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Background: Crizotinib was approved to treat patients with advanced non-small cell lung cancer (aNSCLC) with ROS proto-oncogene 1 (ROS1) gene fusion in 2016. We conducted a systematic literature review to identify real-world evidence (RWE) studies and estimated the efficacy and safety of crizotinib using meta-analyses (MA) for objective response rate (ORR), real-world progression-free survival (PFS), and overall survival (OS)., Methods: We searched MEDLINE®, Embase, and Cochrane CENTRAL from January 2016 to March 2023 using Ovid® for published single-arm or comparative RWE studies evaluating patients (N ≥ 20) receiving crizotinib monotherapy for aNSCLC with ROS1 gene fusion. Pooled estimates for ORR and grade 3/4 adverse events (AEs) were derived using the metafor package in R while pooled estimates for median real-world PFS (rwPFS) and OS were derived using reconstructed individual patient data from published Kaplan-Meier curves. The primary analysis included all studies regardless of crizotinib line of therapy; a subgroup analysis (SA) was conducted using studies evaluating patients receiving first-line crizotinib., Results: Fourteen studies met the eligibility criteria and were considered feasible for MA. For the primary analysis, the pooled ORR (N = 9 studies) was 70.6 % (95 % confidence interval [CI]: 57.0, 81.3), median rwPFS was 14.5 months (N = 11 studies), and OS was 40.2 months (N = 9 studies). In the SA, the pooled ORR (N = 4 studies) was 81.1 % (95 % CI: 76.1, 85.2) and the median rwPFS (N = 4 studies) and OS (N = 2 studies) were 18.1 and 60 months, respectively. All MAs were associated with significant heterogeneity (I 2  > 25 %). Grade 3/4 AEs occurred in 18.7 % of patients (pooled estimate)., Conclusion: The results from this study are consistent with clinical trial data and, taken collectively, supports crizotinib as a safe and effective treatment across different lines of therapy in patients with ROS1 aNSCLC in the real-world setting., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Ernest Nadal is a consultant for and receives research funding from Pfizer. Nada Rifi and Hannah Le are employees of Pfizer and own Pfizer stock. Imtiaz A. Samjoo, Sarah Kane, Sokhna Mbacke, Lindsey Starkman, and Beatrice Suero are employees of EVERSANA, Canada, a paid consultant to Pfizer in connection with the development of this manuscript. EN is a consultant for and receives research funding from Pfizer. NR and HL are employees of Pfizer and own Pfizer stock. IAS, SK, SM, LS, and BS are employees of EVERSANA, Canada, a paid consultant to Pfizer in connection with the development of this manuscript., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor and is prevalent among children and adolescents. In recent years, following the emergence of high-throughput sequencing techniques, rearrangements in genes, such as ALK, ROS1, NTRK, RET, and PDGFRβ, have been detected in a considerable proportion of IMT patients. However, the practice of targeted therapy for those patients remains extremely limited. In this study, we report about a 14-year-old boy diagnosed with pulmonary IMT with a mass measuring 12 × 8 cm in the right lower lobe., Materials and Methods: Immunohistochemistry (IHC) assay and comprehensive next-generation sequencing (NGS) were performed on the biopsied tumor tissue., Results: The IHC assay revealed an ALK-negative tumor, while NGS detected aTFG-ROS1 rearrangement. The patient achieved continuous remission after treatment with crizotinib (250 mg, bid)., Conclusion: This case broadens the experience regarding targeted therapy forROS1-rearranged IMT and supports the use of broad molecular profiling testing for optimizing therapeutic options., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: Crizotinib is a standard treatment for advanced anaplastic lymphoma kinase (ALK)- or ROS1-fusion-gene-positive non-small cell lung cancer; however, serious adverse events (AEs), including elevated alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and interstitial lung disease (ILD), develop occasionally. Here, we evaluated relationships between clinically significant crizotinib-associated AEs and germline variations., Materials and Methods: DNA obtained from 75 patients allowed selection of 147 genes according to function, exon identification and sequencing, and determination of germline single nucleotide variants (SNVs). Correlations between clinically significant AEs and presence of germline variants were estimated by Fisher's exact test., Results: We defined clinically significant AEs as grade 4 hematological toxicity, grade ≥3 non-hematological toxicity, and any grade of ILD. These AEs were observed in 26 patients (35%), with elevated AST/ALT (15%) the most common, followed by neutropenia (5%), ILD (4%), and thromboembolic events (4%). Nonsynonymous SNVs in epoxide hydrolase 1 (EPHX1) [odds ratio (OR): 3.86; p = 0.0009) and transcription factor 7-like 2 (TCF7L2) (OR: 2.51; p = 0.025) were associated with the presence of clinically significant AEs., Conclusion: Nonsynonymous EPHX1 and TCF7L2 SNVs might be associated with clinically significant crizotinib-associated AEs. These data indicated that target-gene sequencing could be feasible for predicting anticancer-agent toxicity, and that germline multi-gene information might be useful for predicting patient-specific AEs to promote precision medicine., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: The tyrosine kinase inhibitor crizotinib may affect renal function. The mechanism of this effect is not understood. We aimed to get more insight by measuring renal hemodynamics in patients treated with crizotinib., Materials and Methods: Renal hemodynamics (i.e. glomerular filtration rate and effective renal plasma flow) were measured with radioactive tracers in three patients with stage IV non small-cell lung cancer during treatment with crizotinib. The results were compared with simultaneous creatinine based renal function measurements in the same patients., Results: Patients had been treated with crizotinib between 155 and 320 days at the first measurement. In one patient the measurement was repeated after a total of one year and two months of treatment. All patients had been treated with chemotherapy containing cisplatin before. In these patients true glomerular filtration rate was 64-83% higher than estimated by creatinine based measurements. Filtration fraction, a measure of glomerular pressure, was increased in all three patients. The glomerular pressure was even further increased in a follow-up measurement., Conclusion: Creatinine-based estimates of GFR on crizotinib may underestimate the true GFR. However, evidence of increased glomerular pressure may increase risk of long term true nephrotoxicity., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

We present a 45-year-old patient diagnosed with anaplastic lymphoma kinase (ALK)-rearranged metastatic lung cancer who developed grade 4 interstitial lung disease (ILD) while on crizotinib treatment and was lately treated with brigatinib with no reappearance of ILD. To our knowledge, this is the first case report of successful treatment with brigatinib after crizotinib-induced ILD. Even though ILD secondary to brigatinib has been reported in clinical trials, no pulmonary toxicity has been seen in our patient, suggesting no crosslink lung toxicity between crizotinib and brigatinib., (Copyright © 2018 Elsevier B.V. All rights reserved.)