Alectinib

Alectinib is an orally administered targeted anticancer medicine belonging to the anaplastic lymphoma kinase tyrosine kinase inhibitor class. It selectively inhibits ALK signaling, including abnormal ALK fusion proteins that can drive the growth and survival of cancer cells in ALK-positive non-small cell lung cancer. Alectinib also has activity against several ALK mutations associated with resistance to earlier ALK inhibitors and has substantial penetration into the central nervous system, making it clinically important for patients at risk of or affected by brain metastases. It is used as monotherapy in adults with ALK-positive advanced or metastatic non-small cell lung cancer and as adjuvant treatment after complete tumor resection in eligible patients with ALK-positive disease. Alectinib is administered orally as capsules and should be taken with food. Treatment for advanced disease is generally continued until disease progression or unacceptable toxicity, while adjuvant treatment is generally administered for a defined two-year period unless recurrence or unacceptable toxicity occurs. Because alectinib can affect the liver, lungs, heart rate, muscles and kidneys, appropriate laboratory and clinical monitoring is required throughout treatment.

Alectinib was developed as a selective ALK inhibitor designed to provide activity against ALK-positive cancers, including tumors with resistance to earlier ALK-targeted therapy and disease involving the central nervous system. The medicine was first approved in Japan in 2014 for ALK-positive non-small cell lung cancer. The U.S. Food and Drug Administration granted accelerated approval for Alecensa in December 2015 for ALK-positive metastatic non-small cell lung cancer in patients whose disease had progressed on or who were intolerant to crizotinib. FDA subsequently expanded the indication in November 2017 to include ALK-positive metastatic non-small cell lung cancer without restriction to prior crizotinib treatment. On 18 April 2024, FDA approved alectinib as adjuvant treatment following tumor resection for eligible adults with ALK-positive non-small cell lung cancer. In the European Union, Alecensa received marketing authorisation on 16 February 2017 for ALK-positive advanced non-small cell lung cancer, including first-line treatment and treatment after crizotinib, and its current European indication also includes adjuvant treatment after complete tumor resection in adults at high risk of recurrence. Indian regulatory records indicate CDSCO approval for 150 mg alectinib capsules in January 2017 for metastatic ALK-positive non-small cell lung cancer after crizotinib and in March 2018 for first-line locally advanced or metastatic ALK-positive non-small cell lung cancer, with subsequent regulatory consideration of the adjuvant indication. Key clinical programmes include AF-001JP, NP28673, NP28761, J-ALEX, ALEX and ALINA.

Alectinib is used as monotherapy for adults with ALK-positive non-small cell lung cancer. In advanced or metastatic disease, it is used as an ALK-targeted treatment, including in patients who have not previously received an ALK inhibitor and in applicable settings following treatment with crizotinib. Alectinib is also used as adjuvant treatment after complete surgical resection in eligible adults with ALK-positive non-small cell lung cancer who have a significant risk of recurrence, with eligibility criteria varying according to the regulatory jurisdiction. The postoperative indication is supported by the ALINA clinical trial, which evaluated alectinib against platinum-based chemotherapy in patients with resected ALK-positive disease. Treatment selection should be based on confirmed ALK status, disease stage, previous systemic therapy, surgical status and the approved indication applicable to the specific product and jurisdiction.

Alectinib is administered orally at a recommended adult dose of 600 mg twice daily with food. Treatment for advanced or metastatic disease is generally continued until disease progression or unacceptable toxicity. For the adjuvant treatment of eligible patients after tumor resection, alectinib is generally administered at 600 mg twice daily for two years or until disease recurrence or unacceptable toxicity. Dose reductions may be required for clinically significant adverse reactions, with reduced dosing commonly progressing to 450 mg twice daily and then 300 mg twice daily when necessary. The current U.S. prescribing information recommends a reduced dose of 450 mg twice daily for patients with severe hepatic impairment. Treatment should be administered consistently with food, and capsules should be swallowed as directed rather than opened or dissolved. Dose interruption, reduction or permanent discontinuation may be required depending on the type and severity of toxicity.

Common side effects of alectinib include fatigue, constipation, muscle pain, swelling of the hands or feet, anemia, rash, nausea and changes in liver laboratory tests. Cough and other respiratory symptoms may occur, while increases in creatine phosphokinase can be associated with muscle-related adverse effects. In patients receiving alectinib after surgery, commonly reported adverse reactions also include hepatotoxicity, constipation, myalgia, fatigue, rash and cough. The frequency and severity of adverse effects can vary according to the treatment setting, duration of therapy and individual patient factors. Many adverse reactions can be managed with supportive treatment, laboratory monitoring, dose interruption or dose reduction under medical supervision.

Important serious risks associated with alectinib include hepatotoxicity, interstitial lung disease or pneumonitis, symptomatic bradycardia, severe myalgia and marked creatine phosphokinase elevation, hemolytic anemia and renal impairment. Liver injury can require treatment interruption, dose modification or permanent discontinuation depending on the severity of laboratory abnormalities. New or worsening respiratory symptoms such as cough, shortness of breath or fever require evaluation for possible interstitial lung disease or pneumonitis. Alectinib can reduce heart rate and may cause clinically significant bradycardia, particularly in patients receiving other medicines that affect heart rate. Muscle pain or weakness accompanied by substantial creatine phosphokinase elevation requires appropriate assessment. Hemolytic anemia and kidney-related toxicity should also be considered when compatible clinical or laboratory findings develop. Alectinib can cause fetal harm, and appropriate pregnancy prevention measures are required for patients who may become pregnant.

Before starting treatment, healthcare professionals should confirm ALK-positive disease using an appropriate validated diagnostic test and assess baseline liver function, kidney function, blood counts and relevant cardiovascular history. Liver laboratory tests should be monitored regularly, particularly during the early months of treatment, and creatine phosphokinase should be assessed periodically and when unexplained muscle symptoms occur. Heart rate and blood pressure should be monitored when clinically appropriate, particularly in patients receiving other medicines that can cause bradycardia. Patients should be assessed promptly for new respiratory symptoms because interstitial lung disease or pneumonitis can require permanent treatment discontinuation. Alectinib is metabolized primarily through CYP3A pathways, and strong CYP3A inhibitors or inducers may alter exposure, although the effect of moderate CYP3A inhibitors is generally less clinically significant. Medication review should include drugs that can lower heart rate or otherwise increase the risk of clinically relevant interactions. Effective contraception is recommended for patients who may become pregnant, and breastfeeding is generally not recommended during treatment.

Prescribers should confirm ALK status, disease stage, treatment setting and the applicable regulatory indication before initiating alectinib. Baseline assessment should include liver function, renal function, complete blood count, creatine phosphokinase and cardiovascular status, with additional assessment based on the patient's clinical history. Liver tests should be monitored regularly, especially during the initial months of therapy, while creatine phosphokinase should be evaluated when muscle pain, tenderness or weakness develops. Heart rate should be monitored in patients at risk of bradycardia or receiving medicines that can reduce heart rate. Patients should be counselled to report new or worsening cough, breathing difficulty, severe muscle symptoms, marked weakness, jaundice, dark urine, dizziness or fainting. Pharmacists should verify the twice-daily schedule, administration with food, formulation, potential CYP3A interactions and any required dose modifications before dispensing. For adjuvant treatment, coordination between oncology, thoracic surgery and pharmacy teams can help maintain appropriate treatment duration and toxicity monitoring.