Combination therapies integrating immune checkpoint inhibitors (ICIs) with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs), or dual ICI regimens, currently represent the standard of care for advanced clear cell renal cell carcinoma (ccRCC). However, in most favorable-risk patients according to the IMDC classification-particularly those with a low disease burden and without disease-related symptoms-first-line monotherapy with VEGFR-TKIs remains a valid option. This review summarizes the preclinical and clinical evidence supporting this approach, with the aim of guiding oncologists in personalizing therapy while minimizing overtreatment and toxicity.

Despite many treatment strategies available for metastatic renal cell carcinoma (mRCC), predictive biomarkers of response to immunotherapy are still needed. In this context, growing efforts have been devoted to translational research, especially focusing on the immune tumor microenvironment (I-TME). The Meet-URO 18 is a multicentric retrospective study assessing the I-TME of mRCC patients receiving ≥ 2nd line nivolumab, divided into responders and non-responders according to clinical benefit [progression-free survival ≥ 12 and ≤ 3 months]. The primary objective was to identify differential immunohistochemical and molecular patterns between the two groups. We present the transcriptomic analysis performed on primary tumor tissues using a custom NanoString panel of 66 genes from the D’Costa et al. signature, grouped into angiogenesis, T-effector response, tumor invasion, and calcium signaling. Forty-two samples (25 responders and 17 non-responders) underwent transcriptomic analysis using the NanoString 66-gene immune-oncology panel. Hierarchical clustering recapitulated the transcriptional axes described by D’Costa et al. but did not distinguish patients by immunotherapy response. No genes were significantly differentially expressed after multiple testing correction; however, CD34 showed the strongest nominal association with responder tumors and was upregulated in this group, but did not retain statistical significance after adjustment. CD34 expression also correlated with CD8+ T-cell infiltration. Our findings confirm the applicability of the D’Costa molecular signature and identify CD34 as the strongest nominally associated transcript in responder tumors, warranting further orthogonal and prospective validation.

CONTEXT:With new treatment strategies approved in metastatic hormone-sensitive prostate cancer (mHSPC), heterogeneity across trials hinders the physicians' choice for first-line treatment. OBJECTIVE:We conducted a systematic review and network meta-analysis to assess the efficacy of currently approved treatments for mHSPC stratifying patients according to their disease burden (high- vs. low-volume as per CHAARTED criteria) and onset of metastatic disease (synchronous vs. metachronous). INTERVENTION:Eleven randomized controlled trials (RCTs) published until October 30, 2024 were included. Treatment regimens were grouped as triplets for combinations of docetaxel, androgen receptor pathway inhibitors (ARPIs) and androgen-deprivation therapy (ADT), separate doublets for docetaxel plus ADT, ARPI plus ADT, or monotherapy for ADT alone. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Overall survival (OS) and radiographic progression-free survival (rPFS) outcomes were collected. OS as primary endpoint, and rPFS as secondary endpoint, were analyzed separately in high- and low-volume patients. Additional subgroup analyses accounted for timing of metastases categorized as high-volume/synchronous, high-volume/metachronous, low-volume/synchronous, and low-volume/metachronous disease. EVIDENCE SYNTHESIS:Triplet combinations prolonged significantly OS and rPFS in high-volume disease (P-score 0.99), and high-volume/synchronous disease (P-score 0.99). ARPI/ADT doublets performed best in low-volume patients (P-score 0.94), and low-volume/metachronous (P-score 0.99). In the high-volume/metachronous population, triplets, and doublets were equally effective. CONCLUSIONS:The results provide collective evidence for treatment selection based on disease volume and timing of metastasis with strongest survival benefits of triplets for high-volume/synchronous mHSPC patients and of ARPI doublets for low-volume disease.

Recent advances in metastatic prostate cancer (mCaP) have increasingly focused on molecularly targeted therapies, particularly those addressing alterations in DNA damage repair (DDR) pathways. Poly(ADP-ribose) polymerase inhibitors (PARPis) have demonstrated substantial and clinically meaningful efficacy in patients harboring homologous recombination repair (HRR) gene alterations, most notably BRCA1/2, as well as selected additional DDR genes. To expand the population that may benefit from PARPi therapy, multiple combination strategies are currently being explored. This narrative review provides an overview of the current evidence on the role of PARPi in mCaP, summarizes their clinical implementation, and discusses future perspectives, including rational combination approaches and potential applications in earlier disease stages. PARPi demonstrate the most pronounced and consistent efficacy in BRCA-mutated CaP. Patients with non-BRCA HRR alterations may derive heterogeneous but potentially meaningful benefit from PARPi, particularly when PARPi are combined with androgen-receptor pathway inhibitors (ARPI). While activity of PARPi monotherapy is limited in patients without detectable HRR alterations, emerging data indicate clinically relevant benefit in selected subgroups treated with PARPi-based combinations, potentially mediated by functional DNA repair deficiencies, androgen-receptor (AR)-PARP pathway crosstalk, or treatment-induced "BRCAness." Refinement of biomarker strategies and improved molecular stratification are, therefore, critical to extend PARPi benefit beyond classical HRR alterations. Nevertheless, a standardized framework defining the optimal timing of HRR testing and the clinical relevance of individual gene alterations remains to be established. PARPi are now firmly established as an important targeted treatment option in metastatic castration-resistant CaP (mCRCaP), with therapeutic efficacy closely linked to tumor genomic features. However, the identification of robust predictive biomarkers beyond BRCA1/2 and the optimal integration of combination therapies remain key challenges. Emerging evidence supports further evaluation of PARPi-based combinations, as well as their earlier use in disease stages such as metastatic hormone-sensitive CaP (mHSCaP), which may ultimately broaden their clinical impact.

BACKGROUND:Effective risk stratification is essential for guiding treatment decisions in patients with metastatic renal cell carcinoma (mRCC). The Meet-URO score is a novel prognostic model that integrates the International Metastatic RCC Database Consortium (IMDC) criteria with neutrophil-to-lymphocyte ratio (NLR) and the presence of bone metastases. Developed in the immunotherapy era, it has demonstrated superior prognostic accuracy compared to the IMDC score across various clinical settings and treatment strategies. Its validation in the context of first-line immune-based combinations has been awaited. METHODS:External validation of Meet-URO was performed using a large retrospective real-world cohort of mRCC patients treated with first-line immune-based combinations. Secondary analyses included a comparison with the IMDC score for predicting overall survival (OS) and progression-free survival (PFS). Additionally, restricted mean survival time (RMST) was assessed. RESULTS:A total of 1,418 patients were included in the analysis: 54% received ICI-ICI regimen (nivolumab plus ipilimumab), while 46% received the ICI-TKI combination. At baseline, 52.5% of patients had an NLR ≥ 3.2, and 32% had bone metastases. After a median follow-up of 26.8 months, the median OS and median PFS were 34.7 and 11.3 months, respectively. Meet-URO demonstrated effective prognostic stratification, identifying patient groups with markedly different outcomes (median OS 11.5-51.4 months; 3-year OS 26-66%; RMST 20.0-42.8 months). Compared to IMDC, Meet-URO showed a significantly better OS (c-index 0.675 vs 0.643; Δc = 0.032, P < .001) and PFS (c-index 0.60 vs 0.58; P < .001) prediction performance. CONCLUSIONS:Meet-URO demonstrated robust prognostic accuracy. Its integration into routine clinical practice and use as a stratification factor in clinical trials may support more personalized treatment strategies and enhance clinical trial design.

Sexual dysfunction is common after prostate radiotherapy, yet communication barriers remain unclear. This multinational study assessed radiation oncologists’ practices, attitudes, and sexual-health training. The International Geriatric Radiotherapy Group (IGRG) disseminated a 38-item cross-sectional survey to radiation oncologists across 17 countries. The instrument captured demographics, discussion frequencies, perceived barriers, referral patterns, and attitudes toward oncosexuality. Data was analyzed with descriptive statistics, chi-square tests, and multivariable logistic regression. An exploratory sensitivity analysis restricted to respondents reporting regular management of patients receiving radiotherapy with potential impact on sexual health (≥ 1 such patient per month) was performed. Among 117 radiation oncologists, 87

Predicting response to PD-L1 immunotherapy in metastatic cancer from computed tomography (CT) is challenging in data-scarce, imbalanced cohorts requiring generalization from few annotated lesions and subtle pre-treatment phenotypes. We present HypDeformNet, an edge-deployable framework combining morphology-conditioned hyperbolic deformations with Jacobian stability constraints and Lipschitz-controlled online teacher-student distillation in hyperbolic space. Experiments on 44 metastatic urothelial carcinoma (mUC) patients with four outcome classes (Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD)) under patient-stratified validation achieve patient-level accuracy of 90.9 × fewer parameters. Lesion-level upper bounds reach 94.7

Metastatic renal cell carcinoma remains clinically challenging because of heterogeneous outcomes and limited predictive biomarkers for immunotherapy. We performed an explainable machine learning analysis using data from the multicenter retrospective Meet-URO 15 study, including 571 patients with metastatic renal cell carcinoma treated with second-line or later nivolumab. Clinical and inflammatory variables were used to develop classification models for disease control rate, progression-free survival at 3 and 9 months, and overall survival at 6, 18 and 24 months, as well as survival models for continuous progression-free and overall survival. Model performance was assessed using weighted F1-score for classification and concordance index for survival analysis, with interpretability provided through Shapley additive explanations. The best classification performance was observed for 6-month overall survival using a support vector machine model combined with minimum redundancy maximum relevance feature selection, achieving an F1-score of 0.81 on the test set and 0.77 in external validation. In survival analysis, random survival forest achieved a test-set concordance index of 0.68 for overall survival. Inflammatory indices, IMDC score, hemoglobin, lymphocytes and platelets consistently emerged as relevant prognostic features. These findings support explainable machine learning as a transparent approach to refine outcome prediction in immunotherapy-treated metastatic renal cell carcinoma.

Background: Immune checkpoint inhibitors have revolutionized the treatment landscape for metastatic renal cell carcinoma (mRCC). However, some patients fail to experience durable benefits, especially those with bone metastases. Objective: This study aimed to evaluate the impact of bone-targeting agents (BTAs), specifically denosumab and zoledronic acid (ZA), on the clinical outcomes of patients with mRCC treated with nivolumab. Methods: This retrospective study analyzed data from the Meet-URO 15 trial on patients with mRCC who received nivolumab, categorizing them into BTA and non-BTA groups. Survival outcomes were assessed, with inverse probability of treatment weighting (IPTW) adjustment for confounding variables. Subsequently, the specific impact of different BTAs on the clinical outcomes was explored. Results: Of 203 mRCC patients with bone metastases, 38 received BTAs (BTA group) while 138 did not (non-BTA group). BTA treatment significantly improved the median progression-free survival (PFS) (291 vs. 117 days, p = 0.005) and overall survival (OS) (960 vs. 397 days, p = 0.008) compared with the non-BTA group, with a reduced risk of death (HR = 0.57, 95%CI = 0.34-0.95, p = 0.031) and progression or death (HR = 0.57, 95%CI = 0.35-0.92, p = 0.023) at multivariate analyses. IPTW adjustment confirmed these survival benefits, with a reduced risk of death (HR = 0.55-95%CI = 0.39-0.76, p < 0.001) and progression or death (HR = 0.58, 95%CI = 0.42-0.79, p < 0.001) in BTA patients. Furthermore, denosumab, compared with ZA and the non-BTA group, demonstrated superior OS (1,662 vs. 681 vs. 411 days, p < 0.001) and PFS (1,101 vs. 242 vs. 132 days, p < 0.001) in the same IPTW-adjusted population. Conclusion: This study suggests a potential beneficial impact of BTAs, especially denosumab, on the clinical outcomes after nivolumab therapy in mRCC patients with bone metastases. Prospective trials are needed to better define the impact of BTAs in these patients.

BACKGROUND:Outcomes of metastatic castration-resistant prostate cancer (mCRPC) treated with androgen receptor signaling inhibitors (ARSIs) vary widely and may not be fully reflected by PSA and standard clinicopathologic factors. We evaluated the prognostic value of serum neuron-specific enolase (NSE) at baseline and early on-treatment dynamics. METHODS:We retrospectively analyzed ARSI-treated mCRPC patients with available baseline NSE (n = 120). NSE was dichotomized by the upper limit of normal (ULN, 12.5 ng/mL). Radiographic progression-free survival (rPFS) and overall survival (OS) were estimated by Kaplan-Meier methods and compared by log-rank test. Multivariable Cox models adjusted for age, baseline PSA (per 100 ng/mL), line of therapy (2-4 vs 1), Gleason score (> 7 vs ≤ 7), metastatic timing (synchronous vs metachronous), and visceral metastases (present vs absent). NSE dynamics were evaluated using a 28-day landmark approach among patients alive and at risk at day 28 with available baseline and week-4 NSE (rPFS landmark n = 47; OS landmark n = 48); follow-up was redefined from day 28 and dynamics were modeled as log2(NSE4w/NSE0) (per doubling). RESULTS:Median follow-up was 44.7 months (95% CI 35.7-48.3). Baseline NSE > ULN was associated with shorter rPFS (9.4 vs 20.8 months) and OS (23.5 vs 38.2 months). In multivariable analyses, baseline NSE > ULN remained independently associated with inferior outcomes (rPFS HR 1.81, 95% CI 1.15-2.85, p = 0.011; OS HR 1.85, 95% CI 1.12-3.05, p = 0.017). In landmark models, higher NSE dynamics were independently associated with worse outcomes (rPFS HR 4.30, 95% CI 1.06-17.39, p = 0.041; OS HR 8.78, 95% CI 2.15-35.77, p = 0.002). CONCLUSIONS:In ARSI-treated mCRPC, baseline NSE above ULN and early 4-week NSE dynamics provide independent prognostic information for rPFS and OS, supporting NSE as a pragmatic adjunct to clinical risk stratification.

BACKGROUND:Androgen deprivation therapy (ADT) + androgen receptor pathway inhibitor (ARPI)  ± docetaxel represent the standard of care in patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, some patients still have early progression (EP). EMETPRO is a multicentric, retrospective registry of patients with EP mHSPC. METHODS:Patients with EP mHSPC were defined as patients who had progression ≤6 months under ADT+docetaxel or ADT + ARPI or ≤9 months from ADT monotherapy start. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS). RESULTS:Data from eligible patients treated between 2005 and 2023 were retrospectively collected. 201 (50%) patients received ADT monotherapy, while 124 (31%) and 76 (19%) received ADT+docetaxel and ADT + ARPI, respectively. 365 (91%) patients underwent first-line treatment for mCRPC-majority of the ADT monotherapy received ARPI (38%) or docetaxel (34%), whereas 69% of the ADT+docetaxel received ARPI and 62% of the ADT + ARPI received docetaxel. In the group of patients treated with ADT the median PFS was 6.8 months while the median OS was 26.4. In the group of patients treated with combination therapy the median PFS and OS was 4.9 and 18.6 months for patients who received docetaxel and 5.6 and 19.5 months for patients who received ARPI, respectively. Neither the first-line mCRPC treatment nor the genetic profiles were associated with survival outcomes. CONCLUSIONS:The results of our study suggest that patients with EP mHSPC are characterized by poor outcomes regardless of the type of treatment received at progression. The optimal first-line mCRPC therapy to use in these patients remains a crucial unmet clinical need.

Bladder cancer remains a major global health challenge, characterized by diagnostic uncertainty, substantial treatment costs and high recurrence rates. Current diagnostic and treatment modalities, including cystoscopy, transurethral resection of bladder tumour and standard histopathology, have limitations, including the inability to detect flat lesions, frequent understaging and interobserver variability, highlighting a crucial need for improved approaches. Advances in artificial intelligence (AI), blue-light cystoscopy, narrow-band imaging, cytology and urinary markers show promise in enhancing early detection and diagnosis. Developments in multiparametric MRI, radiomics, genomics and AI-driven algorithms for histopathological analyses have demonstrated considerable improvements in staging and risk stratification of bladder tumours, enabling personalized therapy selection and prognostication. Despite these promising developments, challenges remain regarding standardization, external validation, cost-effectiveness and ethical considerations in clinical implementation. Future research should prioritize addressing these barriers through collaborative, multi-institutional studies and robust validation frameworks. Ultimately, adopting a comprehensive multimodal strategy, such as proposed, novel, multimodal decision-making frameworks in which these advances and technologies are integrated, promises to considerably advance precision oncology in bladder cancer, improving patient outcomes and reducing health care burdens. In this Review, the authors describe and discuss how advances in artificial intelligence, genomics, radiomics and cytology can be integrated into decision-making processes to improve the management of bladder cancer.

Background Immune checkpoint inhibitor doublet (ICI–ICI) and ICI plus tyrosine kinase inhibitor (ICI–TKI) regimens are the cornerstone of treatment for metastatic renal cell carcinoma (mRCC), although no head-to-head comparisons are currently available. This study aimed to compare the real-world effectiveness of ICI-ICI vs ICI-TKI combinations in patients with intermediate- and poor-risk mRCC according to International Metastatic RCC Database Consortium (IMDC). Methods The Meet-URO 33 study is a multicentre retrospective-prospective registry collecting real-world data on patients with mRCC. Multivariable logistic and Cox models were built for objective response rate (ORR), PFS and OS, with a propensity score (PS) adjustment for baseline imbalances. Results Among 1497 patients, 755 were intermediate-risk (199 ICI-ICI, 556 ICI-TKI) and 312 poor-risk (77 ICI-ICI, 212 ICI-TKI). Median follow-up was 14.2 months (8.0 months and 14.5 months in poor- and intermediate-risk subgroups, respectively). In poor-risk patients, median OS was 20.3 vs 12.9 months (HR 0.87, 95% CI: 0.59–1.28, p = 0.49), and median PFS was 6.7 vs 8.7 months (HR 1.10, 95% CI: 0.79–1.54, p = 0.53), for ICI–ICI vs ICI–TKI, respectively. In the intermediate-risk patients treated with ICI-ICI vs ICI-TKI, median OS was 37.8 vs 35.5 months (HR: 1.08; 95% CI: 0.77–1.50; p = 0.65), and median PFS was 17.8 vs 18.6 months (HR 1.29, 95% CI: 1.00–1.66, p = 0.050). ORR was 42.9% vs 45.8% in poor-risk patients (OR 0.72, 95% CI: 0.39–1.34, p = 0.303) and 48.1% vs 54.3% in intermediate-risk patients (OR 0.71, 95% CI: 0.48–1.04, p = 0.075). Conclusions No statistically significant differences in survival or response were observed between ICI-ICI and ICI-TKI combinations in patients with IMDC intermediate- and poor-risk mRCC.

BACKGROUND:Cisplatin-based neoadjuvant chemotherapy (NAC) improves survival in muscle-invasive urothelial cancer (MIUC), yet pathological complete response (pCR) is achieved in a minority of patients. Relative dose intensity (RDI) is a potentially modifiable determinant of chemotherapy efficacy, but its impact during NAC in MIUC remains unexplored. METHODS:This multicenter retrospective study included patients with MIUC treated with cisplatin-gemcitabine NAC followed by radical cystectomy. Relative dose intensity was calculated from original administration records and categorized as ≥85% vs <85%. The primary endpoint was pCR (ypT0N0M0). Secondary endpoints included overall survival (OS) and event-free survival (EFS). RESULTS:A total of 330 patients were included; 66% maintained RDI ≥ 85%. Overall pCR rate was 25.2%. Patients with RDI ≥ 85% achieved higher pCR rates compared with those with RDI < 85% (29.7% vs 16.2%; P = .008). Relative dose intensity  ≥ 85% remained independently associated with pCR in multivariable analysis (odds ratio = 2.10; P = .032). Preserved RDI was also associated with improved EFS (hazard ratio [HR] = 0.65; P = .039) and OS (HR = 0.53; P = .026) at univariate analysis. Achievement of pCR was strongly associated with superior EFS (HR = 0.23; P < .001) and OS (HR = 0.35; P = .009). CONCLUSION:Preservation of cisplatin RDI ≥ 85% during NAC is independently correlated with higher pCR rates and associated to a better survival trend in MIUC. Optimization of chemotherapy delivery represents a clinically actionable strategy to enhance neoadjuvant efficacy.

While neoadjuvant chemotherapy and radical surgery represent mainstay treatments for muscle-invasive urothelial carcinoma (MIUC), recurrence with lethal metastasis remains high and highlights the need for adjuvant therapies in MIUC, like immunotherapy, already in use for metastatic UC with favourable results. This review provides an overview of the key clinical trials investigating adjuvant immune checkpoint inhibitors (ICIs) for MIUC and their clinical implications; in particular, examining factors that may be relevant in guiding adjuvant therapy to patients, such as ICI therapy choice, tumour subtype and the clinical utility of biomarkers, specifically PD-L1 status and circulating tumour DNA (ctDNA). Of the three key trials CheckMate-274, IMvigor010 and AMBASSADOR, anti-PD1 inhibitors nivolumab and pembrolizumab have shown statistically significant improvements in disease-free survival (DFS) compared to controls, highlighting their promising use as seen with nivolumab's approval into clinical practice. Results are conflicting on the association of PD-L1 tumour expression with treatment outcome, yet ctDNA has emerged as a key biomarker from IMvigor010, showing not only prognostic value but also association between its clearance and atezolizumab treatment benefit derived. Notably, it remains uncertain across the trials whether adjuvant treatment efficacy differs by tumour origin (upper tract or lower tract disease), and larger subgroup numbers are needed for future trials in order to adequately assess statistical significance of speculative associations. Altogether, study findings support increasing clinical incorporation of adjuvant nivolumab and pembrolizumab into the MIUC setting, and emphasise ctDNA's utility as a biomarker for MIUC, demonstrating roles in both prognostication and prediction of treatment benefit.

Background: Despite the availability of several first-line (1L) systemic therapies for metastatic renal cell carcinoma (mRCC), no validated biomarkers currently guide the selection of 1L systemic treatment. Objectives: To identify baseline clinical features associated with 1L treatment selection in a large real-world mRCC population. Design: Meet-URO 33–REGAL is a multicenter study with prospective and retrospective components, enrolling patients with mRCC receiving 1L systemic therapy since January 2021. Methods: Baseline patient and disease characteristics were analyzed to compare treatment selection among dual immune checkpoint inhibitor therapy (ICI–ICI), ICI plus tyrosine kinase inhibitor combinations (ICI–TKI), and TKI monotherapy. Multivariable logistic regression models were used to evaluate clinical features associated with pairwise treatment selection. Results: A total of 1695 patients from 58 centers were included: 248 (14.6%) received TKI monotherapy, 338 (20.0%) ICI–ICI, and 1109 (65.4%) ICI–TKI. ICI–ICI was more commonly selected in patients with sarcomatoid features (14.5% vs 7.4% for ICI–TKI, p < 0.001) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate/poor-risk disease (92.0% vs 80.1%, p < 0.001). In multivariable analysis, compared with TKI monotherapy, ICI–TKI selection was associated with IMDC intermediate-risk disease (odds ratio (OR) 2.16, 95% confidence interval (CI) 1.25–3.74, p = 0.006), poor-risk disease (OR 2.89, 95% CI 1.38–6.06, p = 0.005), and bone metastases (OR 1.79, 95% CI 1.29–2.49, p = 0.001). In regimen-specific comparisons, nivolumab plus cabozantinib was associated with bone metastases and non-clear cell histology; pembrolizumab plus lenvatinib with eastern cooperative oncology group (ECOG) performance status 0 and pancreatic involvement; and nivolumab plus ipilimumab with cardiovascular and metabolic comorbidities and lymph node metastases. TKI monotherapy was more commonly selected in older patients and those with comorbidities, consistent with a more selected clinical phenotype in routine clinical practice. Conclusion: Meet-URO 33 provides a real-world snapshot of 1L decision-making in mRCC. Distinct clinical patterns, including histology, metastatic sites, performance status, comorbidities, and prognostic risk, were associated with treatment selection. These findings characterize clinical phenotypes in routine practice and provide context for future effectiveness, safety, and treatment-sequencing analyses of 1L therapeutic strategies within the Meet-URO 33 cohort over time.

Antibody-drug conjugates (ADCs) are a promising strategy in non-small cell lung cancer (NSCLC), but early-generation drugs were limited by suboptimal target selection, heterogeneous drug-antibody ratios, and linker instability, resulting in modest efficacy and relevant toxicities. We performed a narrative review based on a literature search of PubMed and major oncology congresses up to October 2025, with the aim to critically analyzing the evolving biomarker landscape and engineering strategies shaping next-generation ADC development in NSCLC. Emerging approaches to identify targets for ADCs and refine patient selection include digital pathology with artificial intelligence technologies, transcriptomic and proteomic profiling, and liquid biopsy. Modern platforms incorporate site-specific conjugation technologies to achieve controlled and homogeneous drug-to-antibody ratio (DAR) distributions, improving pharmacokinetic predictability and reducing off-target effects. Advances in linker chemistry enhance plasma stability while preserving efficient intracellular payload release, balancing bystander effect with safety. These innovations are designed to enhance tumor selectivity, mitigate off-target toxicity and overcome resistance mechanisms. In conclusion, next-generation ADCs in NSCLC integrate refined biomarker strategies with advances in antibody engineering, linker design and payload biology. Emerging approaches, including immune-stimulating and bispecific ADCs, novel payloads, and combinations with tyrosine kinase inhibitors (TKIs) or immunotherapy, may improve efficacy, overcome resistance and expand the therapeutic window. Bispecific and dual-payload ADCs, as well as immune-stimulating ADCs, further aim to overcome resistance, exploiting both direct cytotoxicity and immune system activation and positioning ADCs as a crucial component of precision oncology in NSCLC.

INTRODUCTION:Even though PD-(L)1 inhibitors have dramatically changed the prognosis of patients with advanced non-small-cell lung cancer (NSCLC), resistance to treatment remains common. Rechallenge with PD-(L)1 based regimens has been explored in this context, but clinical benefit remains uncertain. METHODS:Two independent reviewer teams performed parallel searches of MEDLINE and EMBASE from 2019 to 2025 to identify clinical trials evaluating PD-(L)1 inhibitor based rechallenge strategies in patients with advanced NSCLC previously treated with PD-(L)1-based regimens. Randomised controlled trials (RCTs) were included in quantitative meta-analysis, while non-randomised single-arm studies were synthesised descriptively. The primary endpoint was overall survival (OS). Sensitivity analyses examined outcomes according to resistance pattern. All analyses used fixed-effects models. FINDINGS:A total of 10 RCTs (n = 3,081) and 106 non-randomised interventional trials were included. Across RCTs, PD-(L)1 based rechallenge strategies yielded modest improvements in both OS (HR 0.91, 95%CI: 0.82-0.99) and PFS (HR 0.89, 95%CI: 0.81-0.99) compared with the control arms, with no improvement in objective response rate (ORR). In sensitivity analyses, no benefit was observed in patients with primary resistance, whereas those with acquired resistance features (i.e., clinical benefit to prior immunotherapy) demonstrated a more favourable effect for OS (HR 0.86, 95%CI: 0.77-0.97). A more restrictive analysis excluding patients with < 3 months of prior PD-(L)1 exposure confirmed this pattern. Across the 106 single-arm trials, ORR varied widely, with only speculative signals of higher activity in regimens incorporating VEGF-targeting or chemotherapy. CONCLUSIONS:In the largest synthesis of rechallenge strategies to date, PD-(L)1 rechallenge produced statistically significant but clinically marginal improvements in OS and PFS compared with standard treatments, with no benefit in patients with primary resistance. A signal of benefit was observed in patients with acquired resistance to prior immunotherapy although this exploratory analysis was limited by heterogeneous resistance definitions across trials and a non-significant interaction test.