2f:I[703058,["/_next/static/immutable/chunks/3bhq_5eh1d760.js","/_next/static/immutable/chunks/2iy5wruuedsh6.js","/_next/static/immutable/chunks/2pfsjpn6k6zlg.js","/_next/static/immutable/chunks/26c7v3_3uwnwu.js","/_next/static/immutable/chunks/00yc7rcvua6a7.js","/_next/static/immutable/chunks/37ktb71aq3480.js","/_next/static/immutable/chunks/2d50b-7eu4558.js","/_next/static/immutable/chunks/06_yt270h41rg.js","/_next/static/immutable/chunks/2d6noqpp6ehas.js","/_next/static/immutable/chunks/1sx186c93bpzg.js","/_next/static/immutable/chunks/3dc-1n866s65i.js","/_next/static/immutable/chunks/20x2y96ldu5wx.js","/_next/static/immutable/chunks/2w1bvggzb0ga8.js","/_next/static/immutable/chunks/2051ffx3xzio9.js"],"PaperListPageClient"] 30:T657,Radiation therapy (RT) remains a cornerstone of management for metastatic breast cancer (mBC), though systemic therapy drives overall disease control. Administering RT concomitantly with systemic treatment may raise concerns regarding toxicity. This multicentre retrospective study evaluated the safety of trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate, when delivered alongside RT. Data from six European centres were analysed. Concomitancy was defined as RT administered during T-DXd or within 10 days of a treatment cycle. The primary endpoint was the incidence of grade ≥3 adverse events (AEs). Exploratory endpoints included progression-free survival (PFS) and overall survival (OS). A total of 147 patients were included; 67 received concomitant RT (71 courses) and 80 received T-DXd alone. Median age was 49 years (range 25-85). The central nervous system was the most frequent RT site (54.9 %). Grade ≥3 AEs occurred in 24 patients (16.3 %), with no significant difference between RT and no-RT cohorts (11.9 % vs 20.0 %; p = 0.30). Permanent T-DXd discontinuation due to toxicity occurred in 19 patients (12.9 %), with similar rates in the RT and no-RT groups (11.9 % vs 13.8 %). One case of symptomatic radionecrosis was observed after intracranial RT. Exploratory analyses showed no adverse effect of concomitant RT on PFS or OS. Concomitant administration of T-DXd and RT appears feasible and well tolerated, without increased risk of severe or treatment-limiting toxicity. These real-world findings support the safety of this combination and warrant confirmation in prospective studies.31:T699,Abstract Trastuzumab Deruxtecan (T-DXd) is clinically beneficial in HER2-positive and HER2-low metastatic breast cancer. However, therapeutic resistance emerges over time in most patients, with poorly defined resistance mechanisms. Through a molecular characterization of paired patient specimens before and after T-DXd treatment, we found that 49% cases had major decreases in HER2 expression at progression, and among them, 52% exhibited complete HER2 loss. Using isogenic model systems, we demonstrated that decreases in HER2 expression corresponded to reductions in T-DXd internalization and major increases in drug IC50 value for tumor growth inhibition. We further identified and validated ERBB2 mutations in the trastuzumab binding interface (V597M and P593R) that promoted T-DXd resistance. As a strategy to overcome impaired T-DXd binding and internalization, we tested low-dose combinations of T-DXd with TROP2-directed antibody–drug conjugates (ADC) and found that these could more uniformly deliver DXd payloads and thereby overcome resistance mediated by HER2 loss. Significance: The mechanisms underlying clinical T-DXd resistance have not been established. We now report on two mechanisms of resistance that converge on loss of target binding and propose combinations of distinct ADCs with shared payloads as a strategy to overcome resistance by enhancing intratumor delivery. 25:[[["$","script","0",{"type":"application/ld+json","dangerouslySetInnerHTML":{"__html":"{\"@context\":\"https://schema.org\",\"@type\":\"CollectionPage\",\"name\":\"trastuzumab deruxtecan: generic Research & Clinical Takeaways\",\"description\":\"Explore peer-reviewed papers on trastuzumab deruxtecan (generic). Clinician-written summaries and actionable practice insights. 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Organizing pneumonia was the dominant imaging pattern (67.7%); diffuse alveolar damage (DAD, 12.6%) was the most common pattern in fatal cases (26/30). Overall recovery rate was 83.5%, and 79.3% of corticosteroid-treated patients responded; high-dose steroids plus immunosuppressants were ineffective in 7 DAD cases.","limitations":"- Japanese-only population limits generalizability to non-Asian patients.\n- Post-marketing surveillance design lacks a control arm and may have variable case ascertainment.\n- Post hoc analysis; outcomes followed only up to 12 months from ILD onset.","practice_takeaway":"Monitor all patients on T-DXd continuously for ILD — there is no safe window, including beyond 12 months of therapy. Prompt corticosteroid initiation is effective for most cases, but DAD pattern carries high mortality and does not reliably respond to intensified immunosuppression."}},{"doi":"10.1016/s2213-2600(26)00253-5","pmid":"42702211","title":"Targeted therapies in advanced non-small-cell lung cancer: new biomarkers and treatment strategies","journal_title":"The Lancet Respiratory Medicine","journal_issn":"2213-2600","published_at":"2026-09-06T00:00:00.000Z","url":"https://doi.org/10.1016/s2213-2600(26)00253-5","source_score":20,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-09-12T06:20:02.915Z","updated_at":"2026-09-12T06:20:02.915Z","tags":[{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"brand","value":"Alecensa","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"brand","value":"Enhertu","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"brand","value":"Krazati","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"brand","value":"Lorbrena","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"brand","value":"Lumakras","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"brand","value":"Rybrevant","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"brand","value":"Tagrisso","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"category","value":"Respiratory System","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"condition","value":"Non-Small-Cell Lung Cancer","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"generic","value":"adagrasib","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"generic","value":"alectinib","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"generic","value":"amivantamab","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"generic","value":"capmatinib","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"generic","value":"dabrafenib","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"generic","value":"lazertinib","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"generic","value":"lorlatinib","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"generic","value":"osimertinib","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"generic","value":"pralsetinib","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"generic","value":"repotrectinib","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"generic","value":"sacituzumab tirumotecan","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"generic","value":"selpercatinib","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"generic","value":"sotorasib","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"generic","value":"tepotinib","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"generic","value":"trametinib","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"generic","value":"trastuzumab deruxtecan","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"generic","value":"zenocutuzumab","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"level_of_evidence","value":"5","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"modality","value":"Antibody-Drug Conjugate","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"modality","value":"Bispecific Antibody","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"modality","value":"Tyrosine Kinase Inhibitor","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"study_design","value":"Narrative Review","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"warning","value":"Full text was paywalled and not available; all structured data are derived from the abstract, reference list, and publisher page only — specific trial outcomes, hazard ratios, and patient-level data could not be verified.","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"warning","value":"Sex of the studied population is not reported in the available abstract text and was omitted from tags.","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"warning","value":"Study design classified as 'Narrative Review'; level of evidence set to 5 accordingly. No single sample size applies to this review.","value_numeric":null},{"paper_doi":"10.1016/s2213-2600(26)00253-5","tag_type":"warning","value":"This is a narrative review series paper, not a primary study; the 'practice_changing' impact flag reflects the breadth of evidence synthesized across multiple approved therapies, not a single trial result.","value_numeric":null}],"summaries":{"what_studied":"This review (second in a Lancet Respiratory Medicine series) summarizes the current landscape of biomarker-matched targeted therapies in advanced NSCLC, covering established drivers (EGFR, ALK, ROS1, KRAS, BRAF, RET, HER2, MET, NTRK) and emerging targets (NRG1 fusions, MTAP loss, SMARCA4 deficiency), including newer TKI generations, bispecific antibodies, and antibody-drug conjugates (ADCs).","key_result":"Across established drivers, next-generation TKIs, bispecific antibodies (e.g., amivantamab–lazertinib), and ADCs (e.g., trastuzumab deruxtecan, sacituzumab tirumotecan) have improved response durability, intracranial disease control, and in some settings overall survival; however, acquired resistance, tumor heterogeneity, lineage plasticity, and off-target escape remain key barriers to durable benefit.","limitations":"Full text was not accessible — the summary is based solely on the abstract and reference list, which limits extraction of specific outcome data, patient numbers, and granular trial results. This is a narrative review series paper, not a primary study, so no single efficacy estimate applies.","practice_takeaway":"For advanced NSCLC, comprehensive upfront molecular profiling and timely biomarker testing are essential, as an expanding number of drivers now have matched therapies that outperform chemotherapy. Repeat tissue biopsy or circulating-tumor DNA testing at progression is increasingly important to identify actionable resistance mechanisms and guide next-line therapy."}},{"doi":"10.1007/s12282-026-01908-6","pmid":"42684568","title":"Real-world outcomes of datopotamab deruxtecan after trastuzumab deruxtecan in hormone receptor–positive, HER2-negative metastatic breast cancer","journal_title":"Breast Cancer","journal_issn":"1340-6868","published_at":"2026-09-02T00:00:00.000Z","url":"https://doi.org/10.1007/s12282-026-01908-6","source_score":4,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-09-05T06:20:05.116Z","updated_at":"2026-09-05T06:20:05.116Z","tags":[{"paper_doi":"10.1007/s12282-026-01908-6","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1007/s12282-026-01908-6","tag_type":"brand","value":"Datroway","value_numeric":null},{"paper_doi":"10.1007/s12282-026-01908-6","tag_type":"brand","value":"Enhertu","value_numeric":null},{"paper_doi":"10.1007/s12282-026-01908-6","tag_type":"category","value":"Obstetrics & Gynecology","value_numeric":null},{"paper_doi":"10.1007/s12282-026-01908-6","tag_type":"condition","value":"Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer","value_numeric":null},{"paper_doi":"10.1007/s12282-026-01908-6","tag_type":"generic","value":"datopotamab deruxtecan","value_numeric":null},{"paper_doi":"10.1007/s12282-026-01908-6","tag_type":"generic","value":"trastuzumab deruxtecan","value_numeric":null},{"paper_doi":"10.1007/s12282-026-01908-6","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1007/s12282-026-01908-6","tag_type":"level_of_evidence","value":"4","value_numeric":null},{"paper_doi":"10.1007/s12282-026-01908-6","tag_type":"modality","value":"Antibody-Drug Conjugate","value_numeric":null},{"paper_doi":"10.1007/s12282-026-01908-6","tag_type":"sample_size","value":"n=45","value_numeric":45},{"paper_doi":"10.1007/s12282-026-01908-6","tag_type":"sex","value":"female","value_numeric":null},{"paper_doi":"10.1007/s12282-026-01908-6","tag_type":"study_design","value":"Retrospective Cohort Study","value_numeric":null},{"paper_doi":"10.1007/s12282-026-01908-6","tag_type":"warning","value":"Brand name 'Datroway' (FDA-approved name for datopotamab deruxtecan) used; paper uses non-proprietary name only.","value_numeric":null},{"paper_doi":"10.1007/s12282-026-01908-6","tag_type":"warning","value":"Sex not explicitly reported as female-only in the paper, but breast cancer context and no mention of male patients strongly implies a female cohort — tagged as female with low uncertainty.","value_numeric":null},{"paper_doi":"10.1007/s12282-026-01908-6","tag_type":"warning","value":"Study is from a single Japanese cancer center, which may limit generalizability to other practice settings and ethnic populations.","value_numeric":null},{"paper_doi":"10.1007/s12282-026-01908-6","tag_type":"warning","value":"The T-DXd-naïve group median TTF had an extremely wide 95% CI (0.3–8.3 months), indicating high uncertainty in that subgroup estimate.","value_numeric":null}],"summaries":{"what_studied":"This single-center retrospective study evaluated real-world efficacy of datopotamab deruxtecan (Dato-DXd) in 45 heavily pretreated patients with HR+/HER2− metastatic breast cancer (median 6 prior lines), comparing outcomes in 19 patients with prior T-DXd exposure vs. 26 T-DXd-naïve patients.","key_result":"Overall DCR was 57.8% and ORR 24.4%; in the prior T-DXd group, DCR was 52.6% and ORR 10.5%, with median TTF 3.4 months and median PFS 3.0 months. In T-DXd-naïve patients, DCR was 61.5%, ORR 34.6%, and median PFS 5.1 months. Among 16 patients with evaluable prior T-DXd TTF data, 5 (31.3%) had a longer TTF with Dato-DXd than with prior T-DXd.","limitations":"- Small single-center cohort (n=45) limits generalizability and statistical power; wide CIs reflect substantial uncertainty.\n- Prior T-DXd group was more heavily pretreated (2 additional chemotherapy lines), making unadjusted between-group comparisons prone to confounding.\n- No comparator arm; relative efficacy of Dato-DXd vs. other post-T-DXd options is unknown.","practice_takeaway":"Dato-DXd can yield disease control in over half of patients previously treated with T-DXd, but response rates and PFS are modest—clinicians should counsel patients on limited but real benefit in this heavily pretreated setting. The ongoing TRADE-DXd trial (NCT06533826) will provide prospective sequencing data."}},{"doi":"10.1016/j.breast.2026.104902","pmid":"42612559","title":"Beyond safety: rethinking concomitant radiotherapy and trastuzumab deruxtecan in metastatic breast cancer — from feasibility to precision practice","journal_title":"The Breast","journal_issn":"0960-9776","published_at":"2026-08-12T00:00:00.000Z","url":"https://doi.org/10.1016/j.breast.2026.104902","source_score":1,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-08-22T06:53:24.722Z","updated_at":"2026-08-22T06:53:24.722Z","tags":[{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"brand","value":"Enhertu","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"category","value":"Obstetrics & Gynecology","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"condition","value":"HER2-Low Breast Cancer","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"condition","value":"Metastatic Breast Cancer","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"generic","value":"trastuzumab deruxtecan","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"generic","value":"trastuzumab emtansine","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"level_of_evidence","value":"7","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"modality","value":"Antibody-Drug Conjugate","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"modality","value":"Radiotherapy","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"study_design","value":"Expert Opinion / Viewpoint","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"warning","value":"HER2-low metastatic breast cancer is discussed as a subgroup of interest but no outcome data specific to this population are presented.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"warning","value":"No sample size is applicable — the 'largest real-world evidence' cited belongs to the Visani et al. study being critiqued, not this paper.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"warning","value":"Study design classification as 'Expert Opinion / Viewpoint' is inferred from abstract language; the journal section label is not explicitly stated.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"warning","value":"This is a viewpoint/commentary with no original patient data; findings are opinion-based and reference a single real-world study (Visani et al.) not reproduced here.","value_numeric":null}],"summaries":{"what_studied":"This viewpoint critiques and extends real-world evidence on the safety of concomitant trastuzumab deruxtecan (T-DXd) and radiotherapy (RT) in metastatic breast cancer, arguing for stratified decision-making beyond binary safety assessments across RT intent, site, fractionation, and tumor biology.","key_result":"The authors contend that 'concomitant' is not a sufficient biological concept; radiosensitization risk varies by RT site, fractionation, and payload (distinguishing T-DM1 vs. T-DXd radionecrosis profiles), and three high-priority gaps remain: thoracic irradiation safety, HER2-low metastatic breast cancer, and cardiac vulnerability during combined therapy.","limitations":"This is an expert viewpoint/commentary — no original patient data, no comparator arm, and no quantitative outcomes are reported. Conclusions are largely opinion-based and derive from critique of a single referenced real-world study.","practice_takeaway":"Do not treat all concomitant T-DXd + RT combinations as equivalent; stratify decisions by anatomical site, fractionation schedule, and HER2 status. Treat thoracic irradiation and cardiac exposure during combined therapy as priority areas requiring extra caution until prospective data are available."}},{"doi":"10.1016/j.breast.2026.104883","pmid":null,"title":"Trastuzumab Deruxtecan Rechallenge in HER2-Positive Metastatic Breast Cancer: EN-SEMBLE","journal_title":"The Breast","journal_issn":"0960-9776","published_at":"2026-07-22T00:00:00.000Z","url":"https://doi.org/10.1016/j.breast.2026.104883","source_score":9,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":false,"crossref":true,"unpaywall":true},"created_at":"2026-07-27T14:09:16.677Z","updated_at":"2026-07-27T14:09:16.677Z","tags":[{"paper_doi":"10.1016/j.breast.2026.104883","tag_type":"brand","value":"Enhertu","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104883","tag_type":"category","value":"Obstetrics & Gynecology","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104883","tag_type":"condition","value":"HER2-Positive Metastatic Breast Cancer","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104883","tag_type":"generic","value":"trastuzumab deruxtecan","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104883","tag_type":"modality","value":"Antibody-Drug Conjugate","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104883","tag_type":"study_design","value":"Clinical Trial","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104883","tag_type":"warning","value":"The paper metadata provided contains only the title, DOI, journal, and publication date — no abstract, methods, results, or full text were supplied. All summary fields requiring study details (key results, limitations, practice takeaway, sample size, sex, age group, level of evidence, impact flag) cannot be determined and have been omitted or set to null to avoid speculation. Full extraction should be repeated once the paper text is available.","value_numeric":null}],"summaries":{"what_studied":"The EN-SEMBLE study evaluated trastuzumab deruxtecan (T-DXd) rechallenge in patients with HER2-positive metastatic breast cancer who had previously received and progressed on T-DXd."}},{"doi":"10.1016/j.jhep.2026.02.030","pmid":null,"title":"Systemic therapy of biliary tract cancer: The road to personalised strategies","journal_title":"Journal of Hepatology","journal_issn":"0168-8278","published_at":"2026-07-02T00:00:00.000Z","url":"https://doi.org/10.1016/j.jhep.2026.02.030","source_score":11,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":false,"crossref":true,"unpaywall":true},"created_at":"2026-07-07T13:26:09.823Z","updated_at":"2026-07-07T13:26:09.823Z","tags":[{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"brand","value":"Enhertu","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"brand","value":"Lytgobi","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"brand","value":"Pemazyre","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"brand","value":"Tibsovo","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"category","value":"Gastroenterology & Hepatology","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"condition","value":"Ampullary Cancer","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"condition","value":"Biliary Tract Cancer","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"condition","value":"Cholangiocarcinoma","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"condition","value":"Gallbladder Cancer","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"generic","value":"dabrafenib","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"generic","value":"durvalumab","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"generic","value":"entrectinib","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"generic","value":"futibatinib","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"generic","value":"ivosidenib","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"generic","value":"larotrectinib","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"generic","value":"lirafugratinib","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"generic","value":"neratinib","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"generic","value":"pembrolizumab","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"generic","value":"pemigatinib","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"generic","value":"selpercatinib","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"generic","value":"tinengotinib","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"generic","value":"trametinib","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"generic","value":"trastuzumab deruxtecan","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"generic","value":"tucatinib","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"generic","value":"zanidatamab","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"level_of_evidence","value":"5","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"modality","value":"Antibody-Drug Conjugate","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"modality","value":"BRAF/MEK Inhibitor","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"modality","value":"FGFR Inhibitor","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"modality","value":"HER2-Targeted Therapy","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"modality","value":"IDH1 Inhibitor","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"modality","value":"Immune Checkpoint Inhibitor","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"study_design","value":"Narrative Review","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"warning","value":"HER2 IHC scoring in BTC is extrapolated from breast/gastric cancer criteria — no BTC-specific validated system exists, which may affect patient selection in practice.","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"warning","value":"Several referenced trials (FIGHT-302, FOENIX-CCA3) were terminated early due to low accrual; results for some are still pending as of publication date.","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"warning","value":"Some emerging targets (MTAP, MDM2, MET, RAS) are represented only by early-phase or case-series data; these should not be considered standard of care.","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"warning","value":"The paper's DOI suggests a 2026 publication date, which is consistent with today's date; some cited references are also from 2025–2026 and may not yet be widely available.","value_numeric":null},{"paper_doi":"10.1016/j.jhep.2026.02.030","tag_type":"warning","value":"This is a narrative review (not a systematic review or meta-analysis); clinical outcome data cited are from individual trials with varying designs and patient populations.","value_numeric":null}],"summaries":{"what_studied":"This review covers the evolving systemic therapy landscape of biliary tract cancer (BTC), including cholangiocarcinoma, gallbladder cancer, and ampullary cancer, with a focus on chemo-immunotherapy as first-line standard of care and precision oncology strategies targeting FGFR2 fusions, IDH1 mutations, HER2 alterations, and tumour-agnostic biomarkers (BRAF V600E, MSI-H/dMMR, RET/NTRK/NRG1 fusions).","key_result":"Chemo-immunotherapy (CisGem + durvalumab or pembrolizumab) is now first-line standard of care; approved targeted agents include pemigatinib (ORR 37%, mPFS 7.0 mo, mOS 17.5 mo) and futibatinib (ORR 42%, mPFS 9.0 mo, mOS 21.7 mo) for FGFR2 fusion+ iCCA, ivosidenib for IDH1-mutant CCA (mOS 10.3 mo vs. 7.5 mo placebo, crossover-adjusted HR 0.49), and zanidatamab for HER2 IHC3+ BTC (ORR 41.3%, mOS 15.5 mo); lirafugratinib shows promising next-gen FGFR2 selectivity (ORR 47%, mPFS 11.3 mo, mOS 22.8 mo).","limitations":"- All targeted therapy approvals are in previously treated patients only; no first-line phase III targeted therapy trial has completed successfully (three closed early due to low accrual).\n- Biomarker testing is heterogeneous and incompletely standardised, with up to 25% of tissue samples failing NGS; no BTC-specific HER2 IHC scoring system exists.\n- This is a narrative review without systematic methods or meta-analysis; cross-trial comparisons are confounded by differing patient populations and the potential prognostic effect of molecular subtypes.","practice_takeaway":"All patients with advanced BTC should receive hybrid-capture DNA/RNA NGS at diagnosis to identify actionable alterations (FGFR2 fusions, IDH1 mutations, HER2 status, and tumour-agnostic targets) before second-line therapy decisions are made. In the absence of a targetable alteration, CisGem plus durvalumab or pembrolizumab is first-line standard of care; when actionable alterations are found, approved targeted agents should be prioritised over second-line chemotherapy."}},{"doi":"10.1016/j.breast.2026.104853","pmid":"42398129","title":"Antibody–drug conjugates beyond HER2: Translating evidence into practice for HR+ HER2-negative and triple-negative metastatic breast cancer","journal_title":"The Breast","journal_issn":"0960-9776","published_at":"2026-06-30T00:00:00.000Z","url":"https://doi.org/10.1016/j.breast.2026.104853","source_score":11,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-07-11T13:32:58.677Z","updated_at":"2026-07-11T13:32:58.677Z","tags":[{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"brand","value":"Enhertu","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"brand","value":"Trodelvy","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"category","value":"Obstetrics & Gynecology","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"condition","value":"HR-Positive HER2-Negative Breast Cancer","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"condition","value":"Metastatic Breast Cancer","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"condition","value":"Triple-Negative Breast Cancer","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"generic","value":"datopotamab deruxtecan","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"generic","value":"pembrolizumab","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"generic","value":"sacituzumab govitecan","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"generic","value":"sacituzumab tirumotecan","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"generic","value":"trastuzumab deruxtecan","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"level_of_evidence","value":"5","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"modality","value":"Antibody-Drug Conjugate","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"modality","value":"HER2-Targeted ADC","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"modality","value":"Immune Checkpoint Inhibitor","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"modality","value":"TROP2-Targeted ADC","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"sex","value":"female","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"study_design","value":"Narrative Review","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"warning","value":"No brand name tags added for Dato-DXd or sac-TMT as they lack widely established proprietary names in Western markets at time of publication.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"warning","value":"Sac-TMT (sacituzumab tirumotecan) is approved only in China as of the publication date; its safety data derive exclusively from East Asian populations and may not generalize to Western patients.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"warning","value":"Sample size tag omitted: this is a review article aggregating multiple trials with no single overall N.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"warning","value":"The paper is published June 2026; some trial data cited (e.g., ASCENT-03, ASCENT-04, TROPION-Breast02 OS) were recently presented and may have been updated since publication.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"warning","value":"This is a narrative review with multiple authors disclosing financial relationships with manufacturers of the reviewed agents (AstraZeneca/Daiichi Sankyo, Gilead, MSD, Pfizer, Novartis, among others); potential influence on recommendations should be considered.","value_numeric":null}],"summaries":{"what_studied":"This narrative review synthesizes clinical trial evidence for four ADCs—trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), datopotamab deruxtecan (Dato-DXd), and sacituzumab tirumotecan (sac-TMT)—in HR+/HER2-negative and triple-negative metastatic breast cancer, covering mechanisms, efficacy, toxicity management, biomarkers, and sequencing strategies.","key_result":"All four ADCs improved PFS vs chemotherapy in their pivotal phase 3 trials. Key highlights include: T-DXd vs chemo in chemotherapy-naïve HR+/HER2-low mBC (PFS 13.2 vs 8.1 months; HR 0.62); SG vs chemo in pretreated HR+ mBC (OS 14.4 vs 11.2 months; HR 0.79); Dato-DXd vs chemo in first-line TNBC (OS 23.7 vs 18.7 months; HR 0.79); sac-TMT vs chemo in pretreated HR+ mBC (PFS 8.3 vs 4.1 months; HR 0.35). SG plus pembrolizumab improved PFS over chemo plus pembrolizumab in first-line PD-L1–positive TNBC (11.2 vs 7.8 months; HR 0.65).","limitations":"- All cross-ADC comparisons are indirect; no head-to-head randomized trials exist between ADCs.\n- Sac-TMT data derive exclusively from East Asian populations, limiting generalizability to Western patients.\n- Most sequencing and biomarker data (including post-ADC outcomes) come from retrospective analyses with small samples and selection bias.","practice_takeaway":"For HR+/HER2-low or ultralow mBC after CDK4/6 inhibitor progression, T-DXd is preferred when ADC therapy is indicated, especially with symptomatic or rapidly progressing disease; SG or Dato-DXd are alternatives for HER2-null tumors. In first-line TNBC, SG plus pembrolizumab is the preferred option for PD-L1–positive disease, while Dato-DXd monotherapy is an emerging option for PD-L1–negative or immunotherapy-ineligible patients—clinicians should individualize ADC choice based on HER2 status, toxicity profile (ILD risk with T-DXd, neutropenia/diarrhea with SG, stomatitis with Dato-DXd/sac-TMT), and infusion logistics."}},{"doi":"10.1158/2159-8290.cd-25-1459","pmid":"41925564","title":"HER2 Heterogeneous Breast Cancer Models Reveal Novel Therapeutic Targets and Subclonal Dynamics during Evolution to Resistance to HER2-Targeted Therapies","journal_title":"Cancer Discovery","journal_issn":"2159-8274","published_at":"2026-06-17T00:00:00.000Z","url":"https://doi.org/10.1158/2159-8290.cd-25-1459","source_score":32,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-06-20T13:25:04.149Z","updated_at":"2026-06-20T13:25:04.149Z","tags":[{"paper_doi":"10.1158/2159-8290.cd-25-1459","tag_type":"brand","value":"Enhertu","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-1459","tag_type":"category","value":"Oncology","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-1459","tag_type":"condition","value":"HER2-Positive Breast Cancer","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-1459","tag_type":"condition","value":"Intratumor Heterogeneity","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-1459","tag_type":"generic","value":"trastuzumab deruxtecan","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-1459","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-1459","tag_type":"level_of_evidence","value":"6","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-1459","tag_type":"modality","value":"Antibody-Drug Conjugate","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-1459","tag_type":"modality","value":"CRISPR Screen","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-1459","tag_type":"modality","value":"HER2 Kinase Inhibitor","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-1459","tag_type":"modality","value":"USP9X Inhibitor","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-1459","tag_type":"study_design","value":"Preclinical Laboratory Study","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-1459","tag_type":"warning","value":"No sample size (N) is reportable as this is a cell/model-based study without a defined patient cohort.","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-1459","tag_type":"warning","value":"Study design is categorized as 'Preclinical Laboratory Study'; no standard RCT or observational design applies.","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-1459","tag_type":"warning","value":"T-DXd is listed under its brand name 'Enhertu' (trastuzumab deruxtecan); the paper uses the abbreviation 'T-DXd' throughout.","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-1459","tag_type":"warning","value":"The impact_flag 'practice_changing' reflects the novelty of the USP9X finding and its therapeutic implications, but this is entirely preclinical — no patient data are presented; clinical translation is speculative at this stage.","value_numeric":null}],"summaries":{"limitations":"Findings are from preclinical (in vitro/cell line) models only — clinical validation in patients is lacking; models may not fully capture the spatial and clonal complexity of HER2 heterogeneity in human tumors.","practice_takeaway":"HER2 intratumor heterogeneity is a key driver of T-DXd resistance; USP9X inhibition is a candidate strategy to re-sensitize HER2lo clones to T-DXd and warrants clinical investigation. Clinicians should consider HER2 heterogeneity when sequencing or combining HER2-targeted therapies.","what_studied":"This preclinical study used human HER2-heterogeneous breast cancer models (paired ERBB2-amplified HER2hi and non-amplified HER2lo cell populations from the same tumor) with cellular barcoding and CRISPR screens to map subclonal dynamics and identify resistance mechanisms to HER2-targeted ADCs (T-DXd) and kinase inhibitors.","key_result":"HER2lo subpopulations drove resistance to T-DXd but remained sensitive to HER2 kinase inhibitors; CRISPR screens identified ABCC1 and USP9X as T-DXd sensitizers in HER2lo cells, and USP9X inhibition enhanced lysosomal HER2 targeting, boosting ADC payload release and reducing tumor recurrence after T-DXd treatment."}},{"doi":"10.1016/j.clgc.2026.102583","pmid":null,"title":"Targeting HER2 in urothelial carcinoma: why histologic subtypes and divergent histologies matter","journal_title":"Clinical Genitourinary Cancer","journal_issn":"1558-7673","published_at":"2026-05-18T00:00:00.000Z","url":"https://doi.org/10.1016/j.clgc.2026.102583","source_score":10,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":false,"crossref":true,"unpaywall":true},"created_at":"2026-05-23T13:24:43.995Z","updated_at":"2026-05-23T13:24:43.995Z","tags":[{"paper_doi":"10.1016/j.clgc.2026.102583","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1016/j.clgc.2026.102583","tag_type":"brand","value":"Aidixi","value_numeric":null},{"paper_doi":"10.1016/j.clgc.2026.102583","tag_type":"brand","value":"Enhertu","value_numeric":null},{"paper_doi":"10.1016/j.clgc.2026.102583","tag_type":"category","value":"Urology & Nephrology","value_numeric":null},{"paper_doi":"10.1016/j.clgc.2026.102583","tag_type":"condition","value":"Micropapillary Urothelial Carcinoma","value_numeric":null},{"paper_doi":"10.1016/j.clgc.2026.102583","tag_type":"condition","value":"Plasmacytoid Urothelial Carcinoma","value_numeric":null},{"paper_doi":"10.1016/j.clgc.2026.102583","tag_type":"condition","value":"Sarcomatoid Urothelial Carcinoma","value_numeric":null},{"paper_doi":"10.1016/j.clgc.2026.102583","tag_type":"condition","value":"Urothelial Carcinoma","value_numeric":null},{"paper_doi":"10.1016/j.clgc.2026.102583","tag_type":"generic","value":"disitamab vedotin","value_numeric":null},{"paper_doi":"10.1016/j.clgc.2026.102583","tag_type":"generic","value":"trastuzumab deruxtecan","value_numeric":null},{"paper_doi":"10.1016/j.clgc.2026.102583","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1016/j.clgc.2026.102583","tag_type":"level_of_evidence","value":"7","value_numeric":null},{"paper_doi":"10.1016/j.clgc.2026.102583","tag_type":"modality","value":"Antibody-Drug Conjugate","value_numeric":null},{"paper_doi":"10.1016/j.clgc.2026.102583","tag_type":"modality","value":"HER2-Directed Therapy","value_numeric":null},{"paper_doi":"10.1016/j.clgc.2026.102583","tag_type":"study_design","value":"Commentary","value_numeric":null},{"paper_doi":"10.1016/j.clgc.2026.102583","tag_type":"warning","value":"Brand name identifications for disitamab vedotin (Aidixi) and trastuzumab deruxtecan (Enhertu) are based on known drug approvals referenced in the paper; the paper itself does not explicitly list brand names.","value_numeric":null},{"paper_doi":"10.1016/j.clgc.2026.102583","tag_type":"warning","value":"Full text was not available; summary is based on the abstract and publisher page only. Some details may be incomplete.","value_numeric":null},{"paper_doi":"10.1016/j.clgc.2026.102583","tag_type":"warning","value":"Sex distribution of the patient population is not reported.","value_numeric":null},{"paper_doi":"10.1016/j.clgc.2026.102583","tag_type":"warning","value":"This is a commentary, not an original research study — no primary patient data or statistical outcomes are reported.","value_numeric":null}],"summaries":{"what_studied":"This commentary evaluates the biological and therapeutic significance of HER2 (ERBB2) as a target across histologic subtypes and divergent histologies of urothelial carcinoma (UC), including micropapillary, plasmacytoid, squamous, sarcomatoid, and glandular variants, in the context of emerging antibody-drug conjugates (ADCs).","key_result":"ERBB2 alterations are most consistently enriched in micropapillary UC; plasmacytoid, squamous, sarcomatoid, and glandular histologies show lower and more variable HER2 overexpression or amplification rates. Patient selection for HER2-directed therapy is complicated by assay discordance and the lack of standardized HER2 scoring criteria for UC.","limitations":"Evidence is largely from small retrospective series with no prospective trial data specific to histologic subtypes; HER2 assay methods are discordant across studies; no standardized HER2 scoring criteria exist for UC variants.","practice_takeaway":"When considering HER2-directed ADCs (e.g., trastuzumab deruxtecan, disitamab vedotin) in UC, histologic subtype matters — micropapillary tumors have the strongest ERBB2 enrichment signal, while other variants have less certain benefit. Standardized HER2 testing in UC is not yet established, so interpret biomarker results with caution across subtypes."}},{"doi":"10.1200/jco-25-02958","pmid":"41747202","title":"Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline Update","journal_title":"Journal of Clinical Oncology","journal_issn":"0732-183X","published_at":"2026-02-26T00:00:00.000Z","url":"https://doi.org/10.1200/jco-25-02958","source_score":51,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-05-26T13:35:16.443Z","updated_at":"2026-05-26T13:35:16.443Z","tags":[{"paper_doi":"10.1200/jco-25-02958","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"brand","value":"Cyramza","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"brand","value":"Enhertu","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"brand","value":"Herceptin","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"brand","value":"Keytruda","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"category","value":"Oncology","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"condition","value":"Esophageal Squamous Cell Carcinoma","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"condition","value":"Gastric Adenocarcinoma","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"condition","value":"Gastroesophageal Cancer","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"condition","value":"Gastroesophageal Junction Adenocarcinoma","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"generic","value":"paclitaxel","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"generic","value":"pembrolizumab","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"generic","value":"ramucirumab","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"generic","value":"trastuzumab","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"generic","value":"trastuzumab deruxtecan","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"generic","value":"zolbetuximab","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"level_of_evidence","value":"1","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"modality","value":"Antibody-Drug Conjugate","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"modality","value":"Anti-VEGFR2 Therapy","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"modality","value":"CLDN18.2-Targeted Therapy","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"modality","value":"HER2-Targeted Therapy","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"modality","value":"Immune Checkpoint Inhibitor","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"sample_size","value":"n=12","value_numeric":12},{"paper_doi":"10.1200/jco-25-02958","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"study_design","value":"Clinical Practice Guideline (Systematic Review of Phase III RCTs)","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"warning","value":"No specific survival or response rate numbers are provided in the abstract; all quantitative clinical outcomes are absent from this summary.","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"warning","value":"Study design is a guideline/systematic review hybrid; level of evidence reflects the underlying RCT evidence base, not the guideline document itself.","value_numeric":null},{"paper_doi":"10.1200/jco-25-02958","tag_type":"warning","value":"The sample_size tag reflects the number of included phase III RCTs in the systematic review, not a patient enrollment count — no aggregate patient N is reported in the abstract.","value_numeric":null}],"summaries":{"what_studied":"This ASCO guideline update evaluated immunotherapy and targeted therapy strategies for patients with unresectable locally advanced, advanced, or metastatic gastroesophageal cancer, based on a systematic review of 12 newly published or updated phase III RCTs.","key_result":"Key recommendations include: (1) immunotherapy + doublet chemo for pMMR/MSS HER2-negative disease with PD-L1 ≥1; (2) zolbetuximab for CLDN18.2-positive, PD-L1 <1 adenocarcinoma; (3) trastuzumab + doublet chemo for HER2-positive gastric/GEJ adenocarcinoma, with pembrolizumab added if PD-L1 ≥1; (4) immunotherapy alone or with chemo for dMMR/MSI-H disease; (5) second-line options include ramucirumab/paclitaxel, trastuzumab deruxtecan (HER2+), and immunotherapy for PD-L1 ≥1 esophageal SCC.","limitations":"Recommendations are based on phase III RCTs but the guideline does not report individual trial-level efficacy data (e.g., OS, PFS numbers); guidance for dual PD-L1/CLDN18.2-positive patients relies on shared decision making due to limited direct comparative evidence.","practice_takeaway":"Test all patients for HER2, PD-L1, MMR/MSI status, and CLDN18.2 as early as possible—these biomarkers now drive distinct first-line regimen choices. For dual PD-L1/CLDN18.2-positive adenocarcinoma, involve patients in shared decision making given the absence of head-to-head data."}},{"doi":"10.1016/j.breast.2026.104691","pmid":"41496431","title":"Concomitant radiation therapy and trastuzumab deruxtecan in metastatic breast cancer: feasibility, safety, and outcomes from a real-life multicentre international cohort","journal_title":"The Breast","journal_issn":"0960-9776","published_at":"2026-01-07T00:00:00.000Z","url":"https://doi.org/10.1016/j.breast.2026.104691","source_score":40,"is_retracted":false,"is_open_access":true,"raw_metadata":{"ooir":{"day":"2026-01-08","doi":"10.1016/j.breast.2026.104691","days":"14","issn":"0960-9776","rank":"1","field":"Clinical Medicine","score":"40","category":"Obstetrics & Gynecology","categories":["Obstetrics & Gynecology"],"_categories":["Obstetrics & Gynecology"]},"pubmed":{"doi":"10.1016/j.breast.2026.104691","title":"Concomitant radiation therapy and trastuzumab deruxtecan in metastatic breast cancer: feasibility, safety, and outcomes from a real-life multicentre international cohort.","journal":"Breast (Edinburgh, Scotland)","methods":"","results":"A total of 147 patients were included; 67 received concomitant RT (71 courses) and 80 received T-DXd alone. Median age was 49 years (range 25-85). The central nervous system was the most frequent RT site (54.9 %). Grade ≥3 AEs occurred in 24 patients (16.3 %), with no significant difference between RT and no-RT cohorts (11.9 % vs 20.0 %; p = 0.30). Permanent T-DXd discontinuation due to toxicity occurred in 19 patients (12.9 %), with similar rates in the RT and no-RT groups (11.9 % vs 13.8 %). One case of symptomatic radionecrosis was observed after intracranial RT. Exploratory analyses showed no adverse effect of concomitant RT on PFS or OS.","abstract":"$30","keywords":["Adverse events","Brain metastases","Concomitant therapy","Metastatic breast cancer","Radiotherapy","Trastuzumab deruxtecan"],"pubmed_id":"41496431","conclusions":"Concomitant administration of T-DXd and RT appears feasible and well tolerated, without increased risk of severe or treatment-limiting toxicity. These real-world findings support the safety of this combination and warrant confirmation in prospective studies.","publication_date":"2026-01-07T00:00:00"},"crossref":{"DOI":"10.1016/j.breast.2026.104691","URL":"https://doi.org/10.1016/j.breast.2026.104691","ISSN":["0960-9776"],"link":[{"URL":"https://api.elsevier.com/content/article/PII:S0960977626000019?httpAccept=text/xml","content-type":"text/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https://api.elsevier.com/content/article/PII:S0960977626000019?httpAccept=text/plain","content-type":"text/plain","content-version":"vor","intended-application":"text-mining"}],"page":"104691","type":"journal-article","issue":null,"score":1,"title":["Concomitant radiation therapy and trastuzumab deruxtecan in metastatic breast cancer: feasibility, safety, and outcomes from a real-life multicentre international cohort"],"author":[{"given":"Luca","family":"Visani","sequence":"first","affiliation":[]},{"given":"Ivica","family":"Ratosa","sequence":"additional","affiliation":[]},{"given":"Rupert","family":"Bartsch","sequence":"additional","affiliation":[]},{"given":"Barbro","family":"Linderholm","sequence":"additional","affiliation":[]},{"given":"Gaia","family":"Griguolo","sequence":"additional","affiliation":[]},{"given":"Calogero","family":"Saieva","sequence":"additional","affiliation":[]},{"given":"Carlotta","family":"Becherini","sequence":"additional","affiliation":[]},{"given":"Marianna","family":"Valzano","sequence":"additional","affiliation":[]},{"given":"Viola","family":"Salvestrini","sequence":"additional","affiliation":[]},{"given":"Angelika M.","family":"Starzer","sequence":"additional","affiliation":[]},{"given":"Peter","family":"Kus","sequence":"additional","affiliation":[]},{"given":"Niccolò","family":"Bertini","sequence":"additional","affiliation":[]},{"given":"Andrea","family":"Rampini","sequence":"additional","affiliation":[]},{"given":"Chiara","family":"Mattioli","sequence":"additional","affiliation":[]},{"given":"Domen","family":"Ribnikar","sequence":"additional","affiliation":[]},{"given":"Jacopo","family":"Nori Cucchiari","sequence":"additional","affiliation":[]},{"given":"Lorenzo","family":"Orzalesi","sequence":"additional","affiliation":[]},{"given":"Simonetta","family":"Bianchi","sequence":"additional","affiliation":[]},{"given":"Matteo","family":"Lambertini","sequence":"additional","affiliation":[]},{"given":"Valentina","family":"Guarneri","sequence":"additional","affiliation":[]},{"given":"Lorenzo","family":"Livi","sequence":"additional","affiliation":[]},{"given":"Icro","family":"Meattini","sequence":"additional","affiliation":[]}],"issued":{"date-parts":[[2026,2]]},"member":"78","prefix":"10.1016","source":"Crossref","volume":"85","created":{"date-time":"2026-01-02T23:49:38Z","timestamp":1767397778000,"date-parts":[[2026,1,2]]},"indexed":{"date-time":"2026-01-17T06:36:01Z","timestamp":1768631761188,"date-parts":[[2026,1,17]]},"license":[{"URL":"https://www.elsevier.com/tdm/userlicense/1.0/","start":{"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000,"date-parts":[[2026,2,1]]},"delay-in-days":0,"content-version":"tdm"},{"URL":"https://www.elsevier.com/legal/tdmrep-license","start":{"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000,"date-parts":[[2026,2,1]]},"delay-in-days":0,"content-version":"tdm"},{"URL":"http://creativecommons.org/licenses/by-nc-nd/4.0/","start":{"date-time":"2026-01-02T00:00:00Z","timestamp":1767312000000,"date-parts":[[2026,1,2]]},"delay-in-days":0,"content-version":"vor"}],"subject":[],"abstract":null,"language":"en","relation":{},"resource":{"primary":{"URL":"https://linkinghub.elsevier.com/retrieve/pii/S0960977626000019"}},"subtitle":[],"assertion":[{"name":"publisher","label":"This article is maintained by","value":"Elsevier"},{"name":"articletitle","label":"Article Title","value":"Concomitant radiation therapy and trastuzumab deruxtecan in metastatic breast cancer: feasibility, safety, and outcomes from a real-life multicentre international cohort"},{"name":"journaltitle","label":"Journal Title","value":"The Breast"},{"name":"articlelink","label":"CrossRef DOI link to publisher maintained version","value":"https://doi.org/10.1016/j.breast.2026.104691"},{"name":"content_type","label":"Content Type","value":"article"},{"name":"copyright","label":"Copyright","value":"© 2026 The Authors. 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The TENDANCE multicentric French study","journal-title":"Breast","doi-asserted-by":"crossref"},{"DOI":"10.1200/JCO.2025.43.16_suppl.e13000","key":"10.1016/j.breast.2026.104691_bib32","year":"2025","issue":null,"author":"Bouziane","volume":null,"first-page":null,"unstructured":null,"article-title":"Concurrent trastuzumab deruxtecan and radiation therapy in HER2-positive and HER2-low metastatic breast cancer: assessing the efficacy","journal-title":"Am J Clin Oncol","doi-asserted-by":"crossref"},{"DOI":"10.1038/s41523-024-00711-w","key":"10.1016/j.breast.2026.104691_bib33","year":"2024","issue":null,"author":"Khatri","volume":"10","first-page":"100","unstructured":null,"article-title":"Multi-institutional report of trastuzumab deruxtecan and stereotactic radiosurgery for HER2 positive and HER2-low breast cancer brain metastases","journal-title":"npj Breast Cancer","doi-asserted-by":"crossref"},{"DOI":"10.1016/j.radonc.2023.110060","key":"10.1016/j.breast.2026.104691_bib34","year":"2024","issue":null,"author":"Kaidar-Person","volume":"195","first-page":null,"unstructured":null,"article-title":"Essential requirements for reporting radiation therapy in breast cancer clinical trials: an international multi-disciplinary consensus endorsed by the European society for radiotherapy and oncology (ESTRO)","journal-title":"Radiother Oncol","doi-asserted-by":"crossref"},{"DOI":"10.1016/j.radonc.2025.111035","key":"10.1016/j.breast.2026.104691_bib35","year":"2025","issue":null,"author":"Meattini","volume":"210","first-page":null,"unstructured":null,"article-title":"Repositioning radiation oncology at the centre of integrated oncology care: a manifesto of the European society for radiotherapy and oncology (ESTRO)","journal-title":"Radiother Oncol","doi-asserted-by":"crossref"}],"short-title":[],"update-policy":"https://doi.org/10.1016/elsevier_cm_policy","alternative-id":["S0960977626000019"],"article-number":"104691","content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","thebreastonline.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"original-title":[],"container-title":["The Breast"],"published-print":{"date-parts":[[2026,2]]},"reference-count":35,"published-online":null,"references-count":35,"special_numbering":"C","short-container-title":["The Breast"],"is-referenced-by-count":0},"unpaywall":{"doi":"10.1016/j.breast.2026.104691","is_oa":true,"title":"Concomitant radiation therapy and trastuzumab deruxtecan in metastatic breast cancer: feasibility, safety, and outcomes from a real-life multicentre international cohort","updated":"2026-01-19T05:56:36+00:00","published_date":"2026-01-02","best_oa_location":{"url":"https://www.thebreastonline.com/article/S0960-9776(26)00001-9/pdf","pmh_id":null,"url_for_pdf":"https://www.thebreastonline.com/article/S0960-9776(26)00001-9/pdf","url_for_landing_page":"https://doi.org/10.1016/j.breast.2026.104691"}}},"created_at":"2026-01-14T18:30:49.575Z","updated_at":"2026-01-21T12:05:26.220Z","tags":[{"paper_doi":"10.1016/j.breast.2026.104691","tag_type":"age_group","value":"mixed","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104691","tag_type":"category","value":"Obstetrics & Gynecology","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104691","tag_type":"condition","value":"Metastatic Breast Cancer","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104691","tag_type":"generic","value":"trastuzumab deruxtecan","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104691","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104691","tag_type":"level_of_evidence","value":"3","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104691","tag_type":"modality","value":"Antibody-Drug Conjugate","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104691","tag_type":"modality","value":"Radiation Therapy","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104691","tag_type":"sample_size","value":"n=147","value_numeric":147},{"paper_doi":"10.1016/j.breast.2026.104691","tag_type":"study_design","value":"Retrospective Cohort Study","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104691","tag_type":"warning","value":"Design classification and endpoints are based on the abstract; full protocol details are not available here.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104691","tag_type":"warning","value":"Exploratory PFS/OS analyses are described without effect sizes or hazard ratios in the abstract.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104691","tag_type":"warning","value":"RT dose, technique, and fractionation are not reported in the abstract, which may affect toxicity risk.","value_numeric":null}],"summaries":{"what_studied":"A multicentre retrospective cohort across six European centres evaluated the safety of giving radiation therapy (RT) concomitantly with trastuzumab deruxtecan (T-DXd) in metastatic breast cancer, versus T-DXd alone. Concomitancy was defined as RT during T-DXd or within 10 days of a cycle; the primary endpoint was grade ≥3 adverse events, with exploratory progression-free and overall survival.","key_result":"Grade ≥3 adverse events occurred in 24/147 patients (16.3%), with no significant difference between concomitant RT and no-RT groups (11.9% vs 20.0%; p=0.30); permanent T-DXd discontinuation for toxicity occurred in 19/147 (12.9%) with similar rates (11.9% vs 13.8%). One symptomatic radionecrosis was reported after intracranial RT, and exploratory analyses showed no adverse effect of concomitant RT on progression-free or overall survival.","limitations":"Retrospective, non-randomized, multicentre design may introduce selection and treatment heterogeneity. The abstract does not report RT dosing/fractionation or effect estimates for PFS/OS, limiting interpretation of efficacy signals.","practice_takeaway":"In real-world practice, concomitant RT with T-DXd for metastatic breast cancer appears feasible without excess severe AEs or treatment-limiting toxicity compared with T-DXd alone. Monitor for rare intracranial radionecrosis; confirmation in prospective studies is needed."}},{"doi":"10.1016/j.jtho.2025.12.080","pmid":"41448488","title":"Trastuzumab Deruxtecan in Patients with HER2-Overexpressing Non-Small Cell Lung Cancer: Results From Part 1 of the Open-label, Multicenter, Phase 1b DESTINY-Lung03 Trial","journal_title":"Journal of Thoracic Oncology","journal_issn":"1556-0864","published_at":"2025-12-26T00:00:00.000Z","url":"https://doi.org/10.1016/j.jtho.2025.12.080","source_score":9,"is_retracted":false,"is_open_access":true,"raw_metadata":{"ooir":{"day":"2025-12-24","doi":"10.1016/j.jtho.2025.12.080","days":"30","issn":"1556-0864","rank":"10","field":"Clinical Medicine","score":"9","category":"Respiratory System","categories":["Respiratory System"],"_categories":["Respiratory System"]},"pubmed":{"doi":"10.1016/j.jtho.2025.12.080","title":"Trastuzumab Deruxtecan in Patients with HER2-Overexpressing Non-Small Cell Lung Cancer: Results From Part 1 of the Open-label, Multicenter, Phase 1b DESTINY-Lung03 Trial.","journal":"Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer","methods":"","results":"At data cutoff (April 1, 2024), 11, 24, and 36 patients received treatment in Arms 1A, 1B, and 1D, respectively. DLTs reported in Arm 1A: febrile neutropenia (n=1; Grade [G] 5; 4.4 mg/kg / 1120 mg / 60 mg/m","abstract":"HER2-directed treatments for HER2-overexpressing (HER2-OE; immunohistochemistry [IHC] 3+/2+) non-small cell lung cancer (NSCLC) are needed.\nDESTINY-Lung03 is an open-label, multi-arm, phase 1b study. Part 1 evaluated trastuzumab deruxtecan (T-DXd, 4.4 or 5.4 mg/kg) plus durvalumab (1120 mg) and cisplatin (60 or 75 mg/m\ndose-limiting toxicities (DLTs) and adverse events (AEs: Arms 1A and 1B). Secondary endpoints: safety (Arm 1D) and efficacy (all arms).\nAt data cutoff (April 1, 2024), 11, 24, and 36 patients received treatment in Arms 1A, 1B, and 1D, respectively. DLTs reported in Arm 1A: febrile neutropenia (n=1; Grade [G] 5; 4.4 mg/kg / 1120 mg / 60 mg/m\nData confirm activity of T-DXd monotherapy in pretreated HER2-OE NSCLC, but do not support T-DXd plus durvalumab and platinum chemotherapy use in this population.","keywords":["HER2-directed therapy","HER2-overexpressing","non-small cell lung cancer","trastuzumab deruxtecan"],"pubmed_id":"41448488","conclusions":"","publication_date":"2025-12-26T00:00:00"},"crossref":{"DOI":"10.1016/j.jtho.2025.12.080","URL":"https://doi.org/10.1016/j.jtho.2025.12.080","ISSN":["1556-0864"],"link":[{"URL":"https://api.elsevier.com/content/article/PII:S1556086425030217?httpAccept=text/xml","content-type":"text/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https://api.elsevier.com/content/article/PII:S1556086425030217?httpAccept=text/plain","content-type":"text/plain","content-version":"vor","intended-application":"text-mining"}],"page":null,"type":"journal-article","issue":null,"score":1,"title":["Trastuzumab Deruxtecan in Patients with HER2-Overexpressing Non-Small Cell Lung Cancer: Results From Part 1 of the Open-label, Multicenter, Phase 1b DESTINY-Lung03 Trial"],"author":[{"given":"David","family":"Planchard","sequence":"first","affiliation":[]},{"given":"Hye Ryun","family":"Kim","sequence":"additional","affiliation":[]},{"given":"Thatthan","family":"Suksombooncharoen","sequence":"additional","affiliation":[]},{"given":"Rubi","family":"Li","sequence":"additional","affiliation":[]},{"given":"Diego","family":"Cortinovis","sequence":"additional","affiliation":[]},{"given":"Ji-Youn","family":"Han","sequence":"additional","affiliation":[]},{"given":"Jens","family":"Samol","sequence":"additional","affiliation":[]},{"given":"Yotsawaj","family":"Runglodvatana","sequence":"additional","affiliation":[]},{"given":"Kang-Yun","family":"Lee","sequence":"additional","affiliation":[]},{"given":"Gee-Chen","family":"Chang","sequence":"additional","affiliation":[]},{"given":"Chun-Hui","family":"Lee","sequence":"additional","affiliation":[]},{"given":"Dariusz","family":"Kowalski","sequence":"additional","affiliation":[]},{"given":"Stephanie P.L.","family":"Saw","sequence":"additional","affiliation":[]},{"given":"Yiqing","family":"Huang","sequence":"additional","affiliation":[]},{"given":"Gerrina","family":"Ruiter","sequence":"additional","affiliation":[]},{"given":"Myung-Ju","family":"Ahn","sequence":"additional","affiliation":[]},{"given":"Tsung-Ying","family":"Yang","sequence":"additional","affiliation":[]},{"given":"Cheng-Ta","family":"Yang","sequence":"additional","affiliation":[]},{"given":"Aumkhae","family":"Sookprasert","sequence":"additional","affiliation":[]},{"given":"Erica C.","family":"Nakajima","sequence":"additional","affiliation":[]},{"given":"Jose","family":"Alfon","sequence":"additional","affiliation":[]},{"given":"Robert","family":"McEwen","sequence":"additional","affiliation":[]},{"given":"Yi-Ting","family":"Chang","sequence":"additional","affiliation":[]},{"given":"James C.H.","family":"Yang","sequence":"additional","affiliation":[]}],"issued":{"date-parts":[[2025,12]]},"member":"78","prefix":"10.1016","source":"Crossref","volume":null,"created":{"date-time":"2025-12-23T16:57:25Z","timestamp":1766509045000,"date-parts":[[2025,12,23]]},"indexed":{"date-time":"2026-01-15T23:31:00Z","timestamp":1768519860915,"date-parts":[[2026,1,15]]},"license":[{"URL":"https://www.elsevier.com/tdm/userlicense/1.0/","start":{"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000,"date-parts":[[2025,12,1]]},"delay-in-days":0,"content-version":"tdm"},{"URL":"https://www.elsevier.com/legal/tdmrep-license","start":{"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000,"date-parts":[[2025,12,1]]},"delay-in-days":0,"content-version":"tdm"},{"URL":"http://creativecommons.org/licenses/by/4.0/","start":{"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000,"date-parts":[[2025,12,23]]},"delay-in-days":22,"content-version":"vor"}],"subject":[],"abstract":null,"language":"en","relation":{},"resource":{"primary":{"URL":"https://linkinghub.elsevier.com/retrieve/pii/S1556086425030217"}},"subtitle":[],"assertion":[{"name":"publisher","label":"This article is maintained by","value":"Elsevier"},{"name":"articletitle","label":"Article Title","value":"Trastuzumab Deruxtecan in Patients with HER2-Overexpressing Non-Small Cell Lung Cancer: Results From Part 1 of the Open-label, Multicenter, Phase 1b DESTINY-Lung03 Trial"},{"name":"journaltitle","label":"Journal Title","value":"Journal of Thoracic Oncology"},{"name":"articlelink","label":"CrossRef DOI link to publisher maintained version","value":"https://doi.org/10.1016/j.jtho.2025.12.080"},{"name":"content_type","label":"Content Type","value":"article"},{"name":"copyright","label":"Copyright","value":"© 2025 The Author(s). Published by Elsevier Inc. on behalf of International Association for the Study of Lung Cancer."}],"deposited":{"date-time":"2026-01-15T07:57:24Z","timestamp":1768463844000,"date-parts":[[2026,1,15]]},"issn-type":[{"type":"print","value":"1556-0864"}],"published":{"date-parts":[[2025,12]]},"publisher":"Elsevier BV","reference":null,"short-title":[],"update-policy":"https://doi.org/10.1016/elsevier_cm_policy","alternative-id":["S1556086425030217"],"content-domain":{"domain":["jto.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"original-title":[],"container-title":["Journal of Thoracic Oncology"],"published-print":{"date-parts":[[2025,12]]},"reference-count":0,"published-online":null,"references-count":0,"short-container-title":["Journal of Thoracic Oncology"],"is-referenced-by-count":0},"unpaywall":{"doi":"10.1016/j.jtho.2025.12.080","is_oa":true,"title":"Trastuzumab Deruxtecan in Patients with HER2-Overexpressing Non-Small Cell Lung Cancer: Results From Part 1 of the Open-label, Multicenter, Phase 1b DESTINY-Lung03 Trial","updated":"2025-12-24T00:55:44+00:00","published_date":"2025-12-01","best_oa_location":{"url":"https://doi.org/10.1016/j.jtho.2025.12.080","pmh_id":null,"url_for_pdf":null,"url_for_landing_page":"https://doi.org/10.1016/j.jtho.2025.12.080"}}},"created_at":"2026-01-15T20:51:27.064Z","updated_at":"2026-01-21T12:05:26.220Z","tags":[{"paper_doi":"10.1016/j.jtho.2025.12.080","tag_type":"category","value":"Respiratory System","value_numeric":null},{"paper_doi":"10.1016/j.jtho.2025.12.080","tag_type":"condition","value":"Non-Small Cell Lung Cancer","value_numeric":null},{"paper_doi":"10.1016/j.jtho.2025.12.080","tag_type":"generic","value":"cisplatin","value_numeric":null},{"paper_doi":"10.1016/j.jtho.2025.12.080","tag_type":"generic","value":"durvalumab","value_numeric":null},{"paper_doi":"10.1016/j.jtho.2025.12.080","tag_type":"generic","value":"trastuzumab deruxtecan","value_numeric":null},{"paper_doi":"10.1016/j.jtho.2025.12.080","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1016/j.jtho.2025.12.080","tag_type":"modality","value":"Antibody-Drug Conjugate","value_numeric":null},{"paper_doi":"10.1016/j.jtho.2025.12.080","tag_type":"modality","value":"PD-L1 Inhibitor","value_numeric":null},{"paper_doi":"10.1016/j.jtho.2025.12.080","tag_type":"modality","value":"Platinum Chemotherapy","value_numeric":null},{"paper_doi":"10.1016/j.jtho.2025.12.080","tag_type":"study_design","value":"Phase 1b Trial","value_numeric":null},{"paper_doi":"10.1016/j.jtho.2025.12.080","tag_type":"warning","value":"Abstract text appears truncated; several doses and outcomes are incomplete.","value_numeric":null},{"paper_doi":"10.1016/j.jtho.2025.12.080","tag_type":"warning","value":"Only one DLT event is quantified; efficacy data are qualitative in this excerpt.","value_numeric":null},{"paper_doi":"10.1016/j.jtho.2025.12.080","tag_type":"warning","value":"Randomization and control status are not described beyond 'open-label, multi-arm'.","value_numeric":null}],"summaries":{"what_studied":"Part 1 of an open-label, multi-arm, phase 1b study tested trastuzumab deruxtecan (T-DXd 4.4 or 5.4 mg/kg) plus durvalumab (1120 mg) and cisplatin (60 or 75 mg/m) in HER2-overexpressing NSCLC; T-DXd monotherapy was also assessed. Primary endpoints were DLTs and AEs in Arms 1A/1B; secondary endpoints were safety (Arm 1D) and efficacy (all arms); at the April 1, 2024 cutoff, 11, 24, and 36 patients were treated in Arms 1A, 1B, and 1D, respectively.","key_result":"In Arm 1A, a DLT of febrile neutropenia occurred in 1 patient (Grade 5) at the 4.4 mg/kg T-DXd + 1120 mg durvalumab + 60 mg/m cisplatin dose. The authors report T-DXd monotherapy showed activity in pretreated HER2-overexpressing NSCLC, while the T-DXd + durvalumab + platinum regimen was not supported.","limitations":"Early-phase, open-label design with small arm sizes (n=11, 24, 36) limits precision. The abstract excerpt provides few quantitative efficacy and safety results beyond a single DLT, and several dosing/outcome details are truncated.","practice_takeaway":"T-DXd monotherapy demonstrated activity in pretreated HER2-overexpressing NSCLC in this study, whereas adding durvalumab and platinum chemotherapy was not supported. Apply with caution given the phase 1b, small-arm data."}},{"doi":"10.1158/2159-8290.cd-25-0647","pmid":"41212147","title":"Trastuzumab Deruxtecan Resistance via Loss of HER2 Expression and Binding","journal_title":"Cancer Discovery","journal_issn":"2159-8274","published_at":"2025-11-10T00:00:00.000Z","url":"https://doi.org/10.1158/2159-8290.cd-25-0647","source_score":94,"is_retracted":false,"is_open_access":true,"raw_metadata":{"ooir":{"day":"2025-12-30","doi":"10.1158/2159-8290.cd-25-0647","days":"14","issn":"2159-8274","rank":"4","field":"Clinical Medicine","score":"94","category":"Oncology","categories":["Oncology"],"_categories":["Oncology"]},"pubmed":{"doi":"10.1158/2159-8290.CD-25-0647","title":"Trastuzumab Deruxtecan (T-DXd) Resistance via Loss of HER2 Expression and Binding.","journal":"Cancer discovery","methods":"","results":"","abstract":"T-DXd is clinically beneficial in HER2 positive and HER2 low metastatic breast cancer. However, therapeutic resistance emerges over time in most patients, with poorly defined resistance mechanisms. Through a molecular characterization of paired pre- and post-T-DXd treatment patient specimens, we found that 49% cases had major decreases in HER2 expression at progression, among them, 52% exhibited complete HER2 loss. Using isogenic model systems, we demonstrated that decreases in HER2 expression corresponded to reductions in T-DXd internalization and major increases in drug IC50 for tumor growth inhibition. We further identified and validated HER2 mutations in the trastuzumab binding interface (V597M and P593R) that promoted T-DXd resistance. As a strategy to overcome impaired T-DXd binding and internalization, we tested low dose combinations of T-DXd with TROP2-directed ADCs and found these could more uniformly deliver DXd payloads and thereby overcome resistance mediated by HER2 loss.","keywords":[],"pubmed_id":"41212147","conclusions":"","publication_date":"2025-11-10T00:00:00"},"crossref":{"DOI":"10.1158/2159-8290.cd-25-0647","URL":"https://doi.org/10.1158/2159-8290.cd-25-0647","ISSN":["2159-8274","2159-8290"],"link":[{"URL":"https://aacrjournals.org/cancerdiscovery/article-pdf/doi/10.1158/2159-8290.CD-25-0647/3669759/cd-25-0647.pdf","content-type":"application/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https://aacrjournals.org/cancerdiscovery/article-pdf/doi/10.1158/2159-8290.CD-25-0647/3719943/cd-25-0647.pdf","content-type":"application/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https://aacrjournals.org/cancerdiscovery/article-pdf/doi/10.1158/2159-8290.CD-25-0647/3719943/cd-25-0647.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"page":"OF1-OF15","type":"journal-article","issue":null,"score":1,"title":["Trastuzumab Deruxtecan Resistance via Loss of HER2 Expression and Binding"],"author":[{"given":"Wanyi","family":"Chen","sequence":"first","affiliation":[{"name":"1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"2Weill Cornell Graduate School, Weill Cornell Medicine, New York, New York."}]},{"given":"Avantika","family":"Gupta","sequence":"additional","affiliation":[{"name":"1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"Nicholas","family":"Mai","sequence":"additional","affiliation":[{"name":"3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"Sharanya","family":"Nag","sequence":"additional","affiliation":[{"name":"1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"Joshua S.","family":"Lau","sequence":"additional","affiliation":[{"name":"4Gerstner Sloan Kettering Graduate School, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"Sukrit","family":"Singh","sequence":"additional","affiliation":[{"name":"5Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"John D.","family":"Chodera","sequence":"additional","affiliation":[{"name":"2Weill Cornell Graduate School, Weill Cornell Medicine, New York, New York."},{"name":"5Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"Bo","family":"Liu","sequence":"additional","affiliation":[{"name":"1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"Elisa","family":"de Stanchina","sequence":"additional","affiliation":[{"name":"6Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"Fresia","family":"Pareja","sequence":"additional","affiliation":[{"name":"7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"Atif Ali","family":"Hashmi","sequence":"additional","affiliation":[{"name":"7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"Miriam M.","family":"Lieberman","sequence":"additional","affiliation":[{"name":"3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"Shanu","family":"Modi","sequence":"additional","affiliation":[{"name":"3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"8Weill Cornell Medical College, Weill Cornell Medicine, New York, New York."}]},{"given":"Jacqueline","family":"Bromberg","sequence":"additional","affiliation":[{"name":"3Department of Medicine, Memorial Sloan Kettering Cancer Center, 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New York."},{"name":"4Gerstner Sloan Kettering Graduate School, Memorial Sloan Kettering Cancer Center, New York, New York."}]}],"funder":[{"name":"Sussman Family Fund","award":["Sussman Family Fund"],"award-info":[{"award-number":["Sussman Family Fund"]}]},{"id":[{"id":"10.13039/100001006","id-type":"DOI","asserted-by":"publisher"}],"DOI":"10.13039/100001006","name":"Breast Cancer Research Foundation","award":["BCRF-24-185"],"award-info":[{"award-number":["BCRF-24-185"]}],"doi-asserted-by":"publisher"},{"id":[{"id":"10.13039/100031022","id-type":"DOI","asserted-by":"publisher"}],"DOI":"10.13039/100031022","name":"Center for Cancer Research","award":["P30 CA008748"],"award-info":[{"award-number":["P30 CA008748"]}],"doi-asserted-by":"publisher"},{"id":[{"id":"10.13039/100000025","id-type":"DOI","asserted-by":"publisher"}],"DOI":"10.13039/100000025","name":"National Institute of Mental Health","award":["P50 CA247749-01"],"award-info":[{"award-number":["P50 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deruxtecan","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-0647","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-0647","tag_type":"modality","value":"Antibody-Drug Conjugate","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-0647","tag_type":"study_design","value":"Case Series","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-0647","tag_type":"warning","value":"Design classification is approximate; this is a translational study using paired patient specimens and preclinical models.","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-0647","tag_type":"warning","value":"The T-DXd plus TROP2-directed ADC combination was tested in models only; no clinical outcomes were reported.","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-0647","tag_type":"warning","value":"Total sample size and patient characteristics are not provided in the abstract.","value_numeric":null}],"summaries":{"what_studied":"Paired pre- and post–trastuzumab deruxtecan (T-DXd) specimens from metastatic HER2-positive and HER2-low breast cancer were profiled to define resistance mechanisms, with validation in isogenic models and testing of low-dose T-DXd plus TROP2-directed ADC combinations.","key_result":"At progression, 49% of cases showed major decreases in HER2 expression; among these, 52% had complete HER2 loss. Lower HER2 reduced T-DXd internalization and increased IC50 in isogenic models; HER2 binding-site mutations (V597M, P593R) promoted resistance; low-dose T-DXd plus TROP2-directed ADCs improved DXd delivery and overcame HER2-loss–mediated resistance in models.","limitations":"The abstract does not report total sample size or patient characteristics. Combination strategy and mechanistic validation are preclinical with no clinical outcomes reported.","practice_takeaway":"HER2 expression can fall or be lost at progression on T-DXd, and binding-site HER2 mutations may drive resistance; rechecking HER2 at progression may be informative. Combining T-DXd with a TROP2-directed ADC is investigational and supported only by preclinical data here."}}],"initialOffset":13,"fetchConfig":{"kind":"tags","tags":[{"tag_type":"generic","value":"trastuzumab deruxtecan"}]},"breadcrumbItems":[{"name":"Home","href":"/"},{"name":"Research Hub","href":"/hub"},{"name":"Generics","href":"/hub/tag/generic"},{"name":"trastuzumab deruxtecan"}],"hrefConfig":{"basePath":"/hub/papers","webViewQueryParams":{"hub_ctx":"tag","hub_tag_type":"generic","hub_tag_value":"trastuzumab deruxtecan"}}}]]

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