Cost analysis of the management of brain metastases in patients with advanced ALK+ NSCLC: alectinib versus crizotinib

Aim: To estimate management cost of NSCLC ALK+ patients with and without brain metastasis (BM), and to compare annual costs in patients treated with alectinib or crizotinib. Methods: Management cost/year (€ 2018) in patients with and without BM was estimated with disaggregated resource consumption provided by local oncologists, including medical visits, hospitalizations, diagnostic/laboratory tests, imaging techniques and surgical procedures. The comparison of costs/year with alectinib and crizotinib, considered the cumulative 12-month incidence of BM in ALEX trial (9.4 and 41.4%, respectively). Results: Management cost was €6173.42/patient-year without BM and €21,637.50/patient-year with BM. With alectinib, average cost/patient was lower than crizotinib (€4948.51/patient-year) Conclusion: Prevention of BM with alectinib may result in reductions of cost/year in the management of advanced ALK+ NSCLC. READ ARTICLE

LUNG CANCER MANAGEMENT DOI:10.2217/lmt-2019-0011

Authors: Dolores Isla, Bartomeu Massuti, Martín Lázaro, Lucía Ruiz de Alda, Rocio Gordo, Nuria Ortega-Joaquín & Itziar Oyagüez

Clinical Utility of Targeted Sequencing in Lung Cancer: Experience From an Autonomous Swedish Health Care Center

Objectives: Mutation analysis by massive parallel sequencing (MPS) is routinely performed in the clinical management of lung cancer in Sweden. We describe the clinical and mutational profiles of lung cancer patients subjected to the first 1.5 years of treatment predictive MPS testing in an autonomous regional health care region... Conclusion: Although the increasing importance of MPS as a predictor of response to targeted therapies is indisputable, its role in prognostics or as a predictor of clinical course in nontargetable advanced stage lung cancer requires further investigation. READ ARTICLE

JTO Clinical and Research Reports DOI:10.1016/j.jtocrr.2020.100013

Authors: Sofi Isaksson, Bassam Hazem, Mats Jönsson, Christel Reuterswärd, Anna Karlsson, Håkan Griph, Jens Engleson, Gudrun Oskarsdottir, Ronny Öhman, Karolina, Holm, Frida Rosengren, Karin Annersten, Göran Jönsson, Åke Borg, Anders Edsjö, Per Levéen, Hans Brunnström, Kajsa Ericson Lindquist, …Maria Planck

Computed Tomography Imaging Features and Distribution of Metastases in ROS1-rearranged Non–Small-cell Lung Cancer

Background: ROS proto-oncogene 1 (ROS1) rearrangements are a known molecular target in non–small-cell lung cancer (NSCLC). Our goal was to determine whether ROS1-rearranged NSCLC has imaging features and patterns of metastasis, which differ from those of anaplastic lymphoma kinase (ALK)-rearranged or epidermal growth factor receptor (EGFR)-mutant NSCLC... Conclusion: Although considerable overlap exists in the imaging features of ROS1-rearranged, ALK-rearranged, and EGFR-mutant NSCLC, we found that ROS1-rearranged NSCLC has certain distinct imaging features and patterns of spread. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2019.10.006

Authors: Subba R. Digumarthy, Dexter P. Mendoza, Jessica J. Lin, Tianqi Chen, Marguerite M. Rooney, Emily Chin, Lecia V. Sequist, Jochen K. Lennerz, Justin F. Gainor, Alice T. Shaw

Real-World OutcomesKirk SmithMarch 1, 2020ALK, Lung cancer, Radiology, Rearrangement, ROS1

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

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

Treatment with Next-Generation ALK Inhibitors Fuels Plasma ALK Mutation Diversity

Purpose: Acquired resistance to next-generation ALK tyrosine kinase inhibitors (TKIs) is often driven by secondary ALK mutations. Here, we investigated utility of plasma genotyping for identifying ALK resistance mutations at relapse on next-generation ALK TKIs.
Experimental design: We analyzed 106 plasma specimens from 84 patients with advanced ALK-positive lung cancer treated with second- and third-generation ALK TKIs using a commercially available next-generation sequencing (NGS) platform (Guardant360). Tumor biopsies from TKI-resistant lesions underwent targeted NGS to identify ALK mutations.
Results: By genotyping plasma, we detected an ALK mutation in 46 (66%) of 70 patients relapsing on a second-generation ALK TKI. When post-alectinib plasma and tumor specimens were compared, there was no difference in frequency of ALK mutations (67% vs. 63%), but plasma specimens were more likely to harbor ≥2 ALK mutations (24% vs. 2%, P = 0.004). Among 29 patients relapsing on lorlatinib, plasm..... READ ARTICLE

Clinical Cancer Research DOI:10.1158/1078-0432.CCR-19-1436

Authors: Dagogo-Jack I, Rooney M, Lin JJ, Nagy RJ, Yeap BY, Hubbeling H, Chin E, Ackil J, Farago AF, Hata AN, Lennerz JK, Gainor JF, Lanman RB, Shaw AT.

Real-World OutcomesKirk SmithNovember 15, 2019Next-Generation ALK Inhibitors, Plasma, Mutation Diversity

Management of Central Nervous System Metastases in Patients With Advanced Anaplastic Lymphoma Kinase-Rearranged Non–Small-Cell Lung Cancer During Crizotinib Treatment

"Background: Central nervous system (CNS) progression is a common manifestation of acquired resistance to crizotinib in anaplastic lymphoma kinase (ALK)-rearranged non–small-cell lung cancer (NSCLC). However, an optimal tailored treatment approach has not been established in patients with CNS failure during crizotinib treatment. Conclusion: Although CBPD is an option in patients with isolated CNS progression during crizotinib treatment, sequential treatment with a second ALK TKI, particularly brigatinib, might be preferable. The newly approved TKI, brigatinib, showed promise in the control of brain metastases, even without radiotherapy. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2019.06.013

Authors: Yiming Zhao, Bo Zhang, Shuyuan Wang, Rong Qiao, Jianlin Xu, Lele Zhang, Yanwei Zhang, Baohui Han"

$Efficacy of Platinum/Pemetrexed Combination Chemotherapy in ALK-Positive NSCLC Refractory to Second-Generation ALK Inhibitors$

Efficacy of Platinum/Pemetrexed Combination Chemotherapy in ALK-Positive NSCLC Refractory to Second-Generation ALK Inhibitors

This was a retrospective study performed at three institutions. Patients were eligible if they had advanced ALK-positive NSCLC refractory to one or more second-generation ALK TKI(s) and had received platinum/pemetrexed-based chemotherapy. Among 58 patients eligible for this study, 37 had scans evaluable for response with measurable disease at baseline. The confirmed objective response rate to platinum/pemetrexed-based chemotherapy was 29.7% (11 of 37 patients; 95% confidence interval [CI]: 15.9% – 47.0%), with median duration of response of 6.4 months (95% CI: 1.6 months – not reached). The median progression-free survival for the entire cohort was 4.3 months (95% CI: 2.9 – 5.8 months). Progression-free survival was longer in patients who received platinum/pemetrexed in combination with an ALK TKI compared to those who received platinum/pemetrexed alone (6.8 months vs. 3.2 months, respectively; hazard ratio ¼ 0.33; p ¼ 0.025). Platinum/pemetrexed-based chemotherapy shows modest efficacy in ALK-positive NSCLC after failure of second-generation ALK TKIs. The activity may be higher if administered with an ALK TKI, suggesting a potential role for continued ALK inhibition. READ ARTICLE

Journal of Thoracic Oncology DOI: 10.1016/j.jtho.2019.10.014

Authors: Jessica J. Lin, Adam J. Schoenfeld, Viola W. Zhu, Beow Y. Yeap, ScD, Emily Chin, BA, Marguerite Rooney, BA, Andrew J. Plodkowski, Subba R. Digumarthy, Ibiayi Dagogo-Jack, Justin F. Gainor, Sai-Hong Ignatius Ou, Gregory J. Riely, Alice T. Shaw

Real-World OutcomesKirk SmithOctober 12, 2019Chemotherapy, Efficacy, ALK, non-small cell lung cancer (NSCLC)

ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib

Objective: Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH+). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC)+). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases. Conclusion: ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2019.09.023

Authors: E. Thunnissen, B.I. Lissenberg-Witte, M.M. van den Heuvel, K. Monkhorst, B.G. Skov, J.B. Sørensen, A. Mellemgaard, A.M.C. Dingemans, E.J.M. Speel, A.J. de Langen, S.M.S. Hashemi, I. Bahce, M.A. van der Drift, M.G. Looijen-Salamon, J. Gosney, P.E. Postmus, S.M.S. Samii, F Duplaquet, B. Weynand, X. Durando, F. Penault-Llorca, S. Finn, A.O Grady, B. Oz, N. Akyurek, R. Buettner, J. Wolf, L. Bubendorf, S. Duin, I. Marondel, L.C. Heukamp, W. Timens, E.M.D. Schuuring, P. Pauwels, E.F. Smit

P201-35 Acquired MET-Aberrance Is a Mechanism of Resistance to ALK Inhibitors in ALK-Positive Advanced Non-Small-Cell Lung Cancer

Totally 136 ALK-positive advanced NSCLC patients were screened for ALK rearrangement detected by tumor tissue or plasma Next-generation sequencing (NGS) at the Guangdong Lung Cancer Institute from January 2016 to December 2018. MET-aberrance was defined as c-Met overexpression performed by immunohistochemical(IHC) staining method with SP44 antibody and MET amplification assessed by tumor tissue or plasma Next-generation sequencing (NGS) or fluorescent in situ hybridization (FISH)The study found acquired MET-aberrance maybe a mechanism of acquired resistance to the second-generation ALK-TKIs for ALK-rearranged advanced NSCLC patients. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1379

Authors: Q. Deng, J. Kang, H. Wang, J. Yang, H. Yan, Z. Wang

OA0206 The Sequential Therapy of Crizotinib Followed by Alectinib: Real World Data of 840 Patients with NSCLC Harboring ALK-Rearrangement (WJOG9516L)

Previous clinical trials demonstrated that alectinib (ALEC) had a longer time-to-progression than crizotinib (CRZ) in 1st-line settings. Information on long-term overall survival (OS), however, is still limited with a few studies having reported that the sequential strategy of “CRZ followed by other ALK-inhibitor” can provide extended OS. In Japan, ALEC was approved for a 1st-line setting earlier than in other countries.We reviewed the clinical data of ALK-rearranged NSCLC patients who received CRZ or ALEC between May 2012 and Dec 2016. Patients were divided into two groups according to the first-administered ALK inhibitor, the CRZ or ALEC group. In order to evaluate the efficacy of the sequential strategy of “CRZ followed by ALEC”, the combined time to treatment failure (TTF) was calculated in the CRZ group as defined by the sum of the “TTF of CRZ” plus the “TTF of ALEC” if patients were treated with ALEC followed by CRZ. In the ALEC group, the “TTF of ALEC” was calculated. The primar..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.415

Authors: S. Watanabe, T. Yamanaka, K. Ito, S. Sakata, H. Daga, T. Kijima, K. Hirano, I. Okamoto, A. Nakamura, T. Kozuki, M. Ishihara, K. Azuma, T. Seto, T. Yokoyama, Y. Oya, H. Kobayashi, K. Nishino, Y. Hattori, K. Nakagawa, N. Yamamoto

Brigatinib in patients with ALK-positive advanced non-small-cell lung cancer pretreated with sequential ALK inhibitors: A multicentric real-world study (BRIGALK study)

Brigatinib is a next-generation ALK inhibitor initially developed in ALK-positive NSCLC pretreated with crizotinib.This retrospective multicentric study analyzed ALK-positive advanced NSCLC patients pretreated with at least one tyrosine-kinase inhibitor, including crizotinib, and enrolled in the brigatinib French early access program. The primary endpoint was investigator-assessed progression-free survival (PFS).Real-world results confirm that the efficacy of brigatinib in a cohort of patients heavily pretreated for ALK-positive advanced NSCLC. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2019.08.010

Authors: Renaud Descourt, Maurice Perol, Gaëlle Rousseau-Bussac, David Planchard, Bertrand Mennecier, Marie Wislez Alexis Cortot, Florian Guisier, Loïck Galland, Pascal Dô, Roland Schott, Eric Dansin, Jennifer Arrondeau, Jean-Bernard Auliac, Christos Chouaid

Short progression-free survival of ALK inhibitors sensitive to secondary mutations in ALK-positive NSCLC patients

Most non-small cell lung cancer (NSCLC) patients relapse on anaplastic lymphoma kinase-tyrosine kinase inhibitor (ALK-TKI) therapy because of acquired resistance. Rebiopsy is recommended to provide optimal therapy after relapse for some ALK-TKI therapies; however, little clinical data exists on the clinical efficacy of ALK-TKI tailored to secondary mutation. READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.13143

Authors: Naoki Haratake, Takashi Seto, Shinkichi Takamori, Ryo Toyozawa, Kaname Nosaki, Naoko Miura, Taro Ohba, Gouji Toyokawa, Kenichi Taguchi, Masafumi Yamaguchi, Mototsugu Shimokawa, Mitsuhiro Takenoyama

PCN129 PREVENTING BRAIN METASTASES WITH ALECTINIB IN ALK-POSITIVE NON-SMALL CELL LUNG CANCER: ECONOMIC IMPACT UNDER THE BRAZILIAN PRIVATE HEALTHCARE SYSTEM PERSPECTIVE

Objectives: Results of the ALEX trial demonstrated that alectinib decreased the risk of Central Nervous System (CNS) progression and prolonged progression-free survival of NSCLC ALK+ patients, compared with crizotinib. The objective of this study is to compare the economic burden of CNS progression with alectinib versus crizotinib, on the Brazilian private healthcare system. Conclusions: Alectinib can potentially decrease the economic burden of CNS metastasis of NSCLC ALK+ patients in the Brazilian private healthcare system, compared with the current standard of care. READ ARTICLE

Value in Health DOI:10.1016/j.jval.2019.04.253

Authors: D.Kashiura, M.Santos, L.Carmo, R.Leme-Souza

Impact of Tyrosine Kinase Inhibitor Starting Dose on Outcomes in Patients With Non-Small Cell Lung Cancer

Background: Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) can cause intolerable adverse events in patients with non-small cell lung cancer (NSCLC) and may be prescribed at a lower dose. Conclusion: Patients who initiated TKI therapy at a RD did not have different PFS and 15-month survival outcomes than patients who initiated TKI therapy at the FDA SD. READ ARTICLE

Journal of Pharmacy Practice DOI:10.1177/0897190019840596

Authors: Emily Miao, Nagashree Seetharamu, Kevin Sullivan, Stephen Eng, Chung-Shien Lee

Frequency, clinical features and differential response to therapy of concurrent ALK/EGFR alterations in Chinese lung cancer patients

Purpose: EGFR and anaplastic lymphoma kinase (ALK) alterations have been regarded as oncogenic drivers and incorporated into clinical practices to manage nonsmall cell lung cancer (NSCLC). Alterations of these two genes were traditionally considered to be mutually exclusive, but recent studies have suggested that they can occur concomitantly. Here, we investigated the prevalence, clinical features and outcomes in response to the treatment of NSCLC patients who harbor EGFR and ALK co-alterations. Conclusion: EML4-ALK/EGFR and non-EML4-ALK/EGFR co-alterations displayed distinct clinical features and responses to EGFR-TKIs, suggesting that non-EML4-ALK co-alterations are likely to occur as a resistance mechanism to EGFR-TKI. In addition, dual-TKI therapy might be a better choice than single-TKI treatments for these co-altered patients. To the best of our knowledge, this is the largest dual-positive EGFR/ALK cohort study in People's Republic of China. READ ARTICLE

Drug Design and Development Therapies DOI:10.2147/DDDT.S196189

Authors: Jixian Liu, Zhimin Mu, Li Liu, Kang Li, Richeng Jiang, Peng Chen, Qiang Zhou, Meiling Jin, Yuxiang Ma, Yuancai Xie, Jianxing Xiang, Bing Li, Yafeng Ma, Xinru Mao, Lu Zhang, Tengfei Zhang, Da Wu

Clinical Utility of Cerebrospinal Fluid Cell-Free DNA as Liquid Biopsy for Leptomeningeal Metastases in ALK-Rearranged NSCLC

Introduction: Leptomeningeal metastases (LMs) indicated a poor prognosis in NSCLC. LMs were more frequent in driver gene–mutated patients, and cerebrospinal fluid (CSF) cell-free DNA has shown unique genetic profiles of LM in EGFR-mutated LM. However, studies in patients with ALK receptor tyrosine kinase gene (ALK)-rearranged NSCLC with LMs are scarce. Conclusion: Liquid biopsy of CSF is more sensitive than liquid biopsy of plasma to detect targetable alterations, characterizing resistance mechanisms on progression and monitoring tumor response in patients with ALK-rearranged NSCLC with LM. Thus, CSF might be promising as a medium of liquid biopsy in LM. READ ARTICLE

Journal of Thoracic Oncology
DOI:10.1016/j.jtho.2019.01.007

Authors: Mei-Mei Zheng, Yang-Si Li, Ben-Yuan Jiang, Hai-Yan Tu, Wen-Fang Tang, Jin-Ji Yang, Xu-Chao Zhang, Jun-Yi Ye, Hong-Hong Yan, Jian Su, Qing Zhou, Wen-Zhao Zhong, Xue-Ning Yang, Wei-Bang Guo, Shannon Chuai, Zhou Zhang, Hua-Jun Chen, Zhen Wang, Chao Liu, Yi-Long Wu

PCN165 ESTIMATION OF THE NUMBER OF ALK-POSITIVE CASES AMONG PEOPLE LIVING WITH CANCERS IN THE UNITED STATES

Objectives: Considering the scarcity of data on anaplastic lymphoma kinase (ALK) cancer biomarker, a review of literature was performed to collate information on its prevalence across all common tumor sites, and the estimates of diagnosed incidence of each tumor were used to determine the total number of incident ALK-positive cases for the year 2018 in the United States (US). Conclusions: ALK-mutations are found in multiple tumor sites, and collectively represent 19,800 cases of cancer in 2018 in US. READ ARTICLE

Value in Health DOI:10.1016/j.jval.2019.04.289

Authors: N. J. Zhang

Real-World OutcomesKirk SmithMay 1, 2019ALK-POSITIVE CANCER, UNITED STATES

Clinical features and therapeutic options in non-small cell lung cancer patients with concomitant mutations of EGFR, ALK, ROS1, KRAS or BRAF

Background: Although oncogenic driver mutations were thought to be mutually exclusive in non-small cell lung cancer (NSCLC), certain tumors harbor co-occurring mutations and represent a rare molecular subtype. The evaluation of the clinical features and therapeutic response associated with this NSCLC subtype will be vital for understanding the heterogeneity of treatment response and improving the management of these patients. Conclusion: In this study, concomitant mutations were found in 1.7% of the NSCLC. EGFR-TKI therapy was more effective than chemotherapy for patients harboring EGFR concomitant mutation, and ROS1 concomitant mutations were more frequent in male patients. For patients harboring coalterations with an ALK or ROS1 rearrangement, we should be cautious when considering the therapeutic options. READ ARTICLE

Cancer Medicine DOI:10.1002/cam4.2183

Authors: Xibin Zhuang, Chao Zhao, Jiayu Li, Chunxia Su, Xiaoxia Chen, Shengxiang Ren, Xuefei Li, Caicun Zhou

Application of time-dependent modeling for the exposure-efficacy analysis of ceritinib in untreated ALK-rearranged advanced NSCLC patients

Purpose: Ceritinib 750 mg/day was approved for the treatment of patients with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) based on ASCEND-4 study. The objective of this article is to introduce the use of time-dependent modeling approach in the updated exposure-efficacy analysis of ceritinib for the first-line indication. READ ARTICLE

Cancer Chemotherapy and Pharmacology DOI:10.1007/s00280-019-03830-5

Authors: Yvonne Y Lau, Wen Gu, Yu-Yun Ho, Ying Hong, Xinrui Zhang and Patrick Urban