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Introduction: Inflammatory myofibroblastic tumor (IMT) is a rare entity, classified within soft tissue sarcomas. It is an intermediate malignancy tumor, which seldom presents as metastatic disease. The treatment of choice is surgery, except in cases where surgery is not possible due to localization or if it presents with metastatic disease. Approximately 50% of IMTs will exhibit ALK translocation, providing a therapeutic target for these patients. Case Presentation: A case is presented of a patient with metastatic IMT in complete response to treatment with alectinib, maintained for over 4 years. Conclusion: This case showed a long time complete response in patient with IMT treated with alectinib.

Background: Salivary gland carcinomas harboring anaplastic lymphoma kinase (ALK) rearrangements are rare. Here, we present the pathological characteristics, clinical course, and changes in the genetic status of a salivary gland carcinoma harboring a catenin alpha 1 (CTNNA1)::ALK rearrangement during treatment with an ALK tyrosine kinase inhibitor (TKI). Methods: A 59‐year‐old man with a parotid tumor and cervical lymph node metastases underwent total parotidectomy and radical neck dissection. One month after completion of postoperative radiotherapy, the patient experienced multiple recurrences. Results: Subsequent treatment with the ALK‐TKI alectinib was initially effective against the intraductal carcinoma harboring CTNNA1::ALK rearrangement and TP53 mutation. However, 10 months later the patients' condition deteriorated, and an additional phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA) mutation was detected. The patient ultimately succumbed to multiple organ failure. Conclusion: The clinical course suggested the concurrent emergence of TP53 and PIK3CA mutations and ALK‐TKI drug‐selective growth of non‐ALK rearrangement gene tumor cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma characterized by large T-cells with strong CD30 and ALK expression. Approximately 30% of patients treated with conventional chemotherapy experience a relapse or refractory disease and have a poor prognosis. Several risk factors associated with poor prognosis have been identified in pediatric ALK-positive ALCL, such as the morphological pattern of the small cell variant or lymphohistiocytic variant, leukemic presentation, the presence of minimal disseminated disease, or involvement of the central nervous system. Relapsed or refractory ALK-positive ALCL requires salvage therapy. Recently, targeted therapies such as ALK inhibitors and brentuximab vedotin have demonstrated dramatic responses in chemoresistant ALK-positive ALCL. Hematopoietic stem cell transplantation has also been reported to be an effective therapy. This article reviews pediatric ALK-positive ALCL, focusing on the risk factors associated with poor prognosis and treatment strategies for relapsed or refractory disease. Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma characterized by large T-cells with strong CD30 and ALK expression. Although conventional chemotherapy is effective in most patients, approximately 30% experience a relapse or refractory disease and have a poor prognosis. Several risk factors associated with poor prognosis have been identified in pediatric ALK-positive ALCL. These include morphological patterns with the small cell variant or lymphohistiocytic variant, leukemic presentation, the presence of minimal disseminated disease, or involvement of the central nervous system. Relapsed or refractory ALK-positive ALCL is often resistant to conventional chemotherapy; therefore, salvage therapy is required. In recent years, targeted therapies such as ALK inhibitors and brentuximab vedotin (BV) have been developed. ALK inhibitors block the continuous activation of ALK kinase, a driver mutation that leads to cell proliferation in ALK-positive ALCL. Additionally, BV is an antibody–drug conjugate that targets CD30-positive cells. Both ALK inhibitors and BV have displayed dramatic effects in chemoresistant ALK-positive ALCL. Weekly vinblastine treatment and hematopoietic stem cell transplantation have also been reported to be effective therapies. This article reviews pediatric ALK-positive ALCL, focusing on risk factors and treatment strategies for pediatric patients with relapsed or refractory ALK-positive ALCL. [ABSTRACT FROM AUTHOR]

Introduction: EML4-ALK is an oncogenic driver, seen in around five per cent of advanced non-small-cell lung cancer (NSCLC) patients, which can be targeted with anaplastic lymphoma kinase tyrosine kinase inhibitors with great response rates. Disease flare refers to sudden rapid disease worsening on tyrosine kinase inhibitors (TKI) discontinuation, which is associated with shorter survival and worse outcomes. Here, we review cases previously published in the literature where patients developed disease flares, and contrast this with our patients who had prolonged survival despite TKI discontinuation. Case description: We report three different patients with advanced ALK-positive NSCLC seen at our institute, who had EML4-ALK translocation variant 1 oncogenic driver on next-generation sequencing. They received treatment with several different ALK inhibitors before opting to discontinue TKI. They were able to come off TKI safely without developing disease flare and had prolonged survival. Discussion: Shorter time to progression on TKI, presence of symptoms with disease progression or central nervous system/pleural metastasis have been previously linked with development of flare, although this was not seen in our case series. Tumour response at the time of treatment discontinuation, line of therapy, overall disease burden, fusion variant and co-alteration status can affect the prognosis of these patients after ALK TKI cessation. In particular, variant 1 and wild-type TP53 status may be a suitable patient population for dose optimisation strategies. Intermittent TKI dosing strategies may help to avoid acquiring resistance mutations and prevent long-term treatment toxicities. Conclusion: It is important for clinicians to identify patients at risk for developing disease flare on TKI discontinuation to improve outcomes. Intermittent TKI dosing strategies require further investigation.

Abstract Objective To date, no direct comparisons have compared the effectiveness of all ALK inhibitors (ALKis) against ALK‐positive non‐small cell lung cancer (NSCLC). The aim of the present study was to investigate the efficacy and safety of ALKis in ALK‐positive NSCLC. Methods The effectiveness of ALKis was evaluated by assessing progression‐free survival (PFS), overall survival (OS), overall response rate (ORR), and PFS with baseline brain metastasis (BM). The serious adverse events (SAEs: Grade ≥ 3) and adverse events (AEs) leading to discontinuation were pooled to evaluate safety. We conducted an indirect treatment comparison between all ALKis by using a Bayesian model. Results Twelve eligible trials including seven treatments were identified. All of the ALKis improved PFS and ORR relative to chemotherapy. Consistent with alectinib, brigatinib, lorlatinib, and ensartinib showed significant differences versus crizotinib and ceritinib. Lorlatinib seemed to prolong PFS compared with alectinib (0.64, 0.37 to 1.07), brigatinib (0.56, 0.3 to 1.05), and ensartinib (0.53, 0.28 to 1.02). No significant difference was found among them in OS except for alectinib versus crizotinib. Moreover, alectinib was significantly more effective than crizotinib (1.54, 1.02 to 2.5) in achieving the best ORR. Subgroup analyses based on BM indicated that PFS was dramatically lengthened by lorlatinib. Compared with other ALKis, alectinib notably reduced the rate of SAEs. There was no striking difference between discontinuation for AEs, except for ceritinib versus crizotinib. The ranking of validity showed that lorlatinib had the longest PFS (98.32%) and PFS with BM (85.84%) and the highest ORR (77.01%). The rank of probabilities showed that alectinib had the potentially best safety in terms of SAEs (97.85%), and ceritinib had less discontinuation (95.45%). Conclusion Alectinib was the first choice for patients with ALK‐positive NSCLC and even for those with BM, whereas lorlatinib was the second choice. Long‐term follow‐up and prospective studies are warranted to compare ALKis and to verify our conclusions directly.

Fusions and mutations of anaplastic lymphoma kinase (ALK), a tyrosine kinase receptor, have been identified in several neoplastic diseases. Rearranged ALK is a driver of tumorigenesis, which activates various signaling pathway associated with proliferation and survival. To date, several agents that target and inhibit ALK have been developed. The most studied ALK-positive disease is non-small cell lung cancer, and three generations of ALK tyrosine kinase inhibitors (TKIs) have been approved for the treatment of metastatic disease. Nevertheless, the use of ALK-TKIs is associated with acquired resistance (resistance mutations, bypass signaling), which leads to disease progression and may require a substitution or introduction of other treatment agents. Understanding of the complex nature and network of resistance mutations may allow to introduce sequential and targeted therapies. In this review, we aim to summarize the efficacy and safety profile of ALK inhibitors, describe off-target anticancer effects, and discuss resistance mechanisms in the context of personalized oncology. [ABSTRACT FROM AUTHOR]

Copyright of Practical Pharmacy & Clinical Remedies is the property of Editorial Department of Practical Pharmacy & Clinical Remedies and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Simple Summary: ALK inhibitors have improved survival and quality of life for patients compared to chemotherapy. These treatments can cause haematological toxicities, particularly neutropenia. The management of side effects to avoid treatment interruptions is essential. Our literature review aims to improve the knowledge of ALK inhibitor-induced neutropenia in order to improve their management. Lung cancers with ALK rearrangement represent less than 5% of all lung cancers. ALK inhibitors are currently used to treat first-line metastatic non-small cell lung cancer with ALK rearrangement. Compared to chemotherapy, ALK inhibitors have improved progression-free survival, overall survival, and quality of life for patients. The results of several phase 3 studies with a follow-up of over 6 years suggest that the life expectancy of these patients treated with targeted therapies is significantly higher than 5 years and could approach 10 years. Nevertheless, these treatments induce haematological toxicities, including neutropenia. Few data are available on neutropenia induced by ALK inhibitors and on the pathophysiological mechanism and therapeutic adaptations necessary to continue the treatment. Given the high efficacy of these treatments, managing side effects to avoid treatment interruptions is essential. Here, we have reviewed the data from published clinical studies and case reports to provide an overview of neutropenia induced by ALK inhibitors. [ABSTRACT FROM AUTHOR]

Introduction: Epithelioid type inflammatory myofibroblastic sarcoma (EIMS) is a subtype of inflammatory myofibroblastic tumor (IMT). It consists of round or epithelioid cells, and almost all types of EIMS contain rearrangements of the anaplastic lymphoma kinase (ALK) gene. Case presentation: We describe a 20-year-old female presenting with abdominal pain and a rapidly growing intraabdominal mass who underwent surgical tumor resection. She was diagnosed with EIMS. ALK and ki-67 expressions were detected in immunohistochemistry assessment. She was started with Crizotinib 200 mg twice a day, and chemotherapy was also initiated due to the recurrence of the disease 4 months after the initial treatment. She was unresponsive to all the medical regimens and died in 8 months. Conclusion: Approach to patients with EIMS is really challenging in terms of both diagnosis and treatment. Patients with combined surgical and non-surgical treatment regimen were seen to have a more favorable outcome in some EIMS cases. Therefore, it is essential to implement a multidisciplinary approach to diagnose and treat patients suspicious of EIMS. [ABSTRACT FROM AUTHOR]

Introduction. We prospectively examined current clinical practices in patients with inoperable epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) fusion-positive (EGFR+ and ALK+, respectively) non-small cell lung cancer (NSCLC) in Nagano Prefecture, Japan. Material and methods. The study population consisted of newly diagnosed patients with inoperable EGFR+ and ALK+ NSCLC in 14 hospitals in Nagano between May 2016 and March 2019. Both initial and subsequent treatment decisions were made at the discretion of the attending physician. Results. A total of 281 patients with EGFR+ NSCLC (mean age, 74 years, 59.1% female) and 26 patients with ALK+ NSCLC (mean age, 66 years, 53.8% female) were included in the study. The study population consisted of 148/107/29/20/3 cases with performance status 0/1/2/3/4 and 6/2/31/194/75 cases with clinical stage I/II/III/IV/recurrence, respectively. First-line therapy with tyrosine kinase inhibitors was performed in 259 (92.2%) and 22 (84.6%) patients with EGFR+ and ALK+ NSCLC, respectively. The median overall survival rate was 41.2 months (95% CI 36.8-45.6 months) with EGFR+. It was not reached with ALK+. Conclusions. This observational analysis represents a valuable resource for evaluating the outcomes of treatment in patients with NSCLC. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) involvement in anaplastic large cell lymphoma (ALCL) at diagnosis is rare and leads to poor prognosis with the use of the standard ALCL99 protocol alone. CNS-directed intensive chemotherapy, such as an increased dose of intravenous MTX, increased dose of dexamethasone, intensified intrathecal therapy, and high-dose cytarabine, followed by cranial irradiation, has been shown to improve survival in this population. In this paper, the authors describe a 14-year-old male with an intracranial ALCL mass at onset who received CNS-directed chemotherapy followed by 23.4 Gy of whole-brain irradiation. After the first systemic relapse, the CNS-penetrating ALK inhibitor, alectinib, was applied; it has successfully maintained remission for 18 months without any adverse events. CNS-penetrating ALK inhibitor therapy might prevent CNS relapse in pediatric ALK-positive ALCL. Next-generation ALK inhibitors could be introduced as a promising treatment option, even for primary ALCL with CNS involvement, which could lead to the omission of cranial irradiation and avoid radiation-induced sequalae. Further evidence of CNS-penetrating ALK inhibitor combined therapy for primary ALK-positive ALCL is warranted to reduce radiation-induced sequalae in future treatments.

Abstract Approximately one‐third children with anaplastic large cell lymphoma (ALCL) relapse after completion of chemotherapy, particularly for those high‐risk patients. The introduction of novel therapeutic modalities is much needed for these sub‐group patients. Two groups (n = 3, n = 4) of ALCL patients were treated with crizotinib‐ and alectinib‐included ALCL‐99 therapy, respectively, achieving complete remission rates of 66.7% and 100%. Two patients of crizotinib group relapsed, while none relapsed among the alectinib‐treated patients. Adding alectinib instead of crizotinib sufficiently suppressed and maintained the deep NPM‐ALK molecular response. ALK inhibitors were well tolerated with only grade 1 adverse events in both groups. Though a relatively small case number, this study raised the possibility that alectinib‐included therapeutic regimens may benefit the early response, in‐depth molecular remission, and persistent remission to some extent. Further studies are warranted to validate our preliminary findings.

Fusions and mutations of anaplastic lymphoma kinase (ALK), a tyrosine kinase receptor, have been identified in several neoplastic diseases. Rearranged ALK is a driver of tumorigenesis, which activates various signaling pathway associated with proliferation and survival. To date, several agents that target and inhibit ALK have been developed. The most studied ALK-positive disease is non-small cell lung cancer, and three generations of ALK tyrosine kinase inhibitors (TKIs) have been approved for the treatment of metastatic disease. Nevertheless, the use of ALK-TKIs is associated with acquired resistance (resistance mutations, bypass signaling), which leads to disease progression and may require a substitution or introduction of other treatment agents. Understanding of the complex nature and network of resistance mutations may allow to introduce sequential and targeted therapies. In this review, we aim to summarize the efficacy and safety profile of ALK inhibitors, describe off-target anticancer effects, and discuss resistance mechanisms in the context of personalized oncology.

Objective: To date, no direct comparisons have compared the effectiveness of all ALK inhibitors (ALKis) against ALK‐positive non‐small cell lung cancer (NSCLC). The aim of the present study was to investigate the efficacy and safety of ALKis in ALK‐positive NSCLC. Methods: The effectiveness of ALKis was evaluated by assessing progression‐free survival (PFS), overall survival (OS), overall response rate (ORR), and PFS with baseline brain metastasis (BM). The serious adverse events (SAEs: Grade ≥ 3) and adverse events (AEs) leading to discontinuation were pooled to evaluate safety. We conducted an indirect treatment comparison between all ALKis by using a Bayesian model. Results: Twelve eligible trials including seven treatments were identified. All of the ALKis improved PFS and ORR relative to chemotherapy. Consistent with alectinib, brigatinib, lorlatinib, and ensartinib showed significant differences versus crizotinib and ceritinib. Lorlatinib seemed to prolong PFS compared with alectinib (0.64, 0.37 to 1.07), brigatinib (0.56, 0.3 to 1.05), and ensartinib (0.53, 0.28 to 1.02). No significant difference was found among them in OS except for alectinib versus crizotinib. Moreover, alectinib was significantly more effective than crizotinib (1.54, 1.02 to 2.5) in achieving the best ORR. Subgroup analyses based on BM indicated that PFS was dramatically lengthened by lorlatinib. Compared with other ALKis, alectinib notably reduced the rate of SAEs. There was no striking difference between discontinuation for AEs, except for ceritinib versus crizotinib. The ranking of validity showed that lorlatinib had the longest PFS (98.32%) and PFS with BM (85.84%) and the highest ORR (77.01%). The rank of probabilities showed that alectinib had the potentially best safety in terms of SAEs (97.85%), and ceritinib had less discontinuation (95.45%). Conclusion: Alectinib was the first choice for patients with ALK‐positive NSCLC and even for those with BM, whereas lorlatinib was the second choice. Long‐term follow‐up and prospective studies are warranted to compare ALKis and to verify our conclusions directly. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) involvement in anaplastic large cell lymphoma (ALCL) at diagnosis is rare and leads to poor prognosis with the use of the standard ALCL99 protocol alone. CNS-directed intensive chemotherapy, such as an increased dose of intravenous MTX, increased dose of dexamethasone, intensified intrathecal therapy, and high-dose cytarabine, followed by cranial irradiation, has been shown to improve survival in this population. In this paper, the authors describe a 14-year-old male with an intracranial ALCL mass at onset who received CNS-directed chemotherapy followed by 23.4 Gy of whole-brain irradiation. After the first systemic relapse, the CNS-penetrating ALK inhibitor, alectinib, was applied; it has successfully maintained remission for 18 months without any adverse events. CNS-penetrating ALK inhibitor therapy might prevent CNS relapse in pediatric ALK-positive ALCL. Next-generation ALK inhibitors could be introduced as a promising treatment option, even for primary ALCL with CNS involvement, which could lead to the omission of cranial irradiation and avoid radiation-induced sequalae. Further evidence of CNS-penetrating ALK inhibitor combined therapy for primary ALK-positive ALCL is warranted to reduce radiation-induced sequalae in future treatments. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK) fusion gene is an important tumor driver gene of non-small cell lung cancer, accounting for about 5% of patients with non-small cell lung cancer, of which 97% are patients with lung adenocarcinoma. Since the first discovery of echinoderm microtubule associated protein-like 4 (EML4)-ALK fusion in patients with lung adenocarcinoma in 2007, a variety of ALK fusion partners have been detected. CLIP1-ALK fusion gene was detected by next generation sequencing (NGS) in this patient with advanced lung squamous cell carcinoma, and Alectinib and Ensartinib were taken orally on May 5, 2021. Aletinib was effective for this patient but the patients died on September 30, 2021. This is a report of lung squamous cell carcinoma patients with CLIP1-ALK fusion gene treated with ALK inhibitors.

Approximately one‐third children with anaplastic large cell lymphoma (ALCL) relapse after completion of chemotherapy, particularly for those high‐risk patients. The introduction of novel therapeutic modalities is much needed for these sub‐group patients. Two groups (n = 3, n = 4) of ALCL patients were treated with crizotinib‐ and alectinib‐included ALCL‐99 therapy, respectively, achieving complete remission rates of 66.7% and 100%. Two patients of crizotinib group relapsed, while none relapsed among the alectinib‐treated patients. Adding alectinib instead of crizotinib sufficiently suppressed and maintained the deep NPM‐ALK molecular response. ALK inhibitors were well tolerated with only grade 1 adverse events in both groups. Though a relatively small case number, this study raised the possibility that alectinib‐included therapeutic regimens may benefit the early response, in‐depth molecular remission, and persistent remission to some extent. Further studies are warranted to validate our preliminary findings. [ABSTRACT FROM AUTHOR]

Lorlatinib, a third‐generation anaplastic lymphoma kinase (ALK)‐tyrosine kinase inhibitor (TKI) with a broad coverage against ALK mutations, has demonstrated dramatic effects in patients with ALK‐rearranged lung cancer. The mechanisms of acquired resistance to lorlatinib by secondary ALK compound mutations have recently been reported; however, resistance mechanisms other than secondary mutations remain unclear. Here, we investigated the molecular mechanisms of the acquired resistance in ALK‐rearranged lung cancer cells in vitro. We established two different lorlatinib‐resistant ALK‐rearranged lung cancer cell lines (H3122LR and A925LLR) via long‐term administration of lorlatinib. These resistant cells did not harbor the secondary ALK mutations and showed cross‐resistance to the other kinds of ALK‐TKIs (crizotinib or alectinib) compared with the parental cells; however, these resistant cells overexpressed the phosphorylated human epidermal growth factor receptor 3 (HER3) protein and the ligand of HER3 (neuregulin 1; NRG1). Pharmacological inhibition of HER3 with pan‐HER inhibitors or genetic knockdown of HER3 with siRNA resensitized H3122LR and A925LLR cells to lorlatinib in vitro, indicating that H3122LR and A925LLR acquired resistance by NRG1/HER3 activation. These findings demonstrated that targeting NRG1/HER3 is a potential novel therapeutic option for lorlatinib‐resistant ALK‐rearranged lung cancer. [ABSTRACT FROM AUTHOR]

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer, usually with an indolent course. ALK fusions are rare in PTC but may give rise to a more aggressive behavior. We report a novel ALK fusion, CCDC149–ALK, not previously described in PTC, detected by next-generation sequencing in a 30-year-old woman with progressive widely metastatic radioiodine-refractory (RAIR) disease to lung, muscle, and brain. The patient was started on alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor. Within eight weeks, her palpable disease had completely regressed, and the serum thyroglobulin decreased dramatically. Restaging imaging demonstrated an objective partial response. Our case highlights the role of ALK fusions in thyroid cancer and highlights its clinical significance in PTC. We recommend deep mutational sequencing in BRAFV600E-negative RAIR PTC to identify targetable genetic alterations, including gene fusions, that may result in dramatic therapeutic benefits. [ABSTRACT FROM AUTHOR]

Cancer of unknown primary (CUP) accounts for 5% of all malignancies. Patients with CUP may live averagely for 8 months after diagnosis, and thus, rapid and reasonable diagnosis is necessary. Among patients with CUP, anaplastic lymphoma kinase (ALK)-overexpressing CUPs, whose primary sites were confirmed to be the lungs (Lung-CUP) by using antibodies against cytokeratin 7, thyroid transcription factor-1, and Napsin A, along with clinical characteristics progressed rapidly and were very sensitive to the ALK inhibitor alectinib. The incidence of ALK alteration in Lung-CUP is 19%. Consequently, it is advised that Lung-CUP be examined by immunohistochemistry (IHC) with an anti-ALK antibody. Alternative examinations, such as a cancer genome test, require as much as 2 months to complete, whereas IHC can be completed within days. In this report, a rapid assessment by IHC led to alectinib treatment, which resulted in good outcomes in 2 cases of Lung-CUP. Alectinib was effective for ALK-altered Lung-CUPs.

Little is known about the efficacy of alectinib for papillary thyroid cancer with STRN-ALK fusion. A 64-year-old female presented with metastatic papillary thyroid cancer, widespread to lungs, mediastinal lymph nodes and brain 20 years after surgery. Disease progression still occurred after radioactive iodine therapy, chemotherapy, and radiotherapy. Tissue obtained from left cervical lymph node confirmed metastatic papillary thyroid cancer. Molecular profiling from re-biopsy tissue identified an STRN-ALK fusion rearrangement. After multidisciplinary discussion, alectinib was administered to the patient. Treatment was well tolerated, and follow-up images confirmed a partial response. ALK occurs rarely, with limited data suggesting the efficacy of ALK inhibitors in thyroid cancer. We presented the first case of a patient with PTC and STRN-ALK fusion to be treat effectively with alectinib. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Lung Cancer is the property of Chinese Journal of Lung Cancer and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objectives: Lorlatinib, a brain-penetrant, third-generation anaplastic lymphoma kinase (ALK) inhibitor, demonstrated robust overall and intracranial antitumor activity in patients with advanced ALK-positive non-small cell lung cancer (NSCLC) previously treated with an ALK inhibitor in a global phase 1/2 study (NCT01970865) and a multicenter phase 2 study conducted in China (NCT03909971). We report updated 3-year follow-up data from the phase 2 study., Materials and Methods: Chinese patients with locally advanced or metastatic ALK-positive NSCLC that progressed after crizotinib as the only prior ALK inhibitor (cohort 1) or after 1 non-crizotinib ALK inhibitor (cohort 2), were enrolled in the study. All patients received lorlatinib 100 mg once daily., Results: At data cutoff, of 109 enrolled patients, the median duration of follow-up for progression-free survival (PFS) was 35.8 months in cohort 1 (n = 67) and 33.1 months in cohort 2 (n = 42). Median PFS (95% CI) per independent central review was 26.3 months (16.6-35.9) and 5.6 months (2.9-12.4), respectively. The median duration of follow-up for overall survival (OS) was 36.4 months and 37.5 months, respectively. Median OS (95% CI) was not reached (NR; NR-NR) and 21.9 months (11.9-NR), respectively. Median intracranial time to progression (95% CI) was NR (NR-NR) and NR (9.7 months-NR), respectively. No new safety signals emerged with long-term treatment., Conclusion: The long-term data confirm robust overall and intracranial clinical activity of lorlatinib, with no new safety signals emerging. These results support using lorlatinib in Chinese patients with previously treated ALK-positive NSCLC with or without brain metastases., Clinicaltrials: gov NCT03909971., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Zotizalkib (TPX-0131), a fourth-generation macrocyclic anaplastic lymphoma kinase (ALK) inhibitor, is designed to overcome resistance due to secondary ALK mutations in non-small cell lung cancer (NSCLC). We here evaluated the pharmacokinetic roles of the ABCB1 (P-gp/MDR1) and ABCG2 (BCRP) efflux transporters, OATP1 influx transporters and the metabolizing enzymes CES1 and CYP3A in plasma and tissue disposition of zotizalkib after oral administration in relevant mouse models. Zotizalkib was efficiently transported by hABCB1 in vitro. In vivo, a significant ∼9-fold higher brain-to-plasma ratio was observed in Abcb1a/b -/- and Abcb1a/b;Abcg2 -/- compared to wild-type mice. No change in brain disposition was observed in Abcg2 -/- mice, suggesting that mAbcb1a/b markedly restricts the brain accumulation of zotizalkib. ABCB1-mediated efflux of zotizalkib was completely inhibited by elacridar, a dual ABCB1/ABCG2 inhibitor, increasing brain exposure without any signs of acute CNS-related toxicities. In Oatp1a/b -/- mice, no marked changes in plasma exposure or tissue-to-plasma ratios were observed, indicating that zotizalkib is not a substantial in vivo substrate for mOatp1a/b. Zotizalkib may further be metabolized by CYP3A4 but only noticeably at low plasma concentrations. In Ces1 -/- mice, a 2.5-fold lower plasma exposure was seen compared to wild-type, without alterations in tissue distribution. This suggests increased plasma retention of zotizalkib by binding to the abundant mouse plasma Ces1c. Notably, the hepatic expression of human CES1 did not affect zotizalkib plasma exposure or tissue distribution. The obtained pharmacokinetic insights may be useful for the further development and optimization of therapeutic efficacy and safety of zotizalkib and related compact macrocyclic ALK inhibitors.

What Is This Study About?: This is a summary of the results of an ongoing study called CROWN. In the CROWN study, researchers looked at the effects of two medicines called lorlatinib (Lorbrena) and crizotinib (Xalkori) for people with advanced non-small cell lung cancer (NSCLC) who had not been treated yet. Everyone in the study had changes in a gene called anaplastic lymphoma kinase, or ALK , in their cancer cells. The changes in the ALK gene can make cancer grow. This analysis looked at how well lorlatinib and crizotinib worked and their side effects in people with advanced ALK -positive NSCLC after 5 years., What Did This Study Find?: After observing people for an average of 5 years, researchers found that more people who took lorlatinib were still alive without their cancer getting worse than the people who took crizotinib. At 5 years, the probability of being alive without their cancer getting worse was 60% in people who took lorlatinib compared with 8% in people who took crizotinib. Fewer people who took lorlatinib had their cancer spread within or to the brain than the people who took crizotinib. In more than half of the people who took lorlatinib, tumors that had spread to the brain did not get worse, and no new tumors spread to the brain after 5 years. In contrast, in about half of the people who took crizotinib, tumors that had spread to the brain got worse or new tumors spread to the brain after 16.4 months. More people who took lorlatinib (115 out of 149, or 77%) had severe or life-threatening side effects than people who took crizotinib (81 out of 142, or 57%). These side effects were like the ones reported in the earlier 3-year analysis., What Do the Findings of the Study Mean?: The 5-year results from the CROWN study showed that more people who took lorlatinib continued to benefit from their treatment than those who took crizotinib. The 5-year benefit of lorlatinib in people with ALK -positive NSCLC has never been seen before. Clinical Trial Registration: NCT03052608 (Phase 3 CROWN study) (ClinicalTrials.gov).

Abstract More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU‐MP‐5 as a new‐generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU‐MP‐5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild‐type or mutant EML4‐ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU‐MP‐5. In addition, XMU‐MP‐5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological efficacy and potential for clinical application. These preclinical data support XMU‐MP‐5 as a novel selective ALK inhibitor with high potency and selectivity. XMU‐MP‐5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations.

Introduction: Although driver gene mutations have been believed to be mutually exclusive, some patients with NSCLC and concomitant EGFR mutations and EML4-ALK rearrangements have been reported. In this study, we reported a case of a patient with lung cancer who harbored both EGFR mutation and the EML4-ALK rearrangement after acquiring resistance to the EGFR tyrosine kinase inhibitor treatment. EGFR-mutant and ALK fusion proteins were detected in the same tumor cells through immunohistochemical analysis. Investigation of the molecular mechanisms of concomitant EGFR mutation and the EML4-ALK rearrangement in the same tumor cell can help discover an appropriate treatment for these patients. Methods: PC-9 cells, expressing EGFR exon 19 deletion, were transfected with EML4-ALK variant 3a (v3a) and variant 3b (v3b) separately and selected, and the effect of EGFR and ALK inhibitors was evaluated in vitro and in vivo. Results: PC-9_v3a-gef and PC-9_v3b-gef cells were resistant to gefitinib and ALK inhibitors alone, but ALK inhibitors enhanced gefitinib-induced cytotoxicity. In animal studies, gefitinib completely inhibited the tumor growth in PC-9_vector cells but not in PC-9_v3a-gef and PC-9_v3b-gef cells. A combination of ALK inhibitor and gefitinib was found to be more potent than gefitinib alone in PC-9_v3a-gef and PC-9_v3b-gef cells. Furthermore, combination treatment with osimertinib and ceritinib caused a decrease in liver tumor size of the patient with liver metastases. Conclusions: Our data suggest that combination treatment with EGFR and ALK inhibitors can be a therapeutic strategy for treating NSCLC with concomitant EGFR mutation and EML4-ALK rearrangement.

Aim: To conduct an indirect treatment comparison (ITC) of the relative efficacy of brigatinib and alectinib for progression-free survival in people with tyrosine kinase inhibitor (TKI)-naive ALK-positive non-small-cell lung cancer (NSCLC). Methods: Final aggregate and patient-level data from the ALTA-1L trial comparing brigatinib to crizotinib and published aggregate data from ALEX (comparing alectinib to crizotinib) were contrasted using Bucher ITC and matching-adjusted indirect comparisons (MAICs). Results: No statistically significant differences were identified between brigatinib and alectinib in reducing the risk of disease progression overall and in patients with baseline central nervous system metastases. Conclusion: Brigatinib appeared similar to alectinib in reducing risk of disease progression for people with TKI-naive ALK-positive NSCLC. [ABSTRACT FROM AUTHOR]

Background: Rearrangements of Anaplastic lymphoma kinase (ALK) have been discovered as a novel driver mutation in patients with non–small-cell lung cancer (NSCLC). Patients' responses to ALK tyrosine kinase inhibitors (TKIs) may vary depending on the variations of ALK rearrangements they have. It is imperative for clinicians to identify druggable ALK fusions in routine practice. Case Presentation: In this study, we discovered a rare ALK rearrangement type (SDK1–ALK) in a Chinese lung adenocarcinoma patient who responded well to ALK inhibitor SAF-189s. The positive expression of ALK in lung biopsy tissue was verified by IHC analysis. A new SDK1-ALK fusion was discovered using NGS. The patient was treated with SAF-189s (160 mg per day) as a first-line therapy and went into continuous remission, with a 12 months progression-free survival at the last follow-up. Conclusion: This is the first case of SDK1-ALK fusion with an excellent response to an ALK inhibitor, which will provide better understanding of ALK-TKI applications for NSCLC patients with ALK fusion in the future. [ABSTRACT FROM AUTHOR]

ALK-positive histiocytosis (APH) is a rare and recently described, solitary or generalized, histiocytic proliferative disorder with a characteristic gene translocation involving the fusion of the ALK gene at chromosome 2p23. To date, only 25 cases of APH have been reported. The patient presented with multiple nodules in the lung, liver, gallbladder, pancreas, kidney, and skin rashes, along with recurrent pancreatitis and cholecystitis. The histiocytes from the lesion were positive for CD68 and ALK and negative for S100 and CD1α. A reduced dose of the ALK inhibitor alectinib was administered rather than the standard dose of alectinib or chemotherapy because of recurrent pancreatitis, which has not been previously reported in APH cases. After 18 months of follow-up, the patient was maintained on alectinib, and a partial response (PR) was achieved.

BackgroundRearrangements of Anaplastic lymphoma kinase (ALK) have been discovered as a novel driver mutation in patients with non–small-cell lung cancer (NSCLC). Patients’ responses to ALK tyrosine kinase inhibitors (TKIs) may vary depending on the variations of ALK rearrangements they have. It is imperative for clinicians to identify druggable ALK fusions in routine practice.Case PresentationIn this study, we discovered a rare ALK rearrangement type (SDK1–ALK) in a Chinese lung adenocarcinoma patient who responded well to ALK inhibitor SAF-189s. The positive expression of ALK in lung biopsy tissue was verified by IHC analysis. A new SDK1-ALK fusion was discovered using NGS. The patient was treated with SAF-189s (160 mg per day) as a first-line therapy and went into continuous remission, with a 12 months progression-free survival at the last follow-up.ConclusionThis is the first case of SDK1-ALK fusion with an excellent response to an ALK inhibitor, which will provide better understanding of ALK-TKI applications for NSCLC patients with ALK fusion in the future.

More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU‐MP‐5 as a new‐generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU‐MP‐5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild‐type or mutant EML4‐ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU‐MP‐5. In addition, XMU‐MP‐5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological efficacy and potential for clinical application. These preclinical data support XMU‐MP‐5 as a novel selective ALK inhibitor with high potency and selectivity. XMU‐MP‐5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations. Synopsis: Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC. XMU‐MP‐5 is a new ALK inhibitor with high potency and selectivity.XMU‐MP‐5 overcomes acquired resistance to first and second generation ALK inhibitors, including ALKL1196M and ALKG1202R.XMU‐MP‐5 induces significant regression of lung tumors in ALK wild‐type and L1196M GEM models. [ABSTRACT FROM AUTHOR]

Cancer of unknown primary (CUP) accounts for 5% of all malignancies. Patients with CUP may live averagely for 8 months after diagnosis, and thus, rapid and reasonable diagnosis is necessary. Among patients with CUP, anaplastic lymphoma kinase (ALK)-overexpressing CUPs, whose primary sites were confirmed to be the lungs (Lung-CUP) by using antibodies against cytokeratin 7, thyroid transcription factor-1, and Napsin A, along with clinical characteristics progressed rapidly and were very sensitive to the ALK inhibitor alectinib. The incidence of ALK alteration in Lung-CUP is 19%. Consequently, it is advised that Lung-CUP be examined by immunohistochemistry (IHC) with an anti-ALK antibody. Alternative examinations, such as a cancer genome test, require as much as 2 months to complete, whereas IHC can be completed within days. In this report, a rapid assessment by IHC led to alectinib treatment, which resulted in good outcomes in 2 cases of Lung-CUP. Alectinib was effective for ALK-altered Lung-CUPs. [ABSTRACT FROM AUTHOR]

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 delayed the regrowth following cessation of these treatments. Together, our results demonstrated that JNK pathway activation plays a pivotal role in the intrinsic resistance to ALK-TKIs and the emergence of ALK-TKI-tolerant cells in ALK-rearranged NSCLC, thus indicating that optimal inhibition of tolerant signals combined with ALK-TKIs may potentially improve the outcome of ALK-rearranged NSCLC. [ABSTRACT FROM AUTHOR]

Inflammatory myofibroblastic tumor (IMT) is a distinctive neoplasm that frequently arises in the lung and accounts for ~1% of lung tumors. Distant metastatic IMT is extremely rare and has been poorly investigated. This analysis was specifically performed to explore the clinicopathological and genetic features of early distant metastatic IMT. Two typical patients with distant metastatic IMTs were selected, which accounted for 1.13% of all diagnosed IMTs in the last 5 years. One patient was a 55 year-old male, and the other patient was a 56 year-old female. Both primary tumors arose from the lung, and the initial clinical symptoms of the two patients involved coughing. Both of the imaging examinations showed low-density nodular shadows in the lungs with enhancement around the mass. Microscopically, dense arranged tumor cells, prominent cellular atypia, and high mitotic activity with atypical form were more prominent in the metastatic lesions than in the primary lesions. All of the primary and metastatic tumors in both cases showed positive anaplastic lymphoma kinase (ALK) immunostaining and ALK rearrangement via fluorescence in situ hybridization. The EML4 (exon 6)-ALK (exon 20) fusion variant (v3a/b) was identified by using next-generation sequencing (NGS) and was verified by using reverse transcription polymerase chain reaction (RT-PCR). Furthermore, intronic variants of NOTCH1 and synonymous variants of ARAF were also detected via NGS in one IMT for the first time and were verified in all of the primary and metastatic lesions via PCR. Distant metastasis occurred during a short period of time (1 and 2 months) after the first surgery. One patient presented with multiple metastases to the subcutaneous tissue and bone that responded to ALK inhibitor alectinib therapy, and the tumor was observed to regress 10 months after the initial ALK inhibitor therapy. In contrast, the other patient presented with subcutaneous neck metastasis without ALK inhibitor treatment and succumbed to the disease within 3 months after the surgery. This study demonstrated the possible role of EML4-ALKv3a/b in the malignant progression of IMT and proposed certain therapeutic effects of ALK inhibitors on multiple metastatic IMTs.

Introduction: Inflammatory myofibroblastic tumor (IMT) is a rare entity, classified within soft tissue sarcomas. It is an intermediate malignancy tumor, which seldom presents as metastatic disease. The treatment of choice is surgery, except in cases where surgery is not possible due to localization or if it presents with metastatic disease. Approximately 50% of IMTs will exhibit ALK translocation, providing a therapeutic target for these patients., Case Presentation: A case is presented of a patient with metastatic IMT in complete response to treatment with alectinib, maintained for over 4 years., Conclusion: This case showed a long time complete response in patient with IMT treated with alectinib., Competing Interests: Johana Benedetti Pedroza has collected research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, AROG, Bayer, Eisai, Lixte, Karyopharm, Deci-phera, GlaxoSmithKline, Novartis, Blueprint, Nektar, Forma, Amgen, and Daichii-Sankyo. Irene Carrasco García has received personal fees for advisory board, consulting, and travel expenses from Pharmamar. She has also gotten research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, AROG, Bayer, Eisai, Lixte, Karyopharm, Deci-phera, GlaxoSmithKline, Novartis, Blueprint, Nektar, Forma, Amgen, and Daichii-Sankyo. Gala Martínez Bernal has obtained research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, AROG, Bayer, Eisai, Lixte, Karyopharm, Deci-phera, GlaxoSmithKline, Novartis, Blueprint, Nektar, Forma, Amgen, and Daichii-Sankyo. Lastly, Isabel Miras Rodriguez has obtained research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, AROG, Bayer, Eisai, Lixte, Karyopharm, Deci-phera, GlaxoSmithKline, Novartis, Blueprint, Nektar, Forma, Amgen, and Daichii-Sankyo., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Introduction: EML4-ALK is an oncogenic driver, seen in around five per cent of advanced non-small-cell lung cancer (NSCLC) patients, which can be targeted with anaplastic lymphoma kinase tyrosine kinase inhibitors with great response rates. Disease flare refers to sudden rapid disease worsening on tyrosine kinase inhibitors (TKI) discontinuation, which is associated with shorter survival and worse outcomes. Here, we review cases previously published in the literature where patients developed disease flares, and contrast this with our patients who had prolonged survival despite TKI discontinuation., Case Description: We report three different patients with advanced ALK-positive NSCLC seen at our institute, who had EML4-ALK translocation variant 1 oncogenic driver on next-generation sequencing. They received treatment with several different ALK inhibitors before opting to discontinue TKI. They were able to come off TKI safely without developing disease flare and had prolonged survival., Discussion: Shorter time to progression on TKI, presence of symptoms with disease progression or central nervous system/pleural metastasis have been previously linked with development of flare, although this was not seen in our case series. Tumour response at the time of treatment discontinuation, line of therapy, overall disease burden, fusion variant and co-alteration status can affect the prognosis of these patients after ALK TKI cessation. In particular, variant 1 and wild-type TP53 status may be a suitable patient population for dose optimisation strategies. Intermittent TKI dosing strategies may help to avoid acquiring resistance mutations and prevent long-term treatment toxicities., Conclusion: It is important for clinicians to identify patients at risk for developing disease flare on TKI discontinuation to improve outcomes. Intermittent TKI dosing strategies require further investigation., Learning Points: Patients who develop disease flare after cessation have poor survival and worse outcomes.Certain phenotypic and molecular characteristics of the tumour may help clinicians identify which patients are likely and which are unlikely to develop disease flare on TKI discontinuation.Advanced ALK-positive NSCLC with variant 1 and wild-type TP53 may be a suitable patient population for intermittent TKI dosing investigations., Competing Interests: Conflicts of Interests: SAH and HF have no conflicts of interest to declare. GKD received consulting fees/honoraria from the following within the past three years: Amgen, Astra Zeneca, Bayer, Eli Lilly, Janssen, Mirati, Novartis, Regeneron., (© EFIM 2024.)

• This study quantified the toxicity profiles of different ALK-TKIs. • Alectinib might be the safest ALK-TKI drug according to the combined evidence of grade 3–4 AEs and the combined incidence. • The findings provide a safety reference for personalized ALK-TKI administration. Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) are new treatment for advanced non-small cell lung cancer. Here, we quantified the toxicity profiles of different ALK-TKIs to guide clinical decision making. We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials. Data were analyzed using random effects and consistency models under the frequency framework. Of 865 relevant studies, 13 RCTs (encompassing 3,353 patients) were finally included. A network meta -analysis of all-grade AEs, fatal AEs, and treatment discontinuation due to AEs revealed no significant differences among the six ALK-TKIs. The rates of grade 3–4 AEs were: alectinib (16.2%), crizotinib (46.4%), brigatinib (63.7%), ensartinib (75.6%), ceritinib (78.3%), and lorlatinib (91.6%). The toxicity spectra of ALK-TKIs were different. The most frequent AEs associated with crizotinib were gastrointestinal reactions, visual disorders, neutropenia, edema, fatigue, and elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels, while those in the alectinib group were anemia and constipation. Diarrhea, hepatotoxicity, and increased serum creatinine were most common with ceritinib. The most frequent AEs in the brigatinib group were gastrointestinal reactions, hypertension, cough, headache, and elevated ALT or AST levels. The most significant toxicities of ensartinib were skin disorders, including pruritus and rash. Changes in lipid levels were the most frequent AEs associated with lorlatinib; weight gain, cognitive effects, and mood effects were lorlatinib-specific AEs. The toxicity spectra of ALK-TKIs differed. Alectinib might be the safest ALK-TKI drug according to the combined evidence of grades 3–4 AEs and the combined incidence. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer deaths worldwide, with the majority consisting of non-small cell lung cancer (NSCLC). Genetic mutations present an opportunity for targeted therapy, in addition to current mainstay treatments such as chemotherapy and radiotherapy. Overall, 5% of NSCLCs have an anaplastic lymphoma kinase (ALK) mutation, often prevalent in a younger population. Crizotinib is an ALK inhibitor that was approved to treat ALK-mutated advanced NSCLC. While common side effects such as nausea, fatigue, and diarrhea are mostly well tolerated, adverse side effects can lead to treatment discontinuation or adjustment or can be fatal. This systematic review used articles searched on Google Scholar and PubMed which were assessed using the Cochrane risk-of-bias tool and Newcastle-Ottawa Scale. This yielded nine papers consisting of randomized controlled trials and cohort studies. Side effects resulting in cessation of treatment or dose reduction included liver dysfunction, nausea, neutropenia, and QT prolongation. This review showed that crizotinib has a better side effect profile than chemotherapy in ALK-positive NSCLC, even though toxicities leading to treatment withdrawal are present. Adverse effects were tackled by dose reduction, temporary withdrawal from treatment, and close monitoring., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, George et al.)

Targeting the Echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK) fusion gene is a promising therapeutic strategy for non–small-cell lung cancer (NSCLC) patients. With the advent of the first- and second-generation ALK inhibitors, the mortality rate of lung cancer has shown a downward trend, but almost inevitably, patients will eventually develop resistance, which severely limits the clinical application. Hence, developing new ALK inhibitors which can overcome resistance is essential. Here, we synthesized a novel ALK inhibitor 1-[4-[[5-Chloro-4-[[2-[(1-methylethyl)sulfonyl]phenyl]amino]-2-pyrimidinyl]amino]-3-methoxyphenyl]-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-2-imidazolidinone (ZYY-B-2) based on the structure of the second-generation ALK inhibitor ceritinib. ZYY-B-2 exhibited impressive anti-proliferative effect in the EML4-ALK positive H2228 cells and ceritinib-resistant H2228 (H2228/Cer) cells. Meanwhile, ZYY-B-2 inhibited the activation of p-ALK in a concentration-dependent manner, and inactivated its downstream target proteins p-AKT and p-ERK to inhibit cell proliferation. Subsequently, we found that ZYY-B-2 blocked H2228 cells and H2228/Cer cells in G0/G1 phase and induced cells to undergo apoptosis through the mitochondrial pathway. The ability of its anti-proliferation and pro-apoptosis was significantly stronger than the second generation ALK inhibitor ceritinib. In addition, high expression of P-gp was found in H2228/Cer cells compared with H2228 cells. ZYY-B-2 could inhibit the expression of P-gp in a dose-dependent manner to overcome ceritinib resistance, and the suppression effect of ZYY-B-2 on P-gp might be related to its inhibition of PI3K/AKT signaling pathway. In summary, ZYY-B-2, a promising ALK inhibitor, shows potent activity against ceritinib-resistant cells, which provides experimental and theoretical basis for the further development of new ALK inhibitors. • ZYY-B-2, a novel ALK inhibitor, shows excellent activity against ALK-positive H2228 and H2228/Cer cells in vitro. • ZYY-B-2 inhibits ALK and its downstream signaling pathway. • ZYY-B-2 blocks cells in G0/G1 phase and induces cells to undergo apoptosis through the mitochondrial pathway. • ZYY-B-2 inhibits the expression of P-gp to overcome ceritinib resistance. [ABSTRACT FROM AUTHOR]