmatinib or to any of the excipients.

The most common reactions are peripheral oedema (68.1%), nausea (45.0%), fatigue (35.6%), increased blood creatinine (35.0%), vomiting (25.6%), dyspnoea (23.8%), decreased appetite (21.9%) and back pain (21.3%). The most common grade 3 or 4 reactions are peripheral oedema (17.5%), increased lipase (9.4%), fatigue (8.8%), increased ALT (8.1%), dyspnoea (6.9%) and increased amylase (5.6%). The frequencies below come from 160 patients with METex14 skipping mutations in the GEOMETRY mono-1 study; laboratory changes are counted as a worsening of at least one grade from baseline, so they are higher than the percentages of reported adverse events.

Very common (≥1/10): decreased appetite (21.9%); dyspnoea (23.8%), cough (17.5%); nausea (45.0%), vomiting (25.6%), diarrhoea (16.9%), constipation (13.1%); pruritus (10.6%), rash (10.0%); peripheral oedema (68.1%), fatigue (35.6%), pyrexia (11.9%), back pain (21.3%), weight decreased (12.5%); laboratory changes: decreased albumin (78.3%), increased creatinine (74.5%), increased ALT (45.9%), increased AST (33.8%), increased amylase (37.2%), increased lipase (33.3%), decreased phosphate (30.1%), decreased sodium (22.9%).

Common (≥1/100 to <1/10): cellulitis (5.6%); interstitial lung disease/pneumonitis (7.5%); urticaria (2.5%); non-cardiac chest pain (9.4%); increased bilirubin (8.3%).

Uncommon (≥1/1,000 to <1/100): hypersensitivity (0.3%), seen in patients with solid tumours treated with capmatinib alone (580 patients) and in post-marketing use and expanded-access programmes.

Serious adverse reactions occurred in 23.8% of patients (38 of 160); those in more than 2% were dyspnoea (6.3%), interstitial lung disease/pneumonitis (5.0%), cellulitis (3.1%) and peripheral oedema (3.1%). Doses were interrupted in 52.5% of patients, reduced in 33.1% and permanently stopped in 13.8%; the most frequent reasons for stopping were interstitial lung disease/pneumonitis (3.8%) and peripheral oedema (2.5%). In patients with MET amplification in the same study, acute kidney injury (1 patient), renal failure (4 patients) and acute pancreatitis (1 patient) were also reported.

Capmatinib is metabolised by CYP3A4 and aldehyde oxidase. The risk of an interaction through aldehyde oxidase has not been evaluated, as there are no confirmed clinically relevant inhibitors.

• Strong CYP3A inhibitors (clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole): itraconazole raised capmatinib AUC by 42% with no change in Cmax. Monitor closely for adverse reactions.
• Strong CYP3A inducers (carbamazepine, phenobarbital, phenytoin, rifampicin, St John’s wort): rifampicin lowered capmatinib AUC by 67% and Cmax by 56%, which may reduce anti-tumour activity. Avoid the combination and consider an alternative with no or minimal CYP3A induction.
• Moderate CYP3A inducers (for example efavirenz): modelling predicted a 44% lower AUC and 34% lower Cmax. Use with caution.
• Gastric acid-reducing agents: the proton pump inhibitor rabeprazole lowered capmatinib AUC by 25% and Cmax by 38%, without a clinically meaningful effect; a relevant interaction is unlikely.
• CYP1A2 substrates: capmatinib moderately inhibits CYP1A2 (caffeine AUC rose by 134%). With narrow therapeutic index CYP1A2 substrates such as theophylline and tizanidine, a dose reduction of the other medicine may be needed.
• CYP3A substrates: no clinically meaningful effect on a CYP3A probe substrate, so clinically relevant interactions are unlikely.
• P-gp and BCRP substrates: digoxin (P-gp) AUC rose by 47% and Cmax by 74%; rosuvastatin (BCRP) AUC rose by 108% and Cmax by 204%. Use caution with P-gp substrates (digoxin, dabigatran etexilate, colchicine, sitagliptin, saxagliptin, posaconazole) and BCRP substrates (methotrexate, rosuvastatin, pravastatin, mitoxantrone, sulphasalazine); a dose reduction may be needed for narrow therapeutic index substrates.
• Transporters, in vitro: capmatinib may inhibit the renal transporters MATE1 and MATE2K at clinically relevant concentrations.
• Food: can be taken with or without food (a high-fat meal raises exposure only slightly, not to a clinically significant extent).

Treatment should be started by a physician experienced in the use of anticancer therapies. Patients must be selected on the presence of a genetic alteration leading to METex14 skipping in tumour tissue or plasma, using a validated test; if the alteration is not detected in plasma, tumour tissue should be tested. Tablets are swallowed whole to give the full dose, with or without food; patients with swallowing difficulties are advised to take them with food.

Recommended Dose

• 400 mg twice daily (two 200 mg tablets twice daily), continued as long as the patient benefits and tolerates it.

Dose Reduction Schedule

• Starting dose: 400 mg twice daily (two 200 mg tablets).
• First reduction: 300 mg twice daily (two 150 mg tablets).
• Second reduction: 200 mg twice daily (one 200 mg tablet). Doses below 200 mg twice daily have not been investigated.

Dose Modifications for Adverse Reactions

• Interstitial lung disease/pneumonitis: permanently discontinue for any treatment-related grade.
• Isolated ALT/AST increase (no concurrent bilirubin rise): grade 3 (above 5.0 to 20.0 × ULN) withhold until recovery to baseline; if recovered within 7 days resume at the same dose, otherwise at a reduced dose. Grade 4 (above 20.0 × ULN): permanently discontinue.
• ALT/AST above 3 × ULN with total bilirubin above 2 × ULN (without cholestasis or haemolysis, irrespective of baseline grade): permanently discontinue.
• Isolated bilirubin increase (no concurrent ALT/AST rise): grade 2 (above 1.5 to 3.0 × ULN) withhold until baseline, then resume at the same dose if recovered within 7 days, otherwise at a reduced dose. Grade 3 (above 3.0 to 10.0 × ULN) withhold until baseline, then resume at a reduced dose if recovered within 7 days, otherwise permanently discontinue. Grade 4 (above 10.0 × ULN): permanently discontinue.
• Serum creatinine increase: grade 2 (above 1.5 to 3.0 × ULN) withhold until baseline, then resume at the same dose. Grade 3 (above 3.0 to 6.0 × ULN) withhold until baseline, then resume at a reduced dose. Grade 4 (above 6.0 × ULN): permanently discontinue.
• Vomiting: grade 2 withhold until grade 1 or better, then resume at the same dose. Grade 3 or 4 withhold until grade 2 or better, then resume at a reduced dose.
• Other adverse reactions: grade 2 maintain the dose, and if intolerable consider withholding until resolved and resuming at a reduced dose. Grade 3 withhold until resolved, then resume at a reduced dose. Grade 4: permanently discontinue.

Special Populations

• Elderly: no dose adjustment in patients 65 years or older.
• Renal impairment: no adjustment in mild or moderate impairment; use caution in severe impairment, which has not been studied.
• Hepatic impairment: no adjustment in mild, moderate or severe impairment.
• Children and adolescents: safety and efficacy from 0 to 18 years have not been established.

Missed or Vomited Dose

Do not make up the dose; take the next dose at the scheduled time.

Testing for METex14 Skipping

A well-validated and robust test must be used, whether on tissue or plasma, to avoid false-negative or false-positive results.

Interstitial Lung Disease/Pneumonitis

ILD/pneumonitis, which can be fatal, has occurred. Any patient with new or worsening pulmonary symptoms (such as dyspnoea, cough or fever) should be investigated promptly. Capmatinib should be withheld immediately if ILD/pneumonitis is suspected and permanently discontinued if no other potential cause is found.

Liver Function

Transaminase elevations have occurred. Liver function tests (ALT, AST and total bilirubin) should be done before the start of treatment, every 2 weeks during the first 3 months, then monthly or as clinically indicated, and more often in patients who develop elevations. Depending on severity, withhold, reduce the dose or discontinue.

Pancreatic Enzymes

Amylase and lipase elevations have occurred. Monitor them at baseline and regularly during treatment; withhold, reduce the dose or discontinue according to severity.

Photosensitivity

There is a potential risk of photosensitivity reactions, based on animal findings. In the pivotal study, patients limited direct ultraviolet exposure and used sunscreen, protective clothing and sunglasses, and these measures should continue for at least 7 days after the last dose.

Pregnancy, Breastfeeding and Fertility

• Contraception: sexually active women of childbearing potential must use effective contraception (methods with less than 1% pregnancy rate) during treatment and for at least 7 days after the last dose. Pregnancy status must be verified before starting. Male patients with partners who are pregnant, possibly pregnant or able to become pregnant should use condoms during treatment and for at least 7 days after the last dose.
• Pregnancy: there are no data in pregnant women. Animal studies show reproductive toxicity, and capmatinib is suspected to cause congenital malformations; it should not be used in pregnancy unless the woman’s condition requires it.
• Breastfeeding: it is unknown whether capmatinib passes into breast milk, and a risk to the infant cannot be excluded. Breastfeeding should stop during treatment and for at least 7 days after the last dose.
• Fertility: no human fertility data are available, and no animal fertility studies were done.

Excipients

The tablets contain less than 1 mmol sodium (23 mg) per dose, so they are essentially sodium-free.

Effect on Driving

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

No special temperature conditions are needed. Store in the original package to protect from moisture. The tablets are packed in PVC/PE/PVDC blisters with aluminium lidding foil, in packs of 60 or 120 tablets (not all pack sizes may be marketed).

3 years.

Prescription only (Rx), subject to restricted medical prescription (Annex II B); treatment is started by a physician experienced in the use of anticancer therapies. Tabrecta is taken at home, so it is supplied to the patient or to the treating clinic on prescription.