Real-world circulating tumor DNA analysis depicts resistance mechanism and clonal evolution in ALK inhibitor-treated lung adenocarcinoma patients

Sequential postprogression plasma profiling revealed that increased lines of ALK inhibitors can accelerate the accumulation of ALK resistance mutations and may lead to treatment-refractory compound ALK mutations. The selection for optimal first-line TKI is very important to achieve a more efficacious long-term strategy and prevent the emergence of on-target resistance, which may provide guidance for clinical decision making. READ ARTICLE

ESMO Open DOI:100337. doi: 10.1016/j.esmoop.2021.100337

Authors: Hua G, Zhang X, Zhang M, Wang Q, Chen X, Yu R, Bao H, Liu J, Wu X, Shao Y, Liang B, Lu K.

ALK Inhibitors or Chemotherapy for Third Line in ALK-positive NSCLC? Real-world Data

We conducted a real-world multi-institutional analysis, aiming to compare the efficacy of third-line ALKi versus chemotherapy in these patients. Consecutive ALK-positive metastatic NSCLC patients treated with at least one ALKi were identified in the working databases of 7 Israeli oncology centers (the full cohort). Demographic and clinical data were collected. Patients receiving any systemic treatment beyond 2 ALKi comprised the third-line cohort, whether a third ALKi (group A) or chemotherapy (group B). Groups A and B were compared in terms of overall survival (OS) and time-to-next-treatment line (TNT). At a median follow-up of 41 months (95% confidence interval [CI]: 32-55), 80 (47.1%) have died. Median OS (mOS) in the full cohort (n = 170) was 52 months (95% CI: 32-65). Number of ALKi (hazard ratio [HR] 0.765; 95% CI: 0.61-0.95; P = .024) and age (HR 1.02, 95% CI: 1.01-1.04, P = .009) significantly associated with OS in the full cohort. The third-line cohort included 40 patients, of..... READ ARTICLE

The Oncologist DOI:10.1093/oncolo/oyab005

Authors: Moskovitz, Mor, Dudnik, Elizabeth, Shamai, Sivan, Rotenberg, Yakir, Popovich-Hadari, Noa, Wollner, Mira, Zer, Alona, Gottfried, Maya, Mishaeli, Moshe, Rosenberg, Shoshana Keren, Onn, Amir, Merimsky, Ofer, Urban, Damien, Peled, Nir, Maimon, Natalie, Bar, Jair

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.

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

Brain metastases (BM) from non-small-cell lung cancer (NSCLC) are frequent and carry significant morbidity, and current management options include varying local and systemic therapies. Here, we performed a systematic review and network meta-analysis to determine the ideal treatment regimen for NSCLC BMs with targetable EGFR-mutations/ALK-rearrangements.</sec><sec>MethodsWe searched MEDLINE, EMBASE, Web of Science, ClinicalTrials.gov, CENTRAL and references of key studies for randomized controlled trials (RCTs) published from inception until June 2020. Comparative RCTs including ≥10 patients were selected. We used a frequentist random-effects model for network meta-analysis (NMA) and assessed the certainty of evidence using the GRADE approach. Our primary outcome of interest was intracranial progression-free survival (iPFS).</sec><sec>ResultsWe included 24 studies representing 19 trials with 1623 total patients. Targeted tyrosine kinase inhibitors (TKIs) significantly improved iPFS, wit..... READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2021.739765

Authors: Taslimi Shervin, Brar Karanbir, Ellenbogen Yosef, Deng Jiawen, Hou Winston, Moraes Fabio Y., Glantz Michael, Zacharia Brad E., Tan Aaron, Ahluwalia Manmeet S., Khasraw Mustafa, Zadeh Gelareh, Mansouri Alireza

Safety issues with the ALK inhibitors in the treatment of NSCLC: A systematic review

Tyrosine Kinase inhibitors (TKIs) are known to have peculiar toxicity profile, hence, increasing awareness to the safety profile of ALK inhibitors is essential.
A comprehensive systematic review of literature has been conducted to include prospective trials that used the ALK inhibitors Crizotinib, Ceritinib, Alectinib, Brigatinib and Lorlatinib in patients with advanced NSCLC and have available efficacy and toxicity results.
Most of adverse effects of ALKi can be managed efficiently via dose modifications or interruptions. Timely identification of each ALKi pattern of toxicity can prevent treatment-related morbidity and mortality in this palliative setting. READ ARTICLE

Critical Reviews in Oncology/Hematology
DOI:10.1016/j.critrevonc.2018.11.004

Authors: Loay Kassem, Kyrillus S. Shohdy, Shaimaa Lasheen, Omar Abdel-Rahman, Ahmad Ali and Raafat R.Abdel-Malek

Review Paper, group2Kirk SmithNovember 29, 2021ALK inhibitors, Non-small cell lung cancer, Adverse effects

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

ALK inhibitor-induced bradycardia: A systematic-review and meta-analysis

Anaplastic Lymphoma Kinase (ALK) inhibitors have revolutionized the treatment of advanced ALK-positive non-small cell lung cancer (NSCLC), improving progression-free survival. Bradycardia is a potential adverse effect of these agents. We aimed to determine the risk of bradycardia associated with ALK inhibitors in patients with advanced NSCLC.We find that crizotinib for the treatment of NSCLC is associated with a higher risk for bradycardia compared to standard chemotherapy. There is no evidence of a difference in bradycardia risk between crizotinib and newer ALK inhibitors. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2021.08.014

Authors: Filipe Cirne, Shijie Zhou, Coralea Kappel, Adam El-Kadi, Carly C. Barron, Peter M. Ellis, Stephanie Sanger, Darryl P. Leong

Genomic and experimental evidence that alternate transcription initiation of the Anaplastic Lymphoma Kinase (ALK) kinase domain does not predict single agent sensitivity to ALK inhibitors

Genomic data can facilitate personalized treatment decisions by enabling therapeutic hypotheses in individual patients. Conditional selection, which includes mutual exclusivity, is a signal that has been empirically useful for identifying mutations that may be sensitive to single agent targeted therapies. However, a low mutation frequency can underpower this signal for rare variants and prevent robust conclusions from genomic data. We develop a resampling based method for the direct pairwise comparison of conditional selection between sets of gene pairs. This effectively creates positive control guideposts of mutual exclusivity in known driver genes that normalizes differences in mutation abundance. We applied this method to a transcript variant of anaplastic lymphoma kinase (ALK) in melanoma, termed ALKATI, which has been the subject of a recent controversy in the literature. We reproduced some of the original cell transformation experiments, performed rescue experiments, and analyzed..... READ ARTICLE

BioRxiv DOI:10.1101/696294

Authors: Haider Inam, Ivan Sokirniy, Yiyun Rao, Anushka Shah, Farnaz Naeemikia, Edward O’Brien, Cheng Dong, David McCandlish, Justin R Pritchard

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

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

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

ALK Inhibitors Do Not Increase Sensitivity to Radiation in EML4-ALK Non-small Cell Lung Cancer

ALK inhibitors like Crizotinib, Ceritinib and Alectinib are targeted therapies used in patients with anaplastic lymphoma kinase (ALK)-positive, advanced non-small cell lung cancer (NSCLC). Since in this tumor entity radiotherapy is employed sequentially or concomitantly, potential synergistic effects were investigated, which may support the hypothesis of induced radiosensitization by using ALK inhibitors. Two cell lines expressing wild-type (WT) or echinoderm microtubule-associated protein-like 4 (EML4)-ALK were treated with ALK inhibitors, followed by irradiation. Cell survival, cell death, cell cycle and phosphorylation of H2A histone family, member X (H2AX) were examined. Combined treatment with ALK-inhibitors plus 10 Gy-irradiation led to effects similar to those of sole radiotherapy, but was more effective than sole drug treatment. There is no clear evidence of sensitization to radiation by treating EML4-ALK mutated cells with ALK inhibitors. READ ARTICLE

Anticancer Research DOI:10.21873/anticanres.14497

Authors: Kathrin Fleschutz, Lisa Walter, Tumo Leistner, Lucie Heinzerling

Lung Adenocarcinoma during Pregnancy: 11-Year Follow-Up

The incidence of lung cancer during pregnancy is rising due to the high rate of smokers in young women and the late mean age of pregnancy; in addition, considering that the patients are young women with a higher incidence of molecular alterations, molecular testing in lung adenocarcinoma should always be performed, even in pregnancy. Here, we report the case of a lung adenocarcinoma diagnosed during pregnancy with a long survival who benefitted from brain radiotherapy, conventional chemotherapy, and ALK TKI-targeted treatment. It reveals the safety of whole brain radiotherapy during pregnancy and consideration of other brain radiation techniques even in palliative cases, which should be personalized and managed by a multidisciplinary team. However, upfront management of brain metastasis in ALK-positive patients remains unresolved. READ ARTICLE

Case Reports in Oncology DOI:10.1159/000508360

Authors: Acosta Rojas A., Collazo-Lorduy A., Remon J., Hernando Requejo O., Jiménez-Munarriz B., Rubio Rodríguez M.C., De Castro J.

Retrospective Observational Study of ALK-Inhibitor Therapy Sequencing and Outcomes in Patients with ALK-Positive Non-small Cell Lung Cancer

Data are sparse concerning the sequential use of multiple anaplastic lymphoma kinase (ALK) inhibitors for ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC).This study investigated sequencing and outcomes among patients receiving multiple ALK inhibitors.This study provides initial information on real-world treatment patterns following the introduction of new ALK inhibitors, and supports the use of sequential ALK therapies. READ ARTICLE

Drugs - Real World Outcomes DOI:10.1007/s40801-020-00207-6

Authors: David M. Waterhouse, Janet L. Espirito, Marc D. Chioda, Bismark Baidoo, Jack Mardekian, Nicholas J. Robert, Elizabeth T. Masters

Efficacy of Crizotinib, Ceritinib, and Alectinib in ALK-Positive Non-Small Cell Lung Cancer Treatment: A Meta-Analysis of Clinical Trials

This study aimed to evaluate the efficacy of anaplastic lymphoma kinase (ALK)-inhibitors in the treatment of ALK-positive non-small cell lung cancer (NSCLC) by using a meta-analysis of clinical trials. We searched PubMed, EMBASE, Cochrane Library, and Clinicaltrials.gov by using keywords related to the topic in August 2018. The pooled effect sizes were calculated based on a random-effects model. We also performed subgroup meta-analysis by types of ALK inhibitors (crizotinib, ceritinib, and alectinib). A total of 20 clinical trials with 10 single-arm trials and 10 double-arm trials were included in the final meta-analysis. The median overall survival (OS), progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), 1 year survival rate, and 2 year survival rate were 19.14 months, 8.47 months, 62%, 78%, 74%, and 62%, respectively. ALK inhibitors showed a significantly superior efficacy compared with chemotherapy (hazard ratio (HR) for OS, 0.83; HR for PFS, 0..... READ ARTICLE

Cancers DOI:10.3390/cancers12030526

Authors: Hoang, T.; Myung, S.-K.; Pham, T.T.; Park, B.

Overcoming resistance by ALK compound mutation (I1171S + G1269A) after sequential treatment of multiple ALK inhibitors in non-small cell lung cancer

Background: Anaplastic lymphoma kinase (ALK) fusion genes are found in 3%–5% of non-small cell lung cancers (NSCLCs). ALK inhibitors show a very high response rate to ALK-positive NSCLCs. However, the emergence of acquired resistance is inevitable. In this study, we investigated the drugs for overcoming resistance especially compound mutations after sequential treatment with crizotinib, alectinib, and lorlatinib. Conclusions: With the sequential ALK inhibitors treatment, cancer cells accumulate new mutations in addition to mutations acquired previously. The identified compound mutation (I1171S + G1269A) was found to be sensitive to ceritinib and brigatinib, and indeed the patient's tumor partially responded to ceritinib. READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.13299

Authors: Ken Takahashi, Yosuke Seto, Koutaroh Okada, Shinya Uematsu, Ken Uchibori, Mika Tsukahara, Tomoko Oh-hara, Naoya Fujita, Noriko Yanagitani, Makoto Nishio, Kenichi Okubo, Ryohei Katayama

Transformation of EML4-ALK fusion-positive adenocarcinoma into squamous cell carcinoma in association with acquired resistance to crizotinib

Background: Targeted therapies are a standard of care for first-line treatment of Anaplastic lymphoma kinase (ALK)-rearranged non small cell lung cancer (NSCLC). Giving the rapid pace of drug discovery and development in this area, reporting of adverse effects of ALK inhibitors is crucial. Here, we report a case of osteitis induced by an ALK inhibitor mimicking bone metastasis, a previously undescribed side effect of crizotinib. Conclusions: This is the first report of crizotinib-induced osteitis. Crizotinib differs from other ALK inhibitors as it targets other kinases as well, which may have been responsible for the osteitis. Crizotinib can induce rapidly extensive osteitis, which can mimic tumor progression. READ ARTICLE

BMC Cancer DOI:10.1186/s12885-019-6486-3

Authors: F. Guisier, N. Piton, M. Bellefleur, N. Delberghe, G. Avenel, E. Angot, O. Vittecoq, M. Ould-Slimane, H. Morisse-Pradier, M. Salaun, L. Thiberville

Case StudyKirk SmithJanuary 6, 2020ALK-rearranged NSCLC, ALK inhibitors, Crizotinib, Ceritinib, Drug toxicity, Osteitis

Discovery of 2-aminopyridines bearing a pyridone moiety as potent ALK inhibitors to overcome the crizotinib-resistant mutants

Despite the initial benefit demonstrated in clinical setting with ALK inhibitors, the challenging resistant mutants (F1174L, L1196M and G1202R) invariably developed. In this work, a series of 2-aminopyridine derivatives were designed and synthesized by C-5 position incorporation of a 2-pyridone moiety and bioisosteric replacement of the C-3 position linkers. Optimization of the 2-aminopyridine derivatives led to the identification of hit 18d displaying a significant growth inhibition against a variety of ALK-addicted cancer cells. Especially in the case of ALK-positive Karpas-299 cell, 18d exhibited excellent anti-proliferative potency with an IC50 value of about 40 nM. Moreover, 18d demonstrated encouraging activities against wild-type ALK (19 nM), ROS1 (2.3 nM) as well as challenging crizotinib-resistant ALKL1196M and ALKG1202R mutants with IC50 values of 45 nM and 22 nM, respectively. Additionally flow cytometric analysis indicates that 18d inhibited Karpas-299 cell viability via G1 phase arrest. Taken together, this work provided a promising ALK inhibitor to circumvent the clinical crizotinib-resistant mutants. READ ARTICLE

European Journal of Medicinal Chemistry DOI:10.1016/j.ejmech.2019.111734

Authors: Wenteng Chen, Xiao Guo, Can Zhang, Di Ke, Guolin Zhang, Yongping Yu

Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK-rearranged lung cancer

Clinical benefit of ALK tyrosine kinase inhibitors (ALK-TKIs) in ALK-rearranged lung cancer has been limited by the inevitable development of acquired resistance, and bypass-molecular resistance mechanisms remain poorly understood. We investigated a novel therapeutic target through screening FDA-approved drugs in ALK-TKI-resistant models. Cerivastatin, the rate-limiting enzyme inhibitor of the mevalonate pathway, showed anti-cancer activity against ALK-TKI resistance in vitro/in vivo, accompanied by cytoplasmic retention and subsequent inactivation of transcriptional co-regulator YAP. The marked induction of YAP-targeted oncogenes (EGFR, AXL, CYR61, and TGFβR2) in resistant cells was abolished by cerivastatin. YAP silencing suppressed tumor growth in resistant cells, patient-derived xenografts, and EML4-ALK transgenic mice, whereas YAP overexpression decreased the responsiveness of parental cells to ALK inhibitor. In matched patient samples before/after ALK inhibitor treatment, nuclear..... READ ARTICLE

EMBO Molecular Medicine DOI:10.15252/emmm.201910581

Authors: Mi Ran Yun, Hun Mi Choi, You Won Lee, Hyeong Seok Joo, Chae Won Park, Jae Woo Choi, Dong Hwi Kim, Han Na Kang, Kyoung-Ho Pyo, Eun Joo Shin, Hyo Sup Shim, Ross A Soo, James Chih-Hsin Yang, Sung Sook Lee, Hyun Chang, Min Hwan Kim, Min Hee Hong, Hye Ryun Kim, Byoung Chul Cho

Pre-ClinicalKirk SmithOctober 21, 2019YAP, acquired resistance, ALK inhibitors, ALK-rearranged lung cancer

Management of CNS disease in ALK-positive non-small cell lung cancer: Is whole brain radiotherapy still needed?

Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (3 to 5% of all non-small cell lung cancers) carries a particularly high risk of central nervous system dissemination (60% to 90%). As the use of ALK inhibitors improves treatment outcomes over chemotherapy, the determent of central nervous system metastases has become an increasingly relevant therapeutic dilemma considering young age and possible extended overall survival. The goal of brain metastases management is to optimize both overall survival and quality of life, with the high priority of neurocognitive function preservation. Unfortunately in the first year on crizotinib, the pioneering ALK inhibitors, approximately one third of these patients fail in the central nervous system, which is explained by an inadequate central nervous system drug penetration through the blood-brain barrier. Central nervous system-directed radiotherapy represents the most important strategy to control intracranial disease burden and ..... READ ARTICLE

Cancer/Radiothérapie DOI:10.1016/j.canrad.2019.03.009

Authors: A. Wrona