Alectinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of ALK-positive non-small cell lung cancer. Population pharmacokinetic (PK) models were developed for alectinib and its major active metabolite M4 using phase I/II PK data in crizotinib-failed patients (N = 138). The PK profiles were best described by two separate models with similar structure for both entities: open one-compartment models with sequential zero/first-order input and first-order elimination rate. Body weight with fixed allometric scaling factor on clearance and volume of both entities was the only significant covariate. Bayesian feedback analyses of the PK data collected from Japanese and global treatment-naïve patients in phase III studies (N = 334) confirmed the body weight effect. Landmark Cox proportional hazards analyses of progression-free survival in treatment-naïve patients identified the average molar concentrations of both entities alectinib and M4 during the first 6 weeks of trea..... READ ARTICLE
CPT: Pharmacometrics & Systems Pharmacology DOI:10.1002/psp4.12702
Authors: Joy C. Hsu, Felix Jaminion, Elena Guerini, Bogdana Balas, Walter Bordogna, Peter N. Morcos, Nicolas Frey
Anaplastic lymphoma kinase (ALK) fusion is a well-defined biomarker for ALK tyrosine kinase inhibitors (TKIs) treatment in non-small cell lung cancer (NSCLC). Alectinib, a second-generation ALK-TKI, has been shown to have significantly longer progression-free survival (PFS) than first-generation ALK inhibitors in untreated ALK-rearranged NSCLC patients. However, its clinical efficacy on rare ALK fusions remains unclear. Herein, two advanced NSCLC patients received first-line alectinib treatment, given their positive ALK fusion status as determined by immunohistochemistry (IHC) testing results. Patients showed limited clinical response (PFS: 4 months) and primary resistance to alectinib respectively. Molecular profiling using next-generation sequencing (NGS) further revealed a striatin (STRN)-ALK fusion in the first patient accompanied by MET amplification, and a LIM domain only protein 7 (LMO7)-ALK fusion in another patient without any other known oncogenic alterations. Both patients d..... READ ARTICLE
Wiley DOI:10.1111/jcmm.16897
Authors: Mengnan Li, Zhou An, Qiusu Tang, Yutong Ma, Junrong Yan, Songan Chen, Yina Wang
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that is mutated in approximately 10% of pediatric neuroblastoma (NB). To shed light on ALK-driven signaling processes, we employed BioID-based in vivo proximity labeling to identify molecules that interact intracellularly with ALK. NB-derived SK-N-AS and SK-N-BE(2) cells expressing inducible ALK-BirA* fusion proteins were generated and stimulated with ALKAL ligands in the presence and absence of the ALK tyrosine kinase inhibitor (TKI) lorlatinib. LC/MS-MS analysis identified multiple proteins, including PEAK1 and SHP2, which were validated as ALK interactors in NB cells. Further analysis of the ALK-SHP2 interaction confirmed that the ALK-SHP2 interaction as well as SHP2-Y542 phosphorylation was dependent on ALK activation. Use of the SHP2 inhibitors, SHP099 and RMC-4550, resulted in inhibition of cell growth in ALK-driven NB cells. In addition, we noted a strong synergistic effect of combined ALK and SHP2 inhibition that was specific to ALK-driven NB cells, suggesting a potential therapeutic option for ALK-driven NB. READ ARTICLE
Journal of Molecular Biology
Authors: Ezgi Uçkun, Joachim T. Siaw, Jikui Guan, Vimala Anthonydhason, Johannes Fuchs, Georg Wolfstetter, Bengt Hallberg and Ruth H.Palmer
Read MorePemetrexed is currently mainly considered for the treatment of advanced nonsquamous non-small-cell lung cancer (NSCLC) negative for gene mutations/rearrangements (wild-type disease (WTD)). This narrative review aimed to highlight the role of pemetrexed in the treatment of onco-driven nonsquamous advanced NSCLC by reviewing published clinical studies. For epidermal growth factor receptor (EGFR) mutations, patient survival following first-line pemetrexed–platinum was longer than for WTD. Later-line pemetrexed-based treatment after tyrosine kinase inhibitor (TKI) failure provided greater benefits than non-pemetrexed regimens. First- and later-line pemetrexed-based therapy also provided survival benefits in patients with anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 (ROS1) rearrangements. In patients with rearranged during transfection (RET) proto-oncogene rearrangements, survival with pemetrexed was similar to that in ALK- and ROS1-positive patients and longer than that in pati..... READ ARTICLE
Cancers DOI:10.3390/cancers12092658
Authors: Jin-Yuan Shih, Akira Inoue, Rebecca Cheng, Rocio Varea, Sang-We Kim
Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8+ T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients. READ ARTICLE
Nature DOI:10.1038/s41467-021-25728-8
Authors: Johannes Brägelmann, Carina Lorenz, Sven Borchmann, Kazuya Nishii, Julia Wegner, Lydia Meder, Jenny Ostendorp, David F. Ast, Alena Heimsoeth, Takamasa Nakasuka, Atsuko Hirabae, Sachi Okawa, Marcel A. Dammert, Dennis Plenker, Sebastian Klein, Philipp Lohneis, Jianing Gu, Laura K. Godfrey, Jan Forster, Marija Trajkovic-Arsic, Thomas Zillinger, Mareike Haarmann, Alexander Quaas, Stefanie Lennartz, Marcel Schmiel, Joshua D’Rozario, Emily S. Thomas, Henry Li, Clemens A. Schmitt, Julie George, Roman K. Thomas, Silvia von Karstedt, Gunther Hartmann, Reinhard Büttner, Roland T. Ullrich, Jens T. Siveke, Kadoaki Ohashi, Martin Schlee & Martin L. Sos
To our knowledge, this is the first description of an STRN-ALK fusion(+) MPM sequentially treated with two different ALK inhibitors. This case underlines the benefit of molecular testing in MPM. Furthermore, it suggests the generalizability of the lessons learned from lung cancer to another entity, which can offer some guidance in the treatment of this rare disease. READ ARTICLE
Journal of Clinical Oncology: Precision Oncology DOI:10.1200/PO.21.00184
Authors: Valeria Gerthofer, Alexander Scheiter, Florian Lüke, Felix Keil, Kirsten Utpatel, Laura-Maria-Giovanna
Pöhmerer, Johannes Seitz, Christoph Niessen, Atanas Ignatov, Wolfgang Dietmaier, Diego F. Calvisi, Matthias Evert, Olaf Ortmann, and Stephan Seitz
We conducted a study to explore the relationship between pathological cytomorphologic features and the percentage of anaplastic lymphoma kinase (ALK)-positive cells to better predict pulmonary adenocarcinoma prognosis with crizotinib treatment.
We investigated 60 cases of patients with ALK-positive advanced or metastatic non-small cell lung cancer (NSCLC). Immunohistochemistry was performed to screen for ALK rearrangement. Fluorescence in situ hybridization (FISH) was used to detect the percentage of ALK-positive cells. The primary objectives of the study were the progression-free survival (PFS), the 3-year overall survival, and the 3-year overall survival (OS) rates. The secondary objectives of the study were the disease control rate (DCR) and the overall response rate (ORR).
We concluded that signet ring cell cytomorphologic characteristics of pulmonary adenocarcinoma are associated with the percentage of ALK-positive cells. Signet ring cell cytomorphologic characteristics and the percentage of ALK-positive cells might predict the prognosis of pulmonary adenocarcinoma with crizotinib treatment. READ ARTICLE
World Journal of Surgical Oncology DOI:10.1186/s12957-021-02386-0
Authors: Fenge Jiang, Congcong Wang, Ping Yang, Ping Sun, Jiannan Liu
About 20% of patients with ALK-rearranged non-small cell lung cancer (NSCLC) develop acquired resistance to tyrosine kinase inhibitor (TKI) during the first 6 months. This study aimed to examine the molecular mechanisms of early TKI resistance and prognosis in ALK-rearranged NSCLC.Ten patients with ALK-rearranged NSCLC were included: five who developed rapid resistance to crizotinib (progression-free survival (PFS) ≤3 months) and five who exhibited a good response to crizotinib (PFS ≥36 months). The study finds a higher mutation burden and mutations in DNA repair gene, including TP53, were potentially associated with primary resistance to crizotinib in ALK-rearranged NSCLC. An immune-checkpoint inhibition strategy could be examined, which might overcome primary resistance to crizotinib in ALK-rearranged NSCLC. READ ARTICLE
OncoTargets and Therapy DOI:10.2147/OTT.S325443
Authors: Dakai Xiao, Qiuhua Deng, Dongyun He, Ying Huang, Wenchi Liang, Fengnan Wang, Haihong Yang
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
Tyrosine kinase inhibitors of anaplastic lymphoma kinase (ALK-TKIs) including alectinib have been the standard therapy against ALK fusion gene-positive non-small cell lung cancers (NSCLCs). Many ALK fusion variants have been identified in NSCLCs, and the predominant variants are echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) variant 1 (V1), V2 and V3a/b. However, there have been conflicting reports on the clinical responses of these variants to ALK-TKIs, and there are few reports on other less common ALK variants. To examine the influence of ALK variants on the efficacy of ALK-TKIs, we analyzed the sensitivity to alectinib of eight types of ALK variant: three major variants (V1, V2 and V3a) and five less common variants (V4; kinesin family member 5-ALK; kinesin light chain 1-ALK; striatin, calmodulin-binding protein-ALK; and tropomyosin-receptor kinase fused gene-ALK). Analysis was done by cell-free kinase assays using the recombinant proteins and by cell, growth assay..... READ ARTICLE
Anticancer Drugs DOI:10.1097/CAD.0000000000001249
Authors: Furugaki K, Harada N, Yoshimura Y.
Dr. Laura Petrillo speaks to the ALK Positive community about Palliative Care. Some website of interest: getpalliativecare.org, https://www.mghpact.org/
Here is the ASCO guideline recommending the early integration of palliative care, cites a lot of evidence and includes information about the domains of palliative care:https://ascopubs.org/doi/full/10.1200/JCO.2016.70.1474
Cancer.net also has a nice section on what palliative care is: https://www.cancer.net/coping-with-cancer/physical-emotional-and-social-effects-cancer/what-palliative-care WATCH VIDEO
ALK Positive Inc.
Authors: Laura Petrillo
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
Neuroblastoma (NBL) is an embryonic malignancy of the sympathetic nervous system and mostly affects children under the age of five. NBL is highly heterogeneous and ranges from spontaneously regressing to highly aggressive disease. One of the risk factors for poor prognosis are aberrations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK), which is involved in the normal development and function of the nervous system. ALK mutations lead to constitutive activation of ALK and its downstream signalling pathways, thus driving tumorigenesis. A wide range of steric ALK inhibitors has been synthesized, and several of these inhibitors are already in clinical use. Major challenges are acquired drug resistance to steric inhibitors and pathway evasion strategies of cancer cells upon targeted therapy. This review will give a comprehensive overview on ALK inhibitors in clinical use in high-risk NBL and on the potential and limitations of novel inhibitors. Because combinatory treatment..... READ ARTICLE
Pharmaceutics DOI:10.3390/pharmaceutics13091427
Authors: Annette K. Brenner and Maria W. Gunnes
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
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,
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
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
Since 2011, with the approval of crizotinib and subsequent approval of four additional targeted therapies, anaplastic lymphoma kinase (ALK) inhibitors have become important treatments for a subset of patients with lung cancer. Each generation of ALK inhibitor showed improvements in terms of central nervous system (CNS) penetration and potency against wild-type (WT) ALK, yet a key continued limitation is their susceptibility to resistance from ALK active-site mutations. The solvent front mutation (G1202R) and gatekeeper mutation (L1196M) are major resistance mechanisms to the first two generations of inhibitors while patients treated with the third-generation ALK inhibitor lorlatinib often experience progressive disease with multiple mutations on the same allele (mutations in cis, compound mutations). TPX-0131 is a compact macrocyclic molecule designed to fit within the ATP-binding boundary to inhibit ALK fusion proteins. In cellular assays, TPX-0131 was more potent than all five approv..... READ ARTICLE
Molecular Cancer Therapeutics DOI:1535-7163.MCT-21-0221
Authors: Brion W. Murray, Dayong Zhai, Wei Deng, Xin Zhang, Jane Ung, Vivian Nguyen, Han Zhang, Maria Barrera, Ana Parra, Jessica Cowell, Dong J. Lee, Herve Aloysius and Evan Rogers
Next-generation targeted therapies for anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer are associated with improved clinical outcomes, however, tumors develop resistance thus requiring subsequent therapies. Limited data are available on ALK TKI sequencing. The aim of our study was to understand duration of post-brigatinib ALK TKI therapy in the real-world setting.The results indicate that brigatinib has real-world durable clinical effects for patients. Treatment with subsequent TKIs, can still bring benefit to patients after discontinuing brigatinib. More formalized prospective data are needed to establish sequencing recommendations. READ ARTICLE
Annals of Oncology DOI:10.1016/j.annonc.2021.08.1810
Authors: M.O. Jahanzeb, H.M. Lin, Y. Wu, M. Gorritz, C.B. McGuiness, K. Sun, C-C. Chen, P. Zhang, D.R. Camidge
Lorlatinib, a potent, brain-penetrant, 3rd-generation (gen) ALK/ROS1 tyrosine kinase inhibitor (TKI) active against most known resistance mutations, showed robust clinical activity in ALK+ or ROS1+ NSCLC in a Ph 1/2 study that enrolled mostly heavily pretreated pts with CNS metastases. We evaluated potential resistance mechanisms, pre-existing or acquired, and efficacy in these settings.Limitations apply to ctDNA analyses, but in this heavily pretreated group of pts with ALK+ NSCLC, presence of TP53 mutations at BL was potentially associated with decreased lorlatinib efficacy, while presence of bypass mechanism aberrations with reduced activity. Upon progression, ALK compound mutations and bypass mechanism aberrations emerged in ∼28% of pts. READ ARTICLE
Annals of Oncology DOI:10.1016/j.annonc.2021.08.1801
Authors: B.J. Solomon, J-F. Martini, A. Bearz, E.H. Tan, R. Soo, B. Besse, T.M. Bauer, D. Shepard, F. Toffalorio, A. Abbattista, E. Felip, A.T. Shaw, S. Viteri, D.R. Camidge, T. Seto, S-H.I. Ou