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Objective: The main adjuvant therapies for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer include ALK tyrosine kinase inhibitors (TKI) and chemotherapy. We aimed to compare differences in the incidence of thromboembolism (TE) among different treatment options., Design: Using a systematic review and Bayesian network meta-analysis (NMA)., Data Sources: We searched PubMed, Embase, Cochrane Library, ClinicalTrials.gov and Web of Science databases before 10 June 2023., Eligibility Criteria: We included published randomised controlled trials (RCT) involving comparisons of treatments between chemotherapy and ALK-TKI drugs., Data Extraction and Synthesis: Assessed risk bias with Cochrane tool. Conducted NMA with GEMTC in R, we evaluate the model fit using the deviation information criteria. Estimated posterior distribution using Markov Chain Monte Carlo, 4 chains, 10 fine-tuned iterations, 10 000 iterations per chain, total 50 000 iterations. Monitored potential scale reduction factor for convergence. And checked convergence with Gelman-Rubin statistics and trace plot. Provided surface under the cumulative ranking, lower values indicate less TE event probability., Results: Analysis of eight RCTs showed that, compared with that for crizotinib, there was a lower risk of total TE with chemotherapy (OR, 0.28; 95% credible intervals (CrI) 0.11 to 0.63), brigatinib (OR 0.31; 95% CrI 0.11 to 0.79) and ceritinib (OR 0.13; 95% CrI 0.03 to 0.45). In addition, analysis of venous TE (VTE) showed similar results, with a lower occurrence for chemotherapy (OR 0.27; 95% CrI 0.1 to 0.62), brigatinib (OR 0.18; 95% CrI 0.04 to 0.6) and ceritinib (OR 0.1; 95% CrI 0.02 to 0.43) compared with that for crizotinib. There were no significant differences in the occurrence of arterial TE among the different treatment options., Conclusion: Compared with chemotherapy, alectinib, lorlatinib, brigatinib and ceritinib, crizotinib significantly increased the risk of TE and VTE., Prospero Registration Number: CRD42023373307., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Alterations in the ALK (anaplastic lymphoma kinase) gene play a critical role in pathogenesis of anaplastic large cell lymphoma (ALCL). Crizotinib is a small molecule competitive inhibitor of ALK, ROS1, and MET kinases and was approved for pediatric patients with ALK-positive relapsed or refractory, systemic ALCL, and ALK-positive unresectable, recurrent, or refractory inflammatory myofibroblastic tumors (IMT)., Procedure: Crizotinib data from pediatric patients with relapsed or refractory solid tumors, IMT, or ALCL were included in the analyses. All patients received crizotinib orally at doses ranging from 100 to 365 mg/m 2 twice daily (BID). PopPK analyses were conducted to characterize crizotinib disposition in pediatric patients. Exposure-response (ER) safety and antitumor analyses were conducted to characterize relationships between crizotinib dose or exposure with safety and antitumor activity endpoints of interest., Results: The population pharmacokinetic (popPK), ER safety, and ER antitumor analysis included 98, 110, and 36 pediatric patients, respectively. A one-compartment pharmacokinetic model with allometric scaling, first-order elimination, and first-order absorption with lag time adequately described the data. Natural log-transformed model-predicted crizotinib AUC ss (steady-state area under the concentration-time curve) demonstrated a significant, positive relationship with Grade ≥3 NEUTROPENIA and Any Grade VISION DISORDER. Crizotinib dose demonstrated a positive relationship with objective response rate., Conclusions: No significant differences in PK were identified across a wide range of ages or across tumor types, suggesting body surface area (BSA)-based dosing adequately adjusted for differences in patient size to achieve similar systemic crizotinib exposures across young children and adolescent pediatric patients. None of the myelosuppressive events except Grade ≥3 NEUTROPENIA had significant relationships identified with crizotinib dose or exposure, suggesting crizotinib is a tolerable treatment with less hematological toxicity than traditional chemotherapy regimens for pediatric patients with ALK-mutated cancers. Results from the presented analyses support the pediatric dosing recommendations in the product label., (© 2024 Wiley Periodicals LLC.)

Introduction: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are standard first- and second-line treatment for advanced ALK+ non-small cell lung cancer (NSCLC). We evaluated outcomes in patients with ALK+ NSCLC receiving third-line ALK TKI versus non-ALK-directed therapy., Methods: Flatiron Health OncoEMR data were extracted for patients with ALK+ NSCLC initiating first-line ALK TKI between January 2015 and March 2022 followed by second-line ALK TKI and third-line ALK TKI (group A) or non-TKI therapy (group B). Time-to-treatment discontinuation (TTD) and overall survival (OS) were analyzed using multivariate modelling., Results: Among patients receiving third-line ALK TKI (A, n = 85) or non-TKI therapy (B, n = 43), most received first-line crizotinib (A/B: 64%/60%) and second-line alectinib (36%/30%), ceritinib (24%/19%), or lorlatinib (15%/30%). Common third-line treatments were lorlatinib/alectinib (41%/33%) in A and immunotherapy, chemotherapy, or chemotherapy + immunotherapy (30%/28%/21%) in B. Group A versus B had longer TTD of first-line treatment (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.41-0.93; p = 0.020) and second-line treatment (HR 0.50, 95% CI 0.33-0.75; p < 0.001) and longer OS from start of first-line treatment (HR 0.32, 95% CI 0.19-0.54; p < 0.001) and second-line treatment (HR 0.40, 95% CI 0.24-0.66; p < 0.001). For third-line treatment, median TTD (A/B) was 6.2/2.4 months (HR 0.61, 95% CI 0.37-1.00; p = 0.049) and OS was 17.6/6.5 months (HR 0.57, 95% CI 0.33-0.98; p = 0.042)., Conclusions: Patients receiving third-line non-ALK-directed therapy had suboptimal outcomes on prior TKIs. Patients with longer duration of prior ALK TKI treatment appeared to benefit from third-line ALK TKIs., (© 2024. The Author(s).)

Purpose: There is a lack of real-world data in Asian populations for brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor for patients with non-small cell lung cancer (NSCLC). This study analysed real-world outcomes and dosing patterns for brigatinib in patients with crizotinib-refractory ALK+ NSCLC in South Korea., Methods: This retrospective, non-interventional, cohort study used South Korean Health Insurance and Review Assessment claims data for adults with ALK+ NSCLC who initiated brigatinib between 19 April 2019 and 31 March 2021 after receiving prior crizotinib. Patients' characteristics, time to discontinuation (TTD), time to dose reduction, overall survival (OS) and treatment adherence were assessed., Results: The study included 174 patients (56.9% male; 27.0% with a history of brain metastases). Median duration of prior crizotinib was 17 (range 0.3-48) months. Median follow-up after brigatinib initiation was 18 (range 0-34) months. Overall, 88.5% of patients received full-dose brigatinib (180 mg/day) and 93.1% of patients were adherent (proportion of days covered ≥0.8). The median TTD was 24.9 months (95% CI 15.2-not reached). The probability of continuing treatment was 63.2% at 1 year and 51.5% at 2 years. The probability of continuing at full or peak dose was 79.7% at 1 year and 75.6% at 2 years. Median OS was not reached. The 2-year OS rate was 68.7%., Conclusions: In this first nationwide retrospective study using national insurance claim data, brigatinib demonstrated real-world clinical benefit as second-line treatment after prior crizotinib in ALK+ NSCLC patients in South Korea., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and represents <2% of thyroid carcinomas. A therapeutic target for ATC is represented by anaplastic lymphoma kinase (ALK) rearrangements, involved in tumor growth. Crizotinib is an oral small-molecule tyrosine kinase inhibitor of the ALK, MET, and ROS1 kinases, approved in ALK-positive non-small cell lung cancer. Until now, the effect of crizotinib in "primary human ATC cells" (pATCs) with transforming striatin (STRN)-ALK fusion has not been reported in the literature. In this study, we aimed to obtain pATCs with STRN-ALK in vitro and evaluate the in vitro antineoplastic action of crizotinib. Thyroid surgical samples were obtained from 12 ATC patients and 6 controls (who had undergone parathyroidectomy). A total of 10/12 pATC cultures were obtained, 2 of which with transforming STRN-ALK fusion (17%). Crizotinib inhibited proliferation, migration, and invasion and increased apoptosis in 3/10 pATC cultures (2 of which with/1 without STRN-ALK), particularly in those with STRN-ALK. Moreover, crizotinib significantly inhibited the proliferation of AF cells (a continuous cell line obtained from primary ATC cells). In conclusion, the antineoplastic activity of crizotinib has been shown in human pATCs (with STRN-ALK) in preclinical studies in vitro, opening the way to future clinical evaluation in these patients.

Introduction: Iruplinalkib (WX-0593) is a new-generation, potent ALK tyrosine kinase inhibitor (TKI) that has been found to have systemic and central nervous system (CNS) efficacy in ALK-positive NSCLC. We compared the efficacy and safety of iruplinalkib with crizotinib in patients with ALK TKI-naive, locally advanced or metastatic ALK-positive NSCLC., Methods: In this open-label, randomized, multicenter, phase 3 study, patients with ALK-positive NSCLC were randomly assigned to receive iruplinalkib 180 mg once daily (7-d run-in at 60 mg once daily) or crizotinib 250 mg twice daily. The primary end point was progression-free survival (PFS) assessed by Independent Review Committee (IRC) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included PFS by investigator, objective response rate (ORR), time to response, duration of response, intracranial ORR and time to CNS progression by IRC and investigator, overall survival, and safety. An interim analysis was planned after approximately 70% (134 events) of all 192 expected PFS events assessed by IRC were observed. Efficacy was analyzed in the intention-to-treat population. Safety was assessed in the safety population, which included all randomized patients who received at least one dose of the study drugs. This study is registered with Center for Drug Evaluation of China National Medical Products Administration (CTR20191231) and Clinicaltrials.gov (NCT04632758)., Results: From September 4, 2019, to December 2, 2020, a total of 292 patients were randomized and treated; 143 with iruplinalkib and 149 with crizotinib. At this interim analysis (145 events), the median follow-up time was 26.7 months (range: 3.7-37.7) in the iruplinalkib group and 25.9 months (range: 0.5-35.9) in the crizotinib group. The PFS assessed by IRC was significantly longer among patients in the iruplinalkib group (median PFS, 27.7 mo [95% confidence interval (CI): 26.3-not estimable] versus 14.6 mo [95% CI: 11.1-16.5] in the crizotinib group; hazard ratio, 0.34 [98.02% CI: 0.23-0.52], p < 0.0001). The ORR assessed by IRC was 93.0% (95% CI: 87.5-96.6) in the iruplinalkib group and 89.3% (95% CI: 83.1-93.7) in the crizotinib group. The intracranial ORR was 90.9% (10 of 11, 95% CI: 58.7-99.8) in the iruplinalkib group and 60.0% (nine of 15, 95% CI: 32.3-83.7) in the crizotinib group for patients with measurable baseline CNS metastases. Incidence of grade 3 or 4 treatment-related adverse events was 51.7% in the iruplinalkib group and 49.7% in the crizotinib group., Conclusions: Iruplinalkib was found to have significantly improved PFS and improved intracranial antitumor activity versus crizotinib. Iruplinalkib may be a new treatment option for patients with advanced ALK-positive and ALK TKI-naive NSCLC., Funding: This study was funded by Qilu Pharmaceutical Co., Ltd., Jinan, People's Republic of China, and partly supported by the National Science and Technology Major Project for Key New Drug Development (2017ZX09304015)., Competing Interests: Disclosure Dr. Si, Ms. Mao, Dr. H. Li, Dr. L. Li, and Dr. Kang are full-time employees of Qilu Pharmaceutical Co., Ltd., Jinan, People’s Republic of China. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Relapsed and refractory ALK-positive anaplastic large cell lymphoma (ALCL) has a poor prognosis. In this report, we present 3 relapsed/refractory pediatric ALCL patients, 1 of these with central nervous system involvement. All 3 patients were treated with ALK inhibitor and achieved complete response. Both crizotinib and alectinib have shown significant activity in pediatric patients with refractory ALK-positive ALCL., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Crizotinib is highly efficacious and more tolerable than chemotherapy for ALK +  non-small-cell lung cancer (NSCLC), but its progression-free survival benefit and intracranial efficacy have limitations. Head-to-head comparisons of next-generation ALK inhibitors in patients with ALK + NSCLC progressing on crizotinib will contribute toward optimizing survival. This international, Phase III, randomized, open-label study (ALTA-3) will therefore assign patients with locally advanced or metastatic ALK + NSCLC progressing on crizotinib to receive either brigatinib 180 mg qd (7-day lead-in at 90 mg qd) or alectinib 600 mg twice daily. The primary end point is progression-free survival as assessed by a blinded Independent Review Committee; the key secondary end point is overall survival. Clinical trial registration number: NCT03596866 (ClinicalTrials.gov).

ALK targeting with tyrosine kinase inhibitors (TKIs) is a highly potent treatment option for the therapy of ALK positive non-small cell lung cancer (NSCLC). However, pharmacokinetics of TKIs leads to clinically significant drug interactions, and the interfering co-medication may hamper the anti-cancer therapeutic management. Here, we present for the first time a drug interaction profile of ALK-TKIs, crizotinib and alectinib, and immunosuppressive agent cyclosporine A in kidney transplant recipients diagnosed with ALK+ lung cancer. Based on therapeutic drug monitoring of cyclosporin A plasma level, the dose of cyclosporine A has been adjusted to achieve a safe and effective therapeutic level in terms of both cancer treatment and kidney transplant condition. Particularly, 15 years upon the kidney transplantation, the stage IV lung cancer patient was treated with the 1st-line chemotherapy, the 2nd-line ALK-TKI crizotinib followed by ALK-TKI alectinib. The successful therapy with ALK-TKIs has been continuing for more than 36 months, including the period when the patient was treated for COVID-19 bilateral pneumonia. Hence, the therapy of ALK+ NSCLC with ALK-TKIs in organ transplant recipients treated with cyclosporine A may be feasible and effective., (Copyright © 2021. Published by Elsevier B.V.)

Purpose: European Organisation for Research and Treatment of Cancer (EORTC) 90101 (CREATE) was a prospective, multicentric, non-randomised, open-label phase II basket trial to assess the efficacy and safety of crizotinib in patients with different types of cancers, including advanced inflammatory myofibroblastic tumour (IMT) with or without anaplastic lymphoma kinase (ALK) rearrangements. Here, we report updated results with long-term follow-up., Patients/methods: After central reference pathology, eligible ALK-positive and ALK-negative patients with advanced/metastatic IMT deemed incurable with surgery, radiotherapy or systemic therapy received oral crizotinib 250 mg twice daily. The ALK status was assessed centrally using immunohistochemistry and fluorescence in situ hybridisation. The primary end-point was the proportion of patients who achieved an objective response (i.e. complete or partial response). If ≥6 ALK-positive patients achieved a confirmed response, the trial would be deemed successful., Results: At data cut-off on 28th January 2021, we performed the final analysis of this trial. Of the 20 eligible and treated patients (19 of whom were evaluable for efficacy), with a median follow-up of 50 months, five were still on crizotinib treatment (4/12 ALK-positive and 1/8 ALK-negative patients). The updated objective response rate (ORR) was 66.7% (95% confidence interval [CI] 34.9-90.1%) in ALK-positive patients and 14.3% (95% CI 0.0-57.9%) in ALK-negative patients. In the ALK-positive and ALK-negative patients, the median progression-free survival was 18.0 months (95% CI 4.0-NE) and 14.3 months (95% CI 1.2-31.1), respectively; 3-year overall survival rates were 83.3% (95% CI 48.2-95.6) and 34.3% (95% CI 4.8-68.5). Safety results were consistent with previously reported data., Conclusion: These updated results confirm previous findings that crizotinib is effective, with durable responses, in patients with locally advanced or metastatic ALK-positive IMT. With further follow-up after the original primary analysis, the ORR increased, as patients derived long-term benefit and some responses converted from stable disease to partial responses., Clinical Trial Number: EORTC 90101, NCT01524926., Competing Interests: Conflict of interest statement P.S. reports no competing interest related to crizotinib, Pfizer or EORTC, received research support to the institution outside of the scope of this study and reports an advisory or consulting role outside of the scope of this study. M.K., T.S. and A.W. report no competing interest. J-Y.B. reports research support and honoraria from Pfizer outside the scope of this study. S.J.S. received honoraria from Lilly for educational activities. Si.S. reports no competing interest, research support, honoraria and advisory or consulting role outside the scope of this study. P.R. received honoraria from Pfizer outside the scope of this study. V.B., M.G.L., A.I., N.I., M.D-R., R.S., F.S., Ax.N. and An.N. report no competing interest. B.K. reports no competing interest related to crizotinib, Pfizer or EORTC, received research support to the institution outside of the scope of this study and reports an advisory or consulting role outside of the scope of this study., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Anaplastic lymphoma kinase ( ALK ) rearrangement is a well-known driver oncogene in non-small-cell lung cancer and has also been identified in other types of tumors. However, there is limited evidence on the clinical response to ALK tyrosine kinase inhibitors (TKIs), such as alectinib and crizotinib, in rare tumors with ALK fusion. We evaluated the therapeutic effect of ALK-TKIs in rare ALK -rearranged tumors., Patients and Methods: Between April 2012 and April 2019, clinical outcomes and characteristics of patients with ALK -rearranged nonlung solid tumors who received ALK-TKIs (alectinib and/or crizotinib) outside of clinical trials were reviewed. Expression and/or rearrangement of ALK was evaluated by immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing. The tumor response was assessed according to RECIST (version 1.1). Progression-free survival was estimated from initial ALK-TKI initiation until progression., Results: We identified seven patients (inflammatory myofibroblastic tumors, n = 3; ALK-positive histiocytosis, n = 1; histiocytic sarcoma, n = 1; osteosarcoma, n = 1; and parotid adenocarcinoma, n = 1), with a median age of 17 years. Two rare ALK fusions, namely, CTNNA1-AL K and ITSN2-ALK , were identified. As initial ALK-TKI therapy, five patients received alectinib and two received crizotinib. The objective response rate for the initial ALK-TKI therapy was 85.7% (95% CI, 44 to 97), including two patients who received alectinib and achieved complete response. The median progression-free survival was 8.1 months (range, 1.7 to not estimable). There were no treatment interruptions or dose reductions because of adverse events caused by alectinib., Conclusion: This study highlights the potential benefit of ALK-TKIs, especially alectinib, in patients with ALK -rearranged nonlung solid tumors., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Tadaaki Nishikawa Honoraria: AstraZeneca, Eisai Consulting or Advisory Role: Eisai Speakers' Bureau: AstraZeneca, EisaiKazuki Sudo Honoraria: AstraZeneca, PfizerEmi Noguchi Honoraria: Nippon Kayaku Speakers' Bureau: Sysmex, AstraZeneca, Pfizer, Eisai, Lilly Japan, Taiho Pharmaceutical, Chugai PharmaAyumu Arakawa Research Funding: Chugai Pharma Travel, Accommodations, Expenses: AmgenKuniko Sunami Honoraria: Sysmex, Chugai Pharma, AstraZeneca, Novartis, Eisai, Riken Genesis, LillyTakashi Kubo Consulting or Advisory Role: SysmexTakashi Kohno Consulting or Advisory Role: LOXO Oncology, Lilly Japan Research Funding: Daiichi Sankyo, SysmexNoboru Yamamoto Honoraria: AstraZeneca, Pfizer, Chugai Pharma, Bristol Myers Squibb Japan, Ono Pharmaceutical, Lilly Japan, Sysmex Consulting or Advisory Role: Eisai, Takeda, Otsuka, Boehringer Ingelheimm, CMIC, Chugai Pharma Research Funding: Chugai Pharma, Taiho Pharmaceutical, Eisai, Astellas Pharma, Novartis, Daiichi Sankyo, Lilly Japan, Boehringer Ingelheim, Takeda, Kyowa Hakko Kirin, Bayer, Pfizer, Ono Pharmaceutical, Janssen, IQVIA, Merck Sharp & Dohme, Abbvie, Bristol Myers Squibb, Merck Serono, GlaxoSmithKline, Sumitomo Dainippon, Chiome Bioscience, OtsukaKan Yonemori Honoraria: Eisai, Pfizer, AstraZeneca, Novartis, Taiho Pharmaceutical Consulting or Advisory Role: Chugai Pharma, Ono Pharmaceutical, Novartis, Eisai Research Funding: Ono Pharmaceutical No other potential conflicts of interest were reported.Tadaaki Nishikawa Honoraria: AstraZeneca, Eisai Consulting or Advisory Role: Eisai Speakers' Bureau: AstraZeneca, Eisai Kazuki Sudo Honoraria: AstraZeneca, Pfizer Emi Noguchi Honoraria: Nippon Kayaku Speakers' Bureau: Sysmex, AstraZeneca, Pfizer, Eisai, Lilly Japan, Taiho Pharmaceutical, Chugai Pharma Ayumu Arakawa Research Funding: Chugai Pharma Travel, Accommodations, Expenses: Amgen Kuniko Sunami Honoraria: Sysmex, Chugai Pharma, AstraZeneca, Novartis, Eisai, Riken Genesis, Lilly Takashi Kubo Consulting or Advisory Role: Sysmex Takashi Kohno Consulting or Advisory Role: LOXO Oncology, Lilly Japan Research Funding: Daiichi Sankyo, Sysmex Noboru Yamamoto Honoraria: AstraZeneca, Pfizer, Chugai Pharma, Bristol Myers Squibb Japan, Ono Pharmaceutical, Lilly Japan, Sysmex Consulting or Advisory Role: Eisai, Takeda, Otsuka, Boehringer Ingelheimm, CMIC, Chugai Pharma Research Funding: Chugai Pharma, Taiho Pharmaceutical, Eisai, Astellas Pharma, Novartis, Daiichi Sankyo, Lilly Japan, Boehringer Ingelheim, Takeda, Kyowa Hakko Kirin, Bayer, Pfizer, Ono Pharmaceutical, Janssen, IQVIA, Merck Sharp & Dohme, Abbvie, Bristol Myers Squibb, Merck Serono, GlaxoSmithKline, Sumitomo Dainippon, Chiome Bioscience, Otsuka Kan Yonemori Honoraria: Eisai, Pfizer, AstraZeneca, Novartis, Taiho Pharmaceutical Consulting or Advisory Role: Chugai Pharma, Ono Pharmaceutical, Novartis, Eisai Research Funding: Ono Pharmaceutical No other potential conflicts of interest were reported.Tadaaki Nishikawa Honoraria: AstraZeneca, Eisai Consulting or Advisory Role: Eisai Speakers' Bureau: AstraZeneca, Eisai Kazuki Sudo Honoraria: AstraZeneca, Pfizer Emi Noguchi Honoraria: Nippon Kayaku Speakers' Bureau: Sysmex, AstraZeneca, Pfizer, Eisai, Lilly Japan, Taiho Pharmaceutical, Chugai Pharma Ayumu Arakawa Research Funding: Chugai Pharma Travel, Accommodations, Expenses: Amgen Kuniko Sunami Honoraria: Sysmex, Chugai Pharma, AstraZeneca, Novartis, Eisai, Riken Genesis, Lilly Takashi Kubo Consulting or Advisory Role: Sysmex Takashi Kohno Consulting or Advisory Role: LOXO Oncology, Lilly Japan Research Funding: Daiichi Sankyo, Sysmex Noboru Yamamoto Honoraria: AstraZeneca, Pfizer, Chugai Pharma, Bristol Myers Squibb Japan, Ono Pharmaceutical, Lilly Japan, Sysmex Consulting or Advisory Role: Eisai, Takeda, Otsuka, Boehringer Ingelheimm, CMIC, Chugai Pharma Research Funding: Chugai Pharma, Taiho Pharmaceutical, Eisai, Astellas Pharma, Novartis, Daiichi Sankyo, Lilly Japan, Boehringer Ingelheim, Takeda, Kyowa Hakko Kirin, Bayer, Pfizer, Ono Pharmaceutical, Janssen, IQVIA, Merck Sharp & Dohme, Abbvie, Bristol Myers Squibb, Merck Serono, GlaxoSmithKline, Sumitomo Dainippon, Chiome Bioscience, Otsuka Kan Yonemori Honoraria: Eisai, Pfizer, AstraZeneca, Novartis, Taiho Pharmaceutical Consulting or Advisory Role: Chugai Pharma, Ono Pharmaceutical, Novartis, Eisai Research Funding: Ono Pharmaceutical No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Background: Crizotinib is the approved treatment for advanced non-small cell lung cancers (NSCLCs) of anaplastic lymphoma kinase (ALK) fusion. Failure of crizotinib treatment frequently involves drug intolerance or resistance. Comparison of using second-generation ALK inhibitors in this setting remains lacking., Methods: Sixty-five ALK-positive advanced NSCLC patients receiving second-generation ALK inhibitors following treatment failure of crizotinib were retrospectively analyzed for the therapeutic efficacy., Results: Forty-three (66.2%) and 22 (33.8%) patients received alectinib and ceritinib, respectively. Comparing alectinib to ceritinib treatment: the 12-month progression-free survival (PFS) rate (61.0% [95% confidence interval, 47.1 to 78.9%] vs. 54.5% [95% CI, 37.3 to 79.9%]); the hazard ratio (HR) for disease progression or death, 0.61 (95% CI, 0.31-1.17; p = 0.135). Multivariate Cox regression showed ECOG PS (0-1 vs. 2-3 HR 0.09 [95% CI, 0.02-0.33]; p < 0.001) and cause of crizotinib treatment failure (resistance vs. intolerance HR 2.75 [95% CI, 1.26-5.99]; p = 0.011) were the independent predictors for the PFS of second-generation ALK inhibitors. Treatment of alectinib, compared to ceritinib, was associated with a lower incidence of CNS progression (cause-specific HR, 0.10; 95% CI 0.01-0.78; p = 0.029) and a higher efficacy in patients whose cause of crizotinib treatment failure was intolerance (HR 0.29 [95% CI, 0.08-1.06]; p = 0.050). The most commonly noted adverse events were elevated AST/ALT in 10 (23.3%) patients treated with alectinib and diarrhea in 8 (36.4%) patients treated with ceritinib., Conclusion: Second-generation ALK inhibitors in crizotinib-treated patients showed a satifactory efficacy. Alectinib treatment demonstrated a CNS protection activity and a higher PFS in selected patients failing crizotinib treatment.

Purpose: Crizotinib is the first-line small molecule tyrosine kinase inhibitor for ALK-positive non-small cell lung cancer. In this study, a retrospective pharmacogenomics investigation was conducted to explore the relationship between genes related to RTK downstream signaling pathways and crizotinib-induced hepatic toxicity in ALK-positive NSCLC patients., Methods: The variable importance analysis of random forest algorithm was applied to identify the significant features which contribute to the crizotinib sensitivity in Cancer Cell Line Encyclopedia (CCLE) database. The KEGG and reactome pathway enrichment analysis were conducted with EnrichR. The differential expression genes were identified with R package DESeq2 in CCLE liver derived cell lines between crizotinib sensitive and resistant groups. From 2012 to 2015, 42 NSCLC patients were enrolled in this study. 90 polymorphisms were genotyped using the Sequenom Massarray system. Sequencing of HGFR (c-Met) genes was carried out on the Ion Torrent Proton., Results: In total, 66.7% NSCLC patients suffered from crizotinib-induced liver toxicity and 11.9% progressed to severe hepatic toxicity. The features with the top importance from classification and regression random forest model were enriched in RTK downstream signaling pathways (JAK/STAT, RAS/RAF/MAPK, PI3K/AKT pathways) and immune system-related pathways. Collagen family genes (COL1A1, COL1A2, COL6A1, COL5A1) and other extracellular matrix protein (TNC, TAGLN, TENM2, EDIL3, VCAN, CNN1, SH3BP4, TAGLN), which were closely related to MAPK-ERK signaling pathways, were significantly enriched in crizotinib resistant cell lines. In multiple logistic regression, STAT1 rs10208033 (T > C) was significantly associated with crizotinib-induced liver toxicity (OR = 6.733, 95% CI 1.406-32.24, P = 0.017). Compared with non-CC, OR is 5.5 (95% CI 1.219-24.81, P = 0.027) for STAT1 rs10208033 CC genotype to develop crizotinib-induced liver toxicity. Further cell viability test in human fetal hepatocyte line, L-02, reveals that the STAT1 inhibitor might protect hepatocyte cells from the toxicity caused by crizotinib., Conclusion: Polymorphism of rs10208033 is a potential biomarker for predicting crizotinib-induced hepatotoxicity. These results suggest that STAT1 plays an important role in crizotinib-induced hepatotoxicity. Further studies are needed to confirm our finding and understand the underlying mechanisms.

The inhibitor of anaplastic lymphoma kinase (ALK) crizotinib significantly increases survival in patients with ALK-positive non-small cell lung cancer (NSCLC). When evaluating crizotinib pharmacokinetics (PKs) in patients taking the standard flat oral dose of 250 mg b.i.d., interindividual PK variability is substantial and patient survival is lower in the quartile with the lowest steady-state trough plasma concentrations (C min,ss ), suggesting that concentrations should be monitored and doses individualized. We investigated whether the CYP3A inhibitor cobicistat increases C min,ss of the CYP3A substrate crizotinib in patients with low exposure. Patients with ALK-positive NSCLC of our outpatient clinic treated with crizotinib were enrolled in a phase I trial (EudraCT 2016-002187-14, DRKS00012360) if crizotinib C min,ss was below 310 ng/mL and treated with cobicistat for 14 days. Crizotinib plasma concentration profiles were established before and after a 14-day co-administration of cobicistat to construct the area under the plasma concentration-time curve in the dosing interval from zero to 12 hours (AUC 0-12 ). Patients were also monitored for adverse events by physical examination, laboratory tests, and 12-lead echocardiogram. Enrolment was prematurely stopped because of the approval of alectinib, a next-generation ALK-inhibitor with superior efficacy. In the only patient enrolled, cobicistat increased C min,ss from 158 ng/mL (before cobicistat) to 308 ng/mL (day 8) and 417 ng/mL (day 14 on cobicistat), concurrently the AUC 0-12 increased by 78% from 2,210 ng/mL*h to 3,925 ng/mL*h. Neither safety signals nor serious adverse events occurred. Pharmacoenhancement with cobicistat as an alternative for dose individualisation for patients with NSCLC with low crizotinib exposure appears to be safe and is cost-effective and feasible., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

An inflammatory myofibroblastic tumor (IMT) is a rare invasive soft tissue mass with intramuscular penetration that is primarily treated via a surgical procedure. However, with unclear boundaries and a high rate of relapse, there is no standard treatment for recurrence or unresectable tumors. It is noteworthy that approximately half of IMTs harbor genetic rearrangements of the anaplastic lymphoma kinase (ALK). ALK inhibitors have been used successfully in the treatment of IMTs with a variety of ALK fusions. Here, we present a case of a 15-year-old patient with IMT around the hip. Next-generation sequencing (NGS) revealed an LRRFIP1-ALK fusion, which has not yet been reported in the literature. Crizotinib, an ALK inhibitor, was effective in the treatment of this patient, indicating that ALK inhibitors may be effective for IMT with LRRFIP1-ALK fusions. This report expands the list of gene fusions in IMTs and highlights a new target for treatment.

Crizotinib and alectinib are anaplastic lymphoma kinase (ALK)-inhibitors indicated for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC). At the currently used fixed doses, interindividual variability in exposure is high. The aim of this study was to investigate whether minimum plasma concentrations (C min ) of crizotinib and alectinib are related to efficacy and toxicity. An observational study was performed, in which ALK-positive NSCLC patients who were treated with crizotinib and alectinib and from whom pharmacokinetic samples were collected in routine care, were included in the study. Exposure-response analyses were explored using previously proposed C min thresholds of 235 ng/mL for crizotinib and 435 ng/mL for alectinib. Forty-eight crizotinib and 52 alectinib patients were included. For crizotinib, median progression-free survival (mPFS) was 5.7 vs. 17.4 months for patients with C min  < 235 ng/mL (48%) and ≥ 235 ng/mL, respectively (P = 0.08). In multivariable analysis, C min  < 235 ng/mL resulted in a hazard ratio (HR) of 1.79 (95% confidence interval (CI), 0.90-3.59, P = 0.100). In a pooled analysis of all crizotinib patients (not only ALK-positive, n = 79), the HR was 2.15 (95% CI, 1.21-3.84, P = 0.009). For alectinib, mPFS was 12.6 months vs. not estimable (95% CI, 19.8-not estimable) for patients with C min  < 435 ng/mL (37%) and ≥ 435 ng/mL, respectively (P = 0.04). Multivariable analysis resulted in an HR of 4.29 (95% CI, 1.33-13.90, P = 0.015). In conclusion, PFS of crizotinib and alectinib treated NSCLC patients is prolonged in patients with C min  ≥ 235 ng/mL and 435 ng/mL, respectively. Therefore, therapeutic drug monitoring should be part of routine clinical management for these agents., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Lorlatinib, a third-generation inhibitor of anaplastic lymphoma kinase (ALK), has antitumor activity in previously treated patients with ALK -positive non-small-cell lung cancer (NSCLC). The efficacy of lorlatinib, as compared with that of crizotinib, as first-line treatment for advanced ALK -positive NSCLC is unclear., Methods: We conducted a global, randomized, phase 3 trial comparing lorlatinib with crizotinib in 296 patients with advanced ALK -positive NSCLC who had received no previous systemic treatment for metastatic disease. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included independently assessed objective response and intracranial response. An interim analysis of efficacy was planned after approximately 133 of 177 (75%) expected events of disease progression or death had occurred., Results: The percentage of patients who were alive without disease progression at 12 months was 78% (95% confidence interval [CI], 70 to 84) in the lorlatinib group and 39% (95% CI, 30 to 48) in the crizotinib group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.19 to 0.41; P<0.001). An objective response occurred in 76% (95% CI, 68 to 83) of the patients in the lorlatinib group and 58% (95% CI, 49 to 66) of those in the crizotinib group; among those with measurable brain metastases, 82% (95% CI, 57 to 96) and 23% (95% CI, 5 to 54), respectively, had an intracranial response, and 71% of the patients who received lorlatinib had an intracranial complete response. The most common adverse events with lorlatinib were hyperlipidemia, edema, increased weight, peripheral neuropathy, and cognitive effects. Lorlatinib was associated with more grade 3 or 4 adverse events (mainly altered lipid levels) than crizotinib (in 72% vs. 56%). Discontinuation of treatment because of adverse events occurred in 7% and 9% of the patients, respectively., Conclusions: In an interim analysis of results among patients with previously untreated advanced ALK -positive NSCLC, those who received lorlatinib had significantly longer progression-free survival and a higher frequency of intracranial response than those who received crizotinib. The incidence of grade 3 or 4 adverse events was higher with lorlatinib than with crizotinib because of the frequent occurrence of altered lipid levels. (Funded by Pfizer; CROWN ClinicalTrials.gov number, NCT03052608.)., (Copyright © 2020 Massachusetts Medical Society.)

Purpose: Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, demonstrated superior progression-free survival (PFS) and improved health-related quality of life (QoL) versus crizotinib in advanced ALK inhibitor-naive ALK-positive non-small cell lung cancer (NSCLC) at first interim analysis (99 events; median brigatinib follow-up, 11.0 months) in the open-label, phase III ALTA-1L trial (ClinicalTrials.gov identifier: NCT02737501). We report results of the second prespecified interim analysis (150 events)., Methods: Patients with ALK inhibitor-naive advanced ALK-positive NSCLC were randomly assigned 1:1 to brigatinib 180 mg once daily (7-day lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was PFS as assessed by blinded independent review committee (BIRC). Investigator-assessed efficacy, blood samples for pharmacokinetic assessments, and patient-reported outcomes were also collected., Results: Two hundred seventy-five patients were randomly assigned (brigatinib, n = 137; crizotinib, n = 138). With median follow-up of 24.9 months for brigatinib (150 PFS events), brigatinib showed consistent superiority in BIRC-assessed PFS versus crizotinib (hazard ratio [HR], 0.49 [95% CI, 0.35 to 0.68]; log-rank P < .0001; median, 24.0 v 11.0 months). Investigator-assessed PFS HR was 0.43 (95% CI, 0.31 to 0.61; median, 29.4 v 9.2 months). No new safety concerns emerged. Brigatinib delayed median time to worsening of global health status/QoL scores compared with crizotinib (HR, 0.70 [95% CI, 0.49 to 1.00]; log-rank P = .049). Brigatinib daily area under the plasma concentration-time curve was not a predictor of PFS (HR, 1.005 [95% CI, 0.98 to 1.031]; P = .69)., Conclusion: Brigatinib represents a once-daily ALK inhibitor with superior efficacy, tolerability, and QoL over crizotinib, making it a promising first-line treatment of ALK-positive NSCLC.

N-[ 18 F]fluoroacetylcrizotinib, a fluorine-18 labeled derivative of the first FDA approved tyrosine kinase inhibitor (TKI) for the treatment of Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC), crizotinib, was successfully synthesized for use in positron emission tomography (PET). Sequential in vitro biological evaluation of fluoracetylcrizotinib and in vivo biodistribution studies of [ 18 F]fluoroacetylcrizotinib demonstrated that the biological activity of the parent compound remained unchanged, with potent ALK kinase inhibition and effective tumor growth inhibition. These results show that [ 18 F]fluoroacetylcrizotinib has the potential to be a promising PET ligand for use in NSCLC imaging. The utility of PET in this context provides a non-invasive, quantifiable method to inform on the pharmacokinetics of an ALK-inhibitor such as crizotinib prior to a clinical trial, as well as during a trial in the event of acquired drug resistance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: The anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) alectinib was approved in Japan in 2014 for the treatment of ALK fusion gene-positive advanced non-small cell lung cancer (NSCLC). With the approvals of crizotinib in 2012 and ceritinib in 2017, Japan became the first country with multiple ALK TKIs available for first-line or later use in patients with ALK-positive advanced NSCLC. Here, we collected and evaluated real-world data on ALK TKI clinical usage patterns and sequencing in patients with ALK-positive NSCLC in Japan., Methods: This retrospective observational study used the Japanese Medical Data Vision database to analyze data from patients with a confirmed diagnosis of lung cancer who visited a healthcare facility in the database between April 2010 and March 2017, underwent an ALK test, received a prescription for an ALK TKI, and were at least 18 years old as of the date of the first ALK TKI prescription. There were no exclusion criteria. Descriptive analyses of demographics, baseline characteristics, ALK TKI treatment patterns and sequences, non-ALK TKI treatments received before, during, and after ALK TKI treatment, and treatment durations were reported., Results: A total of 378 patients met the inclusion criteria and were evaluated in mutually exclusive groups of patients receiving one, two, or three ALK TKIs. The initial ALK TKI prescribed was crizotinib for 52.1% of patients and alectinib for 47.9% of patients; however, the proportion of patients receiving alectinib as the initial ALK TKI increased over time following the Japanese approval of alectinib in 2014. Of the 117 patients who received two or three ALK TKIs, 106 received crizotinib as the first ALK TKI and 11 received alectinib. Before the date of the patient's first ALK TKI prescription, 153 of 378 patients (40.5%) had received chemotherapy. Of 104 patients who discontinued ALK therapy, 46.2% received chemotherapy and 5.8% received immunotherapy as their next treatment., Conclusion: At the time of this analysis, most patients who received more than one ALK TKI received crizotinib as the initial ALK TKI. Additional ALK TKIs have since been approved in Japan as first-line or later therapeutic options for patients with ALK-positive NSCLC, but the optimal sequence of ALK TKI usage remains undetermined. As new data continue to emerge, additional research will be warranted to evaluate ALK TKI sequences that do not include crizotinib as the first therapy in this patient population.

Despite the huge success of tyrosine kinase inhibitors as anticancer agents, severe side effects are a major problem. In order to overcome this drawback, the first hypoxia-activatable 2-nitroimidazole-based prodrugs of the clinically approved ALK and c-MET inhibitor crizotinib were developed. The 2-aminopyridine functionality of crizotinib (essential for target kinase binding) was considered as ideal position for prodrug derivatization. Consequently, two different prodrugs were synthesized with the nitroimidazole unit attached to crizotinib either via carbamoylation (A) or alkylation (B) of the 2-aminopyridine moiety. The successful prodrug design could be proven by docking studies and a dramatically reduced ALK and c-MET kinase-inhibitory potential. Furthermore, the prodrugs showed high stability in serum and release of crizotinib in an enzymatic nitroreductase-based cleavage assay was observed for prodrug A. The in vitro activity of both prodrugs was investigated against ALK- and c-MET-dependent or -overexpressing cells, revealing a distinct hypoxia-dependent activation for prodrug A. Finally, inhibition of c-MET phosphorylation and cell proliferation could also be proven in vivo. In summary of the theoretical, chemical and biological studies, prodrug derivatization of the 2-aminopyridine position can be considered as a promising strategy to reduce the side effects and improve the anticancer activity of crizotinib., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Although kinase-targeted drugs have achieved significant clinical success, they are frequently subject to the limitations of drug resistance, which has become a primary vulnerability to targeted drug therapy. Therefore, deciphering resistance mechanisms is an important step in designing more efficacious, antiresistant drugs. Here we studied two FDA-approved kinase drugs: Crizotinib and Ceritinib, which are first- and second-generation anaplastic lymphoma kinase (ALK) targeted inhibitors, to unravel drug-resistance mechanisms. We used an on-the-fly, function-site interaction fingerprint (on-the-fly Fs-IFP) approach, combining binding free-energy surface calculations with the Fs-IFPs. Establishing the potentials of mean force and monitoring the atomic-scale protein-ligand interactions, before and after L1196M-induced drug resistance, revealed insights into drug-resistance/antiresistant mechanisms. Crizotinib prefers to bind the wild-type ALK kinase domain, whereas Ceritinib binds more favorably to the mutated ALK kinase domain, in agreement with experimental results. We determined that ALK kinase-drug interactions in the region of the front pocket are associated with drug resistance. Additionally, we find that the L1196M mutation does not simply alter the binding modes of inhibitors but also affects the flexibility of the entire ALK kinase domain. Our work provides an understanding of the mechanisms of ALK drug resistance, confirms the usefulness of the on-the-fly Fs-IFP approach, and provides a practical paradigm to study drug-resistance mechanisms in prospective drug discovery.

Background: Targeted therapies are a standard of care for first-line treatment of Anaplastic lymphoma kinase (ALK)-rearranged non small cell lung cancer (NSCLC). Giving the rapid pace of drug discovery and development in this area, reporting of adverse effects of ALK inhibitors is crucial. Here, we report a case of osteitis induced by an ALK inhibitor mimicking bone metastasis, a previously undescribed side effect of crizotinib., Case Presentation: A 31-year-old woman with stage IV ALK-rearranged NSCLC presented with back pain after 3 months of crizotinib treatment. Diagnostic work-up showed osteitis on the 4th and 5th thoracic vertebrae, anterior soft tissue infiltration and epiduritis, without any sign of infection. Spinal cord decompression, histological removal and osteosynthesis were performed. Histologic examination showed necrosis with abundant peripheral neutrophils, no microorganism nor malignant cell. Symptoms and Computarized Tomography-abnormalities rapidly diseappeared after crizotinib withdrawal and did not recur after ceritinib onset., Conclusions: This is the first report of crizotinib-induced osteitis. Crizotinib differs from other ALK inhibitors as it targets other kinases as well, which may have been responsible for the osteitis. Crizotinib can induce rapidly extensive osteitis, which can mimic tumor progression.

Aim: This first-in-human, dose-finding study evaluated safety, pharmacokinetics and pharmacodynamics of crizotinib and established a recommended Phase II dose (RP2D) among patients with advanced solid malignancies. Patients & methods: Patients received oral crizotinib in a 3 + 3 dose escalation design. Results: Thirty-six patients received crizotinib (50 mg once daily-300 mg twice daily); maximum tolerated dose (and RP2D) was 250 mg twice daily. Most patients (89%) experienced ≥1 treatment-related adverse event. Three patients had grade 3 dose-limiting toxicities: alanine aminotransferase increased (n = 1) and fatigue (n = 2). Generally, an increase in soluble MET was found with increasing crizotinib concentrations. Conclusion: Crizotinib demonstrated a favorable safety profile. The observed pharmacodynamic effect on soluble MET provide evidence for targeted MET inhibition by crizotinib. Clinicaltrials. gov identifier: NCT00585195.

Non-small cell lung cancer with ALK rearrangements can be targeted effectively with ALK inhibitors such as crizotinib. However, cancer progression typically occurs within a year as drug resistance develops. One strategy to overcome this drug resistance is to determine if novel cytotoxic agents retain the ability to kill lung cancer cells that have developed ALK inhibitor resistance. We therefore examined curcumin, a drug with anticancer properties, and 2 s-generation curcumin derivatives (1-methyl-3,5-bis[(E)-4-pyridyl) methylidene]-4-piperidone (RL66) and 1-isopropyl-3,5-bis[(pyridine-3-yl) methylene]piperidin-4-one (RL118)) in lung cancer cell lines. The cytotoxicity of curcumin, RL66, and RL118 were tested in both ALK + lung cancer cells (H3122), crizotinib resistant ALK + cells (CR-H3122) and ALK - lung cancer cells (A549), both alone and in combination with crizotinib. ALK + cells were 2-3x more sensitive to RL66 and RL118 than ALK - cells, with the drugs' eliciting IC 50 values in the range of 0.7-1 μM in H3122 cells. Retained cytotoxic potency of the curcumin derivatives in crizotinib resistant cells indicated that mechanisms of resistance to the two drug types are independent, with resistance to ALK inhibitors not necessarily causing cross-resistance to curcumin derivatives. This was further corroborated by drug combination analysis where the effect of the drugs in combination was consistent with Bliss additivity, consistent with independent targets for crizotinib and curcumin derivatives. Results from Western blotting showed that RL118 (2 μM) inhibited p-ALK/ALK by ~50%, which was not as potent as the 90% inhibition elicited by crizotinib (0.25 μM). Since this is the primary mechanism of crizotinib cytotoxicity this provides further evidence of independent mechanisms of toxicity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Anaplastic lymphoma kinase (ALK) rearrangement, a key oncogenic driver in a small subset of non-small cell lung cancers, confers sensitivity to ALK tyrosine kinase inhibitors (TKIs). Crizotinib, a first generation ALK-TKI, has superiority to standard chemotherapy with longer progression-free survival and higher objective response rate. However, clinical benefit is limited by development of resistance, typically within a year of therapy. In this study the combined effect of crizotinib and the MEK inhibitor selumetinib was investigated in both crizotinib naïve (H3122) and crizotinib resistant (CR-H3122) ALK-positive lung cancer cells. Results showed that combination treatment potently inhibited the growth of both H3122 and CR-H3122 cells, resulting from increased apoptosis and decreased cell proliferation as a consequence of suppressed downstream RAS/MAPK signalling. The drug combination also elicited a greater than 3-fold increase in Bim, a mediator of apoptosis, and p27, a cyclin dependent kinase inhibitor compared to crizotinib alone. The results support the hypothesis that combining MEK inhibitors with ALK inhibitor can overcome ALK inhibitor resistance, and identifies Bim, PARP and CDK1 as druggable targets for possible triple drug therapy.

Background: ALK is a prognostic and predictive tumor marker in non-small cell lung carcinoma (NSCLC), and is more often found in lung adenocarcinomas., Methods: The clinical and pathological data of 87 patients confirmed to have NSCLC by pathology or cytology were selected from April 2014 to January 2017 at the Tumor Hospital of Hebei Province., Results: Of the 87 ALK-positive-patients, 47 patients were treated with oral administration of crizotinib. The objective response rate (ORR) was 61.7%, the disease control rate (DCR) was 93.6%, and the mPFS was 19 months. In an analysis of the number of metastatic sites, the patients who had more than three metastatic sites, the ORR, DCR, and mPFS were 63.9%, 94.5%, and 19 months, compared with the 45.5%, 91%, and 11 months in the patients with less sites (P = 0.040). For patients of 60 years or older, ORR and DCR were 40% and 100%, the other group was 71.9% and 90.6%, respectively(P = 0.036). The timing of treatment was analyzed. At the first application of crizotinib, ORR and DCR were 78.2% and 100% corresponding 45.8% and 87.5% at the second and final application of crizotinib group (P = 0.022). Baseline brain metastases were present in 25.5% (12/47) of patients in this study. 9 of the patients who developed disease progression during crizotinib treatment had new brain metastases or increased preexisting cranial foci. Most of them took the treatment strategy of continuing crizotinib or replacing the second/third generation ALK-TKI treatment combined with local radiotherapy for brain metastases., Conclusions: The efficacy of crizotinib in patients with advanced NSCLC is related to the number of metastatic organs, age and timing of treatment. The use of crizotinib is prone to intracranial progression, and progression of simple brain metastases is not an indication that crizotinib is discontinued. Patients will continue to benefit from combination of local radiotherapy., (Copyright © 2019. Published by Elsevier GmbH.)

Despite the initial benefit demonstrated in clinical setting with ALK inhibitors, the challenging resistant mutants (F1174L, L1196M and G1202R) invariably developed. In this work, a series of 2-aminopyridine derivatives were designed and synthesized by C-5 position incorporation of a 2-pyridone moiety and bioisosteric replacement of the C-3 position linkers. Optimization of the 2-aminopyridine derivatives led to the identification of hit 18d displaying a significant growth inhibition against a variety of ALK-addicted cancer cells. Especially in the case of ALK-positive Karpas-299 cell, 18d exhibited excellent anti-proliferative potency with an IC 50 value of about 40 nM. Moreover, 18d demonstrated encouraging activities against wild-type ALK (19 nM), ROS1 (2.3 nM) as well as challenging crizotinib-resistant ALK L1196M and ALK G1202R mutants with IC 50 values of 45 nM and 22 nM, respectively. Additionally flow cytometric analysis indicates that 18d inhibited Karpas-299 cell viability via G1 phase arrest. Taken together, this work provided a promising ALK inhibitor to circumvent the clinical crizotinib-resistant mutants., (Copyright © 2019. Published by Elsevier Masson SAS.)

Anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase, is a therapeutic target in various cancers, including non-small cell lung cancer. Although several ALK inhibitors, including crizotinib, ceritinib, and alectinib, are approved for cancer treatment, their long-term benefit is often limited by the cancer's acquisition of resistance owing to secondary point mutations in ALK. Importantly, some ALK inhibitors cannot cross the blood-brain barrier (BBB) and thus have little or no efficacy against brain metastases. The introduction of a lipophilic moiety, such as a fluoroethyl group may improve the drug's BBB penetration. Herein, we report the synthesis of fluoroethyl analogues of crizotinib 1, alectinib 4, and ceritinib 9, and their radiolabeling with 18 F for pharmacokinetic studies. The fluoroethyl derivatives and their radioactive analogues were obtained in good yields with high purity and good molar activity. A cytotoxicity screen in ALK-expressing H2228 lung cancer cells showed that the analogues had up to nanomolar potency and the addition of the fluorinated moiety had minimal impact overall on the potency of the original drugs. Positron emission tomography in healthy mice showed that the analogues had enhanced BBB penetration, suggesting that they have therapeutic potential against central nervous system metastases., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

ALK and ROS1 kinases have become promising therapeutic targets since Crizotinib was used to treat non-small-cell lung cancer clinically. Aiming to explore new potent inhibitors, a series of 2-amino-4-(1-piperidine) pyridine derivatives that stabilized a novel DFG-shifted conformation in the kinase domain of ALK were designed and synthesized on the base of lead compound A. Biological evaluation highlighted that most of these new compounds could also potently inhibit ROS1 kinase, leading to the promising inhibitors against both ROS1 and ALK. Among them, the representative compound 2e stood out potent anti-proliferative activity against ALK-addicted H3122 and ROS1-addicted HCC78 cell lines (IC 50  = 6.27 μM and 10.71 μM, respectively), which were comparable to that of Crizotinib. Moreover, 2e showed impressive enzyme activity against clinically Crizotinib-resistant ALK L1196M with an IC 50 value of 41.3 nM, which was about 2-fold more potent than that of Crizotinib. 2e also showed potent inhibitory activity in about 6-fold superior to Crizotinib (IC 50 : 104.7 nM vs. 643.5 nM) in Ba/F3 cell line harboring ROS1 G2032R . Furthermore, molecular modeling disclosed that all the representative inhibitors could dock into the active site of ALK and ROS1, which gave a probable explanation of anti Crizotinib-resistant mutants. These results indicated that our work has established a path forward for the generation of anti Crizotinib-resistant ALK/ROS1 dual inhibitors., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background/aims: Although crizotinib is standard chemotherapy for advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), clinical factors affecting progression-free survival (PFS) have not been reported. The purpose of this study was to identify clinical factors affecting PFS of crizotinib and develop a prognostic model for advanced ALK-positive NSCLC., Methods: Clinicopathologic features of patients enrolled in PROFILE 1001, 1005, 1007, and 1014 (training cohort) were reviewed. We conducted multivariate Cox analysis for PFS and overall survival (OS) in the training cohort (n = 159) and generated a proportional hazards model based on significant clinicopathologic factors, and then validated the model in an independent validation cohort (n = 40)., Results: In the training cohort, the objective response rate was 81.5%. Median PFS and OS from the start of crizotinib were 12.4 and 31.3 months, respectively. Multivariate Cox analysis showed poor performance status, number of metastatic organs (≥ 3), and no response to crizotinib independently associated shorter PFS. Based on a score derived from these three factors, median PFS and OS of patients with one or two factors were significantly shorter compared to those without these factors (median PFS, 22.4 months vs. 10.5 months vs. 6.5 months; median OS, not reached vs. 29.1 months vs. 11.8 months, respectively; p < 0.001 for each group). This model also had validated in an independent validation cohort., Conclusion: Performance status, number of metastatic organs, and response to crizotinib affected PFS of crizotinib in ALK-positive NSCLC. Based on these factors, we developed a simple and useful prediction model for PFS.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that has been recognized as a therapeutic target for EML4-ALK fusion-positive nonsmall cell lung cancer (NSCLC) treatment using type I kinase inhibitors such as crizotinib to take over the ATP binding site. According to Shaw's measurements, ALK carrying G1202R mutation shows reduced response to crizotinib (IC 50  = 382 nM vs. IC 50  = 20 nM for wild-type), whereas L1198F mutant is more responsive (IC 50  = 0.4 nM). Interestingly, the double mutant L1198F/G1202R maintains a similar response (IC 50  = 31 nM) to the wild-type. Herein we conducted molecular modeling simulations to elucidate the varied crizotinib sensitivities in three mutants carrying L1198F and/or G1202R. Both L1198 and G1202 are near the ATP pocket. Mutation G1202R causes steric hindrance that blocks crizotinib accessibility, which greatly reduces efficacy, whereas mutation L1198F enlarges the binding pocket entrance and hydrophobically interacts with crizotinib to enhance sensitivity. With respect to the double mutant L1198F/G1202R, F1198 indirectly pulls R1202 away from the binding entrance and consequently alleviates the steric obstacle introduced by R1202. These results demonstrated how the mutated residues tune the crizotinib response and may assist kinase inhibitor development especially for ALK G1202R, analogous to the ROS1 G2302R and MET G1163R mutations that are also resistant to crizotinib treatment in NSCLC.

Objectives: Brigatinib is a second-generation ALK inhibitor which demonstrated activity over crizotinib-resistance, especially on brain metastasis by increased blood-brain penetration. However, its activity on lepto-meningeal disease is unknown and scarcely reported., Materials and Methods: We hereby report the case of lepto-meningeal disease in crizotinib- and ceretinib- treated patient who was successfully treated by brigatinib., Results: The patient achieved intracranial response to brigatinib more than 14 months., Conclusion: Our case provides additional data on brigatinib's intracranial activity, not only on brain metastasis but also on leptomeningeal disease, after experiencing resistance to both crizotinib and ceretinib, 1 st and 2 nd generation ALK inhibitors., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have shown efficacy in the treatment of ALK-rearranged non-small-cell lung cancer (NSCLC), but the disease eventually progresses in all patients. In many cases, resistance to ALK TKIs arises through ALK mutations. Although clinical and biological data suggest variations in TKI efficacy according to the mechanism of resistance, ALK mutations are still rarely investigated in routine practice., Materials and Methods: We performed a retrospective multicentric study with an aim to determine the frequency and clinical relevance of ALK alterations detected using targeted next-generation sequencing in patients with advanced ALK-rearranged NSCLC after progression during an ALK TKI treatment. Data on clinical, pathological, and molecular characteristics and patient outcomes were collected., Results: We identified 23 patients with advanced ALK-rearranged NSCLC who, between January 2012 and May 2017, had undergone at least 1 repeat biopsy at progression during an ALK TKI treatment. A resistance mechanism was identified in 9 of the 23 patients (39%). The anomalies involved included 9 ALK mutations in 8 patients and one ALK amplification. The ALK mutation rate was 15% after failure of a first ALK TKI and 33% after failure of 2 ALK TKI treatments. Five of 7 patients who received a different ALK TKI after detection of an ALK mutation achieved an objective response. All of the patients who received a TKI presumed to act on the detected ALK mutant achieved disease control., Conclusion: Targeted next-generation sequencing is suitable for detecting ALK resistance mutations in ALK-rearranged NSCLC patients in routine practice. It might help select the best treatment at the time of disease progression during treatment with an ALK TKI., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: To assess the cost-effectiveness of alectinib versus crizotinib as first-line treatments for advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) patients from the perspective of China's healthcare system., Methods: A Markov model was developed to assess the clinical outcomes and costs of alectinib and crizotinib, which included five health states: progression-free (PF) without central nervous system (CNS) progression, PF with CNS progression, post-progression (PP) without CNS progression, PP with CNS progression, and death. Clinical data for transition probabilities were obtained from the ALEX trial at the updated data cutoff. Healthcare resource utilization and costs were derived from clinical expert opinions and published literature. One-way sensitivity analysis and probabilistic sensitivity analysis were conducted to assess the uncertainty of the results. Scenario analyses were conducted including using clinical data from the ALESIA trial in Asian patients, using utilities from the ALEX trial, and choosing different parametric survival models., Results: In base case analysis, alectinib yielded an additional 1.04 quality-adjusted life years (QALYs) with incremental costs of $54,827, resulting in an incremental cost-effectiveness ratio (ICER) of $52,869/QALY. In scenario analysis, the ICER was $56,787/QALY using clinical data from the ALESIA trial. In probabilistic sensitivity analysis, the probabilities of alectinib being cost-effective were 0.4% and 43.7% when the willingness-to-pay (WTP) thresholds were $28,109/QALY and $50,000/QALY, respectively., Conclusion: Alectinib could prolong the mean time of PF and delay the time to CNS progression. However, because of its high drug cost, alectinib was unlikely to be cost-effective for untreated ALK-positive NSCLC patients in China.

There is an increasing interest for anaplastic lymphoma kinase (ALK) inhibitors in pediatric oncology for specific entities such as ALK-driven inflammatory myofibroblastic tumor (IMT). IMT treatment can be challenging due to localization of the tumor and in rare cases of metastasis. When standard surgical treatment is not feasible, ALK inhibitors may play an important role, as recently reported for the first-generation ALK inhibitors (crizotinib). However, data on the second-generation ALK inhibitors are limited. We report two emblematic cases of IMT in pediatric patients, treated with the second-generation ALK inhibitor ceritinib in the context of a clinical trial (NCT01742286)., (© 2019 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.)

Crizotinib is an oral tyrosine kinase inhibitor, approved by the FDA in 2011, for use in anaplastic lymphoma kinase positive, metastatic, non-small cell lung cancer. Crizotinib inhibits oncogenic protein expression and impairs cellular proliferation in tumors with an overexpressed anaplastic lymphoma kinase gene. Currently used most frequently in the adult patient population, pediatric use is becoming more prominent, specifically in disease states exhibiting anaplastic lymphoma kinase-positive, metastatic disease, such as neuroblastoma. Approximately 8% of neuroblastomas have activating anaplastic lymphoma kinase-mutations, making this a promising target for a difficult-to-treat disease. Studies in the pediatric population are limited. However, targeted anaplastic lymphoma kinase-inhibitor therapies have shown improved outcomes at both one-year and two-year marks in both overall survival and progression free survival in anaplastic lymphoma kinase-positive adult patients with non-small cell lung cancer. One Children's Oncology Group phase I trial examined toxicities associated with anaplastic lymphoma kinase inhibitor therapy in pediatric patients. Results revealed varying grades in severity of neutropenia, dizziness, and liver function test elevation. In the adult population, severe toxicities reported by the manufacturer include effects on liver, cardiac and lung function. Additionally, several cases of severe, erosive, pill-esophagitis due to crizotinib therapy have been documented in the adult population. Erosive esophagitis is common in the pediatric population due to a variety of factors. Ingestion of medications or other corrosive agents accounts for approximately 3-5% (5000-10,000 cases per year) of esophagitis presentation in the pediatric population. Common causative medications include non-steroidal anti-inflammatory drugs, antibiotics such as doxycycline and tetracycline, and ferrous sulfate. Presented here is the first reported case of crizotinib-induced pill esophagitis in a pediatric patient.

The identification of anaplastic lymphoma kinase rearrangements in 2-5% of patients with non-small-cell lung cancer led to rapid advances in the clinical development of oral tyrosine kinase inhibitors. Anaplastic lymphoma kinase inhibitors are an effective treatment in preclinical models and patients with anaplastic lymphoma kinase-translocated cancers. Four anaplastic lymphoma kinase inhibitors (crizotinib, ceritinib, alectinib, and brigatinib) have recently been approved. Post-marketing studies provided additional pharmacokinetic information on their pharmacokinetic parameters. The pharmacokinetic properties of approved anaplastic lymphoma kinase inhibitors have been reviewed herein. Findings from additional studies on the effects of drug-metabolizing enzymes, drug transporters, and drug-drug interactions have been incorporated. Crizotinib, ceritinib, and alectinib reach their maximum plasma concentrations after approximately 6 h and brigatinib after 1-4 h. These drugs are primarily metabolized by cytochrome P450 3A with other cytochrome P450 enzymes. They are mainly excreted in the feces, with only a minor fraction being eliminated in urine. Crizotinib, ceritinib, and brigatinib are substrates for the adenosine triphosphate binding-cassette transporter B1, whereas alectinib is not. The different substrate specificities of the transporters play a key role in superior blood-brain barrier penetration by alectinib than by crizotinib and ceritinib. Although the absorption, distribution, and excretion of anaplastic lymphoma kinase inhibitors are regulated by drug transporters, their transporter-mediated pharmacokinetics have not yet been elucidated in detail in patients with non-small-cell lung cancer. Further research to analyze the contribution of drug transporters to the pharmacokinetics of anaplastic lymphoma kinase inhibitors in patients with non-small-cell lung cancer will be helpful for understanding the mechanisms of the inter-individual differences in the pharmacokinetics of anaplastic lymphoma kinase inhibitors.

Background: Despite development of several next-generation tyrosine kinase inhibitors (TKIs), crizotinib remains one of the first-line treatment options for advanced ALK-positive NSCLC and is widely used in situations where next-generation TKIs aren't yet approved or economically inaccessible. However, the pattern of failure and clinical value of radiotherapy in metastatic crizotinib-treated ALK-mutant lung cancer, with or without baseline brain metastases (BBM), are largely unknown., Methods: Consecutive crizotinib-treated NSCLC patients with adequate imaging and measurable disease were retrospectively enrolled. Disease progression in original sites (primary/metastatic), new sites, or both, are classified as original failure (OF), distant failure (DF) and ODF, respectively. Progression free survival, from crizotinib initiation to the first disease progression, and from that to the second disease progression, were calculated as PFS1 and PFS2., Results: Ninety-three patients were identified. With a median follow up of 22.0 (range, 2.0-72.0) months, 52 patients had crizotinib-treatment failure. The frequencies of OF, ODF, and DF, were 50.0, 26.9, and 23.1%, respectively. Histology, primary tumor size and presence of BBM, were independently associated with OF, using competing risks analyses. The brain was the most common site of initial disease progression. Patients with BBM had a significant higher possibility developing multiple-progressive lesions in the brain (p = 0.002). Importantly, four of the ten patients who had baseline oligo-metastatic cranial disease but didn't receive upfront brain radiation, developed multiple-progressive disease in the brain. Brain radiation before crizotinib could alter the disease failure patterns and improve PFS1 among patients with BBM (p = 0.006). Extracranial radiation was efficient in controlling symptoms but it was not associated with PFS1 (p = 0.223), and the majority of patients were eligible for salvage radiotherapy upon disease progression to crizotinib. By the time of data cut-off, 28 patients had second disease progression, with a median PFS2 of 7.0 (95% CI 5.4-8.6) months and salvage radiotherapy significantly prolonged PFS2 (p = 0.003). Additionally, patients receiving any radiotherapy during their treatment course had a significant longer overall survival (p = 0.048)., Conclusions: Among patients with baseline oligo-metastatic brain lesions which are suitable for stereotactic radiosurgery, upfront brain radiotherapy provides considerable clinical benefits. While, extracranial radiation may be deferred in asymptomatic patients with multiple-metastatic lesions.

Rationale: The anaplastic lymphoma kinase (ALK) rearrangements represent a subtype of nonsmall-cell lung cancer (NSCLC), and targeting ALK has radically changed the treatment of NSCLC. Crizotinib, as an ALK inhibitor, has been used in the treatment of ALK-rearranged NSCLC for several years and some adverse effects should be given attention., Patient Concerns: A 64-year-old woman with a no-smoking history visited hospital in November 2016 because of a persistent cough, expectoration, and progressive dysphagia for 2 months., Diagnoses and Interventions: She was diagnosed with primary lung adenocarcinoma, accompanied by pleural and bone metastases. After receiving chemotherapy for nearly 1 year, she showed progressive disease. DNA-sequencing identified an intergenic ALK rearrangement. Surprisingly, RNA-sequencing revealed the EML4-ALK fusion transcript. Subsequently, this patient switched to crizotinib therapy., Outcomes: The patient achieved partial response after 1-month treatment. However, this patient suffered a severe sinus bradycardia after 4 months of treatment. When reducing the dose of crizotinib, the side effect was alleviated and this patient showed stable disease until now., Lessons: Given that the severe sinus bradycardia was an unusual adverse effect, physicians should be aware of these side effects when using crizotinib. Moreover, it should be noted that this patient harbored an intergenic ALK rearrangement identified by DNA-sequencing, but EML4-ALK fusion transcript verified by RNA-sequencing. However, the mechanism remains unknown and requires further research.

Drug resistance to anaplastic lymphoma kinase (ALK) inhibitors (crizotinib and ceritinib) is caused by mutation in the region encoding kinase domain of ALK. Compounds with potential ability to inhibit all strains of ALK are a solution to tackle the problem of drug resistance. In this study, we delineated positions of residues possessing the ability to make ALK drug resistant upon mutation by assessing them using five parameters (conservation index, binding-site root-mean-square deviation, protein structure stability, change in ATP, and drug-binding affinity). Four residual positions (Leu 1122, Thr 1151, Phe 1245, and Gly 1269) were ascertained. This study will be beneficial for designing drugs with better proficiency against ALK and the issues of drug resistance. This study can be taken as a pipeline for investigating drug-resistant mutations in other diseases as well., (© 2018 Wiley Periodicals, Inc.)

Objectives: ALK tyrosine kinase inhibitors (TKIs), including crizotinib and several next generation TKIs, have demonstrated beneficial clinical outcomes in ALK-positive non-small cell lung cancer (NSCLC). However, resistance mechanisms following multiple TKI treatments in ALK-positive NSCLC are not fully elucidated., Materials and Methods: Mutation profiles of 422 cancer-relevant genes in 52 patients with post-TKI biopsy samples were analyzed using next-generation sequencing (NGS), and compared between patients receiving crizotinib alone (n = 35) and multi-TKIs (n = 17)., Results: EML4-ALK variant 3 is the most frequent ALK variants in this cohort, followed by EML4-ALK variant 1. Half of the patients harbored ALK activating mutations upon progression on crizotinib treatment. After multi-TKIs treatment, 59% of the cases developed resistant ALK mutations, and concomitant ALK activating mutations were more commonly observed in this cohort (P = 0.031). Specifically, ALK G1269 A, L1196 M, and C1156Y substitutions were more common in crizotinib-alone samples, while ALK G1202R was significantly more enriched post-multi-TKIs (P = 0.009). Activated bypass signaling tended to be more prevalent in patients post-multi-TKIs. Furthermore, dual activation of ALK and bypass signaling was more frequently found in the multi-TKIs group (5/17, 29%) in contrast to crizotinib-alone (2/35, 6%) (P = 0.031). Additionally, concurrent TP53 mutation demonstrated significantly shorter progression-free survival (PFS) compared with TP53 wildtype in crizotinib-alone group (median PFS: 8 vs 13 months, Hazard Ratio = 1.494, P = 0.019)., Conclusion: Concurrent ALK activating mutations and/or upregulated bypass signaling are more enriched in patients undergoing multiple ALK TKI treatments compared to crizotinib alone. Concomitant TP53 mutation correlated to unfavorable survival when receiving a single TKI crizotinib., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: In the absence of head-to-head trials, this study indirectly compared progression free survival (PFS) and overall survival (OS) between ceritinib and crizotinib among patients with previously untreated advanced anaplastic lymphoma kinase ( ALK )-positive non-small cell lung cancer (NSCLC). Methods: A matching-adjusted indirect comparison method was implemented to adjust for cross-trial differences in patient characteristics between ASCEND-4 and PROFILE 1014 trials. Patient-level data from ASCEND-4 and published summary data from PROFILE 1014 were used. Patients in ASCEND-4 were reweighted to match average baseline characteristics (i.e. age, sex, race, tumor histology, ECOG score, smoking status, extent of disease, and presence of brain metastases) reported for PROFILE 1014 patients using propensity score weighting. PFS and OS were then compared between balanced populations. Results: ASCEND-4 included more current smokers (8.0% vs 4.4%) and fewer patients under the age of 65 years (78.5% vs 84.0%) compared to PROFILE 1014. After matching, these and all other patient characteristics were balanced between the two trial populations. Compared to crizotinib, ceritinib was associated with a significantly longer PFS (hazard ratio [95% confidence interval] (HR [CI]) = 0.64 [0.47-0.87]; median PFS: 25.2 vs 10.8 months, log-rank p -value = 0.003). OS did not differ significantly, with a HR of 0.82 [0.54-1.27] for ceritinib compared to crizotinib. Conclusions: In the adjusted indirect comparison with external controls, the second generation ALK inhibitor, ceritinib, was associated with a significantly prolonged PFS compared to crizotinib as first-line treatment for ALK -positive NSCLC.

Introduction: Crizotinib was approved to treat anaplastic lymphoma kinase (ALK)- positive non-small cell lung cancer (NSCLC) by the Food and Drug Administration in 2011.We conducted a systematic review of clinical trials and retrospective studies to compare the efficacy and safety of crizotinib with chemotherapy., Methods: We searched electronic databases from inception to Dec. 2016. Clinical trials and retrospective studies regarding crizotinib and crizotinib versus chemotherapy in treatment of NSCLC were eligible. The primary outcomes were the objective response rate (ORR) and disease control rate (DCR)., Results: Nine studies (five clinical trials and four retrospective studies) including 729 patients met the inclusion criteria. Crizotinib treatment revealed 1-year OS of 77.1% and PFS of 9.17 months. And crizotinib had a better performance than chemotherapy in ORR (OR: 4.97, 95%CI: 3.16 to 7.83, P<0.00001, I2=35%). DCR revealed superiority with crizotinib than chemotherapy (OR: 3.42, 95% CI: 2.33 to 5.01, P<0.00001, I2=0%). PR (partial response) were significant superior to that of chemotherapy through direct systematic review. No statistically significant difference in CR (complete response) was found between crizotinib-treated group and chemotherapy-treated group. Regarding SD (stable disease), chemotherapy-treated group had a better performance than crizotinib-treated group. Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, nausea, and hematologic toxicity., Conclusion: This systematic review revealed improved objective response rate and increased disease control rate in crizotinib group comparing with chemotherapy group. Crizotinib treatment would be a favorable treatment option for patients with ALK-positive NSCLC. ALK inhibitors may have future potential applications in other cancers driven by ALK or c-MET gene mutations., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

To more accurately and rapidly achieve quantitative detection of clinical crizotinib samples, stable isotope labeled crizotinib was required as an internal standard. We have developed a method to prepare racemic [D 9 ] crizotinib using a base-catalyzed H/D exchange of both nitroso compound 2 and the acetophenone compound 6 with D 2 O and NaBD 4 reduction of 7 as the key steps to introduce the 9 deuterium atoms. Starting with 4-hydroxypiperidine, 14-step synthesis furnished the desired racemic [D 9 ] crizotinib 18. The deuterium-labeled compound 18 with the chemical purity of 99.62% was applicable for use as internal standards in the drug clinical study., (© 2018 John Wiley & Sons, Ltd.)