Background Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for advanced non-small cell lung cancer (NSCLC), yet primary resistance remains common, with only ~50% of patients responding to first-line chemo-immunotherapy and 20-30% to monotherapy. Existing biomarkers such as PD-L1 expression and Tumor Mutational Burden (TMB) demonstrate limited predictive accuracy, underscoring the need for more comprehensive, integrative approaches. Methods We conducted a prospective, multicenter study involving 439 patients with advanced NSCLC treated with anti-PD-(L)1 ICI across first-line combo with chemotherapy and later-line monotherapy settings. A total of 443 pre-treatment tumor and blood-derived biomarkers-including genomic alterations, immune cell phenotypes, proteic markers, and routine laboratory tests-were profiled. Extensive biostatistics adjusted for PD-L1 expression were conducted. A rigorously benchmarked machine learning (ML) pipeline including 36 feature selection methods embedded into an optimism-correction framework was applied to identify predictors of primary resistance (PrR). Results Single biomarkers showed limited predictive utility, with PD-L1 (AUC 0.62, positive predictive value (PPV) 49.6%), TMB (AUC 0.55, PPV 43.1%), and key gene mutations (e.g., STK11, KEAP1) failing to achieve significance after multiple testing correction. A gradient boosting ML model integrating 18 selected features yielded a corrected AUC of 0.69 and a Positive Predictive Value (PPV) of 60% for PrR, outperforming standard biomarkers. In first-line patients, the model achieved a PPV of 51% and Negative Predictive Value (NPV) of 79% (baseline PrR rate: 29.9%); in subsequent-line patients, PPV reached 64% (PrR rate: 55.1%). Importantly, the signature also stratified Progression-Free Survival (PFS): high-risk patients had a median PFS of 3.9 vs. 14.6 months in low-risk patients (HR 0.307, p < 0.0001). Features from routine blood tests-such as serum chloride, albumin, CRP, and monocyte-to-lymphocyte ratio (MLR)-accounted for half of the final model and demonstrated independent associations with both PrR and PFS (e.g., chloride: OR 0.616, AUC 0.626; HR 0.685, C-index 0.61). SHAP-based individual-level model explainability revealed heterogeneous and nonlinear biomarker contributions, including cases where high CRP, low albumin, or elevated MLR overrode favorable PD-L1 or Treg profiles. A biomarker dashboard including interactive visualizations is available at https://compo.inria.fr/pioneer-website/. Conclusions Multimodal machine learning integration of clinical, genomic, immune, and laboratory data enables improved prediction of ICI resistance in NSCLC beyond current biomarkers. This approach not only captures the multifaceted nature of tumour-host interactions but also highlights the underrecognized predictive value of accessible blood-based markers, offering a path toward individualized immunotherapy decision-making. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work benefited from a government grant handled by the French National Research Agency (ANR) as part of the France 2030 investment plan, under the reference ANR-17-RHUS-0007. This work was supported by a partnership of Aix-Marseille Universite (AMU), Assistance Publique Hopitaux de Marseille (APHM), Centre National de La Recherche Scientifique (CNRS), Institut National de la Sante et de la Recherche Medicale (INSERM), Centre Leon Berard (CLB), Institut Paoli Calmettes (IPC), Gustave Roussy (GR), AstraZeneca (AZ), Veracyte (VERA), Innate Pharma (IPH) & ImCheck Therapeutics (ICT), and initiated by Marseille Immunopole. The authors gratefully acknowledge the support of the APHM, which sponsored the PIONeeR clinical studies. Its role was to control the appropriateness of ethical and legal considerations for all centers and to perform the monitoring of the consents signed and the clinical data recorded and coded as part of the study. The authors are grateful to all the patients and their families, as well as all the investigators, for their participation in the study. This work benefited from support from ITMO Cancer AVIESAN and French Institut National du Cancer (grant #19CM148-00) and from the French National Research Agency (ANR), under the France 2030 program, reference ANR-22-PESN-0017. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was conducted in accordance with the Helsinki declaration, French laws and regulations and the International Conference on Harmonization (ICH) E6 Guideline for Good Clinical Practice. The study was approved by the French ethics committee (Comite de Protection des Personnes Ouest II Angers, no. 2018/08) and the French drug and device regulation agency (Agence Nationale de Securite du Medicament, no. 2018020500208). Informed consent was obtained from each participant before any study procedure. The study is registered at ClinicalTrials.gov ([NCT03493581][1]). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03493581&atom=%2Fmedrxiv%2Fearly%2F2026%2F01%2F11%2F2026.01.09.26343779.atom

BACKGROUND:The phase II trial CABRAMET evaluates the efficacy of the VEGFR tyrosine kinase inhibitor (TKI) cabozantinib in patients with non-locally pretreated brain metastases (BM) from renal cell carcinoma (RCC). Faced with historical challenges in treating BM in RCC, this study aimed to provide prospective data on systemic treatment outcomes. PATIENTS AND METHODS:This multicenter open-label trial included RCC patients with BM with less than three prior systemic treatments excluding cabozantinib. Eligible patients received 60mg/day oral cabozantinib with dose adjustments for toxicity. The primary endpoint was the 6-month progression-free rate in brain metastases (6m-BM-PFR). The main secondary endpoints included BM objective response rate (ORR) and response duration in BM, extra-cranial ORR, BM and overall progression-free survival (PFS), overall survival (OS), and safety. RESULTS:The study enrolled 26 patients, with a median follow-up of 38.8 months (range 28.3-52.7 months). The 6m-BM-PFR was 56% (unilateral 95%CI 37.9-) by central review. BM partial responses were achieved in 16/26 patients (BM ORR of 61.5%) by investigator assessment. The median BM response duration was not reached and 58.3% (95%CI 29.3-78.9%) of the patients were event-free at 24 months. The median BM-PFS was 10.7 (95%CI 5.4-NR) months, and the median overall PFS was 8.1 (95%CI 4-11.9) months. The median OS was 15.0 (95%CI 9.3-35.0) months. Cabozantinib exhibited significant efficacy as first-line treatment with BM ORR of 86%, 67% in patients with prior immunotherapy, 40% in patients previously treated with TKI. CONCLUSION:The CABRAMET trial is the first to prospectively assess cabozantinib in the challenging population of non-locally pretreated brain metastases from RCC, highlighting its prolonged efficacy and tolerability in selected patients with BM. CLINICAL TRIAL REGISTRATION:NCT03967522.

BackgroundThe human epidermal growth factor receptor 2 (HER2)-targeted therapy trastuzumab deruxtecan has demonstrated significantly improved efficacy versus chemotherapy in HER2-low or -ultralow, hormone receptor (HR)-positive metastatic breast cancer (mBC) following endocrine therapy (ET). This study describes current real-world characteristics and outcomes for this population in France to inform optimized treatment sequencing, including the potential benefits of novel treatments.MethodsData were obtained from the Unicancer Epidemiological Strategy and Medical Economics (ESME) MBC database of adult patients with mBC. Patients were diagnosed with HER2-low, HR-positive mBC between 2008–2022 and initiated a chemotherapy-based regimen (index line of therapy [LOT]) after ≥1 qualifying line of ET. Real-world overall survival (rwOS) and progression-free survival (rwPFS) were assessed from the start of index LOT. ResultsAmong 326 patients selected, index LOT was third line (3L) or greater (“index 3L+ group”) for 202 (62.0%) patients and second line for 124 (38.0%) patients; 101 (31.0%) patients initiated index LOT after progression within 6 months of first-line ET + cyclin-dependent kinase 4/6 inhibitor (“rapid progressors”). Median rwOS (95% confidence interval [CI]) for the overall cohort, index 3L+ group, and rapid progressors was 23.1 (19.7, 27.5), 27.6 (22.7, 31.3), and 18.6 (14.3, 23.0) months, respectively. Median rwPFS (95% CI) for the overall cohort, index 3L+ group, and rapid progressors was 5.1 (4.8, 5.7), 5.2 (4.7, 6.0), and 5.6 (4.6, 6.3) months, respectively.ConclusionsThese real-world data suggest limited long-term efficacy of chemotherapy-based treatments for patients with ET-resistant HER2-low, HR-positive mBC, emphasizing high unmet need in this population.

TPS9614 Background: cSCC is the second most common skin cancer, predominantly affecting elderly individuals. Most cSCCs are diagnosed at an early stage and cured with surgery. Recurrences are usually detected during routine clinical examinations or imaging (lymph-node ultrasound, cervicothoracic CT scan). In patients considered at high-risk, local recurrence rates may reach up to 30%. To date, no randomized trial has established the optimal management of cSCCs at high risk of recurrence after complete resection, and indications for adjuvant radiotherapy are only based on local practices or retrospective studies showing variable and contradictory results. Methods: This ongoing randomized phase III trial (NCT06692556) compares the efficacy and safety of two commonly used strategies (adjuvant radiotherapy versus surveillance) in patients with cSCC at high risk of recurrence. Key eligibility criteria include age ≥ 18 years, histologically confirmed localized cSCC, complete surgical resection and high-risk of recurrence, defined as: 1) microscopic peri nerval involvement (PNI) with or without one additional risk factor, or 2) the presence of two or three risk factors (excluding microscopic PNI): immunosuppression, tumor diameter > 20 mm, specific location (lip/ear/temple), deep invasion (thickness > 6 mm or invasion beyond the subcutaneous fat), poor differentiation or desmoplasia. The primary endpoint is recurrence free-survival, defined as the time from the date of randomization to the date of first documented relapse (local, regional or metastatic) or the date of death. Secondary endpoints include local and metastatic recurrence-free survival, overall survival, safety and quality of life (EORTC QLQ-C30 and QLQ-ELD14). Exploratory objectives include progression-free survival after treatment for local recurrence in the surveillance arm. A total of 120 events will provide 80% power to detect a significant improvement of the recurrence-free survival in favor of the radiotherapy arm (HR=0.6) at a 2-sided alpha risk of 5%. Considering a two-years recurrence-free survival rate of 60% in the control arm, an accrual period of 18 months, 36 months follow-up for the last patient, and 10% of non-evaluable patients, a total of 266 patients is required (133 par arm). Since the start of recruitment (February 2025), 38 patients have been randomized. 35 French health institutions will contribute to recruitment. Clinical trial information: NCT06692556 .

Background Large-cell neuroendocrine carcinomas (LCNECs) of the lung are rare tumours with poor prognosis. A platinum-based regimen is currently the recommended first-line treatment for advanced LCNECs. Retrospective studies suggest potential benefit from immune checkpoint inhibitors (ICIs) but prospective data is lacking. Methods and analysis The ongoing phase II FIRST-NEC (First-line treatment for NeuroEndocrine Carcinoma) externally-controlled trial evaluates the efficacy and safety of durvalumab combined with platinum-etoposide as first-line treatment in locally advanced, ineligible for local therapy or patients with metastatic LCNEC. Histopathological diagnosis is centrally confirmed. All patients receive four induction cycles once every 3 weeks with durvalumab 1500 mg and platinum-etoposide. Durvalumab is maintained once every four weeks for up to 24 additional cycles. The primary endpoint is the 12-month progression-free rate (12M-PFR) as per central radiological review. Secondary endpoints include progression-free survival (PFS), overall survival (OS) and safety. Efficacy is assessed every 10 patients using a Bayesian approach, with a futility rule stopping the trial if the probability that 12M-PFR ≤15% exceeds 80%. Based on an A’Hern-Fleming design, 51 evaluable patients are required. Given the rarity of LCNEC, we developed an innovative approach based on target trial emulation to compare the survival outcomes of ICI plus chemotherapy (PFS and OS) to an external control arm (real-world PFS and OS), using real-world data from the Epidemiological Strategy and Medical Economics-Advanced and Metastatic Lung Cancer database. Ethics and dissemination This clinical trial received approval from the competent authorities on 14 March 2024. The results from the final clinical report will be published in medical journals. Protocol identifier V.2.0 dated 11 December 2024. Trial registration number NCT06393816

Background: Triple-negative breast cancer (TNBC), accounts for 15% to 20% of all breast cancers. It is characterized by the absence of 3 receptors (estrogen/progesterone/human epidermal growth factor 2) which limits the treatment options. Currently a therapeutic sequence for patients with mTNBC is first-line chemotherapy with or without immunotherapy, followed by sacituzumab govitecan then by successive chemotherapy lines. Considering the toxicity of these treatments there is a need to identify and monitor the signs and symptoms (S&S) of adverse events (AE). Early identification of these S&S, with appropriate management may prevent severe and fatal AEs, reduce dose delays and treatment discontinuations, thus optimizing treatment and possibly improving survival outcomes. Cureety is a digital remote monitoring platform, specifically designed to facilitate the monitoring of S&S of treatment-specific AEs and disease progression in cancer patients. Cureety integrates the Cureety TechCare algorithm for patient clinical classification, a CE-marked medical device. We hypothesize that patients with mTNBC may benefit from Cureety during systemic treatments by improving the identification of S&S of potentially severe/ AEs at early stages or early progression symptoms. Trial design: ALTERNATIVE is a French, multicentre, randomized, phase III trial comparing standard of care (SoC) with or without telemonitoring. The telemonitoring will comprise weekly AE and S&S evaluations and their analyses by Cureety. The randomization will be stratified by planned first-line treatment (immunotherapy: yes vs no) and ECOG PS (0 vs 1-2). Eligibility criteria: Patients aged ≥18 years, with mTNBC, ECOG PS ≤2, initiating first-line systemic treatment. The patient must be able and willing to complete web-based self-report questionnaires. Specific aims: To assess the effectiveness of SoC with digital telemonitoring compared to SoC alone, in terms of Time to definitive Health-Related Quality-of-Life score Deterioration (TUDD), Hospitalization Free Survival (HFS) and OS. The secondary objectives will include contribution on patient’s safety, treatment compliance and extent of exposure, compliance with telemonitoring, patient and medical team satisfaction with telemonitoring, global patient satisfaction with care, and socio-economic data. Sample size: A two-sided sequential logrank test with an overall sample size of 472 subjects for 384 events achieves 90% power at a 5% two-sided significance level to detect a hazard ratio (HR) of 0.72 when the median TUDD is 4.3 months without telemonitoring and 6 months with telemonitoring. The planned study duration is 42 months (18 months of accrual and 24 months of follow up). An interim futility analysis is planned after 157 TUDD events using an alpha-spending function of O'Brien-Fleming Analog. Statistical methods: TUDD, defined as the time from randomization to the first deterioration of ≥ 10 points out of 100 in the global health status (GHS) score (items 29 and 30 of the QLQ-C30), will be analysed using the Kaplan-Meier method. The median and Q1, Q3 event times for each arm and the corresponding 2-sided 95% confidence intervals (CIs) will be provided. A two-sided log-rank test stratified for the randomization stratification factors will be used to compare TUDD between the two study groups. The Cox regression model, stratified for the same stratification factors, will be fitted, and the estimated HR and 2-sided 95% CIs will be provided. To preserve the alpha risk at 5% for the two analyses, the p-value will be 0.00325 at the first analysis and 0.0492 at the final analysis. To control the overall type I error at 5%, once the superiority with TUDD is established, and the study is conclusive, HFS then OS will also be tested at 5% significance level using a hierarchical order. If the study is not conclusive for TUDD these endpoints will still be analysed but will be interpreted as exploratory. Funding Bpifrance and Cureety Citation Format: Martin Babau, Florence Joly, Frederic Fiteni, Aurore Caumont-Prim, Trevor Stanbury, David Perol, Charles Parnot, Francois-Guirec Champoiseau, Adeline Poitou, Jerome Lemoonier, Francois Montestruc. randomized phase III study comparing the digital telemonitoring platform “CUREETY TECHCARE” to usual standard of care in patients with triple negative metastatic breast cancer initiating a first-line systemic treatment: ALTERNATIVE [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 P3-08-25.

BACKGROUND:Triple negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy (NAC) face high risk of recurrence. BREASTIMMUNE-03 trial evaluates the efficacy of nivolumab and ipilimumab combination compared to capecitabine as adjuvant treatment. METHODS:This multicentre, randomized open-label phase II trial included TNBC patients with Residual Cancer Burden (RCB) of class II-III after NAC and surgery, and allocated them to randomization (1:1) to receive nivolumab plus ipilimumab or capecitabine for 24 weeks. Randomization was stratified by center, ECOG performance status (PS) 0 or 1, and RCB Class. Primary endpoint was disease free survival (DFS), assessed in the intent-to-treat population. Safety analysis according to NCI-CTCAE V5.0 included all patients who received at least one dose of study drug. RESULTS:From July 2019 to October 2021, 95 patients were randomized to the nivolumab plus ipilimumab arm (NIVO + IPI n = 45), or to the capecitabine arm (CT n = 50). With a median follow-up of 34.3 (IQR 33-36) months, 39 events (relapse or death) were reported: 17 (38 %) for NIVO + IPI; 22 (44 %) for CT (HR 0.84, 95 %CI 0.45-1.59; log-rank test p-value 0.5938). 17 (38 %) patients in the NIVO + IPI arm prematurely discontinued treatment due to treatment-related adverse events (AEs), versus 7 (14 %) in the CT arm. CONCLUSION:A 6-month post-operative nivolumab plus ipilimumab treatment did not significantly improve DFS compared to capecitabine in TNBC patients with RCB II-III and resulted in increased immune-mediated AEs. Despite premature trial termination, our results do not support nivolumab plus ipilimumab adjuvant treatment in this setting. TRIAL REGISTRATION:NCT03818685.

BACKGROUND:Clinical emergencies may occur at any time in paediatric palliative care (PPC). Our PPC team offers an on-call 24 hours a day, 7 days a week medical hotline assistance (MHLA). We report the experience of our MHLA during 2021, focusing on phone calls registered out of working hours. METHODS:Patients/families followed up by our team and who used the MHLA during 2021 were considered. The aims were to characterise the use of MHLA and to describe the immediate patient's pathway. RESULTS:232 children/families were followed. Half had disabilities or multiple disabilities. Though each patient benefited from advanced care planning, medical advice requests to/from families (N=864) were registered out of working hours in 160 (19%) cases. They concerned 31 different patients. Incoming calls were made by parents (n=130: 81%), or caregivers (n=19: 12%), while our team called a hospital team (n=11: 7%) to either announce and discuss hospitalisation (n=9) or discuss medical plan while the child stayed at home (n=2). Most calls dealt with a combination of symptom management (n=150), coordination of care (n=9), psychological support (n=3) and/or coordination of the home-hospital trajectory (n=11). 76 (47%) were classified as emergencies: 55/76 concerned clinical situations deemed 'biomedical emergencies' (need for therapeutic adaptation), while 21/76 were solved by reassurance. Only 9/76 (12%) were transferred to the hospital unit. CONCLUSION:Day and night medical advice requests managed by our PPC team out of working hours helped to avoid admission to the emergency unit in 88% of overall emergency calls received.

TPS8657 Background: LCNECs of the lung are rare lung tumors (2%) with difficult histopathological diagnosis (70-80% confirmation rate after centralized review). Platinum–based regimen is currently the recommended first-line treatment for advanced LCNECs. However it results in poor median progression-free survival (PFS) and overall survival (OS) of 5 months and 7.7 months, respectively. Retrospective studies have suggested efficacy of immune checkpoint inhibitors against LCNECs with significantly prolonged OS. In addition, the CASPIAN trial demonstrated the superiority of durvalumab plus platinum-etoposide over chemotherapy alone in patients with extensive-stage neuroendocrine small cell lung cancer, with an acceptable toxicity profile. Methods: This ongoing single-arm phase II trial is designed to evaluate the efficacy and safety of durvalumab in combination with platinum-etoposide as first line treatment in pts with locally diagnosed advanced LCNEC. Key selection criteria are age ≥ 18 years, ECOG PS 0-1, measurable disease (RECIST 1.1) and locally advanced (Stage III) ineligible for loco-regional therapy or metastatic (Stage IV). Central confirmation of the histopathological diagnosis will be performed for all pts at the start of treatment. All pts will receive 4 cycles of induction with durvalumab 1500mg, platinum (either carboplatin AUC5 or cisplatin 80mg/m² at D1) and etoposide 100mg/m² (D1-D3), repeated every 3 weeks. Durvalumab 1500mg will be continued alone every 4 weeks for a maximum of 24 additional cycles or until disease progression or unacceptable toxicity. The primary endpoint is to determine, in pts with confirmed diagnosis, 12-month progression-free rate (12M-PFR) as per central radiological review. Secondary endpoints include PFS, OS and safety. Radiological criteria will be described using the RECIST 1.1 both as per investigator’s assessment and as per central radiological review. Biomarkers will be studied as predictive and prognostic factors of efficacy. Efficacy will be assessed sequentially every ten pts using a Bayesian approach. Analogous to a frequentist approach from an A’Hern-Fleming single-stage design, 51 evaluable pts will be enrolled. A futility stopping rule will stop the trial if there is a high probability (>80%) that the 12M-PFR is less than or equal to P0 (15%). Finally, a trial emulation will be performed as an exploratory analysis to assess PFS and OS compared to an external control arm by using real-world data from the ESME database. Since the start of recruitment (June 2024), 13 patients with a confirmed diagnosis have been included. Clinical trial information: NCT06393816 .

TPS3177 Background: PD-1/PD-L1 blockade has transformed oncology by offering durable responses in various cancers. However, many patients develop resistance, highlighting the need for novel therapeutic strategies. Epithelial-to-Mesenchymal Transition (EMT) plays a pivotal role in immune checkpoint inhibitor efficacy, with epithelial tumors exhibiting greater immunoreactivity than mesenchymal ones. NP137, a first-in-class anti-Netrin-1 monoclonal antibody, has shown in phase I study the ability to inhibit EMT, potentially overcoming resistance (Cassier et al., Nature , 2023). This phase I data demonstrated NP137’s ability to shift tumors toward an epithelial phenotype, supporting its combination with immune checkpoint inhibitor to sensitize tumors and alleviate resistance. The goal of IMMUNONET study (NCT05605496) is to evaluate NP137’s ability to re-sensitize advanced solid tumors to anti-PD-1/PD-L1 therapy. Methods: This proof-of-concept study assess NP137 (14 mg/kg, IV, Q3W) as add-on therapy to standard PD-1/PD-L1 inhibitors across three independent cohorts of patients with advanced/metastatic solid tumors of any histological types: Cohort 1 (Stable Disease [SD]): Radiological SD after ≥12 weeks of anti-PD-1/PD-L1 therapy. Cohort 2 (Primary Refractory): Radiological progressive disease (PD) and no response under anti-PD-1/PD-L1 therapy. Cohort 3 (Secondary Refractory): Radiological PD following initial response under anti-PD-1/PD-L1 therapy. Treatment continues until progression, unacceptable toxicity, or consent withdrawal. The primary endpoint is clinical activity: objective response rate (ORR)-12W for cohort 1 and progression-free rate (PFR)-12W for cohorts 2 and 3. Secondary endpoints include ORR-12W (cohorts 2 and 3), Time to Objective Response (ToR), Duration of Response (DoR) and safety for all cohorts. Evolution of EMT, Netrin-1, and receptor expression will be analysed and correlated with clinical outcomes. An adaptive 2-stage design is being used for this study (Lin and Shih, Biometrics 2004). The target levels of clinical activity are set at 20% (relevant) and 25% (high). In stage 1, 18 patients will be enrolled at 1-sided alpha of 5%. Depending on the observed success rate, additional 11 patients (if 1 or 2 successes) or 5 patients (if > 2 successes) could be recruited into stage 2. Null hypotheses will be rejected if ≥4 successes are observed in 29 [test p 0 = 0.05 vs. 0.20, 80% power] or 23 patients [test p 0 = 0.05 vs. 0.25, 90% power], respectively. Current Status: Cohort 1 has been closed due to non-feasibility. Prespecified goals for the first stage were met, stage 2 enrolment is underway. Cohort 2 has enrolled 21 patients, and cohort 3 has enrolled 19 of 23 planned evaluable patients. Clinical trial information: NCT05605496 .

Large genomic programs have contributed to improving drug development in cancer. To assess the potential benefit of using larger gene panels to guide molecular-based treatments, we conducted a multicenter randomized trial in patients with advanced and/or metastatic solid cancer. Molecular alterations were determined using either a panel of 324 cancer-related genes (Foundation OneCDX (F1CDX)) or a limited panel of 87 single-nucleotide/indel genes and genome-wide copy number variations (CTL) and reviewed by a molecular tumor board to identify molecular-based recommended therapies (MBRTs). Using paired data from both panels for each patient, the primary endpoint was the proportion of patients with an MBRT identified. Main secondary endpoints included the number of patients with at least one actionable alteration leading to MBRT identification, the number of patients with and without MBRTs initiated, progression-free survival, best overall response, duration of response and safety. Among the 741 patients screened, 45.7% had quality-checked tumor samples. MBRTs were identified with F1CDX in 175 (51.6%) patients and with CTL in 125 (36.9%) patients, translating to a significant increase of 14.8 percentage points (P < 0.001) with the more comprehensive gene panel versus the more limited panel, meeting the primary endpoint. However, no differences in clinical outcomes were observed in these patients with advanced and/or metastatic cancer in need of treatment beyond standard genomic alterations. These findings illustrate the potential for larger gene panels to increase the number of molecularly matched therapies. Larger studies are needed to assess the clinical benefit of expanded MBRTs. ClinicalTrials.gov registration: NCT03163732 .

In keeping with the spirit of the Giens Workshops, this article reports on desirable developments in the functioning of the Committees for the Protection of Persons (CPP) and the Research Ethics Committees (CER) in France. These committees play a crucial role in the ethical evaluation of clinical research projects, a process that has become more complex, particularly given recent legislative, regulatory and methodological developments. The result of this reflection highlights the current challenges faced by CPPs, in particular the increasing workload, the complexity of the files to be processed and the need for better use of their resources. To address these, several recommendations are proposed. These include improving support for promoters before submitting files, simplifying administrative tasks for CPP members and improving IT tools. The article also highlights the need for continuous evaluation of the activities of the CPPs to contribute to the quality and consistency of their opinions, as well as the importance of making this activity more attractive to qualified professionals, by offering them adequate compensation and professional recognition. For the benefit of all stakeholders in health research, the development of a single documentary base accessible to all and bringing together all the information and models of useful documents is strongly desired. Concerning the CERs, which currently operate without a legal framework, it is particularly proposed that their development be carried out in conditions of compliance with essential principles of collegiality, transparency and appropriate management of conflicts of interest. Finally, it appeared necessary for the National Human Research Commission (CNRIPH) to benefit from appropriate resources to effectively fulfill its missions including the coordination of the CPPs and the development of appropriate training programs for their members. These recommendations aim to improve the operating conditions of the CPPs and CERs, ensuring the ethics of the research undertaken, as well as the quality of the results of the latter.

In line with the spirit of the Giens workshops, this article reports on the recommended evolution of the Ethics Committees (CPPs) and the Committees for Research Ethics (CER) in France. These committees play a crucial role in the ethical evaluation of clinical research projects, a process that has become more complex, particularly in view of recent legislative, regulatory and methodological developments.This reflection highlights the current challenges faced by the CPPs, including the increasing workload, the complexity of the issues to be addressed and the need for better use of their resources. To address this, several recommendations are proposed. These include improving support to sponsors prior to submission, simplifying administrative tasks for CPP members and improving IT tools.The article also highlights the need for continuous evaluation of the activities of the CPPs to contribute to the quality and consistency of their opinions, as well as the importance of making this activity more attractive to qualified professionals, by offering them adequate compensation and professional recognition.For the benefit of all involved in health research, there is a strong desire to develop a single document management system accessible to all and inclusive of relevant information and document templates.Regarding the CERs, which currently operate without a legal framework, the proposition is that their development should take place under conditions of compliance with essential principles of collegiality, transparency and appropriate management of conflict of interest.Finally, it appeared necessary that the National Commission for Research Involving the Human Person (CNRIPH) be given adequate resources to carry out its tasks effectively, including the coordination of the CPPs and the development of appropriate training programs for their members.These recommendations aim to improve the operating conditions of the CPPs and CERs, ensuring the ethics of the research undertaken, as well as the quality of their results.

Introduction International medical oncology societies recommended early integration of palliative care to alleviate symptoms, improve quality of life and significantly reduce aggressiveness of care near the end of life, defined as the use of chemotherapy, high rate of hospitalisation/visits to emergency or intensive care unit in the last month of life or death in acute care unit. However, the most appropriate schedule for patient referral is still to be determined. Scores and criteria are debated, with uncontrolled symptoms (pain, dyspnoea, distress, etc) being one of the main indicators. These symptoms are also the leading causes for patients with cancer to seek care in emergency units. Several studies in North America suggested that referral to palliative care from emergency units is feasible and efficient.The aim of this study is to determine if systematic early referral to palliative care in a context of emergency reduces aggressiveness of care near the end of life compared with referral on medical team request.Methods and analysis This multicentric randomised study plans to enrol patients with a PALLIA-10 score >3 attending unscheduled on-site visits in French comprehensive cancer centres, and allocate them to randomisation (1:1) to receive palliative care systematically (experimental group) or on medical oncology team request (standard group). The primary objective is to compare the proportion of patients meeting at least one criterion of clinical care aggressiveness near the end of life, in each group. Secondary objectives include a description of clinical care aggressiveness components, palliative care requirement (psychologist, social worker, nutritional counselling, etc), patient-reported outcomes (FACT-G7, Hospital Anxiety and Depression Scale, Edmonton Symptoms Assessment System), the place of death and overall survival. Health economics and human and social sciences substudies will be presented.The study needs to include 192 patients (96 patients per arm) to reach a 20% decrease in care aggressiveness in the last month of life from 65% to 45%, with a statistical power of 80%, and a 2-sided type I error rate of 5%, using systematic referral. Considering a 20% rate of dropout or patients still alive at the time of analysis, 240 patients will need to be allocated to randomisation.Ethics and dissemination This clinical study received approval from the Ethics committee CPP Est III on 25 October 2023, and complies with the MR001 Commission Nationale de l’Informatique et des Libertés (#1994173, 27 September 2016). The first consent was signed on 12 September 2024.Results will be presented and published in international academic journals.Protocol identifier V.2.1 dated 10 July 2024.Trial registration number NCT06150027.

BACKGROUND:Paclitaxel-induced peripheral neuropathy (PIPN) is a severe side effect frequently associated with premature treatment discontinuation. Frozen gloves (FG) therapy reported moderate efficiency, but FG are often poorly tolerated. Surgical gloves (SG) showed encouraging results. We investigated the efficacy of SG vs FG to prevent PIPN. METHODS:This prospective monocentric self-controlled case series study included breast cancer patients receiving 12 cycles weekly paclitaxel treatment. During each cycle, patients wore two superimposed SG on their dominant hand and FG on their other hand. The primary objective was patient satisfaction at the end of paclitaxel treatment using 10-point numeric scale (10p-NS). Secondary objectives included the rate of patients with PN, patient comfort and pain using 10p-NS and nurses' preference. A total of 84 patients was required to identify a 2-point difference in satisfaction with 2-sided paired Student t-test (α: 5 %; β:5 %). RESULTS:Between September 2019 and December 2020, 94 patients were included. The median dose of paclitaxel received per cycle was 132 mg (107-164) for a median of 12 (4-12) cycles. 21 (22 %) patients required ≥ 1 paclitaxel dose reduction related to PN occurrence. Median overall satisfaction was significantly improved (SG: 9/10; FG: 6/10; p < 0.001) with increased comfort (8/10; 5/10; p < 0.001) and less pain (1/10; 4/10; p < 0.001). Less patients reported at least one grade ≥ 2 PN (18 %; 28 %; p = 0.0117). CONCLUSION:Compression therapy with SG reported high patient satisfaction and is effective to reduce PIPN. Such PN prevention is easy to implement and improves patient quality of life. ELEGANT trial has been registered on www. CLINICALTRIALS:gov; NCT03872908 (first post: March 8th, 2019).