Targeted Oncology最新文献

{"title":"MET Alterations in Cancer and MET-Targeted Therapy: Detection Strategies, Treatment Efficacy, and Emerging Technologies.","authors":"Jieun Park, Chaithanya Chelakkot, Ji-Hye Nam, Hun Seok Lee, Chae Rin Kim, Yeonwoo Lee, Mi-Sook Lee, Yoon-La Choi, Young Kee Shin","doi":"10.1007/s11523-025-01166-0","DOIUrl":"10.1007/s11523-025-01166-0","url":null,"abstract":"<p><p>The MET signaling pathway is dysregulated in several cancers through various mechanisms, including gene mutations, amplifications, rearrangements, and protein overexpression. MET inhibitors have demonstrated clinical benefits in solid tumors including non-small-cell lung cancer (NSCLC), highlighting the importance of optimizing MET alteration detection methods and cut-off values to enhance the efficacy of MET-targeted therapies and improve patient outcomes. Research on MET alterations has primarily focused on MET exon 14 skipping mutations, MET amplification, and MET overexpression. This review summarizes the frequency of MET alterations across different cancer types and the clinical validation of MET alterations in MET-targeted therapies, offering a detailed comparison of objective response rates (ORR) for therapies including crizotinib, capmatinib, tepotinib, savolitinib, telisotuzumab vedotin, telisotuzumab adizutecan, and amivantamab. The review also addresses the challenges in detecting MET exon 14 skipping mutations, such as issues with false positives and negatives, and underscores the need for standardization in MET amplification detection. Trials vary in their cut-offs for MET gene copy number (GCN) and MET/CEP7 ratio and MET expression detection methods, leading to inconsistencies in detection. Additionally, emerging technologies such as circulating tumor DNA (ctDNA) and circulating tumor cell (CTC) analyses have been investigated for their potential to improve MET alterations detection. This review also highlights studies that demonstrate the potential of MET ctDNA and CTC analyses to predict treatment responses and identify resistance mechanisms in MET-targeted therapies.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"767-789"},"PeriodicalIF":4.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144660292","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":"MYC as a Target for Cancer Treatment: from Undruggable to Druggable?","authors":"Michael J Duffy, Minhong Tang, John Crown","doi":"10.1007/s11523-025-01169-x","DOIUrl":"10.1007/s11523-025-01169-x","url":null,"abstract":"<p><p>MYC is one of the most frequently altered genes in cancer with an estimated 70% prevalence of deregulation. Deregulated MYC is believed to promote cancer formation/progression via multiple mechanisms including tumour cell intrinsic mechanisms, altering the tumour microenvironment and promoting host immune suppression. Owing to the high prevalence of alterations and its causative role in tumorigenesis, MYC is a highly attractive target for new anticancer therapies. However, as MYC lacks a readily identifiably pocket for potential low molecular weight inhibitors and is predominantly located in the cell nucleus, it has proved difficult to target using standard pharmacological approaches. Recently, however, these problems appear to have been successfully resolved, with the discovery of promising anti-MYC compounds such as Omomyc or MYCi975. Both Omomyc and MYCi975 exhibit anti-cancer activity in several different animal models, with apparently little short-term toxicity. Furthermore, consistent with the ability of MYC to promote a pro-tumour microenvironment and induce immune evasion, treatment with Omomyc or MYCi975 was shown to increase uptake of anti-tumour lymphocytes and enhance response to immunotherapy. Currently, at least five anti-MYC compounds are being evaluated for potential anti-cancer activity in clinical trials. Results from a phase I trial with OMO-103 (a form of Omomyc) suggest that the inhibitor is well tolerated, with most of its adverse effects being at grade 1 level. Evidence of target inhibition was the finding of decreased expression of multiple MYC regulated genes.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"791-801"},"PeriodicalIF":4.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12454499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144856416","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":"A Podcast on Real-World Evidence with Avelumab First-Line Maintenance and Treatment Sequencing in Locally Advanced or Metastatic Urothelial Carcinoma.","authors":"Petros Grivas, Helen H Moon","doi":"10.1007/s11523-025-01162-4","DOIUrl":"10.1007/s11523-025-01162-4","url":null,"abstract":"<p><p>Avelumab first-line maintenance is an approved treatment for cisplatin-eligible or -ineligible patients with advanced urothelial carcinoma (UC) who are progression free following first-line platinum-based chemotherapy, based on the results of the JAVELIN Bladder 100 phase 3 trial. In recent years, an increasing number of real-world studies have examined the effectiveness and safety of avelumab first-line maintenance in heterogeneous populations from different countries, expanding the clinical evidence base. In this podcast, we discuss findings from these real-world studies, which have complemented clinical trials and provided additional insights about overall effectiveness, treatment sequencing involving second-line enfortumab vedotin monotherapy or other options, and healthcare resource utilization. We also briefly discuss the evolving treatment landscape in advanced UC in addition to benefits and limitations of real-world studies in general. Overall, across multiple studies involving more than 3000 patients worldwide, real-world outcomes with avelumab first-line maintenance treatment have been consistent with findings from the JAVELIN Bladder 100 trial, confirming the clinical benefits of this treatment approach for patients with advanced UC who are encountered in day-to-day practice.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"743-754"},"PeriodicalIF":4.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12454455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144544884","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":"Discontinuation of Immune Checkpoint Inhibition in Patients with Advanced Unresectable Melanoma Achieving CR, PR, or SD.","authors":"Anna M Czarnecka, Paweł Teterycz, Krzysztof Ostaszewski, Piotr Błoński, Magdalena Zielińska, Łukasz Galus, Robert Dziura, Natasza Kempa-Kamińska, Katarzyna Galwas, Bożena Cybulska-Stopa, Jacek Mackiewicz, Marcin Ziętek, Grażyna Kamińska-Winciorek, Katarzyna Kozak, Piotr Rutkowski","doi":"10.1007/s11523-025-01156-2","DOIUrl":"10.1007/s11523-025-01156-2","url":null,"abstract":"<p><strong>Background: </strong>The optimal duration of immunotherapy (ITH) remains undefined for patients with metastatic melanoma, and debates on de-escalation strategies are ongoing. Patients in the pivotal KEYNOTE and CheckMate trials who experienced a complete response (CR) on ITH had long-term responses, even after treatment was terminated early because of toxicity or at the physician's discretion.</p><p><strong>Objective: </strong>Our study explores the duration of planned ITH drug holidays-intentional ITH suspension until disease progression off treatment-in patients with unresectable and metastatic melanoma treated for at least 6 months with ITH.</p><p><strong>Patients and methods: </strong>We enrolled 222 patients who received anti-programmed cell death protein-1-based ITH, experienced stable disease, partial response, or complete response during ITH, and had no treatment-limiting toxicities.</p><p><strong>Results: </strong>At a median follow-up of 63 months since the first ITH cycle, median overall survival after the drug holiday start (OS3) was not reached, and the 5-year OS3 rate was 79.3%. Median progression-free survival since the start of drug holiday (PFS3) was not reached, with a 3-year PFS3 rate of 65% for all patients, and the highest rate was in the complete response group (72.3%). After the drug holidays, upon disease progression off treatment, the objective response rate to ITH reintroduction was 58.9%. Again, durable, ongoing objective responses were achieved on ITH reintroduction after drug holidays. The best radiological response achieved before drug holidays correlated with the duration of ITH drug holidays, with the longest duration of disease control without treatment for complete responders.</p><p><strong>Conclusions: </strong>Drug holidays in patients with unresectable and metastatic melanoma after an objective response or prolonged disease stabilization during ITH result in durable control of the disease, particularly in patients with complete response.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"693-705"},"PeriodicalIF":4.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12307567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476802","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":"Precision Oncology in Rare Endocrine and Neuroendocrine Neoplasms: Experiences and Challenges of the CCCMunich^LMU Molecular Tumor Board.","authors":"Klara Dorman, Christoph J Auernhammer, Christine Spitzweg, Ralf Schmidmaier, Svenja Nölting, Matthias Kroiss, Martin Reincke, Christian Schulz, Martin Angele, Jens Werner, Christine Schmid-Tannwald, Josefine Rauch, Mathias Zacherl, Thomas Knösel, Jörg Kumbrink, Andreas Jung, Frederick Klauschen, Amanda Tufman, Danmei Zhang, Lena Weiss, Stefan Boeck, Michael von Bergwelt-Baildon, Volker Heinemann, C Benedikt Westphalen, Kathrin Heinrich","doi":"10.1007/s11523-025-01152-6","DOIUrl":"10.1007/s11523-025-01152-6","url":null,"abstract":"<p><strong>Background: </strong>Comprehensive genomic profiling (CGP) has become more generally accessible to patients with rare cancer, but data on the results and benefits are limited.</p><p><strong>Objective: </strong>Our objective was to gain a real-world understanding of the molecular landscape and targeted treatment options in neuroendocrine tumors, neuroendocrine carcinomas, adrenocortical carcinomas, pheochromocytomas, and carcinoids.</p><p><strong>Patients and methods: </strong>In this retrospective cohort study, we analyzed CGP results and clinical data from patients with neuroendocrine tumors, neuroendocrine carcinomas, adrenocortical carcinomas, pheochromocytomas, and carcinoids who were discussed in the CCCMunich^LMU Molecular Tumor Board (MTB) between May 2017 and April 2023.</p><p><strong>Results: </strong>In total, 104 patients with endocrine and neuroendocrine neoplasms were discussed in the MTB. CGP was technically successful in 99 patients. The most commonly mutated genes were TP53 (29.3%), RB1 (11.1%), and KRAS (10.1%). The highest overall prevalence of pathogenic alterations was detected in neuroendocrine carcinomas (76.9%) and carcinoids (83.3%), and the lowest prevalence of pathogenic alterations was seen in adrenocortical carcinoma (37.5%). Of the 99 patients with successful CGP, 35 received a treatment recommendation from the MTB based on the CGP results. Of these, ten patients ultimately received the recommended treatment. Of the ten treated patients, four experienced a longer progression-free survival under the targeted treatment than under their previous treatment.</p><p><strong>Conclusions: </strong>One-third of patients with rare endocrine and neuroendocrine neoplasms who underwent CGP had a druggable alteration and received a treatment recommendation from the MTB. However, only 28.6% of these patients were treated accordingly. Our experience highlights the unmet medical need for targeted treatment options in patients with rare cancers.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"715-724"},"PeriodicalIF":4.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12307483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529614","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":"Circulating Tumor DNA in Advanced EGFRex20+ NSCLC: Concordance with Tissue Biopsy, Monitoring of Response, and Resistance to High-Dose Osimertinib.","authors":"Fenneke Zwierenga, M Benthe Muntinghe-Wagenaar, Pim Rozendal, Adrianus J de Langen, Lizza E L Hendriks, Michel van den Heuvel, Cor van der Leest, Sayed M S Hashemi, Paul van der Leest, T Jeroen N Hiltermann, Ed Schuuring, Anthonie J van der Wekken","doi":"10.1007/s11523-025-01153-5","DOIUrl":"10.1007/s11523-025-01153-5","url":null,"abstract":"<p><strong>Background: </strong>High-dose osimertinib shows modest anti-tumor activity and acceptable toxicity in patients with advanced non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor exon 20 mutation (EGFRex20+). Plasma-derived circulating tumor DNA (ctDNA) is promising in monitoring responses and detecting resistance mechanisms to therapy.</p><p><strong>Objective: </strong>We aimed to assess the concordance between variants detected in ctDNA to those found in corresponding tissue samples at baseline and progression, to analyze alterations in mutant ctDNA levels of EGFRex20+ variants as predictors of therapy response, and to identify resistance mechanisms to high-dose osimertinib as well as examine changes in mutant ctDNA levels of EGFRex20+ variants.</p><p><strong>Patients and methods: </strong>Twenty-five patients with EGFRex20+ NSCLC received double dose (160 mg) osimertinib daily. Blood plasma was collected at baseline, 6 weeks after therapy start (T6), and at progression. ctDNA analysis was performed using the NGS Guardant360 CDx panel. The molecular profile at progression was compared with baseline/T6, and changes in ctDNA levels of the EGFRex20+ variants were linked to response or resistance.</p><p><strong>Results: </strong>Collected ctDNA samples were analyzed retrospectively. Baseline ctDNA showed somatic alterations in 19/20 patients (95%) and the corresponding tumor biopsy NGS EGFRex20+ variant in 65%. Among 14 patients with profiling at all timepoints, there was no significant correlation between changes in mutant ctDNA levels and osimertinib response. At T6, nine patients showed decreased EGFRex20+ levels, with eight also showing tumor shrinkage. At disease progression, 9/14 (64%) patients had increased EGFRex20+ levels, correlating with tumor growth. Variants potentially associated with resistance were found in 11/18 patients (61%): single nucleotide variants (SNV, n = 14), insertions (n = 2), and gene fusions (n = 1). Mutations previously related to osimertinib resistance were found, including EGFR p.C797S (n = 1).</p><p><strong>Conclusions: </strong>ctDNA analysis tracks variant dynamics and can identify resistance mechanisms in patients with EGFRex20+ NSCLC treated with high-dose osimertinib, offering valuable new insights.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"663-677"},"PeriodicalIF":4.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12307451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144235312","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":"PSMA PET Imaging in the Management of Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Radioligand Therapy.","authors":"Phillip H Kuo, Jeremie Calais, Mike Crosby","doi":"10.1007/s11523-025-01151-7","DOIUrl":"10.1007/s11523-025-01151-7","url":null,"abstract":"<p><p>Despite an evolving treatment landscape for people with metastatic castration-resistant prostate cancer, prognosis for this patient population remains poor. Prostate-specific membrane antigen positron emission tomography (PSMA PET) imaging may be used to identify patients with PSMA-positive (and no significant PSMA-negative) metastatic castration-resistant prostate cancer who could benefit from PSMA-targeted radioligand therapy. As the PSMA PET imaging and treatment landscape expands, there is a growing need for guidance and greater utilization of PSMA-targeted tracers and radioligand therapies to improve outcomes for patients with metastatic castration-resistant prostate cancer. This review discusses the current clinical considerations of PSMA PET, including the various imaging agents available and how best to identify patients eligible for PSMA PET imaging and subsequent PSMA-targeted radioligand therapy. This review also examines opportunities to mitigate discordant findings, as well as considerations around the standardization of reporting of PSMA PET imaging, key gaps in the evidence base, and guidance around the use of PSMA PET in clinical and research settings.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"597-613"},"PeriodicalIF":4.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12307550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143611","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":"A Bayesian Network Meta-analysis of Systemic Treatments for Metastatic Castration-Resistant Prostate Cancer in First- and Subsequent Lines.","authors":"Marie Wosny, Stefanie Aeppli, Stefanie Fischer, Tobias Peres, Christian Rothermundt, Janna Hastings","doi":"10.1007/s11523-025-01148-2","DOIUrl":"10.1007/s11523-025-01148-2","url":null,"abstract":"<p><strong>Background: </strong>Metastatic castration-resistant prostate cancer (mCRPC) presents a challenge for clinicians in determining the optimal treatment sequence because of the lack of direct head-to-head comparisons, which is further complicated by the now-widespread use of androgen receptor pathway inhibitors (ARPIs) in metastatic hormone-sensitive prostate cancer (mHSPC).</p><p><strong>Objective: </strong>This study is a Bayesian network meta-analysis (NMA) intended to provide a comprehensive evaluation and comparison of the efficacy of mCRPC treatments across different treatment lines.</p><p><strong>Patients and methods: </strong>We performed a systematic search of ClinicalTrials.gov, extracted information, assessed the risk of bias, and reconstructed missing outcomes. We performed an NMA to evaluate treatment efficacy for overall survival (OS) and progression-free survival (PFS) in first and subsequent lines. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) NMA guidelines and was registered with PROSPERO (CRD42024499607).</p><p><strong>Results: </strong>The NMA included 43 trials with 33,494 patients. ARPI-based therapies, particularly in combination with poly(ADP-ribose) polymerase inhibitors, demonstrated the most significant benefits for OS and PFS in first-line mCRPC treatment, followed by chemotherapy regimens. However, ARPI re-treatment showed limited effectiveness in subsequent lines, leading to weaker OS and PFS benefits.</p><p><strong>Conclusions: </strong>This NMA highlights the superiority of ARPI-based therapies and chemotherapies as first-line options for mCRPC while emphasizing the need for treatment class switching after ARPI failure. To refine treatment sequencing and enable precision care, future research should integrate individual participant data to better address patient-level heterogeneity and identify biomarkers for personalized therapy.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"569-595"},"PeriodicalIF":4.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12307537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258999","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":"Relationship of Prior Anticancer Treatments with Palbociclib Clinical Outcomes in Patients with HR⁺/HER2^- Advanced Breast Cancer in Real-World Settings.","authors":"Gabrielle B Rocque, Joanne L Blum, Yan Ji, Timothy Pluard, John Migas, Shailendra Lakhanpal, Erin Jepsen, Yao Wang, Monica Z Montelongo, Zhe Zhang, Eric Gauthier, Debu Tripathy","doi":"10.1007/s11523-025-01158-0","DOIUrl":"10.1007/s11523-025-01158-0","url":null,"abstract":"<p><strong>Background: </strong>In the real-world POLARIS study, patients with hormone receptor-positive (HR⁺)/human epidermal growth factor receptor 2-negative (HER2^-) advanced/metastatic breast cancer (ABC) who had received palbociclib + endocrine therapy (ET) had a median real-world progression-free survival (rwPFS) of 20.9 months in the first line of therapy (1LOT) and 13.5 months in second or later LOTs (≥ 2LOT).</p><p><strong>Objective: </strong>The aim of this study is to assess the relationship of prior anticancer treatments with clinical outcomes.</p><p><strong>Patients and methods: </strong>Kaplan-Meier estimates of rwPFS and overall survival (OS) are described by prior anticancer treatments in patients with HR⁺/HER2^- ABC who received palbociclib + ET.</p><p><strong>Results: </strong>A total of 1250 patients received ≥ 1 palbociclib dose (1LOT: 901 [72.1%]; ≥ 2LOT: 349 [27.9%]). In the 1LOT group, 563 (62.5%) had received prior (neo)adjuvant treatments: 24.3% ET alone, 26.6% chemotherapy alone, 45.5% ET + chemotherapy, and 3.6% other treatments; both median rwPFS and OS were numerically longer in patients who had received ET alone (30.4 months and not reached, respectively) and had had no prior treatment (23.7 and 53.3 months, respectively) than in patients with prior chemotherapy alone (15.9 and 38.4 months, respectively). In the ≥ 2LOT group, patients with prior ET alone (21.5%; 19.8 months) or chemotherapy alone (16.6%; 15.5 months) in the (neo)adjuvant and/or metastatic setting had numerically longer median rwPFS than those with prior ET + chemotherapy (41.3%; 11.6 months); OS was comparable regardless of prior treatment.</p><p><strong>Conclusions: </strong>Patients with HR⁺/HER2^- ABC who had received ET alone prior to palbociclib tended to have better clinical outcomes, while those with prior chemotherapy had less clinical benefit.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov, NCT03280303.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"679-692"},"PeriodicalIF":4.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12307473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476803","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":"Teclistamab Dosing in Responders: Modeling and Simulation Results from the MajesTEC-1 Study in Relapsed/Refractory Multiple Myeloma.","authors":"Yue Guo, Jin Niu, Natalia A Quijano Cardé, Liviawati Wu, Xin Miao, Shalla Hanson, Yaming Su, Carlos Pérez Ruixo, Deeksha Vishwamitra, Katherine Chastain, Mahesh N Samtani, Weirong Wang, Nahor Haddish-Berhane","doi":"10.1007/s11523-025-01149-1","DOIUrl":"10.1007/s11523-025-01149-1","url":null,"abstract":"<p><strong>Background: </strong>Based on the phase I/II MajesTEC-1 study, the B-cell maturation antigen (BCMA) and cluster of differentiation (CD)3 bispecific antibody, teclistamab, is approved for relapsed/refractory multiple myeloma (RRMM) at a dose of 1.5 mg/kg weekly (QW), with the option to switch to 1.5 mg/kg every other week (Q2W) in patients maintaining complete response (CR) or better for ≥ 6 months on the QW schedule.</p><p><strong>Objective: </strong>We report the pharmacokinetics (PK), pharmacodynamics, and anticancer activity of teclistamab 1.5 mg/kg Q2W, and the PK of teclistamab 3 mg/kg every 4 weeks (Q4W), on the basis of modeling and simulation results from MajesTEC-1.</p><p><strong>Methods: </strong>Teclistamab PK was assessed using a population PK approach. Exposure-response analysis was based on individual estimated teclistamab serum trough concentration (C_trough). The impact of responders switching to Q2W teclistamab dosing on the formation of the key pharmacological species that drive the mechanism of action of teclistamab (i.e., the trimer formed by simultaneous engagement of teclistamab with BCMA on target multiple myeloma cells and CD3 on effector T cells) was estimated using a quantitative systems pharmacology (QSP) model. Additionally, steady-state teclistamab PK and trimer was simulated for the 1.5 mg/kg Q2W and Q4W (3 mg/kg or 1.5 mg/kg) doses.</p><p><strong>Results: </strong>Median estimated teclistamab serum C_trough was lower after the first and fourth Q2W doses (14.4 and 11.7 µg/mL, respectively) than after QW doses (20.4 µg/mL) but remained above the 90% maximal effective concentration. No statistically significant exposure-response trend was observed for duration of response (DOR), progression-free survival, or overall survival in responders who switched to teclistamab 1.5 mg/kg Q2W dosing. Despite the lower teclistamab serum C_trough, the QSP model estimated comparable target cell-biologics-effector cell (TBE) trimer formation, tumor volume reduction, and DOR for responders switching to 1.5 mg/kg Q2W dosing versus not switching. Steady-state exposure metrics and trimer formation with teclistamab 3 mg/kg Q4W were estimated to be comparable with those at 1.5 mg/kg Q2W.</p><p><strong>Conclusions: </strong>MajesTEC-1 modeling and simulation results, which contributed to the teclistamab label update, support the approved switch to teclistamab 1.5 mg/kg Q2W in patients maintaining ≥ CR for ≥ 6 months on the QW dose, without negatively impacting clinical efficacy. In addition, it is estimated that the 3 mg/kg Q4W schedule will provide maintenance of response comparable with the 1.5 mg/kg Q2W schedule. Teclistamab 3 mg/kg Q4W dosing will be evaluated in > 800 patients in three phase III studies in early line RRMM (MajesTEC-3, MajesTEC-9, and MonumenTAL-6) and in 100 patients in RRMM in the phase I MajesTEC-10 study.</p><p><strong>Clinical trial registration: </strong>NCT03145181 (phase I,","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"651-661"},"PeriodicalIF":4.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12307566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144014706","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}