Capmatinib

Capmatinib is an orally administered targeted anticancer medicine belonging to the class of receptor tyrosine kinase inhibitors. It selectively inhibits the mesenchymal-epithelial transition factor, commonly known as MET, which is involved in signaling pathways that regulate cell growth, survival, movement, and proliferation. Certain alterations in the MET gene, particularly mutations that cause MET exon 14 skipping, can lead to abnormal persistence and signaling of the MET protein and contribute to cancer progression. Capmatinib binds to the MET kinase domain and inhibits MET phosphorylation and downstream signaling, thereby reducing MET-dependent tumor cell activity. It is available as film-coated tablets and is generally taken twice daily, with or without food. Its principal clinical role is in adults with advanced or metastatic non-small cell lung cancer whose tumors have a confirmed MET exon 14 skipping alteration. The molecule became clinically important because it provided a biomarker-directed treatment option for a molecularly defined subgroup of non-small cell lung cancer. Capmatinib has also demonstrated activity against intracranial disease in patients with MET exon 14 skipping-positive disease, consistent with its ability to cross the blood-brain barrier.

Capmatinib, originally developed as INC280, was developed as a selective inhibitor of the MET receptor tyrosine kinase. Its clinical development focused on identifying patients whose tumors showed MET pathway dysregulation, particularly MET exon 14 skipping alterations. The pivotal GEOMETRY mono-1 study was a multicohort phase 2 study evaluating capmatinib in advanced non-small cell lung cancer with MET exon 14 skipping mutations or MET amplification. The United States Food and Drug Administration approved capmatinib on May 6, 2020, for adults with metastatic non-small cell lung cancer whose tumors have a mutation leading to MET exon 14 skipping as detected by an FDA-approved test. The original U.S. indication received accelerated approval based on overall response rate and duration of response, with subsequent verification of clinical benefit. The European Medicines Agency issued a positive CHMP opinion in April 2022 and European Union marketing authorization was granted on June 20, 2022 for advanced non-small cell lung cancer with MET exon 14 skipping alterations in the specified treatment setting. In India, the Central Drugs Standard Control Organisation listed approval of capmatinib 150 mg and 200 mg film-coated tablets on May 12, 2021 for metastatic non-small cell lung cancer with MET exon 14 skipping.

Capmatinib is used for adults with advanced or metastatic non-small cell lung cancer whose tumors harbor alterations leading to MET exon 14 skipping. In the United States, the indication is based on confirmation of the relevant MET exon 14 skipping alteration using an FDA-approved test. In the European Union, capmatinib is indicated as monotherapy for adults with advanced non-small cell lung cancer with MET exon 14 skipping alterations who require systemic therapy following prior immunotherapy and/or platinum-based chemotherapy. Treatment selection therefore depends on molecular testing rather than histology alone. Capmatinib is generally used as a targeted systemic therapy rather than as a conventional cytotoxic chemotherapy combination, although the overall treatment strategy may involve previous or subsequent anticancer therapies according to disease status and clinical judgment.

Capmatinib is administered orally as film-coated tablets and may be taken with or without food. The standard adult dosage is 400 mg twice daily on a continuous treatment schedule. Tablets should be swallowed whole rather than crushed or broken. Treatment is generally continued while clinical benefit persists and until disease progression or unacceptable toxicity, although the duration varies between patients. Dose interruption or reduction may be required when clinically significant adverse reactions occur, with lower-dose regimens used according to the severity and type of toxicity. Patient selection should be based on confirmation of a MET exon 14 skipping alteration using an appropriate validated diagnostic test. Renal and hepatic function, concomitant medicines, and treatment-related laboratory abnormalities should be considered when determining whether treatment can be continued or modified.

Common adverse effects associated with capmatinib include peripheral edema, nausea, fatigue, vomiting, musculoskeletal pain, shortness of breath, cough, decreased appetite, diarrhea, and changes in liver function tests. Peripheral swelling may involve the legs, ankles, hands, or other areas and can vary in severity. Nausea, fatigue, vomiting, and reduced appetite may affect nutritional intake and daily activities in some patients. Increased creatinine and other laboratory abnormalities can also occur. Patients should report persistent or worsening symptoms so that supportive treatment, dose interruption, or dose modification can be considered when appropriate.

Important serious risks associated with capmatinib include interstitial lung disease or pneumonitis, hepatotoxicity, pancreatic toxicity, serious hypersensitivity reactions, photosensitivity, and embryo-fetal toxicity. Interstitial lung disease or pneumonitis may present with new or worsening cough, shortness of breath, fever, or other respiratory symptoms and requires prompt clinical assessment; permanent discontinuation is recommended when this toxicity is confirmed according to current prescribing information. Liver injury may require regular liver function monitoring and treatment interruption, dose reduction, or discontinuation depending on severity. Amylase and lipase should be monitored because pancreatic toxicity can occur. Hypersensitivity may present with fever, chills, itching, rash, low blood pressure, nausea, or vomiting. Patients should also be counselled about limiting excessive ultraviolet exposure because capmatinib may increase photosensitivity. Because capmatinib can cause fetal harm, pregnancy and reproductive considerations should be addressed before and during treatment.

Before starting capmatinib, molecular testing should confirm the relevant MET exon 14 skipping alteration and baseline clinical assessment should include liver function, pancreatic enzymes, renal status, respiratory symptoms, concomitant medications, and pregnancy potential where applicable. Liver function tests and amylase and lipase should be monitored regularly during treatment, while new or worsening respiratory symptoms require prompt evaluation for interstitial lung disease or pneumonitis. Capmatinib can interact with medicines that affect CYP3A activity, and strong or moderate CYP3A inducers should generally be avoided because they can reduce capmatinib exposure. Strong or moderate CYP3A inhibitors may increase capmatinib exposure and require careful consideration. Capmatinib can also affect certain drug-metabolizing or transporter pathways, so concomitant medicines with narrow therapeutic ranges should be reviewed carefully. Patients should limit direct ultraviolet exposure and use appropriate protective measures. Pregnancy should be avoided during treatment because of potential embryo-fetal toxicity, and breastfeeding is not recommended during therapy.

Prescribers should confirm the MET exon 14 skipping alteration using an appropriate validated molecular diagnostic method before initiating treatment. Baseline liver function, amylase, lipase, renal function, respiratory status, pregnancy potential where relevant, and the complete medication list should be reviewed. During therapy, liver tests and pancreatic enzymes should be monitored periodically, while respiratory symptoms should be assessed promptly because interstitial lung disease or pneumonitis can be serious. Pharmacists should review concomitant medicines for CYP3A interactions and other clinically relevant transporter or enzyme effects, particularly when medicines with narrow therapeutic windows are involved. Patients should be counselled to take the tablets consistently twice daily, report new breathing difficulty, persistent nausea or vomiting, jaundice, severe abdominal symptoms, or hypersensitivity symptoms promptly, and use sun-protection measures. Dose interruptions and reductions should follow the severity-specific recommendations in the current prescribing information rather than being managed independently by the patient.