Search Results (506)

Antibody–drug conjugates (ADCs) targeting HER2 (encoded by ERBB2), Trop2 (TACSTD2), and Nectin-4 (NECTIN4) have demonstrated clinical activity in bladder cancer. However, the co-expression relationships among these three targets at both the transcriptomic and protein levels, and their spatial organization within the tumor microenvironment, remain incompletely characterized. To address this, we performed a multi-platform, multi-resolution analysis integrating ten bulk RNA-seq datasets (n = 1628 samples), six spatial transcriptomics datasets (10x Visium and Visium HD, n = 31 specimens), and multiplex immunofluorescence (mIF) staining on three paired tumor–adjacent normal bladder specimens. Pairwise Pearson correlation analyses were conducted for ERBB2, TACSTD2, and NECTIN4 across bulk transcriptomes and spatial compartments (tumor core, interface, and stroma). High-resolution co-expression hotspot mapping was performed using Visium HD data. Preliminary protein-level evidence was obtained using mIF, with quantitative three-dimensional surface plot reconstructions illustrating the spatial distribution of marker co-expression. Given the limited number of specimens (three paired tumor–normal samples), these findings should be regarded as exploratory and illustrative rather than definitive validation. Moderate-to-strong positive correlations among the three genes were consistently observed across all ten bulk datasets, with the strongest association between TACSTD2 and NECTIN4 (Pearson r up to 0.969). Spatial transcriptomic analyses recapitulated these positive correlations across all histopathological compartments, with the tumor core generally exhibiting the highest coefficients. No consistent spatial gradient was observed, indicating preservation of co-expression across tissue niches. Visium HD analysis confirmed positive pairwise correlations and identified discrete co-expression hotspots. mIF revealed extensive Trop2–Nectin-4 protein colocalization across all tumors, whereas HER2 showed more restricted and heterogeneous expression. Triple-positive subpopulations were identified but were limited. Strikingly, all three markers exhibited pronounced tumor-specific upregulation relative to paired adjacent normal tissues, with surface plot analysis showing markedly elevated cumulative fluorescence intensities in tumors (Z-values approaching 240 arbitrary units) compared with a flattened landscape in normal tissues (Z-values < 100–120 arbitrary units). These findings provide a multi-scale description of ADC-target co-expression in bladder cancer and generate hypotheses for biomarker-driven patient stratification, which require validation in larger, independent cohorts. Full article

Primary bone sarcomas are rare, heterogeneous malignancies with limited therapeutic options, particularly in metastatic disease where outcomes remain poor. This study synthesizes current literature to evaluate emerging therapeutic strategies and biological determinants of response across osteosarcoma, Ewing sarcoma, and chondrosarcoma, as presented at the ESMO Annual Meeting, 2025. Key approaches reviewed include VEGFR-targeted tyrosine kinase inhibitors (TKIs), DNA damage response (DDR) inhibition, MYC targeting, immune checkpoint inhibitors (ICIs), and surfaceome-directed therapies such as antibody–drug conjugates (ADCs) and chimeric antigen receptor T cell therapy. Across studies, TKIs demonstrated short lasting activity as monotherapy but improved outcomes in some of the studies when combined with ICIs or chemotherapy, reflecting their role in remodeling the tumor microenvironment (TME); importantly, controlled studies with TKI and chemotherapy upfront are ongoing. DDR- and MYC-targeted therapies have shown strong preclinical rationale but limited clinical efficacy, highlighting challenges in translation. Immune-based therapies exhibited variable responses, with dedifferentiated chondrosarcoma (DDCS) emerging as a responsive histotype. Surfaceome-targeting strategies, particularly ADCs, demonstrated promising early clinical activity. Overall, bone sarcoma rarity, tumor heterogeneity, immunosuppressive TME, and lack of predictive factors challenge drug discovery for bone sarcoma patients. These findings underscore the importance of combination strategies and biomarker-driven patient selection and suggest that continued integration of targeted and immunotherapeutic approaches will be critical to improving outcomes in bone sarcoma. Full article

Background/Objectives: Antibody–drug conjugates (ADCs) targeting Nectin-4 (enfortumab vedotin) and TROP-2 (sacituzumab govitecan) have transformed the management of advanced urothelial carcinoma (UC), but evidence on their molecular targets in rare non-urothelial bladder carcinomas (N-UC) is scarce. We evaluated the immunohistochemical expression of TROP-2 and Nectin-4 in muscle-invasive UC and N-UC and assessed their association with tumour stage, nodal status and overall survival. Methods: In this retrospective single-centre study, 111 consecutive patients with primary muscle-invasive bladder carcinoma (73 UC, 38 N-UC including squamous, adenocarcinoma, neuroendocrine and sarcomatoid variants) were analysed. TROP-2 and Nectin-4 expression was quantified using the H-score; positivity was defined as ≥15. Marker expression was correlated with clinicopathological characteristics and overall survival (OS) using chi-squared, linear-by-linear, log-rank, and Cox regression analyses. Results: TROP-2 positivity was observed in 46.6% of UC and 36.8% of N-UC (p = 0.925); Nectin-4 positivity in 17.8% and 28.9%, respectively (p = 0.275). Among positive cases, TROP-2 H-scores were higher in N-UC than in UC (mean 109 vs. 70; Mann–Whitney p = 0.045; Cliff’s delta 0.37, 95% CI 0.05–0.66); as no adjustment for multiple testing was applied, this difference is regarded as nominally significant and exploratory. Nectin-4 H-scores were numerically higher in UC (mean 82 vs. 53) but did not reach statistical significance (p = 0.84). Across the cohort, TROP-2 expression increased with advancing T stage (linear-by-linear p = 0.026) and was associated with nodal involvement (p = 0.043). Nectin-4 showed no significant stage association. Sarcomatoid carcinomas were negative for both markers. Median OS was 41 months in UC versus 19 months in N-UC (p = 0.668). Neither marker independently predicted OS, whereas advanced T stage (p = 0.003) and nodal involvement (p = 0.021) were significantly associated with poorer survival; T stage remained independently prognostic in multivariable analysis. Conclusions: TROP-2 and Nectin-4 are expressed at comparable rates in muscle-invasive UC and rare N-UC, except in sarcomatoid variants. TROP-2 expression increased with advancing tumour stage, suggesting stage-dependent regulation in muscle-invasive disease. Therefore, both markers should be interpreted as potential therapeutic targets whose expression can be demonstrated in these tumours, rather than as prognostic biomarkers or as validated predictive biomarkers of ADC response; because no patient received an ADC, the present study cannot determine whether expression predicts clinical benefit, and this distinction requires prospective, treatment-linked evaluation that includes patients with N-UC. Full article

Background: Antibody-drug conjugates (ADCs) are gaining rapidly expanding clinical utility, with a growing number of approved indications across compounds that differ in target antigen, payload mechanism, and linker design. However, treatment response remains heterogeneous, and predictive biomarkers to identify patients most likely to benefit are limited. Given that ADC efficacy depends on sufficient target antigen expression and distribution across tumor lesions, positron emission tomography (PET) imaging offers a unique opportunity to non-invasively assess whole-body target availability. We therefore conducted a systematic literature review to evaluate the relationship between PET-measured tumor antigen expression and the therapeutic response to ADCs targeting the same antigen. Method: A systematic comprehensive search of PubMed, EMBASE and Web of Science databases was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, using terms related to targeted PET, ADC treatment and response assessment. Article screening, eligibility assessment, and data extraction were performed independently using predefined criteria by two reviewers. Disagreements were resolved by consensus. Results: A total of 5628 records were identified. After removing duplicates, 4323 records were screened by title and abstract. Fifty-eight underwent full-text review and seven were included in the final review. Four trials investigated human epidermal growth factor receptor 2 (HER2)-targeted therapy, one Nectin-4, one mesothelin and one STEAP1. In all HER2- and Nectin-4-related trials, patients with a higher uptake on targeted PET had a higher probability of responding to targeted treatment. Included trials were generally small and had a moderate risk of bias. Conclusion: Targeted PET imaging showed potential to predict treatment response in trials evaluating clinically active agents. Additional clinical trials across a broader range of targets, along with standardized acquisition protocols and harmonized study designs, are needed to enable the integration of this technique into clinical practice and ultimately translate its benefits to patients. Full article

Antibody–drug conjugates (ADCs) have emerged as a powerful class of targeted therapeutics in many clinical areas, such as in oncology. Despite their efficacy, the onset of adverse events has been a major drawback in their clinical use. Among other explanations, the clinical performance of the ADCs has been associated with the chemistry of the linker connecting the antibody and payload. Linkers determine plasma stability, intracellular activation, and payload diffusibility, thereby influencing the therapeutic index, off-tumour toxicity, and by-stander activity. Mechanistic insights increasingly show that linker–payload properties govern catabolite permeability and intratumoral distribution, particularly in antigen-heterogeneous settings. Current developments include enzyme-cleavable and tumour-selective linkers, polarity-modulating masking strategies, alternative self-immolative spacers, and dual-trigger systems designed to enhance selectivity and decouple efficacy from toxicity. In parallel, linker behaviour intersects with broader mechanisms of tumour resistance. This review focuses on understanding these processes, which are essential for designing the next generation of linkers capable of improving stability, safety, and long-term therapeutic effectiveness across diverse tumour contexts. Full article

The epidermal growth factor receptor (EGFR) was the first receptor tyrosine kinase identified soon after v-Src was recognized as a tyrosine kinase. EGFR signaling begins when EGF binds to EGFR at the cell surface, inducing receptor dimerization, activation, and autophosphorylation. The resulting phosphotyrosine sites recruit downstream effectors that activate signaling cascades such as the RAS-RAF-MEK-ERK and PI3K-Akt pathways, thereby regulating cell growth, proliferation, and survival. EGF binding also promotes EGFR endocytosis, which can direct the receptor to lysosomal degradation. Aberrant EGFR activity is associated with many cancers, and the receptor has been therapeutically targeted using small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs). Furthermore, EGFR endocytosis has been exploited for the targeted delivery of anticancer agents into EGFR-expressing cancer cells through antibody–drug conjugates (ADCs) and antibody–nanoparticle conjugates (ANCs). Although ADCs and ANCs both utilize mAbs as homing mechanisms to recognize cancer-associated antigens, they further harness EGFR endocytosis to deliver therapeutic payloads directly into target cells. In this review, we briefly discuss EGFR structure, activation, signaling, and endocytosis, as well as the mechanisms underlying EGFR function in cancer development. We then focus on current advances and future perspectives in using EGFR endocytosis pathways to improve targeted cancer drug delivery and therapy, particularly in the context of ANCs. Full article

Human epidermal growth factor receptor 2 (HER2) and trophoblast cell surface antigen 2 (Trop-2) are tumor-associated antigens widely overexpressed in multiple malignant tumors, which drive malignant proliferation, invasion, metastasis, and therapeutic resistance by activating key downstream signaling pathways. Antibody–drug conjugates (ADCs) targeting HER2 and Trop-2 leverage their antigen-specific binding capacity to achieve precise targeted delivery of cytotoxic drugs, representing a significant breakthrough in solid tumor therapy. This review systematically outlines the biological functions and carcinogenic mechanisms of HER2 and Trop-2, focusing on the latest research and development progress of related ADCs. We also summarize and analyze key clinical data and application prospects in breast cancer (BC), gastric cancer (GC), non-small cell lung cancer (NSCLC), and urothelial carcinoma (UC), while also delving into the challenges and future directions within this field. Full article

The emergence of antibody-drug conjugates (ADCs) targeting trophoblast cell-surface antigen 2 (TROP2) represents a potential paradigm shift in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC), a setting historically characterized by limited therapeutic options following progression on EGFR tyrosine kinase inhibitors (TKIs). This review examines the biological rationale and clinical challenges underpinning the development of anti-TROP2 ADCs in EGFR-mutated NSCLC. From a mechanistic standpoint, TROP2 occupies a unique and dynamic role in EGFR-mutated NSCLC, providing strong biological rationale for clinical development of anti-TROP2 ADCs in this population. Three TROP2-directed ADCs are currently in clinical development in this setting. Available clinical data in previously treated EGFR-mutated patients are critically reviewed here, focusing on efficacy, toxicity profiles, clinical challenges and potential future perspectives. Full article

Immune checkpoint inhibitors and antibody–drug conjugates have rapidly expanded treatment options for gynecologic malignancies, although the magnitude of benefit varies substantially across tumor types and biomarker-defined populations. This narrative review summarizes the biologic rationale, predictive biomarkers, pivotal clinical trials, regulatory approvals, guideline-supported strategies, and emerging directions for immune checkpoint blockade and antibody–drug conjugates in endometrial, cervical, and ovarian cancers. In endometrial cancer, molecular classification and mismatch repair status have transformed treatment selection, with PD-1 or PD-L1 blockade now integrated into first-line chemoimmunotherapy and recurrent disease management. HER2-directed and TROP-2-directed antibody–drug conjugates are also emerging as biomarker-directed strategies. In cervical cancer, human papillomavirus-driven tumor biology, PD-L1 expression, and tissue factor expression support the use of checkpoint inhibitors, antibody–drug conjugates, and therapeutic vaccine approaches across locally advanced and recurrent or metastatic settings. In ovarian cancer, single-agent checkpoint blockade has shown limited activity in unselected populations, but recent advances include biomarker-selected chemoimmunotherapy in platinum-resistant disease and clinically meaningful activity of folate receptor alpha-directed and HER2-directed antibody–drug conjugates. Across gynecologic cancers, key challenges include refining predictive biomarkers, optimizing sequencing after prior immunotherapy exposure, managing overlapping toxicities, and designing trials that enrich for biologically responsive subgroups. Future progress will depend on integrating molecular classification, immune contexture, ADC target expression, and patient-specific clinical factors into treatment selection. Full article

Background: Enhancing the binding affinity of monoclonal antibodies (mAbs) has the potential to improve their therapeutic efficacy. In this study, we generated a novel mAb, PB-223, through affinity maturation of the parental antibody NEO-102. NEO-102 (Ensituximab) is a chimeric human IgG1 mAb that targets a cancer-specific glycosylated variant of MUC5AC expressed on colorectal and pancreatic cancers while sparing healthy tissues. In a Phase 2 clinical study involving heavily pretreated patients with advanced, refractory colorectal cancer, NEO-102, as a monotherapy, exhibited modest efficacy. Methods: We engineered the VH and VL regions of NEO-102 through affinity maturation to enhance antigen binding while preserving target specificity. The optimized clone, PB-223, was evaluated for improved binding by Biacore T200, flow cytometry, and immunohistochemistry (IHC). The specific PB-223 target antigen was discovered using an O-glycan array. An internalization assay evaluated the ability of PB-223 to be internalized into human cancer cell lines expressing its target antigen. Results: Analysis performed with the Biacore T200 evaluation (version 3.2) software revealed that PB-223 exhibits a 4.55-fold lower equilibrium dissociation constant (KD) compared with NEO-102 towards recombinant human Bovine Submaxillary Mucin (BSM), a protein rich in O-glycans. PB-223 has enhanced binding to human cancer cell lines recognized by NEO-102 using flow cytometry. O-glycan array analysis identified O-glycans terminating with α(2,6) sialic acids, including core 2 O-glycans and sTn glycans, expressed by human cancer cell lines reactive with PB-223 in flow cytometry, as the specific binding epitope of PB-223. IHC analysis of human tumor tissues showed that PB-223 does not bind to healthy tissues tested in this study, and that demonstrates an increase in the number of cancer tissues recognized and in the IHC score compared to NEO-102. PB-223 is internalized into a human cancer cell line expressing its target antigen. Conclusions: PB-223 can potentially be used as a targeting moiety for antibody-based therapeutics, including antibody–drug conjugates (ADCs), bispecific antibodies, immune-engaging constructs, and radiopharmaceuticals, for the treatment of human cancers expressing O-glycans terminating with α(2,6) sialic acids, including core 2 O-glycans and sTn glycans. Full article

Background/Objectives: Lutetium (¹⁷⁷Lu) TLX591 (¹⁷⁷Lu-TLX591) is a radio antibody–drug conjugate (rADC) that utilizes a novel monoclonal antibody-based approach for treatment of patients with prostate-specific membrane antigen (PSMA)-expressing metastatic castration-resistant prostate cancer (mCRPC). ProstACT SELECT (NCT04786847) was a multicenter, single-arm, open-label Phase 1 trial evaluating patient selection for ¹⁷⁷Lu-TLX591 therapy using ⁶⁸Ga-PSMA-11 PSMA positron emission tomography (PET) in a heterogenous sample of patients with mCRPC. Primary and key secondary objectives were to evaluate safety and tolerability, biodistribution, and organ radiation dosimetry of ¹⁷⁷Lu-TLX591 in combination with the best standard of care (SOC) for patients with PSMA-expressing mCRPC who progressed despite prior treatment with an androgen receptor pathway inhibitor. Methods: Thirty patients received ¹⁷⁷Lu-TLX591 intravenously in combination with investigator-determined SOC. Cohort 1 (n = 5) received an imaging dose of ¹⁷⁷Lu-TLX591 (1 GBq [27 mCi]), followed 14 days later by one therapeutic dose (2.8 GBq [76 mCi]). Cohort 2 received two therapeutic doses of ¹⁷⁷Lu-TLX591, 14 days apart. Baseline ⁶⁸Ga-PSMA-11 PET was performed to confirm eligibility and was qualitatively compared with serial ¹⁷⁷Lu-TLX591 single-photon emission computed tomography (SPECT)/CT, which was performed at five timepoints following the first ¹⁷⁷Lu-TLX591 administration and also used to evaluate organ radiation dosimetry. Safety assessments included monitoring for treatment-emergent adverse events and collection of laboratory samples at specified timepoints used for biomarker analyses. Results: Tumor targeting observed on ¹⁷⁷Lu-TLX591 SPECT/CT imaging was qualitatively consistent with uptake observed on ⁶⁸Ga-PSMA-11 PET imaging. No new safety signals were observed. Radiation exposure was within safety limits, with the highest absorbed dose to liver (clearance organ; 2.44 ± 0.56 Gy/GBq) and with lower exposure to salivary glands (0.07 ± 0.03 Gy/GBq) and kidneys (0.64 ± 0.17 Gy/GBq). Activity was retained in tumor lesions through to the final protocol-specified imaging timepoint (312 h) following administration. Conclusions: In this Phase 1, single-arm study, ⁶⁸Ga-PSMA-11 PET supported patient selection for ¹⁷⁷Lu-TLX591 therapy. In a heterogenous population representative of a real-world setting, ¹⁷⁷Lu-TLX591 therapy in combination with SOC demonstrated a manageable and predictable safety profile, durable retention, and low salivary gland radiation exposure. Further evaluation in larger, randomized studies is warranted. Full article

Background: Urothelial carcinoma (UC) is a significant clinical problem, especially in locally advanced and metastatic stages, where the prognosis remains poor despite advances in immunotherapy. Enfortumab vedotin (EV), an antibody–drug conjugate (ADC) targeting Nectin-4, extends beyond direct cytotoxicity by actively modulating the immunosuppressive tumor microenvironment (TME) in preclinical models, creating a strong rationale for combination strategies. This systematic review aimed to evaluate the clinical efficacy, safety, and hypothesized immune-modulating potential of EV in the treatment of UC, particularly in combination with immunotherapy. Materials and Methods: The review was conducted in accordance with the PRISMA 2020 guidelines. PubMed, Web of Science, and ClinicalTrials.gov databases were searched to identify interventional clinical studies published between 2020 and 2026. Studies evaluating EV used as monotherapy or in combination with immunotherapy in adult patients with UC were analyzed. ORR, PFS, OS, and the incidence of treatment-related adverse events were evaluated. Individual publications originating from the same clinical trial programs were treated as linked records and analyzed collectively. Results: The analysis was primarily based on key clinical trial programs, including EV-103, EV-301, and EV-302, along with their subgroup analyses, follow-up reports, and patient-reported outcomes. EV demonstrated significant clinical efficacy in the treatment of locally advanced UC (laUC). In the EV-301 study, EV therapy significantly prolonged overall survival compared to chemotherapy (12.88 vs. 8.97 months). In the EV-302 study, EV combination therapy with pembrolizumab showed a significant improvement in progression-free survival and overall survival compared to platinum-based chemotherapy. Conclusions: EV represents a significant therapeutic advance not only as a cytotoxic agent but as a potent immune modulator with clinical efficacy that may be enhanced by its biologically hypothesized immunomodulatory mechanisms in mUC. Its clinical development reflects a critical shift from later-line monotherapy toward earlier-line combination strategies designed to target both tumor cells and the microenvironment. Further studies are needed to better define its role in the context of alternative treatment approaches and across different stages of disease. Full article

Transformative therapeutic innovation should not begin with a molecule—or even a molecular target. It should begin with a clearly defined unmet clinical need. Here, we present a seven-step Translational Therapeutic Development Roadmap that systematically connects an unmet medical need to a developable drug candidate through the disciplined sequence of (i) defining the need, (ii) understanding disease and resistance biology, (iii) building a mechanistic hypothesis, (iv) defining a target product profile (TPP), (v) molecular design and experimental validation, (vi) developability and manufacturability assessment, and (vii) clinical translation. A central conclusion emerging from this review is that resistance biology should be viewed not merely as a cause of therapeutic failure, but as a primary design input for next-generation therapeutic innovation. Our analysis identifies continuous alignment among unmet clinical needs, resistance biology, mechanistic hypothesis, molecular design, developability, and clinical translation as the defining characteristic of successful therapeutic development. We use dual-payload antibody–drug conjugates (ADCs) as a contemporary and highly illustrative case study of this resistance-informed therapeutic development approach. Single-payload ADCs such as trastuzumab deruxtecan and sacituzumab govitecan have transformed treatment across multiple solid tumors, yet most patients ultimately relapse through antigen loss, defective intracellular trafficking, drug efflux, payload-target alterations, and tumor heterogeneity, creating an emerging post-ADC treatment gap. Dual-payload ADCs, which deliver two mechanistically distinct warheads from a single antibody, represent a form of molecular combination therapy designed to increase the barrier to resistance and address multiple escape pathways simultaneously, as well as provide a clinically relevant model for resistance-informed therapeutic design. Using dual-payload ADCs as a worked example, we demonstrate how resistance biology directly informs payload pairing, molecular architecture, conjugation strategy, experimental validation, and developability. Our analysis indicates that successful dual-payload ADC design depends not simply on combining two cytotoxic payloads, but on selecting complementary mechanisms with non-overlapping resistance liabilities while satisfying predefined target product profiles and manufacturability requirements. We further summarize resistance-guided payload pairing strategies, including topoisomerase I plus tubulin inhibitors, topoisomerase I plus DNA-damage-response inhibitors, cytotoxic plus immunomodulatory payloads, and cell-permeable plus non-permeable combinations; the conjugation chemistries that enable defined dual-payload products; the preclinical validation, pharmacological optimization, and developability hurdles that separate promising biology from viable therapeutics; and the rapidly expanding clinical landscape, including the first-in-human program KH815 and emerging bispecific dual-payload constructs. Finally, we demonstrate that the same translational roadmap extends beyond ADCs to radiopharmaceutical conjugates, multispecific antibodies, targeted protein degraders, and cell and gene therapies, indicating that it represents a general framework for therapeutic innovation rather than an ADC-specific strategy. Collectively, this review supports the concept that therapeutic innovation is most successful when unmet clinical needs, resistance biology, molecular design, developability, and clinical translation are considered as an integrated continuum rather than as independent stages of drug discovery. This Translational Therapeutic Development Roadmap provides an organizing framework for guiding the rational development of next-generation targeted therapeutics across diverse therapeutic modalities. Full article

Pancreatic cancer remains one of the most aggressive and lethal malignancies, characterized by late-stage diagnosis, profound molecular heterogeneity, and limited responsiveness to conventional cytotoxic therapies. Recent advances in molecular diagnostics and biomarker-driven treatment stratification have accelerated the development of precision therapeutic approaches aimed at improving outcomes in selected patient populations. This review highlights three mechanistically distinct yet complementary therapeutic strategies that illustrate the evolving landscape of personalized pancreatic cancer management. Adagrasib represents targeted inhibition of oncogenic KRAS G12C signaling, reflecting recent progress in directly targeting historically “undruggable” driver mutations. Dostarlimab illustrates the tissue-agnostic application of immune checkpoint blockade in pancreatic cancers harboring mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H), highlighting the growing importance of biomarker-defined immunotherapy-responsive subsets despite the limited pancreatic cancer-specific clinical evidence currently available. Trastuzumab deruxtecan represents a next-generation HER2-directed antibody–drug conjugate (ADC) and demonstrates the potential of HER2-targeted therapy in the small subgroup of patients with HER2-positive pancreatic cancer, although the available evidence is derived primarily from basket trials and tumor-agnostic clinical development. Collectively, these therapeutic approaches underscore the expanding role of biomarker-guided treatment strategies integrating targeted inhibition, immunotherapy, and precision cytotoxic payload delivery. This review summarizes the molecular rationale, available clinical evidence, therapeutic limitations, and resistance mechanisms associated with these approaches while discussing emerging directions in translational research, rational combination strategies, liquid biopsy applications, and precision oncology that may further refine individualized treatment algorithms for pancreatic cancer. Full article

The treatment landscape of oncogene-driven non-small-cell lung cancer (NSCLC) has evolved substantially with the development of targeted therapies directed against actionable molecular alterations. Tyrosine kinase inhibitors (TKIs) remain the cornerstone of treatment for many driver-defined subsets; however, acquired resistance, central nervous system progression, and tumor heterogeneity continue to limit long-term disease control. This review examines the mechanistic foundations, clinical evidence, resistance patterns, and emerging therapeutic roles of TKIs, antibody–drug conjugates (ADCs), and bispecific antibodies (bsAbs) in oncogene-driven NSCLC. Relevant preclinical studies, clinical trials, and recent therapeutic advances across major actionable driver alterations were reviewed and compared. TKIs provide potent and selective inhibition of oncogenic signaling and remain the preferred frontline therapy in most molecular subgroups, whereas ADCs offer targeted payload delivery that may overcome diverse resistance mechanisms, and bsAbs provide dual-target blockade and immune-mediated antitumor activity. Emerging evidence supports the expanding role of ADCs and bsAbs in post-TKI settings and selected biomarker-defined populations. Resistance mechanisms differ across therapeutic classes and include secondary target alterations, bypass pathway activation, antigen loss, payload resistance, and receptor adaptation. Collectively, these modalities are increasingly being integrated into biomarker-guided treatment strategies, with future management likely to rely on rational sequencing and combination approaches tailored to resistance mechanisms, target expression, central nervous system involvement, and tumor heterogeneity. Full article