Lorlatinib in pretreated ALK- or ROS1-positive lung cancer and impact of TP53 co-mutations: results from the German early access program

We report on the results of the German early access program (EAP) with the
third-generation ALK- and ROS1-inhibitor lorlatinib. Our data from real-life practice demonstrate the efficacy of lorlatinib in mostly heavily pretreated patients, providing a clinically meaningful option for patients with resistance mutations not covered by other targeted therapies and those with BM or leptomeningeal carcinomatosis. READ ARTICLE

Therapeutic advances in Medical Oncology DOI: 10.1177/1758835920980558

Authors: Nikolaj Frost, Petros Christopoulos, Diego Kauffmann-Guerrero, Jan Stratmann, Richard Riedel, Monica Schaefer, Jürgen Alt, Sylvia Gütz, Daniel C. Christoph, Eckart Laack, Martin Faehling, Richard Fischer, Klaus Fenchel, Sebastian Haen, Lukas Heukamp, Christian Schulz, Frank Griesinger

Real-World OutcomesKirk SmithFebruary 1, 2021ALK, brain metastases, early access program, NSCLC, ROS1, TP53, lorlatinib

Out-of-Pocket Costs for Tyrosine Kinase Inhibitors and Patient Outcomes in EGFR- and ALK-Positive Advanced Non–Small-Cell Lung Cancer

Among patients with advanced EGFR- and ALK-positive NSCLC, higher TKI Out-Of-Pocket costs are associated with decreased TKI adherence, a higher likelihood of TKI discontinuation, and inferior survival. READ ARTICLE

Journal of Clinical Oncology: Oncology Practice DOI: 10.1200/OP.20.00692 JCO

Authors: Bernardo H.L. Goulart, Joseph M. Unger, Shasank Chennupati, Catherine R. Fedorenko, Scott D. Ramsey

Real-World OutcomesKirk SmithFebruary 1, 2021Cost, TKI, Patient Outcomes, EGFR, ALK, Advanced NSCLC

Challenges of diagnostic genomics in Latin America

Cancer genome sequencing methods have now become essential for diagnostic purposes, for devising treatment strategies, and for monitoring disease regression and progression. However, access to these benefits has not permeated homogeneously throughout the world; certain regions, such as Latin America, have been slower at adopting these technologies in terms of their routine use, development and patient access. There are also differences among Latin American subregions with respect to their prioritized types of neoplasia and the drugs that are available and approved in them. An overview of the current situation, including the status of genomics for cancer diagnostics and efforts by type of cancer is presented. In addition, we discuss the perspective of initiatives, alliances, and educational/research programs that pledge to make cancer genomics diagnosis a reality for Latin American individuals’ health. READ ARTICLE

Current Opinion in Genetics & Development DOI:10.1016/j.gde.2020.12.010

Authors: Rosa Maria Alvarez-Gomez, Marcela Angelica De la Fuente-Hernandez, Luis Herrera-Montalvo and Alfredo Hidalgo-Miranda

Review PaperKirk SmithJanuary 28, 2021Latin America, cancer genomics

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

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: Oncology

Authors: Ross Camidge

EditorialKirk SmithJanuary 26, 2021Antibody-Drug Conjugates, NSCLC

Revisiting a lower starting dose of alectinib in ALK-Positive non-small cell lung cancer

We present here a case of ALK-positive lung adenocarcinoma that has been started on Alectinib. Treatment has been initiated at the recommended initial dose, but it subsequently required a dose adjustment following adverse drug events. Alectinib is a second-generation, CNS-active, tyrosine kinase inhibitor used in the treatment of ALK-positive non-small cell lung cancer. Its efficacy as a first-line treatment and as a second-line agent after Crizotinib has been proven across several trials both in terms of overall response rate and progression-free survival. The use of Alectinib is associated with side effects that occasionally lead to treatment discontinuation, interruption, or dose adjustment. Several studies have used two starting doses – 300 mg and 600 mg twice daily – across different populations and have consistently shown efficacy of Alectinib for both treatment doses. Results of these studies have also revealed that body weight, rather than race, affect the pharmacokinetics of A..... READ ARTICLE

Cancer Treatment and Research Communications DOI:10.1016/j.ctarc.2021.100319

Authors: Danielle Benedict Sacdalan and Josephine Anne Luceroc

Dr. Christine Lovly shares her lab and helps with a question and answer session with members of the ALK Positive group.

Dr. Christine Lovly shares her lab and helps with a question and answer session with members of the ALK Positive group. Moderated by Amanda Nerstad and hosted by Marc Rosenzweig. WATCH VIDEO

ALK Positive Inc.

Authors: Christine Lovly

VideoKirk SmithJanuary 21, 2021ALKtALK

Therapeutic Sequencing in ALK+ NSCLC

Anaplastic lymphoma kinase-rearranged non-small-cell lung cancer (ALK+ NSCLC) is a model disease for the use of targeted pharmaceuticals in thoracic oncology. Due to higher systemic and intracranial efficacy, the second-generation ALK tyrosine kinase inhibitors (TKI) alectinib and brigatinib have irrevocably displaced crizotinib as standard first-line treatment, based on the results of the ALEX and ALTA-1L trials. Besides, lorlatinib and brigatinib are the preferred second-line therapies for progression under second-generation TKI and crizotinib, respectively, based on the results of several phase II studies. Tissue or liquid rebiopsies at the time of disease progression, even though not mandated by the approval status of any ALK inhibitor, are gaining importance for individualization and optimization of patient management. The potential clinical utility of longitudinal ctDNA assays for earlier detection of disease progression and improved guidance of therapy in these patients is a cur..... READ ARTICLE

Pharmaceuticals DOI: 10.3390/ph14020080

Authors: Elsayed M., Christopoulos P.

Review PaperKirk SmithJanuary 21, 2021ALK, NSCLC, TKI, EML4-ALK fusion variant 3, chemotherapy, sequential treatment

Targeting Cysteine Located Outside the Active Site: An Effective Strategy for Covalent ALKi Design

Potent inhibitors of ALK are highly desired because of the occurrence of drug resistance. We herein firstly report the development of a rationally designed inhibitor, Con B-1, which can covalently bind to Cys1259, a cysteine located outside the ALK active site by linking a warhead with Ceritinib through a 2,2′-Oxybis(ethylamine) linker. The in vitro and in vivo assays showed ConB-1 is a potent selective ALKi with low toxicity to normal cells. In addition, the molecule showed significant improvement of anticancer activities and potential antidrug resistant activity compared with Ceritinib, demonstrating the covalent inhibitor of ALK can be a promising drug candidate for the treatment of NSCLC. This work may provide a novel perspective on the design of covalent inhibitors. READ ARTICLE

Journal of Medicinal Chemistry DOI:10.1021/acs.jmedchem.0c01707

Authors: Guoyi Yan, Xinxin Zhong, Chunlan Pu, Lin Yue, Huifang Shan, Suke Lan, Meng Zhou, Xueyan Hou, Jie Yang, Deyu Li, Shilong Fan, and Rui Li

Pre-ClinicalKirk SmithJanuary 20, 2021Cells, Inhibitors, Inhibition, Peptides and proteins, Molecules

Detecting Resistance to Therapeutic ALK Inhibitors in Tumor Tissue and Liquid Biopsy Markers: An Update to a Clinical Routine Practice

The survival of most patients with advanced stage non-small cell lung cancer is prolonged by several months when they are treated with first- and next-generation inhibitors targeting ALK rearrangements, but resistance inevitably emerges. Some of the mechanisms of resistance are sensitive to novel ALK inhibitors but after an initial tumor response, more or less long-term resistance sets in. Therefore, to adapt treatment it is necessary to repeat biological sampling over time to look for different mechanisms of resistance. To this aim it is essential to obtain liquid and/or tissue biopsies to detect therapeutic targets, in particular for the analysis of different genomic alterations. This review discusses the mechanisms of resistance to therapeutics targeting genomic alterations in ALK as well as the advantages and the limitations of liquid biopsies for their identification. READ ARTICLE

Cells DOI:10.3390/cells10010168

Authors: Paul Hofman

Review PaperKirk SmithJanuary 15, 2021liquid biopsy, lung cancer, ALK, resistance, targeted therapy

Real-world adherence and persistence with anaplastic lymphoma kinase inhibitors in nonsmall cell lung cancer

Several anaplastic lymphoma kinase (ALK) inhibitors have been approved for the treatment of metastatic ALK-positive nonsmall cell lung cancer (NSCLC), including alectinib, crizotinib, brigatinib, ceritinib, and lorlatinib. While efficacy and safety are well documented, real-world data on the use of ALK inhibitors are currently limited. In this pooled analysis of 3 US insurance claims databases, alectinib was associated with longer real-world persistence than other ALK inhibitors, despite similar adherence. This is the first study to assess adherence and persistence with ALK inhibitors for the treatment of patients with ALK-positive NSCLC in real-world clinical practice. READ ARTICLE

Journal of Managed Care and Specialty Pharmacy DOI:10.18553/jmcp.2021.21310

Authors: Apar Kishor Ganti, Chia-Wei Lin, Erru Yang, William B Wong, and Sarika Ogale

Real-World OutcomesKirk SmithJanuary 12, 2021ALK inhibitors, adherence, persistence

Therapeutic Strategies to Overcome ALK Resistance in Cancer

Therapeutic Strategies to Overcome ALK Resistance in Cancer, Volume 13, presents current strategies to improve and prolong clinical benefit in ALK driven cancers. Most patients with ALK-driven cancer are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops. This book discusses topics such as structure and function of ALK, ALK rearranged lung cancer, resistance mechanisms to ALK TKI tumors, and novel therapeutic strategies to enhance crizotinib anti-tumor efficacy in ALCL. Additionally, it encompasses information on drug combinations to enhance ALK TKI anti-tumor efficacy in neuroblastoma and future perspectives in the field. This book is a valuable resource for cancer researchers, clinicians and several members of biomedical field who need to understand more about how to fight ALK resistance in cancer treatment. READ ARTICLE

Academic Press DOI: 10.1016/C2019-0-03295-5

Edited by: Luc Friboulet

NPM-ALK: A Driver of Lymphoma Pathogenesis and a Therapeutic Target

Initially discovered in anaplastic large cell lymphoma (ALCL), the ALK anaplastic lymphoma kinase is a tyrosine kinase which is affected in lymphomas by oncogenic translocations, mainly NPM-ALK. To date, chemotherapy remains a viable option in ALCL patients with ALK translocations as it leads to remission rates of approximately 80%. However, the remaining patients do not respond to chemotherapy and some patients have drug-resistant relapses. It is therefore crucial to identify new and better treatment options. Nowadays, different classes of ALK tyrosine kinase inhibitors (TKI) are available and used exclusively for EML4-ALK (+) lung cancers. In fact, the significant toxicities of most ALK inhibitors explain the delay in their use in ALCL patients, who are predominantly children. Moreover, some ALCL patients do not respond to Crizotinib, the first generation TKI, or develop an acquired resistance months following an initial response. Combination therapy with ALK inhibitors in ALCL is th..... READ ARTICLE

Cancers (Basel) DOI:10.3390/cancers13010144

Authors: Elissa Andraos, Joséphine Dignac, Fabienne Meggetto

Dr. Ross Camidge answers questions from members of ALK Positive.

Dr. Ross Camidge answers questions from members of ALK Positive. WATCH VIDEO

ALK Positive Inc.

Authors: Ross Camidge

VideoKirk SmithJanuary 3, 2021ALKtALK

Impact of STAT1 polymorphisms on crizotinib-induced hepatotoxicity in ALK-positive non-small cell lung cancer patients

Polymorphism of rs10208033 is a potential biomarker for predicting crizotinib-induced hepatotoxicity. These results suggest that STAT1 plays an important role in crizotinib-induced hepatotoxicity. Further studies are needed to confirm our finding and understand the underlying mechanisms. READ ARTICLE

Journal of Cancer Research and Clinical Oncology DOI:10.1007/s00432-020-03476-4

Authors: Xin, S., Fang, W., Li, J. et al.

Treatment of Brain Metastases of Non-Small Cell Lung Carcinoma

Lung cancer is one of the most common malignant neoplasms. As a result of the disease’s progression, patients may develop metastases to the central nervous system. The prognosis in this location is unfavorable; untreated metastatic lesions may lead to death within one to two months. Existing therapies—neurosurgery and radiation therapy—do not improve the prognosis for every patient. The discovery of Epidermal Growth Factor Receptor (EGFR)—activating mutations and Anaplastic Lymphoma Kinase (ALK) rearrangements in patients with non-small cell lung adenocarcinoma has allowed for the introduction of small-molecule tyrosine kinase inhibitors to the treatment of advanced-stage patients. The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein with tyrosine kinase-dependent activity. EGFR is present in membranes of all epithelial cells. In physiological conditions, it plays an important role in the process of cell growth and proliferation. Binding the ligand to the EGFR causes ..... READ ARTICLE

International Journal of Molecular Science DOI:10.3390/ijms22020593

Authors: Agnieszka Rybarczyk-Kasiuchnicz, Rodryg Ramlau, and Katarzyna Stencel

Evolutionary analyses guide selection of model systems to investigate proto-oncogene function in ALK and LTK

Model systems to investigate oncogene-driven cancer have played an essential role in the development of therapies for cancer. However, not all systems are appropriate for all therapeutic targets. Knowing where and when proto-oncogenes and their interactors originated in evolutionary history is key to understanding which organisms can serve as models. Here we investigate two tyrosine kinase receptors that underlie tumorigenesis in cancer: anaplastic lymphoma kinase (ALK) and leukocyte tyrosine kinase (LTK). In Drosophila melanogaster, Caenorhabitis elegans, and Homo sapiens, the discovery of putative ligands Jeb, Hen-1, and AUG has the potential to accelerate the development of novel therapeutics. However, homology of these ligands and receptors is unclear. We performed an exhaustive search for their homologs spanning the metazoan tree of life. Jeb and Hen-1 were restricted to species that diverged prior to the origin of all vertebrates. No non-vertebrate species had ligands orthologous..... READ ARTICLE

Genome Biology and Evolution DOI:10.1101/795468

Authors: Alex Dornburg, Zheng Wang, Junrui Wang, Elizabeth S Mo, Francesc López-Giráldez, Jeffrey P Townsend

Pre-ClinicalKirk SmithJanuary 1, 2021Proto-oncogene function, ALK, leukocyte tyrosine kinase (LTK)

Alectinib following brigatinib: an efficient sequence for the treatment of advanced anaplastic lymphoma kinase-positive lung cancer patients

Anaplastic lymphoma kinase (ALK)-translocations are present in up to 5% of non-small cell lung cancer (NSCLC), most of them being adenocarcinomas. Even though the availability of five potent ALK-inhibitors for the treatment of ALK-positive NSCLC patients, there is no consensus about the ideal therapy sequence. Alectinib has been so far successfully and routinely used as first-line therapy, especially in patients presenting central nervous system lesions; however, with the very recent European approval of brigatinib in the first line, a new treatment option is now available for ALK+ patient collective. In this case series, efficient systemic and intracranial responses to alectinib late-line treatment following brigatinib therapy are reported. This therapeutic sequence is going to gain therefore more importance in a near future READ ARTICLE

Anti-Cancer Drugs DOI:10.1097/CAD.0000000000000989

Authors: Hochmair, Maximilian Johannesa; Prosch, Helmutb; Krenbek, Dagmarc; Weinlinger, Christopha; Fabikan, Hannaha; Valipour, Arschang

The effect of metformin in EML4-ALK+ lung cancer alone and in combination with crizotinib in cell and rodent models

Cell based studies have suggested that the diabetes drug metformin may combine with the anaplastic lymphoma kinase receptor (ALK) inhibitor crizotinib to increase ALK positive lung cancer cell killing and overcome crizotinib resistance. We therefore tested metformin alone and in combination with crizotinib in vivo, by employing a xenograft mouse model of ALK positive lung cancer. We found that 14 days of daily oral metformin (100 mg/kg) alone had a moderate but statistically significant effect on tumour growth suppression, but in combination with crizotinib, produced no greater tumour suppression than crizotinib (25 mg/kg) alone. We also reassessed the effect of metformin on EML4-ALK positive lung cancer (H3122) cell viability. Although metformin alone did have a moderate effect on cell viability (30% suppression) this was only at a clinically irrelevant concentration (5 mM) and there was no additive effect with cytotoxic concentrations of crizotinib. Moreover, metformin did not overco..... READ ARTICLE

Biochemical Pharmacology DOI:10.1016/j.bcp.2020.114345

Authors: A.R. Bland, N. Shrestha, R.L. Bower, R.J. Rosengren, J.C. Ashton

Pre-ClinicalKirk SmithJanuary 1, 2021Crizotinib, Metformin, EML4-ALK+ lung cancer

APOBEC3A drives acquired resistance to targeted therapies in non-small cell lung cancer

Acquired drug resistance to even the most effective anti-cancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified, the underlying molecular mechanisms shaping tumor evolution during treatment are incompletely understood. The extent to which therapy actively drives tumor evolution by promoting mutagenic processes or simply provides the selective pressure necessary for the outgrowth of drug-resistant clones remains an open question. Here, we report that lung cancer targeted therapies commonly used in the clinic induce the expression of cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Induction of A3A facilitated the formation of double-strand DNA breaks (DSBs) in cycling drug-treated cells, and fully resistant clones that evolved from drug-tolerant intermediates exhibited an elevated burden of chromosomal aberrations such as copy number..... READ ARTICLE

BioRxIV DOI:10.1101/2021.01.20.426852

Authors: Hideko Isozaki, Ammal Abbasi, Naveed Nikpour, Adam Langenbucher, Wenjia Su,
Marcello Stanzione, Heidie Frisco Cabanos, Faria M. Siddiqui, Nicole Phan, Pégah Jalili,
Sunwoo Oh, Daria Timonina, Samantha Bilton, Maria Gomez-Caraballo, Hannah L.
Archibald, Varuna Nangia, Kristin Dionne, Amanda Riley, Matthew Lawlor, Mandeep Kaur Banwait, Rosemary G. Cobb, Lee Zou, Nicholas J. Dyson, Christopher J. Ott, Cyril
Benes, Gad Getz, Chang S. Chan, Alice T. Shaw, Jessica J. Lin, Lecia V. Sequist,
Zofia Piotrowska, Jeffrey A. Engelman, Jake June-Koo Lee, Yosef Maruvka, Rémi
Buisson, Michael S. Lawrence, Aaron N. Hata