PAI-1 mediates acquired resistance to MET-targeted therapy in non-small cell lung cancer.

Mechanisms underlying primary and acquired resistance to MET tyrosine kinase inhibitors (TKIs) in managing non-small cell lung cancer remain unclear. In this study, we investigated the possible mechanisms acquired for crizotinib in MET-amplified lung carcinoma cell lines. Two MET-amplified lung cancer cell lines, EBC-1 and H1993, were established for acquired resistance to MET-TKI crizotinib and were functionally elucidated. Genomic and transcriptomic data were used to assess the factors contributing to the resistance mechanism, and the alterations hypothesized to confer resistance were validated. Multiple mechanisms underlie acquired resistance to crizotinib in MET-amplified lung cancer cell lines. In EBC-1-derived resistant cells, the overexpression of SERPINE1, the gene encoding plasminogen activator inhibitor-1 (PAI-1), mediated the drug resistance mechanism. Crizotinib resistance was addressed by combination therapy with a PAI-1 inhibitor and PAI-1 knockdown. Another mechanism of resistance in different subline cells of EBC-1 was evaluated as epithelial-to-mesenchymal transition with the upregulation of antiapoptotic proteins. In H1993-derived resistant cells, MEK inhibitors could be a potential therapeutic strategy for overcoming resistance with downstream mitogen-activated protein kinase pathway activation. In this study, we revealed the different mechanisms of acquired resistance to the MET inhibitor crizotinib with potential therapeutic application in patients with MET-amplified lung carcinoma.

The cost-effectiveness of iruplinalkib versus alectinib in anaplastic lymphoma kinase-positive crizotinib-resistant advanced non-small-cell lung cancer patients in China.

Background: Iruplinalkib is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) with efficacy in patients with ALK-positive crizotinib-resistant advanced non-small cell lung cancer (NSCLC), which is independently developed by a Chinese pharmaceutical company. This study examined the cost-effectiveness of iruplinalkib versus alectinib in the Chinese healthcare setting. Methods: A partitioned survival model was developed to project the economic and health outcomes. Efficacy was derived using unanchored matching-adjusted indirect comparison (MAIC). Cost and utility values were obtained from the literature and experts' opinions. Deterministic and probabilistic sensitivity analyses (PSA) were carried out to evaluate the model's robustness. Results: Treatment with iruplinalkib versus alectinib resulted in a gain of 0.843 quality-adjusted life years (QALYs) with incremental costs of $20,493.27, resulting in an incremental cost-effectiveness ratio (ICER) of $24,313.95/QALY. Parameters related to relative efficacy and drug costs were the main drivers of the model outcomes. From the PSA, iruplinalkib had a 90% probability of being cost-effective at a willingness-to-pay threshold of $37,863.56/QALY. Conclusion: Compared to alectinib, iruplinalkib is a cost-effective therapy for patients with ALK-positive crizotinib-resistant advanced NSCLC.

A multicenter, retrospective archive study of radiological and clinical features of ALK-positive non-small cell lung cancer patients and crizotinib efficacy.

To evaluate radiological and clinical features in metastatic anaplastic lymphoma kinase+ non-small cell lung cancer patients and crizotinib efficacy in different lines. This national, non-interventional, multicenter, retrospective archive screening study evaluated demographic, clinical, and radiological imaging features, and treatment approaches in patients treated between 2013-2017. Totally 367 patients (54.8% males, median age at diagnosis 54 years) were included. Of them, 45.4% were smokers, and 8.7% had a family history of lung cancer. On radiological findings, 55.9% of the tumors were located peripherally, 7.7% of the patients had cavitary lesions, and 42.9% presented with pleural effusion. Pleural effusion was higher in nonsmokers than in smokers (37.3% vs. 25.3%, P = .018). About 47.4% of cases developed distant metastases during treatment, most frequently to the brain (26.2%). Chemotherapy was the first line treatment in 55.0%. Objective response rate was 61.9% (complete response: 7.6%; partial response: 54.2%). The highest complete and partial response rates were observed in patients who received crizotinib as the 2nd line treatment. The median progression-free survival was 14 months (standard error: 1.4, 95% confidence interval: 11.2-16.8 months). Crizotinib treatment lines yielded similar progression-free survival (P = .078). The most frequent treatment-related adverse event was fatigue (14.7%). Adrenal gland metastasis was significantly higher in males and smokers, and pleural involvement and effusion were significantly higher in nonsmokers-a novel finding that has not been reported previously. The radiological and histological characteristics were consistent with the literature data, but several differences in clinical characteristics might be related to population characteristics.

Efficacy and safety of crizotinib in the treatment of advanced non-small cell lung cancer with ROS1 gene fusion: a systematic literature review and meta-analysis of real-world evidence.

BACKGROUND: Crizotinib was approved to treat patients with advanced non-small cell lung cancer (aNSCLC) with ROS proto-oncogene 1 (ROS1) gene fusion in 2016. We conducted a systematic literature review to identify real-world evidence (RWE) studies and estimated the efficacy and safety of crizotinib using meta-analyses (MA) for objective response rate (ORR), real-world progression-free survival (PFS), and overall survival (OS). METHODS: We searched MEDLINE®, Embase, and Cochrane CENTRAL from January 2016 to March 2023 using Ovid® for published single-arm or comparative RWE studies evaluating patients (N ≥ 20) receiving crizotinib monotherapy for aNSCLC with ROS1 gene fusion. Pooled estimates for ORR and grade 3/4 adverse events (AEs) were derived using the metafor package in R while pooled estimates for median real-world PFS (rwPFS) and OS were derived using reconstructed individual patient data from published Kaplan-Meier curves. The primary analysis included all studies regardless of crizotinib line of therapy; a subgroup analysis (SA) was conducted using studies evaluating patients receiving first-line crizotinib. RESULTS: Fourteen studies met the eligibility criteria and were considered feasible for MA. For the primary analysis, the pooled ORR (N = 9 studies) was 70.6 % (95 % confidence interval [CI]: 57.0, 81.3), median rwPFS was 14.5 months (N = 11 studies), and OS was 40.2 months (N = 9 studies). In the SA, the pooled ORR (N = 4 studies) was 81.1 % (95 % CI: 76.1, 85.2) and the median rwPFS (N = 4 studies) and OS (N = 2 studies) were 18.1 and 60 months, respectively. All MAs were associated with significant heterogeneity (I2 > 25 %). Grade 3/4 AEs occurred in 18.7 % of patients (pooled estimate). CONCLUSION: The results from this study are consistent with clinical trial data and, taken collectively, supports crizotinib as a safe and effective treatment across different lines of therapy in patients with ROS1 aNSCLC in the real-world setting.

Clinical treatment patterns, molecular characteristics and survival outcomes of ROS1-rearranged non-small cell lung cancer: A large multicenter retrospective study.

BACKGROUND: Non-small cell lung cancer (NSCLC) harboring ROS1 rearrangements is a molecular subset that exhibits favorable responses to tyrosine kinase inhibitor (TKI) treatment than chemotherapy. This study investigated real-world treatment patterns and survival outcomes among patients with ROS1-rearranged advanced NSCLC. METHODS: We conducted a retrospective analysis of patients with ROS1-rearranged advanced NSCLC treated in four different hospitals in China from August 2018 to March 2022. The study analyzed gene fusion distribution, resistance patterns, and survival outcomes. RESULTS: ROS1 rearrangement occurs in 1.8 % (550/31,225) of our study cohort. CD74 was the most common ROS1 fusion partner, accounting for 45.8 %. Crizotinib was used in 73.9 % of patients in the first-line treatment, and an increased use of chemotherapy, ceritinib, and lorlatinib was seen in the second-line setting. Lung (43.2 %) and brain (27.6 %) were the most common sites of progression in first-line setting, while brain progression (39.2 %) was the most common site of progression in second-line. Median overall survival was 46 months (95 % confidence intervals: 39.6-52.4). First-line crizotinib use yielded significantly superior survival outcomes over chemotherapy in terms of progression-free (18.5 vs. 6.0; p < 0.001) and overall survival (49.8 vs. 37; p = 0.024). The choice of treatment in the latter line also had survival implications, wherein survival outcomes were better when first-line crizotinib was followed by sequential TKI therapy than first-line chemotherapy followed by TKI therapy. CONCLUSIONS: Our study provided insights into the real-world treatment, drug resistance patterns, and survival outcomes among patients with ROS1-rearranged NSCLC. This information serves as a valuable reference for guiding the treatment of this molecular subset of NSCLC.

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.

[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)".

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.

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.

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.

Inflammation-related molecular signatures involved in the anticancer activities of brigatinib as well as the prognosis of EML4-ALK lung adenocarcinoma patient.

Although ALK tyrosine kinase inhibitors (ALK-TKIs) have shown remarkable benefits in EML4-ALK positive NSCLC patients compared to conventional chemotherapy, the optimal sequence of ALK-TKIs treatment remains unclear due to the emergence of primary and acquired resistance and the lack of potential prognostic biomarkers. In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. Based on the patient-derived models and clinical responses of the patient, we found that crizotinib might inhibit proliferation of EML4-ALK positive tumors resistant to alectinib and lorlatinib. In addition, NSCLC patients harboring the G1269A mutation, which was identified in alectinib, lorlatinib and crizotinib-resistant NSCLC, showed responsiveness to brigatinib and ceritinib. Transcriptomic analysis revealed that brigatinib suppressed the activation of multiple inflammatory signaling pathways, potentially contributing to its anti-tumor activity. Moreover, we constructed a prognostic model based on the expression of IL6, CXCL1, and CXCL5, providing novel perspectives for predicting prognosis in EML4-ALK positive NSCLC patients. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.

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.

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.

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.

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.

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.

Different effects of crizotinib treatment in two non-small cell lung cancer patients with SDC4::ROS1 fusion variants.

The possibility of stratifying patients according to differences in ROS proto-oncogene 1 (ROS1) fusion partners has been discussed. This study aimed to clarify the clinicopathological differences between two SDC4::ROS1 positive NSCLC cases who had different responses to crizotinib. Cytology and pathology samples from two NSCLC cases with SDC4::ROS1 who were diagnosed and treated with crizotinib at Nihon University Itabashi Hospital were obtained. Case 1 has been well-controlled with crizotinib for over 5 years, but case 2 was worse and overall survival was 19 months. Sequencing analysis of ROS1 fusion genes was performed by reverse-transcription-PCR and Sanger's sequencing methods. In addition, thyroid transcription factor (TTF)-1, ROS-1, Ki67, and phosphorylated extracellular signal-regulated kinase (pERK)1/2 expression were investigated using immunohistochemistry. Sequencing analysis showed SDC4 exon2::ROS1 exon 32 (exon33 deleted) in case 1, and coexistence of SDC4 exon2::ROS1 exon 34 and SDC4 exon2::ROS1 exon35 in case 2. The Ki67 index was not different, but ROS1 and pERK1/2 expression levels tended to be higher in the tumor cells of case 2 than in case 1. Therapeutic response to crizotinib and patients' prognosis in ROS1 rearranged NSCLC may be related to the activation of ROS1 signaling, depending on ROS1 and pERK1/2 overexpression status, even if the ROS1 fusion partner is the same.

CD74/SLC34A2-ROS1 Fusion Variants Involving the Transmembrane Region Predict Poor Response to Crizotinib in NSCLC Independent of TP53 Mutations.

INTRODUCTION: Variable partners and breakpoints have been reported in patients with ROS1-rearranged NSCLC. Here, we investigated the association of fusion partners and breakpoints with crizotinib efficacy in NSCLCs with common ROS1 fusions. METHODS: DNA and RNA next-generation sequencing (NGS) and immunohistochemistry were performed to characterize ROS1 fusions. RESULTS: Using DNA NGS, we identified ROS1 fusions in 210 cases, comprising 171 common (CD74/EZR/TPM3/SDC4/SLC34A2-ROS1) and 39 uncommon (variants identified in <5%) ROS1 fusion cases. DNA NGS detected variable ROS1 genomic breakpoints in common ROS1 fusions, whereas RNA NGS found ROS1 breakpoints mainly occurring in exons 32, 34 and 35, resulting in long (exon 32) and short (exon 34 or 35) ROS1 fusions. ROS1 immunohistochemistry revealed that membranous and cytoplasmic staining was predominant in long ROS1 fusions, whereas cytoplasmic staining was predominant in short ROS1 fusions (p = 0.006). For patients who received first-line crizotinib, median progression-free survival (mPFS) was lower in patients with long ROS1 fusions than those with short ROS1 fusions (8.0 versus 24.0 mo, p = 0.006). Moreover, mPFS for patients with and without TP53 mutations was 8.0 and 19.0 months, respectively (p = 0.159); mPFS for patients with and without BIM deletion polymorphism was 5.0 and 22.0 months, respectively (p = 0.003). When analyzing together with fusion partners, patients with long CD74/SLC34A2-ROS1 fusions were found to have shorter PFS than those with other ROS1, regardless of the presence or absence of TP53 mutations (p < 0.001 and p = 0.002, respectively). CONCLUSIONS: Long CD74/SLC34A2-ROS1 fusions, which retain transmembrane regions in ROS1 and fusion partners, are associated with poor response to crizotinib independent of TP53 mutations.

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.