This is the first report on one patient with a novel NBEA-ALK, EML4-ALK double-ALK fusion beneficial from alectinib. Alectinib may be a viable therapeutic option for NSCLC patients with double-ALK fusion, and liquid biopsy could dynamically monitor clinical curative effect. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2021.10.015
Authors: Qi Liang, Huanhuan Xu, Yiqian Liu, Weiming Zhang, Chongqi Sun, Meng Hu, Yizhi Zhu, Shanyue Tan, Xian Xu, Sumeng Wang and Lingxiang Liu
Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have improved clinical outcomes in non-small cell lung cancer (NSCLC) harboring ALK- rearrangements. However, a small population of tumor cells survives due to adaptive resistance under drug pressure and ultimately acquires drug resistance. Thus, it is necessary to elucidate the mechanisms underlying the prevention of drug resistance to improve the prognosis of patients with ALK-rearranged NSCLC. We identified novel adaptive resistance, generated through c-Jun N-terminal kinase (JNK)/c-Jun signaling, to initial ALK-TKIs—alectinib and brigatinib—in ALK-rearranged NSCLC. Inhibition of JNK/c-Jun axis showed suppression of growth and promotion of apoptosis induced by ALK-TKIs in drug-tolerant cells. JNK inhibition, in combination with the use of ALK-TKIs, increased cell apoptosis through repression of the Bcl-xL proteins, compared with ALK-TKI monotherapy. Importantly, combination therapy targeting JNK and ALK significantly d..... READ ARTICLE
Cancer Letters DOI:10.1016/j.canlet.2021.09.018
Authors: Keiko Tanimura, Tadaaki Yamada, Mano Horinaka, Yuki Katayama, Sarina Fukui, Kenji Morimoto, Takayuki Nakano, Shinsaku Tokuda, Yoshie Morimoto, Masahiro Iwasaku, Yoshiko Kaneko, Junji Uchino, Kazue Yoneda, SeijiYano, ToshiyukiSakai and KoichiTakayama
EGFR and ALK alternations often contribute to human malignancies, including lung cancer. EGFR and ALK mutations are usually sensitive to EGFR-tyrosine kinase inhibitors (TKIs) and ALK-TKIs. Although generally mutually exclusive, these mutations do co-exist in rare cases. This study investigated the frequencies, clinical characteristics, therapeutic efficacies, and genetic profiles of lung cancer patients with EGFR and ALK co-mutations. ALK and EGFR mutations coincide at a relatively low frequency in lung cancer patients. ALK mutations developed either synchronously or heterochronously with EGFR mutations. Two ALK mutations (L1152R and STRN-ALK) may co-exist with EGFR mutations at a higher frequency than others. Most EGFR/ALK co-alteration patients (other than the EGFR/ALK L1152R type) can benefit from first line EGFR-TKIs. READ ARTICLE
BMC Cancer DOI:10.1186/s12885-021-08824-2
Authors: Xiaodan Yang, Jia Zhong, Zhuo Yu, Minglei Zhuo, Min Zhang, Rongrong Chen, Xuefeng Xia & Jun Zhao
Background: Lorlatinib is a novel potent ALK inhibitor, with only a few studies reporting the results of its clinical use. Methods: This study describes the outcomes of lorlatinib treatment for 35 non-small cell lung cancer patients with ALK rearrangements, who had 2 ( n = 5), 1 ( n = 26) or none ( n = 4) prior tyrosine kinase inhibitors and received lorlatinib mainly within the compassionate use program. Results: Objective tumor response (OR) and disease control (DC) were registered in 15/35 (43%) and 33/35 (94%) patients, respectively; brain metastases were particularly responsive to the treatment (OR: 22/27 (81%); DC: 27/27 (100%)). Median progression free survival (PFS) was estimated to be 21.8 months, and median overall survival (OS) approached to 70.1 months. Only 4 out of 35 patients experienced no adverse effects; two of them were the only subjects who had no clinical benefit from lorlatinib. PFS and OS in the no-adverse-events lorlatinib users were strikingly lower as compared..... READ ARTICLE
Translational Oncology DOI:10.1016/j.tranon.2021.101121
Authors: Sergey V. Orlov, Aglaya G. Iyevleva, Elena A. Filippova, Alexandra M. Lozhkina, Svetlana V. Odintsova, Tatiana N. Sokolova, Natalia V. Mitiushkina, Vladislav I. Tiurin, Elena V. Preobrazhenskaya, Alexandr A. Romanko, Alexandr S. Martianov, Alexandr O. Ivantsov, Svetlana N. Aleksakhina, Alexandr V. Togo, Evgeny N. Imyanitov.
Patients with oligometastatic (OM) non-small cell lung cancer (NSCLC) have favorable outcomes compared to patients presenting with diffuse metastatic disease. Recent randomized trials have demonstrated safety and efficacy signals for local ablative therapies with radiotherapy, surgery, or radiofrequency ablation for OM-NSCLC patients alongside systemic therapies. However, it remains unclear whether local ablative therapy (LAT) should be offered either upfront preceding systemic therapies or following initial systemic therapies as local consolidative therapy (LCT). Establishing optimal timing of RT and systemic therapy combinations is essential to maximize efficacy while maintaining safety. Most published randomized trial evidence surrounding the benefits of LAT and systemic therapies were generated from OM-NSCLC patients receiving cytotoxic chemotherapy agents. With increasing use of novel agents such as targeted therapies (i.e., tyrosine kinase inhibitors) and immune checkpoint inhibitors in management of metastatic NSCLC patients, LAT timing may need to be modulated based on the use of specific agents. This narrative review will discuss the current evidence on either upfront LAT or LCT for OM-NSCLC based on published trials and cohort studies. We briefly explored the possible biological mechanisms of the potential clinical advantages of either approach. This review also summarized the ongoing trials incorporating both upfront LAT and LCT, and considerations for future LAT strategies. READ ARTICLE
Translational Lung Cancer Research DOI:10.21037/tlcr-20-994
Authors: Tjong MC, Louie AV, Iyengar P, Solomon BJ, Palma DA, Siva S.
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
Our data suggest that the aberrant expression of EML4-ALK leads to JAK2-STAT signaling pathway activation, which is essential for the development of non-small cell lung cancer. READ ARTICLE
BMC Pulmonary Medicine DOI:10.1186/s12890-021-01553-z
Authors: Ying Li, Yongwen Li, Hongbing Zhang, Ruifeng Shi, Zihe Zhang, Hongyu Liu, and Jun Chen
Purpose: Anaplastic lymphoma kinase (ALK) is now a validated kinase target in non-small cell lung cancer (NSCLC). We implemented three ALK laboratory methodologies: fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) and next-generation sequencing (NGS) to detect EML4-ALK fusions and compared the predictive value for Crizotinib efficacy in ALK-positive patients. Conclusion: FISH present a certain false-negative rate although considered the gold standard. Ventana-D5F3 IHC is qualified as a screening tool, while NGS positive may predict clinical benefit of Crizotinib more accurately, allowing efficient test for specific variants and concurrent genomic alterations. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2019.03.018
Authors: Chen Lin, Xun Shi, Shao Yang, Jun Zhao, Qiong He, Ying Jin, Xinmin Yu,
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
Tyrosine kinase inhibitors are the first-line treatment for Anaplastic Lymphoma Kinase-positive lung adenocarcinomas. However, chemotherapy is still an option in patients who are unresponsive or intolerant of tyrosine kinase inhibitors. There is a high likelihood of brain metastasis in patient with lung adenocarcinomas with Anaplastic Lymphoma Kinase rearrangement. Surveillance brain imaging may have a role in clinical follow up. Brigatinib and lorlatinib are two tyrosine kinase inhibitors with excellent intracranial penetrance. READ ARTICLE
Cancer Treatment and Research Communications DOI:10.1016/j.ctarc.2020.100291
Authors: Oranus Mohammadi, Kayla Haines, Mohammad Jahanzeb,
Lung cancer is the leading cause of cancer death worldwide. In the past decade EGFR, ALK and ROS1 TKIs lead to an unprecedented survival improvement of oncogene-addicted NSCLC patients, with better toxicity profile compared to chemotherapy. In recent years the implementation of high-throughput sequencing platforms led to the identification of uncommon molecular alterations in oncogenic drivers, such as BRAF, MET, RET, HER2 and NTRK. Moreover, newly developed drugs have been found to be active against hard to target drivers, such as KRAS. Specific TKIs targeting these genomic alterations are currently in clinical development and showed impressive activity and survival improvement, leading to FDA-accelerated approval for some of them. However, virtually all patients develop resistance to TKIs by on-target or off-target mechanisms. Here we review the clinicopathological features, the emerging targeted therapies and mechanisms of resistance and strategies to overcome them of KRAS, BRAF, MET, RET, HER2 and NTRK-addicted advanced NSCLCs. READ ARTICLE
Critical Reviews in Oncology/Hematology DOI: 10.1016/j.critrevonc.2020.103119
Authors: Giuseppe Lamberti, Elisa Andrini, Monia Sisi, Alessandro RizzoaClaudia Parisi, Alessandro Di Federico, Francesco Gelsomino and Andrea Ardizzoni
Read MoreBackground Patients with lung cancer are at an increased risk for venous thromboembolism (VTE). Approximately 8–15% of patients with advanced non-small-cell lung cancer (NSCLC) experience a VTE throughout the course of the disease. However, the incidence of VTE in different NSCLC molecular subtypes is rarely reported, although there are significant differences in clinical feature and prognosis. Tissue factor (TF) expressed in many solid tumors could trigger the downstream coagulation cascade and lead to thrombin generation and clot formation. Results: At a median follow up of 2.5 years, 5.85% (n=30/513) patients with advanced lung adenocarcinoma experienced VTE. Compared to patients with EGFR mutation (n=11/218, 5.05%) or both negative (n=13/266, 4.89%), patients with ALK-rearrangement were more likely to develop VTE (n=6/29, 20.69%; P=0.006, P=0.004; respectively). In ALK-rearrangement-positive tissues, 41.67% (n=10/24) had a high TF protein expression; the incidence was significantly..... READ ARTICLE
Annals of Translational Medicine DOI:10.21037/atm-20-6619
Authors: Yang S, Yang L, Wu Y, Zhang C, Wang S, Ma N, Wang L, Wang
While significant advancements have been made in the available therapies for metastatic non-small cell lung cancer (NSCLC), acquired resistance remains a major barrier to treatment. We have not yet achieved the ability to cure advanced NSCLC with systemic therapy, despite our growing understanding of many of the oncogenic drivers of this disease. Rather, the emergence of drug-tolerant and drug-resistant cells remains the rule, even in the face of increasingly potent targeted therapies. In this review, we provide a broad overview of the mechanisms of resistance to targeted therapy that have been demonstrated across molecular subtypes of NSCLC, highlighting the dynamic interplay between driver oncogene, bypass signaling pathways, shifting cellular phenotypes, and surrounding tumor microenvironment. READ ARTICLE
Pharmacology & Therapeutics DOI:10.1016/j.pharmthera.2020.107522
Authors: Catherine B. Meador, Aaron N. Hata
Rapidly developing molecular biology techniques have been employed to identify cancer driver genes in specimens from patients with non-small cell lung cancer (NSCLC). Inhibitors and antibodies that specifically target driver gene-mediated signaling pathways to suppress tumor growth and progression are expected to extend the survival time and further improve the quality of life of patients. However, the health of patients with advanced and metastatic NSCLC presents significant challenges due to treatment resistance, mediated by cancer driver gene alteration, epigenetic alteration, and tumor heterogeneity. In this review, we discuss two different resistance mechanisms in NSCLC targeted therapies, namely changes in the targeted oncogenes (on-target resistance) and changes in other related signaling pathways (off-target resistance) in tumor cells. We highlight the conventional mechanisms of drug resistance elicited by the complex heterogeneous microenvironment of NSCLC during targeted ther..... READ ARTICLE
Pharmacology & Therapeutics DOI:10.1016/j.pharmthera.2019.107438
Authors: Wen-juan Liu, Yue Du, Ru Wen, Ming Yang, JianXu
Introduction: ALK rearrangements are present in 2-7% of non-small cell lung cancer (NSCLC) cases, where the EML4-ALK fusion is the most frequent. Rearrangement of ALK with other fusion partners occurs only in ≈5% of NSCLC ALK-positive. These patients have benefited from ALK inhibitors, and currently, there are three generations of drugs as the standard of care. The first-generation ALK inhibitor crizotinib is approved in the front-line setting for the treatment of advanced NSCLC; unfortunately, these tumors may eventually develop resistance to this molecule. The Second-generation ALK inhibitors, ceritinib, alectinib, and brigatinib, are approved for patients recently diagnosed or in relapse. The third-generation inhibitor lorlatininb is approved for patients who have developed resistance to any ALK inhibitor. Expert opinion: Currently, there are a growing number of options of therapeutic agents against ALK+ NSCLC (approved and in development); however, adequate selection and sequencin..... READ ARTICLE
Expert Review of Respiratory Medicine DOI:10.1080/17476348.2020.1721285
Authors: Joseph A Pinto, Luis E Raez, Gelenis Domingo,
Non-small cell lung cancer with ALK rearrangements can be targeted effectively with ALK inhibitors such as crizotinib. However, cancer progression typically occurs within a year as drug resistance develops. One strategy to overcome this drug resistance is to determine if novel cytotoxic agents retain the ability to kill lung cancer cells that have developed ALK inhibitor resistance. We therefore examined curcumin, a drug with anticancer properties, and 2 s-generation curcumin derivatives (1-methyl-3,5-bis[(E)-4-pyridyl) methylidene]-4-piperidone (RL66) and 1-isopropyl-3,5-bis[(pyridine-3-yl) methylene]piperidin-4-one (RL118)) in lung cancer cell lines. The cytotoxicity of curcumin, RL66, and RL118 were tested in both ALK+ lung cancer cells (H3122), crizotinib resistant ALK+ cells (CR-H3122) and ALK- lung cancer cells (A549), both alone and in combination with crizotinib. ALK+ cells were 2-3x more sensitive to RL66 and RL118 than ALK- cells, with the drugs' eliciting IC50 values in the ..... READ ARTICLE
European Journal of Pharmacology DOI:10.1016/j.ejphar.2019.172749
Authors: Abigail R Bland, Rebekah L Bower, Mhairi Nimick, Bill C Hawkins, Rhonda J Rosengren, John C Ashton
Background: ALK is a prognostic and predictive tumor marker in non-small cell lung carcinoma (NSCLC), and is more often found in lung adenocarcinomas. Conclusions:The efficacy of crizotinib in patients with advanced NSCLC is related to the number of metastatic organs, age and timing of treatment. The use of crizotinib is prone to intracranial progression, and progression of simple brain metastases is not an indication that crizotinib is discontinued. Patients will continue to benefit from combination of local radiotherapy. READ ARTICLE
Pathology - Research and Practice DOI:10.1016/j.prp.2019.152695
Authors: Huiyan Deng, Bin Li, Lina Li, Jingcui Peng, Tongshuai Lv, Yueping Liu, CuiminDing
Objective: Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH+). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC)+). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases. Conclusion: ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2019.09.023
Authors: E. Thunnissen, B.I. Lissenberg-Witte, M.M. van den Heuvel, K. Monkhorst, B.G. Skov, J.B. Sørensen, A. Mellemgaard, A.M.C. Dingemans, E.J.M. Speel, A.J. de Langen, S.M.S. Hashemi, I. Bahce, M.A. van der Drift, M.G. Looijen-Salamon, J. Gosney, P.E. Postmus, S.M.S. Samii, F Duplaquet, B. Weynand, X. Durando, F. Penault-Llorca, S. Finn, A.O Grady, B. Oz, N. Akyurek, R. Buettner, J. Wolf, L. Bubendorf, S. Duin, I. Marondel, L.C. Heukamp, W. Timens, E.M.D. Schuuring, P. Pauwels, E.F. Smit
Crizotinib is initially effective in the treatment of ALK-rearranged NSCLC, but the disease eventually progresses. PLB1003, a high-efficiency second generation ALK inhibitor, was developed due to the increased resistance of EML4-ALK fusion genes. Preclinical data show that PLB1003 is safe and effective in cell-based assays and Crizotinib-resistant animal models. This is the ongoing phase Ia study of PLB1003. An open-label, multicenter phase I clinical trial was conducted in patients with locally advanced or metastatic NSCLC who had previously failed or were intolerable to Crizotinib or chemotherapy. The study result shows PLB1003 is safe, tolerable and has potential clinical benefit to locally advanced or metastatic NSCLC patients with ALK rearrangement mutation and had disease progression or were intolerable to previously treatment of Crizotinib or chemtherapy. (ClinicalTrials.gov number, NCT03130881) READ ARTICLE
Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1375
Authors: B. Han, T. Chu, J. Qian, B. Yan, Y. Zhang, Q. Chang
Objectives: Results of the ALEX trial demonstrated that alectinib decreased the risk of Central Nervous System (CNS) progression and prolonged progression-free survival of NSCLC ALK+ patients, compared with crizotinib. The objective of this study is to compare the economic burden of CNS progression with alectinib versus crizotinib, on the Brazilian private healthcare system. Conclusions: Alectinib can potentially decrease the economic burden of CNS metastasis of NSCLC ALK+ patients in the Brazilian private healthcare system, compared with the current standard of care. READ ARTICLE
Value in Health DOI:10.1016/j.jval.2019.04.253
Authors: D.Kashiura, M.Santos, L.Carmo, R.Leme-Souza
