Polyclonal on- and off-target resistance mutations in an EML4-ALK positive non-small cell lung cancer patient under ALK inhibition

Treatment of advanced stage anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) with ALK tyrosine kinase inhibitors (TKIs) has been shown to be superior to standard platinum-based chemotherapy. However, secondary progress of disease frequently occurs under ALK inhibitor treatment. The clinical impact of re-biopsies for treatment decisions beyond secondary progress is, however, still under debate. Here, we report on two novel subsequent polyclonal on- and off-target resistance mutations in a patient with ALK-fused NSCLC under ALK inhibitor treatment. A 63-year-old male patient with an advanced stage EML4-ALK fused pulmonary adenocarcinoma was initially successfully treated with the second-generation ALK inhibitor alectinib and upon progressions subsequently with brigatinib, lorlatinib and chemoimmunotherapy (CIT). Progress to alectinib was associated with a so far undescribed ALK mutation (p.A1200_G1201delinsW) which was, however, tractable by brigatinib. An off..... READ ARTICLE

Oncotarget DOI:10.18632/oncotarget.28062

Authors: Marcel Kemper, Georg Evers, Arik Bernard Schulze, Jan Sperveslage, Christoph Schülke, Georg Lenz, Thomas Herold, Wolfgang Hartmann, Hans-Ulrich Schildhaus, and Annalen Bleckmann

Case StudyKirk SmithSeptember 14, 2021NSCLC, resistance mutations, ALK, KRAS, ALK inhibitors

Use of tyrosine kinase inhibitors during pregnancy for oncogenic-driven advanced non-small cell lung carcinoma

Lung cancer associated with pregnancy is rare but on the increase. The use of tyrosine kinase inhibitor (TKI) therapy for advanced oncogenic-driven non-small cell lung carcinoma (NSCLC) has improved overall survival. Oncological and obstetric outcomes of patients diagnosed with NSCLC and treated by TKIs during pregnancy have been poorly evaluated. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2021.09.001

Authors: Anne-Sophie Boudy, Noémie Grausz, Lise Selleret, Cyril Touboul, Emile Daraï, Jacques Cadranel

ALK Rearrangement–Positive Pancreatic Cancer with Brain Metastasis Has Remarkable Response to ALK Inhibitors: A Case Report

Patients with metastatic pancreatic cancer typically have poor prognosis due to the limited effectiveness of existing treatment options. ALK rearrangement–positive is rare in pancreatic cancer, but may occur in those with KRAS-wild type. We present a 34-year-old young man with ALK rearrangement–positive and KRAS-wild pancreatic cancer who had a remarkable response to crizotinib after resistance to prior chemotherapy and re-response to alectinib after brain metastases developed. This clinical observation suggests that comprehensive molecular profiling to guide targeted therapies is not only feasible, but also significantly improves survival outcomes for a subgroup of patients with pancreatic cancer. READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2021.724815

Authors: Kai Ou, Xiu Liu, Weihua Li, Yi Yang, Jianming Ying and Lin Yang

Case Study, group3Kirk SmithSeptember 6, 2021ALK, KRAS, pancreatic cancer

VCL-ALK renal cell carcinoma in adult patient without sickle cell trait

Anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC) is a provisional renal cell carcinoma subtype with a growing list of published fusion partners. VCL-ALK gene fusion represents an uncommon fusion partner (only 6 reported cases), almost always associated with sickle cell trait and typically in a pediatric population. Herein, we report only the second case of VCL-ALK gene fusion ALK-RCC from a 31-year-old female without associated sickle cell trait, and also only the third reported case occurring in an adult patient. The tumor (measuring 8.5 cm and confined to the kidney) demonstrated mostly solid growth, pleomorphic nuclei, variably rhabdoid to vacuolated cytoplasm, and showed diffuse strong immunoreactivity for both PAX8 and ALK stains. Gene panel sequencing confirmed VCL-ALK gene fusion in the tumor. This study expands the clinical framework for diagnostic consideration of this rare tumor with potential targeted pharmacotherapy. READ ARTICLE

Human Pathology: Case Reports DOI:10.1016/j.ehpc.2021.200528

Authors: Ankur R. Sangoi, Simon Y. Kimm, EmilyChan

Case StudyKirk SmithSeptember 1, 2021Kidney, Renal cell carcinoma, ALK, VCL, Sickle cell

68-months progression-free survival with crizotinib treatment in a patient with metastatic ALK positive lung adenocarcinoma and sarcoidosis: A case report

Lung cancer still ranks first among the most common and most lethal cancers today. The most common subtype is non-small cell lung cancer, and in this group, adenocarcinoma has the worst prognosis. EGFR, ROS1 and ALK-EML4 gene fusion mutations are common in non-small cell lung cancer.In this article, we wanted to share our experience of crizotinib in a 68-months progression-free survival in a 62-years old non-smoking female patient with metastatic lung adenocarcinoma who is also diagnosed with sarcoidosis. READ ARTICLE

Journal of Oncology Pharmacy Practice DOI:10.1177/1078155220951242

Authors: Ozgur Tanriverdi, Mehmet L Tarimer, Ceren D Pak, Selcuk Uylas, Ali Alkan, Ozgur Ilhan Celik, Rabia M Kilic, Arife Zeybek

Lorlatinib in a Child with ALK-Fusion–Positive High-Grade Glioma

A child near death with an ALK-fusion–positive high-grade glioma refractory to standard treatment had a dramatic response when treatment with lorlatinib was begun. The drug was stopped once the child had an apparent complete remission, but treatment with lorlatinib resumed when relapse occurred 6 months later. At this time, the child is attending preschool and has normal neurologic function. READ ARTICLE

New England Journal of Medicine DOI:10.1056/NEJMc2101264

Authors: Aditi Bagchi, Brent A Orr, Olivia Campagne, Sandeep Dhanda, Sreenath Nair, Quynh Tran, Anthony M Christensen, Amar Gajjar, Larissa V Furtado, Aksana Vasilyeva, Frederick Boop, Clinton Stewart and Giles W Robinson

Case Study, group3Kirk SmithAugust 19, 2021ALK, glioma, loraltinib, pediatric

Case Report: Identification of Two Rare Fusions, PDK1-ALK and STRN-ALK, That Coexist in a Lung Adenocarcinoma Patient and the Response to Alectinib

Several double ALK fusions coexisting in one patient have been reported. However, few studies have reported the clinical efficacy of ALK inhibitors in rare double ALK fusions. Here, we described a rare PDK1-ALK, STRN-ALK double-fusion variant in a patient with metastatic lung adenocarcinoma. The patient responded well to alectinib (600 mg) twice daily. This case shows a promising treatment option for patients with rare ALK double-fusion variants. READ ARTICLE

Frontiers in oncology DOI:10.3389/fonc.2021.722843

Authors: Zeng H, Li Y, Wang Y, Huang M, Zhang Y, Tian P, Li W.

Resistance profiles of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced non–small-cell lung cancer: a multicenter study using targeted next-generation sequencing

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for advanced non–small-cell lung cancer (NSCLC) with ALK rearrangement. However, the mechanisms of resistance remain largely unclear. This prospective multicenter study analyzed cell-free DNA (cfDNA) and/or cancer tissues of patients with NSCLC after progression on ALK TKI(s), using targeted next-generation sequencing. Patients’ clinicopathologic characteristics and treatment outcomes were analyzed. Overall, 88 patients were enrolled; 31 cancer tissues and 90 cfDNA samples were analyzed. The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers. READ ARTICLE

European Journal of Cancer DOI:10.1016/j.ejca.2021.06.043

Authors: Yen-Ting Lin, Chi-Lu Chiang, Jen-Yu Hung, Mei-Hsuan Lee, Wu-Chou Su, Shang-Yin Wu, Yu-Feng Wei, Kang-Yun Lee, Yen-Han Tseng, Jian Su, Hsin-Pei Chung, Chih-Bin Lin, Wen-Hui Ku, Tsai-Shin Chiang, Chao-Hua Chiu, Jin-Yuan Shih

An unusual fusion gene EML4-ALK in a patient with congenital mesoblastic nephroma

Congenital mesoblastic nephroma (CMN), the most common renal tumor of infancy, is a mesenchymal neoplasm histologically classified into classic, cellular, or mixed types. Most cellular CMNs harbor a characteristic ETV6-NTRK3 fusion. Here, we report an unusual congenital mesoblastic nephroma presenting in a newborn boy with a novel EML4-ALK gene fusion revealed by Anchored Multiplex RNA Sequencing Assay. The EML4-ALK gene fusion expands the genetic spectrum implicated in the pathogenesis of congenital mesoblastic nephroma, with yet another example of kinase oncogenic activation through chromosomal rearrangement. The methylation profile of the tumor corresponds with infantile fibrosarcoma showing the biological similarity of these two entities. READ ARTICLE

Genes Chromosomes & Cancer DOI:10.1002/gcc.22990

Authors: Adela Misove, Ales Vicha, Michal Zapotocky, Josef Malis, Jan Balko, Tereza Nemeckova, Jana Szabova, Martin Kyncl, Daniela Novakova-Kodetova, Lucie Stolova, Pavla Jencova, Petr Broz, Lenka Krskova

Case StudyKirk SmithAugust 10, 2021EML4-ALK, congenital mesoblastic nephroma

Drug interaction profile of TKI alectinib allows effective and safe treatment of ALK+ lung cancer in the kidney transplant recipient

ALK targeting with tyrosine kinase inhibitors (TKIs) is a highly potent treatment option for the therapy of ALK positive non-small cell lung cancer (NSCLC). However, pharmacokinetics of TKIs leads to clinically significant drug interactions, and the interfering co-medication may hamper the anti-cancer therapeutic management. Here, we present for the first time a drug interaction profile of ALK-TKIs, crizotinib and alectinib, and immunosuppressive agent cyclosporine A in kidney transplant recipients diagnosed with ALK+ lung cancer.Based on therapeutic drug monitoring of cyclosporin A plasma level, the dose of cyclosporine A has been adjusted to achieve a safe and effective therapeutic level in terms of both cancer treatment and kidney transplant condition. Particularly, 15 years upon the kidney transplantation, the stage IV lung cancer patient was treated with the 1st-line chemotherapy, the 2nd-line ALK-TKI crizotinib followed by ALK-TKI alectinib. The successful therapy with ALK-TKIs h..... READ ARTICLE

International Immunopharmacology DOI:10.1016/j.intimp.2021.108012

Authors: Ondrej Bilek, Milos Holanek, Jan Jurica, Sona Stepankova, Jiri Vasina, Iveta Selingerova, Alexandr Poprach, Simona Borilova, Tomas Kazda, Igor Kiss, Lenka Zdrazilova-Dubska

Dramatic response to alectinib in a patient with ALK-rearranged squamous cell lung cancer

Lung cancers with anaplastic lymphoma kinase (ALK) rearrangements are highly sensitive to treatment with ALK tyrosine kinase inhibitors (TKIs). Due to the very low rate of patients with squamous cell carcinoma enrolled in clinical trials, the efficacy of ALK inhibitors in patients with ALK-rearranged squamous cell carcinoma in the lung remains unclear. Herein, we present the case of a 70-year-old female patient with squamous cell lung cancer harboring the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene. The patient was treated with the ALK-TKI alectinib as first-line regimen and achieved a dramatic response without severe adverse events, demonstrating alectinib as a therapeutic option for patients with ALK-positive squamous cell carcinoma. READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.14092

Authors: Jun Shiihara,Fumiyoshi Ohyanagi,Hikari Amari,Minemichi Toda,Hiroki Tahara,Motoi Yuzawa,Yuki Maeda,Motoko Nomura,Yoshiko Mizushina,Yoshiaki Nagai,Hiromitsu Ohta,Yasuhiro Yamaguchi

Case StudyKirk SmithJuly 29, 2021ALK, squamous cell carcinoma, EML4-ALK. fusion gene, alectinib

Treatment Strategy of Lung Adenocarcinoma with Concomitant EGFR Mutation and ALK Rearrangement

The incidence of synchronous mutations of Epidermal growth factor receptor (EGFR) and anaplastic large-cell lymphoma kinase (ALK) rearrangements in non-small cell lung cancer (NSCLC) was low. Now clinical experience is still insufficient. Simultaneously the treatment of brain metastasis hemorrhage in the acute phase with lung cancer is still controversial. We described the clinical treatment strategy of a patient with synchronous mutations of EGFR and ALK.We found that the tumor was well controlled. Progression-free survival (PFS)1 was 4 months, PFS2 was 3 months, PFS3 was 5 months, PFS4 was 5 months, and PFS5 was 9 months. At present, the patient still maintains partial response (PR) status. READ ARTICLE

Research Square DOI:10.21203/rs.3.rs-718876/v1

Authors: Li Li , Wei Liu , Chunhua Xu, Jue Zou

Detection of acquired resistance mutation ALK G1202R after treatment with alectinib and response of lorlatinib

In the era of personalized medicine, the identification of driver mutations has paved the way towards targeted therapy. With the identification of anaplastic lymphoma kinase (ALK) as an oncogenic driver mutation, ALK rearrangements became druggable by tyrosine kinase inhibitors and, thus, have improved the prognosis for patients. Nevertheless, these approaches are limited by resistances occurring within the first or second year of administering ALK inhibitors. Among the different ALK resistant mutations, G1202R is the most common mutation, located in the kinase domain of the ALK protein resulting in resistance to treatment with the first- and second-generation kinase inhibitors (e.g., crizotinib, ceritinib, brigatenib and alectinib). Conflicting reports exist regarding the efficacy of lorlatinib, a next generation ALK inhibitor. The aim of this study is to access the potential impact of lorlatinib as a second-line treatment for a metastatic progressive NSCLC disease harboring genomic a..... READ ARTICLE

Magazine of European Medical Oncology (memo) DOI:

Authors: Louisa Hempel, Jakob Molnar, Andreas Gaumann, Sebastian Robert, Josef Scheiber, Axel Kleespies, Kristina Riedmann, Susanne Schreiber, Beate Gandorfer, Armin Piehler & Dirk Hempel

Case Study, group4Kirk SmithJuly 6, 2021alectinib, ALK rearrangement, lorlatinib

Tumor shrinkage with Combination of Alectinib and Trastuzumab in a Patient with ALK-Rearranged NSCLC Harboring HER2-amplification as an Acquired Resistance Mechanism to ALK Inhibitor Therapy

HER2 amplification is an acquired resistance mechanism in ALK-rearranged non-small cell lung cancer. READ ARTICLE

Clinical Lung Cancer DOI: 10.1016/j.cllc.2021.06.012

Authors: David Chun Cheong Tsui, Dara Aisner, Hala Nijmeh, Liming Bao, Alexander Menter and Ross Camidge

Case Study, group4Kirk SmithJuly 3, 2021ALK, HER2, lung cancer, acquired resistance, trastuzumab

$Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912)$

Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912)

Anaplastic lymphoma kinase (ALK) aberrations are a promising target for patients with neuroblastoma. We assessed the activity of first-generation ALK inhibitor crizotinib in patients with no known curative treatments and whose tumors harbored an activating ALK alteration. The objective response rate for patients with neuroblastoma was 15% [95% confidence interval (CI): 3.3%–34.3%]: two with partial responses and 1 with a complete response. All three patients had a somatic ALK Arg1275Gln mutation, the most common ALK hotspot mutation observed in neuroblastoma and the only mutation predicted to be sensitive to ALK inhibition with crizotinib. Two patients had prolonged stable disease (10 and 13 cycles, respectively); both harbored an ALK Arg1275Gln mutation. Three patients with ALK Phe1174Leu mutations progressed during cycle 1 of therapy, and one patient with an ALK Phe1174Val received three cycles before disease progression. The two patients with ALK amplification had no response. The ..... READ ARTICLE

Clinical Cancer Research DOI:10.1158/1078-0432.CCR-20-4224

Authors: Jennifer H. Foster, Stephan D. Voss, David C. Hall, Charles G. Minard, Frank M. Balis, Keith Wilner, Stacey L. Berg, Elizabeth Fox, Peter C. Adamson, Susan M. Blaney, Brenda J. Weigel and Yael P. Mossé

Case Study, group4Kirk SmithJuly 1, 2021ALK, neuroblastoma, pediatric, crizotinib

Clinical features and intervention timing in patients with pregnancy-associated non-small-cell lung cancer

Seventy-seven cases were collected including 11 patients from our center. The anaplastic lymphoma kinase (ALK) gene rearrangement and epidermal growth factor receptor (EGFR) mutation rates were 47% and 32%, respectively. The OS of patients treated during pregnancy, after delivery, and those not treated differed significantly [12 months vs. not reached (NR) vs. 1 month; P<0.001]. However, the OS between patients treated during pregnancy and after delivery was similar (P=0.173). Patients with ALK or EGFR exhibited a significantly better OS than those with wild-type [NR vs. 22 months vs. 8 months; P<0.001; hazard ratio (HR) =0.02, 95% confidence interval (CI): 0.00–0.22; HR =0.08, 95% CI: 0.01–0.76]. Fetal complications were observed in babies whose mothers were treated during pregnancy. The pregnancy-associated NSCLC population exhibited a high prevalence of driver genes and a promising effect of targeted therapy. No significant difference in the OS was observed between patients treated..... READ ARTICLE

Journal of Thoracic Disease DOI:10.21037/jtd-21-234

Authors: Lei Yang, Yun-Ting He, Jin Kang, Ming-Ying Zheng, Zhi-Hong Chen, Hong-Hong Yan, Xu-Chao Zhang, Jin-Ji Yang, Yi-Long Wu and Qing Zhou

Exceptional response to the ALK and ROS1 inhibitor lorlatinib and subsequent mechanism of resistance in relapsed ALK F1174L-mutated neuroblastoma

In summary, we describe a patient with relapsed, refractory neuroblastoma harboring the ALK F1174L mutation resistant to the first-generation ALK inhibitor crizotinib combined with chemotherapy in whom lorlatinib induced a durable complete remission of 13 mo. However, as is often the case with targeted therapeutic approaches, resistance, potentially mediated by new genomic alterations including CDK4 and FGFR1 amplification and NRAS mutation, led to disease recurrence. Our case provides an example of clinical benefit made possible by the development of next-generation ALK inhibitors but also highlights the need for increased understanding of mechanisms of acquired resistance. We propose that molecular monitoring during therapy may guide rational combination multidrug approaches to overcome and prevent resistance. READ ARTICLE

Cold Spring Harbor: Molecular Case Studies DOI:10.1101/mcs.a006064

Authors: Tingting Liu, Matthew D., Merguerian, Steven P. Rowe, Christine A. Pratilas, Allen R. Chen and Brian H. Ladle

Case Study, group4Kirk SmithJuly 1, 2021neuroblastoma, pediatric, ALK, lorlatinib, crizotinib combination

$Case Report: Treatment of Alectinib in NSCLC With Brain Metastasis Patient Refractory to Radiotherapy After Resistance to Crizotinib$

Case Report: Treatment of Alectinib in NSCLC With Brain Metastasis Patient Refractory to Radiotherapy After Resistance to Crizotinib

This case revealed some new insights. First, liquid biopsy is complementary to tissue biopsy in patients with NSCLC, mainly in those with EGFR mutation. However, ALK rearrangement should be assessed using tissue biopsy as much as possible. Second, brain metastasis of NSCLC might respond to second-generation tyrosine kinase inhibitors (TKIs), such as alectinib and ceritinib, after resistance to crizotinib regardless of the presence or absence of ALK rearrangement in liquid biopsy. Finally, combined radiotherapy and TKI therapy appears optimal in patients with brain metastasis of NSCLC after resistance to crizotinib in the absence of a definitive driver gene. READ ARTICLE

Frontiers in Oncology DOI: 10.3389/fonc.2021.709188

Authors: Zhang Chunzhi

Case Study, group4Kirk SmithJune 28, 2021NSCLC, ALK+, radiotherapy

Response to lorlatinib on a patient with ALK-rearranged non-small cell lung cancer harboring 1151Tins mutation with uterine metastasis

We describe a case of an anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer with development of uterine metastasis after crizotinib and alectinib treatment. Gene analysis from the tissue of uterine metastasis revealed the presence of 1151Tins, which was considered to be a crizotinib and alectinib resistance mutation. Subsequent therapy with the third-generation ALK inhibitor lorlatinib, but not ceritinib, showed antitumor activity for 1 year. The uterus is an uncommon site for metastasis from lung cancer, and our case indicated that serial gene analysis could provide new information about ALK inhibitor resistance. READ ARTICLE

Thoracic Cancer DOI: 10.1111/1759-7714.14056

Authors: Kobayashi T, Kanda S, Fukushima T, Noguchi T, Sekiguchi N and Koizumi T.

Case Study, group4Kirk SmithJune 28, 2021ALK, uterine metastasis, lorlatinib

Deciphering the immunosuppressive tumor microenvironment in ALK- and EGFR-positive lung adenocarcinoma

Methods: We performed comparative mRNA expression profiling of 31 ALK-positive, 40 EGFR-positive and 43 ALK/EGFR-negative lung ADC focused on immune gene expression. The presence and levels of tumor infiltration lymphocytes (TILs) as well as fourteen specific immune cell populations were estimated from the gene expression profiles. Results:While total TILs were not lower in ALK-positive and EGFR-positive tumors compared to ALK/EGFR-negative tumors, specific immunosuppressive characteristics were detected in both subgroups: In ALK-positive tumors, regulatory T cells were significantly higher compared to EGFR-positive (fold change: FC = 1.9, p = 0.0013) and ALK/EGFR-negative tumors (FC = 2.1, p = 0.00047). In EGFR-positive tumors, cytotoxic cells were significantly lower compared to ALK-positive (FC = − 1.7, p = 0.016) and to ALK/EGFR-negative tumors (FC = − 2.1, p = 2.0E-05). A total number of 289 genes, 40 part of cytokine–cytokine receptor signaling, were differentially expressed be..... READ ARTICLE

Cancer Immunology, Immunotherapy DOI:doi.org/10.1007/s00262-021-02981-w

Authors: Jan Budczies, Martina Kirchner, Klaus Kluck, Daniel Kazdal, Julia Glade, Michael Allgäuer, Mark Kriegsmann, Claus-Peter Heußel, Felix J. Herth, Hauke Winter, Michael Meister, Thomas Muley, Torsten Goldmann, Stefan Fröhling, Martin Wermke, Cornelius F. Waller, Amanda Tufman, Martin Reck, Solange Peters, Peter Schirmacher, Michael Thomas, Petros Christopoulos, & Albrecht Stenzinger