Targeted Oncology最新文献

{"title":"Model-Informed Development of a Cost-Saving Dosing Regimen for Sacituzumab Govitecan.","authors":"Dirk J A R Moes, Jeroen J M A Hendrikx, Henk-Jan Guchelaar, Ron H J Mathijssen, J L Bakker, Vincent O Dezentjé, Nikki de Rouw, Nielka P van Erp, Egbert F Smit, Michel M van den Heuvel, Thijs H Oude Munnink, Maartje van Kats, Sander Croes, Judith R Kroep, Juliette Zwaveling, Rob Ter Heine","doi":"10.1007/s11523-024-01075-8","DOIUrl":"10.1007/s11523-024-01075-8","url":null,"abstract":"<p><strong>Background: </strong>The antibody-drug conjugate sacituzumab govitecan is approved for metastatic triple-negative breast cancer and has shown promising results in various other types of cancer. Its costs may limit patient access to this novel effective treatment modality.</p><p><strong>Objective: </strong>The purpose of this study was to develop an evidence-based rational dosing regimen that results in targeted drug exposure within the therapeutic range while minimizing financial toxicity, to improve treatment access.</p><p><strong>Patients and methods: </strong>Exposure equivalent dosing strategies were developed based on pharmacokinetic modeling and simulation by using the published pharmacokinetic model developed by the license holder. The alternative dose was based on the principle of using complete vials to prevent spillage and on the established non-linear relationship between body weight and systemic exposure. Equivalent exposure compared to the approved dosing regimen of 10 mg/kg was aimed for. Equivalent exposure was conservatively defined as calculated geometric mean ratios within the 0.9-1.11 boundaries for area under the concentration-time curve (AUC), trough concentration (C_trough) and maximum concentration (C_max) of the alternative dosing regimen compared to the approved dosing regimen. Since different vial sizes are available for the European Union (EU) and United States (US) market, because body weight distributions differ between these populations, we performed our analysis for both scenarios.</p><p><strong>Results: </strong>Dosing regimens of sacituzumab govitecan for the EU (< 50 kg: 400 mg, 50-80 kg: 600 mg, and > 80 kg: 800 mg) and US population (< 40 kg: 360 mg, 40-65 kg: 540 mg, 65-90 kg: 720 mg, and > 90 kg: 900 mg) were developed, based on weight bands. The geometric mean ratios for all pharmacokinetic outcomes were within the predefined equivalence boundaries, while the quantity of drug used was 21.5% and 19.0% lower for the EU and US scenarios, respectively.</p><p><strong>Conclusions: </strong>With the alternative dosing proposal, an approximately 20% reduction in drug expenses for sacituzumab govitecan can be realized while maintaining an equivalent and more evenly distributed exposure throughout the body weight range, without notable increases in pharmacokinetic variability.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"789-796"},"PeriodicalIF":4.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Evidence-Based Rationale for Dose De-escalation of Subcutaneous Atezolizumab.","authors":"Mart P Kicken, Maarten J Deenen, Dirk J A R Moes, Jeroen J M A Hendrikx, Ben E E M van den Borne, Daphne W Dumoulin, Anthonie J van der Wekken, Michiel M van den Heuvel, Rob Ter Heine","doi":"10.1007/s11523-024-01087-4","DOIUrl":"10.1007/s11523-024-01087-4","url":null,"abstract":"<p><strong>Background: </strong>Atezolizumab is a programmed death-ligand 1 (PD-L1) checkpoint inhibitor for the treatment of different forms of cancer. The subcutaneous formulation of atezolizumab has recently received approval. However, treatment with atezolizumab continues to be expensive, and the number of patients needing treatment with this drug continues to increase.</p><p><strong>Objective: </strong>We propose two alternative dosing regimens for subcutaneous atezolizumab to reduce drug expenses while ensuring effective exposure; one may be directly implemented in the clinic.</p><p><strong>Patients and methods: </strong>We developed two alternative dose interval prolongation strategies based on pharmacokinetic modeling and simulation. The first dosing regimen was based on patients' weight while maintaining equivalent systemic drug exposure by adhering to Food and Drug Administration (FDA) guidelines for in silico dose adjustments. The second dosing regimen aimed to have a minimum atezolizumab concentration above the 6 µg/mL threshold, associated with 95% intratumoral PD-L1 receptor saturation for at least 95% of all patients.</p><p><strong>Results: </strong>We found that, for the weight-based dosing regimen, the approved 3-week dosing interval could be extended to 5 weeks for patients < 50 kg and 4 weeks for patients weighing 50-65 kg. Besides improving patient convenience, these alternative dosing intervals led to a predicted 7% and 12% cost reduction for either the USA or European population. For the second dosing regimen, we predicted that a 6-week dosing interval would result in 95% of the patients above the 6 µg/mL threshold while reducing costs by 50%.</p><p><strong>Conclusions: </strong>We have developed and evaluated two alternative dosing regimens that resulted in a cost reduction. Our weight-based dosing regimen can be directly implemented and complies with FDA guidelines for alternative dosing regimens of PD-L1 inhibitors. For the more progressive alternative dosing regimen aimed at the intratumoral PD-L1 receptor threshold, further evidence on efficacy and safety is needed before implementation.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"779-787"},"PeriodicalIF":4.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying Actionable Alterations in KRAS Wild-Type Pancreatic Cancer.","authors":"Ahmed Elhariri, Jaydeepbhai Patel, Himil Mahadevia, Douaa Albelal, Ahmed K Ahmed, Jeremy C Jones, Mitesh J Borad, Hani Babiker","doi":"10.1007/s11523-024-01088-3","DOIUrl":"10.1007/s11523-024-01088-3","url":null,"abstract":"<p><p>The 5-year relative survival rate for pancreatic cancer is currently the lowest among all cancer types with a dismal 13%. A Kirsten rat sarcoma virus (KRAS) gene mutation is present in approximately 90% of patients with pancreatic cancer; however, KRAS-specific drugs are not yet widely used in clinical practice for pancreatic cancer, specifically the KRAS^G12D variant. Advances in genomic testing revealed an opportunity to detect genetic alterations in a subset of patients with no KRAS mutation termed KRAS wild-type. Patients with KRAS wild-type tumors have a propensity to express driver alterations, hence paving the way for utilizing a targeted therapy approach either via clinical trials or standard-of-care drugs. These alterations include fusions, amplifications, translocations, rearrangements and microsatellite instability-high tumors and can be as high as 11% in some studies. Here, we discuss some of the most notable alterations in KRAS wild-type and highlight promising clinical trials.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"679-689"},"PeriodicalIF":4.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase 1a/1b Dose Escalation/Expansion Study of the Anti-PD-1 Monoclonal Antibody Nofazinlimab in Chinese Patients with Solid Tumors or Lymphoma.","authors":"Jifang Gong, Ye Guo, Yanqiao Zhang, Yi Ba, Tong Chen, Wei Li, Caicun Zhou, Mengzhao Wang, Haiyan Yang, Yuhong Zhou, Qiqing Cai, Ziping Wang, Gang Huang, Wei Zhang, Rila Su, Zhongheng Cai, Zenglian Yue, Jinzhou Dou, Peiqi Li, Rachel Wu, Archie N Tse, Lin Shen","doi":"10.1007/s11523-024-01091-8","DOIUrl":"10.1007/s11523-024-01091-8","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint blockade with anti-programmed cell death 1 (PD-1) antibodies has demonstrated efficacy in multiple tumor types. Nofazinlimab is a humanized rat antibody targeting PD-1. A first-in-human study of nofazinlimab conducted in Australia found no dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) was not reached in the range of 1-10 mg/kg.</p><p><strong>Objective: </strong>We evaluated nofazinlimab for multiple advanced malignancies in Chinese patients.</p><p><strong>Patients and methods: </strong>This was a phase 1a/1b, open-label, multicenter, dose-escalation/expansion trial. In phase 1a, patients received an abbreviated dose escalation of nofazinlimab at 60 mg and 200 mg every 3 weeks (Q3W) to determine DLTs and the recommended phase 2 dose (RP2D). In phase 1b, patients received the RP2D (monotherapy/combination) in six arms by tumor type; DLTs were evaluated for nofazinlimab plus lenvatinib in the unresectable hepatocellular carcinoma (uHCC) arm. Safety (continuously monitored in patients who received nofazinlimab) and efficacy (patients with measurable baseline disease) were assessed.</p><p><strong>Results: </strong>Overall, 107 patients were eligible and received nofazinlimab. In phase 1a, no DLTs were observed; the RP2D was 200mg Q3W. In phase 1b, no DLTs were observed with nofazinlimab plus lenvatinib. The safety profile was consistent with that observed in the first-in-human study (NCT03475251). In phase 1b, 21/88 (23.9%) patients achieved confirmed objective responses, 26 (29.5%) had stable disease, and 9/20 (45.0%) patients with uHCC achieved confirmed objective responses to nofazinlimab plus lenvatinib.</p><p><strong>Conclusions: </strong>Nofazinlimab was well tolerated in Chinese patients. Preliminary efficacy was encouraging, particularly for nofazinlimab plus lenvatinib in uHCC, which is being studied in an ongoing phase 3 trial.</p><p><strong>Clinical trial registration: </strong>NCT03809767; registered 18 January 2019.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"723-733"},"PeriodicalIF":4.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"lnsights into Adjuvant Systemic Treatment Selection for Patients with Stage III Melanoma: Data from the Dutch Cancer Registry.","authors":"Loeki Aldenhoven, Merel A Spiekerman van Weezelenburg, Franchette W P J van den Berkmortel, Nick Servaas, Alfred Janssen, Yvonne L J Vissers, Elisabeth R M van Haaren, Geerard L Beets, James van Bastelaar","doi":"10.1007/s11523-024-01090-9","DOIUrl":"10.1007/s11523-024-01090-9","url":null,"abstract":"<p><strong>Background: </strong>Patient demographics and shared decision making might influence the choice of adjuvant therapy for stage III melanoma.</p><p><strong>Objective: </strong>To identify factors for treatment selection of patients diagnosed with stage III melanoma to better understand current treatment decisions and improve further treatment counseling.</p><p><strong>Patients and methods: </strong>Data from 2007 patients diagnosed with stage III melanoma, between December 2018 and 2021, sourced from the Dutch Cancer Registry, were analyzed.</p><p><strong>Results: </strong>Among the cohort, 48.7% received no therapy, 45.8% received checkpoint inhibition, and 5.5% received targeted therapy (TT). Patients foregoing therapy were significantly older [67.0 years (range 53.0-77.0) vs. 62.0 year (range 52.0-72.0)], had poorer performance scores (PS), and higher Charlson Comorbidity Index scores compared to those receiving therapy (p < 0.001). Patients undergoing therapy had significantly higher median Breslow thickness (3.3 mm vs. 2.2 mm) and higher prevalence of ulceration (49.9% vs. 38.1%). Those with connective tissue disease and/or congestive heart disease were more likely to receive TT [odds ration (OR) 8.1; 95% confidence interval (CI) 1.7-37.6 and OR 9.3; 95% CI 1.2-72.2, respectively]. Median treatment time among strata for disease recurrence was 4.26 months (3.69-4.82) for immunotherapy and 3.1 months (0.85-5.36) for TT (p = 0.298). Patients who developed recurrent disease were equal across treatment types (p = 0.656). The number of patients with grade 3 complications was different for each treatment type [immunotherapy: 17.8% vs. TT: 37.3% (p < 0.001)].</p><p><strong>Conclusions: </strong>Age, PS, and Breslow thickness seem to influence adjuvant treatment decisions. Clinicians' preference for immunotherapy might play a role in counseling BRAF-positive patients for adjuvant therapy, this however, cannot be confirmed in this dataset. Overall, only a small proportion of patients completed adjuvant treatment.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"735-745"},"PeriodicalIF":4.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comment on: \"Hematological Toxicity of PARP Inhibitors in Metastatic Prostate Cancer Patients with Mutations of BRCA or HRR Genes: A Systematic Review and Safety Meta‑analysis\".","authors":"Jun Ma, Wei Han","doi":"10.1007/s11523-024-01082-9","DOIUrl":"10.1007/s11523-024-01082-9","url":null,"abstract":"","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"811-812"},"PeriodicalIF":4.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141724567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk Stratification According to Baseline and Early Change in Neutrophil-to-Lymphocyte Ratio in Advanced Non-Small Cell Lung Cancer Treated with Chemoimmunotherapy: A Multicenter Real-World Study.","authors":"Kinnosuke Matsumoto, Yuji Yamamoto, Takayuki Shiroyama, Tomoki Kuge, Masahide Mori, Motohiro Tamiya, Yuhei Kinehara, Akihiro Tamiya, Hidekazu Suzuki, Satoshi Tobita, Kiyonobu Ueno, Toshie Niki, Izumi Nagatomo, Yoshito Takeda, Atsushi Kumanogoh","doi":"10.1007/s11523-024-01084-7","DOIUrl":"10.1007/s11523-024-01084-7","url":null,"abstract":"<p><strong>Background: </strong>Chemoimmunotherapy is a standard treatment for advanced non-small-cell lung cancer (NSCLC). However, data on clinical predictive factors remain scarce.</p><p><strong>Objective: </strong>We aim to identify clinical biomarkers in patients undergoing chemoimmunotherapy.</p><p><strong>Methods: </strong>This multicenter, real-world cohort study included chemonaive patients who underwent chemoimmunotherapy between December 2018 and May 2022. Multivariate analysis was used to determine associations between survival outcomes and patient background, including baseline neutrophil-to-lymphocyte ratio (NLR) and its dynamic change (ΔNLR). To further investigate the clinical significance of NLR, patients were classified based on their peripheral immune status, defined by a combination of NLR and ΔNLR.</p><p><strong>Results: </strong>The study included 280 patients with 30.1 months of median follow-up. Multivariate analysis revealed that older individuals, poor performance status, tumor proportion score < 1%, liver metastasis, baseline NLR ≥ 5, and ΔNLR ≥ 0 independently correlated significantly with shorter progression-free and overall survival (OS). Patients with high peripheral immune status (defined as NLR <5 and ΔNLR < 0) significantly improved long-term survival (2-year OS rate of 58.3%), whereas those with low peripheral immune status (defined as NLR ≥ 5 and ΔNLR ≥ 0) had extremely poor outcomes (2-year OS rate of 5.6%). Safety profiles did not differ significantly in terms of severe adverse events and treatment-related death rates despite the patients' peripheral immune status (P = 0.46 and 0.63, respectively).</p><p><strong>Conclusions: </strong>Our study provides real-world evidence regarding clinical prognostic factors for the efficacy of chemoimmunotherapy. The combined assessment of baseline NLR and ΔNLR could facilitate the identification of patients who are likely to achieve a durable response from chemoimmunotherapy.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"757-767"},"PeriodicalIF":4.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11392963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141580873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and Preliminary Efficacy of Once-Weekly Split-Dose Selinexor in Soft Tissue Sarcoma: Results of the Phase Ib METSSAR Clinical Trial.","authors":"Abdulazeez Salawu, Eoghan R Malone, Esmail Al-Ezzi, Sofia Genta, Olga Vornicova, Lisa Wang, Limore Arones, Madeline Phillips, Jasmine Lee, Geoffrey A Watson, Abha A Gupta, Albiruni R Abdul Razak","doi":"10.1007/s11523-024-01076-7","DOIUrl":"10.1007/s11523-024-01076-7","url":null,"abstract":"<p><strong>Background: </strong>The approved dose of Selinexor, 60 mg twice-weekly, is associated with several clinically relevant toxicities. Preclinical studies show that a sustained-release formulation of selinexor results in a lower toxicity profile.</p><p><strong>Objective: </strong>The phase 1b METSSAR trial assessed the safety and tolerability of an alternative dosing schedule of selinexor (to mimic the sustained-release formulation) in advanced soft tissue sarcoma (STS) patients.</p><p><strong>Patients and methods: </strong>Selinexor was administered in a split-dose schedule (40 mg, 20 mg, 20 mg in the morning, afternoon, and evening, respectively) on days 1, 8, 15, and 22 of a 28-day cycle, until unacceptable toxicity or disease progression. The primary endpoint was the rate of grade ≥ 3 treatment-related adverse events (TRAEs). Secondary objectives were EORTC QLQ-C30 quality of life (QoL) assessment, and preliminary efficacy.</p><p><strong>Results: </strong>Twenty patients with 12 STS subtypes were enrolled and received a median of four cycles of treatment. There were no grade ≥ 3 TRAEs. Dysgeusia, nausea, fatigue, and thrombocytopenia were the most common grade ≤ 2 TRAEs. No treatments were discontinued due to TRAE, but four patients (20%) required dose reduction. Median change in global health status (GHS) score from baseline to cycle 2 (by QLQ-C30 v3.0) was - 8.33, and only 39% of patients reported a clinically meaningful decline in GHS score (≥ 10 points). Median symptom scale scores on treatment were increased for fatigue (+12.35), nausea/vomiting (+18.52), and anorexia (+16.67), but reduced for pain (- 3.70). The median progression-free survival (PFS) was 4.0 months (95% confidence interval 1.9-7.5).</p><p><strong>Conclusions: </strong>Split-dose once-weekly selinexor was reasonably well tolerated in this heterogeneous group of advanced STS patients with a better, or at least similar, clinician- and patient-reported toxicity profile compared to the standard dosing regimen. Further clinical evaluation is warranted, as better dose delivery can lead to improved antitumor efficacy.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"711-721"},"PeriodicalIF":4.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Malignant Peripheral Nerve Sheath Tumor, a Heterogeneous, Aggressive Cancer with Diverse Biomarkers and No Targeted Standard of Care: Review of the Literature and Ongoing Investigational Agents.","authors":"Neeta Somaiah, Bishnuhari Paudyal, Robert E Winkler, Brian A Van Tine, Angela C Hirbe","doi":"10.1007/s11523-024-01078-5","DOIUrl":"10.1007/s11523-024-01078-5","url":null,"abstract":"<p><strong>Background: </strong>Malignant peripheral sheath tumor (MPNST) is a rare, aggressive form of soft-tissue sarcoma that presents a unique set of diagnostic and treatment challenges and is associated with major unmet treatment medical needs.</p><p><strong>Objective: </strong>The chief aim of this review is to consider the epidemiology, histology, anatomic distribution, pathologic signaling pathways, diagnosis, and management of MPNST, with a focus on potential targeted therapies. A subordinate objective was to establish benchmarks for the antitumor activity of such treatments.</p><p><strong>Results: </strong>MPNST has an incidence of 1:100,000 in the general population and 1:3500 among patients with the inherited condition of neurofibromatosis-1. Spindle-cell sarcomas of neural-crest origin, MPNSTs are frequently situated in the extremities and pelvis/trunk, often at the confluence of large nerve roots and bundles. Highly copy-number aberrant and enriched in chromosome 8, MPNSTs have a complex molecular pathogenesis that likely involves the interplay of multiple signaling pathways, including Ras/AKT/mTOR/MAPK, EGFR, p53, PTEN, and PRC2, as well as factors in the tumor microenvironment. A combination of magnetic resonance imaging (MRI) and positron emission tomography with ¹⁸F-fluorodeoxyglucose (FDG-PET) enables comprehensive assessment of both morphology and metabolism, while MRI- and ultrasound-guided core needle biopsy can confirm histopathology. Although surgery with wide excisional margins is now the chief curative approach to localized disease, MPNST-specific survival has not improved in decades. For advanced and metastatic MPNST, radiation and chemotherapy (chiefly with anthracyclines plus ifosfamide) have somewhat promising but still largely uncertain treatment roles, chiefly in local control, downstaging, and palliation. No single druggable target has emerged, no objective responses have been observed with a number of targeted therapies (cumulative disease control rate in our review = 22.9-34.8%), and combinatorial approaches directed toward multiple signal transduction mechanisms are hallmarks of ongoing clinical trials.</p><p><strong>Conclusions: </strong>Despite advances in our understanding of the genetics and molecular biology of MPNST, further research is warranted to: (1) unravel the complex pathogenesis of this condition; (2) improve diagnostic yield; (3) delineate the appropriate roles of chemotherapy and radiation; and (4) develop a targeted therapy (or combination of such treatments) that is well tolerated and prolongs survival.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"665-678"},"PeriodicalIF":4.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11392982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141493498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current State of Targeted Therapy in Adult Langerhans Cell Histiocytosis and Erdheim-Chester Disease.","authors":"He Lin, Xin-Xin Cao","doi":"10.1007/s11523-024-01080-x","DOIUrl":"10.1007/s11523-024-01080-x","url":null,"abstract":"<p><p>The mitogen-activated protein kinase (MAPK) pathway is a key driver in many histiocytic disorders, including Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD). This has led to successful and promising treatment with targeted therapies, including BRAF inhibitors and MEK inhibitors. Additional novel inhibitors have also demonstrated encouraging results. Nevertheless, there are several problems concerning targeted therapy that need to be addressed. These include, among others, incomplete responsiveness and the emergence of resistance to BRAF inhibition as observed in other BRAF-mutant malignancies. Drug resistance and relapse after treatment interruption remain problems with current targeted therapies. Targeted therapy does not seem to eradicate the mutated clone, leading to inevitable relapes, which is a huge challenge for the future. More fundamental research and clinical trials are needed to address these issues and to develop improved targeted therapies that can overcome resistance and achieve long-lasting remissions.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"691-703"},"PeriodicalIF":4.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141580872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}