Remarkable Role of Chemotherapy in Selected ALK-Positive Non–Small-Cell Lung Cancer Before or After Targeted Therapy: Two Case Reports

In both cases, conventional chemotherapy was proven lifesaving for the patients, which enabled them to receive subsequent-line targeted therapy and led to meaningful prolonged survival and an excellent quality of life that they continue to enjoy. The option of chemotherapy, even in this revolutionized era of precision medicine, should not be undermined. Chemotherapy continues to play a vital role in decreasing cancer burden and making this cancer salvageable in appropriately selected patients. READ ARTICLE

JCO Precision Oncology DOI: http://doi.org/10.1200/JCO.20.00505

Authors: Kunal Gawri, Richa Dawar, Kayla Haines, Mohammad Jahanzeb

Case StudyKirk SmithNovember 1, 2020chemotherapy, ALK

Brigatinib Versus Crizotinib in Advanced ALK Inhibitor-Naive ALK-Positive Non-Small Cell Lung Cancer: Second Interim Analysis of the Phase III ALTA-1L Trial

"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 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." READ ARTICLE

Journal of Clinical Oncology DOI: http://doi.org/10.1200/JCO.20.00505

Authors: Camidge DR, Kim HR, Ahn MJ, Yang JCH, Han JY, Hochmair MJ, Lee KH, Delmonte A, García Campelo MR, Kim DW, Griesinger F, Felip E, Califano R, Spira A, Gettinger SN, Tiseo M, Lin HM, Gupta N, Hanley MJ, Ni Q, Zhang P, Popat S.

Clinical TrialsKirk SmithNovember 1, 2020clinical trial, ALTA-1L, TKIs, brigatinib, crizotinib

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

A case of late distant recurrence/metastasis (≧10 years after curative surgery) of anaplastic lymphoma kinase-rearranged lung cancer and the review of similar cases in the literature

We experienced a 70-year-old female with brain and liver tumors. She underwent surgical operations for rectal cancer 8 year ago and lung cancer 16 years ago. Surgical removal of a brain tumor and a liver biopsy were performed. The brain tumor consisted of an adenocarcinoma with a solid signet-ring cell pattern. Under the possibility of metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer in the brain and liver, immunohistochemistries (IHCs) for ALK were performed, returning positive results. Thus, metastasis of ALK-rearranged lung adenocarcinoma in the brain and liver had been confirmed. The patient was administered alectinib, which was well tolerated and has been in partial response for about one year and a half. By the genetic analyses for EML4-ALK variants, both the previous lung cancer and metastatic brain tumor were shown to harbor the same EML4-ALK variant 3 fusion. We thus concluded that ALK-rearranged lung adenocarcinoma has recurred as liver and brain metastases ..... READ ARTICLE

Human Pathology: Case Reports DOI:10.1016/j.ehpc.2020.200421

Authors: Shohei Matsuo, Yoshitane Tsukamoto, Eiichiro Mabuchi, Shunichi Negoro, Seiichi Hirota

Case StudyKirk SmithNovember 1, 2020Lung cancer, Late recurrence/metastasis, EML-ALK fusion

CircRNAs and Fusion-circRNAs in cancer: New players in an old game

Circular RNAs (circRNAs) are generated from 'back-splicing' events. Their circular structure makes them stable in cells and body fluids. These entities are involved in several human diseases including cancer, as they affect the expression of genes promoting proliferation, invasion, apoptosis, and angiogenesis. Moreover, they are secreted in extracellular vesicles, such as exosomes, having a potential role as messengers in cell-to-cell communications. CircRNAs are also generated by the back-splicing of linear fusion transcripts derived from genomic rearrangements, giving rise to fusion circRNAs (f-circRNAs).
Here we discuss the most relevant results achieved by studying the role of circRNAs in cancer onset and progression, particularly focusing on f-circRNAs in hematological and solid tumors. Moreover, we report recent advances in the application of circRNAs as novel “liquid biopsy” biomarkers for early and non-invasive diagnosis of tumors, and as therapeutic targets in human cancer. Th..... READ ARTICLE

Cellular Signalling DOI:10.1111/1759-7714.13376

Authors: Grazia Visci, DoronTolomeo, Antonio Agostini, Debora Traversa, Gemma Macchia, Clelia Tiziana Storlazzi

EditorialKirk SmithNovember 1, 2020CircRNA, Fusion-circRNA, Cancer, Chimera, Biomarker

Effects of ALK inhibitors (PF-02341066 and PF-06463922) with radiotherapy in EML4 – ALK fusion positive (H2228 and 185IG) and negative (A549) experimental lung cancer cell lines

Purpose/Objective(s): The management of non-small cell lung cancer (NSCLC) patients with chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) is challenging. Indeed, the efficacy of the tyrosine kinase inhibitor (TKI) of novel generation may discuss the place of combined treatment with radiotherapy. We aimed to investigate the effects of combined radiotherapy and PF-02341066 or PF-06463922 in A549 and 185IG or H2228 cell lines, the former is a wild type ALK NSCLC model and the two latter are ALK-positive NSCLC models... Conclusion: In the current study, PF-02341066 induced notably cell cycle arrest at G2/M phase and PF-06463922 induced G1 arrest, in H2228 cells. Also, results suggest that the administration of PF-02341066 and PF-06463922 after irradiation could increase the induction of DNA damages due to IR in a panel of 3 NSCLC cell lines, compared to IR first followed by TKI treatment. These results could influence the clinical combination strategy for EML4 – ALK..... READ ARTICLE

International Journal of Radiation Oncology*Biology*Physics DOI:10.1016/j.ijrobp.2020.07.1599

Authors: D.N. Antoni, H. Burckel, G. Noel

A Novel Sequentially Evolved EML4-ALK Variant 3 G1202R/S1206Y Double Mutation In Cis Confers Resistance to Lorlatinib: A Brief Report and Literature Review

Lorlatinib is a third-generation ALK inhibitor that can overcome the largest number of acquired ALK resistance mutations, including the solvent-front mutation G1202R. Here, we report, for the first time, a novel, sequentially-evolved EML4-ALK variant 3 G1202R/S1206Y double mutation in cis detected in a patient with ALK-positive NSCLC after disease progression on sequential crizotinib, alectinib, and then lorlatinib. Three-dimensional computer modeling of this double mutation and other G1202R-based double mutations with lorlatinib (ALK G1202R/L1196M, ALK G1202R/F1174C, ALK G1202R/l1198F, ALK G1202R/G1269A) were provided to reveal how these double mutations may confer resistance to lorlatinib through diverse steric hindrances in the ALK kinase domain. In addition, we performed a comprehensive literature review on published acquired double or triple ALK mutations that are resistant to lorlatinib from both patient samples and in vitro mutagenesis experiments. READ ARTICLE

Journal of Thoracic Oncology DOI: 10.1016/j.jtocrr.2020.100116

Authors: Viola W. Zhu, Misako Nagasaka, Russell Madison, Alexa B. Schrock, Jean Cui, Sai-Hong Ignatius Ou

Review PaperKirk SmithNovember 1, 2020TKI Resistance, Resistance mutation

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,

Lorlatinib and Bevacizumab Activity in ALK- Rearranged Lung Cancers After Lorlatinib Progression

In conclusion, the combination of lorlatinib and bevacizumab demonstrated activity and was safe in patients with heavily pretreated, ALK-rearranged lung cancers that had progressed on single-agent lorlatinib immediately before the combination. These findings add to a growing body of literature on the potential utility of antiangiogenic therapy with TKI therapy in oncogene-driven cancers. READ ARTICLE

JCO Precision Oncology DOI: 10.1200/PO.20.00271

Authors: Choudhury NJ, Young RJ, Sellitti M, Miller A, Drilon A.

Case StudyKirk SmithNovember 1, 2020lorlatinib, bevacizumab

Dual Mechanisms of Novel CD73-Targeted Antibody and Antibody–Drug Conjugate in Inhibiting Lung Tumor Growth and Promoting Antitumor Immune-Effector Function

We found elevated CD73 expression to be prevalent in non–small cell lung cancer (NSCLC) including those harboring the RAS- or RTK (EGFR, EML4-ALK) oncogenes. CD73 expression is enriched closely with the transcriptome signature of epithelial–mesenchymal transition and the immune-tolerant tumor microenvironment, which are increasingly relevant for disease progression and therapy resistance. We developed two novel series of CD73 antibody, Ab001/Ab002 and humanized version Hu001/Hu002, which demonstrated high CD73 binding affinity, potent enzyme inhibition, and efficiently protected effector T lymphocyte function from adenosine/cancer-imposed toxicity. Hu001/Hu002 inhibited growth of RAS-mutant NSCLC tumors in mice via enhanced antibody-dependent cell-mediated cytotoxicity and multifaceted remodeling of the tumor immune environment, reflecting diminished levels of tumor-associated macrophages, myeloid-derived suppressor cells, and tumor vasculature. A novel MMAE-conjugated CD73-ADC (Hu001–..... READ ARTICLE

Molecular Cancer Therapeutics DOI: 10.1158/1535-7163.MCT-20-0076

Authors: Rui Jin, Liang Liu, Yun Xing, Tao Meng, Lanping Ma, Jinpeng Pei, Ying Cong, Xuesai Zhang, Zhiqiang Ren, Xin Wang, Jingkang Shen and Ker Yu

Pre-ClinicalKirk SmithNovember 1, 2020Antibody-Drug Conjugates (ADC)

Later-Line Treatment with Lorlatinib in ALK- and ROS1-Rearrangement-Positive NSCLC: A Retrospective, Multicenter Analysis

In clinical practice, patients with anaplastic lymphoma kinase (ALK)-rearrangement–positive non–small-cell lung cancer commonly receive sequential treatment with ALK tyrosine kinase inhibitors. The third-generation agent lorlatinib has been shown to inhibit a wide range of ALK resistance mutations and thus offers potential benefit in later lines, although real-world data are lacking. This multicenter study retrospectively investigated later-line, real-world use of lorlatinib in patients with advanced ALK- or ROS1-positive lung cancer. Fifty-one patients registered in a compassionate use program in Austria, who received second- or later-line lorlatinib between January 2016 and May 2020, were included in this retrospective real-world data analysis. Median follow-up was 25.3 months. Median time of lorlatinib treatment was 4.4 months for ALK-positive and 12.2 months for ROS-positive patients. ALK-positive patients showed a response rate of 43.2%, while 85.7% percent of the ROS1-positive pa.....READ ARTICLE

Pharmaceuticals DOI: 10.3390/ph13110371

Author: Maximilian J. Hochmair, Hannah Fabikan ,Oliver Illini, Christoph Weinlinger ,Ulrike Setinek, Dagmar Krenbek , Helmut Prosch , Markus Rauter ,Michael Schumacher ,Ewald Wöll ,Romana Wass ,Elmar Brehm ,Gudrun Absenger , Tatjana Bundalo , Peter Errhalt , Matthias Urban and Arschang Valipour

Real-World OutcomesKirk SmithNovember 1, 2020ALK, ROS1, tyrosine kinase inhibitor, sequential treatment, lorlatinib

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.

Emerging EML4-ALK Variant 5 as a Concurrent Resistance Mechanism to Osimertinib in a Patient With EGFR E19del/T790M NSCLC

The management of patients with epidermal growth factor receptor (EGFR)-mutant, metastatic non–small-cell lung cancer (NSCLC) who become resistant to EGFR inhibitors remains challenging given the presence of complex and heterogeneous resistance mechanisms. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2020.05.009

Authors: Yan Yan, Guozhong Jiang, Weijie Ma, Tianhong Li, Liping Wang

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

306P Detection of anaplastic lymphoma kinase (ALK) mutations using circulating tumour DNA (ctDNA) in advanced non-squamous non-small cell lung cancer (non-Sq-NSCLC) in Asia

Background: ... We assessed clinical utility of ctDNA NGS for ALK testing for non-Sq-NSCLC in Asia... Conclusions: NGS testing for ALK fusions and genomic alterations in plasma ctDNA has clinical utility in non-Sq-NSCLC patients in guiding ALK targeted treatment at initial diagnosis and upon cancer progression. Detection rate and distribution of ALK fusion partners are comparable to existing data of tumor ALK testing. Further data on ALK treatment outcomes of patients with detectable ALK fusion on plasma ctDNA is warranted. READ ARTICLE

Annals of Oncology DOI:10.1016/j.annonc.2020.10.300

Authors: K. W. C. Lee, S. T. Wu, P. Y. Lo, C. T. Choy, T. C. Kwong, Y. T. N. Lau, L. Lin, S. W. Lau

410P Frequency and spectrum of primary resistance mechanism in Chinese ALK+ non-small cell lung cancer patients progressing on crizotinib: A multicenter study

Background: Anaplastic lymphoma kinase (ALK) have been recognized as the most important predictor of response to crizotinib. However, 20-30% of patients harboring ALK fusion non-small-cell lung cancer patients show a poor response requiring investigation for underlying mechanisms... Conclusions: BCL2L11 loss, PI3K-AKT-mTOR signaling pathway (PTEN, PIK3CA mutations), SMARCA4 mutations or EML4-ALK fusion (non A20) might contribute to molecular mechanisms of primary resistance to crizotinib in ALK+NSCLC.Further investigations are warranted to overcome these primary resistance. READ ARTICLE

Annals of Oncology DOI:10.1016/j.annonc.2020.10.404

Authors: W-X. Wang, C. Xu, Q-X. Zhang, W. Zhuang, Z-B. Song, Y-C. Zhu, G. Chen, M-Y. Fang, T-F. Lv, Y. Song

Liver and Pancreatic Injury in Response to ALK Inhibitors in a Patient with Primary Signet Ring Cell Carcinoma of the Lung: A Case Report

We report a patient with stage IV anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (primary lung signet ring cell adenocarcinoma) who received serial crizotinib, chemotherapy, and lorlatinib over more than 4 years. The patient discontinued crizotinib after approximately 4 months due to crizotinib-associated hepatotoxicity. Twenty-five days later, when transaminases had normalized, crizotinib was resumed. However, the patient’s liver enzymes rapidly increased again, and crizotinib was discontinued. After 6 cycles of platinum-based chemotherapy, lorlatinib was initiated. Hepatotoxicity did not recur with lorlatinib, a next-generation ALK inhibitor, but grade 4 hypertriglyceridemia and acute pancreatitis were induced by lorlatinib after 4 months. To our knowledge, this is the first case report of acute pancreatitis with lorlatinib. Additionally, stereotactic body radiation therapy (SBRT) was performed for residual small primary lesions in the lung without stopping lorlatinib. Given the rarity of radiation pneumonitis, especially with the relatively small fields treated by SBRT, we suspect that lorlatinib enhanced the pulmonary toxicity. Physicians should be aware that ALK inhibitors, such as lorlatinib and crizotinib, have potentially lethal side effects. READ ARTICLE

Case Reports in Oncology DOI: 10.1159/000512829

Authors: Ibrahim Yildiz

Case StudyKirk SmithOctober 27, 2020Pancreatitis, Hypertriglyceridemia, ALK rearrangement, lorlatinib

Dissecting the landscape of CAF-mediated drug resistance mechanisms in ALK-rearranged NSCLC

Cancer-associated fibroblasts (CAFs) are predominant stromal cells associated with cancer development and drug resistance. Due to the complexity of the crosstalk between CAFs and cancer cells, the underlying mechanism often remains elusive. Here, we aim to elucidate the complex, bidirectional signaling network that governs CAF-mediated resistance to targeted drugs in EML4-ALK-rearranged non-small-cell lung cancer (NSCLC) cells. READ ARTICLE

European Journal of Cancer DOI:10.1016/S0959-8049(20)31205-3

Authors: Q. Hu, L.L. Remsing Rix, X. Li, E.A. Welsh, B. Fang, S. Yun, J. Kroeger, H.R. Lawrence, A. Marusyk, J.M. Koomen, E.B. Haura, U. Rix,

Pre-ClinicalKirk SmithOctober 26, 2020CAF-mediated resistance, ALK, NSCLC

Combined small cell lung carcinoma harboring ALK rearrangement: A case report and literature review

Combined small cell lung cancer (c-SCLC) is a relatively rare subtype of SCLC and is defined by the combination of SCLC and any elements of non-small cell carcinoma (NSCLC). Standard chemotherapy for patients with c-SCLC has not yet been established. Gene mutations such as epidermal growth factor receptor (EGFR) mutations may be detected in patients with c-SCLC. However, little is known about ana-plastic lymphoma kinase (ALK) rearrangement in c-SCLC patients. Here, we report a young female patient who was successfully treated with alectinib for ALK-positive c-SCLC after failure of immunochemotherapy for SCLC and cytotoxic chemotherapy for adenocarcinoma. Moreover, we performed a literature review of EGFR- or ALK-positive c-SCLC patients. Our report suggests that ALK testing may be justified in patients with SCLC that contain an adenocarcinoma component READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.13716

Authors: Takayuki Niitsu, Takayuki Shiroyama, Kotaro Miyake, Yoshimi Noda, Kansuke Kido, Reina Hara,Takatoshi Enomoto, Yuichi Adachi, Saori Amiya,YasuhikoSuga, Kiyoharu Fukushima,Shohei Koyama, Kota Iwahori, Haruhiko Hirata, Izumi Nagatomo, Yoshito Takeda, Atsushi Kumanogoh

Case StudyKirk SmithOctober 25, 2020Alectinib, ALK, combined small cell carcinoma (c-SCLC), immunochemotherapy

Dr. Alice Shaw participated in a question and answer session with ALK-positive patients and caregivers.

Dr. Alice Shaw participated in a question and answer session with ALK-positive patients and caregivers. WATCH VIDEO

ALK Positive Inc.

Author: Alice Shaw

VideoKirk SmithOctober 20, 2020ALKtALK