Browse Articles

Stable colorectal cancer burden in inflammatory bowel disease over a decade: Nationwide U.S. trend analysis, 2012–2022.

e15651 Background: Colorectal cancer (CRC) remains a significant long-term complication of inflammatory bowel disease (IBD). Most risk estimates derive from older, referral-based cohorts that predate modern biologic therapies and current endoscopic surveillance practices. We have yet to fully characterize the current population-level burden of CRC among hospitalized IBD patients in the era of advanced treatments. Methods: We conducted a retrospective cross-sectional analysis of adult IBD hospitalizations using the National Inpatient Sample (2012–2022). We identified CRC cases using a composite diagnostic definition. Using survey-weighted methods, we estimated annual CRC prevalence overall and by IBD subtype, including ulcerative colitis (UC) and Crohn’s disease (CD). Multivariable survey-weighted logistic regression models identified factors associated with CRC, including age, sex, race, payer, income quartile, hospital characteristics, comorbidities, and calendar year, to assess temporal trends formally. Results: CRC prevalence among hospitalized IBD patients was consistently low during the study period, ranging from 0.22% to 0.33% overall. When comparing IBD subtypes, the prevalence was higher among UC admissions (0.26%–0.55%) than among CD admissions (0.13%–0.26%). No consistent change in CRC prevalence over time was observed in either group. In multivariable analyses, increasing age emerged as the strongest and most consistent predictor of CRC. Patients aged 55–64 and 65 years or older had significantly higher odds of CRC compared to those aged 18–39. Compared with CD, UC was independently associated with higher CRC odds in several years. Other variables—such as sex, race, payer type, income quartile, and hospital characteristics—were not consistently associated with CRC. In terms of healthcare utilization, CRC was associated with more extended hospital stays (mean 7.9 vs 5.1 days) and higher total charges (mean $103,863 vs $60,620) compared with non-CRC IBD admissions. Conclusions: In a contemporary, nationally representative cohort of hospitalized IBD patients, CRC prevalence has remained low and stable over the past decade. These findings challenge historical perceptions of an increasing CRC burden in IBD and suggest that advances in surveillance and disease-modifying therapies may have reduced population-level risk. Age and disease phenotype primarily influence CRC risk in IBD, rather than temporal trends or healthcare access, which supports a transition toward individualized, risk-based surveillance strategies.

Adjuvant sintilimab plus bevacizumab following curative resection of spontaneously ruptured hepatocellular carcinoma: A prospective exploratory phase II study (CLEAR-2).

TPS4254 Background: Spontaneous rupture of hepatocellular carcinoma (srHCC) is a life-threatening complication associated with acute hemorrhage, aggressive tumor biology, and an exceptionally high risk of postoperative recurrence. Even after successful hemostasis and curative (R0) resection, outcomes remain poor, with early relapse—particularly peritoneal dissemination—being a dominant failure pattern. Patients with srHCC have been systematically excluded from most pivotal phase III adjuvant trials in hepatocellular carcinoma, resulting in a critical evidence gap for postoperative systemic management. Current adjuvant strategies are largely extrapolated from non-ruptured HCC or based on retrospective analyses, and no prospective studies have specifically evaluated immunotherapy-based adjuvant therapy in this population. Immune checkpoint inhibitor–based combinations with anti-angiogenic agents have demonstrated survival benefits in advanced HCC and have recently been explored in the adjuvant setting for high-risk resected disease. Given the unique biological behavior of srHCC, characterized by tumor cell spillage at rupture and a strong propensity for early systemic and peritoneal relapse, adjuvant systemic therapy targeting micrometastatic disease is biologically rational and urgently needed. The CLEAR-2 study is designed to prospectively explore the efficacy and safety of adjuvant sintilimab combined with bevacizumab following curative resection of srHCC. Methods: CLEAR-2 is a prospective, multicenter, single-arm, exploratory phase II study. Eligible patients are adults (18–75 years) with radiologically or intraoperatively confirmed spontaneous rupture of HCC who have undergone curative (R0) hepatic resection, with Child-Pugh A liver function and ECOG performance status 0–1. Preoperative transarterial embolization (TAE) for hemostasis is permitted if performed once and within 2 weeks prior to surgery, without chemotherapeutic agents. A total of 35 patients will be enrolled. Adjuvant treatment is initiated 4–8 weeks postoperatively and consists of sintilimab 200 mg plus bevacizumab 15 mg/kg intravenously every 3 weeks for up to 1 year or until recurrence, unacceptable toxicity, or withdrawal. Radiologic assessment is performed every 12 weeks. The primary endpoint is disease-free survival (DFS). Secondary endpoints include overall survival (OS), safety graded per CTCAE v5.0, and recurrence patterns (intrahepatic, extrahepatic, and peritoneal). Clinical trial information: NCT07331883 .

Bypassing Hydrogenation Pathway for Sustainable Nitrate Water Remediation via Direct N─N Coupling

ABSTRACT Catalytic nitrate (NO 3 − ) reduction (CNR) to dinitrogen (N 2 ) offers an efficient strategy for remediating nitrogen pollution but is constrained by preferred ammonia (NH 3 ) formation. This selectivity challenge arises because hydrogen atom (H*)‐mediated pathway inherently favors N─H coupling over the desired N─N coupling. Here, we report a formic acid (HCOOH)‐driven proton‐coupled electron transfer (PCET) pathway on a precisely engineered Sn 3 /Pd catalyst. The catalyst design features a synergistic bimetallic interface where Pd sites facilitate HCOOH activation while triangular Sn 3 ensembles selectively adsorb NO 3 − . This direct PCET from HCOOH to NO 3 − achieved a remarkable 96.5% NO 3 − removal and 97.4% N 2 selectivity at environmentally relevant concentrations (100 mg‐N/L). Operando mass spectrometry and density functional theory (DFT) calculations reveal that Sn 3 ensembles thermodynamically favored N─N coupling while also acting as a steric barrier that kinetically impedes H* migration to adsorbed N* intermediates, effectively suppressing NH 3 formation. Furthermore, by integrating the CNR process with electro‐synthesized HCOOH, we demonstrated a synergistic technology that slashed the carbon footprint of wastewater treatment by 43.3%, decreasing from 33.50  kg CO 2 ‐eq t −1 to 19.01  kg  CO 2 ‐eq t −1 . Our work establishes atomic ensemble engineering as a powerful strategy to steer catalytic pathway through PCET, offering a viable solution for sustainable NO 3 − removal.

Nanotechnology for Sustainable Waste Management and Ecosystem Restoration: Applications, Innovations, Ecosystem Services and Disservices, and Contributions to the UN Sustainable Development Goals

Remodelling complex macrocycles

Pressure‐Independent Acoustic‐Vortex Communication With Enhanced‐Capacity and Cryptographic Information by Free‐Flooded Metasurfaces

ABSTRACT Structured vortex beams have driven significant advances in multiplexing communication technologies and have been demonstrated experimentally in optics, electromagnetics, and airborne acoustics. However, the strong vibroacoustic coupling and high hydrostatic pressure hamper the experimental enhancement of acoustic information capacity in underwater communication via passively modulating coaxial beams. Here, we report the experimental realization of simultaneous information capacity enhancement and hybrid physical‐computational camouflage in underwater free‐space pressure‐independent acoustic‐vortex communication. Two inverse‐designed free‐flooded metasurfaces, with hydrostatically resilient stability and customized wave scattering characteristics, synthesize and demodulate experimentally coaxial vortex beams of different topological charges, enabling physically encrypted, port‐to‐port information transfer. A computational‐mask encryption scheme further digitally conceals a plaintext image within two ciphertext bitstreams. Transmission of these ciphertexts through the synthesized hetero‐order vortex beams experimentally confirms physical‐computational anti‐eavesdropping capabilities of the system. Our research charts an unprecedented path toward high‐capacity, highly secure underwater acoustic communication technologies in the deep ocean.

Trade-offs, synergies and scale effects of ecosystem services in the middle reaches of the Yellow River

Oxidative stress impairs processive motility of the axonal transport motor KIF1A

High-risk clinic follow-up after genetic counseling and testing: Uptake patterns and predictors from a tertiary cancer center.

e22541 Background: Patients undergoing genetic counseling (GC) and germline testing (gGT) for hereditary cancer (CA) risk are frequently advised to pursue enhanced CA surveillance in specialized high-risk clinics (HRC) based on identification of a germline pathogenic/likely pathogenic variant (P/LP) or other strong personal or familial risk factors. However, adherence to recommended high-risk follow-up (FU) and factors influencing uptake remain poorly characterized. Methods: We performed a retrospective review of patients referred for GC/GT who were advised to consider FU in a HRC for women (Familial Risk Assessment Program, FRAP) or men (Prostate Risk Assessment Program, PRAP) at our CA center. GC/GT was conducted at the main CA center and 4 satellite clinics and results were disclosed in person or via telemedicine. The primary outcome was > 1 FU visit in a HRC within 2 years of results disclosure. Secondary outcomes included: 1) any d ocumented HRC FU or 2) any d ocumented CA risk screening or FU, including non-high-risk care. Germline testing results were categorized as P/LP or variant of uncertain significance (VUS), and further stratified by whether the affected gene was an HRD gene (ATM, BRCA1/2, BRIP1, CHEK2, PALB2, RAD51C). Demographic and FU data were extracted from the EMR. Results are reported using descriptive summary statistics and chi-square testing. Results: From > 500 pts undergoing GC/GT (1/2021-12/2023), 185 pts recommended to seek HRC FU were identified (88% FRAP, 12% PRAP). Mean age was 50.6 yr; 86.5% were female. Race/ethnicity was 64% White and 36% other. At post-test counseling, 29.7% (55/185) had a P/LP variant, of whom 74.5% (41/55) were in in HRD genes. Additionally, 28.7% (53/185) had > 1 VUS, including 35.8% (19/53) with a VUS in an HRD gene. Only 23.8% (44/185) had FU in FRAP/PRAP. An additional 7% had high risk FU outside FRAP/PRAP, 26.5% had routine (non-high-risk) FU, and 24.90% had no documented FU. Sex and race/ethnicity were not associated with HRC FU. Pts > 50 yr were more likely to have only routine FU (63.3% vs 36.7%, p = 0.08). Pts with prior CA were less likely to attend HRC FU (11.9% vs 26.7%; p = 0.05). FRAP/PRAP FU was more common among pts with any L/LP variant (36.4% vs 18.5%; p = 0.009) and particularly those with an HRD P/LP variant (43.9% vs 18.1%; p = 0.001). Presence of a VUS in an HRD gene was not associated with increased FU. GC/GT performed at satellite clinics was associated with lower FRAP/PRAP FU ( p = 0.017) and any HRC FU ( p = 0.012). Telehealth disclosure was associated with lower HRC FU, particularly among pts > 50 yr p = 0.009). Conclusions: Fewer than 1/3 of pts advised to pursue HRC care after GC/GT completed such FU. Uptake is strongly associated with presence of a P/LP variant in HRD genes, but not with VUS in HRD genes. Novel interventions to improve high-risk clinic engagement following GC/GT are a CA prevention priority.

Low-dose vs. standard-dose trastuzumab deruxtecan in north Indian patients: Balancing efficacy, toxicity, and cost.

e13028 Background: The median target exposure level of trastuzumab deruxtecan (TDxD) with standard dose is approximately 2.5 times higher than the derived from pre-clinical studies and a wide range of drug levels have shown efficacy most likely because of bystander effect. Toxicities are substantial with conventional standard dosage. We report our real-world experience with low dose TDxD aimed at in improving access by reducing cost and adverse effects. Methods: This is two center retrospective study from north India of prospectively maintained data from Jul 2024 to Dec 2025. All consecutive patients who received ≥1 dose of TDxD were included and either received either 2.7mg/kg (LD) or 5.4 mg/kg (SD) every 3 weeks. Overall response rate (ORR = Complete remission + partial remission) and Central nervous system response rate (CNS) were primary objectives as given the recent availability of TDxD and survival data needing longer follow up. Results: 30 women with various cancers, breast cancer being most common (23/30) received TDxD. 85% of patients received TDxD in third or later line. 25 patients received LD. HER2 status and other clinical characteristics are summarized in Table. Response evaluation was available for 18 patients. ORR was 77% and CNS response rate was 66% (4/6). The ORR did not differ in LD versus SD dose cohorts (p = 0.16). Treatment was well tolerated and only one patient had grade 1 lung toxicity. She received SBRT to two lesions prior to TDxD. One patient experienced grade 4 diarrhea. Conclusions: Low-dose at 2.7 mg/kg q 3weeks is as efficacious as standard dose, including CNS RR. Large randomized prospective studies are warranted. Clinical Characteristics (n=30). Clinical variables Values Frequency (%) Age Median 42 years(range:28-70) Gender Female 100 Weight Mean 60kg (range:38-84) Cancer subtype Breast Gallbladder Colon Gastric ^ CUP (NGS-Her2neu amplified) 232111 766333 Disease stage 4 100 Her2neu status (n=29) IHC3+, IHC2+/FISH+ve IHC2+/FISH+ve, IHC1+ IHC+<1 1793 583310 Brain metastases before ** TDxD initiation (n=27) Yes 12 44 Prior Line of therapies 1 2 3 4>=5 259104 616303313 Prior # TDM1 (eligible n=20) Yes 8 44 Dose used (q3weeks) ## LD 2.7mg/kg SD 5.4mg/kg 255 8317 *IHC: Immunohistochemistry, ** TDxD: Trastuzumab deruxtecan, # TDM1: Trastuzumab ado emtansine, ## LD: low dose, SD: standard dose, ^ CUP: Carcinoma of Unknown primary.

Iopofosine I-131 after BTK inhibitors in Waldenström macroglobulinemia: CLOVER-WaM subgroup efficacy and safety.

7094 Background: Waldenström Macroglobulinemia (WM) remains incurable with current available therapeutic options. Treatment options for relapsed/refractory pts are limited and often continuous, underscoring the need for new agents with novel mechanisms of action and pt-centered, fixed duration therapy. Iopofosine I 131 is a novel radiopharmaceutical compound composed of a lipid raft-targeting phospholipid ether covalently bound to 131 I, a beta emitting radioisotope. Here, we report preliminary sub-group results of the CLOVER-WaM study [NCT02952508] in WM pts treated with a Bruton’s Tyrosine Kinase inhibitor (BTKi) immediately prior to iopofosine. Methods: Eligible WM pts had received >2 prior therapies and had symptomatic disease requiring therapy according to consensus recommendations for WM. Treatment consisted of 2 cycles of iopofosine I 131 administered at 15 mCi/m 2 on days 1 and 15 of each 57-day cycle. The primary efficacy endpoint was major response rate (MRR; partial response or better, as determined by the modified IWWM-VI). Secondary and exploratory endpoints included overall response rate (ORR), treatment-free survival (TFS), progression free survival (PFS), duration of response (DOR), and clinical benefit rate (CBR; stable disease or better). Herein, efficacy endpoints were assessed in the modified intent-to-treat (mITT) population (all pts who received ≥60 mCi total administered dose of iopofosine I 131), and whose treatment regimen prior to iopofosine included a BTKi. Safety was evaluated using CTCAE v4.03 in pts who received ≥1 dose of iopofosine. Data cut off for this analysis was Jan. 16, 2026. Results: As previously reported, 65 pts were dosed and 55 are included in the mITT population. Of those, 22 (40%) had received a BTKi containing regimen immediately prior to iopofosine; and 11 who previously received at least 2 regimens utilizing BTKis and 12 who were refractory to rituximab. In this subgroup, median age was 70.5 (range 55-88), 17 (77%) were male, and 5 (23%) were female. The median number of prior therapies was 3 (range 2-7), 15/22 (68%) were MYD88 mutated and 18/22 (82%) were TP53 wildtype. The MRR was 15/22 (68.2%), ORR was 19/22 (86.4%) and CBR was 100%, median PFS was 12 months (range 1.6 to 28.0) and median TFS was 19.1 months (range 2.5-34.4). Grade ≥ 3, related treatment emergent adverse events (TEAE) occurring in > 10% of pts included anemia (41%), leukopenia (41%), neutropenia (58%), and thrombocytopenia (86%). Conclusions: Iopofosine I 131 demonstrated significant efficacy; 100% CBR, 86.4% ORR and 68.2% MRR with a median PFS of 12 months (range: 1.6 – 28.0 months) in a pt population with no current standard of care therapy. The treatment was well-tolerated with a manageable toxicity profile with cytopenias as the only Grade 3 or greater TEAE. Based on the results of this pivotal trial, iopofosine I 131 could be a promising novel treatment for WM pts after BTKi therapy. Clinical trial information: NCT02952508 .

First-line tivozanib in favorable- and very favorable–risk metastatic renal cell carcinoma: Real-world evidence from the TIVOREAL-SOGUG study.

4547 Background: The optimal first-line treatment for favorable-risk metastatic renal cell carcinoma (mRCC) remains debated in the immune checkpoint inhibitor (ICI) era. Real-world data assessing prognostic subgroups treated with VEGFR-TKI monotherapy are limited. Methods: TIVOREAL-SOGUG is a retrospective multicenter study including patients with clear-cell mRCC treated with first-line tivozanib between 2017 and 2024 across 14 Spanish centers. Favorable-risk was defined by IMDC criteria (0 risk factors). A very favorable-risk (VFAV) subgroup was identified according to Zarba et al. criteria (time from diagnosis to systemic therapy >3 years, Karnofsky performance status 90–100%, and absence of brain, liver, or bone metastases). The primary endpoint was time to treatment failure (TTF); secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), subsequent therapies, and safety. Results: Among 198 evaluable patients, 84 (42.4%) had favorable-risk disease, including 23 (27.4%) classified as VFAV. In the overall favorable-risk cohort, ORR was 48.8%, including 7.1% complete responses. Median PFS and TTF were 23.7 and 14.7 months, respectively. Median OS was not reached, with 2- and 5-year OS rates of 85.4% and 67.8%. VFAV-risk patients showed higher ORR (65.2%), prolonged PFS (32.2 months) and TTF (31.1 months), and low primary progression. Treatment discontinuation due to toxicity occurred in 9.5% of patients. Most frequent adverse events were grade 1–2 fatigue, diarrhea, mucositis, dysphonia and hypertension, with grade ≥3 events being infrequent and mainly limited to hypertension. After progression, most favorable-risk patients received ICIs, whereas VFAV-risk patients required subsequent therapy less frequently, reflecting more durable disease control. Conclusions: In routine clinical practice, first-line tivozanib provides durable disease control and long-term survival in IMDC favorable-risk mRCC, and particularly in VFAV-risk patients. ICI and cabozantinib remain effective salvage options in this setting upon disease progression. Key clinical outcomes by prognostic subgroup. Outcome Favorable-risk (n=84) Very favorable-risk (n=23) Median TTF, months (95% CI) 14.7 (9.2–20.1) 31.1 (8.0–54.1) Median PFS, months (95% CI) 23.7 (14.1–33.3) 32.2 (21.1–43.4) ORR, % (CR %) 48.8 (7.1) 65.2 (13.0) Primary progressive disease, % 14.3 4.3 2-year OS, % (95% CI) 85.4 (77.2–92.8) 95.7 (88.1–100) Discontinuation due to toxicity, % 9.5 8.7 TTF and PFS were estimated using Kaplan–Meier methodology; tumor response was assessed according to RECIST 1.1.

The molecular landscape and clinical nomogram of cholangiocarcinoma harboring ESCAT I alterations.

4158 Background: Cholangiocarcinoma (CCA) is the second most common primary liver cancer, with rising global incidence and mortality. Despite molecular advances, most patients present with advanced disease unsuitable for curative resection, resulting in poor prognosis. ESCAT I alterations, including FGFR2 fusions, IDH1/IDH2 mutations, BRAF V600E, HER2 amplification, MSI-high, and NTRK fusions, represent validated therapeutic targets with FDA/EMA-approved treatments, occurring in 25% of CCAs. Here, we analyze genomic and transcriptomic data to characterize the molecular landscape and develop an OS nomogram for CCA patients with ESCAT I alterations. Methods: In this retrospective study, we analyzed publicly available data from 1928 CCA patients, enrolled in participating institutions between 2012 and 2022, sourced from the cBioPortal for Cancer Genomics. We investigated frequencies of ESCAT I alterations, copy number alterations, mRNA expression, clinicopathological factors, and OS. Transcriptomic profiling and pathway enrichment analysis identified survival-associated genes. A nomogram integrating clinical, pathological, and molecular features was constructed and validated for OS prediction. Results: Genomic analysis of 1,845 CCA samples revealed revealed IDH1 mutations (12%), FGFR2 fusions (8%), HER2 amplification (6%), BRAF V600E (4%), MSI-high (4%), NTRK1/2/3 fusions (3.4%) and IDH2 mutations (2%). Notably, ESCAT I alterations were associated with inferior OS (log-rank P = 0.009; mOS altered vs wild-type 33.84 vs 24.31 months). Transcriptomic and GSEA profiling linked these alterations to dysregulation of oncogenic pathways, including DNA damage repair, cell cycle regulation, epithelial-mesenchymal transition, and immune pathways. The prognostic nomogram incorporated age, stage, differentiation, ESCAT I subtype, and top 5 most significantly identified transcriptomic signatures. Conclusions: This study provides comprehensive molecular characterization of ESCAT I-altered CCA, revealing distinct genomic and transcriptomic profiles associated with specific alterations and oncogenic pathway dysregulation. The validated nomogram offers a practical tool for personalized OS prediction, potentially guiding treatment selection, surveillance intensity, and clinical trial stratification. These findings emphasize the importance of routine molecular profiling in CCA and support precision medicine integration to improve outcomes and target therapy resistance mechanisms in this population.

Phase II clinical study of the efficacy and safety of adebrelimab in combination with lenvatinib as second-line treatment for advanced intrahepatic cholangiocarcinoma: Updated results.

e16162 Background: Advanced intrahepatic cholangiocarcinoma (ICC) carries a dismal prognosis, with limited second-line options after failure of gemcitabine-based chemotherapy. Adebrelimab (anti-PD-L1 antibody) plus lenvatinib has shown potential in hepatobiliary cancers. This study evaluated the efficacy and safety of this combination in advanced ICC patients with heavy tumor burden and impaired liver function. Methods: This single-arm, open-label, phase II study enrolled patients with histologically confirmed unresectable or metastatic ICC who progressed on or were intolerant to first-line chemotherapy. Patients received adebrelimab (20 mg/kg IV Q3W) and oral lenvatinib (8 mg/day for weight < 60 kg; 12 mg/day for ≥60 kg). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety (CTCAE v5.0). Results: As of January 12, 2026, 28 patients were enrolled (median age, 60.0 years). The cohort represented an exceptionally high-risk population: 18 patients (64.3%) had extrahepatic metastases, 13 (46.4%) had vascular invasion, and 20 (71.4%) were Child-Pugh class B. Furthermore, 24 patients (85.7%) met the "up-to-seven" criteria. After a median follow-up of 8.5 months (95% CI, 4.5 to 12.2), the median OS reached 12.2 months (95% CI, 6.3 to not reached), with a 12-month OS rate of 59.5% (95% CI, 40.9% to 86.5%). The median PFS was 6.3 months (95% CI, 4.0 to 12.4). In the ITT population, the ORR was 7.1% (2 of 28) and the DCR was 53.6% (15 of 28); however, response assessment was confounded by early treatment discontinuation or pending evaluations in 12 patients (42.9%). Treatment-related adverse events (TRAEs) of any grade occurred in 27 patients (96.4%). Grade 3-4 TRAEs were reported in 6 patients (21.4%), most commonly hepatic encephalopathy (3 patients, 10.7%), limb/shoulder pain (2 patients, 7.1%), and hyperbilirubinemia (2 patients, 7.1%). No treatment-related deaths were observed. Conclusions: Adebrelimab combined with lenvatinib demonstrated an unprecedented median OS of 12.2 months in second-line advanced ICC. Importantly, this survival benefit was maintained even in a population predominantly comprised of Child-Pugh class B patients with significant tumor burden. This combination represents a potential breakthrough for this difficult-to-treat population and warrants further validation in a randomized controlled trial. Clinical trial information: ChiCTR2300078869.

Onvansertib plus standard-of-care chemotherapy plus bevacizumab in first-line RAS-mutated metastatic colorectal cancer (mCRC): Interim results from the phase 2 randomized CRDF-004 trial.

3510 Background: Patients with RAS-mutated mCRC have limited treatment options. Chemotherapy in combination with bevacizumab (Bev) has been the standard first-line treatment for the past two decades, yet the prognosis for these patients remains poor. Onvansertib (Onv), a selective PLK1 inhibitor, has previously demonstrated synergy with chemotherapy in the second line setting. The Phase 2 randomized CRDF-004 trial evaluated onvansertib plus standard-of-care (SoC; FOLFIRI or FOLFOX with Bev) in as first-line RAS-mutated mCRC. Methods: Patients with first-line KRAS or NRAS mutant mCRC were randomized to SoC alone or SoC plus onvansertib (20 mg or 30 mg). The primary endpoint was objective response rate (ORR) as determined by a blinded-independent central review (BICR) using RECIST v1.1. Key secondary endpoints included progression-free survival (PFS), duration of response, and safety. PFS was assessed by BICR and investigator assessments combined. Results are presented in the intent-to-treat population (ITT). Results: At the data cutoff of 22 Jan 2026,110 patients were randomized with a median follow up of approximately 10 months. Baseline characteristics were relatively balanced across arms. Onv 30 mg + FOLFIRI + Bev demonstrated numerically higher ORR (n = 13/18, 72.2%, 95% CI: 46.5, 90.3) compared with the FOLFIRI + Bev control arm (n = 8/19, 42.1%, 95% CI: 20.3, 66.5), the FOLFOX + Bev control arm (n = 8/18, 44.4%, 95% CI: 21.5, 69.2) and the combined control arms (SoC: n = 16/37, 43.2%, 95% CI: 27.1-60.5). Onv 30mg + FOLFIRI + Bev demonstrated a p-value of 0.051 for confirmed ORR vs. SoC; and a p-value of 0.045 for the 6-month ORR compared to FOLFIRI + Bev (n = 10/18, 55.6%, 95% CI: 30.8-78.5 vs. n = 4/19, 21.1%, 95% CI: 6.1-45.6, respectively). The median PFS for the control arms was 10.97 months (95% CI: 7.52, NR) for FOLFIRI + Bev, 9.89 months (95% CI: 9.43, NR) for FOLFOX + Bev and 10.97 months (95% CI: 9.43-15.44) for the combined SoC arms. The median PFS in the Onv 30mg+ FOLFIRI + Bev arm was not reached (95% CI: 9.72-NR). The PFS HR of 30mg + Onv +FOLFIRI + Bev vs FOLFIRI + Bev was 0.38 (95% CI: 0.12-1.17) and vs SoC was 0.37 (95% CI: 0.13-1.02, p = 0.048). The clinical benefit from Onv treatment was further evidenced by the 12-month PFS rates, 61.9% (95% CI: 40.1, 95.8) in the Onv 30 mg + FOLFIRI + Bev arm vs. 28.4% (95% CI: 9.3, 86.9) in the FOLFIRI + Bev arm, and 30.1% (95% CI: 13.8-65.7) in the SoC. Onvansertib was well tolerated, with no unexpected toxicities observed; the most common grade ≥3 adverse event was neutropenia. PK data support moving forward with the onvansertib 30mg dose with FOLFIRI + Bev. Conclusions: Onvansertib plus FOLFIRI and bevacizumab demonstrated improved antitumor activity and manageable safety in first-line RAS-mutated mCRC. These results support further clinical and support planned confirmatory Phase 3 evaluation. Clinical trial information: NCT06106308 .

Projecting 2050 oncology workforce through historical regional trends and economic stratification.

9004 Background: Global oncology workforce planning increasingly relies on predictive modeling to guide policy and investment. However, projections are highly sensitive to baseline stratification. Historical models often use broad geographic regions, which may obscure economic heterogeneity within regions. We analyzed historical workforce trends and compared regional versus income-stratified projection models to quantify how perceptions of the 2050 oncology workforce burden have evolved. Methods: We extracted oncology workforce data from peer-reviewed literature, government and ministry of health reports, and datasets from professional organizations, including ESMO and ASCO. Cancer incidence and population projections were obtained from GLOBOCAN and UN sources. Workforce burden was defined as annual new cancer cases per clinical oncologist. Historical burden velocity was estimated using comparative data from 2012–2018 and applied to current scenario to build projections. Two models were evaluated: a regional model based on geographic trends and an economic model stratified by World Bank income groups. Results: Retrospective analysis (2012–2018) demonstrated substantial regional divergence. Europe showed relative stability, with workforce burden improving by –0.6% per year, while appearing comparable to Asia in 2018 (275 vs. 248 cases per oncologist). However, Asia’s burden increased by +8.6% per year, indicating incidence growth already outpacing workforce expansion despite similar cross-sectional values. Using regional trends, the projected 2050 burden reached 694 cases per oncologist for Africa and 3,499 for Asia. In contrast, income-based stratification revealed a markedly steeper trajectory for the most vulnerable economies. At baseline, high-income countries (HICs) had 30,400 oncologists, upper-middle-income countries (UMICs) 46,140, lower-middle-income countries (LMICs) 6,370, and low-income countries (LICs) only 70 providers combined. Projected through historic trends, 2050 burden reached approximately 295 cases per oncologist in HICs, 1,450 in LMICs, and ~11,500 in LICs. This represents a 16-fold increase when shifting from regional (Africa: 694) to economic (LIC: 11,500) projections, while also revealing lower-than-expected burden in emerging economies . Conclusions: Comparing regional and income-stratified projections reveals a profound predictive divergence. Although there is limited workforce data for higher accuracy projections, geographic averaging masks extreme workforce deficits in low-income countries while overstating burden in middle-income settings. Absolute workforce growth alone is insufficient to assess preparedness. Future oncology workforce planning should prioritize income-based stratification to accurately identify and address the most critical global capacity gaps.

Phase Ib study of POLQ inhibitor SYN818 combined with olaparib in advanced solid tumors.

TPS3181 Background: SYN818 is a selective, potent oral POLQ helicase inhibitor. POLQ is essential for microhomology-mediated end-joining and fills single-stranded DNA (ssDNA) gaps during replication. In tumors with homologous recombination repair (HRR) deficiencies (e.g., BRCA1/2 mutations), inhibition of PARP creates a dependency on POLQ for ssDNA gap filling, providing a synthetic lethal therapeutic strategy. Preclinically, SYN818 significantly enhanced the antitumor activity of Olaparib in breast and ovarian cancer models. Phase 1a monotherapy data demonstrate that SYN818 has a favorable pharmacokinetic profile and is well tolerated, supporting further evaluation of SYN818 in combination with Olaparib in HRR-deficient metastatic solid tumors. Methods: This phase 1b, open-label, multicenter study (NCT07156253; CTR20253189) evaluates SYN818 in combination with Olaparib in adults with locally advanced or metastatic solid tumors harboring BRCA mutations and/or homologous recombination repair (HRR) deficiency. During dose escalation (Part 1), patients receive escalating doses of SYN818 in combination with Olaparib (300 mg BID) administered in 21-day cycles to determine the recommended Phase 2 dose (RP2D), guided by a Bayesian dose-finding model. In the dose-expansion phase (Part 2), tumor-specific cohorts, including ovarian cancer and HER2-negative breast cancer, will further assess safety and preliminary antitumor activity at the RP2D. The primary objectives are to evaluate safety, tolerability, and determine the RP2D. Secondary objectives include characterization of pharmacokinetics, pharmacodynamics, and preliminary antitumor activity per RECIST v1.1. Key eligibility criteria include age ≥18 years, ECOG performance status 0–1, documented BRCA mutation and/or HRR deficiency, and adequate organ function. Prior PARP inhibitor therapy is permitted. Enrollment initiated in September 2025. Clinical trial information: NCT07156253 .

Mandibular preservation with neoadjuvant tislelizumab plus platinum-doublet chemotherapy in locally advanced resectable oral squamous cell carcinoma: A prospective phase II trial.

6090 Background: Segmental mandibulectomy for locally advanced oral squamous cell carcinoma (OSCC) severely compromises quality of life. In patients without radiographic mandibular invasion but still requiring mandibulectomy to achieve negative margins, effective tumor downstaging strategies that enable mandibular preservation are of major clinical importance. Neoadjuvant chemo-immunotherapy may reduce tumor burden, potentially enabling less radical resection and mandibular preservation. This study aimed to evaluate the efficacy and safety of mandibular preservation using neoadjuvant tislelizumab plus platinum-doublet chemotherapy in resectable locally advanced OSCC. Methods: This phase II, open-label, single-arm trial enrolled previously untreated patients with locally advanced, resectable OSCC (stage III-IVB, T3-T4N0-3M0) necessitating mandibulectomy based on conventional surgical criteria despite the absence of definitive clinicoradiologic mandibular invasion. Neoadjuvant treatment consisted of tislelizumab (200 mg), docetaxel (75 mg/m 2 ) and cisplatin (60 mg/m 2 ) on day 1 of each 21-day cycle for three cycles. All patients then proceeded to surgery. The primary endpoint was mandibular preservation rate. Secondary endpoints included pathological complete response (pCR), major pathological response (MPR), margin-negative resection (R0) rate, objective response rate (ORR), progression-free survival, disease-free survival, overall survival and treatment-related adverse events (TRAEs). Results: Between October 2023 and September 2025, a total of 53 patients were enrolled, and 49 were evaluable. All 49 patients completed three cycles of neoadjuvant therapy and underwent surgery. The mandibular preservation rate was 95.9% (47/49), and all patients achieved R0 resection. The ORR was 79.6% (39/49) and the pCR rate was 51.0% (25/49). TRAEs occurred in 100% (49/49) of patients. Grade 3 TRAEs were reported in 10.2% (5/49), including leukopenia, fatigue, and hypertension. No grade 4–5 TRAEs were observed. Conclusions: Neoadjuvant tislelizumab combined with platinum-doublet chemotherapy achieved a high mandibular preservation rate and a favorable pathological response profile with manageable toxicity in patients with locally advanced, resectable OSCC. This strategy represents a promising organ-preserving approach. Longer follow-up is ongoing to determine long-term survival outcomes. Clinical trial information: NCT06130007 .

First-line immune checkpoint inhibitors in elderly colorectal cancer patients in the real world: Retrospective phase of the multicenter ELDER CRC trial.

3539 Background: dMMR/MSI-H metastatic colorectal cancer (mCRC) is more common among the elderly. However, insufficient data about their treatment with immune checkpoint inhibitors (ICIs) are available from interventional and observational trials. Methods: ELDER CRC is an observational, multicenter Italian trial enrolling elderly (≥70 years [yrs]) patients (pts) treated with first-line ICI(s) for dMMR/MSI-H mCRC in the real world. Results from the retrospective cohort are presented. Results: 132 pts aged 77 yrs as median (IQR 74-82, range 70-93; <75: 32.6%; 75-79: 29.5%; ≥80: 37.9%) were enrolled across 10 Centers. They were mainly female (56.1%) in mediocre conditions (ECOG PS 1: 51.9%, ≥2: 22.2%; G8 ≤14: 80.5% [33/41 available]) with BRAF mutated (58.9% [73/124]), right primary tumor (80%), and synchronous metastases (54.5%) involving liver (34.8%) and/or peritoneum (37.9%). Almost all pts received monotherapy (pembrolizumab or nivolumab: 98.5%; nivolumab+ipilimumab: 1.5%) and most discontinued for PD (31.1%) or completion of 2 yrs (13.6%). 65.2% had an adverse event (AE), mainly fatigue (37.9%), skin rash (20.5%), hypothyroidism (17.4%), diarrhea (15.9%), and arthralgia (12.9%). Only 11% had G3-4 AE (G5=0), mainly gastrointestinal (3.8%), lung (3%), and fatigue (2.3%) and 10.6% discontinued ICI for AE. On 122 evaluable pts, ORR was 51.6% (38.5% PR + 13.1% CR) with 26.2% SD and 22.1% primary PD. At median follow-up of 25.9 months [mos] (22.3-30.3), mPFS was 32.2 mos (26.2-NE) with 56 events and mOS 45.8 mos (32.2-NE) with 46 events. 28.8% are still on treatment at the time of this analysis. Survival outcomes were not influenced by age groups. G8 >14 was related with better PFS (HR=0.79, p =0.06) and OS (HR=0.89, p =0.09). At multivariable model only neutrophils/lymphocytes ratio ≥3 was significantly associated with worse PFS (HR=1.91, p =0.03), while no variables with OS. Conclusions: Our results confirm the benefit of first-line immunotherapy for dMMR/MSI-H mCRC even among elderly pts treated in the real world, despite the substantial rate of right-sided and/or BRAF mut CRC pts and regardless of age group. The manageable safety profile of ICI(s) was also confirmed. G8 might be predictive of outcome but needs implementation in daily practice.

Preliminary results of safety and antitumor activity from a first-in-human phase 1 study of AWT020, a bifunctional anti–PD-1/IL-2 fusion protein, in patients with advanced tumors.

2528 Background: Immune checkpoint inhibitors have transformed treatment landscape across multiple cancer types, however, resistance to anti-PD-(L)1 therapies remains a significant unmet medical need. AWT020 is a bifunctional fusion protein comprised of an anti-PD-1 antibody and a potency optimized IL-2. In preclinical studies, the mouse surrogate of AWT020 demonstrated superior antitumor activity compared to anti-mPD-1 alone or in combination with IL-2. These findings suggest that AWT020 monotherapy may benefit patients resistant to anti-PD-1 therapies. Methods: This first-in-human Phase 1 dose escalation study evaluates AWT020 monotherapy in adults with advanced or metastatic cancers who failed or were intolerant to standard therapies. The dose-escalation utilizes a Bayesian Optimal Interval design. Key endpoints include safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), pharmacokinetics (PK), pharmacodynamics, immunogenicity, and antitumor responses. Initial dose escalation results are presented herein. Clinical trial information: NCT06092580. Results: As of January 14, 2026, 41 patients received AWT020 at doses of 0.3, 0.6, and 1 mg/kg, including single-step (0.1 or 0.3 mg/kg) and two-step (0.1→0.3 mg/kg) priming regimens. Preliminary PK analysis showed approximately dose-proportional exposure. The majority of treatment-related adverse events (TRAEs) were low grade. The most frequently reported TRAEs were arthralgia (59%), rash (34%), fatigue (32%), and nausea (32%). Grade ≥3 TRAEs occurring in more than one subject included arthralgia (n=4), colitis (n=2), and thrombocytopenia (n=2). No patient experienced vascular leak syndrome. Among the 27 RECIST-evaluable patients, the overall response rate was 30%, and the disease control rate was 67%. Of the eight responders, five partial responders (thymic carcinoma, thymoma, clear cell renal cell carcinoma, neuroendocrine non-small cell lung cancer, and cholangiocarcinoma) had developed secondary resistance to anti-PD-(L)1 therapies. The remaining three responders were anti-PD-(L)1-naïve, including a cervical cancer patient who experienced confirmed complete response, and two partial responders with proficient mismatch repair (pMMR) tumors (adrenocortical carcinoma and uterine sarcoma). Ten additional patients with diverse cancer types achieved stable diseases, with tumor shrinkage observed in half of the patients, further supporting preliminary antitumor activity across broad tumor types. Conclusions: AWT020 demonstrates a manageable safety profile and promising early antitumor activity, including in patients with acquired resistance to anti-PD-(L)1 therapies and in patients with pMMR tumors which typically are unresponsive to immune monotherapy. Dose escalation is ongoing to establish MTD/RP2D. Clinical trial information: NCT06092580 .