Targeted Oncology最新文献

{"title":"A Phase 1 Study of Intravenous EGFR-ErbituxEDVsMIT in Children with Solid or CNS Tumours Expressing Epidermal Growth Factor Receptor.","authors":"Louise Evans, Rick Walker, Jennifer MacDiarmid, Himanshu Brahmbhatt, Antoinette Anazodo, Geoffrey McCowage, Andrew J Gifford, Maria Kavallaris, Toby Trahair, David S Ziegler","doi":"10.1007/s11523-024-01051-2","DOIUrl":"10.1007/s11523-024-01051-2","url":null,"abstract":"<p><strong>Background: </strong>Recurrent or refractory solid and central nervous system (CNS) tumours in paediatric patients have limited treatment options and carry a poor prognosis. The EnGeneIC Dream Vector (EDV) is a novel nanocell designed to deliver cytotoxic medication directly to the tumour. The epidermal growth factor receptor is expressed in several CNS and solid tumours and is the target for bispecific antibodies attached to the EDV.</p><p><strong>Objective: </strong>To assess the safety and tolerability of EGFR-Erbitux receptor EnGeneIC Dream Vector with mitoxantrone (^EEDVs_Mit) in children with recurrent / refractory solid or CNS tumours expressing EGFR.</p><p><strong>Patients and methods: </strong>Patients aged 2-21 years with relapsed or refractory CNS and solid tumours, or radiologically diagnosed diffuse intrinsic pontine glioma (DIPG), were treated in this phase I open-label study of single agent ^EEDVs_Mit. Thirty-seven patients' tumours were screened for EGFR expression. ^EEDVs_Mit was administered twice weekly in the first cycle and weekly thereafter. Standard dose escalation with a rolling 6 design was employed. Dosing commenced at 5 × 10^{8 E}EDVs_Mit per dose and escalated to 5 × 10^{9 E}EDVs_Mit per dose.</p><p><strong>Results: </strong>EGFR expression was detected in 12 (32%) of the paediatric tumours tested. Nine patients were enrolled and treated on the trial, including three patients with diffuse midline glioma. Overall, ^EEDVs_Mit was well tolerated, with no dose-limiting toxicities observed. The most common drug-related adverse events were grade 1-2 fever, nausea and vomiting, rash, lymphopaenia, and mildly deranged liver function tests. All patients had disease progression, including one patient who achieved a mixed response as the best response.</p><p><strong>Conclusions: </strong>EGFR-Erbitux receptor targeted EnGeneIC Dream Vector with mitoxantrone can be safely delivered in paediatric patients aged 2-21 years with solid or CNS tumours harbouring EGFR expression. The discovery of EGFR expression in a high proportion of paediatric gliomas means that EGFR may be useful as a target for other treatment strategies. Targeted therapeutic-loaded EDVs may be worth exploring further for their role in stimulating an anti-tumour immune response.</p><p><strong>Clinicaltrials: </strong></p><p><strong>Gov identifier: </strong>NCT02687386.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"333-342"},"PeriodicalIF":4.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11111512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140319194","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":"Palbociclib in Older Patients with Advanced/Metastatic Breast Cancer: A Systematic Review.","authors":"Etienne Brain, Connie Chen, Sofia Simon, Vinay Pasupuleti, Kathleen Vieira Pfitzer, Karen A Gelmon","doi":"10.1007/s11523-024-01046-z","DOIUrl":"10.1007/s11523-024-01046-z","url":null,"abstract":"<p><strong>Background: </strong>Palbociclib in combination with endocrine therapy is approved for treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. In addition to clinical trials, several real-world studies have evaluated the effectiveness of palbociclib. With increased life expectancy in the general population, breast cancer in older women is also expected to increase.</p><p><strong>Objective: </strong>The aim was to systematically review evidence from both clinical trials and real-world studies for palbociclib treatment outcomes in older patients with HR+/HER2- advanced/metastatic breast cancer (a/mBC). Older patients are often underrepresented in clinical trials, and real-world evidence (RWE) will enrich the analysis of palbociclib outcomes in this subgroup of patients.</p><p><strong>Design: </strong>A systematic literature search in PubMed, EMBASE, and Cochrane Library through May 4, 2023, yielded 2355 unique articles. A total of 52 articles (13 and 39 articles reporting results from seven randomized controlled trials [RCTs] and 37 RWE studies, respectively) were included based on study eligibility criteria.</p><p><strong>Results: </strong>All RCTs used age cutoffs of ≥ 65 years to define older population (n = 722; 437 received palbociclib); all RWE studies, except one with an age cutoff of > 60 years, had age cutoffs of ≥ 65 years or higher to define older population (n = 9840; 7408 received palbociclib). Overall, in studies that compared efficacy (progression-free survival [seven RCTs, 20 RWE studies], overall survival [four RCTs, 11 RWE studies], tumor response [three RWE studies], and clinical benefit rate [one RCT, two RWE studies]) and safety outcomes (three RCTs, three RWE studies) between older and younger patients, palbociclib showed similar benefits, regardless of age. Results from two RCTs and two RWE studies showed that global quality of life (QoL) was maintained in older patients receiving palbociclib. Overall, palbociclib dose modifications (two RWE studies), dose reductions (one RCT, seven RWE studies), and treatment discontinuation rates (three RCTs, three RWE studies) were higher in older patients compared with younger patients; however, these differences did not appear to adversely impact efficacy outcomes.</p><p><strong>Conclusions: </strong>In this systematic review, data from RCTs showed that palbociclib was effective, well tolerated, and maintained QoL in older patients with HR+/HER2- a/mBC. Palbociclib treatment in older patients in real-world settings was associated with similar clinical benefit as in RCTs.</p><p><strong>Prospero registration: </strong>CRD42023444195.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"303-320"},"PeriodicalIF":5.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11111485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140319218","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":"Emerging Toxicities of Antibody-Drug Conjugates for Breast Cancer: Clinical Prioritization of Adverse Events from the FDA Adverse Event Reporting System.","authors":"Sara Cecco, Stefano Puligheddu, Michele Fusaroli, Lorenzo Gerratana, Miao Yan, Claudio Zamagni, Fabrizio De Ponti, Emanuel Raschi","doi":"10.1007/s11523-024-01058-9","DOIUrl":"10.1007/s11523-024-01058-9","url":null,"abstract":"<p><strong>Background: </strong>Antibody-drug conjugates (ADCs) are gaining widespread use in the treatment of breast cancer, although toxicity remains an underexplored issue in the real-world clinical setting. Individual case safety reports collected in large pharmacovigilance databases can advance our knowledge on their safety profile in routine clinical practice.</p><p><strong>Objective: </strong>We prioritized adverse events (AEs) reported with ADCs approved for breast cancer using the Food and Drug Administration Adverse Event Reporting System (FAERS).</p><p><strong>Methods: </strong>We assessed clinical priority of AEs reported in FAERS (February 2013-March 2022) for trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan (SG) by attributing a score to each AE disproportionally reported with ADCs. Four criteria were assessed: clinical relevance, reporting rate, reported case fatality rate, and stability of disproportionality signals (consistency of the reporting odds ratio across multiple analyses using three different comparators).</p><p><strong>Results: </strong>We retained 6589 reports (77.4% referring to T-DM1 as suspect), and 572 AEs generated a disproportionality signal in at least one analysis. The majority of these AEs (62%) were classified as moderate clinical priorities (e.g., interstitial lung disease with T-DXd, thrombocytopenia, peripheral neuropathy with T-DM1, febrile neutropenia, and large intestine perforation with SG). Three AEs emerged as high clinical priorities (6 points): septic shock and neutropenic colitis with SG (N = 8 and 13, with median onset 13 and 10 days, respectively), without co-reported immunosuppressive agents; and pulmonary embolism with T-DM1 (N = 31, median onset 109 days, 52% with reported metastasis).</p><p><strong>Conclusion: </strong>The heterogeneous spectrum of post-marketing toxicities for ADCs used in breast cancer, as emerging from the FAERS, is largely in line with preapproval evidence. Although causality cannot be proved, we call for increased awareness by oncologists on potential serious unexpected reactions, including early onset of septic shock and neutropenic colitis with SG, and late emergence of pulmonary embolism with T-DM1.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"435-445"},"PeriodicalIF":5.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11111510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140865377","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":"Durable Response to Enfortumab Vedotin Compared to Re-challenging Chemotherapy in Metastatic Urothelial Carcinoma After Checkpoint Inhibitors.","authors":"Taizo Uchimoto, Shuya Tsuchida, Kazumasa Komura, Wataru Fukuokaya, Takahiro Adachi, Yosuke Hirasawa, Takeshi Hashimoto, Atsuhiko Yoshizawa, Masanobu Saruta, Mamoru Hashimoto, Takuya Higashio, Takuya Matsuda, Kazuki Nishimura, Takuya Tsujino, Ko Nakamura, Tatsuo Fukushima, Kyosuke Nishio, Shutaro Yamamoto, Kosuke Iwatani, Fumihiko Urabe, Keiichiro Mori, Takafumi Yanagisawa, Shunsuke Tsuduki, Kiyoshi Takahara, Teruo Inamoto, Jun Miki, Kazutoshi Fujita, Takahiro Kimura, Yoshio Ohno, Ryoichi Shiroki, Hirotsugu Uemura, Haruhito Azuma","doi":"10.1007/s11523-024-01047-y","DOIUrl":"10.1007/s11523-024-01047-y","url":null,"abstract":"<p><strong>Background: </strong>Enfortumab vedotin (EV), an antibody-drug conjugate targeting Nectin-4, has been used for patients with metastatic urothelial carcinoma (mUC) after progressing on checkpoint inhibitors (CPIs). Re-challenging chemotherapy with platinum agents and continuing CPIs beyond progressive disease (PD) have often been chosen following PD on CPIs, and several studies indicate favorable treatment effects of re-challenging chemotherapy. There is little evidence for comparing EV and re-challenging chemotherapy in real-world clinical practice.</p><p><strong>Objective: </strong>The aim was to reveal the real-world treatment outcomes of EV, re-challenging chemotherapy, and continuing CPIs beyond PD in mUC patients.</p><p><strong>Patients and methods: </strong>A multi-institutional dataset of 350 mUC patients treated with CPIs was utilized. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) were evaluated to compare the treatment arms.</p><p><strong>Results: </strong>One hundred and nine mUC patients were treated with EV with a median follow-up of 6.4 months. The ORR and disease control rate (DCR) were 48% and 70%, respectively. The OS from PD on pembrolizumab exhibited significant differences among the three groups, with a median OS of 8, 14, and 29 months in continuing pembrolizumab beyond PD, re-challenging chemotherapy, and EV, respectively. When comparing the survival outcomes from the initiation of the treatment, there is neither a difference in OS (p = 0.124), PFS (p = 0.936), nor ORR (p = 0.816) between EV and re-challenging chemotherapy. Notably, the DOR in patients who achieved an objective response was significantly longer in the EV group than the re-challenging chemotherapy group (a median of 11 and 5 months, p = 0.049). For OS, the difference was not statistically significant (27 and 11 months in EV and re-challenging chemotherapy, respectively: p = 0.05).</p><p><strong>Conclusions: </strong>A superior effect of EV on patient survival compared to re-challenging chemotherapy and continuing pembrolizumab beyond PD was observed in our real-world analysis, which is attributed to the durable DOR in EV treatment despite the similar ORR to re-challenging chemotherapy.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"401-410"},"PeriodicalIF":4.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140319217","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":"Efficacy and Safety of Neoadjuvant Subcutaneous Envafolimab in dMMR/MSI-H Locally Advanced Colon Cancer","authors":"Yuan Li, Weili Zhang, Jie Du, Jinlong Hu, Ruixi Hu, Ziyang Zeng, E-er-man-bie-ke Jin-si-han, Shaopu Lian, Hao Wang, Yunfeng Li, Zhizhong Pan, Cheng Feng, Xuan Zhang, Zhenhai Lu","doi":"10.1007/s11523-024-01064-x","DOIUrl":"https://doi.org/10.1007/s11523-024-01064-x","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Neoadjuvant immunotherapy with programmed death-ligand 1 blockade for colon cancer, especially for mismatch repair-deficient (dMMR)/high microsatellite instability (MSI-H) colon cancer, has gained considerable attention recently.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>This study aimed to assess the safety and efficacy of neoadjuvant subcutaneous envafolimab in patients with dMMR/MSI-H locally advanced colon cancer.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Patients with dMMR/MSI-H locally advanced colon cancer treated with envafolimab at Sun Yat-sen University Cancer Center and Yunnan Cancer Hospital from October 2021 to July 2023 were retrospectively reviewed and analyzed. The primary endpoint was the pathological complete response (CR) rate, and secondary endpoints were treatment-related adverse events and complete clinical response rate.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Overall, 15 patients were analyzed. After neoadjuvant immunotherapy with envafolimab, six patients achieved a CR, with five partial responses, and four stable disease. Three patients achieving a complete clinical response chose to accept a “watch and wait” strategy, and surgery was performed in 12 patients. Postoperative pathology results revealed seven patients achieved pathological CRs, and five patients achieved tumor regression grade 2, with 66.7% of the total CR rate. The most common treatment-related adverse events were pruritus and rash (40%), with no severe cases. No recurrences occurred over a 7.9-month follow-up.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Envafolimab yielded promising surgical outcomes and safety in dMMR/MSI-H locally advanced colon cancer, representing a promising treatment modality for this population.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":"11 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140834299","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":"Adverse Events as Potential Predictive Factors of Activity in Patients with Advanced HCC Treated with Atezolizumab Plus Bevacizumab","authors":"Mara Persano, Margherita Rimini, Toshifumi Tada, Goki Suda, Shigeo Shimose, Masatoshi Kudo, Federico Rossari, Changhoon Yoo, Jaekyung Cheon, Fabian Finkelmeier, Ho Yeong Lim, José Presa, Gianluca Masi, Francesca Bergamo, Elisabeth Amadeo, Francesco Vitiello, Takashi Kumada, Naoya Sakamoto, Hideki Iwamoto, Tomoko Aoki, Hong Jae Chon, Vera Himmelsbach, Massimo Alberto Iavarone, Giuseppe Cabibbo, Margarida Montes, Francesco Giuseppe Foschi, Caterina Vivaldi, Caterina Soldà, Takuya Sho, Takashi Niizeki, Naoshi Nishida, Christoph Steup, Mariangela Bruccoleri, Masashi Hirooka, Kazuya Kariyama, Joji Tani, Masanori Atsukawa, Koichi Takaguchi, Ei Itobayashi, Shinya Fukunishi, Kunihiko Tsuji, Toru Ishikawa, Kazuto Tajiri, Hironori Ochi, Satoshi Yasuda, Hidenori Toyoda, Chikara Ogawa, Takashi Nishimura, Takeshi Hatanaka, Satoru Kakizaki, Noritomo Shimada, Kazuhito Kawata, Atsushi Hiraoka, Fujimasa Tada, Hideko Ohama, Kazuhiro Nouso, Asahiro Morishita, Akemi Tsutsui, Takuya Nagano, Norio..","doi":"10.1007/s11523-024-01061-0","DOIUrl":"https://doi.org/10.1007/s11523-024-01061-0","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>In the context of patients with hepatocellular carcinoma (HCC) treated with systemic therapy, the correlation between the appearance of adverse events (AEs) and reported efficacy outcomes is well-known and widely investigated. From other pathological settings, we are aware of the prognostic and predictive value of the occurrence of immune-related AEs in patients treated with immune-checkpoint inhibitors.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>This retrospective multicenter real-world study aims to investigate the potential prognostic value of AEs in patients with HCC treated with atezolizumab plus bevacizumab in the first-line setting.</p><h3 data-test=\"abstract-sub-heading\">Patients and methods</h3><p>The study population consisted of 823 patients from five countries (Italy, Germany, Portugal, Japan, and the Republic of Korea).</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Of the patients, 73.3% presented at least one AE during the study period. The most common AEs were proteinuria (29.6%), arterial hypertension (27.2%), and fatigue (26.0%). In all, 17.3% of the AEs were grade (G) 3. One death due to bleeding was reported. The multivariate analysis confirmed the appearance of decreased appetite G &lt; 2 [versus G ≥ 2; hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.13–0.90; <i>p</i> &lt; 0.01] and immunotoxicity G &lt; 2 (versus G ≥ 2; HR: 0.70; 95% CI 0.24–0.99; <i>p</i> = 0.04) as independent prognostic factors for overall survival, and the appearance of decreased appetite G &lt; 2 (versus G ≥ 2; HR: 0.73; 95% CI 0.43–0.95; <i>p</i> = 0.01), diarrhea (yes versus no; HR: 0.57, 95% CI 0.38–0.85; <i>p</i> = 0.01), fatigue (yes versus no; HR: 0.82, 95% CI 0.65–0.95; <i>p</i> &lt; 0.01), arterial hypertension G &lt; 2 (versus G ≥ 2; HR: 0.68, 95% CI 0.52–0.87; <i>p</i> &lt; 0.01), and proteinuria (yes versus no; HR: 0.79, 95% CI 0.64–0.98; <i>p</i> = 0.03) as independent prognostic factors for progression-free survival.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>As demonstrated for other therapies, there is also a correlation between the occurrence of AEs and outcomes for patients with HCC for the combination of atezolizumab plus bevacizumab.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":"41 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140834300","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":"ASCT2-Targeting Antibody-Drug Conjugate MEDI7247 in Adult Patients with Relapsed/Refractory Hematological Malignancies: A First-in-Human, Phase 1 Study","authors":"Michael Maris, Gilles Salles, Won Seog Kim, Tae Min Kim, Roger M. Lyons, Martha Arellano, Reem Karmali, Gary Schiller, Elizabeth Cull, Camille N. Abboud, Connie Batlevi, Ioannis Kagiampakis, Marlon C. Rebelatto, Young Lee, Lyndon C. Kirby, Fujun Wang, John Bothos, Danielle M. Townsley, Amir T. Fathi, Vincent Ribrag","doi":"10.1007/s11523-024-01054-z","DOIUrl":"https://doi.org/10.1007/s11523-024-01054-z","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>MEDI7247 is a first-in-class antibody-drug conjugate (ADC) consisting of an anti-sodium-dependent alanine-serine-cysteine transporter 2 antibody-conjugated to a pyrrolobenzodiazepine dimer.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>This first-in-human phase 1 trial evaluated MEDI7247 in patients with hematological malignancies.</p><h3 data-test=\"abstract-sub-heading\">Patients and methods</h3><p>Adults with acute myeloid leukemia (AML), multiple myeloma (MM), or diffuse large B-cell lymphoma (DLBCL) relapsed or refractory (R/R) to standard therapies, or for whom no standard therapy exists, were eligible. Primary endpoints were safety and determination of the maximum tolerated dose (MTD). Secondary endpoints included assessments of antitumor activity, pharmacokinetics (PK), and immunogenicity.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>As of 26 March 2020, 67 patients were treated (AML: <i>n</i> = 27; MM: <i>n</i> = 18; DLBCL: <i>n</i> = 22). The most common MEDI7247-related adverse events (AEs) were thrombocytopenia (41.8%), neutropenia (35.8%), and anemia (28.4%). The most common treatment-related grade 3/4 AEs were thrombocytopenia (38.8%), neutropenia (34.3%), and anemia (22.4%). Anticancer activity (number of responders/total patients evaluated) was observed in 11/67 (16.4%) patients. No correlation was observed between ASCT2 expression and clinical response. Between-patient variability of systemic exposure of MEDI7247 ADC and total antibody were high (AUC_inf geometric CV%: 62.3–134.2, and 74.8–126.1, respectively). SG3199 (PBD dimer) plasma concentrations were below the limit of quantification for all patients after Study Day 8. Anti-drug antibody (ADA) prevalence was 7.7%, ADA incidence was 1.9%, and persistent-positive ADA was 5.8%.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Thrombocytopenia and neutropenia limited repeat dosing. Although limited clinical activity was detected, the dose-escalation phase was stopped early without establishing an MTD.</p><p>The study was registered with ClinicalTrials.gov (NCT03106428).</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":"18 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140834292","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":"Deciphering the Prognostic Significance of MYD88 and CD79B Mutations in Diffuse Large B-Cell Lymphoma: Insights into Treatment Outcomes","authors":"Zucheng Xie, Yan Qin, Xinrui Chen, Sheng Yang, Jianliang Yang, Lin Gui, Peng Liu, Xiaohui He, Shengyu Zhou, Changgong Zhang, Le Tang, Yuankai Shi","doi":"10.1007/s11523-024-01057-w","DOIUrl":"https://doi.org/10.1007/s11523-024-01057-w","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Background&lt;/h3&gt;&lt;p&gt;The clinical and genetic characteristics, as well as treatment outcomes, of diffuse large B-cell lymphoma (DLBCL) patients with different &lt;i&gt;MYD88&lt;/i&gt; and &lt;i&gt;CD79B&lt;/i&gt; mutation status merit further investigation.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Objective&lt;/h3&gt;&lt;p&gt;This study aims to investigate the distinctions in clinical manifestations, genetic characteristics, and treatment outcomes among &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-mut&lt;/sup&gt;, &lt;i&gt;MYD88&lt;/i&gt;/&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;single-mut&lt;/sup&gt;, and &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-wt&lt;/sup&gt; DLBCL patients.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Patients and Methods&lt;/h3&gt;&lt;p&gt;Clinical and genetic characteristics, along with treatment outcomes among 2696 DLBCL patients bearing &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-mut&lt;/sup&gt;, &lt;i&gt;MYD88&lt;/i&gt;/&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;single-mut&lt;/sup&gt;, and &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-wt&lt;/sup&gt; treated with R-CHOP/R-CHOP-like regimens from the Cancer Hospital, Chinese Academy of Medical Sciences &amp; Peking Union Medical College and six external cohorts were analyzed. Potential molecular mechanisms were investigated through Gene Set Enrichment Analysis and xCell methodology.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;In the MCD subtype, patients with &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-mut&lt;/sup&gt; showed comparable progression-free survival (PFS) and overall survival (OS) compared to &lt;i&gt;MYD88&lt;/i&gt;/&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;single-mut&lt;/sup&gt; or &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-wt&lt;/sup&gt;. However, in the non-MCD subtype, patients with &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-mut&lt;/sup&gt; exhibited significantly inferior OS than &lt;i&gt;MYD88&lt;/i&gt;/&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;single-mut&lt;/sup&gt; or &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-wt&lt;/sup&gt;, while there was no significant OS difference between &lt;i&gt;MYD88&lt;/i&gt;/&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;single-mut&lt;/sup&gt; and &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-wt&lt;/sup&gt; (median OS: 68.8 [95% CI 22–NA] vs NA [95% CI 112–NA] vs 177.7 [95% CI 159–NA] months; &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-mut&lt;/sup&gt; vs &lt;i&gt;MYD88&lt;/i&gt;/&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;single-mut&lt;/sup&gt;: &lt;i&gt;p &lt;/i&gt;= 0.02; &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-mut&lt;/sup&gt; vs &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-wt&lt;/sup&gt;: &lt;i&gt;p &lt;/i&gt;= 0.03; &lt;i&gt;MYD88&lt;/i&gt;/&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;single-mut&lt;/sup&gt; vs &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-wt&lt;/sup&gt;: &lt;i&gt;p &lt;/i&gt;= 0.33). Regarding patients with &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-mut&lt;/sup&gt;, there was no significant difference in PFS and OS between the MCD and non-MCD subtypes. Within the &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-mut&lt;/sup&gt; group, patients with &lt;i&gt;PIM1&lt;/i&gt;&lt;sup&gt;mut&lt;/sup&gt; had better PFS than &lt;i&gt;PIM1&lt;/i&gt;&lt;sup&gt;wt&lt;/sup&gt; (median PFS: 8.34 [95% CI 5.56–NA] vs 43.8 [95% CI 26.4–NA] months; &lt;i&gt;p &lt;/i&gt;= 0.02). Possible mechanisms contributing to the superior PFS of &lt;i&gt;PIM1&lt;/i&gt;&lt;sup&gt;mut&lt;/sup&gt; patients may include activated lymphocyte-mediated immunity and interferon response, a higher proportion of natural killer T cells and plasmacytoid dendritic cells, as well as suppressed angiogenesis and epithelial-mesenchymal t","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":"71 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140625367","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 I Trial Evaluating the Addition of Lenalidomide to Patients with Relapsed/Refractory Multiple Myeloma Progressing on Ruxolitinib and Methylprednisolone","authors":"James R. Berenson, Andrea Limon, Stephanie Rice, Tahmineh Safaie, Ralph Boccia, Honghao Yang, Mehdi Moezi, Stephen Lim, Gary Schwartz, Shahrooz Eshaghian, Matthew Brobeck, Regina Swift, Benjamin M. Eades, Sean Bujarski, Yohana Sebhat, Rudra Ray, Susanna Kim, Ashley Del Dosso, Robert Vescio","doi":"10.1007/s11523-024-01049-w","DOIUrl":"https://doi.org/10.1007/s11523-024-01049-w","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Background&lt;/h3&gt;&lt;p&gt;Ruxolitinib (RUX), an orally administered selective Janus kinase 1/2 inhibitor, has received approval for the treatment of myelofibrosis, polycythemia vera, and graft-versus-host disease. We have previously demonstrated the anti-multiple myeloma effects of RUX alone and in combination with the immunomodulatory agent lenalidomide (LEN) and glucocorticosteroids both pre-clinically and clinically.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Objective&lt;/h3&gt;&lt;p&gt;This study aims to evaluate whether LEN can achieve clinical activity among patients with multiple myeloma progressing on the combination of RUX and methylprednisolone (MP).&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;In this part of a phase I, multicenter, open-label study, we evaluated the safety and efficacy of RUX and MP for patients with multiple myeloma with progressive disease who had previously received a proteasome inhibitor, LEN, glucocorticosteroids, and at least three prior regimens; we also determined the safety and efficacy of adding LEN at the time of disease progression from the initial doublet treatment. Initially, all subjects received oral RUX 15 mg twice daily and oral MP 40 mg every other day. Those patients who developed progressive disease according to the International Myeloma Working Group criteria then received LEN 10 mg once daily on days 1–21 within a 28-day cycle in addition to RUX and MP, which were administered at the same doses these patients were receiving at the time progressive disease developed.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;Twenty-nine subjects (median age 64 years; 18 [62%] male) were enrolled in this part of the study and initially received the two-drug combination of RUX and MP. The median number of prior therapies was six (range 3–12). The overall response rate from this two-drug combination was 31% and the clinical benefit rate was 34%. The best responses were 1 very good partial response, 8 partial responses, 1 minor response, 12 stable disease, and 7 progressive disease. The median progression-free survival was 3.5 months (range 0.5–36.2 months). The median time to response was 3.0 months. The median duration of response was 12.5 months (range 2.8–36.2 months). Twenty (69%) patients who showed progressive disease had LEN added to RUX and MP; all patients had prior exposure to LEN and all but one patient was refractory to their last LEN-containing regimen. After the addition of LEN, the overall response rate was 30% and the clinical benefit rate was 40%. The best responses of patients following the addition of LEN were 2 very good partial responses, 4 partial responses, 2 minor responses, 8 stable disease, and 4 progressive disease. The median time to response was 2.6 months (range 0.7–15.0 months). The median duration of response was not reached. The median progression-free survival following the addition of LEN was 3.5 months (range 0.3–25.9 months).&lt;/p&gt;&lt;h3 data-test","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":"3 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140629393","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":"The Molecular Landscape of Gastric Cancers for Novel Targeted Therapies from Real-World Genomic Profiling","authors":"Hiroyuki Yamamoto, Hiroyuki Arai, Ritsuko Oikawa, Kumiko Umemoto, Hiroyuki Takeda, Takuro Mizukami, Yohei Kubota, Ayako Doi, Yoshiki Horie, Takashi Ogura, Naoki Izawa, Jay A. Moore, Ethan S. Sokol, Yu Sunakawa","doi":"10.1007/s11523-024-01052-1","DOIUrl":"https://doi.org/10.1007/s11523-024-01052-1","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Panel-based comprehensive genomic profiling is used in clinical practice worldwide; however, large real-world datasets of patients with advanced gastric cancer are not well known.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>We investigated what differences exist in clinically relevant alterations for molecularly defined or age-stratified subgroups.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>This was a collaborative biomarker study of a real-world dataset from comprehensive genomic profiling testing (Foundation Medicine, Inc.). Hybrid capture was carried out on at least 324 cancer-related genes and select introns from 31 genes frequently rearranged in cancer. Overall, 4634 patients were available for analyses and were stratified by age (≥ 40/&lt; 40 years), microsatellite instability status, tumor mutational burden status (high 10 ≥ /low &lt; 10 Muts/Mb), Epstein–Barr virus status, and select gene alterations. We analyzed the frequency of alterations with a chi-square test with Yate’s correction.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Genes with frequent alterations included <i>TP53</i> (60.1%), <i>ARID1A</i> (19.6%), <i>CDKN2A</i> (18.2%), <i>KRAS</i> (16.6%), and <i>CDH1</i> (15.8%). Differences in comprehensive genomic profiling were observed according to molecularly defined or age-stratified subgroups. Druggable genomic alterations were detected in 31.4% of patients; <i>ATM</i> (4.4%), <i>BRAF</i> V600E (0.4%), <i>BRCA1</i> (1.5%), <i>BRCA2</i> (2.9%), <i>ERBB2</i> amplification (9.2%), <i>IDH1</i> (0.2%), <i>KRAS</i> G12C (0.7%), microsatellite instability-high (4.8%), <i>NTRK1/2/3</i> fusion (0.13%), <i>PIK3CA</i> mutation (11.4%), and tumor mutational burden-high (9.4%). <i>CDH1</i> alterations and <i>MET</i> amplification were significantly more frequent in patients aged &lt; 40 years (27.7 and 6.2%) than in those aged ≥ 40 years (14.7 and 4.0%).</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Real-world datasets from clinical panel testing revealed the genomic landscape in gastric cancer by subgroup. These findings provide insights for the current therapeutic strategies and future development of treatments in gastric cancer.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":"15 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140599051","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}