(Abstracted from N Engl J Med 2024;391(9):789–799) The incidence of leiomyosarcomas in France is 9.7 per 1 million people, and they make up approximately a quarter of soft-tissue sarcomas, which often occur in the uterus. Prognosis is typically not good, although cases have large variation between individuals.

e23542 Background: Angiosarcoma is a rare, aggressive vascular malignancy with limited treatment options. Preclinical data suggest beta-adrenergic blockers like propranolol may have anti-tumor effects. Only one window-of-opportunity trial (Embaby et al., 2024) has prospectively evaluated the activity of propranolol in angiosarcoma. Propranolol's efficacy is believed to fluctuate dose-dependently. We used an innovative phase I-II dose-finding method integrating toxicity, efficacy, and a time-to-event parameter (Rivière et al., 2018), tailored to small samples and optimizing recruitment. The PROPAN trial aimed to determine the optimal dose of propranolol combined with metronomic cyclophosphamide in patients with LAMA, using a sequential dose-finding design based on a bivariate continual reassessment method. Methods: Patients were enrolled in cohorts of 2, with sequential dose adaptations made for the next cohort among three dose levels (80, 120, or 160 mg/d) based on toxicity (grade ≥3 at 1 month per NCI-CTCAE v4.0) and efficacy (non-progression rate at 3 months per RECIST 1.1). The safe most successful dose (sMSD) was determined using a Bayesian model (dfmta package), balancing an non progression efficacy of 15, 30 and 50 % for respectively 80, 120 and 160 mg/j and ≤25% toxicity). This approach determined the next adapted dose based only on toxicity assessed early compared to efficacy, reducing waiting time between cohorts. The trial ended early if all doses failed efficacy or exceeded toxicity targets, with a maximum of 24 patients. Results: Fifteen patients were enrolled, with 12 used for dose optimization. 2 patients were treated in the second line, and the others in the third lines Efficacy data were unavailable for 3 in the final model. One grade 3 toxicity (dyspnea at 120 mg/d) was reported, and 4 patients met the non-progression endpoint at 3 months (3 at 80 mg/d, 1 at 120 mg/d). The final model identifies 80 mg/day as the optimal dose minimizing toxicity, with no efficacy gain at higher doses. Median progression-free survival was 3 months (0.7-6). Conclusions: This trial confirms a favorable safety profile but limited efficacy. This innovative method demonstrates feasibility for rare diseases. However, dose adjustment based on early toxicity assessment optimizes patient recruitment but risks over-reliance on toxicity data for dose optimization. Clinical trial information: NCT02732678 .

OBJECTIVES:Primary ovarian leiomyosarcomas are exceptionally rare, constituting less than 1% of ovarian tumors, and they typically have a poor prognosis. The available data on the management of these tumors are sparse, with limited publications mainly comprising small retrospective series that include multiple histologic types. The aim is to evaluate the clinical, surgical, pathologic characteristics and clinical outcome of patient affected by primary ovarian leiomyosarcomas. METHODS:Using the national database (NetSarc), we conducted a retrospective study of the outcomes of primary ovarian leiomyosarcomas at 18 French Sarcoma Group centers. Patients with any International Federation of Gynecology and Obstetrics stage of primary ovarian leiomyosarcoma at first diagnosis and available follow-up were included. RESULTS:A total of 39 patients with primary ovarian leiomyosarcomas were included: 35 had localized disease and 4 had metastatic disease. The median tumor size was 134 mm. Radical and wide surgery was performed on 21 (62%) and 13 patients (38%), respectively. Tumor grade 3, presence of necrosis, mitoses ≥20 high-power field, and high Ki-67 expression >30% were reported in 17 of 34 (50%), 29 of 34 (85%), 17 of 34 (50%), and 17 of 27 patients (63%), respectively. Positive estrogen receptor expression was reported in 14 of 27 patients (52%), whereas progesterone receptor expression was observed in 10 of 27 patients (37%). Adjuvant chemotherapy was administered in 12 of 34 patients (35%), whereas pelvic adjuvant radiotherapy in 8 of 34 (23%). Of the early-stage primary ovarian leiomyosarcomas, 9 had isolated pelvic recurrence, whereas 18 had parenchymal distant metastases. A total of 15 patients (44%) died of disease. In early-stage primary ovarian leiomyosarcomas, high mitotic counts and progesterone receptor negativity were variables associated with worse survival. CONCLUSIONS:Surgery is the cornerstone of treatment for early-stage primary ovarian leiomyosarcoma, whereas the role of adjuvant treatment remains unclear. Some pathologic features were associated with poorer survival. Owing to the rarity of ovarian leiomyosarcomas, referring patients to expert sarcoma centers is highly recommended.

PURPOSE:Paraneoplastic fever (PF) is an exclusion diagnosis that affects around 10% of patients in oncology, combining fever of unknown origin and the presence of cancer. There is no consensus or guidelines in the literature about the minimum criteria required for the diagnosis of (PF). The objective of this survey was to select clinical and paraclinical criteria to establish the diagnosis of PF. METHODS:After a review of the literature, 23 categories and 48 items were set up in an online survey. A two-round Delphi questionnaire survey was carried out from May to August 2021 with the participation of experts in several specialties in France and abroad. RESULTS:Thirty-seven and 33 experts responded in the first and second rounds respectively. Nine items obtained consensus. Among them, the need to rule out suspected infection by a directed bacteriological statement, an up-to-date imaging and doppler ultrasound of the lower limbs was highly consensual. No biological criteria were retained. Thirty-six propositions did not reach consensus and five were considered useless in this setting. CONCLUSION:The 9 selected criteria confirm the importance to eliminating differential fever aetiologies whereas no specific clinical or biological markers were retained. This survey constitute the first consensus of experts in this field.

High-throughput sequencing has advanced biomarker identification, enabling more targeted cancer treatment. Various gene panels are used to screen for actionable genomic alterations for clinical practice and trial inclusion. We aimed to determine the proportion of cancer patients with a targetable molecular tumor alteration and their inclusion in related trials using a routine panel, and to compare these proportions with results from a larger panel combined with molecular tumor board (MTB) discussion. We analyzed eligibility and inclusion in targeted therapy trials among all cancer patients treated at Poitiers University Hospital who underwent routine NGS. Clinical trials were identified via the French National Cancer Institute (INCa) and ClinicalTrials.gov databases. Inclusion rates were also assessed for patients analyzed with the broader FoundationOne CDx® (FO) panel. Among 1456 patients, 835 targetable mutations were identified: KRAS 43.6

BackgroundSarcomas are rare cancer with a heterogeneous group of tumors. They affect both genders across all age groups and present significant heterogeneity, with more than 70 histological subtypes. Despite tailored treatments, the high metastatic potential of sarcomas remains a major factor in poor patient survival, as metastasis is often the leading cause of death. Currently, metastatic risk assessment relies mainly on histological grading; yet, this method has limitations due to the disease’s heterogeneity. Advances in genomic and transcriptomic research have identified potential molecular signatures, but these approaches lack reproducibility and prognostic reliability. Therefore, new biomarkers are essential for improving risk prediction and therapy adaptation. Recent studies highlight that sarcoma cells secrete extracellular vesicles, particularly small extracellular vesicles (sEVs). These nanovesicles, abundant in bodily fluids such as blood, urine, and saliva, play a crucial role in tumor development, growth, and metastasis. sEVs contain proteins and nucleic acids that mirror tumor characteristics. Given their presence in blood, sEVs offer a promising avenue for noninvasive molecular cancer analysis via liquid biopsy. Preliminary studies in Ewing sarcoma have shown substantial alterations in sEV-derived transcripts, underscoring their potential in tracking disease progression and treatment efficacy. ObjectiveThis study aims to investigate whether sEVs can serve as reliable biomarkers for monitoring sarcoma progression and predicting recurrence risk. MethodsThis prospective, multicentric pilot study will enroll adult patients diagnosed with localized or metastatic liposarcomas, leiomyosarcomas, or undifferentiated pleomorphic sarcomas at 3 French cancer centers. The study’s primary goal is to quantify sEVs and analyze their protein and RNA content in the blood of patients with localized or metastatic sarcomas before and after the treatment. sEVs will be isolated from plasma samples, and protein and microRNA concentration will be determined. Research will last, on average, 6 months for patients with localized sarcoma and 4 months for patients with metastatic sarcoma. ResultsWe expect to identify differences in exosome levels based on disease stage and observe correlations between exosome dynamics and treatment response. If confirmed, these findings could establish sEVs as noninvasive biomarkers for monitoring therapy effectiveness and disease progression in patients with sarcoma. ConclusionsThis study could establish a novel, noninvasive biomarker for sarcoma prognosis and treatment monitoring. If successful, a nationwide study will be launched to confirm findings in a larger patient cohort, potentially revolutionizing sarcoma management and improving patient outcomes. Trial RegistrationClinicalTrials.gov NCT03800121; https://clinicaltrials.gov/ct2/show/study/NCT03800121 International Registered Report Identifier (IRRID)DERR1-10.2196/63718

Introduction: In a phase 1 study, bintrafusp alfa was found to have an encouraging clinical activity in patients with previously treated advanced NSCLC. This study evaluated the safety and efficacy of bintrafusp alfa with chemotherapy in patients with stage IV NSCLC regardless of the programmed death-ligand 1 (PD-L1) expression status. Methods: In this open-label, phase 1b/2 study (NCT03840915), eligible patients were assigned to one of four cohorts. Patients with previously untreated metastatic NSCLC (cohorts A, B, and C) received bintrafusp alfa with chemotherapy as first-line treatment, whereas patients whose disease progressed on previous treatment with programmed cell death protein 1 or PD-L1 inhibitors (cohort D) received bintrafusp alfa with chemotherapy as second-line treatment. The primary objective of this study was to evaluate the safety and tolerability of bintrafusp alfa with chemotherapy. Results: Four serious and one nonserious treatment-emergent adverse events were considered dose-limiting toxicities, none of which were assessed as related to bintrafusp alfa by the investigator. Any-grade bintrafusp alfa-related adverse events occurred in 20.7% of patients in cohorts A+B+C and in 16.7% of patients in cohort D. Keratoacanthoma was the most common transforming growth factor-β inhibition-mediated skin lesion (cohorts A+B+C: 12.1% and cohort D: 8.3%). In cohorts A+B+C, the overall response rate was 48.3%, and in patients with PD-L1 tumor proportion score of more than or equal to 50.0%, it was 71.4%. On the basis of an interim analysis, the data were considered mature, and no further analysis has been planned. Conclusion: Bintrafusp alfa with chemotherapy was found to have a manageable safety profile and encouraging clinical activity in patients with stage IV NSCLC.

Virus-associated tumors, characterized by immune evasion and angiogenic signaling, remain a therapeutic challenge. Human papillomavirus (HPV)-associated cancers such as cervical, anal, and oropharyngeal cancers represent a significant subset of virus-associated tumors and are characterized by immune evasion mediated by viral oncoproteins such as E6 and E7. Toll-like receptor 7/8 (TLR7/8) agonists such as EIK1001 have been shown to activate innate immune pathways, enhancing antigen presentation and inducing a robust adaptive immune response. This is particularly relevant in HPV-related tumors, where viral oncoproteins E6 and E7 suppress immune surveillance. By targeting TLR7/8, EIK1001 may overcome this immune suppression, priming the tumor microenvironment for synergistic effects with immune checkpoint blockade. Additionally, stereotactic radiation therapy of a metastatic site can enhance immunotherapy efficacy by inducing immunogenic cell death, promoting the release of tumor antigens, and facilitating systemic immune activation (the abscopal effect). This phase II trial included 47 patients with metastatic virus-associated tumors across 10 sites between June 2021 and July 2023. Treatment comprised atezolizumab (1200 mg IV every 3 weeks), EIK1001 (0.75 mg/m2 IV on a weekly schedule for 9 weeks, then every 3 weeks), and stereotactic radiotherapy (27-60 Gy in 3-5 fractions to a metastatic site). Primary endpoint was disease control rate (DCR) at 24 weeks per RECIST v1.1. at 24 weeks per RECIST v1.1. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), safety, and biomarkers of immune activation (proteomics and spatial transcriptomics). Forty-one patients with virus-associated tumors were enrolled between June 2021 and July 2023. The majority (85%) had HPV-related tumors, including cervical (40%), anal (30%), and oropharyngeal (15%) cancers. At 24 weeks, the DCR was 56.1% (90% CI: 42.1%-69.4%), with an ORR of 19.5% (90% CI: 10.1%-32.5%). Median PFS was 2.6 months (95% CI: 1.4-2.8), and median OS was 10.4 months (95% CI: 6.9-19.0). The most common Grade 3/4 treatment-related adverse events were fatigue (10%), diarrhea (8%), and pneumonitis (5%). Proteomic analyses of plasma demonstrated significant upregulation of immune effector proteins, indicating systemic immune activation. Spatial transcriptomics on tumor biopsies revealed enhanced T-cell infiltration and reprogramming of the tumor microenvironment, correlating with clinical responses. The combination of atezolizumab, EIK1001, and radiotherapy met its primary endpoint of disease control rate at 24 weeks, underscoring the potential of this regimen. in virus-associated tumors, particularly HPV-related cancers. Biomarker analyses support the immunogenic potential of this regimen, suggesting a paradigm shift in treating immunologically ‘cold’ virus-associated tumors. Further investigations will explore predictive biomarkers and refine patient selection. Antoine Italiano, Carlos Gomez-Roca, François Ghiringhelli, Jean-Philippe Metges, Philippe Rochigneux, Aurelien Carnot, Florian Estrade, Marie-Paule Sablin, Pierre-Emmanuel Brachet, Nicolas Isambert, Jade Dupin, Sophie Cousin, Jean-Philippe Guegan, Alban Bessede, Marina Pulido, Paul Sargos. Immunity induction with atezolizumab, EIK1001, and radiotherapy in virus-associated tumors: Results of the AGADIR Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT129.

Background: Sarcomas are rare cancer with heterogeneous group of tumours. Metastasis is often fatal, and current prognostic methods are limited. Recent findings show that sarcoma cells release small extracellular vesicles. Studying them can help assess cancer development, progression, and treatment effectiveness. This study aims to demonstrate the potential of small extracellular vesicles for monitoring the disease and predicting recurrence risk. Methods: A multicentric, prospective pilot study that will include 30 adults’ patients with localized or metastatic sarcoma. Small extracellular vesicles will be isolated from blood samples and protein and miRNA concentration will be determined. Research will last, on average, 6 months for patients with localized sarcoma and 4 months for patients with metastatic sarcoma. The study is sponsored by the Georges-François Leclerc Center and is currently ongoing. Discussion: Our innovative approach could improve sarcoma patient management through a non-invasive technique to predict treatment response and/or disease progression. Trial Registration: ClinicalTrials.gov identifier NCT03800121. Registered January 11, 2019, https://clinicaltrials.gov/ct2/show/study/NCT03800121 Keywords: Pilot-study, liquid biopsy, exosomes, sarcoma, cancer monitoring.

Background: Diagnosing patients at a non-advanced stage has become a mainstay of lung cancer prevention and control strategies. Understanding socio-demographic inequalities in stage at diagnosis may improve the targeting of interventions on patients at higher risk. This study aimed to identify these socio-demographic determinants in a large-scale French population-based cancer registry. Methods: All incident lung cancers diagnosed between 2008 and 2019 identified from the Poitou-Charentes Cancer Registry (south-west France) were included. Stage at diagnosis was categorised as advanced/nonadvanced (TNM III/IV vs I/II) according to the 8th TNM edition, the objective being to ensure a consistent level of prognosis over time. Socio-demographic variables included age, sex, the French European Deprivation Index (EDI) and patient's place of residence. Their impact on stage at diagnosis was quantified by multivariate logistic regression models with subgroup analyses by histological subtype. Results: Out of the 15,487 included patients, 75% were diagnosed at an advanced stage (66% to 95% depending on the histological subtype), 17% at a non-advanced stage and 10% at a non-specified stage. Multivariate analysis showed different patterns according to histological subtypes. In patients with adenocarcinoma, a higher risk of advanced stage was found for younger and older patients (u-shape), those most deprived, and those living in rural areas. The same effect of age was reported for squamous cell carcinomas, while no association was found for small-cell lung carcinomas. Conclusions: This study highlighted substantial socio-demographic inequalities in stage at diagnosis, specifically for adenocarcinoma patients. Diagnosis strategies could be refined and strengthened in the non-smoker population, in which adenocarcinomas are mainly reported.

BACKGROUND:The addition of trabectedin to doxorubicin, followed by trabectedin maintenance, may have superior efficacy to doxorubicin alone as first-line treatment in patients with advanced leiomyosarcoma. METHODS:We conducted a phase 3 trial involving patients with metastatic or unresectable leiomyosarcoma who had not received chemotherapy previously. Patients were randomly assigned to receive either single-agent doxorubicin (six cycles) or doxorubicin plus trabectedin (six cycles), with continued trabectedin as maintenance therapy in patients in the doxorubicin-trabectedin group who did not have disease progression. Surgery to resect residual disease was allowed in each group after six cycles of therapy. Analyses of progression-free survival (primary end point) and overall survival (secondary end point) were adjusted for two stratification factors: tumor origin site (uterine vs. soft tissue) and disease stage (locally advanced vs. metastatic). The primary end-point results were reported previously. RESULTS:A total of 150 patients underwent randomization. At a median follow-up of 55 months (interquartile range, 49 to 63), a total of 107 patients had died (47 in the doxorubicin-trabectedin group and 60 in the doxorubicin group). The median overall survival was longer in the doxorubicin-trabectedin group (33 months; 95% confidence interval [CI], 26 to 48) than in the doxorubicin group (24 months; 95% CI, 19 to 31); the adjusted hazard ratio for death was 0.65 (95% CI, 0.44 to 0.95). In a finding consistent with earlier reports, progression-free survival was longer in the doxorubicin-trabectedin group (12 months; 95% CI, 10 to 16) than in the doxorubicin group (6 months; 95% CI, 4 to 7); the adjusted hazard ratio for progression or death was 0.37 (95% CI, 0.26 to 0.53). The incidence of adverse events and the percentage of patients with dose reductions were higher with doxorubicin plus trabectedin than with doxorubicin alone. CONCLUSIONS:Combination therapy with doxorubicin and trabectedin induction, followed by trabectedin maintenance, was associated with improved overall survival and progression-free survival, as compared with doxorubicin alone, among patients with metastatic or surgically unresectable uterine or soft-tissue leiomyosarcoma. (Funded by PharmaMar and others; LMS04 ClinicalTrials.gov number, NCT02997358.).

Abstract Background Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor beta receptor II (a TGF-β “trap”) fused to a human immunoglobulin G1 monoclonal antibody blocking programmed cell death 1 ligand 1 (PD-L1). We report the efficacy and safety in patients with non-small cell lung cancer (NSCLC) that progressed following anti-PD-(L)1 therapy. Materials and Methods In this expansion cohort of NCT02517398—a global, open-label, phase I trial—adults with advanced NSCLC that progressed following chemotherapy and was primary refractory or had acquired resistance to anti-PD-(L)1 treatment received intravenous bintrafusp alfa 1200 mg every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal. The primary endpoint was best overall response (by Response Evaluation Criteria in Solid Tumors version 1.1 adjudicated by independent review committee); secondary endpoints included safety. Results Eighty-three eligible patients (62 [74.7%] treated with ≥3 prior therapies) received bintrafusp alfa. Four patients (3 primary refractory, 1 acquired resistant) had confirmed partial responses (objective response rate, 4.8%; 95% CI, 1.3%-11.9%), and 9 had stable disease. Tumor cell PD-L1 expression was not associated with response. Nineteen patients (22.9%) experienced grade ≥3 treatment-related adverse events, most commonly asthenia (3 [3.6%]) and fatigue, eczema, and pruritus (2 each [2.4%]). One patient had grade 4 amylase increased. One patient died during treatment for pneumonia before initiation of bintrafusp alfa. Conclusion Although the primary endpoint was not met, bintrafusp alfa showed some clinical activity and a manageable safety profile in patients with heavily pretreated NSCLC, including prior anti-PD-(L)1 therapy. Tumor responses occurred irrespective of whether disease was primary refractory or had acquired resistance to prior anti-PD-(L)1 therapy.

Supplementary Figure S4. Dose-Normalized CC-90011 Parameters by Dose Level. Box plots of dose-normalized AUC0-168 (A) and Cmax (B) after day 1 dosing. Boxes represent the interquartile range, white horizontal lines indicate the median, and open circles represent individual values. AUC0-168, area under the plasma concentration-time curve from time 0 to 168 hours; Cmax, maximum plasma drug concentration. Data cutoff: 3 May 2019.

Supplementary Figure S1. Antitumor Activity of CC-90011 in SCLC Patient-Derived Xenografts (PDXs). The effects of CC-90011 on a human SCLC PDX (LXFS 1129) model implanted subcutaneously in female athymic nude mice (NMRI-Foxn1nu). Female mice (n = 8) bearing the SCLC tumors were dosed orally with either 1.5 or 5 mg/kg/day of CC-90011 for 60 consecutive days or 10 mL/kg 0.5% methyl cellulose vehicle as a control. SCLC, small cell lung cancer. Data cutoff: 28 January 2019.

Correlation analysis between pharmacodynamic and pharmacokinetic findings in part 1

Table S1. CC-486 Plus Carboplatin Dose Levels in Part 1 Arm A Table S2. CC-486 Plus nab-Paclitaxel Dose Levels in Part 1 Arm B Table S3. CC-486 Dose Levels in Part 1 Arm C Table S4. Number of Patients With Treatment Emergent Adverse Events for Part 1 Table S5. Number of Patients With Treatment-Emergent Adverse Events in Any Treatment Arm in Part 2 Table S6. Mean CC-486 Plasma Pharmacokinetic Parameters Table S7. Efficacy of CC-486 Alone or in Combination With Carboplatin or nab-Paclitaxel in Part 2 Table S8. Prior Treatment History of NPV Patients

BackgroundPreclinical studies showed that capmatinib reversibly inhibits cytochrome P450 (CYP) 3A4 and CYP1A2 in a time‐dependent manner. In this study, we evaluated the effect of capmatinib on the exposure of sensitive substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with mesenchymal–epithelial transition (MET)‐dysregulated solid tumours. Besides pharmacokinetics, we assessed treatment response and safety.MethodsThis open‐label, multicentre, single‐sequence study consisted of a molecular prescreening period, a screening/baseline period of ≤28 days and a drug‐drug interaction (DDI) phase of 12 days. On day 1 of the DDI phase, 37 patients received a single oral dose of midazolam 2.5 mg and caffeine 100 mg as a two‐drug cocktail. Capmatinib 400 mg bid was administered from day 4 on a continuous dosing schedule. On day 9 of the DDI phase, patients were re‐exposed to midazolam and caffeine. After the DDI phase, patients received capmatinib on continuous 21‐day cycles until disease progression at the discretion of the investigator.ResultsA 22% (90% confidence interval [CI] 7‐38%) increase in the midazolam maximum plasma concentration (Cmax) was noted when administered with capmatinib, but this was deemed not clinically meaningful. Co‐administration with capmatinib resulted in 134% (90% CI 108‐163%) and 122% (90% CI 95‐153%) increases in the caffeine area under the plasma concentration‐time curve from time zero to infinity (AUCinf) and area under the plasma concentration‐time curve from time zero to the last measurable point (AUClast), respectively, with no change in Cmax. Adverse events were consistent with the known capmatinib safety profile. No new safety signals were reported in this study.ConclusionThe data from this study demonstrated that capmatinib is a moderate CYP1A2 inhibitor. Capmatinib administration did not cause any clinically relevant changes in midazolam exposure.

PDF file - 68K, Individual median of free to VEGF-bound aflibercept Ctrough ratio observed from cycle.