[A case of crizotinib-associated renal cysts].

Crizotinib-associated renal cysts (CARC) are the development of new renal cysts or pre-existing renal cysts after the treatment with crizotinib. Most CARC disappear after crizotinib is stopped. A few CARC showed aggressive behavior that could go beyond the invasion of the renal cortex into nearby structures, including perirenal space, psoas major muscle, intestine, and abdominal wall. A case of EML4-ALK fusion mutation in invasive lung adenocarcinoma has been reported. Multiple cystic changes occurred repeatedly in both kidneys, right rectus muscle, and psoas major muscle after treatment with crizotinib, and spontaneous absorption and resolution after discontinuation of the drug.

Mesothelin promotes brain metastasis of non-small cell lung cancer by activating MET.

BACKGROUND: Brain metastasis (BM) is common among cases of advanced non-small cell lung cancer (NSCLC) and is the leading cause of death for these patients. Mesothelin (MSLN), a tumor-associated antigen expressed in many solid tumors, has been reported to be involved in the progression of multiple tumors. However, its potential involvement in BM of NSCLC and the underlying mechanism remain unknown. METHODS: The expression of MSLN was validated in clinical tissue and serum samples using immunohistochemistry and enzyme-linked immunosorbent assay. The ability of NSCLC cells to penetrate the blood-brain barrier (BBB) was examined using an in vitro Transwell model and an ex vivo multi-organ microfluidic bionic chip. Immunofluorescence staining and western blotting were used to detect the disruption of tight junctions. In vivo BBB leakiness assay was performed to assess the barrier integrity. MET expression and activation was detected by western blotting. The therapeutic efficacy of drugs targeting MSLN (anetumab) and MET (crizotinib/capmatinib) on BM was evaluated in animal studies. RESULTS: MSLN expression was significantly elevated in both serum and tumor tissue samples from NSCLC patients with BM and correlated with a poor clinical prognosis. MSLN significantly enhanced the brain metastatic abilities of NSCLC cells, especially BBB extravasation. Mechanistically, MSLN facilitated the expression and activation of MET through the c-Jun N-terminal kinase (JNK) signaling pathway, which allowed tumor cells to disrupt tight junctions and the integrity of the BBB and thereby penetrate the barrier. Drugs targeting MSLN (anetumab) and MET (crizotinib/capmatinib) effectively blocked the development of BM and prolonged the survival of mice. CONCLUSIONS: Our results demonstrate that MSLN plays a critical role in BM of NSCLC by modulating the JNK/MET signaling network and thus, provides a potential novel therapeutic target for preventing BM in NSCLC patients.

Development of crizotinib-associated renal cyst in a non-small cell lung cancer patient with ALK fusion: a case report and review of the literature.

BACKGROUND: Crizotinib, an oral first-generation tyrosine kinase inhibitor (TKI), is superior to systemic chemotherapy for the treatment of non-small cell lung cancer (NSCLC) with positive rearrangement of anaplastic lymphoma kinase (ALK). However, an increased incidence of renal and hepatic cysts has been reported in the patients on crizotinib treatment. CASE PRESENTATION: Here, we describe a case of a 71-year-old Chinese women developed multiple cystic lesions in kidney and liver during crizotinib treatment for the primary and metastatic NSCLC. The renal and hepatic cysts were noted by CT scan 3 months after crizotinib treatment, which were spontaneously and significantly regressed after stopping crizotinib. CONCLUSIONS: Based on literature review and our experience in this case report, we concluded that crizotinib-associated renal cyst (CARCs) has features of malignancy and abscess in radiographic imaging, and thus, pathological confirmation is necessary to avoid inappropriate treatment decision. In addition, to benefit the patients with progress-free survival (PFS), switching from crizotinib to alectinib is recommended for the treatment of NSCLC patients who developed CARCs.

Genomic testing and targeted therapy of non-small cell lung cancer in China: a nationwide survey of physicians and clinical pathologists.

BACKGROUND: Genomic diagnostic testing is necessary to guide optimal treatment for non-small cell lung cancer (NSCLC) patients. The proportion of NSCLC patients whose treatment was selected based on genomic testing is still unknown in many countries or needs further improvement. This survey aimed to assess perception of genomic testing and targeted therapy for NSCLC in clinical pathologists and physicians across China. METHODS: The web-based survey was conducted with 150 clinical pathologists and 450 physicians from oncology, respiratory and thoracic surgery departments from May to September 2020, across 135 cities in China. The participants had >5 years of clinical experience in genomic testing, diagnosis or treatment of NSCLC. RESULTS: Clinical pathologists reported capability of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS proto-oncogene 1 (ROS-1) testing as 95.3%, 94.7%, and 84.7%, respectively, but only 81.9%, 75.5%, and 65.6% of physicians believed that the pathology department of the hospital is capable of performing the testing. The proportions of sending out specimens for testing were 21.0% and 49.7% as reported from clinical pathologists and physicians, respectively. Testing for EGFR mutation was recommended by physicians most often, followed by ALK and ROS-1 rearrangement. As first-line treatment, among the newly diagnosed patients with EGFR mutation, 77% received tyrosine kinase inhibitors (TKIs) therapy (49% treated with gefitinib); among patients with ALK rearrangement, 71% received TKI (64% treated with crizotinib); among patients with ROS-1 fusion, 65% received TKI (88% treated with crizotinib). CONCLUSIONS: The improvement of the non-tertiary hospital pathology departments' detection capabilities and the physicians' awareness are needed for enhancing the rate of genomic testing and targeted therapy in NSCLC patients in China.

Rational Design of PARP1/c-Met Dual Inhibitors for Overcoming PARP1 Inhibitor Resistance Induced by c-Met Overexpression.

The emergence of resistance to PARP1 inhibitors poses a current therapeutic challenge, necessitating the development of novel strategies to overcome this obstacle. The present study describes the design and synthesis of a series of small molecules that target both PARP1 and c-Met. Among them, compound 16 is identified as a highly potent dual inhibitor, exhibiting excellent inhibitory activities against PARP1 (IC50 = 3.3 nM) and c-Met (IC50 = 32.2 nM), as well as demonstrating good antiproliferative effects on HR-proficient cancer cell lines and those resistant to PARP1 inhibitors. Importantly, compound 16 demonstrates superior antitumor potency compared to the PARP1 inhibitor Olaparib and the c-Met inhibitor Crizotinib, either alone or in combination, in MDA-MB-231 and HCT116OR xenograft models. These findings highlight the potential of PARP1/c-Met dual inhibitors for expanding the indications of PARP1 inhibitors and overcoming tumor cells' resistance to them.

[Chinese expert consensus on iruplinalkib for the treatment of locally advanced or metastatic ALK-positive non-small cell lung cancer (2024 edition)].

Anaplastic lymphoma kinase (ALK) fusion gene is one of the most common driver gene in non-small cell lung cancer (NSCLC). Epidemiological data showed that ALK gene fusion is detected in 9.06% of Chinese advanced NSCLC patients. ALK-tyrosine kinase inhibitors (TKIs) have become the standard treatment for advanced NSCLC patients with ALK gene fusion. Seven different ALK-TKIs have been approved by the National Medical Products Administration (NMPA) of China, including crizotinib, ceritinib, alectinib, ensartinib, brigatinib, lorlatinib, and iruplinalkib. Iruplinalkib is a novel new-generation ALK-TKI independently developed in China. On June 27, 2023, the NMPA approved iruplinalkib for the treatment of locally advanced or metastatic ALK-positive NSCLC patients whose disease has progressed after previous treatment with crizotinib or who are intolerant to crizotinib. On January 16, 2024, the NMPA approved iruplinalkib for the first-line treatment of locally advanced or metastatic ALK-positive NSCLC patients. In order to better understand the efficacy and safety of iruplinalkib, and facilitate more rationally clinical application of iruplinalkib, the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care and the Chinese Association for Clinical Oncologists co-organized experts to compile the "Chinese expert consensus on iruplinalkib for the treatment of locally advanced or metastatic ALK-positive non-small cell lung cancer (2024 edition)".

CRISPR/Cas9-edited ROS1 + non-small cell lung cancer cell lines highlight differential drug sensitivity in 2D vs 3D cultures while reflecting established resistance profiles.

INTRODUCTION: The study of resistance-causing mutations in oncogene-driven tumors is fundamental to guide clinical decisions. Several point mutations affecting the ROS1 kinase domain have been identified in the clinical setting, but their impact requires further exploration, particularly in improved pre-clinical models. Given the scarcity of solid pre-clinical models to approach rare cancer subtypes like ROS1 + NSCLC, CRISPR/Cas9 technology allows the introduction of mutations in patient-derived cell lines for which resistant variants are difficult to obtain due to the low prevalence of cases within the clinical setting. METHODS: In the SLC34A2-ROS1 rearranged NSCLC cell line HCC78, we knocked-in through CRISPR/Cas9 technology three ROS1 drug resistance-causing mutations: G2032R, L2026M and S1986Y. Such variants are located in different functional regions of the ROS1 kinase domain, thus conferring TKI resistance through distinct mechanisms. We then performed pharmacological assays in 2D and 3D to assess the cellular response of the mutant lines to crizotinib, entrectinib, lorlatinib, repotrectinib and ceritinib. In addition, immunoblotting assays were performed in 2D-treated cell lines to determine ROS1 phosphorylation and MAP kinase pathway activity. The area over the curve (AOC) defined by the normalized growth rate (NGR_fit) dose-response curves was the variable used to quantify the cellular response towards TKIs. RESULTS: Spheroids derived from ROS1G2032R cells were significantly more resistant to repotrectinib (AOC fold change = - 7.33), lorlatinib (AOC fold change = - 6.17), ceritinib (AOC fold change = - 2.8) and entrectinib (AOC fold change = - 2.02) than wild type cells. The same cells cultured as a monolayer reflected the inefficacy of crizotinib (AOC fold change = - 2.35), entrectinib (AOC fold change = - 2.44) and ceritinib (AOC fold change = - 2.12) in targeting the ROS1 G2032R mutation. ROS1L2026M cells showed also remarkable resistance both in monolayer and spheroid culture compared to wild type cells, particularly against repotrectinib (spheroid AOC fold change = - 2.19) and entrectinib (spheroid AOC fold change = - 1.98). ROS1S1986Y cells were resistant only towards crizotinib in 2D (AOC fold change = - 1.86). Overall, spheroids showed an increased TKI sensitivity compared to 2D cultures, where the impact of each mutation that confers TKI resistance could be clearly distinguished. Western blotting assays qualitatively reflected the patterns of response towards TKI observed in 2D culture through the levels of phosphorylated-ROS1. However, we observed a dose-response increase of phosphorylated-Erk1/2, suggesting the involvement of the MAPK pathway in the mediation of apoptosis in HCC78 cells. CONCLUSION: In this study we knock-in for the first time in a ROS1 + patient-derived cell line, three different known resistance-causing mutations using CRISPR/Cas9 in the endogenous translocated ROS1 alleles. Pharmacological assays performed in 2D and 3D cell culture revealed that spheroids are more sensitive to TKIs than cells cultured as a monolayer. This direct comparison between two culture systems could be done thanks to the implementation of normalized growth rates (NGR) to uniformly quantify drug response between 2D and 3D cell culture. Overall, this study presents the added value of using spheroids and positions lorlatinib and repotrectinib as the most effective TKIs against the studied ROS1 resistance point mutations.

Mechanisms of Resistance to Tyrosine Kinase Inhibitors in ROS1 Fusion-Positive Nonsmall Cell Lung Cancer.

BACKGROUND: ROS1 fusion-positive (ROS1+) nonsmall cell lung cancer (NSCLC) patients are highly sensitive to tyrosine kinase inhibitor (TKI) treatments. However, acquired TKI resistance remains the major hurdle preventing patients from experiencing prolonged benefits. METHODS: 107 advanced or metastatic ROS1+ NSCLC patients who progressed on crizotinib and lorlatinib were recruited. Tissue and plasma samples were collected at baseline (N = 50), postcrizotinib (N = 91), and postlorlatinib (N = 21), which were all subject to the 139-gene targeted next-generation DNA sequencing. Molecular dynamics modeling was performed to investigate the effects of ROS1 mutations on binding to different TKIs. RESULTS: In patients with postcrizotinib and postlorlatinib samples, an accumulation of on- and off-target resistance alterations after multiple TKI treatments was observed. ROS1 G2032R and MET amplification were the most common on-target and off-target alterations, respectively. Patients with CD74-ROS1 and SLC34A2-ROS1 had longer progression-free survival (PFS) (P < 0.001) and higher rates of resistance mutations (on-target, P = 0.001; off-target, P = 0.077) than other ROS1 fusion variants following crizotinib treatment. Ten distinct on-target resistance mutations were detected after TKI therapies, of which 4 were previously unreported (ROS1 L2010M, G1957A, D1988N, L1982V). Molecular dynamics simulations showed that all 4 mutations were refractory to crizotinib, while G1957A, D1988N, and L1982V were potentially sensitive to lorlatinib and entrectinib. CONCLUSIONS: This study provided a comprehensive portrait of TKI-resistance mechanisms in ROS1+ NSCLC patients. Using in silico simulations of TKI activity, novel secondary mutations that may confer TKI resistance were identified and may support clinical therapeutic decision-making.

Identifying optimal ALK inhibitors in first- and second-line treatment of patients with advanced ALK-positive non-small-cell lung cancer: a systematic review and network meta-analysis.

OBJECTIVES: To compare the efficacy, safety and effects on quality of life of different ALK-inhibitors for global and Asian patients with advanced ALK-positive non-small-cell lung cancer (NSCLC). METHODS: The included RCTs were identified through a systematic search of PubMed, EMBASE, Cochrane Library, Clinical Trials.gov, and major cancer conferences. The assessment of progression-free survival (PFS), intracranial PFS, overall survival (OS), and patient-reported outcomes (PROs) was carried out using restricted mean survival time (RMST) model, fractional polynomial model and Royston-Parmar model. Time-invariant hazard ratio (HR) models were also used to validate and supplement the primary analysis. Objective response rate (ORR) and adverse events with any grade, grade 3-5 were assessed through a Bayesian network meta-analysis. The primary measures for OS, PFS, and PROs were HR and RMST. The odds ratio was the metric for evaluating safety, ORR, 12-month PFS rate, 24-month OS rate, and the 12-month non-deterioration rate of PROs. Subgroup analyses based on patient characteristics were performed. RESULTS: A total of fourteen studies (ten for first-line, four for second-line) consisting of nine treatments (chemotherapy, crizotinib, alectinib [600mg BID], low-dose alectinib [300mg BID], brigatinib, ceritinib, ensartinib, envonalkib, and lorlatinib) were included. In the first-line setting, alectinib showed a significant advantage over crizotinib and had the longest OS among all ALK-inhibitors. Compared to crizotinib, lorlatinib had the best efficacy regarding PFS for global patients, followed closely by alectinib and brigatinib. For Asian patients, alectinib significantly improved PFS compared to other treatments. In second-line, alectinib had the highest PFS for patients pretreated with crizotinib, followed by brigatinib, ceritinib and chemotherapy. Alectinib, irrespective of the dose, was the safest first-line option, whereas lorlatinib, brigatinib, and ceritinib showed poorer safety profiles. Alectinib was also the safest ALK-inhibitor for crizotinib-resistant patients. Brigatinib had the best performance in terms of PROs. CONCLUSIONS: Considering both efficacy and safety, alectinib appears to be the preferable treatment in first-line and second-line, particularly for Asian patients.

Updated overall survival and circulating tumor DNA analysis of ensartinib for crizotinib-refractory ALK-positive NSCLC from a phase II study.

BACKGROUND: The initial phase II stuty (NCT03215693) demonstrated that ensartinib has shown clinical activity in patients with advanced crizotinib-refractory, anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Herein, we reported the updated data on overall survival (OS) and molecular profiling from the initial phase II study. METHODS: In this study, 180 patients received 225 mg of ensartinib orally once daily until disease progression, death or withdrawal. OS was estimated by Kaplan‒Meier methods with two-sided 95% confidence intervals (CIs). Next-generation sequencing was employed to explore prognostic biomarkers based on plasma samples collected at baseline and after initiating ensartinib. Circulating tumor DNA (ctDNA) was detected to dynamically monitor the genomic alternations during treatment and indicate the existence of molecular residual disease, facilitating improvement of clinical management. RESULTS: At the data cut-off date (August 31, 2022), with a median follow-up time of 53.2 months, 97 of 180 (53.9%) patients had died. The median OS was 42.8 months (95% CI: 29.3-53.2 months). A total of 333 plasma samples from 168 patients were included for ctDNA analysis. An inferior OS correlated significantly with baseline ALK or tumor protein 53 (TP53) mutation. In addition, patients with concurrent TP53 mutations had shorter OS than those without concurrent TP53 mutations. High ctDNA levels evaluated by variant allele frequency (VAF) and haploid genome equivalents per milliliter of plasma (hGE/mL) at baseline were associated with poor OS. Additionally, patients with ctDNA clearance at 6 weeks and slow ascent growth had dramatically longer OS than those with ctDNA residual and fast ascent growth, respectively. Furthermore, patients who had a lower tumor burden, as evaluated by the diameter of target lesions, had a longer OS. Multivariate Cox regression analysis further uncovered the independent prognostic values of bone metastases, higher hGE, and elevated ALK mutation abundance at 6 weeks. CONCLUSION: Ensartinib led to a favorable OS in patients with advanced, crizotinib-resistant, and ALK-positive NSCLC. Quantification of ctDNA levels also provided valuable prognostic information for risk stratification.

Case report: The utilization of crizotinib and brentuximab vedotin as a bridge to autologous stem cell transplantation and followed by CD30-directed CAR-T cell therapy in relapsed/refractory ALK+ ALCL.

Background: Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL) is a rare, mature T-cell non-Hodgkin lymphoma. The prognosis of patients with relapsed or refractory ALCL following first-line chemotherapy is extremely poor. NCCN guidelines recommend intensified chemotherapy with or without ASCT consolidation for r/r ALCL, however, this is not an effective treatment for all ALK+ALCL. Case report: Herein, we report a patient with relapsed/refractory ALK+ ALCL who received crizotinib and brentuximab vedotin as bridging therapy, followed by autologous stem cell transplantation and sequential anti-CD30 CAR T cell therapy. Conclusion: The patient achieved complete remission and long-term disease-free survival of months and continues to be followed up. The combination therapy model in this case may provide guidance for the management of relapsed/refractory ALK+ ALCL, and further prospective trials are needed to confirm its effectiveness.

Overall survival and central nervous system activity of crizotinib in ROS1-rearranged lung cancer-final results of the EUCROSS trial.

BACKGROUND: In 2019, we reported the first efficacy and safety analysis of EUCROSS, a phase II trial investigating crizotinib in ROS1 fusion-positive lung cancer. At that time, overall survival (OS) was immature and the effect of crizotinib on intracranial disease control remained unclear. Here, we present the final analysis of OS, systemic and intracranial activity, and the impact of co-occurring aberrations. MATERIALS AND METHODS: EUCROSS was a prospective, single-arm, phase II trial. The primary endpoint was best overall response rate (ORR) using RECIST 1.1. Secondary and exploratory endpoints were progression-free survival (PFS), OS, and efficacy in pre-defined subgroups. RESULTS: Median OS of the intention-to-treat population (N = 34) was 54.8 months [95% confidence interval (CI) 20.3 months-not reached (NR); median follow-up 81.4 months] and median all-cause PFS of the response-evaluable population (N = 30) was 19.4 months (95% CI 10.1-32.2 months). Time on treatment was significantly correlated with OS (R = 0.82; P < 0.0001). Patients with co-occurring TP53 aberrations (28%) had a significantly shorter OS [hazard ratio (HR) 11; 95% CI 2.0-56.0; P = 0.006] and all-cause PFS (HR 4.2; 95% CI 1.2-15; P = 0.025). Patients with central nervous system (CNS) involvement at baseline (N = 6; 20%) had a numerically shorter median OS and all-cause PFS. Median intracranial PFS was 32.2 months (95% CI 23.7 months-NR) and the rate of isolated CNS progression was 24%. CONCLUSIONS: Our final analysis proves the efficacy of crizotinib in ROS1-positive lung cancer, but also highlights the devastating impact of TP53 mutations on survival and treatment efficacy. Additionally, our data show that CNS disease control is durable and the risk of CNS progression while on crizotinib treatment is low.

Economic Evaluation of Targeted Therapies for Anaplastic Lymphoma Kinase- and ROS1 Fusion-Positive Non-Small Cell Lung Cancer in India.

PURPOSE: Targeted therapies, such as crizotinib and ceritinib, have shown promising results in treating non-small cell lung cancer (NSCLC) with specific oncogenic drivers like anaplastic lymphoma kinase (ALK), c-ros (ROS1) oncogene, etc. This study aims to assess the cost-effectiveness of these therapies for patients with NSCLC in India. METHODS: The Markov model consisted of three health states: progression-free survival, progressive disease, and death. Lifetime costs and consequences were estimated for three treatment arms: crizotinib, ceritinib, and chemotherapy for patients with ALK- and ROS1-positive NSCLC. Incremental cost per quality-adjusted life-year (QALY) gained with crizotinib and ceritinib was compared to chemotherapy and assessed using a willingness-to-pay threshold of one-time per capita gross domestic product in India. RESULTS: The total lifetime cost per patient for ALK-positive NSCLC was ₹332,456 ($4,054 US dollars [USD]), ₹1,284,100 ($15,659 USD), and ₹2,337,779 ($28,509 USD) in the chemotherapy, crizotinib, and ceritinib arms, respectively. The mean QALYs lived per patient were 1.20, 2.21, and 3.34, respectively. For patients with ROS1-positive NSCLC, the total cost was ₹323,011 ($3,939 USD) and ₹1,763,541 ($21,507 USD) for chemotherapy and crizotinib, with mean QALYs lived per patient of 1.16 and 2.73, respectively. Nearly 92% and 81% reduction in the price of ceritinib and crizotinib is required to make it a cost-effective treatment option for ALK- and ROS1-positive NSCLC, respectively. CONCLUSION: Our study findings suggest that the prices of ceritinib and crizotinib need to be reduced significantly to justify their value for inclusion in India's publicly financed health insurance scheme for treatment of patients with locally advanced/metastatic ALK- and ROS1-positive NSCLC, respectively.

The lack of head-to-head randomised trials and the consequences for patients and national health service: The case of non-small cell lung cancer.

INTRODUCTION: To introduce a drug to the market, it's not mandatory for it to be more effective and safer than the current treatment for the same condition. Consequently, head-to-head studies between the two best treatments for the same condition are not required, and this could result in a lack of information for patients, clinicians, and decision-makers. This study aims to evaluate the presence of head-to-head studies among the drugs used for the treatment of non-small cell lung cancer (NSCLC). METHODS: Taking into account the National Comprehensive Cancer Network (NCCN) guidelines updated to 2022, which list all available treatments for each NSCLC subtype, the search engine Pubmed and the platform clinicaltrials.gov were consulted to find all completed and ongoing head-to-head studies among various treatments for NSCLC. RESULTS: Among the anti-EGFR (epidermal growth factor receptor) drugs, 7 studies were found, with 6 completed and 5 registrational for drug commercialisation. No completed study to date has compared osimertinib and afatinib. For anti-ALK (anaplastic lymphoma kinase) drugs, 7 studies were found, with 5 completed. Alectinib, brigatinib, and lorlatinib have no completed comparison studies, but all were compared with crizotinib. Among various immunotherapy-based regimens, 5 studies were found, with only 1 completed. Therapeutic regimens based on pembrolizumab, atezolizumab, or the combination of nivolumab/ipilimumab have not been compared in studies published to date. CONCLUSION: There are few head-to-head studies comparing treatments for NSCLC; there are no such studies between the latest generation of drugs. Consequently, ambiguous areas exist due to the lack of comparative studies among the available evidence, preventing the clinician's choice of the most effective treatment and risking the patient receiving suboptimal therapy. Simultaneously, the price of the drug cannot be determined correctly, relying only on indirect evaluations from different trials. To dispel this uncertainty, it would be desirable to initiate a process that brings together the demands derived from clinical practice and clinical research to provide clinicians and patients with the best possible evidence.

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.

Establishing Meaningful Change Thresholds in Patient-Reported Outcomes Among Patients With Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer in ALTA-1L Trial.

OBJECTIVES: An earlier study from the ALTA-1L trial of patients with anaplastic lymphoma kinase-positive non-small cell lung cancer demonstrated that brigatinib produces superior health-related quality of life (QoL) outcomes over crizotinib. This study aimed to derive meaningful change thresholds (MCTs) for European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and EORTC QLQ-LC13 to refine the earlier results. METHODS: Patients from the ALTA-1L trial were administered the EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires. Responses were analyzed using anchor-based analysis, graphical analysis, distribution-based analysis, longitudinal responder analysis, and time to deterioration. RESULTS: The patient-reported outcome population comprised 262 patients who completed the EORTC QLQ-C30 at baseline and at least 1 follow-up timepoint. Both anchors (QLQ-C30 items for overall health and QoL) had correlations >0.40 or < -0.40 with all functioning domains, fatigue, pain, appetite loss, and all dyspnea scores. Within-group analysis for most scales found the derived MCT was consistent with a cutoff of 10 points for classifying individual-patient change, except for 3-item dyspnea. The probability of improvement/remaining stable was significantly greater in the brigatinib group over crizotinib for the EORTC QLQ-C30 emotional functioning, appetite loss, and constipation domains. CONCLUSIONS: This study derived MCTs for EORTC QLQ-C30 and QLQ-LC13 domains that may be applied in future studies and again demonstrated the superiority of brigatinib over crizotinib in health-related QoL outcomes in patients with non-small cell lung cancer.

Inhibition of PRKAA/AMPK (Ser485/491) phosphorylation by crizotinib induces cardiotoxicity via perturbing autophagosome-lysosome fusion.

Crizotinib, a small-molecule tyrosine kinase inhibitor targeting ALK, MET and ROS1, is the first-line drug for ALK-positive metastatic non-small cell lung cancer and is associated with severe, sometimes fatal, cases of cardiac failure, which increases the risk of mortality. However, the underlying mechanism remains unclear, which causes the lack of therapeutic strategy. We established in vitro and in vivo models for crizotinib-induced cardiotoxicity and found that crizotinib caused left ventricular dysfunction, myocardial injury and pathological remodeling in mice and induced cardiomyocyte apoptosis and mitochondrial injury. In addition, we found that crizotinib prevented the degradation of MET protein by interrupting autophagosome-lysosome fusion and silence of MET or re-activating macroautophagy/autophagy flux rescued the cardiomyocytes death and mitochondrial injury caused by crizotinib, suggesting that impaired autophagy activity is the key reason for crizotinib-induced cardiotoxicity. We further confirmed that recovering the phosphorylation of PRKAA/AMPK (Ser485/491) by metformin re-activated autophagy flux in cardiomyocytes and metformin rescued crizotinib-induced cardiomyocyte injury and cardiac complications. In summary, we revealed a novel mechanism for crizotinib-induced cardiotoxicity, wherein the crizotinib-impaired autophagy process causes cardiomyocyte death and cardiac injury by inhibiting the degradation of MET protein, demonstrated a new function of impeded autophagosome-lysosome fusion in drugs-induced cardiotoxicity, pointed out the essential role of the phosphorylation of PRKAA (Ser485/491) in autophagosome-lysosome fusion and confirmed metformin as a potential therapeutic strategy for crizotinib-induced cardiotoxicity.Abbreviations and Acronyms: AAV: adeno-associated virus; ACAC/ACC: acetyl-Co A carboxylase; AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATG5: autophagy related 5; ATG7: autophagy related 7; CHX: cycloheximide; CKMB: creatine kinase myocardial band; CQ: chloroquine; c-PARP: cleaved poly (ADP-ribose) polymerase; DAPI: 4'6-diamidino-2-phenylindole; EF: ejection fraction; FOXO: forkhead box O; FS: fractional shortening; GSEA: gene set enrichment analysis; H&E: hematoxylin and eosin; HF: heart failure; HW: TL: ratio of heart weight to tibia length; IR: ischemia-reperfusion; KEGG: Kyoto encyclopedia of genes and genomes; LAMP2: lysosomal-associated membrane protein 2; LDH: lactate dehydrogenase; MCMs: mouse cardiomyocytes; MMP: mitochondrial membrane potential; mtDNA: mitochondrial DNA; MYH6: myosin, heavy peptide 6, cardiac muscle, alpha; MYH7: myosin, heavy peptide 7, cardiac muscle, beta; NPPA: natriuretic peptide type A; NPPB: natriuretic peptide type B; PI: propidium iodide; PI3K: phosphoinositide 3-kinase; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; qPCR: quantitative real-time PCR; SD: standard deviation; SRB: sulforhodamine B; TKI: tyrosine kinase inhibitor; WGA: wheat germ agglutinin.

Are novel oral oncolytics underdosed in obese patients?

PURPOSE: Data on the effects of obesity on drug exposure of oral targeted oncolytics is scarce. Therefore, the aim of this study was to investigate the influence of body weight and body mass index (BMI) on trough levels of oral oncolytics with an exposure-response relationship. The oral oncolytics of interest were abiraterone, alectinib, cabozantinib, crizotinib, imatinib, pazopanib, sunitinib and trametinib. METHODS: This retrospective cohort study included patients treated with the selected oral oncolytics at the standard dose, with a measured trough level at steady state and with available body weight. The Spearman's correlation test was used to determine the correlation between body weight and trough levels. The Fisher's exact text was used to compare the frequency of inadequate trough levels between BMI categories. RESULTS: 1265 patients were included across the different oral oncolytics. A negative correlation coefficient was observed between weight and trough levels for crizotinib (n = 75), imatinib (n = 201) and trametinib (n = 310), respectively, ρ = - 0.41, ρ = - 0.24 and ρ = - 0.23, all with a p-value < 0.001. For crizotinib, a higher percentage of patients with a body weight > 100 kg had inadequate trough levels. No statistically significant differences were observed in the frequency of inadequate trough levels between BMI categories. CONCLUSION: Higher body weight was only correlated with lower plasma trough levels for crizotinib, imatinib, and trametinib. Therefore, patients with a high body weight may require dose escalation to obtain adequate target levels when treated with these oral oncolytics.

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.

Brief Report: Tyrosine Kinase Inhibitors for Lung Cancers That Inhibit MATE-1 Can Lead to "False" Decreases in Renal Function.

INTRODUCTION: Select tyrosine kinase inhibitors (TKIs) used to treat oncogene-driven lung cancers also inhibit MATE-1. When MATE-1 is blocked, creatinine is retained in the serum. Elevated creatinine levels raise the specter of drug-induced intrarenal insufficiency despite the lack of true renal injury. We conducted a systematic analysis of MATE-1 inhibitor (MATEi)-treated patients to comprehensively characterize this phenomenon. METHODS: Patients with oncogene-driven lung cancer treated with a wide variety of MATEi TKIs (brigatinib, cabozantinib, capmatinib, crizotinib, entrectinib, lorlatinib, pralsetinib, selpercatinib, and tepotinib) were eligible for an analysis of renal dysfunction. Acute kidney injury was classified on the basis of creatinine levels (Kidney Disease: Improving Global Outcomes criteria) as stage 1 (≥1.5× but <2× baseline), stage 2 (≥2× but <3× baseline), or stage 3 (>3× baseline). When available, cystatin C, a marker of kidney function unaffected by MATE-1, was used to evaluate the glomerular filtration rate (GFR). RESULTS: We identified 863 patients receiving MATEi TKIs including crizotinib (39%, n = 333), lorlatinib (17%, n = 144), cabozantinib (10%, n = 87), selpercatinib (10%, n = 82), capmatinib (9%, n = 77), brigatinib (6%, n = 53), entrectinib (5%, n = 45), tepotinib (5%, n = 41), and pralsetinib (0.1%, n = 1). Of the 90 patients (10%) with acute kidney injury, Kidney Disease: Improving Global Outcomes stages 1, 2, and 3 were observed in 72% (n = 65), 21% (n = 19), and 7% (n = 6) of patients, respectively. Concurrently drawn creatinine and cystatin C levels on TKI therapy were available for 17 patients. In most cases (n = 15 of 17), the calculated GFR was higher using cystatin C versus creatinine. The percentage of patients whose GFR was higher using cystatin C versus creatinine by less than 10 mL/min, 10 to 19 mL/min, 20 to 29 mL/min, and more than or equal to 30 mL/min was 27% (n = four of 15), 20% (n = three of 15), 20% (n = three of 15), and 33% (n = five of 15), respectively. Long-term data in three patients that spanned 3 years revealed that GFR was higher using cystatin C versus creatinine in 96% (n = 49 of 51) of all time points. Using a virtual clinical trial GFR cutoff of 40 mL/min, the percentage of eligible patients rose from 41% (n = seven of 17) using creatinine calculations to 71% (n = 12 of 17) using cystatin C calculations. CONCLUSIONS: The calculated GFR in patients with cancer receiving MATEi TKIs was higher in almost all cases when using cystatin C. When serum creatinine level seems elevated in patients receiving MATE-1 inhibitors, we recommend recalculating GFR using cystatin C before searching for other etiologies of kidney injury and reducing or stopping TKI therapy.