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Cancer-associated myocarditis outside of immunotherapy: National burden and inpatient outcomes in the National Inpatient Sample, 2018–2023.
e23218 Background: Immune checkpoint inhibitor myocarditis is increasingly recognized in oncology, yet myocarditis occurring outside of immunotherapy remains poorly characterized. Understanding the inpatient burden and outcomes of non-immunotherapy myocarditis may broaden recognition of high-acuity cardiac phenotypes during cancer hospitalizations. Methods: A serial cross-sectional analysis was conducted using adult hospitalizations with a principal diagnosis of malignancy in the 2018 to 2023 Healthcare Cost and Utilization Project National Inpatient Sample with discharge-level survey weighting. Myocarditis was identified using ICD-10-CM I40* in any diagnosis field. Because a specific immune-related adverse event indicator was unavailable, a conservative non-immunotherapy proxy cohort was defined by excluding hospitalizations with T45.1X5* codes for adverse effects of antineoplastic and immunosuppressive drugs. Outcomes included in-hospital mortality, shock (R57*), mechanical ventilation (ICD-10-PCS 5A1935Z, 5A1945Z, 5A1955Z), length of stay, and hospitalization cost. National estimates accounted for survey stratification and clustering. Survey-weighted multivariable logistic regression evaluated adjusted associations. Results: Among an estimated 5,788,489 adult cancer hospitalizations nationally, myocarditis prevalence was 0.00397%. In the non-immunotherapy proxy cohort, representing approximately 5,446,609 hospitalizations, myocarditis prevalence was 0.00340%. Compared with hospitalizations without myocarditis, non-immunotherapy myocarditis was associated with substantially worse unadjusted outcomes, including higher in-hospital mortality (24.32% vs 4.35%), mechanical ventilation (24.32% vs 2.58%), and shock (10.81% vs 1.46%). Resource utilization was markedly higher, with longer length of stay (24.76 vs 6.45 days) and higher hospitalization cost ($193,612.80 vs $28,706.34). In adjusted analyses within the non-immunotherapy proxy cohort, myocarditis was not independently associated with in-hospital mortality (odds ratio 1.62, 95% CI 0.21 to 12.50, P = 0.643) or mechanical ventilation (odds ratio 3.02, 95% CI 0.40 to 22.95, P = 0.286), reflecting limited precision due to rarity. Conclusions: Myocarditis occurring outside of immunotherapy is rare during cancer hospitalizations but identifies an extreme-acuity inpatient phenotype marked by high unadjusted mortality, frequent shock and mechanical ventilation, and substantial resource utilization. Although adjusted associations are limited by rarity, these findings underscore the clinical importance of early recognition and escalation for suspected myocarditis in hospitalized oncology populations.
Clinical and translational analysis of a phase Ib/II combination of atezolizumab, cobimetinib, and eribulin (ACE) to demonstrate inflammatory and metabolic programs define divergent response states.
1138 Background: Inflammatory breast cancer (IBC) is a rare, aggressive subtype with poor outcomes and limited immunotherapy data. Preclinical studies suggest MAPK inhibition enhances antitumor immunity and synergizes with checkpoint blockade. We report results from a phase Ib/II trial of atezolizumab (A), cobimetinib (C), and eribulin (E) in metastatic IBC with integrated molecular profiling. Methods: Patients (pts) with metastatic/recurrent IBC received ACE (cohort 1, n=17). Following cobimetinib supply discontinuation, an exploratory cohort received AE (cohort 2, n=10). Primary endpoint: objective response rate (ORR) per RECIST v1.1. Secondary endpoints: safety, progression-free survival (PFS), overall survival (OS), and correlative genomic, transcriptomic, spatial immune, and circulating tumor DNA (ctDNA) analyses. Results: ACE achieved ORR 50% (7/14; 3 patients were unevaluable for response), disease control rate (DCR) 71% (10/14), median PFS 3.7 months (mo), and median OS 10.6 mo, with 2 exceptional responders achieving >5-year survival. AE showed limited activity (ORR 10%, median OS 7.8 mo). No grade 4/5 toxicities occurred. Molecular profiling revealed distinct response states: responders demonstrated immune-activated, epithelial-like transcriptional programs with CD8+ T-cell infiltration; non-responders exhibited metabolically hyperactive, immune-excluded phenotypes with KRAS pathway activation, T-reg enrichment, CD8+ T-cell exclusion, VEGFA/GSDMB upregulation, and elevated ctDNA. Conclusions: ACE demonstrated encouraging activity in metastatic IBC with durable benefit in two pts. Resistance was associated with metabolic reprogramming and stromal immune exclusion, supporting rational development of metabolism-targeting, stroma-modifying, or T-reg/macrophage-directed combinations in this high-risk population. Clinical trial information: NCT03202316 .
A phase 1/2, first-in-human study of AVZO-021, a selective cyclin-dependent kinase 2 inhibitor (CDK2i), as monotherapy and in combination for patients with advanced solid tumors, including hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−) breast cancer (BC) and cyclin E1 (CCNE1)–amplified solid tumors: Updated safety and efficacy results.
1094 Background: AVZO-021 is a potent, once-daily, oral CDK2i with high selectivity against CDK1, thus minimizing off-target toxicity. Initial Phase 1 data from the ongoing first-in-human Phase 1/2 study of AVZO-021 (NCT05867251) showed clinical responses and a favorable tolerability profile. Methods: The ongoing Phase 1 portion of the study is evaluating the safety, pharmacokinetics (PK), and preliminary efficacy of AVZO-021 alone and in combination with fulvestrant. As of January 20, 2026, the safety population included all patients treated with AVZO-021 monotherapy (n=50) or in combination with fulvestrant (n=13). Efficacy evaluable population included patients treated at ≥150 mg once daily (QD) with HR+/HER2- breast cancer or CCNE1-amplified solid tumors with at least 1 post-baseline scan (n=23 in monotherapy and n=12 in combination with fulvestrant). Results: The median age was 63 years for monotherapy patients and 60 years for combination with fulvestrant. Overall, 95% of patients were female, 78% had BC, 10% had ovarian/fallopian tube cancer, and 5% had endometrial/uterine cancer. AVZO-021 monotherapy patients had a median of 3 prior lines of systemic therapy and those in combination therapy had a median of 4 prior lines, in the metastatic setting. All patients with HR+/HER2- BC received prior CDK4/6i and hormonal therapy. Most common (>25%) all-grade treatment-emergent adverse events (TEAEs) were nausea (51%), fatigue (43%), anemia (33%), and vomiting (32%); 13 patients required dose reductions due to TEAEs and 2 patients discontinued due to TEAEs (1 unrelated Grade 3 intestinal obstruction, 1 related Grade 4 neutropenia). Four patients with HR+/HER2- BC and CCNE1-amplified solid tumors had confirmed partial responses and remain ongoing, demonstrating prolonged clinical benefit. Additionally, 23 patients had stable disease for a disease control rate of 77%. Continuous CDK2 target coverage and significant decreases in ctDNA were observed at ≥90 mg QD monotherapy and in combination with fulvestrant. Conclusions: With longer follow-up, AVZO-021 as monotherapy and in combination with fulvestrant continues to show an encouraging tolerability profile and clinically meaningful efficacy. Gastrointestinal and hematologic adverse events continue to be of low incidence and severity allowing for prolonged treatment and potential safe combination with AVZO-023, a highly potent and selective CDK4i currently enrolling patients with HR+/HER2- BC in combination with fulvestrant. Clinical trial information: NCT05867251 .
Female cancer patterns and treatment disparities in southeastern Pará, Brazilian Amazon.
e13115 Background: Cancer disparities disproportionately affect women living in socio-environmentally vulnerable regions of the Brazilian Amazon. In southeastern Pará, a region characterized by intensive mining activity, social inequality, environmental exposure and limited access to specialized healthcare, these factors may influence cancer epidemiology and treatment patterns among women. Methods: This observational, descriptive study analyzed medical records of women diagnosed with cancer and treated at a public oncology referral center in southeastern Pará between 2024 and 2025. Data collected included age at diagnosis (stratified into five age groups), tumor type, and chemotherapy regimens. Analyses were performed descriptively using RStudio. Results: A total of 238 women received oncologic treatment during the study period. Mean age at diagnosis was 53.4 years for breast cancer, 46.7 years for cervical cancer, 49.6 years for ovarian cancer, and 64 years for uterine cancer. Age distribution varied by tumor type: in breast cancer, the highest proportion of patients were aged 50–59 years (32%, n = 68), although 40% were younger than 50 years. Cervical cancer predominated among women aged 41–59 years (54%, n = 8), ovarian cancer showed a higher proportion of patients younger than 40 years (33%, n = 3), and all uterine cancer cases occurred in women aged 60–69 years (100%, n = 2). Breast cancer was the most frequent malignancy (89.1%, n = 212), followed by cervical (6.3%, n = 15), ovarian (3.8%, n = 9), and uterine cancer (0.8%, n = 2). Breast cancer treatment predominantly consisted of anthracycline- and taxane-based chemotherapy, particularly doxorubicin plus cyclophosphamide followed by paclitaxel (AC→T), with carboplatin incorporated in the neoadjuvant setting for patients with triple-negative disease. In gynecologic cancers, treatment was more uniform, with predominance of platinum–taxane combinations, mainly paclitaxel plus carboplatin. Conclusions: Women treated in this mining-impacted region of the Brazilian Amazon exhibited a high burden of breast cancer, a broad age distribution, and a substantial proportion of younger patients. Oncologic care relied predominantly on conventional cytotoxic chemotherapy, with no access to targeted therapies or immunotherapy, including trastuzumab, during the study period. Notably, genetic testing for younger patients was not available, limiting genetic counseling and the identification of hereditary cancer risk. These findings highlight persistent regional disparities and underscore the need for cancer care policies and strategies aimed at expanding equitable access to modern cancer therapies and diagnostic resources in the Amazon region.
Association between metastatic site and survival in non–small cell lung cancer: A SEER-based cohort study.
e20658 Background: The recently updated 9th edition TNM staging system is the most widely used prognostic tool for non-small cell lung cancer (NSCLC). However, it does not incorporate the specific site of distant metastasis. Data are limited on whether survival differs by metastatic site among patients diagnosed with stage IV NSCLC with single-organ metastatic involvement. Methods: We queried the Surveillance, Epidemiology and End Results (SEER) database for adults with metastatic NSCLC and single-organ metastasis at diagnosis, using SEER Research Plus Data (17 Registries, November 2023 submission). Cancer-specific survival (CSS) was estimated using Kaplan–Meier methods, and differences between metastatic sites were compared using the log-rank test. Patients were categorized by metastatic site as lung, distant lymph node, brain, bone, liver, or other. Multivariable Cox proportional hazards models were used to evaluate associations between metastatic site and overall survival (OS) and CSS. Lung metastasis was used as the reference group. Models adjusted for age, race, biological sex, marital status, and receipt of chemotherapy, radiation therapy, and surgery. Results: A total of 18,489 eligible patients with metastatic NSCLC and single-organ involvement were identified, including 4,709 squamous and 13,780 nonsquamous cases. The median age was 68.4 years, and 53% of patients were male. Among patients with nonsquamous NSCLC, liver metastasis was associated with the worst OS (HR 1.915; 95% CI 1.671–2.195; P<0.001) and CSS (HR 1.933; 95% CI 1.670–2.237; P<0.001) compared with lung metastasis. In contrast, among patients with squamous NSCLC, brain metastasis was associated with the worst OS (HR 1.966; 95% CI 1.712–2.258; P<0.001) and CSS (HR 2.176; 95% CI 1.881–2.516; P<0.001) compared with lung metastasis. Conclusions: Among patients with metastatic NSCLC and similar TNM stage, the site of single-organ metastasis is associated with OS and CSS, and these associations differ between squamous and nonsquamous histology. Incorporating metastatic site may improve risk stratification beyond TNM staging in stage IV NSCLC. Adjusted hazard ratios for OS and CSS by metastatic site in single-organ metastatic NSCLC. Metastatic location CCS OS squamous NSCLC Lung 1 - - 1 - - Distant lymph node 1.133 0.939-1.368 0.19 1.075 0.901-1.282 0.42 Brain 2.176 1.881-2.516 <.001 1.966 1.712-2.258 <.001 Bone 1.799 1.597-2.027 <.001 1.698 1.52-1.898 <.001 Other 1.44 1.280-1.621 <.001 1.385 1.241-1.546 <.001 Liver 1.502 1.290-1.753 <.001 1.424 1.234-1.643 <.001 Nonaqueous NSCLC Lung 1 - - 1 - - Distant lymph node 1.049 0.902-1.219 0.54 1.04 0.904-1.198 0.58 Brain 1.55 1.403-1.711 <.001 1.539 1.403-1.689 <.001 Bone 1.674 1.531-1.830 <.001 1.673 1.540-1.818 <.001 Other 1.621 1.492-1.761 <.001 1.588 1.469-1.716 <.001 Liver 1.933 1.670-2.237 <.001 1.915 1.671-2.195 <.001
The evolving landscape of chimeric antigen receptor (CAR) T-cell therapy for plasma cell leukemia: A systematic review of early outcomes.
e19508 Background: Plasma cell leukemia (PCL) is an aggressive and rare manifestation of multiple myeloma with limited therapeutic options and poor survival despite treatment with novel agents and transplantation. Chimeric antigen receptor T-cell (CAR-T) therapy has achieved durable remissions in relapsed myeloma, but its role in PCL remains undefined due to disease rarity and manufacturing challenges associated with leukemic plasma burden. Methods: A systematic search of PubMed, ClinicalTrials.gov, and conferences (Jan 2019–Nov 2025) was conducted in accordance with PRISMA principles. Two reviewers independently screened records and extracted data; discrepancies were resolved by a third reviewer. Studies reporting CAR-T outcomes in plasma cell leukemia were included (bispecific antibodies excluded), and risk of bias was assessed using Joanna Briggs Institute checklists. Cumulative efficacy and safety outcomes were summarized using sample-size–weighted descriptive analyses. Results: Five studies were identified—four early academic series and one multicenter retrospective analysis—comprising 42 PCL patients, all treated with BCMA-directed CAR-T cells (ide-cel, cilta-cel, or academic constructs). Pooled overall response rate (ORR) was approximately 91% with a complete response (CR) of approximately 60%. Median progression-free survival (PFS) across available studies ranged from 5 to 16 months, and median overall survival (OS) was approximately 13 months. Toxicity profiles were similar to CAR-T in relapsed myeloma; grade ≥3 cytokine-release syndrome occurred infrequently (reported up to ~15%), and neurotoxicity was uncommon. Both primary and secondary PCL cases achieved CAR-T infusion, with durable responses observed in select patients. Given that the majority of pooled data derive from a single multicenter cohort, the findings may be disproportionately weighted by that experience and should be interpreted accordingly. Conclusions: CAR-T therapy demonstrates notable activity and manageable safety in plasma cell leukemia, representing a highly promising approach for this ultra-high-risk plasma-cell disorder. Despite encouraging early outcomes, evidence remains limited to small heterogeneous cohorts. Prospective, multi-center trials specifically enrolling PCL patients are urgently needed to define long-term efficacy, optimize antigen targeting, and establish CAR-T sequencing strategies. Summary of included studies and clinical outcomes. Study Year Target PCL Patients (n) ORR (%) CR (%) Median PFS (months) Median OS (months) Li et al. 2020 BCMA CAR-T 1 100 100 — — Li et al. 2021 BCMA CAR-T 2 90 43 5.2 14 Deng et al. 2022 BCMA CAR-T 1 100 100 16 — Zhang et al. (S103) 2025 BCMA dual nanobody CAR-T 4 96 59 — — Fortuna et al. 2025 BCMA CAR-T (ide-cel / cilta-cel) 34 90 59 9 13 Totals / Weighted — — 42 — — — — Abbreviation: BCMA = B-cell maturation antigen.
SGLT-2 inhibitors: More than glycemic control in diabetic patients with renal cell carcinoma? A real-world multicenter retrospective study.
e16560 Background: Renal cell carcinoma (RCC) is the most common primary malignancy of the kidney, and Diabetes Mellitus (DM) is a risk factor for its development. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been associated with decreased RCC incidence in patients with DM, but their impact on clinical outcomes in patients with RCC and DM is yet to be explored. This study examines the effects of SGLT2i on clinical outcomes, including all-cause mortality, thromboembolic events, major adverse cardiac events (MACE), and acute renal failure. Methods: We performed retrospective analysis using deidentified, aggregate patient data from the TriNetX research network. Adult patients aged 18-75 with RCC and DM were identified and stratified into two cohorts: SGLT2i prescribed after RCC and DM diagnosis vs. no SGLT2i use. Patients were then 1:1 propensity matched on variables such as demographic data, comorbidities, procedures, exposure to other diabetic medications, and systemic therapies for RCC. Following matching, there were 5423 patients in each cohort. Multivariable logistic regression analysis was performed to define adjusted Odds ratios (OR) with 95% confidence intervals. Results: SGLT2i exposure was associated with improved clinical outcomes. There was a reduction in all-cause mortality (OR 0.311, 95% CI 0.276-0.350) and ICU admissions (OR 0.511, 95% CI 0.443-0.588). These patients also demonstrated reduced rates of thromboembolic events (OR 0.451, 95% CI 0.379-0.538), MACE (OR 0.684, 95% CI 0.583-0.803), acute renal failure (OR 0.497, 95% CI 0.438-0.556), hypercalcemia (OR 0.661, 95% CI 0.541-0.806), use of calcium-lowering agents (OR 0.668, 95% CI 0.527-0.846), and anemia (OR 0.565, 95% CI 0.497-0.643). However, its effect on polycythemia was found to not be significant (OR 1.705, 95% CI 1.191-2.442). Conclusions: DM and RCC patients who were prescribed SGLT2i were found to have lower rates of all-cause mortality, thromboembolic events, MACE, and renal failure. The consistency of benefit across cardiorenal and thrombotic outcomes suggests SGLT2i may improve physiologic reserve, potentially enabling patients to continue oncologic therapy. Further investigation is warranted to determine whether SGLT2i could serve as adjunctive therapy to improve outcomes. Effects of SGLT2i in patients with RCC and DM. Outcome Odds ratio (95% CI) P value All-cause mortality 0.311 (0.276–0.350) <0.001 ICU admissions 0.511 (0.443–0.588) <0.001 Thromboembolic events 0.451 (0.379–0.538) <0.001 Major adverse cardiac events (MACE) 0.684 (0.583–0.803) <0.001 Calcium-lowering agents 0.668 (0.527–0.846) 0.001 Acute renal failure 0.497 (0.438–0.566) <0.001 Hypercalcemia 0.661 (0.541–0.806) <0.001 Polycythemia 1.705 (1.191–2.442) 0.003 Anemia 0.565 (0.497–0.643) <0.001
Potential and pragmatism: Clinical and public health implications of multi-cancer early detection (MCED) screening via cfDNA in asymptomatic adults.
e22570 Background: Blood-based multi-cancer early detection (MCED) tests analyze cfDNA biomarkers to screen for multiple cancers via a single blood draw . Early detection could improve outcomes by identifying cancers at earlier stages, but initial studies report widely varying accuracy. Methods: We reviewed published studies (through Jan 2026) of blood-based MCED tests in asymptomatic adults, including prospective screening cohorts and diagnostic-accuracy designs. Two reviewers extracted data (sensitivity, specificity, predictive values, stage distribution) and assessed study quality (QUADAS-2). Because of heterogeneity across test platforms and study designs, we summarize findings systematically. Results: 20 studies (109,872 participants) evaluated mainly cfDNA-based MCED assays (e.g., Galleri, CancerSEEK), largely in case–control or single-arm cohorts; few true population-screening trials were available (notable: PATHFINDER n=6,621; CCGA substudy n=4,077; a real-world Galleri series >111,000 tests). Risk of bias was frequently high (case enrichment, partial verification). Reported sensitivity ranged 9.5–100% and specificity 65.7–100%. In CCGA, Galleri showed overall sensitivity 51.5% and specificity 99.5%, with pronounced stage dependence (16.8% stage I vs 90.1% stage IV). In PATHFINDER, 35/92 positives were confirmed cancer (PPV 38%); specificity 99.1%, NPV 98.6%. In a separate real-world cohort, 63% of evaluated signal-positives had cancer; among asymptomatic patients completing workup PPV was 49.4%. MCED-detected cancers were skewed to advanced stages (PATHFINDER: 48% stage I–II vs 73% by usual care; Galleri series n=124; 28% stage I–II, 48% stage IV). Modeling predicts modest early-stage gains (+10–20%) and reduced metastatic incidence (45%), but mortality benefit is unproven. Positive results commonly triggered imaging and invasive procedures (49% biopsy/surgery; 82% TP vs 30% FP); serious adverse events were rare, and long-term harm from false positives appears limited. Conclusions: Published evidence indicates that blood-based MCED tests have very high specificity (99%) but only moderate sensitivity, especially for early-stage disease . In asymptomatic screening, only 30–50% of positive tests yield a cancer diagnosis (PPV) higher than most single-cancer screens, yet many positives prove false. Most initially detected cancers are late-stage; empirical stage-shift or mortality benefit remains to be demonstrated. Larger prospective trials (e.g. NHS-Galleri) with long-term follow-up are needed to determine the true clinical impact of MCED screening and to weigh potential benefits against the burden of false-positive workups.
Factors associated with non-receipt of fertility counseling during cervical cancer treatment: Insights from the ACHIEVE study.
e17530 Background: The American Society of Clinical Oncology recommends that all individuals of reproductive age with cancer receive fertility counseling. However, implementation in routine practice remains inconsistent. Few studies have examined factors associated with non-receipt of fertility counseling among cervical cancer survivors. Methods: We examined factors associated with non-receipt of fertility counseling during cervical cancer treatment using baseline data from the study Assessing Cervical Cancer Healthcare Inequities in Diverse Populations: the ACHIEVE Study. The ACHIEVE Study recruits cervical cancer survivors, diagnosed between 2021-2025, from population-based National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program registries in New Jersey and Los Angeles. Analyses were limited to reproductive-aged participants (21-49 years-old). We assessed differences in fertility counseling receipt across sociodemographic and healthcare factors using t-tests and Fisher’s exact tests. Results: Of the 111 participants included in this study, 23.4% reported non-receipt of fertility counseling during treatment. Those diagnosed between 40-49 years-old had the highest percentage of non-receipt of fertility counseling (58%) compared to participants aged 20-29 years-old (7%) and 30-39 years-old (35%) (p = 0.18). Non-Hispanic White survivors were more likely than non-Hispanic Black survivors to not receive fertility counseling (58% vs. 8%; p = 1). When compared to participants who received fertility counseling, those who did not receive fertility counseling more frequently reported healthcare discrimination (72% vs. 50%; p = 0.07) and low (vs. high) patient-centered communication (19.2% vs. 11.8%; p = 0.34; not significant). Conclusions: Findings underscore the need to better understand how sociodemographic factors and healthcare barriers shape fertility counseling practices during cervical cancer treatment. Interventions to standardize fertility counseling and address healthcare barriers in cancer care are needed to ensure equitable onco-fertility services and outcomes.
Overall survival analysis of a heavily pretreated population of patients with bone sarcomas treated with mecbotamab vedotin, a conditionally binding ADC targeting AXL.
11511 Background: Patients with metastatic bone sarcomas continue to lack effective therapies. AXL, a cell-surface receptor tyrosine kinase, is highly expressed in bone sarcoma subtypes and has been shown to drive increased metastasis, resistance to chemotherapy, and poor outcomes. Mecbotamab vedotin (Mec-V, BA3011, Conditionally Active Biologic CAB-AXL-ADC) is designed to reduce off-tumor toxicity and improve pharmacokinetics by conditionally binding to AXL under low-pH conditions (pH<6.7) of the tumor microenvironment. Methods: A phase 1/2 open-label study evaluated Mec-V among adult and adolescent patients with AXL-expressing locally advanced, unresectable, or metastatic osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordoma with measurable disease by RECIST v1.1. Patients received Mec-V monotherapy intravenously 1.8 mg/kg every 2 weeks (Q2W). Results: This report focuses upon the long term follow up among 33 patients treated with Mec-V with osteosarcoma (n=13), Ewing (n=9), chondrosarcoma (n=8) or chordoma (n=3). Patients received a median of 2 prior lines of treatment. Most related treatment-related adverse events (TEAE) in patients with bone sarcomas were low grade (64%) and reversible; the most common related grade 3/4 TEAE of special interest was neutropenia (18%). No grade 5 TEAE were observed. As of March 25, 2025, disease control rate (DCR) was 100% among patients with chondrosarcoma and chordoma. In patients with osteosarcoma and Ewing sarcoma, DCR was 50% with 3 confirmed responses (14%; osteosarcoma n=2, Ewing n=1). The median OS with Mec-V for all bone sarcoma patients was 17.6 months. Observed median OS by tumor type in months: osteosarcoma (11.9 [95% CI: 3.2-Not Estimable (NE)]), Ewing sarcoma (19.4 [95% CI: 5.2–NE]), chondrosarcoma (NE [95% CI: 16.3-NE]), and chordoma (15.1 [95% CI: 7.2-NE]). Conclusions: Patients with treatment refractory bone sarcomas treated with Mec-V monotherapy achieved a median OS of 17.6 months which compares favorably to reported outcomes with other therapies including combination therapies. Mec-V monotherapy holds considerable promise for these high unmet need indications with potential increased benefit when used in combination. Clinical trial information: NCT03425279 .
A phase 2 multicenter, open-label, parallel cohort study to evaluate the efficacy, safety, and pharmacokinetic profile of ABN401 in patients with advanced solid tumors harboring c-MET dysregulation.
8641 Background: Vabametkib is a small-molecule, tyrosine kinase inhibitor (TKI) that is a highly selective type I inhibitor of c-MET kinase, for the treatment of solid tumors harboring c-MET gene dysregulation. Methods: Phase 2 trial is an open-label, global study designed to evaluate the safety and efficacy of vabametkib in patients with NSCLC harboring MET exon 14 skipping mutations confirmed by NGS. Patients received oral vabametkib at a dose of 800 mg once daily (QD) until disease progression or unacceptable toxicity. The primary endpoint was ORR as assessed by blinded independent central review. Secondary endpoints included pharmacokinetics, DoR, DCR, PFS and OS. Exposure–response relationships of vabametkib were evaluated in enrolled patients to explore the optimal dose and dosing regimen to support further clinical development. Results: Forty-two (42) efficacy patients enrolled and median age were 76 years; 78 years in treatment naive and 75 years in the prior treated patients. Median follow-up duration was 14.1 months overall; 14.6 months for treatment naive and 13.5 months for prior treated patients. BICR confirmed ORR was 55% overall, with comparable response rate in both treatment-naive patients (52%) and prior-treated patients (57%). The median DoR assessed by BICR was 14.5 months with 19.9 months in treatment naive patients and 11.7 months in prior treated patients. Median PFS by BICR was 8.8 months overall, with 10.2 months in treatment naive patients and 7.3 months in prior treated patients. TRAE were experienced in 89% patients, 11% patients experienced Grade ≥3 TRAEs and no Grade 4 TRAE was reported. The most common TRAEs included nausea (75%), diarrhea (34%), hypoalbuminemia (25%), rash (18%), vomiting (18%), peripheral edema (16%), fatigue (14%), and elevated ALT and AST (14%). The most common Grade ≥3 TRAE was pneumonitis (4.5%). TRAEs led to dose reductions in 22.7% of patients, most commonly due to rash (6.8%), nausea (4.5%) and stomatitis (4.5%). TRAEs resulted in dose interruptions in 36.4% of patients most frequently due to nausea (9.1%), vomiting (9.1%), rash (6.8%), and fatigue (4.5%). Median AUC inf values were highest in the PR group (2,946 ng·h/mL) compared to the SD (2,021ng·h/mL) and PD groups (988 ng·h/mL) with a statistically significant difference (p = 0.0347 by Kruskal-Wallis). PK simulation demonstrated BID dosing more effectively maintained EC 90 coverage than QD dosing; sustaining drug conc above EC 90 for 93% of the dosing interval and increasing AUC 0-24hr by 35.3% thereby increasing likelihood of achieving exposure observed in the PR patients. Conclusions: Alternative 350mg BID of Vabametkib had been selected to continue the clinical development. Clinical trial information: NCT05541822 .
Predictors of mortality in patients with HIV and tumor lysis syndrome.
e19038 Background: Patients with Human Immunodeficiency Virus (HIV) are at increased risk for developing cancer, and malignancy represents an important cause of death in this population. Tumor lysis syndrome (TLS) has been noted a predictor of early death in patients with HIV and leukemia and lymphomas, however, overall mortality in patients with HIV who develop TLS is poorly characterized. We evaluated clinical characteristics and in-hospital outcomes among patients with TLS, stratified by HIV status and malignancy subtype. Methods: We performed a retrospective cohort study of adult hospitalizations with TLS using the Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample (NIS) from 2016-2019. The analytic cohort consisted of adult patients hospitalized with a diagnosis of TLS. The primary endpoint was in-hospital mortality. Multivariable logistic regression adjusted for demographics, comorbidities, markers of illness severity, and malignancy subtype. Results: A total of 49,395 patients with TLS were included in the study. HIV was associated with higher in-hospital mortality compared to patients without HIV (30.6% vs 23.6%; p<0.001). The final cohort included 865 patients with concurrent TLS and HIV. The median age was 47 years. 740 patients had lymphoma (85.5%), and 75 patients had leukemia (8.7%). 190 patients had an opportunistic infections (OI) (22%), and 65 patients had an OI associated with a CD4 count < 50 (7.5%). In adjusted models, HL (aOR 3.7; p=0.002) was independently associated with increased mortality. Acute kidney injury, acute respiratory failure, vasopressor use, mechanical ventilation, septic shock, and CD4 < 50 phenotype were the strongest predictors of mortality (all p<0.01). Arrhythmia, MI, pulmonary embolism, and stroke were not associated with increased mortality. Conclusions: TLS is a known risk factor for early mortality in patients with HIV-associated NHL. Our data suggests that HL is most strongly associated with increased mortality in patients with TLS and HIV. Patients with HIV are at increased risk of developing HL, and HL is known to cause an immunosuppressive state. Sepsis and septic shock were associated with increased mortality. CD50 phenotype was independently associated with increased odds of in-hospital mortality, though the broader category of OI were not, suggesting that mortality in TLS with HIV is driven by advanced immunosuppression rather than opportunistic infections in general. Mortality in patients with HL, HIV, and TLS is an area of further investigation. Cancer Subtype Number of patients (N) Deaths Mortality P-value Leukemia 75 20 26.7% p =.435 Acute Myeloid Leukemia (AML) 30 15 50.0% p =.019 Lymphoma 740 225 30.4% p =. 721 Hodgkin’s Lymphoma (HL) 45 20 44.4% p =.039 Non-Hodgkin’s Lymphoma (NHL) 700 210 30.0% p =.403 Solid Tumors 140 55 39.3% p =.015 Kaposi’s sarcoma 45 20 44.4% p =.039 Secondary malignant neoplasm of the liver 45 20 44.4% p = .039 Total 865 265 30.6%
First-in-human study of AAV6-NeuroD1 trans-differentiation therapy in recurrent malignant glioma.
2012 Background: Recurrent glioblastoma (GBM) has a median survival of less than 9 months. NeuroD1 is a neural transcriptional factor that can reprogram both glial cells and glioma cells into neuron-like cells, suppressing the proliferation of glioma cells and inducing cell death, extending the life span of animal models carrying glioblastoma. Therefore, scAAV6-NeuroD1 (NXL-004), a self-complementary adeno-associated virus 6 vector delivering NeuroD1, was developed to initiate a first-in-human study in patients with recurrent malignant glioma (ChiCTR2400080362). Methods: This is a single arm, open-label, dose-escalation study. The primary endpoint was safety, and the secondary endpoint was preliminary efficacy. Enrolled patients must have pathologically confirmed recurrent malignant glioma after standard therapy including surgery and chemoradiotherapy. NXL-004 was delivered intracavitary post-resection or intratumorally post-biopsy during surgery. Three dose levels (from 4.0x10 12 vg to 4.0x10 13 vg) were evaluated, using an accelerated dose escalation design. Up to two additional doses were allowed via an Ommaya reservoir at 2~4-week intervals after surgery. Results: 11 patients (median age 48.0, 81.8% male) were enrolled between 3/2024 and 6/2025. All patients had recurrent WHO grade 4 astrocytoma (10/11 IDH wild, 6/11 MGMT-unmethylated). Ten patients received repeat tumor resection plus intracavitary injection of NXL-004 (1 at low-dose, 3 at medium-dose, and 6 at high-dose), and one received biopsy plus intra-tumoral injection (low dose). All patients were included in the safety and efficacy analysis. No drug-related serious adverse event (SAE) or dose-limiting toxicities (DLT) was observed. All AEs related to NXL-004 were grade 1–2 (fever: 8/11; rash: 1/11; seizure: 1/11). Two grade 3 AEs (hemiplegia, meningitis) were reported but considered unrelated to the drug. Per RANO 2.0 criteria, the best overall response included 1 complete response (CR) and 5 stable disease (SD), yielding a disease control rate (DCR) of 54.5% (6/11). The median overall survival for all treated patients was 13.2 ± 2.0 months (95% CI: 9.3-17.1) from the first dose and 25.2 ± 1.2 months (95% CI: 23.0-27.5) from initial diagnosis. The first enrolled patient survived >18 months after dose. In the high-dose group, a higher DCR of 66.7% (4/6) was observed, with one patient achieving CR and one with SD surviving without progression >6 months (9 and 7 months, respectively, both ongoing). At a median follow-up of 9.0 months for this group, 5 patients were still alive, with 1 patient deceased (OS: 13.2 months). Conclusions: To our knowledge, this is the first clinical evidence of in vivo AAV-based trans-differentiation gene therapy for cancer treatment. NXL-004 showed favorable safety and encouraging efficacy, indicating that AAV-based cell reprogramming approach may represent a new modality for the treatment of glioma. Clinical trial information: ChiCTR2400080362.
Beamion LUNG-3: Zongertinib in resectable <i>HER2</i> -mutant NSCLC.
TPS8129 Background: Zongertinib is an irreversible tyrosine kinase inhibitor that selectively inhibits HER2 while sparing wild-type EGFR, thereby minimizing associated toxicities. Based on recent data from the Phase Ib Beamion LUNG-1 trial (NCT04886804), zongertinib was approved in the USA (accelerated), China (conditional), and Japan for previously treated patients with advanced/metastatic HER2 -mutant NSCLC. Clinically meaningful efficacy has also been seen with zongertinib as first-line therapy in treatment-naïve patients with advanced HER2 -mutant NSCLC. Beamion LUNG-3 (NCT07195695) is an ongoing, global Phase III trial investigating zongertinib as adjuvant monotherapy compared with SoC (immunotherapy [IO] or observation) in patients with early-stage, resectable HER2 -mutant NSCLC. Methods: Patients with histologically confirmed, resectable, Stage II–IIIB (post-operative, AJCC 9 th edition) HER2 -mutant NSCLC will be enrolled. Patients must be aged ≥18 years, have an ECOG PS of 0 or 1, have tumors that harbor a HER2 mutation within the tyrosine kinase domain, and have completed 3–4 cycles of neoadjuvant platinum-based chemotherapy + IO or 4 cycles of adjuvant platinum-based chemotherapy (≥2 cycles permitted if discontinued due to toxicity), followed by complete surgical resection. Patients must have a full recovery from surgical procedures and the ability to be randomized within 2–8 weeks of the last treatment for patients who underwent adjuvant chemotherapy, or within 4–10 weeks of surgery for patients who underwent neoadjuvant therapy. Approximately 400 patients will be randomized 1:1 to receive zongertinib 120 mg once daily or physician’s choice SoC (observation or IO with nivolumab, pembrolizumab, atezolizumab, or durvalumab). Stratification will be based on tumor stage (II, IIIA, IIIB), pretreatment (neoadjuvant/adjuvant), and physician’s choice of SoC (IO/observation). Patients will remain on treatment for up to 3 years (if receiving zongertinib) or up to 1 year (if receiving SoC), or until tumor recurrence, undue toxicity, or any other protocol-defined stopping criterion. The primary endpoint is disease-free survival (DFS) by investigator assessment, defined as the time from randomization until tumor recurrence or death from any cause. Secondary endpoints include overall survival (OS, defined as the time from randomization until death from any cause) and occurrence of grade ≥3 adverse events from first treatment administration (or from randomization for patients in the observation arm) until the earliest of tumor recurrence or 3 years since treatment started. The trial will be conducted at ~200 sites in 32 countries; enrollment is ongoing. Results will inform whether HER2-targeted adjuvant therapy improves DFS and OS in patients with early-stage HER2 -mutant NSCLC. Clinical trial information: NCT07195695 .
Distinctive profile of antiproliferative activity and interaction with doxorubicin of a new indole alkaloid P1 from <i>Petasites hybridus</i> in molecularly diverse breast cancer cell lines.
e12581 Background: Despite the efficacy of anthracyclines in breast cancer (BC) treatment, their use is limited by cardiotoxicity and resistance mechanisms. Secondary plant metabolites offer a reservoir for novel cytostatics. We investigated the in vitro activity of a novel indole alkaloid (P1), isolated from Petasites hybridus, and its interaction with doxorubicin (DOX) across clinically relevant BC subtypes. Methods: Cytotoxicity was evaluated using the MTT assay (48h exposure) in three human BC cell lines: MDA-MB-453 (HER2+, ER-/PR-), BT-474 (Luminal B/HER2+), and BT-20 (Triple-Negative BC), compared to primary normal skin fibroblasts as a non-malignant control. Half-maximal inhibitory concentrations (IC50) were determined. Drug interaction landscapes were analyzed using the Zero Interaction Potency (ZIP) model via SynergyFinderPlus software. Interaction was classified based on Synergy Scores (SS): >10 (synergy), -10 to 10 (additive), <-10 (antagonism). Results: P1 exerted dose-dependent antiproliferative effects in all BC lines. IC50 values were 31.74±3.8 µM for MDA-MB-453, 39.70±2.4 µM for BT-20, and 49.23±5.2 µM for BT-474. Notably, P1 demonstrated selective toxicity towards cancer cells; viability of all BC lines was significantly lower than that of normal fibroblasts at P1 concentrations >22 µM (p<0.05), indicating a favorable therapeutic window. DOX showed expected high potency (IC50 0.51–10.4 µM) but exhibited significant antagonism when combined with P1 in HER2+ cell lines: mean SS was -14.98 for BT-474 and -8.23 for MDA-MB-453 (reaching <-17 at high doses). Conversely, in the TNBC line BT-20, the combination was additive (mean SS -2.66), suggesting no interference with DOX efficacy. Conclusions: The novel indole alkaloid P1 demonstrates selective cytostatic activity against breast cancer cells sparing normal fibroblasts. The drug interaction profile is highly subtype-dependent: while P1 antagonizes DOX in HER2+ models, likely due to cell cycle interference, it shows additive potential in triple-negative breast cancer. These findings position P1 as a promising lead compound for TNBC therapy requiring further mechanistic elucidation. Comparative IC50 and interaction scores. Cell Line Molecular Subtype P1 IC50 (µM) Interaction with Doxorubicin (Mean Synergy Score) Interpretation MDA-MB-453 HER2+ 31.74 ± 3.8 -8.23 Antagonism BT-474 Luminal B / HER2+ 49.23 ± 5.2 -14.98 Antagonism BT-20 Triple-Negative 39.70 ± 2.4 -2.66 Additive
Efficacy of chemotherapy after PARP inhibitor progression in ovarian cancer: A large real-world cohort.
e17592 Background: PARP inhibitors (PARPi) have revolutionized the treatment of ovarian cancer in the maintenance setting. However, accumulating evidence suggests limited efficacy of subsequent therapies following disease progression on PARPi. The aim of this study was to evaluate the clinical activity of chemotherapy after PARPi progression and to explore potential predictive clinical or molecular biomarkers. Methods: We retrospectively reviewed the medical records of ovarian cancer patients treated with PARPi as maintenance therapy following platinum-based chemotherapy for newly diagnosed or recurrent disease at Alexandra Hospital, Greece. Clinicopathological characteristics, molecular data, treatment details, and survival outcomes were collected. Results: A total of 255 patients were included. Median age was 59.9 years (IQR 50.9–67.8). Most patients had serous histology (247/255, 96.9%), ECOG performance status 0–1 at diagnosis (224/255, 87.8%), and advanced-stage disease. Primary debulking surgery was performed in 145 patients (56.9%), and 92 patients (36.1%) harbored BRCA1/2 mutations. PARPi was administered as first-line maintenance in 174 patients (67.4%), with olaparib being the most frequently used agent (195 patients, 76.5%). Median follow-up was 37.9 months. Median progression-free survival (PFS) on PARPi was 15.8 months (95% CI 9.8–21.8). Disease progression occurred in 164 patients, predominantly during PARPi treatment (142 patients, 86.6%), while 22 patients (13.4%) progressed after completion of PARPi maintenance. Median PFS with subsequent chemotherapy was 5.4 months (95% CI 4.5–6.3). Post-PARPi PFS was longer in patients with a platinum-free interval ≥12 months (6.2 vs 5.0 months, p=0.043) and in those progressing after PARPi completion compared with progression during PARPi treatment (11.6 vs 5.1 months, p=0.050). No significant association was observed with line of therapy or BRCA1/2 mutation status. Overall response rate was 23.9%, and disease control rate was 64.8%. Median overall survival following PARPi progression was 22.0 months (95% CI 18.5–25.5), independent of clinical or molecular characteristics. Conclusions: In this large real-world cohort, chemotherapy following progression on PARP inhibitor maintenance demonstrated limited clinical benefit. Modest improvements were observed in patients with longer platinum-free intervals or progression after PARPi completion, while outcomes were not influenced by BRCA mutation status or treatment line. These findings highlight a substantial unmet need and support the urgent development of novel therapeutic strategies for patients progressing after PARPi therapy.
Circulating tumor DNA (ctDNA) tumor fraction (TF) dynamics to refine progression-free survival and radiographic response during anti-EGFR rechallenge in metastatic colorectal cancer.
3572 Background: Reliable biomarkers of benefit from anti-EGFR rechallenge are needed in anti-EGFR-refractory metastatic colorectal cancer (mCRC), where prior studies have shown modest progression-free survival (PFS) and radiographic response may incompletely capture biological sensitivity. We evaluated longitudinal ctDNA dynamics as a real-time biomarker of treatment effect. Methods: This analysis was conducted within a phase II enrichment study of panitumumab with or without trametinib in anti-EGFR-refractory mCRC; crossover was allowed after progression on monotherapy. Plasma was collected at baseline, prior to each infusion, and at progression or end of treatment. Patients with a baseline and ≥ 1 subsequent on-treatment sample were evaluable. ctDNA TF was estimated with the Guardant Reveal assay by normalizing cancer-specific differentially methylated regions with matched controls in each sample. In samples with detectable ctDNA, Guardant360 Liquid was used for genotyping of > 700 genes and tumor mutational burden (TMB). ctDNA TF dynamics were defined by best % change from baseline. Baseline TF, TMB, and focal amplifications in the MAPK pathway were also evaluated. PFS was the primary endpoint and best radiographic response (RECIST 1.1) was the secondary endpoint. Differences were assessed using Kaplan-Meier analyses, Cox proportional hazards models adjusted by age, sex, line of therapy, and treatment regimen, and the Kruskal-Wallis test. Results: A total of 38 patients were included. Consistent with the advanced clinical setting, median TF at baseline was 11.9%. Following adjusted Cox modeling, baseline ctDNA TF was prognostic when dichotomized at 2% (median PFS (mPFS): 3.55 vs 1.97 months, HR 0.32, 95% CI 0.13-0.77), whereas baseline TMB and focal amplifications in the MAPK pathway were not associated with PFS. ctDNA TF % change from baseline to best on-treatment value was strongly associated with PFS in patients with any decrease vs no decrease (mPFS: 3.16 vs 1.77 months, HR 0.24, 95% CI 0.08-0.69, p = 0.008), and the longest PFS was observed in patients achieving ≥ 80% TF decrease vs all others (mPFS: 3.61 vs 1.87 months, HR 0.20, 95% CI 0.08-0.49, p < 0.005). Median best TF % change was -31%, -80%, and -96% for PD, SD, and PR, respectively ( p < 0.001). Among patients achieving SD or PR, 100% had any TF decrease and 61% had a > 80% TF decrease, while in patients with PD as best response, 74% had any TF decrease and 5% had a > 80% TF decrease. No impact of ctDNA-related variables was observed in the crossover setting. Conclusions: ctDNA TF dynamics are strongly associated with PFS and provide clinically meaningful information beyond conventional imaging in mCRC patients undergoing anti-EGFR rechallenge, highlighting ctDNA TF as a powerful tool for refining response assessment and personalizing treatment decisions.
International variation in diagnostic and treatment practices in patients with HER2+ EBC: The RWE PEARL-HER2 study.
517 Background: Pts with HER2+ EBC achieving pCR post neoadjuvant chemotherapy (NACT) with trastuzumab (H) and pertuzumab (P) show favorable outcomes. Yet, management varies widely within healthcare systems, including access to continuation of adjuvant (adj) P. We compared diagnostic and treatment practices across countries. Methods: PEARL-HER2 is an international retrospective real-world cohort including pts with HER2+ EBC achieving pCR (ypT0/isN0) after NACT-HP (Jan 2014 to Dec 2023). This descriptive preliminary analysis (data cut-off Jan-2026) summarizes diagnostic and treatment data stratified by country. Results: 1345 pts with pCR were included. Significant heterogeneity in pts and disease characteristics was observed (Table 1). Diagnostic methods also varied: use of breast MRI ranged from 11-97% across countries (>85% in Spain/Portugal; Peru, 11%), while FDG-PET/CT ranged from 0-72% (overall 20%; Turkey, 72%; p<0.001). Anthracycline-based NACT varied from <20% in Argentina and Brazil to >85% in Portugal and Turkey (p<0.001). Adj P was administered to 33% of pts overall (0-97%; p<0.001), with high use in countries with public reimbursement and minimal in those without. Among ER+ pts, ET use was uniformly high (98%; p=0.590), but regimen selection varied substantially (p<0.001): tamoxifen (42%) and aromatase inhibitor (58%). Events occurred in 6% of pts (invasive/non-invasive relapses and death); median FU was 40 months (IQR 24–62). Conclusions: This analysis indicates marked cross-country variability in management of HER2+ EBC. Use of adj P closely aligned with national reimbursement policies, highlighting access as a major determinant of care beyond clinical risk and guideline recommendations. Characteristics Argentina (N=155) Belgium (N=217) Brazil (N=107) Italy (N=52) Peru (N=18) Portugal (N=603) Spain (N=110) Turkey (N=83) Total (N=1345) P-value Age, median (IQR) 47 (41–56) 54 (45–63) 46 (40–52) 53 (45–61) 45 (41–56) 52 (45–62) 53 (44–59) 51 (45–61) 51 (43–61) <0.001 Pre-/perimenop., n (%) 96 (62) 91 (43) 72 (72) 26 (50) 13 (72) 286 (48) 52 (48) 38 (46) 674 (51) <0.001 NST histology, n (%) 145 (95) 197 (91) 89 (83) 48 (94) 18 (100) 558 (93) 103 (95) 83 (100) 1241 (93) <0.001 ER–, n (%) 77 (50) 95 (44) 61 (58) 16 (31) 5 (28) 277 (46) 57 (52) 44 (53) 632 (47) <0.001 cN0, n (%) 58 (37) 28 (13) 43 (40) 24 (46) 2 (11) 267 (44) 50 (46) 21 (25) 493 (37) <0.001 Breast MRI | PET-CT, n (%) 123 (80) | 14 (9) 126 (58) | 63 (29) 73 (71) | 27 (26) 13 (25) | 13 (25) 2 (11) | 0 (0) 521 (86) | 70 (12) 102 (97) | 21 (19) 35 (42) | 60 (72) 995 (75) | 268 (20) <0.001 | <0.001 Anthracycline-based NACT, n (%) 19 (12) 137 (63) 19 (18) 44 (85) 2 (11) 532 (88) 84 (76) 79 (95) 916 (68) <0.001 ET use in ER+, n (%) 79 (98) 112 (95) 46 (98) 35 (97) 13 (100) 339 (98) 58 (100) 43 (98) 725 (98) 0.590 Adj P, n (%) 89 (57) 210 (97) 63 (59) 20 (39) 0 (0) 49 (8) 9 (8) 0 (0) 440 (33) <0.001 Public adj P reimbursement Yes, high risk Yes, N+ only No Yes, since 2023 No No No No — — Percentages exclude missing data.