Targeted Oncology最新文献

{"title":"Adavosertib in Combination with Olaparib in Patients with Refractory Solid Tumors: An Open-Label, Dose-Finding, and Dose-Expansion Phase Ib Trial.","authors":"Erika P Hamilton, Gerald S Falchook, Judy S Wang, Siqing Fu, Amit M Oza, Esteban Rodrigo Imedio, Sanjeev Kumar, Lone Ottesen, Ganesh M Mugundu, Elza C de Bruin, Mark J O'Connor, Suzanne F Jones, David R Spigel, Bob T Li","doi":"10.1007/s11523-024-01102-8","DOIUrl":"10.1007/s11523-024-01102-8","url":null,"abstract":"<p><strong>Background: </strong>Adavosertib is a first-in-class, selective small-molecule inhibitor of Wee1. Olaparib is an inhibitor of poly(ADP-ribose) polymerase (PARP). Preclinical data suggest that adavosertib enhances the antitumor effect of PARP inhibitors.</p><p><strong>Objective: </strong>The safety, tolerability, and efficacy of adavosertib plus olaparib were evaluated in patients with refractory solid tumors to define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D).</p><p><strong>Patients and methods: </strong>Eligible patients in part A (dose finding) had a refractory solid tumor for which there is no established treatment and had received ≥ 1 prior course of systemic therapy; in part B (dose expansion), patients had platinum-sensitive extensive-stage or relapsed small-cell lung cancer (SCLC). Patients received adavosertib [once (qd) or twice daily (bid)] for 3 consecutive days with 4 days off treatment (3/4), or 5 consecutive days with 2 days off (5/2), plus olaparib (bid) for 14 or 21 days of a 21-day cycle.</p><p><strong>Results: </strong>A total of 130 patients were enrolled in the study, 120 in part A and 10 in part B. The MTD for adavosertib bid was 175 mg (days 1-3, 8-10/21-day cycle) plus continuous olaparib 200 mg bid; the once-daily MTD (and RP2D) was adavosertib 200 mg (days 1-3, 8-10/21-day cycle) plus continuous olaparib 200 mg bid. In the MTD/RP2D cohort, one patient (7%) experienced a dose-limiting toxicity (DLT) of thrombocytopenia. The most common treatment-related adverse events (TRAEs) in the cohorts in which MTD/RP2D for bid dosing and RP2D for qd dosing were determined were fatigue (64.3% and 15.4%, respectively), diarrhea (42.9% and 30.8%), decreased appetite (35.7% and 23.1%), nausea (35.7% and 15.4%), and anemia (35.7% and 38.5%). In the SCLC dose-expansion cohort, TRAEs occurred in eight patients (88.9%), including thrombocytopenia (66.7%) and anemia (55.6%). In part A, objective response rate (ORR) was 14.8% [95% confidence interval (CI) 8.7-22.9] overall; for the cohorts in which MTD/RP2D for bid dosing and RP2D for qd dosing were determined, ORR was 30.8% (9.1-61.4) and 9.1% (0.2-41.3), respectively. ORR was 11.1% [95% CI 0.3-48.2; one partial response (PR)], disease control rate was 22.2% (2.8-60.0; one PR, one stable disease), and median progression-free survival was 1.5 months (1.3-4.2) in the SCLC dose-expansion cohort.</p><p><strong>Conclusions: </strong>Adverse events and DLTs observed in the bid MTD and once-daily MTD/RP2D dosing schedules were manageable and consistent with known adavosertib and olaparib safety profiles. Limited antitumor activity was observed with adavosertib plus olaparib combination therapy.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov, NCT02511795 (registration: 28 July 2015).</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"879-892"},"PeriodicalIF":4.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11557630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565214","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":"Pancreatitis in Patients with Cancer Receiving Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis.","authors":"Mako Koseki, Yoshito Nishimura, Evelyn Elias, Jonathan Estaris, Fnu Chesta, Kensuke Takaoka, Theresa Shao, Nobuyuki Horita, Yu Fujiwara","doi":"10.1007/s11523-024-01098-1","DOIUrl":"10.1007/s11523-024-01098-1","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) occasionally cause immune-related adverse events (AEs), which pose challenges to the continuation of treatment. Although ICIs are widely used in patients with cancer, studies reporting immune-mediated pancreatitis remain scarce.</p><p><strong>Objectives: </strong>We performed a systematic review and meta-analysis to address current knowledge gaps and provide clinical guidance for ICI-associated pancreatitis and lipase elevation.</p><p><strong>Patients and methods: </strong>We searched PubMed/Medline, Embase, and Web of Science for phase 3 randomized controlled trials (RCTs) evaluating ICIs. The incidence of any-grade and grade 3-5 pancreatitis/lipase elevation was calculated. Then, we performed a random-effect model meta-analysis to pool the odds ratios (ORs) of these outcomes using RCTs evaluating the addition of an ICI to systemic therapy to assess the effect of ICIs on pancreatic AEs. A systematic review of the treatment of ICI-related pancreatitis was also conducted.</p><p><strong>Results: </strong>The incidence analysis included 81 articles (79 RCTs) comprising 36,871 patients. The incidence of treatment-related pancreatitis was 0.68% (any-grade) and 0.32% (grade 3-5). Meta-analysis revealed that the addition of ICI therapy significantly increased any-grade (OR 2.12, 95% confidence interval [CI] 1.45-3.11, p < 0.001) and grade 3-5 pancreatitis (OR 1.76, 95% CI 1.01-3.08, p < 0.05) with low heterogeneity among ICI subtype subgroups (any-grade: I² = 0%, p = 0.99; grade 3-5: I² = 0%, p = 0.63). In analysis of treatment outcome among 146 patients from 53 articles, glucocorticoids were used in 80.6% (n = 108/134) and ICIs were discontinued in 76.5% (n = 101/132; permanent discontinuation: 62.5% [n = 35/56]).</p><p><strong>Conclusions: </strong>The overall rate of pancreatitis appears low, but the addition of ICI therapy significantly increased the incidence of pancreatitis. These findings provide insight into the incidence and treatment of pancreatitis associated with ICIs.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"867-877"},"PeriodicalIF":4.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142401404","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 Epidemiology of Biliary Tract Cancer and Associated Prevalence of MDM2 Amplification: A Targeted Literature Review.","authors":"Jeremy David Kratz, Alyssa Barchet Klein, Courtney Beth Gray, Angela Märten, Hanna-Liisa Vilu, Jennifer Francesca Knight, Alexandra Kumichel, Makoto Ueno","doi":"10.1007/s11523-024-01086-5","DOIUrl":"10.1007/s11523-024-01086-5","url":null,"abstract":"<p><p>Biliary tract cancer (BTC) is a rare and aggressive malignancy that is anatomically classified as gallbladder cancer (GBC), extra- and intra-hepatic cholangiocarcinoma (eCCA and iCCA) and ampullary cancer (AC). BTC is often diagnosed at an advanced stage when treatment options are limited and patients have a poor prognosis, so the identification of new drug targets is of critical importance. BTC is molecularly diverse and harbours different therapeutically actionable biomarkers, including mouse double minute 2 homolog (MDM2), which is currently being investigated as a drug target. The aim of this targeted review was to evaluate and synthesise evidence on the epidemiology of BTC and its subtypes in different geographic regions and on the frequency of MDM2 amplifications in BTC tumours. Epidemiological studies (N = 33) consistently demonstrated high incidence rates in South and Central Asia for BTC overall (up to 9.00/100,000) and for all subtypes, with much lower rates in Europe and the US. Among the different types of BTC, the highest global incidence was observed for CCA, mainly driven by iCCA (1.4/100,000), followed by GBC (1.2/100,000) and AC (0.18-0.93 per 100,000). Studies of MDM2 in BTC (N = 19) demonstrated variable frequency of MDM2 amplification according to subtype, with consistently high MDM2 amplification rates in GBC (up to 17.5%), and lower rates in CCA (up to 4.4%). The results from this literature review highlight the geographic heterogeneity of BTC and the need for standardised clinicopathologic assessment and reporting to allow cross-study comparisons.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"833-844"},"PeriodicalIF":4.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11557622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142296036","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":"Real-World Primary Resistance to First-Line Immune-Based Combinations in Patients with Advanced Renal Cell Carcinoma (ARON-1)","authors":"Daniele Santini, Haoran Li, Giandomenico Roviello, Se Hoon Park, Enrique Grande, Jakub Kucharz, Umberto Basso, Ondrej Fiala, Fernando Sabino Marques Monteiro, Alexandr Poprach, Sebastiano Buti, Javier Molina-Cerrillo, Martina Catalano, Tomas Buchler, Emmanuel Seront, Jawaher Ansari, Zin W. Myint, Marwan Ghosn, Fabio Calabrò, Ray Manneh Kopp, Dipen Bhuva, Maria T. Bourlon, Michela Roberto, Mattia Alberto Di Civita, Veronica Mollica, Andrea Marchetti, Andrey Soares, Nicola Battelli, Marco Ricci, Ravindran Kanesvaran, Aristotelis Bamias, Camillo Porta, Francesco Massari, Matteo Santoni","doi":"10.1007/s11523-024-01096-3","DOIUrl":"https://doi.org/10.1007/s11523-024-01096-3","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Therapeutic advancements based on immuno-oncology combinations have revolutionized the management of patients with renal cell carcinoma. However, patients who have progressive disease as the best response, “primary refractory” (<i>P</i>_ref), face dismal outcomes.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>Our multicenter retrospective real-world study aims to assess the prevalence and clinicopathological characteristics of <i>P</i>_ref patients.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>This study collected data from 72 centers across 22 countries (1709 patients), involving patients aged ≥18 years with metastatic clear cell renal cell carcinoma. All patients were treated with first-line immune-oncology combinations. Data included patient demographics, histology, metastatic sites, and treatment responses. Radiological assessments followed Response Evaluation Criteria in Solid Tumors version 1.1. Statistical analyses employed Kaplan–Meier method, Cox proportional hazard models, logistic regression, and the receiver operating characteristic curve.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>In our study, the <i>P</i>_ref rate was 19%. Nivolumab/ipilimumab showed the highest <i>P</i>_ref rate (27%), while pembrolizumab/lenvatinib exhibited the lowest (10%). Primary refactory patients demonstrated significantly lower median overall survival (7.6 months) compared with non-<i>P</i>_ref patients (55.7 months), <i>p</i> &lt; 0.001. At the multivariate analysis, nephrectomy, sarcomatoid de-differentiation, intermediate/poor International Metastatic RCC Database Consortium risk, and bone and brain metastases emerged as significant predictors of overall survival for <i>P</i>_ref patients with renal cell carcinoma. Logistic regression showed a significant relationship between liver metastases, intermediate/poor International Metastatic RCC Database Consortium risk, and no surgery and an increased risk of <i>P</i>_ref. This study presents limitations, mainly because of its retrospective design.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>The ARON-1 study provides valuable insights into <i>P</i>_ref patients, emphasizing the challenges of this precociously resistant subgroup. Identified predictors could guide risk stratification, aiding clinicians in tailored therapeutic approaches.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":"40 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142257954","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":"Evaluation of Drug–Drug Interaction Potential of Talquetamab, a T-Cell-Redirecting GPRC5D × CD3 Bispecific Antibody, as a Result of Cytokine Release Syndrome in Patients with Relapsed/Refractory Multiple Myeloma in MonumenTAL-1, Using a Physiologically Based Pharmacokinetic Model","authors":"Marie-Emilie Willemin, Jue Gong, Brandi W. Hilder, Tara Masterson, Jaszianne Tolbert, Thomas Renaud, Christoph Heuck, Colleen Kane, Loeckie De Zwart, Suzette Girgis, Xuewen Ma, Daniele Ouellet","doi":"10.1007/s11523-024-01093-6","DOIUrl":"https://doi.org/10.1007/s11523-024-01093-6","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Background&lt;/h3&gt;&lt;p&gt;Cytokine release syndrome, commonly associated with T-cell immunotherapies, was observed with talquetamab, a T-cell-redirecting bispecific antibody, in the phase I/II MonumenTAL-1 study, leading to elevated interleukin (IL)-6, which can suppress cytochrome P450 (CYP) enzyme activity.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Objective&lt;/h3&gt;&lt;p&gt;We aimed to evaluate the potential impact of elevated IL-6 on the exposure of co-administered CYP450 substrates for two scenarios: (1) the observed median IL-6 profile and (2) a profile with the highest IL-6 maximum concentration following talquetamab treatment.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;A physiologically based pharmacokinetic model was developed based on the literature and simulations performed using observed IL-6 profiles from patients in MonumenTAL-1 who received the subcutaneous recommended phase 2 doses (RP2Ds) of talquetamab: 0.4 mg/kg weekly (QW) and 0.8 mg/kg every other week (Q2W).&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;Median IL-6 maximum concentration was 18.4 and 7.1 pg/mL, and maximum IL-6 maximum concentration was 213 and 3503 pg/mL for talquetamab QW and Q2W RP2Ds, respectively. For the median IL-6 profile, no interaction between IL-6 and studied CYP substrates was predicted at either RP2D. The maximum IL-6 profile predicted weak-to-moderate impact on exposure of CYP2C19, CYP3A4, and CYP3A5 substrates and minimal impact on exposure of CYP1A2 substrates at both RP2Ds. Impact on exposure of CYP2C9 substrates was predicted as minimal at QW and minimal-to-weak at Q2W RP2Ds. Time to return to 20% difference from baseline enzymatic activity was predicted as 7 and 9 days after start of cycle 1 for QW and Q2W RP2Ds, respectively.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Conclusions&lt;/h3&gt;&lt;p&gt;These modeling results suggest that IL-6 release due to talquetamab-induced cytokine release syndrome has limited impact on potential drug–drug interactions, with the highest likelihood of impact occurring from initiation of talquetamab step-up dosing up to 7 (QW) or 9 (Q2W) days after first treatment dose in cycle 1 and during and after cytokine release syndrome.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Plain Language Summary&lt;/h3&gt;&lt;p&gt;Multiple myeloma can be treated with immunotherapies such as the bispecific antibody, talquetamab, which binds the novel antigen G protein-coupled receptor family C group 5 member D on multiple myeloma cells and CD3 on T cells and induces T-cell-mediated lysis of multiple myeloma cells. Following talquetamab treatment, many patients experience cytokine release syndrome, an inflammatory immune response where levels of proinflammatory cytokines, including interleukin (IL)-6, are increased. Interleukin-6 can suppress the activity of important enzymes in the body (cytochrome [CYP] P450s) that are involved in drug clearance. This study used a physiologically based pharmacokinetic computer model to i","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":"22 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142257955","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":"Diffuse Gastric Cancer: A Comprehensive Review of Molecular Features and Emerging Therapeutics","authors":"Lawrence W. Wu, Sung Joo Jang, Cameron Shapiro, Ladan Fazlollahi, Timothy C. Wang, Sandra W. Ryeom, Ryan H. Moy","doi":"10.1007/s11523-024-01097-2","DOIUrl":"https://doi.org/10.1007/s11523-024-01097-2","url":null,"abstract":"<p>Diffuse-type gastric cancer (DGC) accounts for approximately one-third of gastric cancer diagnoses but is a more clinically aggressive disease with peritoneal metastases and inferior survival compared with intestinal-type gastric cancer (IGC). The understanding of the pathogenesis of DGC has been relatively limited until recently. Multiomic studies, particularly by The Cancer Genome Atlas, have better characterized gastric adenocarcinoma into molecular subtypes. DGC has unique molecular features, including alterations in <i>CDH1</i>, <i>RHOA</i>, and <i>CLDN18-ARHGAP26</i> fusions. Preclinical models of DGC characterized by these molecular alterations have generated insight into mechanisms of pathogenesis and signaling pathway abnormalities. The currently approved therapies for treatment of gastric cancer generally provide less clinical benefit in patients with DGC. Based on recent phase II/III clinical trials, there is excitement surrounding Claudin 18.2-based and FGFR2b-directed therapies, which capitalize on unique biomarkers that are enriched in the DGC populations. There are numerous therapies targeting Claudin 18.2 and FGFR2b in various stages of preclinical and clinical development. Additionally, there have been preclinical advancements in exploiting unique therapeutic vulnerabilities in several models of DGC through targeting of the focal adhesion kinase (FAK) and Hippo pathways. These preclinical and clinical advancements represent a promising future for the treatment of DGC.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":"82 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142257956","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":"Correction to: Moving T‑Cell Therapies into the Standard of Care for Patients with Relapsed or Refractory Follicular Lymphoma: A Review.","authors":"Nathan Hale Fowler, Julio C Chavez, Peter A Riedell","doi":"10.1007/s11523-024-01085-6","DOIUrl":"10.1007/s11523-024-01085-6","url":null,"abstract":"","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"817"},"PeriodicalIF":4.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11392971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141724568","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":"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}