BACKGROUND AND OBJECTIVES:Observational studies evaluating treatment strategies that are indistinguishable at the start of follow-up are prone to immortal-time bias in its misclassification form. The clone-censor-weight (CCW) approach has gained attention for its effectiveness in mitigating immortal-time bias while enhancing the validity of causal inference in observational research within the target trial emulation (TTE) framework. In this methodological systematic review, we assess CCW implementation in observational analyses, evaluate the handling of immortal-time bias, and identify key considerations and potential limitations in CCW application. METHODS:We conducted a comprehensive search in MEDLINE and Embase databases for all studies published from January 1, 2010, to March 18, 2025. We performed an additional manual search by citation searching on nine reviews about the TTE or the CCW method. Screening was conducted by two independent reviewers. Data extraction and evaluation of risk of bias were performed by two reviewers for 10%, and due to high inter-reviewer agreement, a single reviewer evaluated the remaining study sample. Risk of immortal-time bias due to post-baseline eligibility was assessed. RESULTS:Among 113 studies identified, 103 declared implementing the CCW approach within the TTE framework (91.2%). The method was referred as "cloning censoring and weighting" in 55 studies (48.7%), "CCW" in 25 studies (22.1%), or other ways. All studies used either inverse probability of censoring weighting or inverse probability of treatment weighting to account for artificial censoring alone (97/113, 85.8%) and less commonly in combination with loss to follow-up (16/113, 14.2%). Authors used pooled logistic regressions or Cox models for weight estimations (n = 70, 61.9% and n = 26, 23% of studies, respectively), while outcomes were mostly estimated using pooled logistic regressions (n = 58, 51.3%) or nonparametric estimators (n = 40, 35.4%). Potential immortal-time bias was still present in 22 studies (19.5%) where they excluded patients based on post-time zero criteria before implementing CCW (n = 21, 18.6%), or when time zero was not well defined (n = 2, 1.8%). CONCLUSION:CCW implementation varies across studies, particularly in statistical modeling of weights, and considered censoring events, as well as statistical modeling effect of interventions on outcomes. Clarifying key methodological components could support consistent application of CCW and improve reporting. PLAIN LANGUAGE SUMMARY:Researchers increasingly use observational health-care data, such as electronic health records and insurance claims, to evaluate the effects of medical treatments. Unlike randomized clinical trials, these studies can be affected by immortal-time bias if both intervention assignment and eligibility assessment are not set at the start of follow-up. This bias typically occurs when patients must survive long enough to receive a treatment, such as surgery. Patients who die before receiving the surgery are automatically classified as untreated, leading to an unfair comparison. The clone-censor-weight (CCW) approach was developed to reduce this bias in observational studies, with interventions that cannot be distinguished at the start of follow-up. In this paper, we reviewed 113 published studies using this approach to evaluate how researchers implemented the method, whether immortal-time bias was appropriately addressed, and how clearly key methodological details were reported. We found variation in the implementation of the CCW approach, particularly in censoring and weighting processes. Important methodological details were also often incompletely reported, making it difficult to compare studies or reproduce their analyses. Despite the use of CCW approach, 20% of the evaluated studies remained at risk of immortal-time bias, due to eligibility assessment based on characteristics measured after the start of follow-up. Our findings highlight the need for clearer methodological guidance and more transparent reporting to improve the consistency and reliability of studies using the CCW approach.

Background Cognitive sequelae affect 60% of pediatric brain tumor survivors treated with radiotherapy (RT), significantly impacting quality of life. While hippocampal irradiation correlates with memory deficits, dose constraints remain undefined in children. The IPANEMA study aims to establish the discriminative capacity of hippocampal dosimetry to identify declarative memory deficits. Methods IPANEMA (Irradiation in Pediatrics: Neurocognition, Neuroimaging, and Evaluation of Memory and Attention) is a prospective multicenter study recruiting 130 patients aged 4-12 years at RT for brain tumors (ependymomas, medulloblastomas, germ cell tumors, craniopharyngiomas, pinealoblastomas) across 13 French centers. Comprehensive neuropsychological assessments will be conducted at 2 and 4 years post-RT, evaluating declarative, procedural, and working memory. The primary endpoint is the area under the ROC curve for hippocampal dose discriminating declarative memory deficits at 2 years post-RT. Secondary objectives include dose-response relationships for hippocampus, striatum, and cerebellum; neuroimaging biomarkers using multimodal MRI; baseline neurodevelopmental factors; and longitudinal cognitive trajectory. An ancillary study at the coordinating center includes advanced functional MRI. Expected results and Discussion Building on the IMPALA pilot study demonstrating hippocampal dose-episodic memory correlations, IPANEMA will provide robust evidence to establish pediatric dose constraints for memory-related structures. This multicenter longitudinal study incorporates standardized neuropsychological assessment, multimodal neuroimaging, and baseline cognitive evaluation. Results will inform RT planning optimization to preserve cognitive function while maintaining tumor control. Trial registration ID-RCB 2024-A00007-40. NCT06599879. Funded by Institut National du Cancer (INCa).

ABSTRACT Background HER2 (ERBB2) gene mutations are associated with poor prognosis in non‐small cell lung cancer (NSCLC). It is important to identify patients with HER2‐mutant (HER2m) NSCLC, as new targeted treatment options are emerging. However, HER2 testing in clinical practice varies across regions, and real‐world data on HER2m NSCLC are limited. Patients and Methods This retrospective study included patients from the Epidemio‐Strategy and Medical Economics Lung Cancer database (NCT03848052) diagnosed with locally advanced or metastatic (LAM) NSCLC in France (January 1, 2015–December 31, 2020); patients were followed up until April 1, 2022. Data were extracted on April 2, 2022. Primary objectives were to describe the frequency of HER2 testing and test results. Secondary objectives included describing patient characteristics, treatment patterns, and clinical outcomes (stratified by HER2 testing status/results; landmark analyses were conducted to avoid immortal time bias). Results Of 18,069 patients with nonsquamous LAM NSCLC, or squamous LAM NSCLC and no history of smoking, 7530 (41.7%) underwent HER2 testing. Median (interquartile range) time between LAM NSCLC diagnosis and first HER2 test result was 28 days (18–49). Of those tested, 152 (2.0%) had a HER2 mutation (HER2m cohort). In the HER2m cohort, 62.5% (n/N = 85/136) of patients received their first HER2 test result prior to first‐line treatment; platinum‐based chemotherapy was the most frequently received first‐line treatment (52.9%, n/N = 72/136), followed by immunotherapy in the second‐line setting (29.2%, n/N = 26/89). At 6‐month landmark analysis, median (95% confidence interval) overall survival was 18.6 months (14.3–22.5) in the HER2m cohort. Conclusions This real‐world study demonstrates the low frequency of HER2 testing and potential poor prognosis for patients diagnosed with LAM HER2m NSCLC in France between 2015 and 2020. Despite the low prevalence of HER2m NSCLC, these data highlight the importance of routine HER2 testing to enable patients with HER2m NSCLC to receive treatments that can improve clinical outcomes.

BACKGROUND:Adjuvant chemotherapy for hormone receptor-positive (HR+) breast cancer relies on taxanes, but existing tests do not identify which patients benefit from them. The SETER/PR index, a measure of endocrine-related transcriptional activity in HR + tumors, recently predicted benefit from paclitaxel when low (<0.75), but not for anthracycline-based therapy. We tested whether SETER/PR could predict benefit from docetaxel in node-positive, HR + patients enrolled in the PACS-01 trial (docetaxel after fluorouracil-epirubicin-cyclophosphamide (3FEC+3D) versus 6FEC). PATIENTS AND METHODS:SETER/PR index and Recurrence Score (RS) were obtained for 490 patients. SETER/PR was quantified using the QuantiGene Plex assay from RNA remaining after RS testing. Pre-specified analyses assessed SETER/PR as a continuous variable and using the predefined <0.75 cut point, as well as continuous RS and the >25 cut point. The primary endpoint was distant recurrence-free interval (DRFI). Predictive value was assessed using Cox models including biomarker, treatment arm, and interaction term. RESULTS:Continuous SETER/PR demonstrated significant interaction with treatment on DRFI (Pinteraction = 0.028), whereas predefined <0.75 cut point was not predictive (Pinteraction = 0.668). Exploratory analyses identified a cut point at 1.50 (Pinteraction = 0.013): patients with SETER/PR ≥ 1.50 had worse outcomes with 3FEC+3D versus 6FEC (HR 3.16, 95%CI 1.28-7.85), while outcomes were similar between arms when SETER/PR < 1.50 (HR 0.83, 95%CI 0.51-1.35). RS did not predict differential benefit, either continuously (Pinteraction = 0.670) or at the >25 threshold (Pinteraction = 0.534). CONCLUSION:Including sequential docetaxel (3FEC+3D) was less effective than continued anthracycline chemotherapy (6FEC) when breast cancer had high endocrine-related transcriptional activity (i.e., SETER/PR index ≥1.50). TRIAL REGISTRATION:PACS-01.

BACKGROUND:Lung cancer is the main cause of cancer-related death, with recent paradigm shifts including optimized staging, identification of molecular subsets with access to targeted agents, and replacement of chemotherapy by immunotherapy as the backbone of treatment. The Lung Cancer part of the Epidemiological Strategy and Medical Economics (ESME) research program was launched to collect individual data from all consecutive patients treated for lung cancer since 2015 in a network of 38 health facilities in France. METHODS:Main objectives included the description of the treatment patterns and outcomes of patients diagnosed with lung cancer in the database. Univariable and multivariable analyses on overall survival were performed using the Logrank test and the Cox proportional hazards model. RESULTS:Among 52,514 patients included in the advanced and metastatic lung cancer (AMLC) cohort, 45,232 (86%) had non-small cell lung cancer (NSCLC), and 6,301 (12%) had small-cell lung cancer (SCLC). Among those, 34% in the NSCLC cohort and 42% in the SCLC cohort did not receive second-line. In the NSCLC cohort, immune checkpoint inhibitor (ICI)-based therapies became the most commonly used first-line option from 2020 onwards. After a median follow-up of 58.1 (95%CI 57.1-59.0) months, the median OS was 15.7 (95%CI 15.4-16.0) months for patients with NSCLC, and 11.0 (95%CI 10.7-11.3) months for those with SCLC. At multivariable analyses, age, stage, histologic subtype for NSCLC remained significantly associated with OS, as well as gender, ECOG performance status and presence of brain metastases, both for NSCLC and SCLC. CONCLUSIONS:The ESME database provides a realistic overview of lung cancer management in France and a reliable assessment of treatment patterns in real-world setting, which constitutes essential evidence to complement data from clinical trials, and highlights unmet needs in treatment sequences.

Abstract Background: IO efficacy in LA/M HNSCC patients is limited. Identifying biomarkers of resistance and response is crucial to better stratify patients. We characterized the genomic and transcriptomic landscape of IO-naive HNSCC patients to identify specific genomic and transcriptomic signatures of response to IO. Methods: We analyzed baseline FFPE samples of 176 LA/M HNSCC patients treated with IO from CHECK’UP (NCT03412058) and TOPNIVO (NCT03226756) trials, for whom baseline RNAseq data were available. A penalized Cox model with Elastic Net procedure was used to identify gene signatures associated with PFS and OS. Using a resampling procedure, a bootstrap selection stability (BSS) index was computed for each gene and only those with a BSS > 30% were included in the final model to determine a score for both PFS and OS. In addition, 149 paired tumor and germline DNA were sequenced using whole exome. For biostatistics analysis using genomic alterations, only variants (SNVs, Indels, CNVs) in oncogenes, tumor suppressor genes with a variant allele frequency (VAF) of at least 10% and altered signaling pathways were considered. Results: The cohort (median age 62.5 yo) included a majority of oropharynx (39.8%) and oral cavity (29.8%) tumors, 77.8% males, 62.3% with alcohol and 81.7% with tobacco use history and 60.0% of them were metastatic. Objective response rate was 17.4%, median PFS and OS were 1.9 months (mo) (95%CI=[1.8-2.5]) and 8.1 mo (95%CI=[6.1-9.7]), respectively (median follow-up of 33.3 mo, 95%CI=[28.7-36.5]). The most frequent genomic alterations affected CCND1, CDKN2A, FAT1, TERT, TP53 genes and a gain of 3q26-q28. In univariable analyses, the presence of TERT or FAT1 alteration were significantly associated with worse PFS. After adjustment for clinical variable, the presence of FAT1 alteration and the upregulation of Hippo signalling pathway remained associated with worse PFS. The presence of TERT mutation was also associated with worse OS whereas the PI3K/AKT/mTOR pathway was associated with improved OS in univariable and multivariable analysis, respectively. Among the 500 most differentially expressed transcripts, 21- and 18-gene expression signatures were selected to assess their association with PFS and OS, respectively. C-Index was 0.72 and 0.71 (0.58 and 0.57 after internal bootstrap validation) for PFS and OS, respectively. Scores were dichotomized using time-dependent ROC Curve (Low vs High) and HR adjusted for clinical factors were 3.62 (95%CI = [2.42; 5.43]) and 3.86 (95%CI = [2.52; 5.91]; p<0.0001) for PFS and OS, respectively. Conclusions: We identified robust transcriptomic signatures and genomic alterations strongly associated with IO resistance, offering potential biomarkers for patient stratification. TERT or FAT1 alteration were associated with worse prognosis. Citation Format: Elodie Girard, Sonia Canjura-Rodriguez, Bastien Cabarrou, Constance Lamy, Anne Schnitzler, Frédérique Penault-Llorca, Emmanuel Bouilhol, Roger Sun, Eric Deutsch, François Legrand, Séverine Tabone-Eglinger, Valery Attignon, Caroline Even, Christophe Le Tourneau, Ellen Van Obberghen-Schilling, Marta Jimenez, Nicolas Servant, Thomas Filleron, Edith Borcoman, Pierre Saintigny, Ivan Bièche. Transcriptomic and genomic signatures associated with response or resistance to immunotherapy(IO) in locally advanced/metastatic (LA/M) head and neck squamous cell carcinoma (HNSCC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1034.

BACKGROUND:Immune-Checkpoint-Inhibitors (ICIs) have significantly improved the course of advanced/metastatic melanoma and the concept of ICIs curative potential began to appear. To use statistical approaches to determine whether advanced/metastatic melanoma patients treated with nivolumab alone or in combination with ipilimumab may be considered as functionally cured. METHODS:Individual patient data were reconstructed from published Kaplan-Meier curves of the anti-PD1 arms of the Checkmate-067. The assumption of functional cure was assessed using three approaches based on a flexible-parametric survival model. Once the hypothesis of functional cure was confirmed, the time to functional cure (TTFC) was determined using an intuitive approach based on flexible survival model. RESULTS:The three complementary approaches were consistent and confirmed the functional cure assumption. The TTFC (the shortest time defined by fewer than 1% of patients progressing or dying) was estimated to be 61 (95%CI,50.7;79.4) and 63 m (95%CI,51.1;71.4) for nivolumab alone or in combination, respectively. CONCLUSIONS:We showed that metastatic melanoma patients, treated with the combination or nivolumab alone who were alive and had not progressed by the five-year time-point, can be considered as functionally cured. The robust statistical approach proposed could be applied to other clinical settings when the plausibility of cure is to be validated.

BackgroundReal-world observational cohorts generate data based on large cohorts of patients and provide information regarding subsets of patients from real-life clinical practice. Lung cancer is the main cause of cancer-related death, with major paradigm shifts over the past years including optimized staging, identification of molecular subsets with access to targeted agents, and replacement of chemotherapy by immunotherapy as the backbone of systemic treatment.MethodsThe Lung Cancer part of the Epidemiological Strategy and Medical Economics (ESME) research program was launched to collect individual data from all consecutive patients treated for lung cancer since 2015 in a network of 38 health facilities in France.ResultsAmong 52,514 patients included in the advanced and metastatic lung cancer (AMLC) cohort, 45,232 (86%) had non-small cell lung cancer (NSCLC), and 6,301 (12%) had small-cell lung cancer (SCLC). The majority of patients received at least one line of systemic therapy (83% of NSCLC cases, and 91% of SCLC cases). Among those, the attrition rate from first- to second-line was 34% in the NSCLC cohort and 42% in the SCLC cohort. In the NSCLC cohort, chemotherapy (CT) regimen was the most frequently used first-line regimen among initiating treatment before 2020 (71%), whereas immune checkpoint inhibitor (ICI) therapies became the most commonly used first-line option from 2020 onwards . After a median follow-up of 58.1 (95%CI 57.1-59.0) months, the median OS was 15.7 (95%CI 15.4-16.0) months for patients with NSCLC, and 11.0 (95%CI 10.7-11.3) months for those with SCLC.ConclusionsThe ESME LC database is the largest real-world database of lung cancer patients in Europe, and is a robust resource for generating real-world evidence. The availability of detailed clinical variables enables reliable assessment of treatment effectiveness and supports clinical trial emulation, providing essential complementary evidence to clinical trials.

T-cell exhaustion is typically studied in the context of immune checkpoint blockade, where proliferation and reinvigoration of exhausted cells drives therapeutic responses. However, terminal exhaustion may also represent a marker of chronic tumor-specific activation, raising the possibility that exhausted T cells reflect ongoing endogenous tumor control. Here, we sought to evaluate T-cell exhaustion as a prognostic marker using high-grade serous ovarian cancer (HGSC), an immunotherapy-resistant malignancy, as a model. In a cohort of 80 patients with stage III/IV HGSC, we assessed T-cell infiltration and exhaustion according to homologous recombination (HR) deficiency status. While overall immune infiltration was comparable between HR-deficient and proficient tumors, terminally exhausted CD8 and conventional CD4 T cells were enriched in HR-deficient tumors, where their presence correlated with improved progression-free survival. These findings suggest that exhausted T cells may indicate protective immunity even outside the context of immunotherapy and underscore their prognostic relevance in solid tumors.

Abstract The contribution of neoantigen-specific T cells to PD-(L)1 efficacy has largely been inferred from tumor mutational burden. We functionally profiled circulating T cell responses against 7,038 predicted HLA-I–restricted and 21,453 HLA-II–restricted neopeptides in 27 patients with advanced non-small cell lung cancer treated with anti–PD-(L)1. CD4 responses were frequent and correlated with neoantigen availability but not clinical benefit. In contrast, the magnitude and breadth of neoantigen-specific CD8 T cell responses were associated with clinical benefit, progression-free and overall survival, independently of tumor mutational burden. Patients mounting coordinated CD4 and CD8 responses experienced improved progression-free survival. Tumors from CD8 responders displayed immune signatures indicative of both T cell priming and effector functions. Circulating neoantigen-specific CD8 T cells recognized endogenously processed antigens, trafficked to tumors, and selectively expanded under therapy while retaining CD28, CD226, and CXCR3 expression. These findings identify coordinated, functionally engaged neoantigen-specific T cell responses as central determinants of PD-(L)1 efficacy.

Abstract Resistance to targeted cancer therapies often arises from drug-tolerant cells (DTCs), which survive treatment by entering a non-proliferative state. Over time, DTCs can acquire mutations that contribute to cell reproliferation, but how non-proliferating DTCs accumulate such mutations remains unclear. Here, we show that EGFR inhibition in EGFR-mutated lung cancer transiently downregulates tyrosyl-DNA phosphodiesterase 1 (TDP1), a repair enzyme that resolves abortive topoisomerase I cleavage complexes (TOP1ccs). In DTCs, elevated reactive oxygen species promote TOP1cc trapping, while TDP1 downregulation impairs their repair, driving TOP1cc accumulation, resistance mutation acquisition, and cell reproliferation. We further find that TDP1 expression is absent in approximately 25% of EGFR-mutated lung cancers. In TDP1-deficient cells, combining EGFR inhibition with a sublethal concentration of topotecan, which further increases TOP1ccs, abolishes cell reproliferation. Together, these findings establish persistent TOP1cc accumulation as a driver of therapy-induced mutagenesis linking drug tolerance to adaptive resistance, and reveal TDP1 loss as a targetable vulnerability in EGFR-mutated lung cancers. Teaser A drug-tolerant state that fuels mutagenesis and resistance also creates a transient vulnerability.

BACKGROUND:Matching Adjusted Indirect Comparison (MAIC) is a statistical method used to adjust for potential biases when comparing treatment effects between separate data sources, with aggregate data in one arm, and individual patients data in the other. However, acceptance of MAIC in health technology assessment (HTA) is challenging because of the numerous biases that can affect the estimates of treatment effects - especially with small sample sizes, increasing the risk of convergence issues. We suggest statistical approaches to address some of the challenges in supporting evidence from MAICs, applied to a case study. METHODS:The proposed approaches were illustrated with a case study comparing an integrated analysis of three single-arm trials of entrectinib with the French standard of care using the Epidemio-Strategy and Medical Economics (ESME) Lung Cancer Data Platform, in metastatic ROS1-positive Non-Small Cell Lung Cancer (NSCLC) patients. To obtain convergent models with balanced treatment arms, a transparent predefined workflow for variable selection in the propensity score model, with multiple imputation of missing data, was used. To assess robustness, multiple sensitivity analyses were conducted, including Quantitative Bias Analyses (QBA) for unmeasured confounders (E-value, bias plot), and for missing at random assumption (tipping-point analysis). RESULTS:The proposed workflow was successful in generating satisfactory models for all sub-populations, that is, without convergence problems and with effectively balanced key covariates between treatment arms. It also gave an indication of the number of models tested. Sensitivity analyses confirmed the robustness of the results, including to unmeasured confounders. The QBA performed on the missing data allowed to exclude the potential impact of the missing data on the estimate of comparative effectiveness, even though approximately half of the ECOG Performance Status data were missing. CONCLUSIONS:To the best of our knowledge, we present the first in-depth application of QBA in the context of MAIC. Despite the real-world data limitations, with this MAIC, we show that it is possible to confirm the robustness of the results by using appropriate statistical methods. TRIAL REGISTRATION:NA.

565 Background: SET2,3 index measures hormone receptor-related transcriptional activity (SETER/PR) adjusted for a baseline prognosis index (BPI) derived from tumor size, nodes involved and a 4-gene molecular subtype (RNA4). SET2,3 added prognostic information to the 21-gene Breast Recurrence Score (RS) in the SWOG 8814 trial (1). To confirm this, we independently evaluated both tests performed on node-positive, hormone receptor-positive (HR+) cancers from the PACS-01 trial (Roche et al, JCO 2006, PMID: 17116941) that evaluated the addition of adjuvant docetaxel to anthracycline-based chemotherapy. Adjuvant endocrine therapy became standard for premenopausal patients during PACS-01, justifying a sensitivity analysis in the population who received adjuvant endocrine therapy. Methods: SET2,3 was measured with the QuantiGene Plex bead-based hybridization assay (ThermoFisher) using an aliquot of residual RNA from prior RS testing in 791 HR+ tumor samples. Pre-defined cut points defined higher risk if RS >25 or SET2,3 <2.10. SETER/PR index and BPI, individual components of SET2,3 index, were evaluated as continuous variables. The primary endpoint was distant recurrence-free interval (DRFI). Multivariable Cox proportional hazards models were used to calculate hazard ratios with 95% confidence interval (HR, 95%CI) adjusted for treatment arm, and the likelihood ratio (LR) of benefit from addition of SET2,3 to RS with LR test for significance at p <0.05. Results: Of 791 tumor samples, 760 (96.1%) passed quality control (QC) for the SET assay; 724 had pathologic information to calculate SET2,3 index; and 659 had results for RS and SET2,3. At a median follow-up of 8 years, distant recurrence occurred in 144 of 659 (21.9%) patients overall, and 94 of 490 (19.2%) patients in the sensitivity population. Overall, high RS status (HR 2.33, 1.60-3.39) and high SET2,3 (HR 0.43, 0.30-0.62) were independently prognostic. SET2,3 was high in 303/377 (80.4%) patients with RS ≤25, with 5-year DRFI of 93.7% [95%CI 90.2;95.9]; and SET2,3 was low in 171/282 (60.6%) patients with RS >25, with 5-year DRFI 64.6% [95%CI 56.9;71.3]. SETER/PR index of endocrine transcriptional activity and the BPI, each contributed additional prognostic information to RS status in the sensitivity population (Table). Conclusions: SET2,3 index added prognostic information to the Recurrence Score in this independent blinded validation study of the PACS-01 trial for node-positive breast cancer. 1. Speers et al, JCO 2023, PMID: 36649570. [Table: see text]

To evaluate methodological challenges and regulatory considerations of indirect treatment comparisons (ITCs) with the analysis of international health technology assessment guidelines and French Transparency Committee (TC) decisions. We conducted a pragmatic review of ITC guidelines from major health technology assessment (HTA) bodies and multistakeholder organizations. Then, we analyzed TC opinions published between 2021-2023. We extracted data on ITC methodology, therapeutic areas, acceptability, and limitations expressed by the TC. The targeted review of the main guidelines showed mainly agreements between HTA bodies and multistakeholder organizations, with some specificities. 138 TC opinions containing 195 ITCs were analyzed. Only 13.3 TC decision-making. ITCs were more frequently accepted in genetic diseases (34.4 using individual patient data showed higher acceptance rates (23.1 network meta-analyses (4.2 (59 concerns (27 (20 important clinical benefit was lower (60.9 controlled trials were available. While ITCs are increasingly submitted, particularly where direct evidence is impractical, their influence on reimbursement decisions remains limited. There is a need for clear and accessible guides so manufacturers can produce clearer and more robust ITCs that follow regulatory guidelines, from the planning phase to execution.

Resistance to immune checkpoint inhibitors (ICI) in cancer patients is not fully understood, and predictive biomarkers are lacking. MELANFα (NCT03348891) is an open‐label, prospective, multicenter cohort of 60 patients with advanced melanoma receiving ICI (bitherapy: ipilimumab + nivolumab; monotherapy: pembrolizumab or nivolumab). The primary objective was to evaluate whether changes in plasma TNF between baseline (W0) and week 12 (W12) identified patients with non‐progressive disease at W12. Secondary and exploratory objectives were to assess the association between plasma TNF, tumor response, and changes in circulating T cells. Plasma TNF increased along therapy, but its W12/W0 fold change was not associated with non‐progressive disease at W12. However, plasma TNF levels at W12 were significantly higher in non‐responders than in responders across therapies ( p = .0129). The remodeling of circulating T cell subpopulations was mostly triggered by bitherapy. Increased proportions of circulating central memory and effector memory CD8 T cells after bitherapy were positively and negatively associated with response to treatment, respectively. In this cohort, circulating T cells from responders and non‐responders also displayed distinct molecular characteristics. Indeed, responders showed an increased proportion of CD8 T cells with low enrichment of TNF‐related pathways and high cytotoxic potential, while non‐responders displayed increased proportions of circulating CD8 EM T cells enriched for TNF‐related pathways and directed toward cytokine expression. In conclusion, our study shows that elevated plasma TNF and enriched TNF pathways in T cells are associated with poorer clinical outcomes, reinforcing the notion that TNF may dampen ICI efficacy.

Background: In HER2-positive (HER2+) metastatic breast cancer (MBC), the clinical presentation at metastatic diagnosis (dg), de novo (dnMBC) or recurrent (rMBC), is an independent prognostic factor. In contemporary clinical trials, the proportion of patients (pts) with dnMBC is high, likely due to improvements in the efficacy of (neo)adjuvant therapy. ESME-MBC, a national cohort of real-world data, recruiting pts consecutively treated for MBC in all comprehensive cancer centers in France since 2008, allows capturing of this evolution over time. Methods: We selected pts with HER2+ (immunohistochemistry, IHC 3+ or ISH amplified) MBC diagnosed between 2008 and 2022, excluding pts whose hormone receptor (HR) and HER2 status were unknown and those who did not receive systemic treatment for MBC. We compared clinicopathologic characteristics based on presentation at metastatic dg (dnMBC i.e. metastasis found within 6 months from initial diagnosis, or rMBC). We evaluated the trends in presentation according to year of MBC dg (YOD) using a Cochran-Armitage test, and studied factors associated with first-line progression-free survival (PFS1) and overall survival (OS) using multivariable Cox models. Results: Among the 35,687 pts in the ESME MBC cohort, 5,573 pts were treated for HER2+ MBC, including 2,800 (50.2%) with rMBC and 2,773 (49.8%) with dnMBC. Most pts were women (99.4%) with a median age of 57 years (range, 19-97). Compared with rMBC pts, dnMBC pts had significantly more often a premenopausal status (41.6% vs 35.9%, p <0.0001), have a BMI ≥30 (23.5% vs 17.8%; p <0.0001) and have ductal tumors (86.8% vs 78.8%; p <0.0001). In dnMBC pts compared with rMBC pts, there were more visceral involvement in absence of central nervous system (CNS) disease (54.1% vs 42.6%; p <0.0001), and less CNS involvement (4.7% vs 16.9%; p <0.0001), respectively. HR-positive status was similar in both categories (dnMBC vs rMBC, 60.5% vs 59.7%, p= 0.54) while HER2 score 3+ on IHC was more frequent in dnMBC (86.8% vs 82.5%, p <0.0001). Types of therapy by dnMBC and rMBC differed: first-line anti-HER2 treatment + chemotherapy +/- endocrine therapy (ET), anti-HER2 treatment + ET, anti-HER2 treatment alone or no anti-HER2 treatment in 88.4% and 66.6%, 3.2% and 6.6%, 1.6% and 7.6%, and 6.8% and 19.1% of pts, respectively. The proportion of rMBC significantly decreased from 63.5% in 2008 to 32.9% in 2022 (Cochran–Armitage test; p < 0.0001), whereas the proportion of HR+ tumors significantly increased from 53.2% in 2008 to 68.3% in 2022 (Cochran–Armitage test; p < 0.0001) both in dnMBC (50.0% to 67.0%) and rMBC (55.0% to 70.9%) pts from 2008 to 2022 (Cochran–Armitage test; p=0.0197 and 0.0008, respectively). With a median follow-up of 82.8 months (mo) (95%CI: 79.7-84.6), the median OS of dnMBC vs rMBC pts were 72.5 mo (95%CI: 66.4-77.3) vs 43.8 mo (95%CI: 41.6-46.4) and the median PFS1 were 18.9 mo (95%CI: 17.7-20.3) vs 9.4 mo (95%CI: 8.9-9.9). In the multivariable analysis, dnMBC was associated with better OS (adjusted hazard ratio (aHR): 0.65 (95%CI: 0.61-0.70); p < 0.001) and PFS1 (aHR: 0.64 (95% CI: 0.60-0.68); p < 0.001). In both categories of pts, HR- status, older age at metastatic diagnosis, presence of CNS disease, and multiple metastases were independently associated with poorer OS and PFS1. HER2 3+ status was an independent favorable factor for PFS1 in both dnMBC and rMBC pts, and for OS in dnMBC pts only. Conclusion: Between 2008 and 2022, in a large national cohort of pts with HER2+ MBC, we observed an epidemiological shift from a majority of rMBC pts to a vast majority of dnMBC pts, along with an increase in the proportion of HR+ pts among those with HER2+ cancer. Patients with dnMBC experienced significantly longer PFS1 and OS than those with rMBC. Attention to dnMBC vs rMBC enrollment in studies of HER2+ MBC is needed in the design and contextualization of study results. Citation Format: Thomas Grinda, Amélie Lusque, Stefania Morganti, David Pasquier, Aurélie Bertaut, Thierry Petit, Thomas Bachelot, Monica Arnedos, Fanny Le Du, Vincent Massard, Anthony Gonçalves, Caroline Bailleux, Jean-Sebastien Frenel, Paul Cottu, Christelle Levy, Aude-Marie Savoye, Nathalie Olympios, Marie-Ange Mouret-Reynier, Harold J. Burstein, Heather A. Pearsons, Lise Bosquet, Thomas Filleron, Suzette Delaloge, William Jacot, Nancy U. Lin. Trends in Presentation of HER2+ Breast Cancer: A Retrospective study of De Novo Versus Recurrent Metastatic Breast Cancer (MBC) in the Real-World French National ESME Cohort (2008-2022) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-08-03.