Comparative Efficacy of Systemic Agents for Brain Metastases From Non-Small-Cell Lung Cancer With an EGFR Mutation/ALK Rearrangement: A Systematic Review and Network Meta-Analysis

In patients with NSCLC BMs and EGFR/ALK mutations, targeted TKIs improve intracranial and overall PFS compared to conventional modalities such as chemotherapy, with greater efficacy seen using newer generations of TKIs. This data is important for treatment selection and patient counseling, and highlights areas for future RCT research. READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2021.739765

Authors: Taslimi, S., Brar, K., Ellenbogen, Y., Deng, J., Hou, W., Moraes, F. Y., Glantz, M., Zacharia, B. E., Tan, A., Ahluwalia, M. S., Khasraw, M., Zadeh, G., & Mansouri, A.

Successful treatment with lorlatinib in a patient with meningeal carcinomatosis of ALK-positive non-small cell lung cancer resistant to alectinib and brigatinib

Although anaplastic lymphoma kinase (ALK) inhibitors are effective treatment options for ALK-positive non-small cell lung cancer (NSCLC) with central nervous system (CNS) metastasis, achieving long-term survival in patients with NSCLC with meningeal carcinomatosis resistant to ALK inhibitors is difficult. Lorlatinib, a third-generation ALK inhibitor, was designed for selective CNS penetration, and exerts potent antitumor activity against tumors resistant to first- and/or second-generation ALK inhibitors. However, there is limited information about the activity of lorlatinib in ALK inhibitor-resistant meningeal carcinomatosis. Here, we report a case of ALK-positive lung adenocarcinoma with meningeal carcinomatosis in which lorlatinib was used after resistance to alectinib and brigatinib.We find lorlatinib is an effective treatment option for patient with ALK-positive NSCLC who develop meningeal carcinomatosis resistant to second-generation ALK inhibitors. Therefore, lorlatinib should be considered in such cases, even when patients exhibit serious symptoms associated with meningeal carcinomatosis. READ ARTICLE

Medicine DOI:10.1097/MD.0000000000027385

Authors: Nakashima, Koki MD, Demura, Yoshiki MD, PhD, Kurokawa, Kosuke MD, Takeda, Toshihiro MD, Jikuya, Norihiro MD, Oi, Masahiro MD, Tada, Toshihiko MD, Akai, Masaya MD, PhD, Ishizuka, Tamotsu MD, PhD

The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer

Anaplastic lymphoma kinase (ALK) is a validated molecular target for non-small-cell lung cancer (NSCLC). The use of tyrosine kinase inhibitors (TKIs) has led to significantly improved survival benefits. However, the clinical benefits of targeting ALK using TKIs are limited due to the emergence of drug resistance. The landscape of resistance mechanisms and treatment decisions has become increasingly complex. Therefore, continued research into new drugs and combinatorial therapies is required to improve outcomes in NSCLC. In this review, we explore the resistance mechanisms of ALK TKIs in advanced NSCLC in order to provide a theoretical basis and research ideas for solving the problem of ALK drug resistance. READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2021.713530

Authors: Yue Pan, Chao Deng, Zhenhua Qiu, Chenghui Cao and Fang Wu

Ensartinib vs Crizotinib for Patients With Anaplastic Lymphoma Kinase−Positive Non–Small Cell Lung Cancer, A Randomized Clinical Trial

Question Is ensartinib superior to crizotinib for patients with advanced anaplastic lymphoma kinase (ALK)–positive non–small cell lung cancer (NSCLC) who have not been treated previously with an ALK inhibitor?
Findings This randomized clinical phase 3 trial including 290 patients met the primary end point; the median progression-free survival was statistically significantly longer with ensartinib than with crizotinib (25.8 vs 12.7 months), and the confirmed intracranial response rate was 64% with ensartinib vs 21% with crizotinib for patients with brain metastases at baseline. Ensartinib had a favorable safety profile.
Meaning Ensartinib represents a new first-line treatment option for patients with ALK-positive NSCLC. READ ARTICLE

JAMA Oncology DOI:10.1001/jamaoncol.2021.3523

Authors: Leora Horn, Ziping Wang, Gang Wu, Elena Poddubskaya, Tony Mok, Martin Reck, Heather Wakelee, Alberto A. Chiappori, Dae Ho Lee, Valeriy Breder, Sergey Orlov, Irfan Cicin, Ying Cheng, Yunpeng Liu, Yun Fan, Jennifer G. Whisenant, Yi Zhou, Vance Oertel, Kim Harrow, Chris Liang, Li Mao, Giovanni Selvaggi and Yi-Long Wu,

Clinical Trials, group3Kirk SmithSeptember 2, 2021ALK, Ensartinib, eXalt3 trial, non-small cell lung cancer (NSCLC)

1356P Cumulative incidence and baseline imaging patterns of brain metastases in advanced EGFR and ALK positive non-small cell lung cancer (NSCLC)

Background: Up to 40% of NSCLC patients develop brain metastases (mets) during the course of their disease. We explored the impact of histology and EGFR and ALK mutations on cumulative incidence rates of brain mets and influence of brain imaging patterns. Conclusions: Our real-world data confirm a higher cumulative incidence of brain metastases in EGFR+/ALK+ adenocarcinoma compared to WT or SCC and more brain imaging at baseline. Future analyses will focus on treatment-based outcomes (tyrosine kinase inhibitors, different radiation modalities) in EGFR+/ALK+ patients compared to WT adenocarcinoma and SCC. READ ARTICLE

Annals of Oncology DOI:10.1016/j.annonc.2021.08.1956

Authors: M.T. Chowdhury, M. García Pardo de Santayana, S. Schmid, S. Cheng, L.J. Zhan, M.C. Brown, K. Khan, P. Walia, A. Sabouhanian, E. Strom, J. Herman, N. Leighl, P. Bradbury, F.A. Shepherd, A. Sacher, W. Xu, G. Liu, D. Shultz

An overview of alectinib hydrochloride as a treatment option for ALK positive non-small cell lung cancer

Introduction: Alectinib is a second-generation inhibitor of anaplastic lymphoma kinase (ALK) and RET. Phase III clinical trials have established its superiority to crizotinib in the first-line ALK inhibitor-naïve setting. Studies also support its use over chemotherapy in the post-crizotinib setting. It is currently one of several FDA- and EMA-approved ALK inhibitors, and it is listed as a preferred initial therapy for treatment-naïve ALK-positive non-small cell lung cancer (NSCLC).Areas covered: Herein, the authors provide the reader with details of the chemical structure, pharmacologic properties, resistance mutations, phase I, II, and III clinical trials, and safety profile of alectinib. Furthermore, the authors provide the reader with the expert opinion and future perspectives on the drug.Expert opinion: Alectinib compares favorably to other second-generation ALK inhibitors with regards to safety, tolerability, and efficacy. Based on currently available data, it is an appropriate first-line option. Ongoing studies will better resolve the ideal sequencing of ALK inhibitors in the treatment of ALK-positive NSCLC. READ ARTICLE

Expert Opinion on Pharmacotherapy DOI: 10.1080/14656566.2021.1948014

Authors: Schokrpur S, Hilburn V, Giustini N and Bazhenova L.

Impact of rapid multigene assays with short turnaround time (TAT) on the development of precision medicine for non-small cell lung cancer (NSCLC)

Background: A variety of oncogene drivers have been identified in NSCLC and molecularly-stratified precision medicine has led to improved survival in advanced NSCLC. Next-generation sequencing (NGS)-based testing is utilized to detect actionable gene alterations; however, the TAT of NGS is often too long to translate into clinical decision making. Thus, rapid multi-gene testing alternatives are needed. Conclusions: Both the 9-in-1 test and Genexus/OPA had short TATs (3−4 days), high success rates (96−98%) and good concordance (95−98%) compared with another NGS assay (OCA). These rapid multi-gene assays highly contributed to enabling precision medicine and the development of targeted therapies for advanced NSCLC. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.9094

Authors: Shingo Matsumoto, Takaya Ikeda, Kiyotaka Yoh, Akira Sugimoto, Terufumi Kato, Kei Kunimasa, Atsushi Nakamura, Ichiro Nakachi, Shoichi Kuyama, Jun Sakakibara-Konishi, Haruko Daga, Eiji Iwama, Kageaki Taima, Naoki Furuya, Kaname Nosaki, Hiroki Izumi, Yoshitaka Zenke, Koichi Goto

Brigatinib in Japanese patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC): First results from the J-ALTA

Background: Brigatinib is a next-generation ALK inhibitor with demonstrated activity against ALK mutations. We report primary analysis results with brigatinib in Japanese patients with ALK-positive NSCLC who have not previously been treated with an ALK TKI in the phase 2 J-ALTA study (NCT03410108). Conclusions: In the J-ALTA TKI-naive cohort, brigatinib demonstrated substantial efficacy and manageable safety in the Japanese patient population. Brigatinib remains one of the treatment options in Japanese patients. Clinical trial information: NCT03410108. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.9042

Authors: Masashi Kondo, Shunichi Sugawara, Toshihide Yokoyama, Toru Kumagai, Makoto Nishio, Koichi Goto, Yuichiro Ohe, Takashi Seto, Nobuyuki Yamamoto, Kentarou Kudou, Takayuki Asato, Pingkuan Zhang, Kazuhiko Nakagawa

Outcomes of KRAS mutated, EGFR mutated, ALK mutated and wildtype patients in non-small cell lung cancer brain metastases

Background: Non-small cell lung cancer (NSCLC) is the most common primary tumor leading to brain metastases. Multiple genetic markers have been profiled in NSCLC patients for potential targeted therapies. EGFR is mutated in up 50% of NSCLCs, while ALK is mutated in around 4-7%. KRAS is the most commonly overexpressed marker, seen in up to 85% of all lung cancers. In this retrospective study, we evaluated the overall survival (OS) and progression-free survival (PFS) between NSCLCBM patients with KRAS mutations, ALK mutations, EGFR mutations, and wildtype. Conclusions: Molecular mutations serve as both prognostic predictors and alternative targeted therapies for NSCLCBM treatment. Our retrospective study showed improved mOS and mPFS in NSCLCBM patients with ALK rearrangements when compared to patients with EGFR mutations, KRAS mutations, and the wildtype. While these results looked at patient outcomes with specific tumor markers, further investigation needs to be done regarding outcomes..... READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.e21028

Authors: Yasmeen Rauf, Vineeth Tatineni, Patrick joseph Oshea, Xuefei Jia, David M. Peereboom, Manmeet Singh Ahluwalia

Conference PaperKirk SmithMay 28, 2021non-small cell lung cancer (NSCLC), mutations, PFS

Impact of prior ALK-tyrosine kinase inhibitor on pemetrexed-based chemotherapy in patients with advanced ALK positive non-small cell lung cancer

Background: In phase Ⅲ trial comparing crizotinib with chemotherapy in patients with ALK-positive non-small-cell lung cancer (NSCLC) patients, it suggests that pemetrexed is highly effective against ALK-positive NSCLC. However, it is unclear that pemetrexed-based chemotherapy is effective in patients previously treated with ALK-tyrosine kinase inhibitor (ALK-TKI) as well as ALK-TKI naïve patients. Therefore, we investigated the impact of prior ALK-TKI therapy on pemetrexed-based chemotherapy. Conclusions: Pemetrexed-based chemotherapy might be less effective in ALK-positive NSCLC patients previously treated with ALK-TKI. This retrospective study results suggested that ALK-TKI sequence can be a better treatment option in ALK-positive NSCLC patients. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.e21113

Authors: Michitoshi Yabe, Hirotsugu Kenmotsu, Hiroaki Kodama, Naoya Nishioka, Eriko Miyawaki, Taichi Miyawaki, Nobuaki Mamesaya, Haruki Kobayashi, Shota Omori, Kazushige Wakuda, Akira Ono, Tateaki Naito, Haruyasu Murakami, Toshiaki Takahashi

Outcomes of first, second, and third-generation anaplastic lymphoma kinase (ALK) inhibitors in non-small cell lung cancer brain metastases (NSCLCBM)

Background: Non-small cell lung cancer (NSCLC) is the most common cause of brain metastases. ALK, which codes for tyrosine kinase receptors, is rearranged in 4-7% of NSCLC. First-generation ALK inhibitors have restricted efficacy due to poor blood-brain barrier (BBB) penetration and ALK-resistant tumor mutations. Second-generation ALK inhibitors have shown better BBB penetration, while third-generation ALK inhibitors were efficacious even against ALK-resistant mutations. In this retrospective study, we investigated the overall survival (OS) and progression-free survival (PFS) in NSCLCBM patients treated with first, second, and third-generation ALK inhibitors. Conclusions: Newer generations of targeted therapies in NSCLCBM have improved BBB penetration and effectiveness against resistant mutations. We determined that there was a significant 5-year OS benefit in patients who received second and third-generation ALK inhibitors compared to first-generation ALK inhibitors, and a respective..... READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.2034

Authors: Vineeth Tatineni, Patrick Joseph O'Shea, Yasmeen Rauf, Xuefei Jia, Erin Sennett Murphy, Samuel T. Chao, John H. Suh, David M. Peereboom, Manmeet Singh Ahluwalia

Efficacy and Safety of Intrathecal Pemetrexed Combined With Dexamethasone for Treating Tyrosine Kinase Inhibitor-Failed Leptomeningeal Metastases From EGFR-Mutant NSCLC

We aimed to evaluate the efficacy and safety of intrathecal pemetrexed (IP) for treating EGFR-mutant leptomeningeal metastases (LMs) from EGFR-mutant NSCLC. The RD observed in the phase 1 study was 50 mg pemetrexed. A total of 30 cases of LM-NSCLC were enrolled in the phase 2 study, including 14 males and 16 females. Four patients did not survive for 4 weeks and could not be evaluated for efficacy. The clinical response rate was 84.6% (22 of 26). The median overall survival of all patients was 9.0 months (n = 30, 95% confidence interval: 6.6–11.4 mo). Most AEs were mild, and the most frequent AE of any grade was myelosuppression (n = 9, 30%), which returned to normal after symptomatic treatment. This study revealed that 50 mg pemetrexed is the RD which results in few AEs and a good response rate. IP is an effective treatment for patients with EGFR-mutant NSCLC-LM who had failed on tyrosine kinase inhibitor...... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/J.JTHO.2021.04.018

Authors: Chengjuan Fan, Qiuyu Zhao, Li Li, Weixi Shen, Yang Du, Chong Teng, Feng Gao, Xiaowei Song, Qiuying Jiang, Dayong Huang, Yinghua Jin, Yanju Lv, Lingxiao Wei, Tengfei Shi, Xue Zhao, Naisheng Gao, Zhengjun Jiang, Tao Xin

Characteristics of central nervous system progression in non-small cell lung cancer treated with crizotinib or alectinib

Aims: We compared the clinical-radiographic characteristics of CNS metastases among patients undergoing crizotinib and alectinib treatment for ALK-positive NSCLCs. Conclusion: We observed no significant difference in the clinical-radiographic characteristics of CNS progression between patients undergoing crizotinib and alectinib treatments. Local therapy, including stereotactic radiosurgery, for CNS progression may be suitable and important following alectinib and crizotinib treatment. READ ARTICLE

Cancer Reports DOI:doi.org/10.1002/cnr2.1414

Authors: Hiroaki Sakamoto, Noriko Yanagitani, Ryo Manabe, Ryosuke Tsugitomi, Shinsuke Ogusu, Takehiro Tozuka, Hiroshi Yoshida, Yoshiaki Amino, Ryo Ariyasu, Ken Uchibori, Satoru Kitazono, Sadatomo Tasaka, Makoto Nishio

Current Knowledge about Mechanisms of Drug Resistance against ALK Inhibitors in Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer subtypes. Two to seven percent of NSCLC patients harbor gene rearrangements of the anaplastic lymphoma kinase (ALK) gene or, alternatively, harbor chromosomal fusions of ALK with echinoderm microtubule-associated protein-like 4 (EML4). The availability of tyrosine kinase inhibitors targeting ALK (ALK-TKIs) has significantly improved the progression-free and overall survival of NSCLC patients carrying the respective genetic aberrations. Yet, increasing evidence shows that primary or secondary resistance to ALK-inhibitors during the course of treatment represents a relevant clinical problem. This necessitates a switch to second- or third-generation ALK-TKIs and a close observation of NSCLC patients on ALK-TKIs during the course of treatment by repetitive molecular testing. With this review of the literature, we aim at providing an overview of current knowledge about resistance mechanisms to ALK-TKIs in NSCLC. READ ARTICLE

Cancers DOI: 10.3390/cancers13040699

Authors: Elisabeth Smolle, Valentin Taucher, Joerg Lindenmann, Philipp J. Jost, Martin Pichler

An Expert Perspective on Antibody–Drug Conjugates in Non-Small-Cell Lung Cancer

Until recently, the focus for the treatment of lung cancer has been on immunotherapy and targeted therapy, but I think that antibody–drug conjugates (ADCs) are going to have a massive role in the management of this disease in the future. READ ARTICLE

Clinical Care Options

Author: Dr. Ross Camidge

Risk of thromboembolism in patients with ALK- and EGFR-mutant lung cancer: A cohort study

Patients with ALK-mutant advanced lung adenocarcinoma have the highest rate of TE. TE is associated with worse survival across molecular subtypes. These findings should be taken into consideration in decision-making regarding thromboprophylaxis. READ ARTICLE

Journal of Thrombosis and Haemostasis DOI:doi.org/10.1111/jth.15215

Authors: Joanna Roopkumar,Shyam K. Poudel,Lorenzo Gervaso,Chandana A. Reddy,Vamsidhar Velcheti,Nathan A. Pennell,Keith R. McCrae,Alok A. Khorana

Optimal Timing And Technique Of Local Therapy For Brain Metastases From Non-Small Cell Lung Cancer With Driver Mutations

Objective(s): Brain metastases (BM) are frequent in non-small cell lung cancer patients with driver mutations (dm-NSCLC). Since the availability of brain-penetrating tyrosine kinase inhibitors (TKI), the role of local therapy (LT) for BM from dm-NSCLC is frequently discussed. This analysis examines prognostic factors, particularly the effect of LT timing and technique, in patients with BM from dm-NSCLC. Conclusion: In this analysis, early LT improved icPFS but not OS in TKI-naive patients with BM from dm-NSCLC, compared to upfront TKI treatment. No benefit was shown for WBRT over SRS regarding either icPFS or OS. In light of the toxicities of WBRT, the choice of RT technique should be considered carefully in the context of overall prognosis and quality of life. Especially patients presenting initially with multiple BM may benefit from delaying RT or from individualized approaches like the SRS of multiple or only selected BM instead of WBRT. READ ARTICLE

International Journal of Radiation Oncology DOI:10.1016/j.ijrobp.2020.07.096

Authors: R. El Shafie, T. Eichkorn, D. Weber, F. Bozorgmehr, L. König, S. Rieken, M. Thomas, J. Debus, P. Christopoulos

Longitudinal therapy monitoring of ALK-positive lung cancer by combined copy number and targeted mutation profiling of cell-free DNA

Combined copy number and targeted mutation profiling could improve monitoring of ALK+ NSCLC. Potential advantages include the identification of treatment failure, in particular for patients without detectable mutations, and broader detection of genomic changes acquired during therapy, especially in later treatment lines and in high-risk patients. READ ARTICLE

EBioMedicine DOI: 10.1016/j.ebiom.2020.103103

Authors: Steffen Dietz, Petros Christopoulos, Zhao Yuan, Arlou Kristina Angeles, Lisa Gu, Anna-Lena Volckmar, Simon J. Ogrodnik, Florian Janke, Chiara Dalle Fratte, Tomasz Zemojtel, Marc A. Schneider, Daniel Kazdal, Volker Endris, Michael Meister, Thomas Muley, Erika Cecchin, Martin Reck, Matthias Schlesner, Michael Thomas, Albrecht Stenzinger, Holger Sültmann,

Novel Resistance Mechanisms Including L1196Q, P1094H, and R1248_D1249 Insertion in Three Patients With NSCLC After ALK Tyrosine Kinase Inhibitor Treatment

"Nine patients had no known ALK resistance mechanisms. Four had ALK amplification. L1196M, I1171N, and G1269A, mutations that are known to indicate resistance to ALK TKIs, were detected in one patient each. Small cell carcinoma and sarcomatoid transition were found in one case each. L1196Q, P1094H, and exon 24 76-base pair insertion were detected after the second-generation ALK TKIs.The combination of a genetic analysis and a computational simulation model may make a prediction of resistance mechanisms for overcoming ALK TKI resistance, and the construction of a genomic and simulation fused database is important for the development of personalized medicine in this field." READ ARTICLE

Journal of Thoracic Oncology DOI: 10.1016/j.jtho.2020.09.023

Authors: Furuta H, Araki M, Masago K, Sagae Y, Fujita S, Seto K, Shimizu J, Horio Y, Sasaki E, Hosoda W, Katayama R, Okuno Y, Hida T.

Outcomes Based On Brain Metastases Characteristics And Treatment Modality For Patients With EGFR-Mutated And ALK-Rearranged Non-Small Cell Lung Cancer (NSCLC)

Purpose/objective(s): Lung cancer patients with driver mutations and brain metastases can be managed with various modalities given intracranial penetrance of available tyrosine kinase inhibitors (TKIs). We sought to determine these patient’s outcomes based on brain metastases characteristics and the upfront treatment modalities utilized, including stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT). Conclusion: For patients with EGFR-mutated or ALK-rearranged NSCLC and brain metastases, there was no difference in IC-PFS based on number or volume of brain metastases. Those treated with TKI alone experienced similar IC-PFS and risk of neurologic death as those also treated with radiotherapy. Further studies are needed to evaluate optimal treatment strategies for these patients, particularly for those with larger or symptomatic brain metastases when radiation is typically recommended. READ ARTICLE

International Journal of Radiation Oncology DOI:10.1016/j.ijrobp.2020.07.2048

Authors: S.W. Dutta, M.L. Mack, K.A. Ward, E. Aliotta, R. Hall, R.D. Gentzler, J.P. Sheehan