crizotinib and Edema

Anaplastic lymphoma kinase 1 (ALK-1) is a member of the insulin receptor tyrosine kinase family. In clinical practice, three small molecule inhibitors of ALK-1 are used, namely crizotinib, ceritinib and alectinib. Several more agents are in active pre-clinical and clinical studies. Crizotinib is approved for the treatment of advanced ALK-positive non-small cell lung cancer (NSCLC). According to the package insert and published literature, treatment with crizotinib appears to be associated with kidney failure as well as an increased risk for the development and progression of renal cysts. In addition, this agent is associated with development of peripheral edema and rare electrolyte disorders. This review focuses on the adverse renal effects of Crizotinib in clinical practice.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Crizotinib; Cysts; Edema; Humans; Kidney; Kidney Diseases; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Alectinib--a highly selective, CNS-active, ALK inhibitor-showed promising clinical activity in crizotinib-naive and crizotinib-resistant patients with ALK-rearranged (ALK-positive) non-small-cell lung cancer (NSCLC). We aimed to assess the safety and efficacy of alectinib in patients with ALK-positive NSCLC who progressed on previous crizotinib.. We did a phase 2 study at 27 centres in the USA and Canada. We enrolled patients aged 18 years or older with stage IIIB-IV, ALK-positive NSCLC who had progressed after crizotinib. Patients were treated with oral alectinib 600 mg twice daily until progression, death, or withdrawal. The primary endpoint was the proportion of patients achieving an objective response by an independent review committee using Response Evaluation Criteria in Solid Tumors, version 1.1. Response endpoints were assessed in the response-evaluable population (ie, patients with measurable disease at baseline who received at least one dose of study drug), and efficacy and safety analyses were done in the intention-to-treat population (all enrolled patients). This study is registered with ClinicalTrials.gov, number NCT01871805. The study is ongoing and patients are still receiving treatment.. Between Sept 4, 2013, and Aug 4, 2014, 87 patients were enrolled into the study (intention-to-treat population). At the time of the primary analysis (median follow-up 4·8 months [IQR 3·3-7·1]), 33 of 69 patients with measurable disease at baseline had a confirmed partial response; thus, the proportion of patients achieving an objective response by the independent review committee was 48% (95% CI 36-60). Adverse events were predominantly grade 1 or 2, most commonly constipation (31 [36%]), fatigue (29 [33%]), myalgia 21 [24%]), and peripheral oedema 20 [23%]). The most common grade 3 and 4 adverse events were changes in laboratory values, including increased blood creatine phosphokinase (seven [8%]), increased alanine aminotransferase (five [6%]), and increased aspartate aminotransferase (four [5%]). Two patients died: one had a haemorrhage (judged related to study treatment), and one had disease progression and a history of stroke (judged unrelated to treatment).. Alectinib showed clinical activity and was well tolerated in patients with ALK-positive NSCLC who had progressed on crizotinib. Therefore, alectinib could be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib.. F Hoffmann-La Roche.

Topics: Adult; Aged; Alanine Transaminase; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Aspartate Aminotransferases; Carbazoles; Carcinoma, Non-Small-Cell Lung; Constipation; Creatine Kinase; Crizotinib; Drug Resistance, Neoplasm; Edema; Fatigue; Female; Humans; Lung Neoplasms; Male; Middle Aged; Myalgia; Piperidines; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Response Evaluation Criteria in Solid Tumors; Retreatment

Small molecule mesenchymal-epithelial transition (MET) inhibitors, such as crizotinib, capmatinib, and tepotinib, are treatment options for metastatic non-small cell lung cancer (NSCLC) in adult patients whose tumors have a mutation that leads to MET exon 14 skipping. In clinical trials, these MET inhibitors were associated with a high incidence of peripheral edema, although this was generally mild-to-moderate in severity. There is limited information about the mechanism involved in MET inhibitor-induced peripheral edema. Perturbation of hepatocyte growth factor (HGF)/MET signaling may disrupt the permeability balance in the vascular endothelium and thus promote edema development. Another potential mechanism is through effects on renal function, although this is unlikely to be the primary mechanism. Because edema is common in cancer patients and may not necessarily be caused by the cancer treatment, or other conditions that have similar symptoms to peripheral edema, a thorough assessment is required to ascertain the underlying cause. Before starting MET-inhibitor therapy, patients should be educated about the possibility of developing peripheral edema. Patient limb volume should be measured before initiating treatment, to aid assessment if symptoms develop. Since the exact mechanism of MET inhibitor-induced edema is unknown, management is empiric, with common approaches including compression stockings, specific exercises, massage, limb elevation, and/or diuretic treatment. Although not usually required, discontinuation of MET inhibitor treatment generally resolves peripheral edema. Early diagnosis and management, as well as patient information and education, are vital to decrease the clinical burden associated with edema, and to reinforce capmatinib treatment adherence.

Topics: Adult; Benzamides; Carcinoma, Non-Small-Cell Lung; Crizotinib; Diuretics; Edema; Exons; Hepatocyte Growth Factor; Humans; Imidazoles; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Triazines