Transformation of EML4-ALK fusion-positive adenocarcinoma into squamous cell carcinoma in association with acquired resistance to crizotinib

The development of targeted therapies has revolutionized the treatment of patients with lung cancer, especially non-small-cell lung cancer (NSCLC). Anaplastic lymphoma kinase (ALK) is a research hotspot of molecular targeted therapy for lung cancer. ALK tyrosine kinase inhibitors (TKIs) are highly effective for ALK-rearranged NSCLC-positive patients. These targeted therapies have significant clinical effects; however, they inevitably lead to acquired resistance. In previous studies, the histological transformation after ALK inhibitor treatment was mostly based on small-cell lung cancer (SCLC). The transformation from adenocarcinoma into squamous cell carcinoma in NSCLC after treatment with ALK TKI was extremely rare. This study aimed to report a case of lung cancer with a histological transformation from adenocarcinoma into squamous cell carcinoma after crizotinib treatment, still having the original ALK rearrangement at the molecular level. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.01.001

Authors: Fenfang Wang, Jing Qin, Fajun Xie, Qihuan Wu, Hongyang Lu

Clinical consequences of resistance to ALK inhibitors in non-small cell lung cancer

Introduction: ALK rearrangements are present in 2-7% of non-small cell lung cancer (NSCLC) cases, where the EML4-ALK fusion is the most frequent. Rearrangement of ALK with other fusion partners occurs only in ≈5% of NSCLC ALK-positive. These patients have benefited from ALK inhibitors, and currently, there are three generations of drugs as the standard of care. The first-generation ALK inhibitor crizotinib is approved in the front-line setting for the treatment of advanced NSCLC; unfortunately, these tumors may eventually develop resistance to this molecule. The Second-generation ALK inhibitors, ceritinib, alectinib, and brigatinib, are approved for patients recently diagnosed or in relapse. The third-generation inhibitor lorlatininb is approved for patients who have developed resistance to any ALK inhibitor. Expert opinion: Currently, there are a growing number of options of therapeutic agents against ALK+ NSCLC (approved and in development); however, adequate selection and sequencin..... READ ARTICLE

Expert Review of Respiratory Medicine DOI:10.1080/17476348.2020.1721285

Authors: Joseph A Pinto, Luis E Raez, Gelenis Domingo,

Clinicopathological and Prognostic Significance of EML4-ALK Rearrangement in Patients with Surgically Resected Lung Adenocarcinoma: A Propensity Score Matching Study

Objective The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene is a key oncogenic driver in non-small cell lung cancer (NSCLC). This study analyzed the clinicopathological characteristics and prognostic significance of EML4-ALK fusion gene in patients with surgically resected adenocarcinoma. Methods The clinicopathological characteristics of 1056 consecutive patients with surgically resected stage I–IIIA adenocarcinoma were collected from February 2014 to October 2014, and EML4-ALK rearrangement was detected using real-time polymerase chain reaction (RT-PCR) technology. To compare the imaging and pathological features, a propensity score matching (PSM) method was performed. The follow-up information was collected to evaluate the long-term outcomes of patients with EML4-ALK rearrangement. Results The prevalence of EML4-ALK rearrangement was 6.6% in 1056 consecutive patients. A total of 70 EML4-ALK-positive and 210 EML4-ALK-negative patie..... READ ARTICLE

Cancer management and research DOI:10.2147/CMAR.S229217

Authors: Shi J, Gu W, Zhao Y, Zhu J, Jiang G, Bao M, Shi J.

Drug resistance mechanisms in Japanese anaplastic lymphoma kinase-positive non–small cell lung cancer and the clinical responses based on the resistant mechanisms

The treatment for anaplastic lymphoma kinase (ALK)-positive lung cancer has been rapidly evolving since the introduction of several ALK tyrosine kinase inhibitors (ALK-TKI) in clinical practice. However, the acquired resistance to these drugs has become an important issue. In this study, we collected a total of 112 serial biopsy samples from 32 patients with ALK-positive lung cancer during multiple ALK-TKI treatments to reveal the resistance mechanisms to ALK-TKI. Among 32 patients, 24 patients received more than two ALK-TKI. Secondary mutations were observed in 8 of 12 specimens after crizotinib failure (G1202R, G1269A, I1171T, L1196M, C1156Y and F1245V). After alectinib failure, G1202R and I1171N mutations were detected in 7 of 15 specimens. G1202R, F1174V and G1202R, and P-gp overexpression were observed in 3 of 7 samples after ceritinib treatment. L1196M + G1202R, a compound mutation, was detected in 1 specimen after lorlatinib treatment. ALK-TKI treatment duration was longer in th..... READ ARTICLE

Cancer Science DOI:10.1111/cas.14314

Authors: Noriko Yanagitani, Ken Uchibori, Sumie Koike, Mika Tsukahara, Satoru Kitazono, Takahiro Yoshizawa, Atsushi Horiike, Fumiyoshi Ohyanagi, Yuichi Tambo, Shingo Nishikawa, Naoya Fujita, Ryohei Katayama, Makoto Nishio

Tyrosine phosphorylation is critical for ACLY activity in lipid metabolism and cancer

A fundamental requirement for growth of rapidly proliferating cells is metabolic adaptation to promote synthesis of biomass1. ATP citrate lyase (ACLY) is a critical enzyme responsible for synthesis of cytosolic acetyl-CoA, the key building component for de novo fatty acid synthesis and links vital pathways such as carbohydrate and lipid metabolism2. The mechanisms of ACLY regulation are not completely understood and the regulation of ACLY function by tyrosine phosphorylation is unknown... Our results reveal a novel mechanism for direct ACLY regulation that is subverted by multiple oncogenically-activated tyrosine kinases in diverse human cancers. These findings have significant implications for novel therapies targeting ACLY in cancer and metabolism. READ ARTICLE

BioRxiv DOI:10.1101/2020.01.20.910752

Authors: Johnvesly Basappa, Mahmoud A. ElAzzouny, Delphine C.M. Rolland, Anagh A. Sahasrabuddhe, Kaiyu Ma, Gleb A. Bazilevsky, Steven R. Hwang, Venkatesha Basrur, Kevin P. Conlon, Nathanael G. Bailey, John K. Frederiksen, Santiago Schnell, Yeqiao Zhou, David Cookmeyer, Jan M. Pawlicki, Amit Dipak Amin, James L. Riley, Robert B. Faryabi, Jonathan H Schatz, Kathryn E. Wellen, Ronen Marmorstein, Charles F. Burant, Kojo S.J. Elenitoba-Johnson, Megan S. Lim

Osimertinib Overcomes Alectinib Resistance Caused by Amphiregulin in a Leptomeningeal Carcinomatosis Model of ALK-Rearranged Lung Cancer

Introduction: Leptomeningeal carcinomatosis (LMC) occurs frequently in anaplastic lymphoma kinase (ALK)–rearranged NSCLC and develops acquired resistance to ALK tyrosine kinase inhibitors (ALK TKIs). This study aimed to clarify the resistance mechanism to alectinib, a second-generation ALK TKI, in LMC and test a novel therapeutic strategy. Conclusions: These findings indicate the potential of novel therapies targeting both ALK and EGFR for the treatment of ALK TKI–resistant LMC in ALK-rearranged NSCLC. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.01.001

Authors: Sachiko Arai, Shinji Takeuchi, Koji Fukuda, Hirokazu Taniguchi, Akihiro Nishiyama, Azusa Tanimoto, Miyako Satouchi, Kaname Yamashita, Koshiro Ohtsubo, Shigeki Nanjo, Toru Kumagai, Ryohei Katayama, Makoto Nishio, Mei-mei Zheng, Yi-Long Wu, Hiroshi Nishihara, Takushi Yamamoto M.Eng, Mitsutoshi Nakada, Seiji Yano

Pre-ClinicalKirk SmithJanuary 20, 2020Leptomeningeal metastasis, EML4-ALK, Alectinib resistance, Osimertinib

Sequential blinded treatment decisions in ALK-positive non-small cell lung cancers in the era of precision medicine

Next-generation ALK TKIs have become the new standard of care in first-line setting in advanced ALK-positive NSCLC patients. However, sequential strategies at progression are relevant, as may have an impact on patients’ outcome. In this commentary we discuss whether genomic-tailored strategies at progression would be more suitable for improving outcome of ALK-positive NSCLC patients. READ ARTICLE

Clinical and Translational Oncology. DOI: 10.1007/s12094-020-02290-1

Authors: J. Remon, F. Tabbò, B. Jimenez, A. Collazo, J. de Castro, S. Novello

Targeted therapy of oncogenic-driven advanced non-small cell lung cancer: recent advances and new perspectives

The discovery of new actionable oncogenic drivers has led to the development of effective antineoplastic targeted agents in advanced non-small cell lung cancer (NSCLC). While the role of inhibitors of the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS proto-oncogene 1 (ROS1) is widely acknowledged, other oncogenic drivers can be exploited as therapeutic targets. Areas covered: Our aim is to explore the therapeutic role of actionable oncogenic drivers, including well-established targets, such as EGFR, ALK, and ROS1, as well as less frequent drivers for which specific agents are at different stages of clinical development, such as MET, RET, BRAF, and NTRK. Expert opinion: Targeted agents have revolutionized the management of advanced NSCLC; in particular, novel agents and combinations targeting EGFR, ALK, ROS1, BRAF, and NTRK have become available and others are on their way. The molecularly driven approach to advanced NSCLC requires adequate tumor samples, as well as increasingly complex technologies designed to assess multiple targets on limited available tissue in an acceptable time-span. Furthermore, the role of other novel antineoplastic approaches, such as immunotherapy with immune checkpoint inhibitors, needs to be elucidated in the case of patients with oncogenic-driven NSCLC. READ ARTICLE

Expert Review of Respiratory Medicine DOI: 10.1080/17476348.2020.1714441

AUTHORS: Carlo Genova, Giovanni Rossi, Marco Tagliamento, Erika Rijavec, Federica Biello, Luigi Cerbone, Lodovica Zullo, Francesco Grossi

Review PaperKirk SmithJanuary 17, 2020Non-small cell lung cancer, targeted therapy, oncogenic drivers

Longitudinal analysis of cell-free DNA for therapy monitoring of ALK-positive non-small cell lung cancer

Non-small cell lung cancer (NSCLC) patients with ALK rearrangements are routinely treated with tyrosine kinase inhibitors (TKIs), leading to improved survival. However, clinical courses vary widely and the disease remains incurable. Therefore, early detection and molecular characterization of treatment failure is important for therapy guidance. To identify indicators of therapy response and resistance, we performed genotyping of circulating cell-free DNA (cfDNA), including panel-based deep sequencing (>4,200x coverage) and shallow whole-genome sequencing (sWGS; 0.5x coverage) from serial plasma samples (n=282) of 73 patients with ALK rearrangements. Variable mutation levels were marked in all patients and correlated with clinical features. At progression, individual dynamics of resistance mutations were seen: while some mutations became undetectable upon therapy switch, variant fractions of other alterations further increased. We also found mutated TP53 at the time of progression in pa..... READ ARTICLE

Clinical Cancer Research DOI:10.1158/1557-3265.LiqBiop20-A21

Authors: Steffen Dietz, Petros Christopoulos, Lisa Gu, Volker Endris, Zhao Yuan, Simon J. Ogrodnik, Tomasz Zemojtel, Marc A. Schneider, Anna-Lena Volckmar, Michael Meister, Thomas Muley, Martin Reck, Matthias Schlesner, Michael Thomas, Albrecht Stenzinger, Holger Sültmann.

Conference PaperKirk SmithJanuary 16, 2020ALK, sequencing, resistance mutations

SPACEWALK: Plasma NGS for remote evaluation of ALK drug resistance in advanced NSCLC

Introduction: Precision therapy for cancer drug resistance requires detection of resistance mutations and treatment with appropriate targeted therapies. This paradigm is well established in EGFR-mutant NSCLC, yet our understanding of drug resistance in ALK-positive NSCLC is limited. Next-generation sequencing (NGS) of plasma cell-free DNA (cfDNA) now permits noninvasive interrogation of drug resistance. To facilitate improved understanding of ALK drug resistance and the effectiveness of treatment strategies, we launched this remote participation study. Conclusions: Plasma NGS permits the detection of targetable resistance mechanisms in patients with ALK-positive NSCLC and drug resistance. Sensitivity of different plasma NGS assays for ALK fusions varies. This assay may help guide oncologists across the country to select best treatment options after resistance. Such remote-participation studies may offer a new mechanism for characterizing resistance to emerging targeted therapies in rare cancer populations. READ ARTICLE

Clinical Cancer Research DOI:10.1158/1557-3265.LiqBiop20-A28

Authors: Marissa N. Lawrence, Rubii M. Tamen, Alicia Sable-Hunt, Seyed Ali Hosseini, George R. Simon, Jonathan W. Riess, Geoffrey R. Oxnard.

Conference PaperKirk SmithJanuary 16, 2020NGS, resistance mechanisms, ALK, drug resistance

Co-occurring alterations in the RAS-MAPK pathway limit response to MET inhibitor treatment in MET exon 14 skipping mutation positive lung cancer

PURPOSE While patients with advanced-stage non-small cell lung cancers (NSCLCs) harboring MET exon 14 skipping mutations (METex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical benefit is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood. CONCLUSION Our study provides a genomic landscape of co-occurring alterations in advanced-stage METex14-mutated NSCLC and suggests a potential combination therapy strategy targeting MAPK pathway signaling to enhance clinical outcomes. READ ARTICLE

Clinical Cancer Research DOI:10.1158/1078-0432.CCR-19-1667

Authors: Julia K. Rotow, Philippe Gui, Wei Wu, Victoria M. Raymond, Richard B. Lanman, Frederic J. Kaye, Nir Peled, Ferran Fece de la Cruz, Brandon Nadres, Ryan B. Corcoran, Iwei Yeh, Boris C. Bastian, Petr Starostik, Kimberly Newsom, Victor R Olivas, Alexander M. Wolff, James S. Fraser, Eric A. Collisson, Caroline E. McCoach, D. Ross Camidge, Jose Pacheco, Lyudmila Bazhenova, Tianhong Li, Trever G. Bivona, Collin M. Blakely

Drug-drug interaction between crizotinib and entecavir via renal secretory transporter OCT2

Both entecavir and crizotinib are substrates of organic cation transporter 2 (OCT2). The aim of present study was to investigate the mechanisms of drug interactions between these two drugs. Kinetic analysis of entecavir on crizotinib uptake was conduct. Plasma concentration of crizotinib in rats and lung cancer patients, uptake of crizotinib in kidney slices and OCT2 transfected cells, were determined by LC-MS/MS. The clinical pharmacokinetic interactions and impact on adverse reaction of crizotinib in lung cancer patients were investigated. Steady-state through concentration of crizotinib was measured. The crizotinib-related adverse reactions were recorded in lung cancer patients with and without entecavir. Entecavir and 1-methyl-4-phenylpyridinium iodide significantly inhibited the uptake of crizotinib in kidney slices. Kinetic constants for crizotinib uptake by OCT2 were Km 1.16 ± 0.26 µM, Vmax 12.05 ± 0.53 µmol/min mg-1 protein and Ki 9.711 nM. Entecavir can inhibit crizotinib tran..... READ ARTICLE

European Journal of Pharmaceutical Sciences DOI:10.1016/j.ejps.2019.105153

Authors: Wenying Shu, Lei Ma, Xiaoye Hu, Meimei Zhang, Wensheng Chen, Wen Ma, Jianing Huang, JiaLi

Comparison of EML4-ALK fusion gene positive rate in different detection methods and samples of non-small cell lung cancer

Objective: To evaluate differences of EML4-ALK positive rates in tissues samples between immunohistochemistry, reverse transcriptase polymerase chain reaction and the next-generation sequencing method. Besides, to compare the differences of EML4-ALK positive rates in blood samples and tissue samples by next-generation sequencing. The results provide a basis for the selection of a suitable EML4-ALK fusion gene detection method. Conclusion: Among the three methods for detecting EML4-ALK, reverse transcription polymerase chain reaction has the highest positive rate, followed by immunohistochemistry, and next-generation sequencing has the lowest positive rate. The positive detection rate of EML4-ALK in tissue samples by next-generation sequencing was higher than that in blood samples. READ ARTICLE

Journal of Cancer DOI:10.7150/jca.36580

Authors: Shan Lu, Can Lu, YuXuan Xiao, Wei Zhu, QiuYan He, Bin Xie, JianHua Zhou, YongGuang Tao, Shuang Liu, DeSheng Xiao

Targeted degradation of anaplastic lymphoma kinase by gold nanoparticle-based multi-headed proteolysis targeting chimeras

Proteolysis targeting chimeras (PROTACs) are molecules that comprise a ligand for binding a protein of interest (POI), a connecting linker and a ligand for recruiting E3 ligase, and cause degradation of the target POI. Here, the first multi-headed PROTAC, as a proof of concept, is developed as a gold nanoparticle (GNP)-based drug delivery system for delivering PROTACs to target ALK. Pegylated GNPs loaded with both ceritinib and pomalidomide molecules, termed Cer/Pom-PEG@GNPs, showed good stability in several media. The GNP conjugates potently decreased the levels of ALK fusion proteins in a dose- and time-dependent manner, and specifically inhibited the proliferation of NCI-H2228 cells. READ ARTICLE

Colloids and Surfaces B: Biointerfaces DOI: 10.1016/j.colsurfb.2020.110795

Authors: Yingming Wang, Lingfei Han, Fulei Liu, FubaiYang, Xueyang Jiang, Haopeng Sun, FengFeng, Jingwei Xue, Wenyuan Liu

Overcoming resistance by ALK compound mutation (I1171S + G1269A) after sequential treatment of multiple ALK inhibitors in non-small cell lung cancer

Background: Anaplastic lymphoma kinase (ALK) fusion genes are found in 3%–5% of non-small cell lung cancers (NSCLCs). ALK inhibitors show a very high response rate to ALK-positive NSCLCs. However, the emergence of acquired resistance is inevitable. In this study, we investigated the drugs for overcoming resistance especially compound mutations after sequential treatment with crizotinib, alectinib, and lorlatinib. Conclusions: With the sequential ALK inhibitors treatment, cancer cells accumulate new mutations in addition to mutations acquired previously. The identified compound mutation (I1171S + G1269A) was found to be sensitive to ceritinib and brigatinib, and indeed the patient's tumor partially responded to ceritinib. READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.13299

Authors: Ken Takahashi, Yosuke Seto, Koutaroh Okada, Shinya Uematsu, Ken Uchibori, Mika Tsukahara, Tomoko Oh-hara, Naoya Fujita, Noriko Yanagitani, Makoto Nishio, Kenichi Okubo, Ryohei Katayama

Transformation of EML4-ALK fusion-positive adenocarcinoma into squamous cell carcinoma in association with acquired resistance to crizotinib

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. 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. READ ARTICLE

BMC Cancer DOI:10.1186/s12885-019-6486-3

Authors: F. Guisier, N. Piton, M. Bellefleur, N. Delberghe, G. Avenel, E. Angot, O. Vittecoq, M. Ould-Slimane, H. Morisse-Pradier, M. Salaun, L. Thiberville

Case StudyKirk SmithJanuary 6, 2020ALK-rearranged NSCLC, ALK inhibitors, Crizotinib, Ceritinib, Drug toxicity, Osteitis

YAP1 mediates survival of ALK-rearranged lung cancer cells treated with alectinib via pro-apoptotic protein regulation

Despite the promising clinical efficacy of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in patients with ALK-rearranged lung cancer, some tumor cells survive and eventually relapse, which may be an obstacle to achieving a cure. Limited information is currently available on the mechanisms underlying the initial survival of tumor cells against alectinib. Using patient-derived cell line models, we herein demonstrate that cancer cells survive a treatment with alectinib by activating Yes-associated protein 1 (YAP1), which mediates the expression of the anti-apoptosis factors Mcl-1 and Bcl-xL, and combinatorial inhibition against both YAP1 and ALK provides a longer tumor remission in ALK-rearranged xenografts when compared with alectinib monotherapy. These results suggest that the inhibition of YAP1 is a candidate for combinatorial therapy with ALK inhibitors to achieve complete remission in patients with ALK-rearranged lung cancer. READ ARTICLE

Nature Communications DOI:10.1038/s41467-019-13771-5

Authors: Takahiro Tsuji, Hiroaki Ozasa, Wataru Aoki, Shunsuke Aburaya, Tomoko Yamamoto Funazo, Koh Furugaki, Yasushi Yoshimura, Masatoshi Yamazoe, Hitomi Ajimizu, Yuto Yasuda, Takashi Nomizo, Hironori Yoshida, Yuichi Sakamori, Hiroaki Wake, Mitsuyoshi Ueda, Young Hak Kim & Toyohiro Hirai

High-Throughput Label-Free Isolation of Heterogeneous Circulating Tumor Cells and CTC Clusters from Non-Small-Cell Lung Cancer Patients

(1) Background: Circulating tumor cell (CTC) clusters are emerging as clinically significant harbingers of metastases in solid organ cancers. Prior to engaging these CTC clusters in animal models of metastases, it is imperative for technology to identify them with high sensitivity. These clusters often present heterogeneous surface markers and current methods for isolation of clusters may fall short. (2) Methods: We applied an inertial microfluidic Labyrinth device for high-throughput, biomarker-independent, size-based isolation of CTCs/CTC clusters from patients with metastatic non-small-cell lung cancer (NSCLC). (3) Results: Using Labyrinth, CTCs (PanCK+/DAPI+/CD45−) were isolated from patients (n = 25). Heterogeneous CTC populations, including CTCs expressing epithelial (EpCAM), mesenchymal (Vimentin) or both markers were detected. CTCs were isolated from 100% of patients (417 ± 1023 CTCs/mL). EpCAM− CTCs were significantly greater than EpCAM+ CTCs. Cell clusters of ≥2 CTCs were obs..... READ ARTICLE

Cancers DOI:10.3390/cancers12010127

Authors: Mina Zeinali, Maggie Lee, Arthi Nadhan, Anvya Mathur, Casey Hedman, Eric Lin, Ramdane Harouaka, Max S. Wicha, Lili Zhao, Nallasivam Palanisamy, Mathias Hafner, Rishindra Reddy, Gregory P. Kalemkerian, Bryan J. Schneider, Khaled A. Hassan, Nithya Ramnath, Sunitha Nagrath

Diverse Resistance Mechanisms to the Third-Generation ALK Inhibitor Lorlatinib in ALK-Rearranged Lung Cancer

Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor with proven efficacy in patients with ALK-rearranged lung cancer previously treated with first- and second-generation ALK inhibitors. Beside compound mutations in the ALK kinase domain, other resistance mechanisms driving lorlatinib resistance remain unknown. We aimed to characterize the mechanisms of resistance to lorlatinib occurring in patients with ALK-rearranged lung cancer and design new therapeutic strategies in this setting. Resistance mechanisms were investigated in 5 patients resistant to lorlatinib. Longitudinal tumor biopsies were studied using high-throughput next-generation sequencing. Patient-derived models were developed to characterize the acquired resistance mechanisms, and Ba/F3 cell mutants were generated to study the effect of novel ALK compound mutations. Drug combinatory strategies were evaluated in vitro and in vivo to overcome lorlatinib resistance. This study shows that..... READ ARTICLE

Clinical Cancer Research DOI:10.1158/1078-0432.CCR-19-1104

Authors: Recondo G, Mezquita L, Facchinetti F, Planchard D, Gazzah A, Bigot L, Rizvi AZ, Frias RL, Thiery JP, Scoazec JY, Sourisseau T, Howarth K, Deas O, Samofalova D, Galissant J, Tesson P, Braye F, Naltet C, Lavaud P, Mahjoubi L, Abou Lovergne A, Vassal G, Bahleda R, Hollebecque A, Nicotra C, Ngo-Camus M, Michiels S, Lacroix L, Richon C, Auger N, De Baere T, Tselikas L, Solary E, Angevin E, Eggermont AM, Andre F, Massard C, Olaussen KA, Soria JC, Besse B, Friboulet L.

Pre-ClinicalKirk SmithJanuary 1, 2020Lorlatinib, resistance mechanisms

Next-generation ALK inhibitors: is the median the message?

In The Lancet Respiratory Medicine, Yunpeng Yang and colleagues3 provide phase 2 activity data for yet another ALK inhibitor, ensartinib, in the post-crizotinib setting. In the absence of direct head-to-head comparisons of this crowded field of next-generation drugs, how can these new data for ensartinib and, by extension, the potential usefulness of the drug be assessed? In most situations, cross-trial comparisons are frowned upon because of the effect that differences in trial design, inclusion and exclusion criteria, and inherent heterogeneity among patients can have on outcomes with apparently similar interventions.

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The Lancet Respiratory Medicine DOI: 10.1016/S2213-2600(19)30362-5

AUTHORS: Ross Camidge

EditorialKirk SmithJanuary 1, 2020