Browse Articles

Incidence of anal cancer in the United States: An analysis of NPCR data and comparison to SEER, 1998-2017.

e15505 Background: Anal cancer is a rare malignancy with rising incidence in the United States. Most national epidemiologic estimates are derived from the SEER database, which covers approximately 46% of the U.S. population. The National Program of Cancer Registries (NPCR) captures approximately 97% of the population but has been underutilized in describing national anal cancer incidence. We sought to characterize anal cancer incidence trends using NPCR data and compare these patterns with those reported from SEER. Methods: We performed a population-based analysis of incident anal cancer cases in NPCR from 1998–2017. Incidence rates were calculated per 100,000 persons and age-adjusted to the 2000 U.S. standard population. Analyses were stratified by sex. NPCR incidence estimates were compared with published SEER estimates over the same period using Z-tests for age-adjusted rates. Results: A total of 106,434 anal cancer cases were identified. Overall incidence increased from 1.19 per 100,000 in 1998 to 2.60 in 2017. Among men, incidence rose from 0.95 to 1.83, and among women from 1.42 to 3.33. In contrast, SEER reported smaller increases over the same period (overall 1.4 to 1.9; men 1.3 to 1.6; women 1.6 to 2.1). In 1998, the total NPCR AAMR was significantly lower than SEER (1.19 vs 1.4; Z = −2.69, p = 0.007). Stratified by sex, rates were similar for women (Z = −1.39, p = 0.16), while SEER reported higher incidence among men (Z = −2.38, p = 0.017). By 2017, this pattern reversed: NPCR reported a substantially higher total AAMR than SEER (2.60 vs 1.9; Z = 8.44, p < 0.00000001). Rates among men were similar (Z = 1.52, p = 0.13), whereas NPCR demonstrated markedly higher incidence among women (3.33 vs 2.1; Z = 10.95, p < 0.00000000001). Conclusions: Anal cancer incidence in the United States has increased substantially over the past two decades. Incidence estimates derived from NPCR differ meaningfully from those reported using SEER, with divergence widening over time, particularly among women. Broader utilization of NPCR data may provide a more comprehensive understanding of national anal cancer trends. Further investigation is warranted.

Statistical data and mortality rates for prostate cancer from 1999 to 2021 in the population of United States-Mexico border areas: Insights from CDC WONDER.

e17106 Background: Prostate cancer is a leading cause of cancer-related mortality among U.S. men. Thisstudy analyzes prostate cancer mortality data from 1999 to 2021 in populations livingalong the United States–Mexico border. Methods: This cohort study used mortality data from CDC WONDER and U.S. Cancer Statistics.Age-adjusted mortality rates (per 100,000) were analyzed by race/ethnicity, region, andurbanization, with trends assessed using Joinpoint regression to estimate AAPC and95% CIs. Results: A total of 924,528 deaths were identified in the United States and Mexico border from1999 to 2021. Overall, AAMR declined significantly during the study period (AAPC:−2.13; 95% CI, −1.82 to −2.45). Males exhibited higher AAMRs throughout and experienced a marked decline from 1999 to 2014 (APC: −3.51; 95% CI, −2.72 to −3.90), followed by an increase from 2018 to 2020 (APC: 2.64; 95% CI, 0.12 to 4.29). By raceand ethnicity, non-Hispanic Black individuals reported the highest AAMRs, while Asianor Pacific Islanders had the lowest rates. AAMRs across census regions were highest inthe West, whereas the Northeast showed the lowest, with a persistent decline (APC,−2.97; 95% CI, −3.27 to −2.68). Non-metropolitan areas exhibited higher AAMRs with alater upward trend after 2014 (APC, 0.79; 95% CI, −0.26 to 1.85) compared withmetropolitan areas. Conclusions: Prostate cancer mortality declined overall from 1999 to 2021; however, recent increasesand persistent racial and regional disparities—particularly in U.S.–Mexico border andnon-metropolitan populations—highlight the need for targeted public healthinterventions.

Real-world outcomes of breast cancer central nervous system metastases treated with sacituzumab govitecan.

e13095 Background: Prior studies indicate that therapeutic concentrations of sacituzumab govitecan (SG) penetrate the central nervous system (CNS), but real-world data about its intracranial efficacy are limited. Methods: In this single-center retrospective study, we identified patients (pts) with metastatic breast cancer (MBC) with CNS metastases (including brain metastases (BM), leptomeningeal disease (LMD), or both) treated with SG from 2019-2025. Chart review identified treatment history and survival outcomes. CNS and extra-CNS response to SG was verified by independent neuro-radiologist imaging review using RECIST1.1 and Response Assessment in Neuro-Oncology criteria. Results: We identified 30 pts with MBC and CNS disease who received SG. All pts were female with median age 57 yrs (range 36-76). 16 pts (53.3%) had hormone receptor positive (HR+)/human epidermal factor-2 negative (HER2-) disease and 14 pts (46.7%) had triple negative breast cancer (TNBC). Median lines of prior chemo was 3 and 2 for HR+/HER2- and TNBC respectively. 27 pts (90.0%) received prior CNS-directed radiation (n = 17 stereotactic radiosurgery (SRS), n = 3 whole brain (WBRT) or craniospinal radiation, n = 7 SRS and WBRT). At time of SG start, 22 pts (73.3%) had BM, 3 (10.0%) had LMD, and 5 (16.7%) had BM and LMD. Of 27 pts with BM, 20 (74.1%) had stable BM (median time since radiation 1.2 months (mo)) and 7 (25.9%) had active BM. Of the 8 pts with LMD, 4 (50.0%) received prior LMD-directed radiation (median time since radiation 2.1 mo). The table shows CNS and extra-CNS objective response rate (ORR), clinical benefit rate (CBR) at 6 mo, median time to treatment failure (TTF), median CNS and extra-CNS progression-free survival (PFS), and median overall survival (OS). All CNS responses were partial responses and occurred in pts who had received CNS-directed radiation < 1 mo prior to SG start (4 BM, 2 BM/LMD). Conclusions: In a real-world population of pts with MBC and CNS disease, SG demonstrated a modest intracranial response, with a 20% CNS ORR (all objective responses in pts with prior radiation, none in pts with active BM/LMD). Median CNS PFS was 4.5 mo. Limitations of this retrospective data include variations in number of prior therapies, type/timing of prior radiation, and CNS imaging frequency. Larger prospective studies are needed to better characterize CNS response to SG and to identify predictors of CNS response. All pts HR+/HER2- TNBC CNS ORR, % (n) 20.0 (6/30) 25.0 (4/16) 14.3 (2/14) Extra-CNS ORR, % (n) 6.9 (2/29) 0.0 (0/16) 15.4 (2/13) CNS CBR at 6 mo, % (n) 26.7 (8/30) 18.8 (3/16) 35.7 (5/14) Extra-CNS CBR at 6 mo, % (n) 27.6 (8/29) 18.8 (3/16) 38.5 (5/13) Median TTF, mo (interquartile range (IQR)) 3.7 (2.0-6.7) 3.2 (2.0-6.2) 4.5 (1.6-9.4) Median CNS PFS, mo (IQR) 4.5 (2.3-8.5) 4.4 (0.8-4.9) 5.1 (2.3-8.5) Median Extra-CNS PFS, mo (IQR) 3.6 (1.9-9.0) 2.5 (1.6-5.7) 4.5 (2.1-9.3) Median OS, mo (IQR) 11.7 (6.2-24.0) 8.2 (5.9-24.0) 11.8 (6.7-39.1)

Expression of Concern: Steady expression of high oleic acid in peanut bred by marker-assisted backcrossing for fatty acid desaturase mutant alleles and its effect on seed germination along with other seedling traits

Correction to “Toward Ultra‐High‐Quality‐Factor Wireless Masing Magnetic Resonance Sensing”

Cubic magneto-optic Kerr effect in Co(111) thin films

The magneto-optic Kerr effect (MOKE) is often applied as a tool for the magnetic characterization of thin films. Here, the change in polarization upon reflection from the magnetized sample is mainly regarded as being linearly proportional to the magnetization M (LinMOKE). Recently, we reported on third-order MOKE contributions, named cubic MOKE (CMOKE) being ∝ M3 in Ni(111) thin films. This CMOKE manifests itself as an anisotropic contribution to the MOKE signal (with regard to the crystallographic orientation) measured in longitudinal or transversal configuration in full magnetic saturation. While LinMOKE (odd in M) and quadratic MOKE (QMOKE) being ∝M2 (even in M) can easily be separated by methods based on magnetization parity, this no longer holds true for LinMOKE and CMOKE (odd in M). Here, we report on the observation of CMOKE in thin-film heterostructures with structurally twinned and untwinned Co(111) layers, demonstrating that a large CMOKE is not only present in Ni thin films. Additionally, we show that the observed anisotropic contributions cannot stem from LinMOKE by analyzing their dependence on the angle of incidence (AoI) of light. While the QMOKE is almost vanishing in Co(111) using light with wavelengths of 635 and 406 nm, the CMOKE contributions reach up to about 30% of the LinMOKE contribution at an AoI of 45 degrees and become even more dominant toward normal AoI, which emphasizes the importance of higher-order MOKE effects in magneto-optic experiments.

Innovations in targeted drug delivery: From nanotechnology to clinical applications

All‐Solid‐State, Ferroelectric‐Graded‐Doping Reconfigurable Molybdenum Ditelluride Devices

ABSTRACT 2D material‐based reconfigurable devices present a compelling approach to advancing system integration and functionality in the post‐Moore era. The all‐solid‐state design offers enhanced reliability and scalability of reconfigurable devices. However, realizing multifunctional reconfigurability in simple all‐solid‐state configurations remains a significant challenge. In this work, we address this challenge through a ferroelectric‐graded‐doping (FeGD) strategy to develop an all‐solid‐state 2D reconfigurable device featuring both structural simplicity and functional richness. The device incorporates a poly(vinylidene fluoride‐trifluoroethylene) (P(VDF‐TrFE)) ferroelectric layer coupled with a 2D ambipolar MoTe 2 channel, enabling the integration of 12 distinct reconfigurable functionalities within a single‐gate device structure. These functionalities span nonvolatile memory operations, neuromorphic computing capabilities including both homosynaptic and heterosynaptic plasticity, as well as multiple in‐memory logic operations. The device demonstrates exceptional performance metrics, achieving a sub‐millisecond reconfiguration speed (<1 ms), an extended retention time up to 10 7 s and outstanding on/off ratio exceeding 10 6 for nonvolatile memory operations, and large on/off ratios higher than 10 3 for fundamental logic operations (NAND, AND, OR, and NOR) and even more complex logic functions (IMP, RIMP, NIMP, and RNIMP), thereby establishing a versatile platform for next‐generation reconfigurable electronics.

In‐situ p‐Doping of Nanometer Tellurium‐based Oxide for Room‐Temperature CMOS Circuits

ABSTRACT The development of high‐performance p ‐type oxide semiconductors is crucial for scalable CMOS technologies, yet conventional oxides remain intrinsically difficult to p‐dope owing to the localized nature of oxygen orbitals and strong defect compensation. Here, we report a reaction‐metal‐mediated redox strategy that exploits the deposition environment for intrinsic in situ p ‐type doping of tellurium oxide. Mo‐assisted reduction produces nanometer Te‐based oxide films with tunable Te nanochannels, which form percolative pathways that markedly enhance hole transport. Remarkably, films deposited at room temperature (RT) achieve mobilities above 10 cm 2 V −1 s −1 and carrier densities tunable over more than five orders of magnitude. Co‐integration with n ‐type oxide transistors enables the fabrication of all‐oxide CMOS circuits entirely at RT with robust logic functionality. This intrinsically regulated doping pathway provides a generalizable route to overcome long‐standing bottlenecks in p ‐type oxides and advance oxide semiconductors toward large‐area, flexible CMOS electronics.

A nomogram for risk stratification of protein-energy malnutrition in pediatric cancer patients: development and internal validation

Phosphatidylinositol 4-kinase α suppresses glioblastoma progression by inactivating YAP and PI3K/Akt signaling

A response-adapted and genomically informed strategy to optimize neoadjuvant chemotherapy versus endocrine therapy plus CDK4/6 inhibition in high-risk HR+/HER2− breast cancer.

591 Background: Premenopausal patients with locally advanced hormone receptor–positive, HER2-negative (HR+/HER2−) breast cancer are routinely recommended neoadjuvant chemotherapy (NAC) despite heterogeneous and often limited response. In advanced disease, endocrine therapy (ET) plus CDK4/6 inhibition has replaced chemotherapy as first-line treatment. Whether patients with poor early response to NAC may benefit from chemotherapy-sparing strategies remains unclear. We conducted a prospective response-adapted study integrating early chemosensitivity assessment with exploratory genomic profiling to guide neoadjuvant treatment selection. Methods: A total of 116 premenopausal patients with stage II-III HR+/HER2− breast cancer received two initial cycles of TAC chemotherapy (docetaxel, doxorubicin, and cyclophosphamide). Radiologic response was assessed after two cycles. Patients achieving partial response (PR) continued TAC. Patients with stable disease (SD) were randomized to either continue TAC (NAC) or switch to 16 weeks of ET consisting of dalpiciclib (CDK4/6 inhibitor), exemestane, and goserelin (NET). Whole-exome sequencing was performed in an exploratory subset. The primary endpoint was objective response rate (ORR). Results: After two cycles of TAC, 30 patients achieved PR, while 86 exhibited SD and were subsequently randomized. Among evaluable patients, the ORR was 68.3% in the NET group (41 evaluable patients) compared with 48.7% in the continued NAC group (39 evaluable patients), indicating a higher response rate with NET in tumors demonstrating poor early chemosensitivity. Exploratory genomic analyses further showed that NET-sensitive tumors were predominantly TP53 wild-type and lacked PIK3CA or AKT alterations, consistent with a highly endocrine-dependent biology. In contrast, nonresponders to NET frequently harbored TP53 mutations, often in combination with PIK3CA/AKT pathway alterations, whereas patients who responded to continued chemotherapy commonly exhibited TP53 or TTN mutations, suggesting a chemotherapy-responsive but endocrine-refractory phenotype. Conclusions: Taken together, our findings indicate that in premenopausal patients with stage II-III HR+/HER2− breast cancer who demonstrate suboptimal early response to intensive neoadjuvant chemotherapy, continued cytotoxic treatment may not be optimal for all patients. A response-adapted strategy integrating early functional assessment with genomic features, particularly TP53 and PI3K/AKT pathway status, distinguishes endocrine-sensitive from chemotherapy-sensitive disease. These results provide a biologically informed framework for neoadjuvant treatment selection and support biomarker-enriched randomized trials evaluating chemotherapy-sparing strategies in selected patients. Clinical trial information: NCT06009627 .

Genomic determinants of resistance to BRAF/MEK inhibitors in <i>BRAF</i> ^V600E –mutant non–small cell lung cancer.

8647 Background: BRAF V600E mutations occur in approximately 2–3% of non–small cell lung cancer (NSCLC). BRAF/MEK inhibition (BRAFi+MEKi) yields high response rates and durable clinical benefit but acquired resistance is inevitable. BRAFi+MEKi therapy may select for resistant tumor clones, induce secondary genomic alterations, and drive changes in the tumor immunophenotype. However, the landscape of resistance mechanisms to BRAFi+MEKi in NSCLC remains largely unknown. Methods: We conducted a global, multicenter analysis of patients with advanced BRAF V600E–mutant NSCLC treated with BRAFi±MEKi across multiple academic centers and available public datasets. Eligible patients had matched pre- and post-treatment next-generation sequencing (NGS). Analyses were restricted to oncogenic or likely oncogenic alterations per OncoKB and/or ClinVar. Results: Among 33 patients with matched pre- and post– BRAFi±MEKi samples, median age was 66 years; 39.4% were women, 67.7% had a history of tobacco use, and 97.0% had adenocarcinoma at diagnosis. Objective response to BRAFi±MEKi in this cohort was 81.8%, while median progression-free survival was 8 months; only 3 patients (9.1%) had primary resistance. Acquired resistance mechanisms were diverse, encompassing reactivation of the RAS/RAF/ERK signaling pathway (via BRAF -dependent and BRAF -independent mechanisms), activation of alternative bypass pathways (e.g. PI3K/AKT and HIPPO), and alterations associated with cell-cycle dysregulation. Concurrent resistance mechanisms were identified in 12.1% of cases, and one patient developed histologic transformation to small-cell lung cancer (SCLC). No identifiable resistance mechanism was detected in 11 patients (33.3%). The most common acquired genomic alterations were RAS mutations, observed in 21.2% of cases ( NRAS Q61K, n = 1; NRAS Q61R, n = 1; KRAS G12D, n = 1; KRAS G12V, n = 1; KRAS Q61R, n = 1; NRAS Q61R + KRAS 61H, n = 1; KRAS G12V + KRAS Q61H, n = 1), followed by MET amplifications (12.1%, n = 4). Additional acquired events included BRAF kinase-domain duplication, MAP2K1 and NF2 mutations, and FGFR4 amplification. Putative resistance alterations involving DNA damage repair genes (e.g., CHEK2, BRIP1) were also identified. Clinically, one patient with acquired MET amplification showed loss of the MET -amplified clone on liquid biopsy after adding crizotinib to BRAFi+MEKi, without grade≥3 adverse events, suggesting a potentially targetable resistance mechanism with therapeutic implications. Conclusions: Our findings define the genomic landscape of acquired resistance to BRAFi+MEKi in BRAF V600E–mutant NSCLC and highlight the emergence of diverse resistance mechanisms, including SCLC transformation, MET amplification, and RAS mutations, several of which are potentially actionable and may inform rational post-BRAFi/MEKi therapeutic strategies.

Safety and efficacy of daraxonrasib monotherapy as later-line (3L+) treatment for patients (pts) with metastatic pancreatic adenocarcinoma (PDAC).

e15104 Background: Later-line (3L+) treatment for PDAC remains a high unmet need, with historically poor outcomes with chemotherapy (ORR, 3%-6%; mPFS, 2 mo; mOS, 5 mo). Oncogenic RAS mutations occur in &gt; 90% of pts with mPDAC. Daraxonrasib is a potent, oral, RAS(ON) multi-selective, tri-complex inhibitor that targets active GTP-bound RAS, including variants with mutations at codons G12, G13, and Q61, as well as wild-type RAS. Previously reported phase 1/2 data for daraxonrasib (NCT05379985) demonstrated manageable safety and encouraging efficacy in previously treated RAS mutant PDAC (2L+). We now present safety and efficacy outcomes from this study in pts with RAS mutations treated in the 3L+ setting. Methods: Pts with 3L+ RAS-mutant PDAC received daraxonrasib 300 mg QD. The primary objective was safety and tolerability; the secondary objective was efficacy. Results: As of Dec 1, 2025, 46 pts received daraxonrasib 300 mg; median follow-up was 22.6 months (range, 15.1-27.8). The majority of pts enrolled had ECOG PS of 1 (63%); the median number of prior systemic therapies in the metastatic setting was 2 (range, 2-5). Treatment-related adverse events (TRAEs) occurring in ≥15% of all pts were rash (87%), diarrhea (50%), stomatitis/mucositis (48%), nausea (41%), vomiting (35%), dry skin (22%), paronychia (22%), and fatigue (15%); the most common (≥5%) grade ≥3 TRAEs were rash (9%), stomatitis/mucositis (7%), and anemia (7%). Grade 4 platelet count decrease and lymphocyte count decrease were reported in 1 pt each. No grade 5 TRAEs occurred. No pts discontinued treatment due to TRAEs. The mean relative dose intensity was 88%. Efficacy outcomes of daraxonrasib are shown in the table. Conclusions: Daraxonrasib 300 mg QD in 3L+ PDAC demonstrated a manageable safety profile consistent with earlier-line experience. A majority of pts achieved disease control supported by encouraging survival. Clinical trial information: NCT05379985 . Efficacy measures in 3L+ a PDAC All RAS mutant (n=46) ORR (95% CI), % b 20 (9-34) Disease control rate (95% CI), % c 85 (71-94) PFS d , median (95% CI), mo d 4.3 (4.0-7.8) OS d , median (95% CI), mo d 9.0 (6.4-11.1) a Defined as treatment in pts who had received ≥2 prior lines of therapy in the metastatic setting, including pts who had received prior therapy in the neoadjuvant or adjuvant setting whose disease had progressed within 6 mo. b Includes confirmed complete response (CR) and partial response (PR). c Includes confirmed CR, confirmed PR, and stable disease. d Estimate based on Kaplan-Meier method.

Patient characteristics, treatment patterns, and survival in a metastatic pancreatic adenocarcinoma US patient population.

e16379 Background: Pancreatic adenocarcinoma (PDAC) is a leading cause of cancer-related deaths in the US. Clinical guidelines recommend first-line (1L) chemotherapy for patients with advanced or metastatic disease with an ECOG performance status &lt; 3. Few studies have examined treatment patterns and real-world outcomes in patients diagnosed with PDAC. Methods: Medical and pharmacy claims data from the Healthcare Integrated Research Database (HIRD) were used to identify newly diagnosed patients with metastatic PDAC (mPDAC) who were ≥18 years of age with Commercial, Medicare Advantage, or Supplemental Medicare insurance in the US. The index date was the first mPDAC diagnosis, between January 1, 2020, and November 29, 2024. Patients were required to have ≥1 month of enrollment following their initial diagnosis or one day of enrollment if death occurred within one month of follow-up and had to initiate an mPDAC chemotherapy regimen within 90 days of diagnosis. Study follow-up continued through end of enrollment or death, whichever occurred first. Demographics, clinical characteristics, and PDAC treatment patterns were reported descriptively. Results: A total of 1911 patients with mPDAC initiated 1L chemotherapy and had a median follow-up of 6.3 months (range, 0.3-51 months). The average age was 65 years (range, 26-94 years), 57% were male, 68% were commercially insured (32% Medicare Advantage or Supplement), and mean Charlson Comorbidity Index was 3.6 (SD, 3.3). The most common 1L therapy was FOLFIRINOX (43%), followed by nab-paclitaxel + gemcitabine (26%) and FOLFOX (9%) (Table). In this population of patients with mPDAC receiving 1L chemotherapy, the median overall survival (mOS) was 6.3 months. Only 52% of patients who received 1L therapy started second-line (2L) chemotherapy, with nab-paclitaxel + gemcitabine being the most commonly used (27%). Similarly, only 53% of patients who initiated 2L therapy went on to third-line (3L) chemotherapy, with nab-paclitaxel + gemcitabine being the most commonly used (24%). Conclusions: Despite a relatively young mPDAC cohort, the mOS of 6.3 months observed in this real-world study was lower than that reported in prior 1L clinical trials with chemotherapy. Treatment options that improve OS and tolerability are urgently needed for patients with mPDAC. Treated patients with mPDAC (N=1911) mOS (IQR), months 6.3 (3.1-11.4) 1L treatment, n (%)FOLFIRINOXNab-paclitaxel + gemcitabineFOLFOX 1911 (100)820 (43)495 (26)174 (9) 2L treatment, n (% of those from 1L)Nab-paclitaxel + gemcitabineFOLFIRIFOLFIRINOX 1000 (52)270 (27)138 (14)109 (11)

Efficacy and safety of intra-arterial liver–directed therapies in unresectable neuroendocrine carcinoma liver metastases.

e16308 Background: Neuroendocrine carcinoma (NEC) is an aggressive malignancy characterized by rapid progression and high metastatic potential, leading to a dismal median overall survival (OS) of only 11–12 months in patients with metastatic disease. Platinum-based chemotherapy with etoposide plus cisplatin or carboplatin remains the standard first-line treatment; however, its clinical benefit is modest, with an objective response rate (ORR) of approximately 31% and a median progression-free survival (PFS) of merely 4 months, and no established second-line therapy is currently available, underscoring a substantial unmet clinical need. Although intra-arterial liver-directed therapies (IALT) are routinely used to treat liver metastases from well-differentiated neuroendocrine tumors, their efficacy and safety in poorly differentiated and highly proliferative neuroendocrine carcinoma liver metastases (NECLM) remain largely undefined. This study aimed to evaluate the clinical outcomes and safety of IALT in patients with NECLM. Methods: 30 patients with pathologically confirmed NECLM who underwent IALT at Peking University Cancer Hospital from February 2012 to November 2024 were retrospectively analyzed. Treatment modalities included transarterial chemoembolization (TACE) alone (n = 5), transarterial embolization (TAE) alone (n = 2), hepatic arterial infusion chemotherapy (HAIC) alone (n = 1), TACE combined with HAIC (n = 20) and TAE combined with HAIC (n = 2). The primary endpoint was PFS while secondary endpoints included hepatic PFS (hPFS), OS, ORR, disease control rate (DCR) and safety. Results: The study cohort exhibited a substantial disease burden, with 83.3% of patients presenting with synchronous liver metastases and 76.7% with extrahepatic disease; moreover, 86.7% had received prior systemic therapy. The intervention achieved an ORR of 36.7% and a DCR of 70.0%. Median OS was 8.35 months, while median hPFS and PFS were 5.1 months and 4.5 months, respectively. No treatment-related deaths occurred. Grade ≥3 adverse events were generally manageable and most commonly consisted of transaminase elevation (18.9%), abdominal pain (17.0%) and hyperbilirubinemia (7.5%). Conclusions: IALT demonstrated acceptable safety and modest efficacy in the high-risk NECLM patients with aggressive disease and limited therapeutic options. These results indicate that IALT may serve as a feasible locoregional treatment strategy for NECLM, warranting further investigation to refine patient selection and optimize treatment approaches.

A first-in-human phase 1 dose-escalation study of the oral HIF-2α inhibitor JMKX003948 in patients with renal cell carcinoma.

4544 Background: Hypoxia inducible factor-2 alpha (HIF-2α) is a transcription factor and key tumorigenic driver of clear cell renal cell carcinoma (ccRCC). JMKX003948 is a novel, orally administered, selective small-molecule HIF-2α inhibitor that has shown significant antitumor activity in preclinical models of ccRCC. Herein, we present preliminary results from a phase 1 dose-escalation study of JMKX003948 in advanced ccRCC (NCT06321250). Methods: In this study, Patients with advanced ccRCC who had received at least 1 prior standard therapy were enrolled in 40, 80, 120, 180, and 270 mg escalating-dose cohorts sequentially, and received JMKX003948 monotherapy once daily (QD) until progression or unacceptable toxicity. The primary endpoints included safety/tolerability, the maximum tolerated dose (MTD), and the recommended Phase 2 dose (RP2D). Results: As of Dec 23, 2025, 22 patients (17 male) were enrolled. Median age was 57.5 years (range, 32-73 years). 13 patients (59.1%) have received ≥ 2 prior lines of therapy, 20 patients (90.9%) have received immune checkpoint inhibitor, and all patients (100%) have received vascular endothelial growth factor receptor–tyrosine kinase inhibitor (VEGFR-TKI). At data cutoff, the median follow-up was 9.7 months. One dose-limiting toxicity (grade 3 transaminase elevation) was observed at the 120 mg QD dose level, and the MTD was not reached. Treatment-related adverse events (TRAEs) were reported in all patients, with most graded 1-2. The most common TRAEs were anemia (86.4%). Grade 3 TRAEs occurred in 6 patients (27.3%), including hypoxia (13.6%), anemia (9.1%), proteinuria (4.5%), transaminase elevation (4.5%), and hyperkalemia (4.5%). No grade 4 TRAEs occurred. No TRAEs led to treatment discontinuation or death. Of 20 efficacy-evaluable patients, 5 patients (2 patients in 270 mg cohort and 1 patient each in 80, 120, 180 mg cohort) had partial response (PR), and 9 patients had stable disease (SD), objective response rate (ORR) and disease control rate (DCR) per RECIST 1.1 were 25% and 70%, respectively. Mean time to response (TTR) was 3.2 months. Median progression-free survival (PFS) was 7.7 months (95% CI, 1.3-not available). Conclusions: JMKX003948 is well tolerated and shows promising antitumor activity in patients with advanced ccRCC. Clinical trial information: NCT06321250 .

Primary prevention of acute leukemias in high-risk patients: The therapeutic promise of GLP-1 receptor agonists.

10507 Background: Despite advances in understanding leukemogenesis, no validated primary prevention strategies exist. Obesity is a dose-dependent risk factor for leukemia. Emerging data implicate epigenetic regulators, specifically the histone methyltransferase GLP (EHMT1), as a driver of leukemic survival; its inhibition induces cell death in CLL and promotes differentiation in AML. We present the first real-world analysis evaluating GLP-1 receptor agonists (GLP-1RA) for the primary prevention of leukemia in high-risk populations. Methods: Using the TriNetX global research network (150 million patients across 108 healthcare organizations), we identified adults at elevated leukemia risk based on ≥1 factor (prior chemo/radiation, MDS, MPN, family history, genetic syndromes, tobacco use, or BMI ≥30). Patients with ≥2 months of GLP-1RA use were propensity-matched 1:1 to non-users by demographics, comorbidities, and prior chemotherapy. The primary endpoint was the incidence of ALL, AML, CLL, or CML; secondary endpoints were adverse events related to GLP-1RA. Individuals with pre-existing leukemia were excluded. Cox proportional hazards models and sensitivity analyses were used to assess associations. Sensitivity and subgroup analysis confirmed robustness. Results: Of 426,670 high-risk individuals, 213,335 were matched to each cohort; standardized mean differences were &lt;0.1 for all covariates. Across &gt;1.2 million person-years of follow-up, GLP-1RA use was associated with a 63% risk reduction in incident AML (47/213,300 vs 75/213,261; HR 0.37, 95% CI 0.26–0.53; p &lt; 0.001) and a 50% reduction in ALL (42/213,304 vs 53/213,277; HR 0.50, 95% CI 0.33–0.75; p = 0.001). The protective effect for AML remained significant when restricted to patients with prior chemotherapy exposure and was independent of baseline BMI. No significant reductions were observed for CML or CLL. While GI adverse events were higher in the GLP-1RA cohort, the protective signal was consistent across age and ethnic subgroups. Conclusions: This is the first large-scale study to demonstrate a significant reduction in incident AML and ALL using GLP-1 receptor agonists in high-risk patients. By linking clinical metabolic intervention to the EHMT1 epigenetic pathway, these findings provide a novel, scalable pharmacologic strategy for the primary prevention of acute leukemias, potentially transforming the management of high-risk and obese populations.

Prognostic value of PSA nadir ≤0.2 ng/mL in metastatic castration-sensitive prostate cancer: A systematic review and meta-analysis.

5100 Background: The treatment landscape for metastatic castration-sensitive prostate cancer (mCSPC) has changed substantially with the adoption of early treatment intensification using androgen-receptor pathway inhibitors (ARPI) and chemotherapy, in addition to traditional androgen deprivation therapy (ADT). PSA nadir has long been used to support prognosis and inform treatment decisions; however, the historical thresholds were established based on patients treated solely with ADT and may not fully reflect outcomes in the modern era of combination therapy. Although emerging evidence suggests that a PSA nadir of &lt; 0.2 ng/dl is associated with improved disease control and survival, a systematic evaluation across available mCSPC trials is needed to clarify the prognostic value of PSA nadir and its potential role in guiding treatment decisions. Methods: A systematic search of PubMed, Cochrane Library, and ClinicalTrials.gov was conducted through October 31, 2025, to identify studies reporting outcomes by PSA nadir category in men with mCSPC. Eligible studies included patients initiating systemic therapy with ADT alone or in combination with ARPI and/or chemotherapy. The reported hazard ratios (HR) for time-to-event endpoints stratified by PSA nadir (=&lt; 0.2 ng/dl) were analyzed to get pooled HR. The primary outcome was overall survival (OS). Results: A total of eight trials comprising 6,582 patients were included. The pooled HR for the primary endpoint, overall survival (OS), was 0.27 (95% CI: 0.21–0.36; I² = 88.1%), indicating a clinically meaningful survival advantage among patients achieving PSA nadir. Consistent findings were observed for secondary outcomes. Achieving a PSA nadir ≤0.2 ng/mL was associated with longer radiographic progression-free survival (HR 0.23; 95% CI: 0.12–0.45; I² = 87.8%) and longer PSA progression-free survival (HR 0.19; 95% CI: 0.08–0.45; I² = 92.6%). A PSA nadir ≤0.2 ng/mL also correlated with a delayed onset of castration resistance (HR 0.31; 95% CI: 0.16–0.61; I² = 93.5%). Assessment of publication bias using Begg’s and Egger’s tests revealed no significant evidence of small-study effects for any endpoint. Conclusions: Across contemporary mCSPC trials, achieving a PSA nadir of ≤0.2 ng/mL consistently predicts improved survival and delayed disease progression. These findings establish PSA nadir as a clinically meaningful and cost-effective biomarker that can help guide treatment-intensification and de-intensification strategies in routine practice. Study Hazard Ratio (HR) 95% Confidence Interval (CI) Weight (%) SWOG9346 0.23 [0.19, 0.27] 13.80 SWOG S0925 0.20 [0.14, 0.28] 12.06 ARASENS 0.49 [0.37, 0.65] 12.65 CHAARTED 0.41 [0.32, 0.53] 13.00 ARCHES 0.24 [0.17, 0.34] 11.82 TITAN 0.35 [0.25, 0.48] 12.09 ARANOTE 0.14 [0.09, 0.21] 10.79 SWOG S1216 0.25 [0.21, 0.30] 13.78 Overall (Pooled) 0.27 [0.21, 0.36] 100.00

Durable clinical benefit with B-cell maturation antigen (BCMA)–directed therapy, belantamab mafodotin plus pomalidomide and dexamethasone (BPd) in relapsed/refractory multiple myeloma (RRMM): DREAMM-8 long-term responder (LTR) analysis.

7565 Background: BCMA–directed therapies have changed the RRMM treatment landscape. In the phase 3, open-label, randomized DREAMM-8 trial (NCT04484623), BPd demonstrated significant progression-free survival (PFS) benefit compared with pomalidomide, bortezomib, and dexamethasone (PVd) in patients (pts) with RRMM who received ≥1 prior line of therapy (LOT). This post hoc analysis examined the characteristics of and outcomes in pts achieving sustained clinical benefit with BPd. Methods: DREAMM-8 is an ongoing, phase 3, open label study evaluating BPd and PVd in pts with RRMM with ≥1 prior LOT, including lenalidomide. Pts were randomized 1:1 and treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or death, whichever occurred first. The primary endpoint was PFS; secondary endpoints included minimal residual disease (MRD) negativity (10 -5 ), PFS2, response rates, and safety. LTRs were pts with PFS ≥30 months (data cutoff: July 7, 2025; median follow up 36 months in both arms). Results: Of the 302 pts in DREAMM-8 (BPd, n=155; PVd, n=147), 81 were LTRs. The BPd arm had more than twice the proportion of LTRs (n=59 [38%]) as the PVd arm (n=22 [15%]). Baseline characteristics between treatment arms were generally well balanced. In LTRs, median PFS potentially favored BPd (not reached [NR]; 95% CI, NR-NR) vs PVd (NR; 95% CI, 42.7 months-NR), with a hazard ratio (HR) of 0.72 (95% CI, 0.20-2.53). BPd LTRs continued to demonstrate potential benefits after the first subsequent therapy, with median PFS2 (95% CI) of NR (NR-NR) in the BPd LTR arm and NR (44.2 months-NR) in the PVd LTR arm (HR, 0.33; 95% CI, 0.07-1.69). LTRs treated with BPd vs PVd had deeper responses: 76% vs 59% had complete response or better (≥ CR), 56% vs 32% had MRD negativity plus ≥ CR overall (73% vs 54% of pts with ≥ CR), and 39% vs 18% had sustained MRD negativity for ≥12 months, respectively. A higher proportion of pts with high-risk cytogenetics (ie, ≥1 of t[4;14], t[14;16], or del[17p13]) treated with BPd vs PVd achieved long-term response (27% vs 11%). The safety profile in LTRs was generally consistent with that previously reported. Conclusions: More than one-third of pts treated with BPd achieved LTR status, representing a 2.5-fold higher rate than with PVd, with similar rates in pts with high-risk cytogenetics; median PFS with BPd remains unreached. These findings suggest that this broadly accessible BCMA-targeted regimen delivers potential durable clinical benefit, characterized by deep and sustained disease-free survival. Clinical trial information: NCT04484623 .