Skipping Mutations Research Articles

Capmatinib (Tabrecta™)

Capmatinib (Tabrecta™)

Histological characteristics of lung adenocarcinoma with uncommon actionable alterations: special emphasis on MET exon 14 skipping alterations.

In the evolving era of precision medicine, increasing emphasis is placed on detecting molecular alterations driving the development of specific cancers and targeting them with matched therapies that can yield the best outcomes for patients. Lung adenocarcinomas with uncommon actionable alterations, including MET exon 14 skipping (METex14), ERBB2 and BRAF mutations, are rare and poorly characterised cancers. To more clearly understand the histopathological features of lung adenocarcinoma with uncommon actionable alterations, we compared the histological features of 678 cases with mitogenic driver alterations from 996 surgically resected lung adenocarcinomas. Genomic data from our cohort revealed METex14, ERBB2 and BRAF mutations in 13, 16 and 15 cases, respectively. Patients who had lung adenocarcinoma with METex14 were often elderly females. Histological features such as clear cell features (23%), hyaline globules (31%) and nuclear pleomorphism (39%) were the most frequently identified in METex14-positive cases; among those, three cases (23%) had tumour cells with bizarre giant or multilobulated nuclei. Additionally, the micropapillary pattern was the most frequently identified in ERBB2-mutated lung adenocarcinoma (31%). Lung adenocarcinoma with BRAF mutations tended to be less invasive, and the BRAF V600E mutation was identified in only one case with lepidic adenocarcinoma. Immunohistochemically, all METex14, ERBB2 and BRAF-positive tumours, except for invasive mucinous adenocarcinoma, were positive for thyroid transcription factor 1 (TTF-1). Our data from Japanese patients showed that lung adenocarcinoma with METex14 had unique clinicopathological characteristics: tumour cells with marked nuclear pleomorphism, hyaline globules and expression of TTF-1 in elderly women who never or lightly smoked.

Trends in Molecular Testing of Lung Cancer in Mainland People’s Republic of China Over the Decade 2010 to 2019

IntroductionLung cancer is the leading cause of cancer-related morbidity and mortality in the People’s Republic of China. Targeted therapies for patients with lung cancer, which depend on accurate identification of actionable genomic alteration, have improved survival compared with previously available treatments. However, data on the types of molecular testing often used in the People’s Republic of China, and how they have changed over time, are scarce. We explored the overall landscape of molecular testing of lung cancer in mainland People’s Republic of China in the past decade. MethodsWe distributed a stratified random sampling survey of molecular testing to 49 hospitals from members of the Molecular Pathology Collaboration Group of Chinese Anti-Cancer Association which was weighted by the numbers of lung cancer cases in seven different geographic regions in mainland People’s Republic of China from 2010 to 2019. The questionnaire contained four parts for all respondents. The questionnaire ascertained the use of approved in vitro diagnostic (IVD) devices published by the Center for Medical Device Evaluation, National Medical Products Administration of the People’s Republic of China. ResultsA total of 226,227 NSCLC specimens were tested from 2010 to 2019 in the selected hospitals. The annual number of initiated molecular tests increased over time (p < 0.0001), with an average annual growth rate of 31.8%. A notable increase in the number of molecular tests occurred during 2014 and 2016, which coincided with the approval of the National Medical Products Administration to IVD devices. For the diagnosis of molecular subtypes, EGFR mutation testing was first conducted in year 2007, followed by ALK translocation testing in 2010 and ROS1 in 2011. For other rare genetic variations in NSCLC, BRAF mutation testing was first launched in 2012, MET exon 14 skipping mutation in 2014, HER2 exon 20 mutations in 2017, and RET translocation in 2015. A markedly uneven distribution was also observed in the geography of leading units with the largest number of leading units located in east People’s Republic of China (34.7%, 17 of 49) and the smallest number located in northwest People’s Republic of China (6.1%, 3 of 49). The growth trends we observed illustrate the progress and increasing capability of molecular testing of lung cancer achieved in mainland People’s Republic of China in the decade from 2010. ConclusionsIn the decade 2010 to 2019, progress and increased capability of molecular testing of lung cancer were achieved in mainland People’s Republic of China. Further efforts should address the clinical application of next-generation sequencing technology, rare genomic aberrations, and the balance between novel genomic testing techniques and the approval of IVD products.

Long-term efficacy of immune checkpoint inhibitors in non-small cell lung cancer patients harboring MET exon 14 skipping mutations.

MET exon 14 skipping mutation, observed in 3-4% of non-small cell lung cancer (NSCLC), is emerging as a targetable alteration. In recent years, immune checkpoint inhibitors (ICI) have been effective in treating several NSCLCs. Our research aimed to investigate the characteristics of patients with NSCLCs harboring MET exon 14 mutations and their response to ICI in Japan. Among the 1954 consecutive NSCLCs diagnosed at Saitama Cancer Center between 2010 and 2019, MET exon 14 skipping mutations were detected in 68 (3.5%) NSCLCs. We evaluated their characteristics such as programmed cell death ligand 1 (PD-L1) expression. Median age of patients with NSCLCs harboring MET exon 14 skipping mutations was 73years. PD-L1 was highly expressed in 17 (70.8%) of the 24 patients examined. Seven patients received ICI monotherapy, and three out of seven had a remarkable treatment response, resulted in objective response rate (ORR) of 42.9% and progression-free survival of 24.7months. Three patients with donor splice-site mutations showed a long-term treatment response, despite the fact that two with acceptor splice-site mutations demonstrated no response and experienced early disease progression with ICI monotherapy. Our results indicated that patients with NSCLCs harboring MET exon 14 mutations presented with a high rate of positive PD-L1 expression. ICI treatment showed a high ORR and long-term efficacy for NSCLCs harboring MET exon 14 mutations. Variants of MET exon 14 splice-site mutations may be associated with ICI response.

A narrative review of MET inhibitors in non-small cell lung cancer with MET exon 14 skipping mutations.

Treatment of advanced non-small cell lung cancer (NSCLC) has radically improved in the last years due to development and clinical approval of highly effective agents including immune checkpoint inhibitors (ICIs) and oncogene-directed therapies. Molecular profiling of lung cancer samples for activated oncogenes, including epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1) and BRAF, is routinely performed to select the most appropriate up-front treatment. However, the identification of new therapeutic targets remains a high priority. Recently, MET exon 14 skipping mutations have emerged as novel actionable oncogenic alterations in NSCLC, sensitive to MET inhibition. In this review we discuss: (I) MET gene and MET receptor structure and signaling pathway; (II) MET exon 14 alterations; (III) current data on MET inhibitors, mainly focusing on selective MET tyrosine kinase inhibitors (TKIs), in the treatment of NSCLC with MET exon 14 skipping mutations. We identified the references for this review through a literature search of papers about MET, MET exon 14 skipping mutations, and MET inhibitors, published up to September 2020, by using PubMed, Scopus and Web of Science databases. We also searched on websites of main international cancer congresses (ASCO, ESMO, IASLC) for ongoing studies presented as abstracts. MET exon 14 skipping mutations have been associated with clinical activity of selective MET inhibitors, including capmatinib, that has recently received approval by FDA for clinical use in this subgroup of NSCLC patients. A large number of trials are testing MET inhibitors, also in combinatorial therapeutic strategies, in MET exon 14-altered NSCLC. Results from these trials are eagerly awaited to definitively establish the role and setting for use of these agents in NSCLC patients.

P85.05 MET Exon 14 Skipping Mutation Positive Non-Small Cell Lung Cancer: A Population-Based Cohort

MET exon 14 skipping is a potentially targetable molecular alteration. The goals of this study were to identify patients with MET exon 14 skipping to understand prevalence, biology and response to treatment, and to identify molecular signatures that may predict for response or resistance to targeted MET therapy. British Columbia Cancer provides care for a population of 5.1 million. A laboratory-developed focused DNA-based next generation sequencing (NGS) panel was performed on advanced non-squamous non-small cell lung cancer (NSCLC) and selected never-smoking squamous patients. Patients with advanced NSCLC found to have MET exon 14 skipping alterations between January 2016-September 2019 were identified. Retrospective chart review was completed to collect baseline characteristics, response to systemic treatments, and outcomes. Median overall survival (OS) was calculated using the Kaplan Meier method. Forty-three patients out of 1,934 tested were identified with MET exon 14 skipping (2.2%). Forty-one patients had metastatic disease: median age 77 years, female 46%, non-squamous/squamous/mixed adenosquamous 85/12/2%, current or former/never smoking status 61/39%, median number of pack years 30. Thirty-three patients received systemic therapy; 24 patients treated with crizotinib in the first/second line setting 87/13%. Response rate was PR/SD/PD/NE 21/33/25/21% for a disease control rate (DCR) of 54.2% in the evaluable patients. Median time to treatment discontinuation (TTD) for crizotinib was 2.2 months with 5 patients still on therapy and 3 stopping due to toxicity. Eleven patients received platinum-based chemotherapy with PR/SD/PD/NE 9/64/18/9% and DCR of 73% in the evaluable patients. Median time to platinum discontinuation of 2.8 months. Fourteen patients received immunotherapy (IO) with PR/SD/PD/NE 7/43/21/29% and DCR of 50% in the evaluable patients. Median time to IO treatment discontinuation 2.4 months. Median OS for metastatic patients treated with any systemic therapy was 14.6 months. Molecular details of 41 patients: PDL1<1%/PDL1 1-49%/PDL1≥50%/unknown status was 7/17/63/12%. MET variant frequency <50/≥50% 76/24%. MET alteration type: 2% CBL binding domain mutation, 34% poly- pyrimidine tract deletion, 63% splice donor mutation or deletion. Co-mutations: 20% TP53 alterations, 22% other, 59% none. In this small cohort there were no clear correlations between molecular aberrations and response, TTD or OS. The prevalence of MET exon 14 skipping in a North American population was 2.2%. Unlike other targeted mutations, patients were older and more commonly current or former smokers. Patients with MET exon 14 skipping alteration demonstrate disease control with crizotinib, platinum-based chemotherapy and immunotherapy. Co-mutations with p53 were commonly noted. Correlation between co-mutations and efficacy of therapy were not identified in this cohort.

P85.03 PD-L1 Expression and Efficacy of Immunotherapy in Japanese Patients with NSCLC Harboring MET Exon 14 Skipping Mutation.

P85.03 PD-L1 Expression and Efficacy of Immunotherapy in Japanese Patients with NSCLC Harboring MET Exon 14 Skipping Mutation.

Targeted Therapy Approaches for MET Abnormalities in Non-Small Cell Lung Cancer.

The tyrosine kinase receptor mesenchymal epithelial transition (MET) is a proto-oncogene that, through the activation of the MET-hepatocyte growth factor (HGF) pathway, encodes a variety of biological processes, including cell development, proliferation, invasion, and migration. Abnormal activation of the MET pathway, occurring through MET protein overexpression, and gene amplification or mutation, can contribute to oncogenesis and has been implicated in non-small cell lung cancer (NSCLC). Though it is associated with poor clinical outcome in NSCLCs, MET overexpression and its role as a therapeutic target remains somewhat elusive due to discrepancies in its occurrence. Unlike MET overexpression, MET amplification has demonstrated a stronger potential as a biomarker for therapeutic treatment, with clinical data indicating a compelling connection between a high MET gene copy number and a high response rate to targeted therapies. However, MET exon 14 skipping mutations, occurring in 3%-4 % of lung adenocarcinomas, are of particular interest, as tumors harboring these mutations have shown a significant response to MET inhibitors. Following the discovery of MET as a potential therapeutic target, extensive clinical studies have proposed three approaches to targeting MET: (1) MET tyrosine kinase inhibitors (TKIs), including crizotinib, capmatinib, tepotinib, savolinitib, and cabozantinib; (2) MET or HGF monoclonal antibodies, including emibetuzumab and ficlatuzumab; and (3) MET or HGF antibody drug conjugates, including telisotuzumab. Herein, we discuss the relevant clinical trials, particularly focusing on the efficacy as well as the safety and tolerability of the treatment options, in the promising field of targeting MET in NSCLC.

MET exon 14 skipping mutation positive non-small cell lung cancer: Response to systemic therapy

ObjectivesMET exon 14 skipping is a potentially targetable molecular alteration. The goals of this study were to identify patients treated in British Columbia with MET exon 14 skipping to understand prevalence, biology and response to treatment, and to identify molecular signatures that may predict for response or resistance to targeted MET therapy in the setting of advanced disease. Materials and MethodsA retrospective review was completed of patients found to have MET exon 14 skipping alterations between January 2016-September 2019. Information was collected on baseline characteristics, response to systemic treatments, and outcomes. ResultsOut of 1934 advanced, non-squamous and never-smoking squamous NSCLC patients tested, 41 patients were found to have MET exon 14 skipping (2.1 %). MET alteration types: 2% CBL binding-domain mutations, 34 % poly-pyrimidine tract deletions, 63 % splice donor mutations or deletions. The most common co-mutation was TP53 (22 %). Thirty-three patients received systemic therapy. Physician-assessed disease control was 68 % among 19 evaluable patients treated with crizotinib, 80 % among 10 evaluable patients treated with platinum-based chemotherapy, and 70 % among 10 evaluable patients treated with immunotherapy. Median time to treatment discontinuation was 3.0, 2.8, and 2.4 months, respectively. Median overall survival for metastatic patients treated with any systemic therapy was 15.4 months. In this small cohort, there were no clear correlations between molecular aberrations and response, time to treatment discontinuation, or survival for crizotinib, chemotherapy, and immunotherapy. ConclusionThe prevalence of MET exon 14 skipping in a North American population was 2.1 %. Unlike other targetable mutations, patients were older and more commonly current or former smokers. Patients with MET exon 14 skipping alteration demonstrate disease control with crizotinib, platinum-based chemotherapy and immunotherapy. Co-mutations with TP53 were commonly noted, but correlation between co-mutations and efficacy of therapy were not identified in this cohort.

A Real-world Study on the Assessment of Pathological Characteristics and Targeted Therapeutic Effect of Non-small Cell Lung Cancer Patients with Positive Driving Genes and High PD-L1 Expression

背景与目的驱动基因突变阳性患者行靶向治疗，驱动基因阴性但程序性死亡配体1（programmed death-ligand 1, PD-L1）高表达患者行免疫抑制剂治疗，是晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）患者一线治疗的首选，但对于驱动基因阳性且PD-L1高表达患者的治疗选择仍值得探究。方法以315例NSCLC患者为研究对象，分析驱动基因阳性且PD-L1高表达患者的临床病理特征及靶向治疗疗效。结果本研究纳入的315例NSCLC患者中，驱动基因突变总阳性率为62.2%，PD-L1高表达率（≥50.0%）为11.2%，驱动基因阳性且PD-L1高表达的患者比例为10.7%。其中表皮生长因子受体（epidermal growth factor receptor, EGFR）突变、KRAS 突变、ALK融合、BRAF突变和MET 14外显子跳跃突变患者中均有PD-L1高表达，比例分别为7.8%（11/141）、18.2%（4/22）、23.1%（3/13）、50.0%（2/4）和100.0%（1/1）。EGFR突变且PD-L1高表达患者主要为Ⅳ期肺腺癌患者，KRAS突变且PD-L1高表达患者主要为有吸烟史的患者。其中详细跟踪了两例分别为ALK融合阳性且PD-L1高表达（90.0%）和EGFR L858R突变且PD-L1高表达（70.0%）患者的靶向治疗全过程，两例患者总生存期分别仅为5个月和2个月。结论NSCLC患者各驱动基因突变与PD-L1高表达共存的比例和临床病理特征有较大差异。发生敏感突变且PD-L1高表达的患者靶向治疗疗效和预后可能更差。

Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO and OH (CCO) Joint Guideline Update.

To provide evidence-based recommendations updating the 2017 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer (NSCLC) with driver alterations. A guideline update for systemic therapy for patients with stage IV NSCLC without driver alterations was published separately. The American Society of Clinical Oncology and Ontario Health (Cancer Care Ontario) NSCLC Expert Panel updated recommendations based on a systematic review of randomized controlled trials (RCTs) from December 2015 to January 2020 and meeting abstracts from ASCO 2020. This guideline update reflects changes in evidence since the previous update. Twenty-seven RCTs, 26 observational studies, and one meta-analysis provide the evidence base (total 54). Outcomes of interest included efficacy and safety. Additional literature suggested by the Expert Panel is discussed. All patients with nonsquamous NSCLC should have the results of testing for potentially targetable mutations (alterations) before implementing therapy for advanced lung cancer, regardless of smoking status recommendations, when possible, following other existing high-quality testing guidelines. Most patients should receive targeted therapy for these alterations: Targeted therapies against ROS-1 fusions, BRAF V600e mutations, RET fusions, MET exon 14 skipping mutations, and NTRK fusions should be offered to patients, either as initial or second-line therapy when not given in the first-line setting. New or revised recommendations include the following: Osimertinib is the optimal first-line treatment for patients with activating epidermal growth factor receptor mutations (exon 19 deletion, exon 21 L858R, and exon 20 T790M); alectinib or brigatinib is the optimal first-line treatment for patients with anaplastic lymphoma kinase fusions. For the first time, to our knowledge, the guideline includes recommendations regarding RET, MET, and NTRK alterations. Chemotherapy is still an option at most stages.Additional information is available at www.asco.org/thoracic-cancer-guidelines.

The Clinical Impact of Capmatinib in the Treatment of Advanced Non-Small Cell Lung Cancer with MET Exon 14 Skipping Mutation or Gene Amplification.

PurposeCapmatinib, an oral MET kinase inhibitor, has demonstrated its efficacy against non–small cell lung cancer (NSCLC) with MET dysregulation. We investigated its clinical impact in advanced NSCLC with MET exon 14 skipping mutation (METex14) or gene amplification.Materials and MethodsPatients who participated in the screening of a phase II study of capmatinib for advanced NSCLC were enrolled in this study. MET gene copy number (GCN), protein expression, and METex14 were analyzed and the patients’ clinical outcome were retrospectively reviewed.ResultsA total of 72 patients were included in this analysis (group A: GCN ≥ 10 or METex14, n=14; group B: others, n=58). Among them, 13 patients were treated with capmatinib (group A, n=8; group B, n=5), and the overall response rate was 50% for group A, and 0% for group B. In all patients, the median overall survival (OS) was 20.2 months (95% confidence interval [CI], 6.9 to not applicable [NA]) for group A, and 11.3 months (95% CI, 8.2 to 20.3) for group B (p=0.457). However, within group A, median OS was 21.5 months (95% CI, 20.8 to NA) for capmatinib-treated, and 7.5 months (95% CI, 3.2 to NA) for capmatinib-untreated patients (p=0.025). Among all capmatinib-untreated patients (n=59), group A showed a trend towards worse OS to group B (median OS, 7.5 months vs. 11.3 months; p=0.123).ConclusionOur data suggest that capmatinib is a new compelling treatment for NSCLC with MET GCN ≥ 10 or METex14 based on the improved survival within these patients.

Development and characterization of patient-derived xenografts from non-small cell lung cancer brain metastases

Non-small cell lung cancer (NSCLC) brain metastasis cell lines and in vivo models are not widely accessible. Herein we report on a direct-from patient-derived xenograft (PDX) model system of NSCLC brain metastases with genomic annotation useful for translational and mechanistic studies. Both heterotopic and orthotopic intracranial xenografts were established and RNA and DNA sequencing was performed on patient and matching tumors. Morphologically, strong retention of cytoarchitectural features was observed between original patient tumors and PDXs. Transcriptome and mutation analysis revealed high correlation between matched patient and PDX samples with more than more than 95% of variants detected being retained in the matched PDXs. PDXs demonstrated response to radiation, response to selumetinib in tumors harboring KRAS G12C mutations and response to savolitinib in a tumor with MET exon 14 skipping mutation. Savolitinib also demonstrated in vivo radiation enhancement in our MET exon 14 mutated PDX. Early passage cell strains showed high consistency between patient and PDX tumors. Together, these data describe a robust human xenograft model system for investigating NSCLC brain metastases. These PDXs and cell lines show strong phenotypic and molecular correlation with the original patient tumors and provide a valuable resource for testing preclinical therapeutics.

Budget impact of capmatinib for adults with metastatic non-small cell lung cancer harboring a MET exon 14 skipping mutation in the United States

Aims To estimate the budget impact of adding capmatinib, the first FDA approved MET inhibitor, to a US commercial or Medicare health plan for patients with metastatic non-small cell lung cancer (mNSCLC) whose tumors have a mutation that leads to MET exon 14 (METex14) skipping. Methods Target population size was estimated using published epidemiology data. Clinical data were obtained from the GEOMETRY mono-1 capmatinib trial and published trials. Treatments in the market mix included crizotinib, pembrolizumab, ramucirumab, and chemotherapy. Uptake of capmatinib and testing rates were based on market research. All costs (drug acquisition and administration, pre-progression, progression, terminal care, adverse event, and testing) were estimated based on public sources (2020 USD). Results The number of patients eligible for capmatinib in the first three years was estimated to be 2–3 in a hypothetical 1 million member commercial plan and 34–44 in a hypothetical 1 million member Medicare plan each year. The estimated total budget impact ranged from $9,695 to $67,725 for a commercial plan and $141,350 to $985,695 for Medicare. With capmatinib included, a marginal per member per month budget impact was estimated (commercial: $0.0008 to $0.0056; Medicare: $0.0118 to $0.0821). Capmatinib inclusion resulted in lower medical costs (commercial: –$0.0003 to –$0.0007; Medicare: –$0.0037 to –$0.0106), partially offsetting increased drug costs ($0.0011 to $0.0064; $0.0154 to $0.0928, respectively), and were primarily driven by reductions in progression and terminal care costs (–$0.0003 to –$0.0009; –$0.0037 to –$0.0125, respectively). The results were most sensitive to capmatinib market share, capmatinib price, and treatment duration. Limitations Certain assumptions were applied to the model to account for inputs with limited evidence. Conclusions The estimated budget impact of including capmatinib for mNSCLC with a METex14 skipping mutation is minimal, and the increased drug costs were partially offset by savings in AEs, and progression-related and terminal care costs.

Current and future treatment options for MET exon 14 skipping alterations in non-small cell lung cancer.

It has been over three decades since the hepatocyte growth factor (HGF) ligand and its receptor MET proto-oncogene (MET) pathway was established as promoting cancer growth and metastasis. MET exon 14 skipping (METex14) alterations occur in 3–4% of all non-small cell lung cancer (NSCLC) patients, typically in elderly patients (older than 70 years), and result in constitutive activation of the MET receptor by altering a region required for receptor degradation. Multi-kinase inhibitor of MET, such as crizotinib, and more recently selective MET inhibitors, such as capmatinib and tepotinib, have demonstrated clinical efficacy and safety in METex14 NSCLC patients in clinical trials. These results have led to the approval of MET inhibitors by regulatory agencies across the globe. The success also fueled the excitement of further development of therapeutic strategies to target METex14 in lung cancers. This article provides an overview of the clinical development program targeting METex14 in NSCLC, including small molecular tyrosine kinase inhibitors and anti-MET antibodies. Furthermore, combination therapy immune checkpoint inhibitors or other targeted therapies are also under development in various patient populations, with acquired resistance immune or targeted therapy. Clinical trials in different development stages are ongoing and more drugs targeted to c-MET will be available for NSCLC patients with METex14 skipping mutations in the future.

Non-small cell lung cancer with MET exon 14 skip mutation: case report

Non-small cell lung cancer with MET exon 14 skip mutation: case report

MO01.03 Biomarker Testing Patterns and Treatment Outcomes in Patients With Advanced Non-Small Cell Lung Cancer and MET Exon 14 Skipping Mutations

MET exon 14 skipping mutation (METex14) occurs in ∼3% of patients with non-small cell lung cancer (NSCLC) and is a poor prognostic factor. Prior to capmatinib, the first FDA-approved therapy targeting METex14, chemotherapy and immuno-oncology (IO) therapy were commonly used to treat patients with METex14 NSCLC. Because treatment decisions also depend upon biomarker testing results, this study examines biomarker testing patterns and clinical outcomes of chemotherapy and IO in patients with advanced NSCLC (aNSCLC) and METex14. A descriptive retrospective study was conducted using the Flatiron Health–Foundation Medicine Clinico-Genomic Database (CGDB). Adult aNSCLC patients with METex14 confirmed by next-generation sequencing (NGS) testing who received ≥1 line of systemic therapy were included in the biomarker testing pattern analysis. The duration from specimen collection (as testing order date was unavailable) to reported results was assessed for METex14 and PD-L1 tested patients. Duration was only reported for specimens collected in 2019, the most recent year for which data were available, to minimize potential overestimation due to tissue archiving. Clinical outcomes were assessed in patients initiating IO monotherapy or chemotherapy as first-line (1L) and second-line (2L) therapy. Real-world progression-free survival (RW-PFS) was estimated using Kaplan-Meier analysis. Among 91 patients eligible for inclusion in the biomarker testing pattern analysis and confirmed positive for METex14 by NGS testing, 62% received PD-L1 testing, and 60% and 77% received NGS and PD-L1 testing within 3 months post aNSCLC diagnosis, respectively. Among 9 patients who were assessed for both METex14 and PD-L1 with specimen collection dates in 2019, the median duration between specimen collection and reporting for NGS was 7 days longer than that for PD-L1. Median RW-PFS was 5.7 months [95% CI, 4.6-7.1] and 2.4 months [95% CI, 1.4-3.2] in patients on 1L chemotherapy (n=59) and 1L IO monotherapy (n=18), with 3month RW-PFS rates of 78% and 33%, respectively. Median RW-PFS was 3.5 months [95% CI, 1.9-11.1] and 4.7 months [95% CI, 2.8-12.9] in patients on 2L chemotherapy (n=16) and 2L IO monotherapy (n=23), with 3-month RW-PFS rates of 54% and 67%, respectively. Among patients with METex14 aNSCLC in the real-world setting, IO monotherapy was associated with limited RW-PFS, and similar results were observed with chemotherapy. In this study, the difference in median duration between specimen collection and reporting of NGS and PD-L1 results was 7 days. Future real-world studies are needed to assess the effectiveness of different regimens in the METex14 population.

Tepotinib hydrochloride for the treatment of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the most devastating cancers with high mortality worldwide. By inhibiting the activity of specific molecular targets in the cancer cells, tyrosine kinase inhibitors (TKIs) have become a standard treatment in combating NSCLC. Tepotinib hydrochloride is an orally bioavailable, mesenchymal-epithelial transition (MET) TKI developed mainly for selected NSCLC patients with METex14 skipping mutations. Tepotinib demonstrated durable clinical response in phase II clinical trials, which led to its approval for use in Japan and breakthrough therapy designation and accelerated approval in the U.S. These progresses highlighted tepotinib as a promising candidate for NSCLC patients. This review summarizes the pharmacological profile of tepotinib, preclinical studies and landmark clinical trials of tepotinib. In addition, we share our perspectives on the future direction of tepotinib as a novel anticancer drug.

Capmatinib for non-small cell lung cancer

Molecular profiling of non-small cell lung cancer (NSCLC) in the past decade has revealed numerous oncogenic driver events in NSCLC leading to several highly effective therapies. While a promising target, small-molecule inhibition of MET signaling has proven difficult. Capmatinib is a specific inhibitor of MET with Food and Drug Administration (FDA) accelerated approval in 2020 for the treatment of NSCLC harboring MET exon 14 skipping mutations. As a first-line therapy, 68% of patients in phase II clinical trials responded to capmatinib with a median duration of 12.6 months and a manageable safety profile. Although FDA approval is currently limited to MET exon 14 skipping mutations, capmatinib has shown potential in other subsets of MET-dysregulated NSCLC for which ongoing studies are underway. This review covers the preclinical and early clinical data leading to capmatinib's approval, discusses the management of treatment-related toxicities, and offers potential avenues of further research.

4-Phenylbutyric acid enhances the mineralization of osteogenesis imperfecta iPSC-derived osteoblasts

Osteogenesis imperfecta (OI) is a heritable brittle bone disease mainly caused by mutations in the two type I collagen genes. Collagen synthesis is a complex process including trimer formation, glycosylation, secretion, extracellular matrix (ECM) formation, and mineralization. Using OI patient-derived fibroblasts and induced pluripotent stem cells (iPSCs), we investigated the effect of 4-phenylbutyric acid (4-PBA) on collagen synthesis to test its potential as a new treatment for OI. Endoplasmic reticulum (ER) retention of type I collagen was observed by immunofluorescence staining in OI patient-derived fibroblasts with glycine substitution and exon skipping mutations. Liquid chromatography–mass spectrometry analysis revealed excessive glycosylation of secreted type I collagen at the specific sites in OI cells. The misfolding of the type I collagen triple helix in the ECM was demonstrated by the incorporation of heat-dissociated collagen hybridizing peptide in OI cells. Type I collagen was produced excessively by OI fibroblasts with a glycine mutation, but this excessive production was normalized when OI fibroblasts were cultured on control fibroblast-derived ECM. We also found that mineralization was impaired in osteoblasts differentiated from OI iPSCs. In summary, treatment with 4-PBA normalizes the excessive production of type I collagen, reduces ER retention, partially improves misfolding of the type I collagen helix in ECM, and improves osteoblast mineralization. Thus, 4-PBA may improve not only ER retention, but also type I collagen synthesis and mineralization in human cells from OI patients.