Clinical Impact of Switching to Ceritinib After Severe AEs Related to Crizotinib/Alectinib in a Novel PTH2R-ALK Fusion Lung Adenocarcinoma: A Case Report

Lung cancer is still the leading cause of morbidity and mortality by cancer among men, according to the latest epidemiological data in China. Anaplastic lymphoma kinase (ALK) rearrangements act as key oncogenic drivers of non-small cell lung cancer (NSCLC) and have been identified in 5– 6% of NSCLC. Although ALK inhibitors (ALK-TKIs) were proven to be more effective than chemotherapy in ALK-positive NSCLC patients and the safety profile of these drugs was favorable, novel ALK fusions NSCLC might discontinue or switch treatment because of adverse events (AEs) have rarely previously been reported. Here, we describe a male patient with stage IV lung adenocarcinoma who carried a novel PTH2R-ALK fusion identified by next-generation sequencing (NGS). The patient first took crizotinib but switched to alectinib due to gastrointestinal AEs. Although alectinib remained effective on tumors, ceritinib (450 mg) was replaced after the AEs of hyperbilirubinemia occurred. After reducing the dose to 30..... READ ARTICLE

OncoTargets and Therapies DOI:10.2147/OTT.S340984

Authors: Shen G, Du Y, Shen J, Zhang J, Xia X, Huang M and Shen W.

Case Study, group1Kirk SmithDecember 9, 2021PTH2R-ALK, non-small cell lung cancer, ceritinib, adverse events

Targeting EML4-ALK gene fusion variant 3 in thyroid cancer

Finding targetable gene fusions can expand the limited treatment options in radioactive iodine-refractory (RAI-r) thyroid cancer. To that end, we established a novel cell line ‘JVE404’ derived from an advanced RAI-r papillary thyroid cancer (PTC) patient, harboring an EML4-ALK gene fusion variant 3 (v3). Different EML4-ALK gene fusions can have different clinical repercussions. JVE404 cells were evaluated for cell viability and cell signaling in response to ALK inhibitors crizotinib, ceritinib and lorlatinib, in parallel to the patient’s treatment. He received, after first-line lenvatinib, crizotinib (Drug Rediscovery Protocol (DRUP) trial), and lorlatinib (compassionate use). In vitro treatment with crizotinib or ceritinib decreased viability in JVE404, but most potently and significantly only with lorlatinib. Western blot analysis showed a near total decrease of 99% and 89%, respectively, in pALK and pERK expression levels in JVE404 cells with lorlatinib, in contrast to remaining sig..... READ ARTICLE

Endocrine-Related Cancer DOI:10.1530/ERC-20-0436

Authors: Mehtap Derya Aydemirli, Jaap D H van Eendenburg, Tom van Wezel, Jan Oosting, Willem E Corver , Ellen Kapiteijn and Hans Morreau

ALK inhibition activates LC3B-independent, protective autophagy in EML4-ALK positive lung cancer cells

In the present study, we asked whether ALK inhibition affects autophagy, and whether this may influence treatment response. Whereas the impact of targeted therapies on autophagic activity previously have been assessed by surrogate marker proteins such as LC3B, we here thoroughly examined effects on functional autophagic activity, i.e. on the sequestration and degradation of autophagic cargo, in addition to autophagic markers. Interestingly, the ALK inhibitor Ceritinib decreased mTOR activity and increased GFP-WIPI1 dot formation in H3122 and H2228 EML4-ALK+ lung cancer cells, suggesting autophagy activation. Moreover, an mCherry-EGFP-LC3B based assay indicated elevated LC3B carrier flux upon ALK inhibition. In accordance, autophagic cargo sequestration and long-lived protein degradation significantly increased upon ALK inhibition. Intriguingly, autophagic cargo flux was dependent on VPS34 and ULK1, but not LC3B. Co-treating H3122 cells with Ceritinib and a VPS34 inhibitor or Bafilomyci..... READ ARTICLE

Scientific Reports DOI:10.1038/s41598-021-87966-6

Authors: Anna M. Schläfli, Igor Tokarchuk, Sarah Parejo, Susanne Jutzi, Sabina Berezowska, Nikolai Engedal, Mario P. Tschan

Pre-ClinicalKirk SmithApril 27, 2021ceritinib, mTOR, EML4-ALK+, VPS34 inhibitor, Bafilomycin A1, autophagy

Changing ALK-TKI-Resistance Mechanisms in Rebiopsies of ALK-Rearranged NSCLC: ALK- and BRAF-Mutations Followed by Epithelial-Mesenchymal Transition

Anaplastic lymphoma-kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) is prone to developing heterogeneous, only partly known mechanisms of resistance to ALK-tyrosine-kinase-inhibitors (ALK-TKIs). We present a case of a 38-year old male, who never smoked with disseminated ALK-rearranged (EML4 (20) – ALK (20) fusion variant 2) lung adenocarcinoma, who received four sequentially different ALK-TKIs and two lines of chemotherapy in-between. We observed significant clinical benefit by the first three ALK-TKIs (Crizotinib, Ceritinib, Alectinib) and chemotherapy with Pemetrexed, resulting in overall survival over 3 years. Longitudinal assessment of progressions by rebiopsies from hepatic metastases showed different mechanisms of resistance to each ALK-TKI, including secondary ALK-mutations and the downstream p.V600E BRAF-mutation that had not been linked to second-generation ALK-TKIs before. Ultimately, in connection with terminal rapid progression and resistance to Alectinib and Lor..... READ ARTICLE

International Journal of Molecular Sciences DOI:10.3390/ijms21082847

Authors: Urbanska, E.M.; Sørensen, J.B.; Melchior, L.C.; Costa, J.C.; Santoni-Rugiu, E.

Suitability of endobronchial ultrasound-guided transbronchial needle aspiration samples for programmed death ligand-1 testing in non-small cell lung cancer, the Bristol experience

To assess EBUS-TBNA biopsy adequacy for ALK, EGFR and PD-L1 testing, we conducted a prospective study of 279 consecutive NSCLC patients referred to a tertiary EBUS-TBNA centre in South West England. One hundred eight-four (62.6%) patients were found to have adenocarcinoma, 83 (28.2%) had squamous cell carcinoma, and 27 (9.2%) were identified as NSCLC-not otherwise specified. EGFR testing was successful in 166 of 168 patients (98.8%), ALK testing in all 115 and PD-L1 testing in 43 of 49 patients (88.2%). Previous EGFR and ALK testing did not affect biopsy PD-L1 testing success. PD-L1 testing failures occurred in three of five (60.0%) of 22G needle biopsies, one of five (20.0%) of 21G needle biopsies and two of 39 (5.1%) of 19G needle biopsies, P = .016. EBUS-TBNA biopsies are mostly suitable for PD-L1 testing. Larger needle size may improve PD-L1 (but not EGFR and ALK) testing success but requires further study in a controlled trial...... READ ARTICLE

Asia-Pacific Journal of Clinical Oncology DOI:10.1111/ajco.13549

Authors: Joanna Hardy, Nidhi Bhatt, Andrew R L Medford

Real-World OutcomesKirk SmithApril 18, 2021ALK p, ceritinib, resistance, lorlatinib, ALK, NSCLC, next generation sequencing, NGS

392P Clinical data from the real world: Efficacy analysis of ceritinib (450mg) in ALK-positive non-small cell lung cancer patients with brain metastases in China

The real-world intracranial efficacy data of ceritinib at a dose of 450mg QD are still unavailable, thus this study aims to analyze the intracranial efficacy of ceritinib (450mg QD) in ALK-rearrangement NSCLC patients in China. Conclusion Ceritinib administered at a dose of 450mg QD to ALK-rearrangement NSCLC patients with BM in China demonstrates superior ORR and DCR, as well as PFS and EFP that are expected to be improved. Especially the estimated 12-month EFP of intracranial lesions was improved in patients with prior brain radiotherapy. READ ARTICLE

European Society for Medical Oncology. DOI:10.1016/j.annonc.2020.10.386

Authors: Z. Qiu, , K. Wang, M. Huang, M. Yu, C. Liu, X. Xian

Real-World OutcomesKirk SmithDecember 31, 2020ceritinib, brain metastases

The Emerging Therapeutic Landscape of ALK Inhibitors in Non-Small Cell Lung Cancer

Review providing a comprehensive overview of the state-of-the-art targeted therapy options in ALK-positive NSCLCs. Resistance, potential therapeutic strategies to overcome drug resistance, and future perspectives for this subset of patients are critically analyzed and summarized. READ ARTICLE

Pharmaceuticals (Basel) DOI: 10.3390/ph13120474

Authors: Valerio Gristina, Maria La Mantia, Federica Iacono, Antonio Galvano, Antonio Russo, Viviana Bazan

Review PaperKirk SmithDecember 13, 2020ALK inhibitor, NSCLC, TKI, alectinib, brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib

Efficacy and safety of ceritinib 450 mg-fed vs 750 mg-fasted in Asian patients (pts) with ALK+ non-small cell lung cancer (NSCLC) in the ASCEND-8 trial

Asian pts with ALK+ advanced/metastatic NSCLC treated with ceritinib 450 mg-fed showed numerically higher efficacy and less GI toxicity compared to 750 mg-fasted pts. READ ARTICLE

ESMO (European Society for Medical Oncology) Abstract DOI: 10.1016/j.annonc.2020.08.1662

Authors: B.C. Chul Cho, D-W. Kim, U. Batra, K. Park, S-W. Kim, C.T. Yang, V. Pie Jye, V. Sriuranpong, K.G. Babu, K. Amin, Y. Wang, L. Wang, M. Bhering, S. Lucien Geater

Clinical TrialsKirk SmithSeptember 1, 2020ASCEND-8, ceritinib

Optimal Care for Patients with Anaplastic Lymphoma Kinase (ALK)–Positive Non–Small Cell Lung Cancer: A Review on the Role and Utility of ALK Inhibitors

The treatment of advanced non–small-cell lung cancer (NSCLC) has undergone a paradigm shift in the last decade. Molecular characterization of the disease has led to the rapid development of personalized medicine and swift delivery of targeted therapies to patients. The discovery of the anaplastic lymphoma kinase (ALK) gene in patients with NSCLC has resulted in rapid bench–bedside transition of several active drugs, with several others currently in clinical trials. After the first-generation ALK inhibitor crizotinib, next-generation ALK inhibitors have entered clinical applications for ALK-rearranged NSCLC. Ceritinib, alectinib, and brigatinib have all received approval for ALK-positive patients who have failed prior crizotinib, as well as first-line therapy in treatment-naïve patients based on favorable efficacy. Most recently, lorlatinib, a potent, newer-generation ALK inhibitor, has been approved as second- or third-line treatment. These advances have led to better patient outcomes,..... READ ARTICLE

Cancer Management and Research DOI:10.2147/CMAR.S260274

Authors: Abhay Singh, Hongbin Chen

Comprehensive analyses of immunodynamics and immunoreactivity in response to treatment in ALK-positive non-small-cell lung cancer

ALK-positive tumors progressing on ceritinib is not immunogenic enough to respond to immune checkpoint inhibitors. READ ARTICLE

Journal for ImmunoTherapy of Cancer DOI: 10.1136/jitc-2020-000970

Authors: Kyoung-Ho Pyo, Sun Min Lim, Chae-Won Park, Ha-Ni Jo, Jae Hwan Kim, Mi-Ran Yun, Dohee Kim, Chun-Feng Xin, Wongeun Lee, Bianca Gheorghiu, Min Hee Hong, Hye Ryun Kim, Hyo Sup Shim, Mi Jang, Sung Sook Lee, Byoung Chul Cho

Pre-ClinicalKirk SmithJune 1, 2020Pd-1 inhibitor, ceritinib

Efficacy and safety of ceritinib in anaplastic lymphoma kinase-rearranged non-small cell lung cancer: A systematic review and meta-analysis

What is known and objective: Ceritinib is a new, oral, potent and selective second-generation anaplastic lymphoma kinase (ALK) inhibitor approved by the Food and Drug Administration of the United States in April 2014. It is active in crizotinib-resistant patients, especially in patients with non-small cell lung cancer (NSCLC) and brain metastasis. The aim of this study was to analyse the effects and side effects of ceritinib in ALK-rearranged NSCLC. What is new and conclusion: Ceritinib is effective in the treatment of patients with ALK-rearranged NSCLC with crizotinib resistance. The DCR was up to 76%, and PFS was extended to 7.6 months. The AEs were acceptable. READ ARTICLE

Journal of Clinical Pharmacy and Therapeutics DOI:10.1111/jcpt.13157

Authors: Tian, W, Zhang, P, Yuan, Y, Deng, X-H, Yue, R, Ge, X-Z.

Real-World OutcomesKirk SmithMay 5, 2020ceritinib, ALK

Complete response after ceritinib treatment in non-small cell lung cancer in an elderly patient

Introduction Ceritinib is a selective second-generation ALK inhibitor that is highly sensitive to echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) molecule. Case report In this paper, we report a 68-year-old female that was diagnosed with stage 4 ALK-positive non-small cell lung cancer (NSCLC) Management and outcome: She was treated with crizotinib first-line, cisplatin and gemcitabine as second-line. And for third-line, ceritinib was started. She had complete response over 3.5 years under ceritinib treatment. And she is still receiving ceritinib with no adverse event. Discussion Cases achieving complete response with ceritinib treatment are rare. In this paper, we aimed to emphasize the complete response in stage 4 NSCLC in an elderly patient. READ ARTICLE

Journal of Oncology Pharmacy Practice DOI:10.1177/1078155220919172

Authors: Nilay Sengul Samanci, Emir Celik, Burak Akovalı, Sait Sager, Fuat Hulusi Demirelli

Case StudyKirk SmithApril 27, 2020Non-small cell lung cancer, EML4-ALK, ceritinib

Efficacy and safety of ceritinib in anaplastic lymphoma kinase-rearranged non-small cell lung cancer: A systematic review and meta-analysis

What is known and objective: Ceritinib is a new, oral, potent and selective second-generation anaplastic lymphoma kinase (ALK) inhibitor approved by the Food and Drug Administration of the United States in April 2014. It is active in crizotinib-re-sistant patients, especially in patients with non-small cell lung cancer (NSCLC) and brain metastasis. The aim of this study was to analyse the effects and side effects of ceritinib in ALK-rearranged NSCLC.Methods: We searched articles published from January 1980 to March 2019 in PubMed, EMBASE, Cochrane Library and Web of Science. The pooled estimate and 95% CI were calculated with DerSimonian-Laird method and the random effect model.Results and discussion: From 15 articles, 2,598 patients were included in the meta-analysis. Eleven studies reported the ORR, and the DCR was presented in 10 stud-ies. The ORR and DCR of ceritinib were 0.48 (95% CI, 0.39-0.57) and 0.76 (95% CI, 0.69-0.82), respectively. The PFS and OS were presented in nine and ..... READ ARTICLE

Journal of Clinical Pharmacy and Therapeutics DOI:10.1111/jcpt.13157

Authors: Wei Tian, Ping Zhang, Yuan Yuan, Xiao-Hui Deng, Rui Yue, Xiao-Zhu Ge

Clinical characteristics and risk factors of drug-induced lung injury by ALK tyrosine kinase inhibitors: A single center retrospective analysis

A total of seven cases were diagnosed with drug induced lung injury (DILI) due to ALK-TKIs; no DILI-related deaths were observed. Chest computed tomography (CT) scan findings identified six patients with the organizing pneumonia (OP) pattern and one with the hypersensitivity pneumonia pattern. The onset of DILI was significantly different in patients age ≥ 64 years and with a creatinine clearance <80 mL/minute. Extra caution for DILI due to ALK-TKIs may be needed when recommending ALK-TKIs for patients over 64 years of age, or with decreased renal function. CT images of the majority of patients with DILI by ALK-TKIs show an OP pattern. READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.13416

Authors: Ken Koshikawa, Jiro Terada, Mitsuhiro Abe, Shunichiro Iwasawa, Masashi Sakayori, Keiichiro Yoshioka, Yasutaka Hirasawa, Hajime Kasai, Yohei Kawasaki, Kenji Tsushima, Koichiro Tatsumi

Clinical characteristics and risk factors of drug-induced lunginjury by ALK tyrosine kinase inhibitors: A single centerretrospective analysis

If anaplastic lymphoma kinase (ALK) gene rearrangement in lungcancer is identified, ALK-tyrosine kinase inhibitors (ALK-TKIs) can be an effec-tive treatment. However, the details of drug-induced lung injury (DILI) causedby ALK-TKI, which can be a serious side effect of ALK-TKIs, remains unclear.This study aimed to investigate the clinical features and the onset risk factors ofDILI by ALK-TKIs in clinical practice.Methods:The clinical features of 56 consecutive patients who receivedcrizotinib, alectinib, and/or ceritinib at our hospital from 2012 to 2018 were ret-rospectively examined. Among these, patients diagnosed with DILI due to ALK-TKIs were evaluated in terms of clinical features and parameters. Each clinicalparameter before the administration of ALK-TKIs was compared between theDILI onset group and the non-onset group.Results:A total of seven cases were diagnosed with DILI due to ALK-TKIs; noDILI-related deaths were observed. Chest computed tomography (CT) scanfind-ings identified six patients with the organizing pneumonia (OP) pat..... READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.13416

Authors: Ken Koshikawa, Jiro Terada, Mitsuhiro Abe, Shunichiro Iwasawa, Masashi Sakayori, Keiichiro Yoshioka, Yasutaka Hirasawa, Hajime Kasai, Yohei Kawasaki, Kenji Tsushima, Koichiro Tatsumi

Efficacy of Crizotinib, Ceritinib, and Alectinib in ALK-Positive Non-Small Cell Lung Cancer Treatment: A Meta-Analysis of Clinical Trials

This study aimed to evaluate the efficacy of anaplastic lymphoma kinase (ALK)-inhibitors in the treatment of ALK-positive non-small cell lung cancer (NSCLC) by using a meta-analysis of clinical trials. We searched PubMed, EMBASE, Cochrane Library, and Clinicaltrials.gov by using keywords related to the topic in August 2018. The pooled effect sizes were calculated based on a random-effects model. We also performed subgroup meta-analysis by types of ALK inhibitors (crizotinib, ceritinib, and alectinib). A total of 20 clinical trials with 10 single-arm trials and 10 double-arm trials were included in the final meta-analysis. The median overall survival (OS), progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), 1 year survival rate, and 2 year survival rate were 19.14 months, 8.47 months, 62%, 78%, 74%, and 62%, respectively. ALK inhibitors showed a significantly superior efficacy compared with chemotherapy (hazard ratio (HR) for OS, 0.83; HR for PFS, 0..... READ ARTICLE

Cancers DOI:10.3390/cancers12030526

Authors: Hoang, T.; Myung, S.-K.; Pham, T.T.; Park, B.

Meta-analysis comparing incidence of grade 3–4 neutropenia with ALK inhibitors and chemotherapy in patients with non-small-cell lung cancer

Aim: Using the available literature, this meta-analysis aimed to compare reports of the incidence of grade 3–4 neutropenia with ALK inhibitors and chemotherapy in patients with ALK-positive NSCLC. Conclusion: This meta-analysis of Phase III randomized clinical trials found no significant difference in the incidence of grade 3–4 neutropenia among patients with ALK-positive NSCLC treated with either an ALK inhibitor or chemotherapy, and this was not affected by adjusting for baseline tumor stage. READ ARTICLE

FUTURE ONCOLOGY
DOI:10.2217/fon-2018-0863

Authors: Bernardo Rapoport, Ramin B Arani, Nicola Mathieson, Andriy Krendyukov

Ceritinib-related interstitial lung disease improving after treatment cessation without recurrence under either crizotinib or brigatinib: a case report

Anaplastic lymphoma kinase inhibitors (ALKi) like ceritinib are considered standard for front-line treatment of non-small cell lung cancers (NSCLC) harboring a translocation of the anaplastic lymphoma kinase (ALK) gene. We report herein a case of interstitial lung disease (ILD) that developed following a 7-month ceritinib treatment without recurrence under either crizotinib or brigatinib, two others ALKi. READ ARTICLE

Annuals of Translational Medicine DOI:10.21037/atm.2019.01.24

Authors: Laura Bender, Guillaume Meyer, Elisabeth Quoix and Bertrand Mennecier

ALK inhibition in two emblematic cases of pediatric inflammatory myofibroblastic tumor: Efficacy and side effects

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). IMTtreatment 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 thesecond-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). READ ARTICLE

Pediatric Blood & Cancer DOI: 10.1002/pbc.27645

Authors: Erica Brivio and C. Michel Zwaan

Ceritinib for an anaplastic lymphoma kinase rearrangement-positive patient previously treated with alectinib with poor performance status

ALK inhibitors are promising for treating ALK rearrangement non-small-cell lung cancer (NSCLC), but secondary mutations of ALK can sometimes inhibit their effectiveness. A 54-year-old woman with lung adenocarcinoma harboring ALK rearrangement previously treated with first-line alectinib and second-line cisplatin/pemetrexed showed poor performance status (PS) with rapid progression. She was treated with ceritinib as salvage treatment, upon which tumor shrinkage was demonstrated on CT and her PS gradually improved. The best supportive care is recommended for patients with advanced NSCLC with poor PS due to lower treatment efficacy and more toxicities than those with good PS. In this case, rapid progression led to a poor PS; however, ceritinib achieved a breakthrough in this case. The optimal treatment sequence and key drugs in ALK-positive NSCLC remain controversial. READ ARTICLE

OncoTargets and Therapy DOI:10.2147/OTT.S186213

Authors: Rui Kitadai, Yusuke Okuma, and Shoko Kawai