Search Results (981)

Cytoreductive surgery remains one of the key treatment modalities in advanced ovarian cancer. Complete cytoreduction is the main surgical goal. PARP inhibitors are currently established mainly as maintenance therapy after response to platinum-based chemotherapy, particularly in patients with BRCA-mutated or homologous recombination-deficient tumors. Their use before cytoreductive surgery remains investigational. This review evaluates preoperative PARP inhibition from a surgical perspective. This narrative review summarizes current evidence, ongoing clinical trials, and perioperative considerations related to preoperative or neoadjuvant PARP inhibitor strategies in advanced ovarian cancer. Particular attention was given to the review of current clinical trials’ strategies, resectability, complete cytoreduction, patient selection, perioperative safety, treatment timing, and surgery-specific endpoints. Current studies explore several preoperative approaches, including short window-of-opportunity treatment before primary debulking surgery, PARP inhibitor monotherapy as potential conversion therapy in homologous recombination-deficient disease, PARP inhibitor-based strategies before interval debulking surgery, combination regimens with immunotherapy or antiangiogenic therapy, and preoperative PARP inhibitor use before secondary cytoreduction in recurrent disease. These studies suggest that preoperative PARP inhibition may provide biological and surgical insights, but available evidence remains preliminary. Key concerns include hematologic toxicity, surgical postponement, perioperative complications, wound healing, postoperative recovery, and the risk of delaying standard chemotherapy or surgery. Preoperative PARP inhibitor therapy is theoretically promising but an unproven strategy in ovarian cancer. Its future value will depend on prospective trials showing that it can safely improve resectability and complete cytoreduction without compromising treatment timing. Future studies should include surgery-specific endpoints in addition to conventional oncologic outcomes. Full article

Ovarian cancer (OVC) is a leading cause of gynecological cancer mortality due to late-stage diagnosis and chemoresistance. Among the multiple molecular mediators, oncogenic epidermal growth factor receptor (EGFR) signaling has emerged as a key regulator of tumor progression and drug resistance, ultimately governing cancer survival. Therefore, this review focused on the molecular mechanisms of aberrant EGFR signaling to promote chemoresistance in ovarian cancer through multiple interlinking pathways, including the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of the rapamycin (mTOR), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling cascades. These pathways act in concert to confer resistance, including proliferation, antiapoptotic effects, cancer stem cell maintenance, and facilitating epithelial-mesenchymal transition (EMT), which function together to decrease sensitivity towards platinum-based and taxane chemotherapies. Furthermore, we incorporate novel evidence regarding EGFR cross-talk with extracellular matrix (ECM) and metabolic reprogramming, especially their relevance to immune evasion mechanisms, hypoxia, and extracellular vesicles (EVs)-mediated signaling. In addition, we elaborated on the limitation of the current EGFR targeting therapy, which will be beneficial for further designing new combinatorial treatment approaches by using EGFR inhibitors with immunotherapy, nanocarriers, and microbiota modulators. Overall, this review highlights the updated role of EGFR signaling as a key regulator of chemoresistance in ovarian cancer, providing insights for developing targeted therapies to overcome drug resistance and improve patient survival. Full article

Squamous cell lung cancer (SqCLC) accounts for 20–30% of non-small cell lung cancer (NSCLC) and remains associated with a poorer prognosis compared with adenocarcinoma. Despite advances in treatment, 5-year overall survival for advanced (stage IV) disease remains below 10–15%. Unlike non-squamous NSCLC, SqCLC is characterized by a high tumor mutational burden and complex genomic landscape dominated by alterations in tumor suppressor genes and lineage survival pathways including TP53, CDKN2A, PIK3CA, FGFR1, SOX2, and the NFE2L2/KEAP1 oxidative stress pathway, as well as dysregulation of the NOTCH signaling pathway, but it harbors relatively few actionable oncogenic drivers, resulting in limited treatments for targeted therapy. HER2 alterations can occur by multiple mechanisms, including activating mutations, gene amplifications, and protein overexpression. They comprise a very small percentage of NSCLC, with HER2 mutations reported in approximately 1–3% and HER2 amplifications observed roughly in 2–4%. While HER2 alterations are well characterized in lung adenocarcinoma, the prevalence, genomic context, and clinical significance of HER2 alterations in SqCLC remain incompletely defined. Advances in next-generation sequencing have led to improved ability to detect HER2 alterations and facilitated the development of HER2 targeted therapies. Available treatments for advanced/metastatic SqCLC have been historically limited to platinum-doublet chemotherapy, with immune checkpoint inhibitors such as anti-PD-1/PD-L1 newly emerging in the past decade. Selective HER2 tyrosine kinase inhibitors and HER2 antibody/drug conjugates have shown improved efficacy in HER2-altered NSCLC as shown in DESTINY-LUNG02 and BEAMION LUNG-1 trials; however, most of the enrolled patients had non-squamous histology, with minimal or no SqCLC-specific efficacy data reported. Future progress in HER2-altered SqCLC will require inclusion of SqCLC in HER2 basket trials, incorporation of comprehensive molecular profiling and standardized HER2 testing in squamous histology. This review summarizes the current state of knowledge of HER2 biology in SqCLC and highlights areas for future directions for precision oncology in SqCLC. Full article

Ovarian cancer is a major cause of gynecological cancer mortality, frequently associated with platinum-resistant recurrences. Given the limited efficacy of conventional chemotherapy in this setting, alternative targeted therapeutics are needed. Mirvetuximab soravtansine (MIRV) is an antibody–drug conjugate designed to deliver the cytotoxic maytansinoid DM4 to folate receptor alpha (FRα)-overexpressing cells. This systematic review of PubMed, ClinicalKey, and SpringerLink databases (2019–2026) evaluates five publications across three clinical trials (one phase II, two phase III) encompassing 925 patients with platinum-resistant disease. Notably, the phase III MIRASOL trial demonstrated improved survival outcomes with MIRV over standard chemotherapy, extending median overall survival (16.46 vs. 12.75 months; HR 0.67) and progression-free survival (5.62 vs. 3.98 months; HR 0.65), with an objective response rate (ORR) of 42.3% versus 15.9%. Furthermore, the single-arm phase II SORAYA trial reported an ORR of 32.4% in pretreated patients, including those with prior PARP inhibitor and bevacizumab exposure. Although the preceding FORWARD I trial missed its primary endpoint in the unselected population, its high-FRα subgroup analysis revealed a clinical benefit that influenced subsequent biomarker-driven enrollment strategies. From a safety perspective, MIRV exhibited lower rates of severe neutropenia and anemia than chemotherapy, with toxicities primarily consisting of manageable, reversible ocular events. Ultimately, MIRV serves as a therapeutic option for platinum-resistant, FRα-positive ovarian cancer, offering survival advantages; however, rigorous biomarker-based screening remains necessary to optimize therapeutic outcomes. Full article

Background: Metal-based anticancer drugs, particularly platinum and gold complexes, play a central role in chemotherapy but are often limited by systemic toxicity, resistance, and suboptimal selectivity. Peptide conjugation has emerged as a versatile strategy to modulate the pharmacokinetic and biological properties of metal complexes, enabling targeted delivery, improved uptake, and controlled activation. This review aims to critically analyze platinum- and gold-peptide bioconjugates in cancer therapy, focusing on directly reactive metal complexes and redox-activated prodrug systems. Methods: Relevant literature from the past two decades was surveyed across major scientific databases, focusing on the design, conjugation strategies, biological activity, and mechanisms of action of Pt- and Au-peptide bioconjugates. Results: Reviewed studies reveal distinct behavior for platinum- and gold-based systems. Pt(II)-peptide conjugates primarily retain DNA-reactive interaction, with peptides mainly enhancing cellular uptake, selective targeting and solubility, although improved cytotoxicity is not consistently achieved. In contrast, Pt(IV)-peptide conjugates function as prodrugs, where axial peptide functionalization allows greater structural versatility and sometimes improved selectivity, with therapeutic efficacy strongly depending on intracellular reduction kinetics. Au(I)-peptide conjugates act as directly reactive species targeting thiol- and selenol-containing proteins, whereas Au(III) bioconjugates often behave as redox-activated prodrugs, with peptide conjugation influencing stability and cellular fate. Conclusions: Overall, peptide conjugation represents a powerful but non-trivial approach for optimizing metal-based anticancer agents. The success of metal-peptide bioconjugates critically depends on balancing peptide-mediated delivery with the intrinsic reactivity and activation pathways of the metal center. A function-guided design of bioconjugates is essential to achieve genuine selectivity and therapeutic benefit. Full article

Background/Objectives: Homologous recombination deficiency (HRD) is a predictive biomarker in high-grade serous ovarian carcinoma for platinum-based chemotherapy and PARP inhibitors. The implementation of HRD testing in routine diagnostics has generated multiple commercial assays that differ in genomic targets, bioinformatic analysis, and HRD scoring strategies. We aimed to assess the analytical performance and feasibility of a locally semi-automated workflow based on the Agilent SureSelect CD HRR17 panel with SeqOne/SomaHRD analysis, and to compare it with established commercial HRD assays currently used in routine clinical practice: Myriad MyChoice CDx and SOPHiA DDM Dx HRD Solution. Methods: Thirty high-grade serous ovarian carcinoma cases diagnosed between 2019 and 2023 were retrospectively analyzed. HRD status was assessed with the Agilent-SeqOne workflow and compared with Myriad (n = 12) and SOPHiA (n = 18). Concordance and correlation between genomic instability metrics were evaluated. Results: The Agilent/SeqOne workflow showed high concordance with both comparison workflows. Genomic instability metrics strongly correlated across assays (R² up to 0.96). A lower proportion of inconclusive classifications was observed with the Agilent/SeqOne workflow. Discordances were mainly observed in borderline cases near classification thresholds. Variant detection was highly concordant within shared genomic regions. Conclusions: The locally semi-automated HRD workflow demonstrated high analytical concordance with established commercial assays in evaluable cases. Operational advantages related to workflow flexibility and local reanalysis support its potential implementation in routine molecular diagnostics. Full article

Background: Pembrolizumab-based therapy is a standard first-line option for advanced non-small-cell lung cancer (NSCLC), yet pivotal clinical-trial populations may not reflect patients encountered in routine practice. Real-world cohorts enriched for Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 and high metastatic burden remain underreported. We assessed real-world outcomes of first-line pembrolizumab in a heterogeneous cohort enriched for these. Methods: Retrospective cohort analysis of 45 patients with advanced NSCLC who received first-line pembrolizumab-based therapy (monotherapy or with platinum-based chemotherapy) at a single health maintenance organization in Israel between September 2017 and April 2020. Results: Mean age was 69.3 years (SD 9.0), 82.2% were male, 91.1% were current or former smokers, 37.8% had ECOG PS ≥2 (including 17.8% with ECOG ≥3), and 53.3% had three or more metastatic organ sites. PD-L1 expression was ≥50% in 46.7%, 1–49% in 13.3%, and <1% in 22.2%. After a median follow-up of 48.7 months (88.9% event rate), median overall survival (OS) was 8.87 months (95% CI, 5.88–14.32) and median progression-free survival (PFS) was 4.20 months (95% CI, 2.76–6.18), with an objective response rate of 46.7% and a disease control rate of 68.9%. On univariate Cox regression, the number of metastatic sites was most strongly associated with OS (HR 1.41 per site, 95% CI, 1.17–1.70, p = 0.0003). PD-L1 expression was significantly associated with both PFS (p < 0.0001) and OS (p = 0.0012), with the longest survival observed in patients with PD-L1 ≥50%. Conclusions: In this real-world cohort enriched for poor performance status and high metastatic burden, pembrolizumab-based therapy provided clinical benefit, but observed survival was substantially shorter than that reported in pivotal trials. Full article

Background: Platinum-based chemotherapy is the frontline treatment for high-grade serous ovarian cancer (HGSOC); however, the development of therapy resistance greatly limits clinical response. Increasing evidence suggests that platinum agent-driven metabolic programming, particularly within redox-associated pathways, may contribute to chemoresistance. Methods: A syngeneic pair of patient-derived HGSOC cell lines representing cisplatin-sensitive (SE) and cisplatin-resistant (CR) states were evaluated using a multi-omics approach. Differential metabolite abundance and gene expression were assessed, followed by gene set and pathway enrichment analyses to identify coordinated metabolic shifts. In silico analysis of an additional sensitive and resistant HGSOC cell line validated the glutathione pathway upregulation seen in the patient-derived model. The functional contribution of the glutathione pathway on cisplatin resistance was evaluated following glutathione inhibition. Results: Chronic cisplatin exposure induced extensive metabolic rewiring in CR cells, characterized by enrichment of glutathione metabolism at both the metabolite and gene levels. Increased reduced glutathione was observed alongside upregulation of key enzymes involved in its de novo biosynthesis, recycling, and utilization, consistent with enhanced detoxification capacity relating to cisplatin-induced oxidative stress. Additionally, taurine was highly enriched, further highlighting a metabolic shift towards enhanced antioxidant mechanisms. CR cells also demonstrated an increase in NADPH-generating pathways, including amino acid metabolism and fatty acid β oxidation, to support redox balance and biosynthetic demands of increased glutathione metabolism. Transcriptional remodeling of the γ-glutamyl cycle further indicated a shift toward increased glutathione turnover, suggesting that the coordinated changes seen may define a metabolic state enhanced in oxidative stress tolerance and therapeutic resistance. These transcriptional changes were also seen in another model of platinum sensitivity/resistance, indicating a conserved response associated with platinum-induced resistance. Finally, concurrent cisplatin treatment and glutathione inhibition significantly increased sensitivity within the CR cells. Conclusions: These findings suggest that cisplatin-resistant cells, previously exposed to a platinum-based agent, may undergo distinct metabolic rewiring towards antioxidant pathways to survive chronic chemotherapeutic stress. Targeting components of these systems may represent a viable strategy to overcome platinum resistance and improve therapeutic outcomes. Full article

Background: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignancy with a high risk of recurrence. While adjuvant radiotherapy is standard following surgical resection in high-risk disease, the additional benefit of platinum–etoposide chemotherapy and the prognostic role of tumor anatomical location remain uncertain. Methods: We conducted a multicenter retrospective cohort study including patients with high-risk MCC (stage IIB–III) treated with surgery followed by adjuvant radiotherapy with or without platinum–etoposide chemotherapy. Tumor sites were classified according to sun-exposure status. Disease-free survival (DFS) and overall survival (OS) were estimated using Kaplan–Meier methods and compared using the log-rank test, with subgroup analyses by anatomical region and stage. Results: A total of 103 patients were included, of whom 77 (74.8%) received adjuvant chemoradiotherapy and 26 (25.2%) received radiotherapy alone. Patients with non-sun-exposed tumors demonstrated longer survival outcomes than those with sun-exposed tumors, with a median DFS of 57 months versus 42 months (p = 0.15), and a median OS of 179 months versus 109 months (p = 0.054), respectively. Among patients with sun-exposed tumors, chemoradiotherapy was associated with numerically improved DFS (42 vs. 34 months; p = 0.051) and OS (128 vs. 98 months; p = 0.08) compared with radiotherapy alone. In patients with non-sun-exposed tumors, chemoradiotherapy demonstrated a more pronounced improvement in OS (178 vs. 56 months; p = 0.054), while DFS also favored combined treatment (49 vs. 78 months; p = 0.078). Conclusions: In this multicenter cohort, adjuvant chemotherapy did not demonstrate a uniform survival benefit overall but was associated with improved outcomes in head and neck MCC, suggesting a potential site-specific effect. Similar outcomes across stage III subgroups suggest that chemotherapy may mitigate stage-related prognostic differences. These findings support a selective approach to adjuvant chemotherapy and highlight the need for prospective studies incorporating modern immunotherapy strategies. Full article

The disadvantages of Cisplatin in anticancer treatment are connected to its poor selectivity, resistance developed of cancers to the drug, and its toxicity against normal organs. An important strategy in anticancer treatment is the synthesis and clinical investigation of non-platinum metal complexes with superior anticancer activity and improved selectivity compared to Cisplatin, combined with lower toxicity, fewer side effects and decreased resistance of cancer to the drug. In the current study, we aim to summarize the potential of important non-platinum metal-based organic compounds as therapeutic agents against different cancer cell types. The review covers the general principles of chemotherapy. A literature analysis shows that organic complexes of the metalloids arsenic (As), boron (B), antimony (Sb), and selenium (Se), and of metals, such as Ag, Au, Co, Cu, Fe, Mn, Mo, Ni, Zn, Ce, Ga, Gd, Ir, Os, Pd, Re, Rh, Ru, Ti, and V, have been investigated for potential applications in cancer therapy. This is due to their antiproliferative effects against different cancer types: lung [Cd(II), Co(II), Cu(II), Ni(II), Mn(II), Ru(II), Zn(II)]; breast [Ag(I), Cu(I), Cu(II), Ir(III), Ni(II), Mn(II),. Rh(III), Ru(II)]; gastric [Cu(II), Cu(II)-La(III)]; colon [Ag(I), Cu(II), Ir(III), Pd(II), Rh(III), Ru(II), vanadium(V)]; colorectal [Ag(I), Co(II), Cu(II), Zn(II)]; liver [Ag(I), Co(II), Cu(II), Gd(III), vanadium(V)]; pancreatic [vanadium(IV)]; bladder [Ag(I), Cu(II), Ru(II)]; cervical [Ag(I), Au(I), Cu(I), Cu(II), Fe(II), Ir(III), Rh(III), Ru(II)]; testicular [vanadium(IV)]; prostate [Cu(II), Pd(II), Zn(II)]; leukemia [Ag(I), Co(II), Cu(II), Pd(II), Zn(II)]; sarcoma [Co(II), Ni(II), Zn(II)]; mesothelioma [Cu(II)]; neuroblastoma [Cu(II)]; glioma [Cu(II)]; and melanoma [Au(I), Cu(II), Pd(II), Ru(II)]. The main goals for increasing anticancer metal-based complexes include increasing anticancer activity and selectivity, reducing toxicity, and avoiding cancer cell resistance. Compared to Cisplatin, organocomplexes of copper, ferrocene, and ruthenium are more active. Ruthenium and copper complexes, in particular, are also more selective. Notably, ruthenium and ferrocene derivatives are less toxic than Cisplatin. Lastly, cancers appear to exhibit less resistance against copper, gold, ruthenium, palladium, and ferrocene complexes. Full article

Background/Objectives: Perioperative chemo-immunotherapy (CHT-IO) has emerged as a standard treatment strategy for resectable stage II–IIIB NSCLC. However, data regarding surgical feasibility, mini-invasive surgery rates, perioperative outcomes, and postoperative complications in real-world single-center experiences remain limited. Methods: A retrospective single-center analysis was performed including consecutive patients with locally advanced NSCLC treated with perioperative chemo-immunotherapy between March 2024 and March 2026. Patients received platinum-based chemotherapy combined with pembrolizumab or durvalumab, followed by surgical resection with curative intent. Surgical, pathological, and postoperative outcomes were analyzed. Results: Thirty patients received neoadjuvant CHT-IO, of which 25 (83.3%) underwent surgical resection. Reasons for failure to proceed to surgery included treatment-related toxicity or deterioration in performance status (n = 3), disease progression (n = 1), and patient refusal (n = 1). Lobectomy was the most performed procedure (64%), while a minimally invasive approach (uniportal VATS) was adopted in 44% of cases. Moderate-to-severe pleural adhesions (64%) and hilar fibrosis (60%) were observed intraoperatively. Despite these technical challenges, conversion to thoracotomy was required in only one case (4%), no intraoperative complications occurred, and complete (R0) resection was achieved in 96% of patients. Pathological complete response and major pathological response were observed in 36% and 52% of cases, respectively. Postoperative complications occurred in 56% of patients, although most were Clavien–Dindo grade I–II. The presence of comorbidities was the only factor associated with an increased risk of postoperative complications (OR 10.00, 95% CI 0.99–100.46; p = 0.05). Median length of hospital stay was 5.65 ± 2.04 days. One postoperative death due to septic complications was recorded. Conclusions: In this real-world monocentric experience, the combination of perioperative CH-ICIs and surgical resection (including mini-invasive approach) was safe and feasible in patients with locally advanced NSCLC. High rates of complete (R0) resection and encouraging pathological responses were observed, consistent with outcomes reported in randomized trials. Although surgery was overall frequently technically demanding, these changes did not appear to compromise perioperative safety or oncological radicality, even when minimally invasive approaches were adopted. Larger studies with longer follow-up are needed to better define long-term oncological outcomes. Full article

Background: Gemcitabine, cisplatin and durvalumab or pembrolizumab are standard first-line treatments for advanced or metastatic biliary tract cancer (BTC). Older patients with BTC may be frail or have contraindications to cisplatin. At our institution, oxaliplatin has been used as an alternative to cisplatin. Methods: In this evaluation, we report the safety and efficacy of gemcitabine with oxaliplatin and durvalumab as a first-line treatment of BTC. The primary objective was overall survival (OS). Secondary objectives included time to progression (TTP), disease control rate (DCR), and the incidence of treatment-related toxicities. Results: Twenty-nine patients were included. The majority were Caucasian (97%) and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 (97%). Median age was 72 years old. Sixty-six percent had intrahepatic cholangiocarcinoma. Baseline renal insufficiency and/or hearing impairment were the most common reasons for cisplatin contraindication. Median follow-up was 20.6 months. Treatment cycles were every 28 days with durvalumab (1500 mg) given on day 1 and gemcitabine (range 600 mg/m²–1000 mg/m²) plus oxaliplatin (median dose 70 mg/m²) given on days 1 and 15. Median OS was 15.7 months (95% CI: 6.9-NA), median TTP was 6.7 months (95% CI 3.88-NA), and DCR was 76%. Median time on treatment was 3.15 months. Twelve patients (41%) required a dose adjustment, with myelosuppression as the most common toxicity. Conclusions: Oxaliplatin, in combination with durvalumab and gemcitabine, is a suitable platinum substitute for advanced BTC patients when cisplatin is contraindicated. Our analysis showed similar efficacy and no new safety concerns. Given the small sample size, our analysis is hypothesis-generating and calls for a larger prospective analysis. Full article

Background: Platinum-resistant ovarian cancer with peritoneal metastases remains a therapeutic frontier marked by limited systemic efficacy and a persistent unmet clinical need for effective locoregional strategies. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has emerged as a novel minimally invasive platform designed to enhance intraperitoneal drug distribution and overcome biological barriers to chemotherapy delivery. Methods: We performed a PRISMA-compliant systematic review and meta-analysis evaluating clinical outcomes of PIPAC in platinum-resistant ovarian cancer. Primary endpoints included histologic regression (PRGS ≤ 2), severe toxicity, and 12-month overall survival, complemented by exploratory analyses of treatment feasibility, disease burden dynamics, and bidirectional therapy strategies. Results: PIPAC demonstrated a consistent signal of biologic activity, with pooled histologic response rates indicating meaningful tumor regression despite advanced disease. Severe toxicity remained low across studies, supporting the favorable tolerability of repeated intraperitoneal treatment. Survival outcomes were clinically relevant for a heavily pretreated population, while feasibility analyses suggested that PIPAC may facilitate downstream surgical opportunities in selected patients. Exploratory findings further supported the concept of intraperitoneal disease modulation, reflected by reductions in peritoneal cancer index and integration within multimodal treatment pathways. Conclusions: Beyond a purely palliative intervention, PIPAC may represent a biologically active component of personalized treatment strategies for platinum-resistant ovarian cancer. These findings redefine the therapeutic narrative from symptom control toward disease modulation and treatment escalation, underscoring the need for prospective trials to refine patient selection and optimize multimodal sequencing. Full article

Antibody-drug conjugates (ADCs) have transitioned from clinically marginal agents into a defining therapeutic class for solid tumor oncology. In DESTINY-Breast03, trastuzumab deruxtecan achieved a four-fold progression-free survival advantage over trastuzumab emtansine, attributable not to antibody engineering but to the linker-payload axis: a cleavable peptide linker and a topoisomerase I payload with bystander activity. Sacituzumab govitecan extends the same logic to Trop-2-positive disease via extracellular payload release, and the framework now spans breast, urothelial, gynecologic, lung, gastric, and colorectal cancers, with enfortumab vedotin plus pembrolizumab displacing platinum chemotherapy as first-line therapy for urothelial cancer in EV-302 (median overall survival 31.5 versus 16.1 months). This review synthesizes ADC biology along three analytical axes. The mechanistic axis links each linker-payload-DAR configuration to a specific tumor-biology barrier: vascular limitation, which delivers approximately 0.1% of the administered dose to tumor tissue; the binding-site barrier, which concentrates exposure at the perivascular margin; and antigen mosaicism, which defeats internalization-dependent killing. The translational axis examines resistance as a coordinated failure across antigen modulation, trafficking, efflux, apoptotic execution, and lysosomal processing. The clinical axis traces the platform’s migration toward earlier-line and curative-intent settings. We close by examining whether the ADC delivery architecture translates to precision immunosuppression in autoimmune disease, where the glucocorticoid receptor modulator ADC ABBV-154 met placebo-controlled efficacy endpoints in rheumatoid arthritis but was discontinued because its benefit-risk profile did not differentiate it from existing biologic therapies. Full article

Background: Extensive-stage small cell lung cancer (ES-SCLC) carries a poor prognosis, with fewer than 7% of patients surviving for five years. While immune checkpoint inhibitors (ICIs) combined with platinum–etoposide have reshaped first-line treatment, no head-to-head trials exist comparing available regimens, leaving the optimal therapeutic choice undefined. Methods: A systematic literature search identified phase III randomized controlled trials (RCTs) evaluating first-line ICI-based regimens in ES-SCLC. Individual patient data (IPD) were reconstructed from Kaplan–Meier curves using the IPDfromKM algorithm. Indirect treatment comparisons were performed using Cox proportional hazards models, with chemotherapy alone as the common comparator. The indirect comparison of tiragolumab efficacy was unanchored due to the design of the SKYSCRAPER-02 study. Restricted mean survival time (RMST), truncated at 27 months, was calculated as an additional measure of treatment effect. Results: Six RCTs were included. All ICI-based regimens improved overall survival (OS) compared to chemotherapy alone, except ipilimumab (HR 0.97, 95% CI 0.86–1.09). Serplulimab demonstrated the most favorable OS benefit (HR 0.55, 95% CI 0.48–0.64; RMST 16.73 months), representing a gain of approximately 4 months over chemotherapy alone and 1.8–2.3 months over atezolizumab and durvalumab. The addition of tiragolumab to atezolizumab plus chemotherapy yielded no significant advantage over atezolizumab alone. Conclusions: This IPD-based indirect comparison suggests that serplulimab plus chemotherapy may offer the most favorable OS estimates S benefit among first-line ICI regimens for ES-SCLC, while durvalumab and atezolizumab remain effective standards of care. These findings are hypothesis-generating and highlight the need for prospective head-to-head comparative studies. Full article