Efficacy Of Crizotinib Research Articles

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.

Phase 2 trial of crizotinib in Japanese patients with advanced NSCLC harboring a MET gene alteration: a Co-MET study.

MET exon 14 skipping mutations occur in 3-4% and MET high amplifications occur in < 1% of patients with non-small-cell lung cancer (NSCLC). Crizotinib, a selective ATP-competitive small-molecule inhibitor of c-Met, ALK, and ROS1 tyrosine kinases, has shown activity in cancer models with various types of MET activation. The Co-MET study is a single-arm phase 2 trial to assess the safety and efficacy of crizotinib in MET inhibitor-naïve patients with advanced NSCLC harboring MET exon 14 skipping mutation (cohort 1) or high MET gene copy number of ≥ 7 (cohort 2). The primary endpoint was the objective response rate (ORR) per RECIST v1.1 by independent radiology review in cohort 1. The key secondary endpoints were the duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. A total of 28 patients (23 in cohort 1 and 5 in cohort 2) were enrolled between March 2018 and February 2020. The primary endpoint was met as the ORR (90% confidence interval: CI) in cohort 1 was 38.1% (20.6-58.3). Median DoR, PFS, and OS (95% CI) were 7.6 (1.9-NE), 5.7 (2.1-11.3), 9.1 (4.0-19.9) months, respectively, in cohort 1. ORR in cohort 2 was 40.0% (18.9-92.4). The safety signals were generally consistent with the known safety profile of crizotinib. Crizotinib showed a clinical activity similar to that of tepotinib and capmatinib in patients with NSCLC harboring MET exon 14 skipping mutations. UMIN000031623.

Targeting of C-ROS-1 Activity Using a Controlled Release Carrier to Treat Craniosynostosis in a Preclinical Model of Saethre-Chotzen Syndrome

Saethre-Chotzen syndrome (SCS) is one of the most prevalent craniosynostosis, caused by a loss-of-function mutation in the TWIST-1 gene, with current treatment options relying on major invasive transcranial surgery. TWIST-1 haploinsufficient osteogenic progenitor cells exhibit increased osteogenic differentiation potential due to an upregulation of the transmembrane tyrosine kinase receptor, C-ROS-1, a TWIST-1 target gene known to promote bone formation. The present study assessed the efficacy of suppressing C-ROS-1 activity using a known chemical inhibitor to C-ROS-1, crizotinib, to halt premature coronal suture fusion in a preclinical mouse model of SCS. Crizotinib (1 μM, 2 μM, or 4 μM) was administered locally over the calvaria of Twist‐1del/+ heterozygous mice prior to coronal suture fusion using either a nonresorbable collagen sponge (quick drug release) or a resorbable sodium carboxymethylcellulose microdisk (slow sustained release). Coronal suture fusion rates and bone parameters were determined by μCT imaging and histomorphometric analysis of calvaria postcoronal suture fusion. Results demonstrated a dose-dependent increase in the efficacy of crizotinib to maintain coronal suture patency, with no adverse effects to brain, kidney, liver, and spleen tissue, or blood cell parameters. Moreover, crizotinib delivered on microdisks resulted in a greater efficacy at a lower concentration to reduce bone formation at the coronal suture sites compared to sponges. However, the bone inhibitory effects were found to be diminished by over time following cessation of treatment. Our findings lay the foundation for the development of a pharmacological nonsurgical, targeted approach to temporarily maintain open coronal sutures in SCS patients. This study could potentially be used to develop similar therapeutic strategies to treat different syndromic craniosynostosis conditions caused by known genetic mutations.

ROS1 Positive Non-Small Cell Lung Cancer Patient with Brain Metastases Who Overcame Crizotinib Resistance with Lorlatinib: Case Report

Background: ROS1-positive patients account for 1-2% of non small cell lung cancer (NSCLC) cases. Crizotinib is the first tyrosine kinase inhibitor (TKI) indicated in first line treatment of ROS1-rearranged NSCLC. However, crizotinib resistance is frequent within the first 12 months of treatment. Lorlatinib is a novel tyrosine kinase inhibitor of ROS-1 recently indicated for metastatic or locally advanced crizotinib-resistant NSCLC. Case report: We report a case of a 43-year-old female patient with no medical history, diagnosted with stage IVB NSCLC including asymptomatic brain metastasis, and harboring ROS1 rearrangement. Within the first three months of starting crizotinib, the patient showed on CT scan evaluation new bone and brain metastases. Lorlatinib in the second line revealed a noteworthy improvement in metastasis and primary lesion. Conclusion: Brain metastases frequently occur in ROS1-rearranged NSCLC at the time of diagnosis and treatment course. However the efficacy of crizotinib might not translate to intracranial control of the disease, one of the cause of resistance to this drug.

Real-World Outcomes of Crizotinib in ROS1-Rearranged Advanced Non-Small-Cell Lung Cancer

Real-world data on the use and outcomes of crizotinib in ROS1-rearranged non-small-cell lung cancer (NSCLC) are limited. This study aims to analyze the real-world efficacy of crizotinib in South Korea and explore the utilization of liquid biopsies that implement next-generation sequencing (NGS) using cell-free total nucleic acids. In this prospective multicenter cohort study, 40 patients with ROS1-rearranged NSCLC, either starting or already on crizotinib, were enrolled. Patients had a median age of 61 years, with 32.5% presenting brain/central nervous system (CNS) metastases at treatment initiation. At the data cutoff, 48.0% were still in treatment; four continued with it even after disease progression due to the clinical benefits. The objective response rate was 70.0%, with a median duration of response of 27.8 months. The median progression-free survival was 24.1 months, while the median overall survival was not reached. Adverse events occurred in 90.0% of patients, primarily with elevated transaminases, yet these were mostly manageable. The NGS assay detected a CD74–ROS1 fusion in 2 of the 14 patients at treatment initiation and identified emerging mutations, such as ROS1 G2032R, ROS1 D2033N, and KRAS G12D, during disease progression. These findings confirm crizotinib’s sustained clinical efficacy and safety in a real-world context, which was characterized by a higher elderly population and higher rates of brain/CNS metastases. The study highlights the clinical relevance of liquid biopsy for detecting resistance mechanisms, suggesting its value in personalized treatment strategies.

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

IntroductionVariable 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. MethodsDNA and RNA next-generation sequencing (NGS) and immunohistochemistry were performed to characterize ROS1 fusions. ResultsUsing 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). ConclusionsLong CD74/SLC34A2-ROS1 fusions, which retain transmembrane regions in ROS1 and fusion partners, are associated with poor response to crizotinib independent of TP53 mutations.

Abstract B171: BX-795 enhances the efficacy of crizotinib in colorectal cancer cells by altering the activity of aurora kinases

Abstract Background: Metastatic Colorectal cancer (mCRC) is driven by various genetic mutations that, in turn, present potentially actionable targets. Recent improvements in combining therapies have shown modest benefits in patients with BRAF mutated mCRC. Several efforts focusing on various KRAS inhibitors are ongoing in mCRC with outcomes pending. With no significant advances to improve outcomes in most patients with mCRC, it is important to identify novel therapies that have the potential to significantly improve the outcomes of these patients. Aims: To perform high-throughput screening (HTS) using clinically relevant drugs to identify novel and effective therapeutic combinations for patients with KRAS/BRAF mutated mCRC. Methods: We performed unbiased HTS with ~250 drugs that were either currently in clinical trials or approved by the FDA. 57 drugs that decreased cell proliferation in both 2D and 3D cultures and were effective in both HCT116 (KRAS mutated) and HT29 (BRAF mutated) cell lines, were termed as “pan-active” drugs. These drugs were divided into 9 classes based on targets they inhibit. Using the BLISS model, synergistic drug combinations were identified by HTS where the top three effective drugs from each class of “pan-active” drugs were paired with the top three drugs of all other classes. Effects of one such combination (BX-795 with crizotinib) were further validated in vitro by cell growth assays and measuring changes in apoptotic mediators by western blotting (WB) and flow cytometry (FACS). Mechanisms of synergy were examined by Reverse Phase Protein Array (RPPA) followed by WB and immunostaining of CRC cells to assess inhibition of downstream targets. Results: Pairwise HTS studies identified the PDK1/TBK1 inhibitor BX-795 to be synergistic with the MET/ALK inhibitor crizotinib in multiple CRC cell lines. This combination was further validated in vitro by MTT and colony formation assays in various KRAS and BRAF mutated CRC cell lines. Analyses of markers for apoptosis by WB and FACS using FITC-Annexin V and PI confirmed that the drug combination increased cell death in multiple CRC cell lines as compared to single agents. Unbiased RPPA indicated that the combination led to very strong and unexpected inhibition of the Aurora kinases along with decreases in the expected AKT/mTOR pathway in multiple CRC cell lines when compared to monotherapies. Immunostaining revealed significant mitotic defects in CRC cells treated with the drug combination but not with single agents suggesting that mitotic defects was a possible mechanism of cell death. Further, combining an Aurora kinase A inhibitor with crizotinib enhanced the efficacy of crizotinib validating the proposed mechanism. Conclusions: Our unbiased HTS and validation studies demonstrated that combining BX-795 with crizotinib is a potential novel effective therapeutic combination for patients with mCRC. Our in vitro studies serve as the basis for future preclinical and, if warranted, clinical studies to determine the efficacy of this drug combination in patients with mCRC. Citation Format: Susmita Ghosh, Fan Fan, Reid Powell, Yong Sung Park, Clifford Stephan, Jason Roszik, Lee M Ellis, Rajat Bhattacharya. BX-795 enhances the efficacy of crizotinib in colorectal cancer cells by altering the activity of aurora kinases [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B171.

1392P Safety and efficacy of crizotinib in MET mutated (METmut) advanced non-small cell lung Cancer (aNSCLC): Results from the Drug Rediscovery Protocol (DRUP)

1392P Safety and efficacy of crizotinib in MET mutated (METmut) advanced non-small cell lung Cancer (aNSCLC): Results from the Drug Rediscovery Protocol (DRUP)

Efficacy and safety of crizotinib in ALK-positive systemic anaplastic large-cell lymphoma in children, adolescents, and adult patients: results of the French AcSé-crizotinib trial

BackgroundThe French phase II AcSé-crizotinib trial aimed to evaluate the safety and efficacy of crizotinib in patients with ALK, ROS1, and MET-driven malignancies, including ALK-positive anaplastic large-cell lymphoma (ALK+ ALCL). MethodsALK+ ALCL patients 12 months or older with measurable disease and no standard care options available received crizotinib twice daily at 165 mg/m2 in children and adolescents and 250 mg in adults. The primary end-point was the response rate at 8 weeks. ResultsTwenty-eight patients were enroled between February 2014 and March 2018. Three patients who were not treated were excluded from the analysis. The median age was 19 years. The median previous line of chemotherapy was two. In the 24 patients with an evaluable response, the response rate at 8 weeks was 67% (95% CI: 47–82%). All patients discontinued crizotinib after a median treatment duration of 3.7 months: eight for progression, two for adverse events (AEs) related to prior treatments, and 15 by choice, including six for allogeneic stem-cell transplantation. The median follow-up was 45 months. Nine patients experienced an event: eight relapses (seven after crizotinib discontinuation and one after dose reduction), and one died in complete remission. The median duration of response was 43.3 months (95% CI: 8.3–not reached). The 3-year progression-free and overall survival rates were 40% (95% CI: 23–59%) and 63% (95% CI: 43–79%). Grade 3 or 4 treatment-related AEs occurred in 32% of patients. ConclusionCrizotinib shows efficacy and an acceptable safety profile in ALK+ ALCL relapsed/refractory patients. However, a large proportion of patients experience a relapse after crizotinib discontinuation. Future studies will assess if prolonged ALK inhibitor exposure has curative potential without consolidation.

Distinct metastatic spread and progression patterns in patients treated with crizotinib for ROS1- and ALK-rearranged non-small cell lung cancer: a single-center retrospective study.

Crizotinib has been approved for C-ros oncogene 1 (ROS1)- and anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) patients. Few studies have examined the differences in crizotinib treatment outcomes between these patients and the progression sites during treatment. We investigated the metastatic spread, crizotinib efficacy, and progression patterns during crizotinib treatment in ROS1- and ALK-rearranged NSCLC patients. We retrospectively reviewed crizotinib-treated ROS1- and ALK-rearranged NSCLC patients between January 2011 and March 2021. Patient characteristics, clinical outcomes, and progression patterns during treatment were collected from medical records. The metastasis extent, crizotinib response, and progression patterns between the groups were compared. We identified 26 patients with ROS1- and 42 with ALK-positive NSCLC. The baseline proportion of central nervous system (CNS) metastases did not differ between the groups (12% vs. 29%, P=0.10), but the proportion of extrathoracic metastases, including CNS metastases, was significantly higher in ALK-positive than in ROS1-positive NSCLC patients (35% vs. 71%, P=0.003). Regarding the response to crizotinib, the objective response rate (ORR), progression-free survival (PFS), or overall survival (OS) did not significantly differ between the groups (ROS1 vs. ALK, ORR: 69% vs. 69%, P=0.987; PFS: median 10.9 vs. 10.7 months, P=0.232; median OS: not reached vs. 67.7 months, P=0.495). The CNS was the most common metastasis site in both groups [ROS1 vs. ALK, 69% (11/16) vs. 46% (17/37), P=0.127], and the cumulative incidence of CNS metastasis did not differ between the groups (P=0.914). Crizotinib treatment outcomes, including progression patterns, were similar between ROS1- and ALK-positive NSCLC patients.

Clinical Efficacy of Crizotinib as the First-Line Therapy of Advanced Non-Small-Cell Lung Carcinoma with ROS-1 Rearrangement: A Systematic Review

Background: Crizotinib is a drug designed to treat advanced NSCLC with ROS-1 rearrangement. Nevertheless, no reviews have assessed available studies to determine the efficacy and safety of first-line crizotinib against advanced NSCLC with ROS-1 rearrangement.Methods: PubMed, Cochrane Library, EBSCOHost, and ScienceDirect, were searched, filtered by inclusion and exclusion criteria, and read the full text. The researchers summarized and extracted efficacy as the primary outcome, including patients’ best response (complete response, partial response, stable disease, progressive disease, disease control rate, and objective response rate) and prognosis (overall survival rate and progression-free survival rate). Safety was also extracted as the secondary outcome.Results: Out of 91 articles electronically searched, four observational studies were included, extracted, and summarized descriptively. After full-text reading, entire studies were included. Across studies, the median PFS of the first line crizotinib varied from 14.9 months, 23.0 months, and 18.4 months with the median OS being 60 days to “Not Reach.” The patients’ best responses were similar among the studies. However, two out of four studies did not report the adverse event outcome. This study concluded that first-line crizotinib was safe.Conclusions: This systematic review suggests the potency of the first line of crizotinib therapy in advanced NSCLC patients. Regarding the current limitation of included studies, further higher quality with subsequent research in this scope is needed.

Mechanisms of resistance to tyrosine kinase inhibitor treatments in patients with ROS1 fusion-positive non-small cell lung cancer.

9062 Background: ROS1 rearrangement was found in about 1% non-small cell lung cancer (NSCLC), and the fusion proteins created during this process will result in the successive activation of the ROS1 kinase domain. NSCLC patients with ROS1 gene fusions were considered a unique subtype highly sensitive to related tyrosine kinase inhibitor (TKI) treatments. However, the acquired TKI resistance was the major hurdle preventing patients from getting prolonged treatment benefits. Methods: 107 patients diagnosed with advanced or metastatic NSCLC harboring ROS1 fusion were retrospectively recruited. All patients were treated with crizotinib as first-line treatment, and 21 patients received lorlatinib after crizotinib progression. Samples were collected at baseline, after crizotinib progression, and after lorlatinib progression, which all underwent targeted DNA sequencing. TKIs binding to mutated ROS1 fusion proteins was simulated using molecular dynamics simulations. Results: The most witnessed fusion partner of ROS1 was CD74 (58%), followed by SDC4 (14%), EZR (11%), and SLC34A2 (9%). The median progression-free survival was 12.9 months for crizotinib and 6.4 months for lorlatinib. Patients with CD74-ROS1 and SLC34A2-ROS1 had significantly longer PFS than those with other ROS1 fusion types when treated with crizotinib. Patients with baseline TP53 mutations showed worse PFS compared to TP53 wild-type (WT) patients (P &lt; 0.001, HR: 0.19, 95%CI: 0.09-0.39) under crizotinib treatment. An accumulation of both on-target (baseline vs. post-crizotinib vs. post-lorlatinib: 0% vs. 43% vs. 62%) and off-target resistant mutations (baseline vs. post-crizotinib vs. post-lorlatinib: 22% vs. 26% vs. 43%) after multiple TKI treatments was observed. A total of ten on-target resistance mutations were detected after TKI therapies, with 4 first-reported mutations (ROS1 L2010M, G1957A, D1988N, L1982V). According to the molecular dynamics simulation results, ROS1 L2010M mutations (happening in the ROS1 kinase ATP binding cassette) maybe resistant to lorlatinib, entrectinib, cabozantinib, and crizotinib. ROS1 G1957A may lead to resistance to cabozantinib. Moreover, all four novel on-target mutations may lead to resistance to crizotinib. Conclusions: In summary, CD74- and SLC34A2-ROS1 patients showed better crizotinib efficacy with different resistance mutation patterns. Patients of these subtypes are potential beneficiaries of molecular testing after crizotinib progression, directing future treatment strategies. Multiple TKI treatments may lead to the accumulation of both on-target and off-target resistance mutations. In addition, 4 novel ROS1 on-target mutations identified underwent molecular dynamics simulations, unveiling potential resistance to different TKIs, which can provide vital information for future ROS1 fusion-positive NSCLC patient treatment selections.

Potential unreliability of ALK variant allele frequency in the efficacy prediction of targeted therapy in NSCLC.

Anaplastic lymphoma kinase (ALK) is the most common fusion gene involved in non-small cell lung cancer (NSCLC), and remarkable response has been achieved with the use of ALK tyrosine kinase inhibitors (ALK-TKIs). However, the clinical efficacy is highly variable. Pre-existing intratumoral heterogeneity (ITH) has been proven to contribute to the poor treatment response and the resistance to targeted therapies. In this work, we investigated whether the variant allele frequencies (VAFs) of ALK fusions can help assess ITH and predict targeted therapy efficacy. Through the application of next-generation sequencing (NGS), 7.2% (326/4548) of patients were detected to be ALK positive. On the basis of the adjusted VAF (adjVAF, VAF normalization for tumor purity) of four different threshold values (adjVAF < 50%, 40%, 30%, or 20%), the association of ALK subclonality with crizotinib efficacy was assessed. Nonetheless, no statistical association was observed between median progression-free survival (PFS) and ALK subclonality assessed by adjVAF, and a poor correlation of adjVAF with PFS was found among the 85 patients who received first-line crizotinib. Results suggest that the ALK VAF determined by hybrid capture-based NGS is probably unreliable for ITH assessment and targeted therapy efficacy prediction in NSCLC.

A monocentric analysis of the long-term safety and efficacy of crizotinib in relapsed/refractory ALK+ lymphomas.

A monocentric analysis of the long-term safety and efficacy of crizotinib in relapsed/refractory ALK+ lymphomas.

Crizotinib efficacy and safety in patients with advanced NSCLC harboring MET alterations: A real-life data of Turkish Oncology Group

Crizotinib is a multikinase inhibitor, effective in non-small cell lung cancer (NSCLC) harboring mesenchymal-epidermal transition (MET) alterations. Although small prospective studies showed efficacy and safety of crizotinib in NSCLC with MET alterations, there is limited real-life data. Aim of this study is to investigate real-life efficacy and safety of crizotinib in patients with advanced NSCLC harboring MET alterations. This was a retrospective, multicenter (17 centers) study of Turkish Oncology Group. Patients' demographic, histological data, treatment, response rates, survival outcomes, and toxicity data were collected. Outcomes were presented for the study population and compared between MET alteration types. Total of 62 patients were included with a median age of 58.5 (range, 26-78). Major histological type was adenocarcinoma, and 3 patients (4.8%) had sarcomatoid component. The most common MET analyzing method was next generation sequencing (90.3%). MET amplification and mutation frequencies were 53.2% (n = 33) and 46.8% (n = 29), respectively. Overall response rate and disease control rate were 56.5% and 74.2% in whole study population, respectively. Median progression free survival (PFS) was 7.2 months (95% confidence interval [CI]: 3.8-10.5), and median overall survival (OS) was 18.7 months (95% CI: 13.7-23.7), regardless of treatment line. Median PFS was 6.1 months (95% CI: 5.6-6.4) for patients with MET amplification, whereas 14.3 months (95% CI: 6.7-21.7) for patients with MET mutation (P = .217). Median PFS was significantly longer in patients who have never smoked (P = .040), have good performance score (P < .001), and responded to the treatment (P < .001). OS was significantly longer in patients with MET mutation (25.6 months, 95% CI: 15.9-35.3) compared to the patients with MET amplification (11.0 months; 95% CI: 5.2-16.8) (P = .049). In never-smokers, median OS was longer than smoker patients (25.6 months [95% CI: 11.8-39.3] vs 16.5 months [95% CI: 9.3-23.6]; P = .049). The most common adverse effects were fatigue (50%), peripheral edema (21%), nausea (29%) and diarrhea (19.4%). Grade 3 or 4 adverse effects were observed in 6.5% of the patients. This real-life data confirms efficacy and safety of crizotinib in the treatment of advanced NSCLC harboring MET alteration.

Retracted: Efficacy of Crizotinib Combined with Chemotherapy in Treating Advanced Non-Small-Cell Lung Cancer and Effect on Patients' Quality of Life and Adverse Reaction Rate.

[This retracts the article DOI: 10.1155/2022/7898737.].

ADK-VR2, a cell line derived from a treatment-naïve patient with SDC4-ROS1 fusion-positive primarily crizotinib-resistant NSCLC: a novel preclinical model for new drug development of ROS1-rearranged NSCLC

ROS1 fusions are driver molecular alterations in 1-2% of non-small cell lung cancers (NSCLCs). Several tyrosine kinase inhibitors (TKIs) have shown high efficacy in patients whose tumors harbour a ROS1 fusion. However, the limited availability of preclinical models of ROS1-positive NSCLC hinders the discovery of new drugs and the understanding of the mechanisms underlying drug resistance and strategies to overcome it. The ADK-VR2 cell line was derived from the pleural effusion of a treatment-naïve NSCLC patient bearing SDC4-ROS1 gene fusion. The sensitivity of ADK-VR2 and its crizotinib-resistant clone ADK-VR2 AG143 (selected in 3D culture in the presence of crizotinib) to different TKIs was tested in vitro, in both 2D and 3D conditions. Tumorigenic and metastatic ability was assessed in highly immunodeficient mice. In addition, crizotinib efficacy on ADK-VR2 was evaluated in vivo. 2D-growth of ADK-VR2 cells was partially inhibited by crizotinib. On the contrary, the treatment with other TKIs, such as lorlatinib, entrectinib and DS-6051b, did not result in cell growth inhibition. TKIs showed dramatically different efficacy on ADK-VR2 cells, depending on the cell culture conditions. In 3D culture, ADK-VR2 growth was indeed almost totally inhibited by lorlatinib and DS-6051b. The clone ADK-VR2 AG143 showed higher resistance to crizotinib treatment in vitro, compared to its parental cell line, in both 2D and 3D cultures. Similarly to ADK-VR2, ADK-VR2 AG143 growth was strongly inhibited by lorlatinib in 3D conditions. Nevertheless, ADK-VR2 AG143 sphere formation was less affected by TKIs treatment, compared to the parental cell line. In vivo experiments highlighted the high tumorigenic and metastatic ability of ADK-VR2 cell line, which, once injected in immunodeficient mice, gave rise to both spontaneous and experimental lung metastases while the crizotinib-resistant clone ADK-VR2 AG143 showed a slower growth in vivo. In addition, ADK-VR2 tumor growth was significantly reduced but not eradicated by crizotinib treatment. The ADK-VR2 cell line is a promising NSCLC preclinical model for the study of novel targeted therapies against ROS1 fusions and the mechanisms of resistance to TKI therapies.

EP08.02-048 Crizotinib in ROS1+NSCLC: Long-term OS Analysis in Patients with Brain Metastases Included in the Phase II METROS Trial

Crizotinib has a well-established role in ROS1+ non-small cell lung cancer (NSCLC). Few data exist on the activity of the drug in controlling brain disease in ROS1+ patients. The METROS trial was a multicentric phase II trial aiming at investigating the efficacy of crizotinib in pretreated patients with NSCLC and MET deregulation (amplification or exon 14 mutations) or ROS1 rearrangements. The study confirmed the efficacy of the drug in ROS1+, with modest activity in the MET-deregulated cohort (Landi L et al., Clin Cancer Res 2019).

EP08.02-145 An Efficacy Analysis of Advanced Non Small Cell Lung Cancer With MET Exon 14 Skipping in the Real World

Lung cancers harboring mesenchymal-to-epithelial transition factor (MET) genetic alterations, such as exon 14 skipping mutations or high-level gene amplification, respond well to METselective tyrosine kinase inhibitors (TKI). Crizotinib is approved for use in patients with non-small cell lung cancer with MET14 mutations. However, there is a lack of real-world data to support the efficacy of crizotinib.

Durable response to crizotinib in an advanced lung adenocarcinoma patient harboring rare CD47-MET fusion: a case report

BackgroundMET fusion is a rare type of structure rearrangement, reported only in 0.26% of non-small cell lung cancer (NSCLC). Some uncommon genomic variants, including MET fusions, have been detected with advanced detection technology. Therapeutic option for MET-rearranged NSCLC remains largely uncovered.Case DescriptionHerein, we described a 72-year-old male patient with a 10-year history of smoking who presented to our hospital with coughing, blood-tinged sputum, chest distress, and anhelation. He was diagnosed with stage IV lung adenocarcinoma harboring a CD47 (EX7)-MET (EX15) fusion, detected by next-generation sequencing (NGS). After one month of crizotinib treatment, the patient showed partial re-expansion of the collapsed right lower lobe, shrinkages of lymph node lesions, and reduced right pleural effusion. The patient achieved partial response (PR) to first-line treatment of crizotinib with a progression-free survival (PFS) of 8 months. Cabozantinib was subsequently administrated, and a short-term PR of fewer than three months was observed. The patient retained CD47-MET fusion and acquired MET D1228E at cabozantinib progression.ConclusionsThis case provided the first clinical evidence for the efficacy of crizotinib in CD47-MET rearranged NSCLC and suggested MET D1228E as a resistance mechanism. NGS is a powerful tool for identifying rare MET gene variants in patients with NSCLC, which should be encouraged in clinical practice.