SEARCH · PubMed Health

Results for “Immunoconjugates”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

14 recordsLinked to original sources

PubMed2025

Trastuzumab Deruxtecan for ERBB2-Mutant Metastatic Non-Small Cell Lung Cancer With or Without Brain Metastases: A Secondary Analysis of Randomized Clinical Trials.

IMPORTANCE: Brain metastases reduce overall survival rates of patients with non-small cell lung cancer (NSCLC); patients with epidermal growth factor receptor 2 (ERBB2 [formerly HER2])-mutant NSCLC are more likely to have baseline brain metastases. Trastuzumab deruxtecan (T-DXd) is an approved ERBB2-directed treatment for previously treated unresectable or metastatic ERBB2-mutant NSCLC. OBJECTIVE: To assess the clinical effectiveness and safety of T-DXd 5.4 mg/kg and 6.4 mg/kg doses in patients with previously treated ERBB2-mutant metastatic NSCLC with or without untreated or previously treated stable brain metastases. DESIGN, SETTING, AND PARTICIPANTS: This post hoc secondary analysis pooled patients from the DESTINY-Lung01 (data cutoff date: December 3, 2021) and DESTINY-Lung02 (data cutoff date: December 23, 2022) clinical trials by T-DXd dose (5.4 mg/kg and 6.4 mg/kg). DESTINY-Lung01 was a multicenter, open-label, 2-cohort, nonrandomized phase 2 study, while DESTINY-Lung02 was a dose-blinded, multicenter, 2-cohort, randomized phase 2 study. Participants had a previously treated ERBB2-mutant metastatic NSCLC with or without untreated or previously treated stable brain metastases at baseline. All statistical analyses were performed from April 2023 to October 2024. INTERVENTION: Patients received a T-DXd dose of either 5.4 mg/kg or 6.4 mg/kg intravenously every 3 weeks. MAIN OUTCOME AND MEASURE: Systemic and intracranial effectiveness by blinded independent central review using RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1, sites of progression, and safety. RESULTS: This analysis included 102 patients in the T-DXd 5.4-mg/kg dose group (65 females [64%]; median [range] age, 57.5 [37.0-83.0] years and 59.5 [30.0-79.0] years in patients with and without brain metastases, respectively) and 141 patients in the T-DXd 6.4-mg/kg dose group (94 females [67%]; median [range] age, 62.5 [29.0-88.0] years and 59.0 [27.0-83.0] years in patients with and without brain metastases, respectively). In each group, 31% (32 of 102) and 38% (54 of 141) of patients, respectively, had baseline brain metastases and 53% (17 of 32) and 44% (24 of 54), respectively, received prior brain metastasis treatment. In patients with and without brain metastases, systemic confirmed objective response rates (ORRs) were 47% (15 of 32; 95% CI, 29%-65%) and 50% (35 of 70; 95% CI, 38%-62%), respectively, with the T-DXd 5.4-mg/kg dose, and 50% (27 of 54; 95% CI, 36%-64%) and 59% (51 of 87; 95% CI, 48%-69%) with the T-DXd 6.4-mg/kg dose. Median progression-free survival was 7.1 (95% CI, 5.5-9.7) months in the T-DXd 5.4-mg/kg dose group and 7.1 (95% CI, 4.5-9.6) months in the T-DXd 6.4-mg/kg dose group of patients with baseline brain metastases. Among patients with measurable baseline brain metastases, intracranial confirmed ORRs were 50% (7 of 14; 95% CI, 23%-77%) with the T-DXd 5.4-mg/kg dose and 30% (9 of 30; 95% CI, 15%-49%) with the T-DXd 6.4-mg/kg dose. At both doses, the safety profile of T-DXd was generally manageable, regardless of baseline brain metastases, favoring the T-DXd 5.4 mg/kg dose. CONCLUSIONS AND RELEVANCE: In this secondary analysis, T-DXd at the approved dose of 5.4 mg/kg showed antitumor activity in patients with previously treated ERBB2-mutant metastatic NSCLC with or without brain metastases. This finding supports T-DXd 5.4 mg/kg use in this population.

Adult↗

PubMed2026

Spatial Multiomics Reveal Insights Into ADC Efficacy.

Antibody-drug conjugates (ADCs) have transformed the therapeutic landscape of solid tumors; however, responses remain heterogeneous and complex to predict. In addition, a growing number of multiple ADC targets are either approved or in late-stage clinical development, such as NECTIN-4, HER2, or TROP2 for metastatic urothelial cancer. Spatial multiomics-representing next-generation methods that couple high-plex RNA sequencing and multiplex protein imaging with precise x-y-z coordinates within tissues-offer a direct way to correlate (ADC) antigen expression, cell state information, and micro-anatomical context with patient treatment outcomes. In this review, we highlight suitability and technological advancements in current spatial transcriptomics and proteomics approaches to decode modes of action and resistance to ADCs and extract biological insights, particularly in metastatic urothelial cancer-and propose an integrative framework that combines spatial readouts with machine and/or deep learning-driven analytics to stratify patients, forecast on- and off-target toxicities, and guide next-generation linker-payload designs or combination therapies.

Humans↗

PubMed2026

Exploring trop-2-directed ADCs monotherapy and combination therapy in pretreated mTNBC: a real-world study.

PURPOSE: Although Trop-2 antibody-drug conjugates (ADCs) have improved outcomes in pretreated metastatic triple-negative breast cancer (mTNBC), resistance remains common and the optimal combination strategy in routine practice is unclear. METHODS: In this retrospective real-world study, we identified patients with mTNBC from a health record-derived database who received sacituzumab govitecan or sacituzumab tirumotecan in the later-line setting between April 2020 and December 2025. Patients received at least two cycles of Trop-2 ADC therapy as monotherapy, plus a PD-1 inhibitor (dual-agent combination), or plus a PD-1 inhibitor and an antiangiogenic agent (triple-agent combination). RESULTS: Descriptively, the ORR was 57.1% in the triple-agent combination group, 38.5% in the dual-agent combination group, and 31.7% in the monotherapy group. Median follow-up was 15.2 months (95% CI, 8.7-20.6). Median progression-free survival (mPFS) was 15.4 months (95% CI, 5.3-NA) in the triple-agent combination group, 10.0 months (95% CI, 4.2-NA) in the dual-agent combination group, and 3.8 months (95% CI, 3.2-5.2) in the monotherapy group. Severe treatment-related toxicity was not increased in the combination groups. Exploratory analyses identified a genomic scoring system that may enable stratification of patients with a higher likelihood of benefiting from the triple-agent combination. CONCLUSION: To our knowledge, this study represents one of the earliest real-world evaluations of this triple-agent strategy in previously treated mTNBC, providing a basis for further prospective validation and biomarker-guided application.

Humans↗

PubMed2026

Trastuzumab deruxtecan rechallenge in HER2-positive metastatic breast cancer: EN-SEMBLE.

BACKGROUND: Trastuzumab deruxtecan (T-DXd) is a key treatment for HER2-positive metastatic breast cancer (mBC); however, data on T-DXd rechallenge remain limited. PATIENTS AND METHODS: This post-hoc subgroup analysis evaluated T-DXd rechallenge in patients with HER2-positive mBC using data from EN-SEMBLE, a nationwide cohort study in Japan (N = 664). RESULTS: Twenty-six patients were included. Median real-world progression-free survival, real-world time to treatment failure, and overall survival were 6.5, 4.9, and 14.2 months, respectively. The objective response rate was 27%. Patients who discontinued initial T-DXd without progressive disease had numerically longer real-world progression-free survival. No interstitial lung disease occurred during rechallenge. CONCLUSION: T-DXd rechallenge may have clinical activity in selected patients with HER2-positive mBC. CLINICAL TRIAL REGISTRATION NUMBER: jRCT1030220506.

Humans↗

PubMed2026

Antibody-drug conjugates against multidrug-resistant cancers: Biomarker-guided patient selection, payload engineering, linker chemistry, and bystander effects.

Antibody-drug conjugates (ADCs) are one of the most significant advancements in modern cancer therapeutics. Combining the target selectivity of monoclonal antibodies with the cytotoxic potential of payloads, ADCs effectively kill cancer cells and offer hope to patients with even refractory cancer types. Beyond simply increasing the number of therapeutic options available for cancer patients, ADCs have become a powerful frontline agent in overcoming multidrug resistance (MDR). As one of the most challenging obstacles to effective cancer care, MDR is mediated by ATP-binding cassette (ABC) transporter-mediated drug efflux, target-based mutations, and dysregulated apoptosis. The clinical success of ADCs specifically engineered to overcome MDR, including in heterogeneous tumors and cancer cells that exhibit bypass signaling, is well established. This is especially evident with trastuzumab deruxtecan (T-DXd) in HER2-low, HER2-positive, and HER2-mutant cancers; sacituzumab govitecan (SG) in TROP2-expressing triple-negative breast cancer (TNBC) and urothelial carcinoma; and enfortumab vedotin in Nectin-4-positive bladder cancer. By overcoming MDR, ADCs have enabled more effective treatment algorithms across multiple malignancies. Most importantly, the clinical application of ADCs has become inextricably linked to cancer genomics. HER2 testing has evolved from a two-tiered system to a continuous spectrum including HER2-ultralow, HER2-low, HER2-positive, and ERBB2-mutant categories. Each of these categories exhibits different eligibility guidelines for ADC patient selection. As cancer cells continue to evolve and develop resistance to even ADCs through mutations and variants, researchers and clinicians have used pharmacogenomics to predict ADC response and resistance. To define the genomic architecture of ADC-resistant tumor subpopulations, single-cell transcriptomic studies and liquid biopsy approaches are being used to enable real-time examination of the tumor genome during ADC therapy, thereby optimizing treatment and circumventing resistance driven by emerging mutations and variants. This review provides a comprehensive analysis of the molecular structure of ADCs, the pharmacological principles underlying their potent cytotoxic activity against MDR cancer cells, the genomic and transcriptomic biomarkers that guide ADC patient selection, and the emerging resistance mechanisms that will shape the next generation of promising ADC development.

Humans↗

PubMed2026

Antibody-drug conjugates in selected solid tumours: a position statement update based on findings from the third workshop held by the ETOP IBCSG Partners Foundation.

The European Thoracic Oncology Platform (ETOP) International Breast Cancer Study Group (IBCSG) Partners Foundation initiated a series of workshops for experts to review current evidence and offer recommendations to guide future antibody-drug conjugate (ADC) research. Here, we summarise key findings from the third workshop, which included experts in various solid tumours, basic/translational research scientists and pharmaceutical industry representatives. Recent positive phase III trial data have further incorporated ADCs into the standard of care [e.g. lung: sacituzumab tirumotecan; breast: trastuzumab deruxtecan (T-DXd), sacituzumab govitecan, datopotamab deruxtecan; muscle-invasive bladder cancer: enfortumab vedotin; ovarian cancer: mirvetuximab soravastine; cervical cancer: tisotumab vedotin]. Thus, research priorities must be tailored according to tumour type, potentially focussing initially on settings where ADCs could replace chemotherapy. Many phase III ADC trials have been initiated based on positive phase I data and although these trials are larger than those conducted historically, prespecified criteria (e.g. patient numbers and magnitude of efficacy) should be met to justify proceeding directly to phase III. Importantly, although several ADCs have been successfully developed without mandatory biomarker selection, biomarker-driven ADC development enables rational patient selection, as illustrated by multiple ADCs (e.g. T-DXd, mirvetuximab soravtansine and telisotuzumab vedotin). The identification, development and validation of predictive biomarkers are therefore essential, particularly given several critical nuances, including the algorithms used to assess biomarker status and the type of specimen analysed, all of which may be influenced by temporal and spatial heterogeneity. Additional ADC research priorities include the optimisation of ADC constructs to enhance efficacy/tolerability and the identification of reliable ADC targets, including work to elucidate attributes of already-identified targets. Finally, considering the vast amount of ADC-related data being generated, artificial intelligence could be leveraged to analyse combined datasets and generate composite biomarkers, including tumour histology, optimal target expression thresholds, molecular alterations and activated pathways affecting payload activity and target function, to accelerate research.

Humans↗

PubMed2026

Mitigating pH-induced instability in deruxtecan-based ADCs: an onboard-mixing icIEF approach for robust charge heterogeneity characterization.

Accurate charge variant analysis of antibody-drug conjugates (ADCs) is essential for understanding product heterogeneity and ensuring quality control. However, Deruxtecan (DXd)-based ADCs present a unique analytical challenge due to the intrinsic instability of the payload, where the lactone ring readily undergoes hydrolysis under alkaline conditions, resulting in time-dependent shifts in charge distribution during imaged capillary isoelectric focusing (icIEF). In this study, we describe the development of an onboard-mixing icIEF method designed to minimize pH-induced degradation during sample preparation. By separating ADC samples from carrier ampholytes (CAs) prior to injection and enabling real-time mixing within the instrument, this approach effectively suppresses premature lactone ring opening and stabilizes charge variant profiles. Comparative studies between conventional premixing and onboard-mixing approach demonstrated that the latter significantly enhances reproducibility, particularly for acidic variants that are highly sensitive to structural conversion. Comprehensive method validation confirmed excellent precision, linearity, and sensitivity, with consistent performance across run-to-run and intra-day analyses. The results underscore the importance of controlling microenvironmental pH exposure in the analysis of chemically instable ADCs. The proposed onboard-mixing strategy provides a robust and efficient solution for icIEF-based characterization, reducing analytical artifacts while simplifying method development. This approach is broadly applicable to ADCs and other biotherapeutics containing pH-sensitive functional groups.

Hydrogen-Ion Concentration↗

PubMed2026

Clinical and Molecular Evaluation of HER2-Low and HER2-Ultralow Breast Cancer in the Penelope-B Clinical Trial Cohort.

The DestinyBreast (DB)04 and DB06 trials have shown clinical activity of trastuzumab-deruxtecan (T-DXd) in HER2-low and HER2-ultralow metastatic breast cancer. The identification of HER2-low and HER2-ultralow breast cancer is therefore essential for personalized therapy with T-DXd. We evaluated 723 residual tumors from the Penelope-B trial (NCT01864746) and correlated different levels of HER2 protein expression with prognosis and messenger RNA (mRNA) profiles, including HER2 transcripts. In Penelope-B, 57.68% (n = 417) of 723 residual tumors were HER2 low. The HER2-ultralow category was assigned to 109 (15.08%) tumors, and 197 (27.25%) tumors were completely HER2 negative (HER2 0). In Kaplan-Meier analysis, there were no survival differences among these 3 subgroups. There was no significant difference in HER2 mRNA expression between HER2-0 and HER2-ultralow tumors (P = .08). In contrast, there was a highly significant difference in HER2 mRNA expression between HER2-ultralow and HER2-low tumors (P < .0001) and between HER2-low and HER2-positive tumors (P < .0001). The extracellular protease cathepsin L, which has been suggested as a biomarker for extracellular cleavage of T-DXd, was detectable in all HER2-related subgroups and was a negative prognostic factor for invasive disease-free survival and overall survival (P = .0001) in preneoadjuvant core biopsies. In our study, we were able to characterize HER2 low as a clinically relevant and molecular defined tumor group with significantly increased HER2 expression. In contrast, for HER2 ultralow, we did not observe a defined molecular phenotype, despite the clinically relevant regulatory approval of T-DXd also in the ultralow subgroup. Additional investigations are needed to identify biomarkers beyond HER2 for T-DXd response as a basis for refined criteria for treatment eligibility.

Adult↗

PubMed2026

Spatial proteogenomic profiling uncovers sensitization strategies for antibody-drug conjugate in HER2-positive breast cancer.

Antibody-drug conjugates (ADCs) have transformed the treatment of HER2-positive breast cancer, yet resistance remains poorly understood. Using imaging mass cytometry, we profiled 157 regions of interest comprising 912,360 single cells from 47 HER2-positive/hormone receptor-negative breast cancers treated with SHR-A1811 in the FASCINATE-N trial. Spatial proteomic analyses identified two determinants of ADC response: elevated tumor-cell H3K27ac expression was associated with improved ADC efficacy, whereas collagen-positive fibroblasts mediated resistance. Combining ADC with the histone deacetylase inhibitor chidamide or the collagen-modulating agent losartan produced synergistic antitumor effects in preclinical models. These biomarkers and therapeutic vulnerabilities were independently validated in patients with advanced HER2-positive disease receiving trastuzumab deruxtecan. Moreover, based on these spatial features, we developed a clinically applicable ADC barrier prediction model that can be implemented using multiplex immunofluorescence. Taken together, our findings reveal actionable spatial determinants of ADC efficacy and suggest potential combination therapeutic strategies.

Humans↗

PubMed2026

Mirvetuximab soravtansine plus pembrolizumab in recurrent folate receptor alpha-positive uterine serous carcinoma: a phase II trial.

Immune checkpoint inhibitors (ICI) synergize preclinically with antibody drug conjugates (ADC), harboring anti-tubulin maytansinoid payloads. We conducted an investigator-initiated, single-arm, phase 2 trial of mirvetuximab soravtansine (MIRV), a folate receptor alpha (FOLR1/FRα)-targeting ADC with the maytansinoid payload, DM4, combined with pembrolizumab in female patients with recurrent FOLR1-expressing serous endometrial cancer (EC, NCT03835819). Co-primary objectives include objective response rate (ORR) and rate of progression-free survival at 6 months (PFS6); secondary objectives include PFS, overall survival, duration of response and safety. Exploratory objectives include correlation of tumor genomics and immunoprofiling with clinical activity. Eighteen patients initiated protocol therapy [MIRV 6 mg/kg adjusted ideal body weight IV and pembrolizumab 200 mg IV every 3 weeks]. Confirmed ORR is 28% (1 complete and 4 partial responses, 95% CI:10-53%), Kaplan Meier estimate of PFS6 is 24.4% (95% CI:7.7-46.1%) with 4 patients progression free at 6 months; trial was closed early for feasibility (planned sample size of 35 patients not reached) and hence these results are considered preliminary. G3 treatment-related adverse effects were rare with no grade ≥4 toxicities. We report a population of high FOLR1-expressing tumor-associated macrophages (CD163 + FOLR1 + ), suggesting potential on-target, off-tumor immune editing by MIRV. A composite biomarker score derived in this cohort correlates with objective response to MIRV and pembrolizumab.

Adult↗

PubMed2026

Treatment Decisions in Multiple Myeloma.

Revolutions in transplantation and targeted and immune therapies have transformed multiple myeloma from a disease with an associated survival of a few years into one for which functional cure is an emerging goal. This abundance of effective therapies has created clinical complexity. Here we provide a practical framework, anchored in trial evidence and informed by emerging biologic discoveries, for the navigation of treatment decisions across the disease spectrum. We outline how cytogenetic and genomic risk stratification, functional fitness, and measurable residual disease status individualize therapy in newly diagnosed disease, in which quadruplet induction therapy is now standard and the role of autologous transplantation is being reevaluated. Regarding relapse, we address the sequencing of B-cell maturation antigen-directed chimeric antigen receptor (CAR) T cells, bispecific antibodies, and antibody-drug conjugates, emphasizing T-cell fitness and multiantigen targeting to counter exhaustion and antigen escape. We also consider early interception in high-risk smoldering myeloma. Throughout, we underscore that enrollment of patients in clinical trials should be considered in order to ensure continued progress.

Humans↗

PubMed2026

Molecular evaluation of residual disease following neoadjuvant chemotherapy in triple-negative breast cancer CALGB 40603 (Alliance).

BACKGROUNDDespite therapeutic advances in early-stage triple-negative breast cancer (TNBC), residual disease (RD) following neoadjuvant therapy remains a key predictor of a worse prognosis and obstacle to improving patient outcomes.METHODSTo better characterize RD and identify survival-associated features, we performed comprehensive transcriptomic profiling of 340 pretreatment stage II/III TNBCs and 70 matched posttreatment RD samples from the randomized CALGB 40603 (Alliance) phase II clinical trial. To explore preclinical treatment strategies for RD, patient-derived xenograft (PDX) mouse models mimicking RD were treated with antibody-drug conjugates (ADCs).RESULTSOur study shows prognostic genomic features measured pretreatment may differ from prognostic features measured posttreatment from RD specimens. Patients with a genomic PAM50 subtype of basal-like in RD specimens had a poor survival outcome, and their matching pretreatment tumors were characterized by elevated chromosomal amplifications of oncogenic drivers and significantly reduced B and T cell expression features. Paired analyses of basal-like RD and matched pretreatment tumors revealed further lymphocyte depletion in RD, along with lower expression of MHC class I and interferon signaling, indicating an immune-cold RD microenvironment. Treatment of a basal-like and conventional chemotherapy-resistant PDX model, resembling basal-like RD, with sacituzumab govitecan or trastuzumab deruxtecan produced a marked antitumor response.CONCLUSIONRD biology differs from pretreatment tumors, with basal-like subtype RD following neoadjuvant chemotherapy being immune cold and associated with poor survival. Preclinical modeling suggests this high-risk group may benefit from adjuvant ADC therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT00861705.FUNDINGNIH NCI U10CA180821 (Alliance for Clinical Trials in Oncology), NCI U24CA176171 (Alliance for Clinical Trials in Oncology), NCI UG1CA233373 (Alliance for Clinical Trials in Oncology), NCI Breast SPORE program P50-CA058223; Susan G. Komen SAC-160074; Breast Cancer Research Foundation BCRF-23-127; NIH NCI R01-CA229409; UNC LCCC Triple Negative Breast Cancer Center.

Humans↗

PubMed2026

Trastuzumab Deruxtecan in Metastatic Urothelial Carcinoma with NGS-Detected ERBB2 Amplification: A Four-Patient Real-World Case Series.

Background: Next-generation sequencing (NGS)-detected ERBB2 amplification occurs in a subset of urothelial carcinomas, but its role as a treatment-selection marker for trastuzumab deruxtecan (T-DXd) remains uncertain. Methods: We retrospectively reviewed four patients with metastatic urothelial carcinoma treated with T-DXd in routine practice from 2024. Treatment selection was based on NGS-detected ERBB2 amplification because HER2 immunohistochemistry and in situ hybridization were unavailable. Results: Four men aged 65-76 years received T-DXd: one in the second line and three in the fourth or fifth line. The best radiological responses, abstracted from contemporaneous radiology reports and oncology medical records, were complete response in one patient, partial response in one, and stable disease in two. Three patients had previously received enfortumab vedotin. Documented adverse events included fatigue, anemia, diarrhea, rash, and leukopenia. No interstitial lung disease or pneumonitis was documented in the available records. Conclusions: These observations are descriptive and hypothesis-generating. They do not establish the efficacy or safety of T-DXd or validate ERBB2 amplification as a predictive biomarker, but they support prospective evaluation of genomic ERBB2 amplification when standard HER2 testing is unavailable.

Humans↗

PubMed2026

Survey on the current status of novel cancer drug therapies for gynecological cancers in Japan: a nationwide survey by the Japan Society of Obstetrics and Gynecology (JSOG).

OBJECTIVE: To characterize real-world implementation of novel therapies in gynecological oncology in Japan and identify actionable gaps through a nationwide survey. METHODS: A cross-sectional questionnaire was distributed to Japan Society of Obstetrics and Gynecology-affiliated institutions. The items covered institution characteristics; use of poly (ADP-ribose) polymerase (PARP) inhibitors, immune checkpoint inhibitors (ICIs), kinase inhibitors, and antibody-based agents; local adverse event (AE) manuals; availability of expert panels and immune-related adverse event (irAE) teams; and perceptions of educational sufficiency. RESULTS: Valid responses were obtained from 245 institutions, spanning universities, cancer centers, and general hospitals. Most institutions reported the routine use of PARP inhibitors, ICIs, kinase inhibitors, and antibody drugs. However, only 40.4% of institutions had an in-hospital irAE management team, 57.1% had an AE/irAE manual, and 31.0% and 12.2% considered prior educational opportunities sufficient for physicians and nurses/other medical staff, respectively. High-volume institutions and academic centers were significantly more likely to have medical oncology support, expert-panel access, irAE teams, manuals, and higher self-rated evidence-based management capacity. The majority favored e-learning and society-led case conferences, and 76.3% supported the development of drug therapy subspecialties in gynecologic oncology. CONCLUSION: Innovative drug modalities are widely implemented across Japanese gynecological oncology services. However, critical gaps persist in multidisciplinary irAE management, standardized manuals, and practical education. Coordinated society-led programs to expand irAE teams, streamline companion diagnostics, disseminate ready-to-use algorithms, and provide credential-targeted training may enhance safety, equity, and evidence-concordant care nationwide.

Immune Checkpoint Inhibitors↗