How long does crizotinib work? a rare case of recurrent inflammatory myofibroblastic tumor

Inflammatory myofibroblastic tumors (IMTs) are mesenchymal solid tumors, in which anaplastic lymphoma kinase (ALK) gene rearrangement might be detected. A 48-year-old female presented with IMT of lung, treated with surgery. After a 39-month disease-free survival metastatic recurrence was occurred involving soft tissues both infra- and supradiaphragmatic regions. The biopsies obtained from metastatic regions confirmed the recurrence with ALK rearrangement in immunohistochemistry. Initial partial response observed early in treatment course remained as a stable disease with crizotinib treatment. Although an excellent outcome with overall survival of 57 months was observed in our case, there is not enough information about survivals with crizotinib and the treatment options beyond progression. Therefore, every individual case has a unique value paving the way for more effective treatment. READ ARTICLE

Anticancer Drugs DOI:10.1097/CAD.0000000000001137

Authors: Albayrak HC, Gürler F, Sütçüoğlu O, Akyürek N, Özet A.

Fifty-five months progression-free survival with crizotinib treatment in coexistence of ALK and ROS1 rearrangements in lung adenocarcinoma: an extremely rare case and review of the literature

We wanted to present a case with coexistence of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) rearrangements that has been in remission for a long time with crizotinib. A 62-year-old nonsmoker male patient was diagnosed with Non-small cell lung cancer. Progression developed 9 months after the treatment, and coexistence of ALK and ROS1 positivity were detected in driver mutation analysis performed with fluorescent in situ hybridization. Crizotinib 2 × 250 mg was started in November 2016. The treatment of the patient, who has been in remission for approximately 55 months since then, continues. Until recently, the use of next-generation sequencing (NGS) was not common, but the more frequent epidermal growth factor receptor, then ALK, and finally ROS1 mutation were studied in tumor tissues. Sometimes ROS1 was not studied because there was not enough tissue left. We think that this rate will increase a little more with the widespread use of NGS from now on. Showing that ALK a..... READ ARTICLE

Anticancer Drugs DOI:10.1097/CAD.0000000000001224

Authors: Korkmaz M, Eryilmaz MK.

Genetic landscape of patients with ALK-rearranged non–small-cell lung cancer (NSCLC) and response to ceritinib in ASCEND-1 study

NGS data were generated for 85 pts (ALKi-pretreated [n = 54]; ALKi-naïve [n = 31]), 57 were collected from patients before exposure to any ALKi. NGS did not detect ALK rearrangement in 14 of 85 patients; several of these ALK NGS negative cases harbored alternative drivers, e.g. EGFR mutation. Of the 71 biopsies with NGS confirmed ALK rearrangement, the most frequently detected rearrangements were EML4-ALK variant 1 (V1) and EML4-ALK V3 (36.6% [26/71] and 32.4% [23/71] respectively). Eight (six crizotinib-pretreated and two pretreated with crizotinib followed by alectinib) of the 21 ALKi-pretreated patients carried a point mutation of the ALK TKD, and had the biopsy collected between 1 and 14 days before ceritinib; with the exception of one patient with a G1202R point mutation, all patients derived clinical benefit from ceritinib treatment.
Of the 14 ALKi-naïve patients, ceritinib was effective in almost all patients, including a patient carrying a concomitant ERBB4 and HGF amplificatio..... READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2021.11.007

Authors: D.S-W.Tana, M.Thomas, DW.Kim, S. Szpakowski, P. Urban, R. Mehra, L.Q.M. Chow, S. Sharma, B.J. Solomon, E.Felip, D.R. Camidge, J. Vansteenkiste, L. Petruzzelli, S. Pantano and A.T. Shaw

Is Elevation of Alkaline Phosphatase a Predictive Factor of Response to Alectinib in NSCLC?

In the following report, we describe a case of alkaline phosphatase (ALP) elevation occurring during treatment with alectinib (Alecensa™), which was administered for anaplastic lymphoma kinase (ALK) mutated metastatic non-small cell lung cancer (mNSCLC). A 51 year-old female with widespread metastatic disease exhibited a rapid and significant response within a very short period to alectinib therapy, accompanied by a rapid increase of ALP to more than six times the upper limit of normal (grade 3) ALP, decreasing to within normal limits within 3 weeks after initiation of therapy without any dose modification. READ ARTICLE

Current Oncology DOI:10.3390/curroncol29010016

Authors: Walid Shalata, Alexander Yakobson, Rachel Steckbeck, Ashraf Abu Jama, Omar Abu Saleh and Abed Agbarya

Case Study, group1Kirk SmithDecember 31, 2021lung adenocarcinoma, ALK mutation, Alectinib, alkaline phosphatase, toxicity

Effectiveness of alectinib and osimertinib in a brain metastasized lung adenocarcinoma patient with concurrent EGFR mutations and DCTN1-ALK fusion

The echinoderm microtubule associated protein-like 4 gene (EML4) encodes the predominant anaplastic lymphoma kinase (ALK) fusion partner in non-small-cell lung cancer (NSCLC); however, the dynactin subunit 1 (DCTN1)-ALK rearrangement is extremely rare. The co-occurrence of primary epidermal growth factor receptor (EGFR) T790M mutation with EGFR exon 19 deletion (del) in patients with NSCLC is uncommon. Here we report a female lung adenocarcinoma patient with brain metastases and possible coexistence of primary EGFR T790M mutation/EGFR exon 19 del/DCTN1-ALK translocation. The patient received multiline treatment including chemotherapy, antivascular, and targeted therapies. To overcome developed resistance to chemotherapy or targeted therapy to prolong overall survival, the patient's circulating tumor DNA (ctDNA) was dynamically monitored. The patient responded to successive osimertinib and alectinib treatment, and alectinib achieved a nearly complete response for lung and brain lesions ..... READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.14291

Authors: Shuyuan Wang, Bo Yan, Yanwei Zhang, Jianlin Xu, Rong Qiao, Yu Dong, Bo Zhang, Yiming Zhao, Lele Zhang, Jie Qian, Jun Lu, Ruiying Zhao, Baohui Han

Case Study, group1Kirk SmithDecember 28, 2021alectinib, osimertinib, brain metastasis, ALK, lung, EGFR, DCTN1-ALK

CD30-Directed Chimeric Antigen Receptor (CAR)-T Cells for Treatment of Hodgkin Lymphoma and Non-Hodgkin Lymphoma in Pediatric Patients

Chimeric antigen receptor (CAR)-T cell therapy targeting the CD19 antigen has been effective in treating B-cell acute lymphoblastic leukemia. As CAR-T cells targeting new antigens are being explored for the treatment of other cancers in adults, parallel studies are warranted for pediatric cohorts. We have previously shown the safety and efficacy in adults of CAR-T cells targeting CD30, which is expressed in classical Hodgkin Lymphoma (HL) and in some Non-Hodgkin Lymphoma (NHL). We have therefore sought to study the feasibility and the safety of CD30.CAR-T cells in pediatric patients with relapsed/refractory CD30-expressing HL and Anaplastic Large Cell Lymphoma (ALCL). READ ARTICLE

Blood DOI:10.1182/blood-2021-153968

Authors: George E.Hucks Jr., Barbara Savoldo, Gianpietro Dotti, Catherine Joyce, Arago Cheng, Caroline Babinec, Kimberly A.Kasow, Michael Winstead, Arpita Patel, Cammie Presler, Natalie SGrover, J. Kaitlin Morrison, Anne W.Beaven, Marcie L.Riches, Thomas C.Shea, Jonathan S.Serody

Identification of triple gene fusion ALK-LRRN2, LTBP1-ALK, and HIP1-ALK in advanced lung adenocarcinoma and response to alectinib: A case report

Together, we identified a rare triple ALK fusion variant, ALK-LRRN2, LTBP1-ALK and HIP1-ALK, in a patient with lung adenocarcinoma. The patient benefited from alectinib treatment, which could provide a certain reference for the patients with such gene alteration. READ ARTICLE

Medicine DOI:10.1097/MD.0000000000027999

Authors: Ning S, Shi C, Zhang H and Li J.

Case Study, group1Kirk SmithDecember 23, 2021alectinib, ALK-LRRN2, HIP1-ALK, LTBP1-ALK, lung adenocarcinoma, triple fusions

Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

Anaplastic lymphoma kinase (ALK) is validated as a therapeutic molecular target in multiple malignancies, such as non-small cell lung cancer (NSCLC). However, the feasibility of targeted therapies exerted by ALK inhibitors is inevitably hindered owing to drug resistance. The emergence of clinically acquired drug mutations has become a major challenge to targeted therapies and personalized medicines. Thus, elucidating the mechanism of resistance to ALK inhibitors is helpful for providing new therapeutic strategies for the design of next-generation drug. Here, we used molecular docking and multiple molecular dynamics simulations combined with correlated and energetical analyses to explore the mechanism of how gilteritinib overcomes lorlatinib resistance to the double mutant ALK I1171N/F1174I. We found that the conformational dynamics of the ALK kinase domain was reduced by the double mutations I1171N/F1174I. Moreover, energetical and structural analyses implied that the double mutations ..... READ ARTICLE

Frontiers of Cell and Developmental Biology DOI:10.3389/fcell.2021.808864

Authors: Liang Shuai, Wang Qing, Qi Xuesen, Liu Yudi, Li Guozhen, Lu Shaoyong, Mou Linkai, Chen Xiangyu

Pre-Clinical, group1Kirk SmithDecember 23, 2021Gilteritinib, Lorlatinib, Resistance, ALK

Updates on Molecular Targeted Therapies for Intraparenchymal CNS Metastases

Central nervous system (CNS) metastases can occur in a high percentage of systemic cancer patients and is a major cause of morbidity and mortality in these patients. Almost any histology can find its way to the brain, but lung, breast, and melanoma are the most common pathologies seen in the CNS from metastatic disease. Identification of many key targets in the tumorigenesis pathway has been crucial to the development of a number of drugs that have demonstrated successful penetration of the blood–brain, blood–cerebrospinal fluid, and blood–tumor barriers. Targeted therapy and immunotherapy have dramatically revolutionized the field with treatment options that can provide successful and durable control of even CNS disease. In this review, we discuss major targets with successful treatment options as demonstrated in clinical trials. These include tyrosine kinase inhibitors, monoclonal antibodies, and antibody–drug conjugates. We also provide an update on the state of the field and highli..... READ ARTICLE

Cancers DOI:10.3390/cancers14010017

Authors: Akanksha Sharma, Lauren Singer, Priya Kumthekar

Fatal Tumour Lysis Syndrome Induced by Brigatinib in a Lung Adenocarcinoma Patient Treated With Sequential ALK Inhibitors: A Case Report

Tumour lysis syndrome (TLS) represents a group of fatal metabolic derangements resulting from the rapid breakdown of tumour cells. TLS typically occurs soon after the administration of chemotherapy in haematologic malignancies but is rarely observed in solid tumours. Here, we report a case of brigatinib-induced TLS after treatment with sequential anaplastic lymphoma kinase (ALK) inhibitors in a patient with advanced ALK-rearranged lung adenocarcinoma. The patient was treated sequentially with crizotinib, alectinib, and ensartinib. High-throughput molecular profiling after disease progression indicated that brigatinib may overcome ALK resistance mutations, so the patient was administered brigatinib as the fourth-line treatment. After 22 days of therapy, he developed oliguria, fever, and progressive dyspnoea. Clinical manifestations and laboratory findings met the diagnostic criteria for TLS. The significant decrease in the abundance of ALK mutations in plasma indicated a therapeutic res..... READ ARTICLE

Frontiers in Pharmacology DOI:10.3389/fphar.2021.809467

Authors: Wang Yadong, Wang Tiange, Xue Jianchao, Jia Ziqi, Liu Xinyu, Li Bowen, Li Ji, Li Xiaoguang, Wang Weiwei, Bing Zhongxing, Cao Lei, Cao Zhili, Liang Naixin

Case Study, group1Kirk SmithDecember 20, 2021Tumour lysis syndrome (TLS), brigatinib, ALK

Enigma (Elucidating Novel Immune and Genomic Markers for ALK) with Drs Gainor and Lin

Watch to learn how ALK Positive patients can take an active role in accelerating ALK research. Research is what improves our life expectancy and gives us hope. "The purpose of this research study is to obtain and study tissue, saliva, and blood specimens from patients with ALK-positive lung cancer, along with clinical trial information about their disease and treatment. The overall goal is to enhance understanding of the biology of ALK-positive lung cancer."

WATCH VIDEO

ALK Positive Inc.

AUTHORS: Dr. Gainor and Dr. Lin

Video, group1Kirk SmithDecember 20, 2021

Patient Selection for Local Aggressive Treatment in Oligometastatic Non-Small Cell Lung Cancer.

One-fourth of all patients with metastatic non-small cell lung cancer presents with a limited number of metastases and relatively low systemic tumor burden. This oligometastatic state with limited systemic tumor burden may be associated with remarkably improved overall and progression-free survival if both primary tumor and metastases are treated radically combined with systemic therapy. This local aggressive therapy (LAT) requires a multidisciplinary approach including medical oncologists, radiation therapists, and thoracic surgeons. A surgical resection of the often advanced primary tumor should be part of the radical treatment whenever feasible. However, patient selection, timing, and a correct treatment allocation for LAT appear to be essential. In this review, we aimed to summarize and discuss the current evidence on patient selection criteria such as characteristics of the primary tumor and metastases, response to neoadjuvant or first-line treatment, molecular characteristics, mediastinal lymph node involvement, and other factors for LAT in oligometastatic NSCLC. READ ARTICLE

Cancers DOI:10.3390/cancers13246374

Authors: Werner, R.S. and Opitz, I.

Alectinib Together with Intracranial Therapies Improved Survival Outcomes in Untreated ALK-Positive Patients with Non-Small-Cell Lung Cancer and Symptomatic and Synchronic Brain Metastases

Purpose: The performance of alectinib and crizotinib in untreated anaplastic lymphoma kinase (ALK)-positive patients with non-small-cell lung cancer (NSCLC) and symptomatic and synchronic brain metastases is largely unknown. This retrospective study assessed the effectiveness of alectinib and crizotinib, together with intracranial therapies in a cohort of these patients.
Patients and Methods: This study included 34 previously untreated ALK-positive NSCLC patients with three or fewer intracranial metastases. Of these patients, 13 received oral alectinib 600 mg twice daily, and 21 received oral crizotinib 250 mg twice daily, until progressive disease, unacceptable toxicity, or death. All intracranial metastases were treated with craniotomy, CyberKnife, or both.
Results: Median overall progression-free survival (PFS) was 32.8 months (95% CI 24.4– 41.2 months) in patients treated with alectinib and 8.0 months (95% CI 7.3– 8.7 months) in patients treated with crizotinib. Median PFS of brain..... READ ARTICLE

Onco Targets Therapy DOI:10.2147/OTT.S345439

Authors: Yin Q, Li P, Wang P, Zhang Z, Liu Q, Sun Z, Li W, Ma L, Wang X

Analysis of methods in the Prospective Central Lung Cancer Biomarker Registry (LungPath) from the Spanish Society of Pathology (SEAP)

Aims The aim of this study is to extend the analysis of the Lung Cancer Biomarker Testing Registry (LungPath), by analysing the techniques used in the determination of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1) and programmed death ligand-1 (PD-L1) for the diagnostic of patients with advanced non-small-cell lung cancer (NSCLC). Methods Information of the technique used for the determination of EGFR, ALK, ROS1 and PD-L1 was recorded from March 2018 to January 2019 from 44 centres, but only 34 centres matched with the 38 centres previously analysed, allowing to analyse the techniques used in 8970 matched determinations of EGFR, ALK, ROS1 and PD-L1. Therefore, a by-centre analysis studied the level of implementation of the techniques in the 44 centres, while a by-determination analysis made it possible to assess the overall frequency of the techniques used on the 9134 matched samples. Results By-centre analysis showed that only 46.5%..... READ ARTICLE

Journal of Clinical Pathology DOI:10.1136/jclinpath-2021-208034

Authors: Martín-López J, Rojo F, Martínez-Pozo A,Hernández-Iglesias T, Carcedo D, Ruiz de Alda L, García JF, Salas C

Real-World Outcomes, group1Kirk SmithDecember 13, 2021NSCLC, ALK, EGFR, ROS, Biomarker Testing

Outcomes of Gamma Knife Radiosurgery for Brain Metastases From Anaplastic Lymphoma Kinase Rearrangement-Positive and EGFR Mutation-Positive Non-Small Cell Lung Cancer

The outcomes after gamma knife radiosurgery (GKRS) were retrospectively analysed in patients with brain metastases from anaplastic lymphoma kinase (ALK) rearrangement-positive and epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) to evaluate the efficacy, safety and difference for overall survival and local tumor control. ALK rearrangement-positive NSCLC patients tended to have significantly longer survival, but had higher incidence of new intracranial metastases due to long-term survival after GKRS, compared with EGFR mutation-negative and driver gene mutation-negative NSCLC patients. GKRS induced significantly satisfactory local tumor control in driver gene mutation-positive tumors but GKRS-related complication frequency was higher, especially in ALK-positive NSCLC patients. Therefore, more careful imaging follow-up is necessary after GKRS for patients with driver gene mutation-positive NSCLC. READ ARTICLE

Cureus DOI:10.7759/cureus.20398

Authors: Matsunaga S and Shuto T

Real-World Outcomes, group1Kirk SmithDecember 13, 2021Gamma Knife Radiosurgery (GKRS), Brain Metastases, ALK, EGFR, NSCLC

ALKtALK Dr. Shirish Gadgeel

Dr. Gadgeel brings brilliance, compassion and hope to ALKtALK. This talk offers the history of the ALK Positive mutation, the evolutions of its treatments, and current trials- including ADC and TIL Therapy. WATCH VIDEO

ALK Positive Inc.

Authors: Shirish Gadgeel

Video, group1Kirk SmithDecember 12, 2021ALKtALK

Safety and activity of alectinib plus bevacizumab in patients with advanced ALK-rearranged non-small-cell lung cancer: a phase I/II study

Alectinib, a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is highly effective in advanced ALK-rearranged non-small-cell lung cancer and represents a standard first-line therapy. New strategies are needed, however, to delay resistance. We conducted a phase I/II study to assess the safety and efficacy of combining alectinib with bevacizumab, a monoclonal antibody against vascular endothelial growth factor.
Patients with advanced ALK-rearranged non-squamous non-small-cell lung cancer were enrolled. The phase I portion employed a dose de-escalation strategy with alectinib and bevacizumab starting at the individual standard doses. The primary objective was to determine the recommended phase II dose (RP2D). In phase II, the primary objective was to evaluate the safety of the combination at the RP2D; the secondary objective was to determine extracranial and intracranial efficacy.
Eleven patients were enrolled between September 2015 and February 2020. Mos..... READ ARTICLE

ESMO Open, Cancer Horizons DOI:10.1016/j.esmoop.2021.100342

Authors: J.J. Lin, A. Muzikansky, E. Kennedy, I. Dagogo-Jack, A.T. Shaw, J.F. Gainor

Clinical Impact of Switching to Ceritinib After Severe AEs Related to Crizotinib/Alectinib in a Novel PTH2R-ALK Fusion Lung Adenocarcinoma: A Case Report

Lung cancer is still the leading cause of morbidity and mortality by cancer among men, according to the latest epidemiological data in China. Anaplastic lymphoma kinase (ALK) rearrangements act as key oncogenic drivers of non-small cell lung cancer (NSCLC) and have been identified in 5– 6% of NSCLC. Although ALK inhibitors (ALK-TKIs) were proven to be more effective than chemotherapy in ALK-positive NSCLC patients and the safety profile of these drugs was favorable, novel ALK fusions NSCLC might discontinue or switch treatment because of adverse events (AEs) have rarely previously been reported. Here, we describe a male patient with stage IV lung adenocarcinoma who carried a novel PTH2R-ALK fusion identified by next-generation sequencing (NGS). The patient first took crizotinib but switched to alectinib due to gastrointestinal AEs. Although alectinib remained effective on tumors, ceritinib (450 mg) was replaced after the AEs of hyperbilirubinemia occurred. After reducing the dose to 30..... READ ARTICLE

OncoTargets and Therapies DOI:10.2147/OTT.S340984

Authors: Shen G, Du Y, Shen J, Zhang J, Xia X, Huang M and Shen W.

Case Study, group1Kirk SmithDecember 9, 2021PTH2R-ALK, non-small cell lung cancer, ceritinib, adverse events

Treatment Options for Patients with ALK+ NSCLC who Progress on First-line TKIs

Karen Reckamp, MD, and Jyoti Patel, MD, outline their treatment approaches for patients with ALK+ NSCLC who progress on frontline TKIs. WATCH VIDEO

Targeted Oncology

Authors: Karen Reckamp, Jyoti Patel

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.