Management of adverse reactions to ALK inhibitors

Targeted therapy is one of the most important treatments for lung cancer patients. The emergence and iteration of targeted drugs bring the hope of long-term survival to patients with positive driver genes. Among them, ALK fusion is known as the diamond mutation of lung cancer patients. The wide use of ALK-TKI, a targeted drug for ALK gene, has made lung cancer truly chronic, and most patients can return to normal social life. At present, China is one of the countries with the largest number of ALK-TKI accessible drugs. In addition to the imported targeted drugs Crizotinib, Seratinib, Aletinib, Bugatinib and Loratinib, the domestic new drugs Ensatinib, Iruak and Evenak are also on the market one after another, bringing more treatment options to patients with ALK fusion non-small cell lung cancer in China. Retrospective studies have found that the median survival time of ALK-positive patients has exceeded 7 years or even longer. At this stage, the goal of advanced non-small cell lung cancer is to prolong life and improve the quality of life. Targeted drugs not only focus on efficacy, but also need to monitor adverse reactions and deal with them in time. Adverse reactions will not only affect the compliance of patients with treatment, lead to the cessation of treatment, increase the burden of treatment, but also affect the quality of life of patients. Expert consensus is that the management of adverse reactions is an important part of clinical practice to optimize the quality of life. Different ALK-TKIs have different adverse reaction spectra. In long-term treatment, not only doctors, but also patients themselves need to be very familiar with drug-related adverse reactions, check regularly, detect drug-related adverse reactions in the early stage, and deal with them in time to ensure efficacy and safety. Studies have shown that the incidence of adverse reactions of different ALK-TKIs is similar, and the proportion of discontinuation due to adverse reactions is also similar. ALK-TKI has common general adverse reactions, including gastrointestinal toxicity, hepatotoxicity, pulmonary adverse reactions, hematotoxicity, edema, fatigue, etc., as well as specific adverse reactions, such as visual Zhang’an, nervous system adverse reactions, renal toxicity, hyperlipidemia, etc. These adverse reactions are introduced here to facilitate patient familiarity and understanding, as well as self-monitoring. Adverse reactions are generally divided into 1-4 grades according to the severity, and different grades have different treatment principles. (1) Common adverse reactions 1. Gastrointestinal adverse reactions: mainly diarrhea, nausea and vomiting. The highest incidence of serious gastrointestinal adverse reactions is about 5%. For mild gastrointestinal reactions, antidiarrheal and antiemetic symptomatic treatment is recommended; for moderate gastrointestinal reactions, it is recommended to stop the drug temporarily and give symptomatic treatment at the same time, and re-administer the drug after recovery. For severe adverse reactions, hospitalization may be required. It should be differentiated from other digestive system diseases, and the dosage should be reduced after recovery. 2. Hepatotoxicity: It is mainly the increase of glutamic-pyruvic transaminase, glutamic-oxaloacetic transaminase and bilirubin. The higher incidence is common in Seratinib, Crizotinib, Aletinib, etc. Once liver injury occurs, mild maintenance of the original drug regimen combined with liver protection drugs, moderate timely withdrawal of targeted drugs, liver protection, if necessary, corticosteroid therapy, severe hepatic encephalopathy, decompensated cirrhosis, liver transplantation can be considered. 3. Hematotoxicity: anemia is the most common. The incidence of aletinib, loratinib, seratinib, and ensatinib was slightly higher. Mild anemia can be supplemented with hematopoietic raw materials, such as iron, vitamin C, folic acid, etc. Moderate anemia can be treated with erythropoietin if the administration is suspended, and targeted drug therapy can be continued after recovery; moderate anemia can be treated with blood transfusion, and reduced treatment is recommended after recovery. 4. Pulmonary adverse reactions: Interstitial lung disease is the most common, and the incidence of bugatinib is slightly higher. Once interstitial pneumonia is suspected, it is recommended to stop targeted drugs immediately, start glucocorticoid therapy immediately, supplement calcium and vitamin D, monitor blood sugar, and prevent gastrointestinal bleeding. Replacement of targeted drug therapy is recommended in the future. (2) Specific adverse reactions 1. Crizotinib-related: visual disturbances (reported incidence of 73.1%), prolonged QT interval, decreased neutrophil; 2. Serotinib-related: gastrointestinal reactions, hyperglycemia, increased amylase, increased lipase; 3. Aletinib-related: increased blood creatine kinase, edema, photosensitive dermatitis, and increased total bilirubin. 4. Bugtinib-related: hypertension, increased blood creatine kinase, lipase, amylase; 5. Ensatinib-related: rash, pruritus, increased serum creatinine; 6. Loratinib-related: hyperlipidemia, central nervous system toxicity (affective disorders, cognitive dysfunction, speech changes, etc.), peripheral nervous system toxicity. The above are the adverse drug reactions that patients need to continuously pay attention to in ALK targeted drug therapy. It is suggested that different regular visits should be carried out according to the different targeted drugs used, so as to avoid serious adverse reactions while achieving curative effect. It is hoped that the above contents can help patients with long-term disease management.