LTK mutations responsible for resistance to lorlatinib in non-small cell lung cancer harboring CLIP1-LTK fusion.

The CLIP1-LTK fusion was recently discovered as a novel oncogenic driver in non-small cell lung cancer (NSCLC). Lorlatinib, a third-generation ALK inhibitor, exhibited a dramatic clinical response in a NSCLC patient harboring CLIP1-LTK fusion. However, it is expected that acquired resistance will inevitably develop, particularly by LTK mutations, as observed in NSCLC induced by oncogenic tyrosine kinases treated with corresponding tyrosine kinase inhibitors (TKIs). In this study, we evaluate eight LTK mutations corresponding to ALK mutations that lead to on-target resistance to lorlatinib. All LTK mutations show resistance to lorlatinib with the L650F mutation being the highest. In vitro and in vivo analyses demonstrate that gilteritinib can overcome the L650F-mediated resistance to lorlatinib. In silico analysis suggests that introduction of the L650F mutation may attenuate lorlatinib-LTK binding. Our study provides preclinical evaluations of potential on-target resistance mutations to lorlatinib, and a novel strategy to overcome the resistance.

[China expert recommendations on anaplastic lymphoma kinase-tyrosine kinase inhibitors treatment for advanced non-small cell lung cancer (2024 edition)].

Anaplastic lymphoma kinase (ALK) fusion represents one of pivotal driver genes within the realm of non-small cell lung cancer (NSCLC). ALK-tyrosine kinase inhibitors (ALK-TKI) have demonstrated remarkable therapeutic efficacy for patients afflicted with ALK-positive NSCLC. As of June 27, 2023, seven ALK-TKI, including crizotinib, ceritinib, alectinib, ensartinib, brigatinib, lorlatinib, and iruplinalkib, have garnered approval from the China National Medical Products Administration (NMPA)(ranking according to the approval time for marketing by NMPA), providing individualized treatment modalities for ALK-positive NSCLC patients. To standardize the application of ALK-TKI, the Chinese Association for Clinical Oncologists and the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care has organized experts to compile the " China expert recommendations on anaplastic lymphoma kinase-tyrosine kinase inhibitors treatment for advanced non-small cell lung cancer (2024 edition)". This treatment expert recommendation provides recommendations in four aspects, encompassing ALK fusion testing, ALK-TKI targeted therapy, ALK-TKI adverse events management, and patient post-treatment follow-up, thus serving as a valuable reference for the standardized treatment of Chinese advanced ALK fusion-positive NSCLC.

Lung adenocarcinoma with brain metastasis detected dual fusion of LOC399815-ALK and ALK-EML4 in combined treatment of Alectinib and CyberKnife: A case report.

INTRODUCTION: The anaplastic lymphoma kinase (ALK) gene fusion occurs in approximately 3% to 7% of nonsmall cell lung cancer (NSCLC), in which occurs approximately 23% to 31% of brain metastasis patients in poor prognosis. ALK tyrosine kinase inhibitors have shown efficacy in treating ALK-positive (ALK+) NSCLC. More than 90 distinct subtypes of ALK fusions have been identified through sequencing technique and would lead to significant differences in clinical efficacy, it is necessary to guide clinical treatment effectively by gene detection. PATIENT CONCERNS: A 56-year-old nonsmoking female admitted to hospital due to cough, expectoration, and chest pain. Chest computed tomography revealed a space-occupying lesion in the upper left lobe (5.0 cm × 2.4 cm × 2.9 cm), multiple enlarged lymph nodes in mediastinum 3A and 5 (largest size 1.5 cm × 1.4 cm), and evidence of thoracic vertebral metastasis, brain magnetic resonance imaging also showed brain metastasis. DIAGNOSES: Lung adenocarcinoma with brain metastasis. INTERVENTIONS: The patient initially received conventional first-line chemotherapy, which led to a deteriorated condition. Blood-base liquid biopsy by next-generation sequencing resulted in double ALK fusions, in which with a neo-partner of lncRNA (LOC399815-ALK). Following subsequent treatment with Alectinib and stereotactic radiotherapy (CyberKnife) was subsequently employed to manage the brain metastatic lesions, resulting in a substantial decreased in both the number and size of tumor lesions. OUTCOMES: The patient's response to therapy efficacy resulted in a substantial decreased in both the number and size of tumor lesions that assessed comprehensively evaluated through computed tomography imaging and ctDNA sequencing. Patient's condition has been under control for over 29 months. CONCLUSION: Liquid biopsy may reveal the rare fusion forms of ALK, precisely guiding personalized treatment, and providing a reference method for longitudinal monitoring and efficacy evaluation of ALK-tyrosine kinase inhibitors in NSCLC patients.

Real-world outcome of crizotinib for anaplastic lymphoma kinase-positive lung cancer: Multicenter retrospective analysis in South Korea.

BACKGROUND: About 3%-5% of non-small cell lung cancer (NSCLC) presents positive anaplastic lymphoma kinase (ALK). Recently, several target agents have been approved as a treatment for ALK-positive NSCLC. This study aimed to analyze the real-world efficacy and outcome when administered crizotinib, the first approved target agent for ALK-positive NSCLC, according to first- or late-line treatment. METHODS: A total of 290 patients with ALK-positive advanced NSCLC who were treated with crizotinib in 15 institutions in South Korea from January 2009 to December 2018 were enrolled. RESULTS: The median age of patients was 57.0 years, and 50.3% were male. The median follow-up duration was 29.3 months. Among them, 113 patients received crizotinib as first-line therapy. The objective response rate (ORR) was 60.1% (57.0% for first-line recipients, 61.8% for second-/later-line). Median (95% CI) progression-free survival (PFS) was 13.7 (11.6-17.0) months. For first-line recipients, overall survival (OS) was 26.3 (17.6-35.0) months. No significant difference in ORR, PFS and OS, according to the setting of crizotinib initiation, was observed. In a multivariate Cox regression analysis, old age, male gender, initially metastatic, and number of metastatic organs were associated with poor PFS and OS. The most common adverse events were nausea and vomiting, and severe adverse event leading to dose adjustment was hepatotoxicity. CONCLUSIONS: ORR, PFS, OS, and adverse event profiles were comparable to previous clinical trials. Our findings could aid in the efficient management of ALK-positive lung cancer patients.

EML4-ALK fusion protein in Lung cancer cells enhances venous thrombogenicity through the pERK1/2-AP-1-tissue factor axis.

BACKGROUND: Accumulating evidence links the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement to venous thromboembolism (VTE) in non-small cell lung cancer (NSCLC) patients. However, the corresponding mechanisms remain unclear. METHOD: High-throughput sequencing analysis of H3122 human ALK-positive NSCLC cells treated with ALK inhibitor/ dimethyl sulfoxide (DMSO) was performed to identify coagulation-associated differential genes between EML4-ALK fusion protein inhibited cells and control cells. Sequentially, we confirmed its expression in NSCLC patients' tissues and in the plasma of a subcutaneous xenograft mouse model. An inferior vena cava (IVC) ligation model was used to assess clot formation potential. Additionally, pathways involved in tissue factor (TF) regulation were explored in ALK-positive cell lines H3122 and H2228. Statistical significance was determined by Student t-test and one-way ANOVA using SPSS. RESULTS: Sequencing analysis identified a significant downregulation of TF after inhibiting EML4-ALK fusion protein activity in H3122 cells. In clinical NSCLC cases, TF expression was increased especially in ALK-positive NSCLC tissues. Meanwhile, H3122 and H2228 with high TF expression exhibited shorter plasma clotting time and higher TF activity versus ALK-negative H1299 and A549 in cell culture supernatant. Mice bearing H2228 tumor showed a higher concentration of tumor-derived TF and TF activity in plasma and the highest adjusted IVC clot weights. Limiting EML4-ALK protein phosphorylation downregulated extracellular regulated protein kinases 1/2 (ERK1/2)-activating the protein-1(AP-1) signaling pathway and thus attenuated TF expression. CONCLUSION: EML4-ALK fusion protein may enhance venous thrombogenicity by regulating coagulation factor TF expression. There was potential involvement of the pERK1/2-AP-1 pathway in this process.

Lorlatinib as a first-line treatment of adult patients with anaplastic lymphoma kinase-positive advanced non-small cell lung cancer: Α cost-effectiveness analysis in Greece.

OBJECTIVES: To evaluate the cost-effectiveness of lorlatinib compared to 1st generation anaplastic lymphoma kinase (ALK) TKI crizotinib, and 2nd generation TKIs alectinib and brigatinib, for previously untreated patients with ALK+ advanced Non-Small Cell Lung Cancer (aNSCLC). METHODS: A partitioned survival model was locally adapted from a Greek payer perspective over a lifetime horizon. Clinical, safety and utility data were extracted from literature. Direct medical costs reflecting the year 2023 were included in the analysis (€). Model outcomes were patients' life years (LYs), quality-adjusted life years (QALYs), total costs and incremental cost-effectiveness ratios (ICERs). RESULTS: Total cost per patient with lorlatinib, alectinib, crizotinib, and brigatinib was estimated to be €188,205, €183,343, €75,028, and €145,454 respectively. Lorlatinib appeared to yield more LYs and QALYs gained versus alectinib, crizotinib, and brigatinib. Hence, lorlatinib resulted in ICERs of €4,315 per LY gained and €4,422 per QALY gained compared to alectinib, €34,032 per LY gained and €48,256 per QALY gained versus crizotinib and €16,587 per LY gained and €26,271 per QALY gained compared to brigatinib. CONCLUSION: Lorlatinib provides substantial clinical benefit and appears to be a cost - effective treatment option compared to 1st and 2nd generation TKIs for previously untreated patients with ALK+ aNCSLC in Greece.

High-grade intraductal carcinoma of the parotid gland harboring CTNNA1::ALK rearrangement: Changes in genetic status using genetic testing during treatment with an ALK inhibitor.

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.

Clinical Relevance of High Plasma Trough Levels of the Kinase Inhibitors Crizotinib, Alectinib, Osimertinib, Dabrafenib, and Trametinib in NSCLC Patients.

BACKGROUND: the study aims to evaluate whether high plasma trough levels of the kinase inhibitors (K.I.s) crizotinib, alectinib, osimertinib, dabrafenib, and trametinib were associated with a higher risk of toxicity in non-small-cell lung cancer patients. METHODS: In this retrospective cohort study, patients with non-small-cell lung cancer treated with the selected K.I.s were included if at least one plasma trough level at steady state (C min,ss ) was available. Data were extracted from electronic medical records and laboratory databases. The high group for each K.I. was defined as 10% of patients with the highest first C min,ss . The remaining patients were placed in the non-high group. The frequency of dose-limiting toxicities (DLTs), defined as adverse events leading to dose reduction, dose interruption, or permanent discontinuation, was compared between the 2 groups. RESULTS: A total of 542 patients were included in the different K.I. groups. A high C min,ss of crizotinib (n = 96), alectinib (n = 105), osimertinib (n = 227), dabrafenib (n = 52), and trametinib (n = 62) correlated with a C min,ss ≥490, ≥870, ≥405, ≥150, and ≥25 ng/mL, respectively. DLTs were more common in the alectinib high group than in the alectinib non-high group (64% vs. 29%, P = 0.036). Liver toxicity was observed in 4 (36%) patients in the high group and 5 (5%) patients in the non-high group ( P = 0.007). For other K.I.s, no significant differences were observed in the frequency of DLTs between the high and non-high groups. CONCLUSIONS: For alectinib, high C min,ss was correlated with a higher risk of DLT. No differences in the frequency of DLTs were observed between the high and non-high groups for crizotinib, osimertinib, dabrafenib, and trametinib.

In-depth Analysis of Lorlatinib-related neurocognitive Adverse Events in Patients With Non-small-cell Lung Cancer.

INTRODUCTION: Lorlatinib is a potent, brain penetrant, next-generation ALK/ROS1 TKI, with high response rates and durable responses, including the brain. However, a significant drawback is the manifestation of neurocognitive adverse events (NCAEs). Despite being generally low-grade in severity, these NCAEs can be physically and mentally disabling. Extensive neurocognitive testing in this group of patients is lacking; therefore we conducted this study. PATIENTS AND METHODS: This observational prospective study was conducted across 3 Dutch university hospitals. Patients with metastatic NSCLC with an ALK- or ROS1-rearrangement and having an indication to start lorlatinib in daily clinical practice were eligible. The primary endpoints were to identify changes in neurocognitive functioning, measured through neurocognitive assessment at intervals of 2 weeks and 2 months after starting lorlatinib, in comparison to baseline. As a secondary endpoint, the correlation between neurocognitive impairment and self-reported neurocognitive dysfunction was examined. RESULTS: Between June 2019 and October 2022, 22 patients were included. Among the various neurocognitive tests administered, only the Hopkins Verbal Learning Test-Revised parts b and c demonstrated a significant and clinically relevant decrease in scoring 2 weeks post initiation of lorlatinib (P = .036 and P = .003, respectively). However, these returned to baseline at the 2-month evaluation. The questionnaires did not result in significantly different outcomes over time. CONCLUSION: Lorlatinib treatment did not result in a sustained and significant decline within any of the specified neurocognitive domains.

Identification of ALK Mutation in Neuroblastoma on the Point of Molecular Heterogeneity.

BACKGROUND AND AIM: In neuroblastoma, anaplastic lymphoma kinase mutations have recently received attention as molecular targets for the treatment of neuroblastoma, as 6% to 10% of patients with neuroblastoma have anaplastic lymphoma kinase mutations. There are little data from the cases in Turkey. We aimed to detect anaplastic lymphoma kinase mutations and molecular heterogeneity in neuroblastoma using next-generation sequencing. This study is the first one with this many cases in Turkey. METHODS: Next-generation sequencing analysis was performed using an Illumina MiniSeq custom gene panel. Clinically important mutations were selected for the analysis. We also gathered clinical data of the patients from Turkish Pediatric Oncology Group cohorts to associate them with anaplastic lymphoma kinase mutations. This study is a retrospective cross-sectional study. We followed STROBE guideline (https://www.equator-network.org/reporting-guidelines/strobe/) on this study. RESULTS: We analyzed anaplastic lymphoma kinase in 108 patients with neuroblastoma, with a mean age of 43.76 months. Pathogenic anaplastic lymphoma kinase mutations were detected in 13 patients (12.04%). We noted that anaplastic lymphoma kinase mutations were primarily observed in intermediate- and high-risk patients (P = .028). R1275Q and F1174-related mutations were predominant; I1171T, L1226F, S1189F, V1135A, and G1125S mutations were rare. Duplicate samples did not exhibit any heterogeneity. CONCLUSIONS: We found that F1174 and R1275Q-related anaplastic lymphoma kinase mutations are the most common pathogenic mutations in neuroblastoma. Anaplastic lymphoma kinase mutation status did not show any heterogeneity, and the mutations were correlated with intermediate- or high-risk groups.

Clinical Characteristics of Patients with Advanced ALK-Translocated Non-small Cell Lung Cancers and Long-Term Responses to Crizotinib (CRIZOLONG GFPC 05-19 Study).

BACKGROUND: Although ALK-translocated (ALK+) advanced non-small cell lung cancers (aNSCLCs) are currently treated with second- or third-generation ALK inhibitors (ALK-TKIs), some patients respond durably to the first-generation ALK-TKI crizotinib. OBJECTIVE: This study aimed to describe the clinical characteristics of these long-term responders. PATIENTS AND METHODS: This national, multicenter, retrospective, non-interventional study included patients with ALK+ aNSCLCs and long-term responses to first (L1)- or subsequent (≥ L2)-line crizotinib, defined, respectively, as treatments lasting > 18 and > 10 months. Median treatment duration (mDOT) was the primary endpoint. RESULTS: A total of 85 patients (32 L1 and 53 ≥ L2 responders) from 23 centers were included (receiving crizotinib between 10/24/2011-10/02/2018): median age of 59 years, 83.6% non-smokers or ex-smokers, 85.9% performance status (PS) 0/1, 94.1% with adenocarcinomas, median of one metastatic site, and 22.4% with brain metastases (BMs). After median follow-up of 73.4 [95% confidence interval, 67.5-79.9] months, respective L1 and ≥ L2 mDOTs were 43.3 [26.7-56.8] and 29.6 [22.6-35.8] months, with overall survival (OS) not reached (NR) and 116.2 [83.4-NR] months. BM presence or absence did not affect mDOT (31.4 versus 32.9 months) but significantly impacted median OS (70.6 versus 158.6 months; p = 0.0008). Progression on crizotinib was paucisymptomatic (74.1%) and oligometastatic (34.8%), especially BMs (42.4%). After crizotinib discontinuation, 65 (76.5%) patients received subsequent systemic therapy: 57 (67.1%) with second-generation ALK-TKIs. Respective mDOTs of first- and second-line post-crizotinib ALK-TKIs lasted 19.4 [14.9-25.6] and 11.1 [4.8-17.9] months, respectively. CONCLUSIONS: Most ALK+ aNSCLC patients with prolonged crizotinib efficacy had paucisymptomatic and oligometastatic disease without BMs. They subsequently benefited from a sequential strategy with other ALK-TKIs.

Neoadjuvant Lorlatinib Induces Pathological Complete Response in Advanced ALK-Positive Lung Cancer: A Case Report.

BACKGROUND Chemotherapy has been the conventional treatment method for advanced non-small-cell lung cancer (NSCLC). Nevertheless, the identification and comprehension of oncogenic driver alterations have paved the way for targeted therapies, significantly enhancing patient outcomes. The management of locally advanced NSCLC that is positive for ALK presents a challenge due to the lack of reported randomized controlled trials. The efficacy of neoadjuvant and adjuvant targeted therapy in this context remains uncertain. CASE REPORT A 54-year-old man was diagnosed with stage IIIB (pT1N3M0) upper right lung adenocarcinoma carrying the EML4-ALK fusion gene. Clinically, the patient had multiple enlarged lymph nodes in the right hilum and mediastinum, with the largest measuring approximately 28×19 mm by CT scan and we found that the L4 lymph node was invaded by metastasis. Then, the patient received 1 cycle of chemotherapy with paclitaxel in combination with nedaplatin and subsequently received maintenance treatment involving lorlatinib. Two months later, clinical evaluations revealed progressive reduction of the lesions, especially the reduced size of the mediastinal lymph nodes. Therefore, the patient underwent thoracoscopic partial lobectomy and lymphadenectomy and achieved pathological complete response (pCR). After 3 months, a follow-up CT scan was similar to the first postoperative CT scan and no tumor was found. CONCLUSIONS This case demonstrates the potential advantage of lorlatinib as a neoadjuvant therapy in advanced ALK-positive NSCLC. It emphasizes the importance of identifying new therapeutic targets by next-generation sequencing (NGS) and implementing precise treatment strategies in clinical practice.

A non-small cell lung carcinoma patient responded to crizotinib therapy after alectinib-induced interstitial lung disease. / é˜¿æ¥æ›¿å°¼æ²»ç–—éžå°ç»†èƒžè‚ºç™Œæ‚£è€ å‘ç”Ÿé—´è´¨æ€§è‚ºç–¾ç— å†ç”¨å ‹å”‘æ›¿å°¼æ²»ç–—æœ‰æ•ˆ.

A 54-year-old, non-smoking woman was diagnosed as stage ⅣB adenocarcinoma with widespread bone metastasis (cT4N2M1c) in the First Affiliated Hospital, Zhejiang University School of Medicine. Immunohistochemistry result showed the presence of anaplastic lymphoma kinase (ALK) gene rearrangement; next-generation sequencing (NGS) indicated EML4-ALK fusion (E6:A20) with concurrent CCDC148-ALK (C1:A20), PKDCC-ALK (Pintergenic:A20)and VIT-ALK (V15:A20) fusions. After 32 weeks of alectinib treatment, the patient complained cough and exertional chest distress but had no sign of infection. Computed tomography (CT) showed bilateral diffuse ground glass opacities, suggesting a diagnosis of alectinib-related interstitial lung disease (ILD). Following corticosteroid treatment and discontinuation of alectinib, clinical presentations and CT scan gradually improved, but the primary lung lesions enlarged during the regular follow-up. The administration of crizotinib was then initiated and the disease was stable for 25 months without recurrence of primary lung lesions and ILD.

Second-trimester medical abortion after exposure to lorlatinib during early pregnancy, a case report.

Use of Lorlatinib, a third-generation tyrosine kinase inhibitor currently indicated in the treatment of non-small-cell lung cancer (NSCLC) with ALK or ROS1 gene fusion, is formally contra-indicated during pregnancy due to teratogenic effects observed during pre-clinical studies. We report the case of a 38-year-old woman with a ROS1-positive NSCLC, successfully treated with lorlatinib as second line therapy, who became pregnant while on treatment. Due to significant disease progression 12 weeks after lorlatinib stop and the great uncertainty on the pregnancy outcome, she finally decided to interrupt the pregnancy at 22 weeks of gestation. Echography and gross infant examination did not reveal any malformation. Pregnancies occurring under this kind of new oncologic treatment is expected to happen more frequently in the future. It seems therefore important to us to report any information on the topic to increase our level of knowledge and improve decision-making.

Safety and efficacy of alectinib versus crizotinib in alk-positive non-small cell lung cancer: An update meta-analysis.

Our study aimed to evaluate the efficacy and toxicity of alectinib compared with crizotinib and provide a reference for clinical use of ALK-TKI, systematically. We searched articles published update till October, 2021 based on the electronic databases, including PubMed, EMBASE and Cochrane Library. All trials analyzed the summary odds ratios (ORs) of the interesting outcomes. Three RCTs, including six studies were included. The pooled hazard ratio (HR) =0.33 (95%CI=0.21-0.51, P<0.00001) shown that the alectinib group achieved significant progress-free survival (PFS) superiority than crizotinib, consistent with those for the with (P=0.001) or without (P<0.00001) measurable CNS lesions at baseline. Also, the regimen of the alectinib did achieved benefit in the ORR (OR=2.07, 95% CI=1.41-3.06, P=0.0002) than crizotinib. Due to the limited data, the pool result of the difference of overall survival (OS) was without statistically significant (P=0.35). With regard to the safety, grade 3 to 5 adverse events were less frequent with alectinib than crizotinib (OR=0.53, 95% CI=0.31-0.90, P=0.02). As compared with crizotinib, alectinib demonstrated better PFS efficacy and comparable safety as a first-line treatment for advanced ALK-positive Non-Small Cell Lung Cancer (NSCLC). OS data remain immature, further trials with long-term survival rate have future to look forward to.

Interstitial lung disease risk of anaplastic lymphoma kinase tyrosine kinase inhibitor treatment of non-small cell lung cancer: a real-world pharmacovigilance study.

BACKGROUND: Interstitial lung disease (ILD) is a rare but life-threatening and fatal treatment-related pneumonitis. This study investigated the association between anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) and ILD. RESEARCH DESIGN AND METHODS: Cases of ILD that developed after treatment with an ALK-TKI in the Food and Drug Administration' s Adverse Event Reporting System (FAERS) data were assessed. We also described the clinical features of these cases and evaluated onset time, hospitalization, life-threatening condition, and fatality rate of ILD developed after treatment with an ALK-TKI. RESULTS: All five ALK-TKI regimens were significantly associated with ILD. The median onset time to ILD was significantly different for brigatinib, crizotinib, alectinib, lorlatinib, and ceritinib: 4.5, 25, 35.5, 54.5, and 84 days, respectively. ALK-TKI-associated ILD resulted in hospitalization in 55.77% of patients and death or life-threatening outcomes in 43.03%. The highest and lowest proportions of ILD-related fatalities were observed after crizotinib and alectinib treatment, respectively. CONCLUSIONS: ALK-TKIs were associated with ILD; therefore, the risk of developing ILD after treatment with an ALK-TKI should be carefully considered in clinical settings.

Cardiac arrhythmias associated with anaplastic lymphoma kinase (ALK) inhibitors: an analysis of the FDA Adverse Event Reporting System (FAERS).

BACKGROUND: Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) may provoke cardiac arrhythmias. We conducted this pharmacovigilance analysis to research cardiac arrhythmias associated with ALK-TKIs using the Food and Drug Administration Adverse Event Reporting System (FAERS). RESEARCH DESIGN AND METHODS: The first ALK-TKI, named crizotinib, was approved by the Food and Drug Administration (FDA) on 26 August 2011 for the treatment of ALK-rearranged non-small cell lung cancer (NSCLC). We evaluated ALK-TKIs-induced cardiac arrhythmias, by using the reporting odds ratio (ROR) and information component (IC) for mining the adverse event report signals in the FAERS database between January 2016 and June 2022. RESULTS: We identified a total of 362 ALK-TKIs-related cardiac arrhythmia reports which appeared to influence more men (64.44%) than women (30.76%), with a median age of 68 (interquartile range [IQR] 7-74) years. Compared with the full database, ALK-TKIs were detected with pharmacovigilance of cardiac arrhythmias (ROR025 = 1.26, IC025 = 0.26). Crizotinib and alectinib were found to be related to higher reporting of arrhythmias. The median time to onset (TTO) among five ALK-TKI therapies was significantly different (p = 0.044). CONCLUSION: ALK-TKIs present different frequencies of cardiac arrhythmias reporting, with only crizotinib and alectinib producing positive signals in high-level group term (HLGT) level arrhythmia. The time interval between the initial of drug treatment to the onset of arrhythmia varies greatly and cannot be predicted.

ALK Inhibitor Treatment Patterns and Outcomes in Real-World Patients with ALK-Positive Non-Small-Cell Lung Cancer: A Retrospective Cohort Study.

BACKGROUND: Randomized trials have demonstrated that anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) can be safe and efficacious treatments for patients with ALK-positive advanced non-small-cell lung cancer (aNSCLC). However, their safety, tolerability, effectiveness, and patterns of use in real-world patients remain understudied. OBJECTIVE: We sought to assess the overall treatment pattern characteristics, safety, and effectiveness outcomes of real-world patients with ALK-positive aNSCLC receiving ALK TKIs. PATIENTS AND METHODS: This retrospective cohort study using electronic health record data included adult patients with ALK-positive aNSCLC receiving ALK TKIs between January 2012 and November 2021 at a large tertiary medical center, University of California, San Francisco (UCSF), with alectinib or crizotinib as the initial ALK TKI therapy. Our primary endpoints included the incidence of treatment changes (treatment dose adjustments, interruptions, and discontinuations) during the initial ALK TKI treatment, the count and type of subsequent treatments, rates of serious adverse events (sAEs), and major adverse events (mAEs) leading to any ALK TKI treatment changes. Secondary endpoints included the hazard ratios (HRs) for median mAE-free survival (mAEFS), real-world progression-free survival (rwPFS), and overall survival (OS) when comparing alectinib with crizotinib. RESULTS: The cohort consisted of 117 adult patients (70 alectinib and 47 crizotinib) with ALK-positive aNSCLC, with 24.8%, 17.9%, and 6.0% experiencing treatment dose adjustments, interruptions, and discontinuation, respectively. Of the 73 patients whose ALK TKI treatments were discontinued, 68 received subsequent treatments including newer generations of ALK TKIs, immune checkpoint inhibitors, and chemotherapies. The most common mAEs were rash (9.9%) and bradycardia (7.0%) for alectinib and liver toxicity (19.1%) for crizotinib. The most common sAEs were pericardial effusion (5.6%) and pleural effusion (5.6%) for alectinib and pulmonary embolism (6.4%) for crizotinib. Patients receiving alectinib versus crizotinib as their first ALK TKI treatment experienced significantly prolonged median rwPFS (29.3 versus 10.4 months) with an HR of 0.38 (95% CI 0.21-0.67), while prolonged median mAEFS (not reached versus 91.3 months) and OS (54.1 versus 45.8 months) were observed in patients receiving alectinib versus crizotinib but did not reach statistical significance. Yet, it is worth noting that there was a high degree of cross-over post-progression, which could significantly confound the overall survival measures. CONCLUSIONS: We found that ALK TKIs were highly tolerable, and alectinib was associated with favorable survival outcomes with longer time to adverse events (AE) requiring medical interventions, disease progression, and death, in the context of real-world use. Proactive monitoring for adverse events such as rash, bradycardia, and hepatotoxicity may help further promote the safe and optimal use of ALK TKIs in the treatment of patients with aNSCLC.

Pathological Response and Tumor Immune Microenvironment Remodeling Upon Neoadjuvant ALK-TKI Treatment in ALK-Rearranged Non-Small Cell Lung Cancer.

BACKGROUND: Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKI; ALKi) have shown potent antitumor activity in metastatic non-small-cell lung cancer (NSCLC) with ALK rearrangement (ALK+); however, their efficacy in neoadjuvant settings has been poorly explored. OBJECTIVE: This retrospective study aimed to examine the clinical activity and tumor immune microenvironment (TIME) changes of neoadjuvant ALKi therapy. METHODS: ALK+ NSCLC patients treated with neoadjuvant ALKi at three hospitals in China between February 2018 and January 2023 were assessed. Data on clinical features and radiographic and pathological responses were collected and evaluated. Multiplex immunofluorescence was performed on pretreatment biopsy specimens and surgically resected specimens to investigate the impact of ALKi on TIME. RESULTS: A total of 12 patients with stage IIA-IIIB NSCLC who received neoadjuvant ALKi therapy were analyzed. The objective response rate was 91.7% (11/12) and the major pathological response (MPR) rate was 75.0% (9/12), with 58.3% (7/12) achieving a pathological complete response (pCR). After neoadjuvant ALKi therapy, we observed a significant increase in immune infiltration of CD8+ cells (histochemistry score [H-score]: median 10.51 vs. 24.01, p = 0.028; density: median 128.38 vs. 694.09 cells/mm2, p = 0.028; percentage: median 3.53% vs. 15.92%, p = 0.028) and CD4+ cells (density: median 275.56 vs. 651.82 cells/mm2, p = 0.028; percentage: median 5.98% vs. 10.46%, p = 0.028). Similar results were found for CD4+FOXP3+, CD8+PD1+, CD8+PD1-, CD8+GB+, and CD8+GB- cells. However, macrophages, including CD68+CD163- M1 and CD68+CD163+ M2 macrophages, showed little change after neoadjuvant ALKi therapy. CONCLUSION: Neoadjuvant ALKi therapy achieved an encouraging MPR rate of 75% and enhanced immune infiltration, suggesting its safety and feasibility for ALK+ resectable NSCLC. This study advances our understanding of TIME changes by neoadjuvant ALKi therapy and merits further investigation.

ALK inhibitors downregulate the expression of death receptor 4 in ALK-mutant lung cancer cells via facilitating Fra-1 and c-Jun degradation and subsequent AP-1 suppression.

The successful treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) with ALK tyrosine kinase inhibitors (ALK-TKIs) represents a promising targeted therapy. As a result, various ALK-TKIs have been rapidly developed, some of which are approved while some are being tested in clinical trials. Death receptor 4 (DR4; also called TNFRSF10A or TRAIL-R1) is a cell surface protein, which functions as a pro-apoptotic protein that transduces TRAIL death signaling to trigger apoptosis. DR4 expression is positively regulated by MEK/ERK signaling and thus can be downregulated by MEK/ERK inhibition. This study thus focused on determining the effects of AKL-TKIs on DR4 expression and the underlying mechanisms. Three tested ALK-TKIs including APG-2449, brigatinib and alectinib effectively and preferentially inhibited Akt/mTOR as well as MEK/ERK signaling and decreased cell survival in ALK-mutant (ALKm) NSCLC cells with induction of apoptosis. This was also true for DR4 downregulation, which occurred even at 2 h post treatment. These ALK-TKIs did not affect DR4 protein stability, rather decreased DR4 mRNA expression. In parallel, they promoted degradation and reduced the levels of Fra-1 and c-Jun, two critical components of AP-1, and suppressed AP-1 (Fra-1/c-Jun)-dependent transcription/expression of DR4. Hence, it appears that ALK-TKIs downregulate DR4 expression in ALKm NSCLC cells via facilitating Fra-1 and c-Jun degradation and subsequent AP-1 suppression. Our findings thus warrant further investigation of the biological significance of DR4 downregulation in ALK-targeted cancer therapy.