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Multifunctional PANI-Chitosan-ZnO nanocomposites with enhanced anticorrosive, antibacterial, optical, magnetic, and photocatalytic approach

Effect of acute ischemic stroke in 3xTg-AD mouse model of Alzheimer’s disease

Domain-specific functions of LRIT3 in synaptic assembly and retinal signal transmission

A randomized phase Ib/II study of enzalutamide (Enza) with and without ribociclib (Rib) in patients with metastatic castrate-resistant prostate cancer (mCRPC) that retains RB expression: RiboX study.

5057 Background: RB function is often attenuated in tumors through hyperphosphorylation; thus, RB activity can be “re-awakened” in RB+ tumors by suppressing key kinases that phosphorylate RB (CDK4/6). We report a phase Ib/II trial to determine the safety, tolerability and antitumor activity rib with enza in patients (pts) with mCRPC (NCT02555189). Methods: RiboX was a multicenter, phase Ib/II, open label trial which enrolled taxane-naïve pts with progression to mCRPC and retained RB expression. For phase Ib, a traditional 3x3 dose-escalation was used to establish the RP2D for the phase II portion. Pts received rib at 200, 400 or 600mg once daily (QD) Days (D) 1-21 in combination with fixed dose enza (160mg QD D1-28). In phase II, pts were randomized 1:1 to enza monotherapy (Arm A) or enza + rib (Arm B). The study was later modified to a single arm Simon two-stage design using the RP2D of 600mg rib with 160mg enza. The primary phase II endpoint was the proportion of pts a PSA50 response at 12 weeks. The null hypothesis was that the PSA50 response was ≤78% and 31 responses were required to reject the null hypothesis. Secondary endpoints were rPFS, PSA PFS, OS and safety. Results: 12 pts were enrolled in the phase Ib portion across three dose levels upon confirmation of RB expression on tumor biopsy. No DLTs were observed in dose-escalation and the RP2D was established at rib 600mg QD D 1-21 + enza 160mg QD D 1-28. The phase II portion included 12 pts treated with enza mono; 28 phase II pts and 6 phase 1b pts yielded 34 pts treated with combination at RP2D. The PSA50 response at 12 weeks was 75% (95% CI, 43-95) for enza mono and 82% (95% CI, 65-93) for the combination, failing to reject the null hypothesis. Median rPFS for evaluable pts was 10.9 mo (95% CI, 2.5-45.9) for enza mono (n = 12) and 27.0 mo (95% CI, 11.3-37.0) for combination (n = 30). PSA PFS was 10.1 months (95% CI, 1.8-33.1) for enza mono (n = 12) and 14.8 mo (95% CI, 6.7-35.9) for combination (n = 34). OS was 31.2 mo (95% CI, 15.0-NA) for enza mono (n = 12) and 58.1 mo (95% CI, 33.4-NA) for combination (n = 34). Four pts treated with combination were included for PSA PFS but did not have data for rPFS. Among pts treated at RP2D in the combination arm, the most common TEAE’s included fatigue 59%, nausea 26.9%, neutropenia 26.7% (grade 3, 12%), diarrhea 20.9%, dizziness 14.7%, arrhythmia 2.9%, seizure 2.9%. Conclusions: The combination of enza + rib was well tolerated; however, no significant difference in PSA50 response was observed, and the primary endpoint was not met. A disease-stabilizing effect was observed in a subset of patients treated with the enza + rib combination, with evidence of prolonged survival. Further investigation into this disease-stabilizing effect and refinement of patient selection criteria beyond RB expression may be warranted. Funding: Novartis Pharmaceuticals and DOD (W81XWH-22-2-0020). Clinical trial information: NCT02555189 .

Impact of transplant on <i>TP53</i> ^MT configurational dynamics in myeloid neoplasms.

6537 Background: Multihit TP53 clonal configurations in myeloid neoplasms (MN) confers poor prognosis but therapy alters allelic burden in general. Using our previously described algorithm, patients with up-trending or stable (UT/S) TP53 MT had worse OS than those who down-trended (DT); HSCT was associated with DT. We evaluated whether this pattern reflects intrinsic TP53 -driven disease biology or from treatment/ transplant effects. Methods: We analyzed a serially sequenced TP53 MT AML/MDS cohort from four academic centers using targeted NGS (Illumina MiSeqDx; 54-gene TruSight panel). TP53 configurations were defined per Bahaj et al.: single-hit TP53 MT as obligatory biallelic (VAF &gt;50%), probable biallelic (23–50%), or probable monoallelic (&lt;23%); combined VAF was used for double-hit TP53 MT . TP53 clearance was defined as VAF &lt;3%. Associations were tested with chi-square/Fisher tests and survival by Kaplan–Meier analysis. Clonal velocity (CV) was defined as the change in VAF from diagnosis to final serial sample post-transplant (Δ VAF) over post-HSCT survival time and categorized as stable (0 to −1), moderately downtrended (MD) (−1 to −5), or highly downtrended (HD) (≤−5). Results: Among 119 TP53 MT MN patients, 58 (49%) had pAML, 38 (32%) sAML, and 23 (19%) MDS. Median age was 65 years, 55% were male, and 20% had del(17p). Initial therapy included 7+3/CPX (34%), HMA+VEN (30%), or HMA alone (29%). 71 pts (60%) underwent HSCT (mOS 17 vs 5 mos in non-HSCT group; p&lt;0.001). Among 62 with serial samples, 76% down trended TP53 post-HSCT and 72% achieved TP53 clearance. Patients in the UT/S group more often had complex karyotype (93% vs 64%; p=0.04) and numerically shorter time to HSCT (4 vs 5 mos; p=0.11). In the DT group, pre-HSCT therapy included 7+3 (30%), HMA alone (23%), and HMA+VEN (25%); HMA monotherapy was more common in UT/S vs DT (53% vs 23%; p=0.03). Mismatched/haploidentical transplants (in 45%) had numerically lower mOS than matched donor transplant (13 vs 52 mos; p=0.27); class II mismatch showed numerically better survival than class I or haploidentical (37 vs 12 mos; p=0.27). mOS was worse in UT/S (14 vs 22 mos; p=0.03). When stratified by clonal velocity (CV), the DT group showed stepwise differences in mOS: stable (78 mos), MD (26 mos), and HD (11 mos; p&lt;0.0001). Stable CV was enriched for monoallelic TP53 at diagnosis (60% vs 14% vs 6%; p=0.004), higher chronic GVHD (60% vs 24% vs 13%; p=0.03), and greater TP53 clearance (100% vs 71% vs 56%; p=0.05), whereas HD CV was enriched for obligatory biallelic TP53 (p=0.001). PTCy use was highest in the MD group (30% vs 76% vs 50%; p=0.04). Conclusions: UT/S patients had higher pre-HSCT HMA monotherapy use and complex karyotypes. Stable CV was associated with monoallelic TP53 , lower PTCy use, higher chronic GVHD, greater TP53 clearance, and superior survival, suggesting that the rate of TP53 clonal contraction rather than clearance alone best predicts OS and reflects intrinsic TP53 MT disease biology.

Efficacy and safety of neoadjuvant ICI-based regimens in resectable gastric and GEJ cancer: Updated systematic review and meta-analysis.

e16124 Background: Gastric and gastroesophageal junction (GEJ) cancers remain highly lethal, and durable cure relies on curative resection and deep pathologic response. Despite neoadjuvant chemotherapy, relapse is frequent. With newly published, more mature studies reporting resection, downstaging, and perioperative safety for neoadjuvant immune checkpoint inhibitor (ICI) based therapy, we updated prior limited syntheses to refine contemporary efficacy and toxicity estimates. Methods: We performed a PRISMA-compliant systematic review and meta-analysis of studies comparing neoadjuvant ICI-based therapy versus non-ICI regimens in resectable gastric/GEJ cancer, using the most mature reports. Outcomes were overall survival (HR), resection rate, pCR, ypT-0, ypT-1, ypT-2 downstaging, any-grade adverse events, and grade 3–4 adverse events (all pooled as ORs) with random-effects models and I² heterogeneity. Results: We performed a PRISMA-compliant systematic review and meta-analysis of studies comparing neoadjuvant ICI-based therapy versus non-ICI regimens in resectable gastric/GEJ cancer, using the most mature reports. Outcomes were overall survival (HR), resection rate, pCR, ypT-0, ypT-1, ypT-2 downstaging, any-grade adverse events, and grade 3–4 adverse events (all pooled as ORs) with random-effects models and I² heterogeneity. Conclusions: Neoadjuvant ICI-based therapy improved resection and pathological response without clear excess toxicity, but OS benefit was not demonstrated. Prospective trials and standardized reporting are needed to determine whether pathological gains translate into durable survival.

Impact of chemotherapy on gonadal function in pubertal children with Hodgkin lymphoma.

e22001 Background: Hodgkin lymphoma (HL) in pubertal children carries a high risk of reproductive dysfunction, both due to the disease itself and the gonadotoxic effects of chemotherapy (CT), which is especially critical during puberty. The objective was to determine the concentration of sex hormones (estrone – E1, estradiol – E2, estriol – E3, progesterone – P4, total and free testosterone – T, FT) and their receptors (ERα, ERβ, AR) in the blood of adolescents with HL before and after CT. Methods: The study included 20 boys and 20 girls aged 13–17 years with a verified diagnosis of stage II-IV HL. Hormone and receptor levels were measured using an enzyme immunoassay before treatment and 14 days after completion of all CT courses. A comparison group consisted of 40 healthy adolescents of similar age. Statistical analysis was performed using Statistica 10; differences were considered significant at p &lt; 0.05. Results: In girls before treatment, significant decreases were found in levels of E1 (2.4-fold), P4 (3.7-fold), T and FT (more than 2-fold), and AR (3-fold), while E3 concentration was increased 27.5-fold (p &lt; 0.05). Levels of E2, ERα, and ERβ were normal. In boys before treatment, decreases were found in blood levels of E1 (1.9-fold), E2 (2.7-fold), P4 (1.7-fold), FT (1.4-fold), and AR (4.7-fold; p &lt; 0.05). The T level was elevated 1.8-fold in 50% of boys and decreased 42.0-fold in the others (p &lt; 0.05). E3, ERα, and ERβ levels were normal. In girls 14 days after CT, compared to baseline, E1 decreased 3.4-fold and remained 8.0-fold below normal; E3 decreased 3.8-fold but remained 7.3-fold above normal (p &lt; 0.05); ERα decreased 8.3-fold; and P4 decreased 2.0-fold from baseline and was 7.5-fold below normal (p &lt; 0.05). T and FT remained 1.9- and 2.0-fold below normal, respectively (p &lt; 0.05); AR increased 2.2-fold but remained 1.3-fold below normal (p &lt; 0.05). In boys 14 days after CT, E2 decreased 1.7-fold; P4 decreased 2.6-fold from baseline and was 4.5-fold below normal (p &lt; 0.05). T remained 1.7-fold above normal in 50% of patients; in the others, it increased 10.2-fold but remained 4.1-fold below normal (p &lt; 0.05). FT decreased 1.6-fold and was 2.2-fold below normal (p &lt; 0.05). AR increased 3.0-fold but remained 1.6-fold below normal (p &lt; 0.05). Conclusions: Children with HL exhibit persistent hormonal disturbances even before treatment: a progesterone deficiency and sex-specific imbalances (estriol excess with androgen deficiency in girls, and a heterogeneous androgen status with estrogen deficiency in boys), which makes pre-therapeutic gonadal tissue harvesting impractical. These imbalances persist after chemotherapy, forming the basis for a high risk of hypogonadism and infertility. This necessitates mandatory hormonal monitoring and preemptive measures to preserve reproductive health.

Using geospatial visualization to inform mobile lung cancer screening in Maryland.

e20098 Background: Geographic disparities in access to healthcare services may contribute to low uptake of lung cancer screening and increased morbidity and mortality. Mapping prevalent lung cancer cases and their association with location of LDCT services, areas of healthcare professionals’ shortage and medically underserved areas may inform optimal location of new access-focused screening and research projects. Methods: Geospatial data on lung cancer cases diagnosed at University of Maryland Medical System (UMMS) and those identified by the Maryland Department of Health Cancer Registry between 2016 and 2024 were obtained and integrated with publicly available geospatial datasets, including federally designated Health Professional Shortage Areas (HPSAs), Medically Underserved Areas (MUAs), and county-level geographic boundary files. Data were aggregated and harmonized to generate statewide and county-level interactive geospatial maps which were used to visualize the distribution of lung cancer cases relative to LDCT screening centers within HPSA and MUA areas. Interactive web-based maps enable users to hover, zoom in and out, and toggle map layers over counties and view lung cancer cases. Results: Among 6,446 lung cancer cases identified statewide, substantial geographic variation in lung cancer burden was observed across Maryland counties. County-level geospatial maps showed heterogeneous distributions of lung cancer burden, with several high-burden areas co-located in areas with high HPSA and MUA indices. Interactive map visualizations facilitated identification of areas with concurrent elevated lung cancer burden and underserved designations which can be targeted to additional interventions to improve uptake of screening. Conclusions: Interactive geospatial mapping of lung cancer burden, location of screening services, HPSA, and MUA can inform interventions to increase uptake of lung cancer screening. These maps highlight “screening deserts” that may warrant further investigation using facility-level or travel-time–based analyses. Our approach should inform future studies healthcare access and uptake of lung cancer screening.

[ ²¹² Pb] Pb-MP0712 in patients with small cell lung cancer and other Delta-like ligand 3–expressing solid tumors: A phase 1/2a study to assess safety, tolerability, and efficacy.

TPS3176 Background: [ 212 Pb]Pb-MP0712 is a novel radiopharmaceutical comprising a Designed Ankyrin Repeat Protein (DARPin) that binds with high affinity to DLL3 and carries the alpha-emitting isotope lead-212 ( 212 Pb) for targeted delivery of high linear energy transfer radiation. DLL3 is highly expressed in SCLC, large cell neuroendocrine carcinoma (LC-NEC) of the lung, and extrapulmonary NEC (epNEC), while its expression in healthy tissue is virtually absent. In preclinical studies, [ 212 Pb]Pb-MP0712 selectively accumulates in DLL3-positive tumors, exhibits an adequate biodistribution profile, and induces complete and durable tumor regression with prolonged survival and a favorable safety profile (Croset et al. AACR 2025). Initial human imaging data from a patient who received [ 203 Pb]Pb-MP0712 in a Named Patient Access Program under the legal framework for compassionate care in South Africa indicate its specific uptake in tumor (Steiner et al. TRP EU 2025). Methods: This first-in-human Phase 1/2a study evaluates the safety, biodistribution, dosimetry, and preliminary antitumor efficacy of [ 212 Pb]Pb-MP0712 (NCT07278479). Key inclusion criteria are SCLC and progression or recurrence following ≥2 prior lines of systemic therapy, or lung LC-NEC or epNEC with progression or recurrence following ≥1 prior line of systemic therapy, and measurable disease by RECIST v1.1. Patients with clinically stable central nervous system metastasis or prior DLL3-targeted therapy are eligible. Key exclusion criteria are Merkel cell carcinoma, neuroendocrine prostate cancer, interstitial lung disease, and active non-infectious pneumonitis. This study has two parts, a dose escalation (Part 1) and an expansion (Part 2). Primary objectives of Part 1 are to evaluate safety and tolerability of [ 212 Pb]Pb-MP0712, and to determine the maximum tolerated dose and recommended phase 2 dose (RP2D). Primary objective of Part 2 is to assess preliminary antitumor activity of [ 212 Pb]Pb-MP0712. All patients will receive a single dose of [ 203 Pb]Pb-MP0712 as intravenous (IV) injection at 185 MBq to evaluate DLL3-expressing tumor lesions, pharmacokinetics, biodistribution and dosimetry using single-photon emission computerized tomography (SPECT)/CT, followed by [ 212 Pb]Pb-MP0712 treatment. In study Part 1, for SCLC/lung LC-NEC cohorts, treatment proceeds regardless of imaging results; for epNEC cohorts, a DLL3-positive SPECT/CT is required. Patients will be enrolled in sequential cohorts to receive escalating doses of [ 212 Pb]Pb-MP0712 as IV injection on Day 1 of each 28-day cycle for up to six cycles. The dose escalation will be guided by an adaptive Bayesian Logistic Regression Model. Upon completion of Part 1, Part 2 will enroll two groups of patients with DLL3-positive SCLC/lung LC-NEC or epNEC at the RP2D. Clinical trial information: NCT07278479 .

Intensity of chemotherapy regimens for patients with Lynch syndrome and colorectal cancer.

10608 Background: Lynch syndrome (LS), associated with inherited pathogenic variants (PVs) in MLH1, MSH2, MSH6, PMS2 or EPCAM , is the most common inherited colorectal cancer (CRC) syndrome. Nearly all LS-associated CRCs are mismatch repair-deficient and microsatellite instability-high (dMMR/MSI-H), a phenotype associated with low recurrence risk and limited benefit from single-agent chemotherapy. Guidelines recommend no adjuvant chemotherapy for most dMMR/MSI-H stage II CRC. A fluoropyrimidine + oxaliplatin is recommended for all dMMR/MSI-H stage III CRC. Methods: We linked SEER registry records from Georgia and Los Angeles to germline genetic testing results from 4 labs. We included patients with resected stage II or III CRC diagnosed 2013-19 who linked to genetic test results. Chemotherapy details were extracted from SEER text fields completed by registrars. Regimens were classified as 1) No adjuvant chemotherapy; 2) Less intensive (5-FU or capecitabine); 3) More intensive (5-FU or capecitabine + oxaliplatin). We examined associations between genetic testing results and intensity of adjuvant chemotherapy. Covariates included age, sex, race, ethnicity, rurality. Results: Among 2770 patients, 1176 had stage II and 1594 had stage III CRC; 271 had a LS gene PV. The table shows results of multivariable analysis stratified by stage. Adjuvant chemotherapy intensity did not vary between patients with LS versus negative genetic test results. Older age was associated with receipt of no or less intensive chemotherapy in stage II and III CRC. Hispanic patients with Stage III CRC were more likely to receive no chemotherapy compared to non-Hispanic White patients. Conclusions: In this population-based cohort of CRC patients from two states, adjuvant chemotherapy regimen intensity did not vary with germline genetic test results. These findings suggest that patients with LS and stage II CRC are being overtreated. Clinicians may require education about optimizing CRC therapy for patients with LS. Stage II No Chemo (OR, 95% CI) Stage II Less Intensive (OR, 95% CI) Stage III No Chemo (OR, 95% CI) Stage III Less Intensive (OR, 95% CI) Genetic Test Result Negative (Ref)  Lynch PV 1.39 (0.86-2.24) 0.60 (0.29-1.26) 0.94 (0.42-2.11) 1.06 (0.50-2.26)  Other PV 0.80 (0.39-1.65) 1.03 (0.42-2.54) 0.58 (0.23-1.41) 1.29 (0.67-2.51)  VUS only 0.89 (0.61-1.30) 0.57 (0.35-0.94) 0.99 (0.65-1.50) 0.81 (0.53-1.25)  Age (years) 1.05 (1.04-1.07) 1.02 (1.00-1.03) 1.07 (1.05-1.08) 1.05 (1.03-1.06)  Female (vs. male) 0.96 (0.68-1.29) 0.89 (0.59-1.34) 1.00 (0.69-1.46) 1.15 (0.80-1.64) Race/Ethnicity Non-Hispanic White (ref)  Asian 0.75 (0.42-1.32) 1.21 (0.60-2.43) 1.24 (0.60-2.57) 1.22 (0.67-2.24)  Black 1.11 (0.67-1.84) 1.06 (0.56-1.98) 1.30 (0.75-2.25) 0.93 (0.52-1.66)  Hispanic 1.05 (0.66-1.67) 0.60 (0.30-1.18) 1.71 (1.02-2.87) 1.31 (0.77-2.24)  Rural (vs. urban) 1.14 (0.64-2.02) 1.31 (0.63-2.75) 1.08 (0.57-2.03) 1.26 (0.69-2.28)

ONO-4578 combined with nivolumab (NIVO) and chemotherapy (chemo) as first-line (1L) treatment for patients with HER2-negative unresectable advanced or recurrent (adv/rec) gastric/gastroesophageal junction cancer (G/GEJ): A randomized, double-blind, phase 2 trial (ONO-4578-08).

4007 Background: Anti-PD-1 antibodies combined with chemo are the standard 1L treatment for HER2-negative G/GEJ cancer. Prostaglandin E 2 (PGE 2 )-EP4 signaling is known to induce immunosuppressive tumor microenvironment, by inducing the differentiation of MDSCs and M2 macrophages, potentially contributing to resistance to immunotherapy. ONO-4578, an EP4 antagonist, is expected to modulate tumor immunosuppression through inhibiting the PGE 2 -EP4 signaling and to enhance the efficacy of anti-PD-1 antibody. The addition of ONO-4578 appeared to augment the efficacy of NIVO in patients with G/GEJ cancer in the previous phase 1 trial. This study aimed to evaluate the efficacy and safety of ONO-4578 combined with NIVO and chemo compared with placebo combined with NIVO and chemo as 1L treatment for patients with unresectable adv/rec G/GEJ cancer. Methods: ONO-4578-08 study is a randomized, double-blind, phase 2 trial conducted in Japan, Korea, and Taiwan. Chemo-naïve patients with HER2-negative adv/rec G/GEJ cancer were randomized in a 2:1 ratio (ONO-4578 group:placebo group), stratified by PD-L1 expression level (CPS &lt; 5 vs CPS≥5), ECOG performance status (0 vs 1), presence of peritoneal metastasis (yes vs no). Patients in each group received ONO-4578 40 mg or placebo once daily, and all received NIVO 360 mg every 3 weeks and chemo (SOX [S-1 + oxaliplatin]/CAPOX [capecitabine + oxaliplatin]). The primary endpoint was investigator-assessed progression-free survival (PFS), powered (two-sided α = 0.10) to detect a HR of 0.65 with 117 events in a planned enrollment of 210 patients; secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Results: Between December 2023 and September 2024, 226 patients were randomized to each group (150 vs 76 patients). With a median follow-up of 8.5 months, PFS was significantly longer in the ONO-4578 group than the placebo group with a hazard ratio (HR) of 0.67 (90% confidence interval [CI]: 0.48–0.92; P = 0.040; median PFS: 9.0 vs 6.9 months). At a minimum follow-up of 7.4 months, OS favored the ONO-4578 group (median OS: not reached vs 12.7 months; HR: 0.60 [95% CI: 0.37–0.96]). ORR was also higher in the ONO-4578 group (62.0% vs 48.7%). The most common treatment-emergent adverse events (TEAEs) in the ONO-4578 group were diarrhea (55.7% vs 45.3%), anemia (55.0% vs 34.7%), and peripheral sensory neuropathy (50.3% vs 46.7%). Serious TEAEs occurred in 53.7% of patients in the ONO-4578 group and 42.7% in the placebo group. Conclusions: ONO-4578 combined with NIVO and chemo significantly improved PFS compared with placebo combined with NIVO and chemo in treatment-naive patients with HER2-negative unresectable adv/rec G/GEJ cancer with no new safety concerns. Clinical trial information: NCT06256328 .

<i>KMT2C</i> mutation to identify an immunotherapy-sensitive subset of gastrointestinal cancers: A large real-world analysis.

3565 Background: KMT2C (MLL3) encodes a histone methyltransferase involved in enhancer regulation and DNA damage repair. Loss-of-function KMT2C mutations occur in approximately 4–7% of gastrointestinal cancers and represent one of the most recurrent chromatin regulator alterations across GI malignancies. Preclinical studies demonstrate that KMT2C deficiency impairs homologous recombination–mediated DNA repair and increases tumor immunogenicity. We hypothesized that KMT2C mutations define a biologically distinct subset of GI cancers associated with enhanced responsiveness to immune checkpoint inhibitors (ICI). Methods: Using the Tempus Lens Platform, we identified patients with colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), or gastroesophageal adenocarcinoma (GEA) who underwent Tempus xT DNA and RNA sequencing within a de-identified multimodal real-world dataset. Clinical and molecular features were compared between KMT2C -mutant (MUT) and wild-type (WT) tumors. Real-world progression-free survival (rwPFS) and overall survival (rwOS) following ICI initiation were estimated by Kaplan–Meier methods and compared using log-rank tests. Risk-set adjustment was applied to address left truncation and mitigate immortal time bias. Results: Among 14,413 patients, 83% had stage IV disease; CRC comprised 58.1%, PDAC 23.7%, and GEA 18.2%. KMT2C mutations were identified in 4.1% of CRC, 3.4% of PDAC, and 4.3% of GEA. Across all tumor types, KMT2C MUT tumors had significantly higher tumor mutational burden (TMB) compared with WT (CRC: 39.2 vs 4.7 mut/Mb; PDAC: 3.68 vs 3.16; GEA: 7.9 vs 4.6; all p≤0.02). TMB-High status (≥10 mut/Mb) and MSI-High status were markedly enriched in KMT2C MUT tumors (CRC MSI-H: 57% vs 2.6%; PDAC: 6.9% vs 0.1%; GEA: 38% vs 2%; all p &lt; 0.001). High Immune Profile Score (IPS) was more frequent in KMT2C MUT versus WT tumors in CRC (35% vs 8.3%, p &lt; 0.001) and GEA (36% vs 19%, p &lt; 0.001). Following ICI, rwPFS was not reached in both KMT2C MUT CRC and KMT2C MUT GEA compared with 6.2 and 6.0 months in WT tumors (CRC p = 1.1×10⁻¹⁷; GEA p = 0.004). rwOS was significantly improved in CRC KMT2C MUT versus WT (not reached vs 20.2 months; p = 0.0001). Conclusions: KMT2C mutations identify a molecularly and immunologically distinct subset of GI cancers enriched for MSI-High and TMB-High status and associated with superior outcomes following immune checkpoint inhibition. These findings support KMT2C as a potential predictive biomarker for immunotherapy responsiveness in gastrointestinal malignancies.

A methods-forward indirect comparison of IO-IO versus IO-VEGF as first-line therapy for unresectable hepatocellular carcinoma.

e16214 Background: Many immune-based regimens are approved for first-line unresectable hepatocellular carcinoma (uHCC), yet real-world treatment selection frequently centers on choosing between IO–IO and IO–VEGF approaches. While prior comparative analyses have ranked available therapies, few studies have performed a focused indirect comparison between these two classes using transparent assumptions or assessed treatment discontinuation due to toxicity as a clinically meaningful outcome. We conducted a targeted indirect comparison to inform this common clinical decision. Methods: We performed a pairwise Bucher indirect comparison using sorafenib as a common comparator, anchored on two phase III randomized trials: HIMALAYA (tremelimumab + durvalumab [STRIDE] vs sorafenib) and IMbrave150 (atezolizumab + bevacizumab vs sorafenib). Published hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were extracted without imputation. Indirect estimates were calculated on the log scale with variance from reported confidence intervals. Safety outcomes included grade ≥3 treatment-related adverse events (TRAEs). Treatment discontinuation due to adverse events was summarised descriptively as definitions varied across trials. Results: STRIDE improved OS versus sorafenib (HR 0.78), while atezolizumab + bevacizumab demonstrated a greater OS benefit (HR 0.66). The indirect comparison yielded an OS HR of 1.18 (95% CI 0.88–1.59) for IO–IO versus IO–VEGF. For PFS, the indirect HR was 1.38 (95% CI 1.06–1.80), favoring IO–VEGF. STRIDE demonstrated lower rates of grade ≥3 TRAEs compared with sorafenib (25.8% vs 36.9%), whereas atezolizumab + bevacizumab showed higher rates (43%), resulting in an indirect RR of 0.74 (95% CI 0.55–1.00) favoring IO–IO. Discontinuation outcomes were summarized descriptively. Conclusions: In this focused indirect comparison, IO–VEGF was associated with improved PFS and a numerically greater OS benefit compared with IO–IO, whereas IO–IO showed a more favorable severe toxicity profile. Rather than offering another broad ranking of regimens, this analysis addresses the practical clinical choice between IO–IO and IO–VEGF using transparent assumptions and clinically relevant tolerability outcomes. These results suggest that first-line treatment selection may be guided by bleeding risk, immune tolerance, and comorbidities. Trial-level inputs and indirect comparison (Bucher; common comparator = sorafenib). Endpoint HIMALAYA (STRIDE vs sorafenib) IMbrave150 (Atezo+Bevvs sorafenib) Indirect (STRIDE vs Atezo+Bev) OS (HR) 0.78 (96.02% CI 0.65–0.93) 0.66 (95% CI 0.52–0.85) 1.18 (95% CI 0.88–1.59) PFS (HR) 0.90 (95% CI 0.77–1.05) 0.65 (95% CI 0.53–0.81) 1.38 (95% CI 1.06–1.80) Grade ≥3 TRAEs 25.8% 43.0% RR 0.74 (95% CI 0.55–1.00) Discontinuation 8.2% (TRAEs) 15.5% (any AE) Descriptive only

Revisiting the role of immune checkpoint inhibitor–based combination therapies in favorable risk metastatic renal cell carcinoma: An updated pairwise and network meta-analysis of long-term survival outcomes.

e16504 Background: The benefit of immune checkpoint inhibitor (ICI)–based combination therapy in IMDC favorable risk metastatic renal cell carcinoma (mRCC) remains uncertain, with persistent concerns regarding potential overtreatment. Favorable risk mRCC typically follows an indolent disease course with delayed mortality events, underscoring the need for an updated meta-analysis incorporating extended follow-up survival data to accurately assess the long-term efficacy of these regimens in this population. Methods: We systematically searched major bibliographic databases and conference proceedings for recently published phase III randomized trials evaluating ICI-based combination therapies in IMDC favorable risk mRCC, focusing on studies reporting updated and extended follow-up data for progression-free survival (PFS) and overall survival (OS). Both pairwise and network meta-analyses were conducted. Results: Six phase III trials involving 5121 patients (1267 with IMDC favorable risk mRCC) were included. The evaluated regimens comprised ICI plus anti–vascular endothelial growth factor (VEGF) therapies (including VEGF tyrosine kinase inhibitors and anti-VEGF monoclonal antibodies) and dual ICI therapy. In the pairwise meta-analysis, compared with sunitinib, ICI plus anti-VEGF therapy was associated with significantly longer PFS (hazard ratio [HR], 0.68; 95% CI: 0.54-0.79), whereas dual ICI therapy was associated with inferior PFS (HR, 1.76; 95% CI, 1.25-2.48). Neither strategy demonstrated a significant OS benefit, with HRs of 0.97 (95% CI, 0.79-1.19) and 0.82 (95% CI 0.60-1.12), respectively. In the network meta-analysis, pembrolizumab-lenvatinib and nivolumab-cabozantinib showed significant PFS improvements versus sunitinib, with HRs of 0.50 (95% CI, 0.35-0.71) and 0.67 (95% CI, 0.46-0.97), ranking first and second with P-score of 0.94 and 0.67, respectively. Network comparisons using dual ICI therapy as the reference showed significantly longer PFS with all ICI-based anti-VEGF regimens and sunitinib. No ICI-based combination regimen demonstrated a significant OS advantage over sunitinib, although P-score–based ranking suggested a numerical preference for avelumab–axitinib and nivolumab–ipilimumab. Conclusions: Leveraging extended follow-up survival data, this meta-analysis indicates that ICI-based combination therapies do not confer a clear OS benefit over sunitinib in IMDC favorable risk mRCC, calling into question the routine use of intensified upfront therapy in this population. While certain ICI plus anti-VEGF regimens demonstrated improvements in PFS, dual ICI therapy was associated with inferior PFS. These findings favor selective, risk-adapted therapy over routine intensification in indolent disease.

Financial toxicity in early-phase cancer clinical trials: A review of sponsor-supplied information at a large trials unit.

1526 Background: Financial toxicity (FT), the objective financial burden and resulting subjective distress experienced by oncology patients, adversely impacts clinical outcomes and access to care. Reimbursement practices between studies vary, possibly exacerbating the lack of representation of people from socioeconomically deprived areas and marginalized groups in early phase cancer clinical trials (EPCCTs). An ASCO roundtable in 2018 emphasized the need for clear details on out-of-pocket costs for trials. Studies in EPCCTs show FT is a recognized problem; however, management of this remains inconsistent. Methods: A retrospective portfolio review of open EPCCTs at a large UK cancer centre (Jan-Dec 2025) was conducted to assess reimbursement practices. Sources included informed consent forms (ICFs), contract trial agreements (CTAs) and sponsor provided patient materials. Reimbursement details (including amounts and timelines) were also assessed. Results: 64 studies were reviewed, encompassing 41 sponsors (38 industry and 3 academic). Reimbursement was mentioned in ICFs for 62 studies (96.8%) and by 39 sponsors (95.1%). The 2 studies lacking information were academic studies. Specific reimbursable activities were described in 15 studies (23.4%) across 11 sponsors (26.8%). No sponsor included a defined reimbursement timeline in any provided materials. Only 1 sponsor (2.4%) provided additional reimbursement information for patients. Third party vendors for reimbursement were used for 18.8% of studies, with 8 different vendors across 10 sponsors. Reimbursement processes were often detailed in CTAs, with 55 studies (85.9%) outlining specific reimbursable activities. Of 8 academic studies reviewed, 75% listed a maximum budget for each patient to cover the whole study duration (median £350; range £300-£500). Among studies reporting mileage repayment (53; 82.8%), the median rate was £0.45/mile (range £0-£0.45). Median patient travel expense entitlement per visit, where mentioned (55; 85.9%), was £150 (range £40–£700), while refreshment reimbursement was noted in 26 studies (40.6%) with a median value of £15/visit (range £5–£80). The total reimbursement offered per patient per visit was reported in 55 studies (85.9%), with a median of £152.50 (range £40–£1,145). Additional costs covered included reimbursement for carers (9 studies; 14.1%) and unforeseen/inconvenience payments (2 studies; 3.1%). Conclusions: Reimbursement terms are regularly specified in CTAs but there is limited inclusion in patient-facing trial documents and lack of flexibility for additional costs. Academic studies restrict reimbursement. Patients may decline clinical studies due to fear of financial toxicity, compounding health inequity. We are partnering with patients to co-develop clearer communication about reimbursement, supporting informed decision-making prior to study enrollment.

Safety and efficacy of ST316, a first in class ß-catenin antagonist, in metastatic colorectal cancer (mCRC).

e15622 Background: Aberrant activation of the Wnt/ß-catenin pathway is a critical driver of tumor progression and immune evasion in mCRC. Targeting this pathway is challenging due to its role in normal tissue physiology. BCL9 is a co-activator essential for oncogenic ß-catenin activity, but not its physiologic functions, highlighting the ß-catenin/BCL9 interaction as a therapeutic target. ST316 selectively disrupts the ß-catenin and BCL9/9L interaction, resulting in reduced oncogenic Wnt/ß-catenin transcriptional activity and potent antitumor activity, with no negative impact on intestinal or bone physiology. Methods: A phase 1/2 study is ongoing to determine the safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of ST316 alone in solid tumors likely to harbor abnormalities of the Wnt/ß-catenin signaling pathway, and in combination with standard of care FOLFIRI + bevacizumab (SOC) in patients (pts) with metastatic CRC who have progressed after first line chemotherapy-containing regimens. PD analysis was conducted on serial tumor biopsies and blood samples collected at baseline and on-study. Results: Here we report biomarker data from the phase 1 dose escalation and clinical data from the phase 2 study. As of January 5, 2026, 23 pts were enrolled in the Ph1 (median age 62 yrs). Pts received a median of 18 weeks of ST316 monotherapy (0.5mg/kg/QW to 12mg/kg/QW). No DLTs were observed, and the RP2D for combination with SOC was 8 mg/kg. Spatial transcriptomics indicates significantly decreased Wnt/ß-catenin transcriptional signatures in tumor cells, confirming on-target pathway disruption. GSEA identified significant attenuation of EMT and TGF-ß signatures, consistent with potent Wnt/ß-catenin antagonism. In Ph2, 15 2L mCRC pts (median age 53, range 22-62), 100% MSS, 73% RAS mut, were treated with ST316 + FOLFIRI/bevacizumab and evaluable for response. Confirmed ORR is 46.7% (7/15 pts), along with another 46.7% of pts with SD (7/15 pts, of which 3/7 pts display decreased target lesions). Adverse events occurring in ≥20% of pts include nausea, fatigue, ALT/AST elevations and neutropenia; G3 AEs were reported for ALT/AST elevation and neutropenia. ALT/AST elevations were reversible and managed by dose reductions or drug holidays. Conclusions: ST316 monotherapy was generally well tolerated, safe, and resulted in significant on-target suppression of tumor Wnt/ß-catenin transcriptional signatures. In 2L metastatic CRC, ST316 combined with FOLFIRI/bevacizumab reached a confirmed ORR of 46.7% and disease control rate of 93.4%, which compare favorably with 2L FOLFIRI/bevacizumab historical ORR of 11% (Iwamoto et al, EAGLE), supporting a clinically meaningful combination effect. Liver enzyme elevations were reversible and asymptomatic. Together, the data supports further evaluation of ST316 in combination with SOC in early-stage CRC. Clinical trial information: NCT05848739 .

KRAS mutational landscape and immune microenvironment features in pancreatic cancer: Implications for targeted and combination therapeutic strategies.

e16406 Background: The poor prognosis of pancreatic cancer and its high prevalence of KRAS mutations have made KRAS alterations a major focus of clinical research. Although KRAS-targeted inhibitors approved in other solid tumors, such as sotorasib and the combination of avutometinib plus defactinib, have shown clinical activity in pancreatic cancer, durable benefit remains limited. Combination strategies may therefore provide additional therapeutic opportunities. This study aimed to characterize KRAS mutational features and the immune microenvironment in a real-world pancreatic cancer cohort to inform the development of KRAS-targeted and combination treatment approaches. Methods: Next-generation sequencing (NGS) was performed in 93 pancreatic cancer patients to characterize genomic alterations. All samples underwent multiplex immunofluorescence (mIHC) to evaluate the tumor immune microenvironment. Ten immune markers were quantified with APTime Pathology Analysis Software, including T cells, B cells, macrophages, NK cells, and tertiary lymphoid structures. Results: KRAS alterations were identified in 79.6% (74/93) of patients, including 69 single-nucleotide variants and 5 copy number amplifications. The most frequent mutation subtype was G12D (55.3%), and 94.7% of KRAS variants were located in exon 2, consistent with canonical activating mutations. Only three patients harbored KRAS variants of unknown clinical significance, two of whom also carried common KRAS hotspot mutations. The most frequent co-altered genes in KRAS-mutant tumors were TP53 (9.7%) and CDKN2A (5.9%), both of which have been associated with immune-related features in prior studies. All tumors were microsatellite stable. No significant differences were observed between KRAS-mutant and wildtype tumors in tumor mutational burden (median: 4.2 vs 3.4 mut/Mb, P = 0.6) or HRD score (median: 13 vs 5, P = 0.2). However, immune microenvironment analysis revealed that KRAS-mutant tumors had significantly higher levels of M1 macrophages in the tumor stroma ( P = 0.006), PD-L1⁺CD68⁺ cells in the stroma ( P = 0.03), and PD-L1⁺CD68⁺ cells in the tumor compartment ( P = 0.02) compared with KRAS-wildtype tumors. Overall, KRAS-mutant tumors exhibited a more immune-active microenvironment. Conclusions: KRAS mutations are highly prevalent in pancreatic cancer and are predominantly canonical pathogenic variants, supporting strong potential for targeted therapeutic intervention. Although KRAS-mutant tumors did not demonstrate advantages in TMB or MSI, they exhibited enriched M1 macrophage and PD-L1⁺CD68⁺ immune populations, suggesting a more favorable immune microenvironment. These findings support the rationale for exploring KRAS-targeted therapies in combination with immunomodulatory strategies in pancreatic cancer.

Two decades of landscape change in the treatment of multiple myeloma.

e19571 Background: The treatment of newly diagnosed multiple myeloma (NDMM) has evolved rapidly over the past two decades. We aimed to describe temporal trends in treatment patterns and clinical outcomes among patients in China. Methods: This retrospective cohort study utilized electronic medical record data from the National Longitudinal Cohort of Hematological Diseases in China. Eligible patients were ≥18 years at diagnosis and received ≥ 4 cycles induction therapy. Patients were excluded if previously treated for MM. Patients were followed until death, study end (June 30, 2023), or last follow-up via telephone. OS and PFS were estimated by Kaplan–Meier methods. Age group stratified Cox proportional hazards regression was performed to identify prognostic factors for survival. Results: A total of 1,622 patients were included. Median age was 57.0 years, and 18.4% were aged &gt;65 years. Most patients were male. At diagnosis, 41.8% had ISS stage III disease. IgG was the predominant subtype, and high-risk cytogenetic abnormalities were present in 24.1% of patients. Induction therapy shifted from mainly chemotherapy to proteasome inhibitor–based regimens by 2009, and to PI+IMiD-based combinations by 2019. By 2023, about 60% of patients received PI+IMiD-based induction and 30% received anti-CD38 antibody–based induction. Utilization of autologous stem cell transplantation (ASCT) also increased steadily over time, ranging from 22% to 48% annually. With median follow-up of 35.6 months, survival improved steadily over time: median PFS increased from 32.3 months (95% CI: 26.7–38.9) in 2008–2012 to 33.6 months (95% CI: 30.7–36.7) in 2013–2017, and to 48.0 months (95% CI: 44.6–52.5) in 2018–2023, while median OS rose from 78.5 months to 85.6 months to not reached. Advanced ISS stage and high-risk cytogenetics were linked to poorer clinical outcomes. In contrast, ASCT and the use of PI+IMiD-based or CD38 antibody–based induction regimens independently correlated with improved PFS and OS. Among patients aged &gt;65 years, treatment pattern shifts were similar to those in the overall cohort, with increasing use of PI+IMiD-based and anti-CD38 antibody–based induction in recent years. Since 2016, roughly 10% of older patients received ASCT. Improvements in PFS and OS across time periods were likewise observed in this age group as well. Conclusions: Over two decades, NDMM treatment in China has transitioned from chemotherapy-based regimens to widespread use of PI+IMiD combinations and increasing use of anti-CD38 antibodies, and expanding application of ASCT. These advances have driven meaningful improvements in PFS and OS across the study period. Similar trends were observed among patients aged &gt;65 years. Continued efforts to expand access to novel agents and optimize treatment strategies are essential to sustain and accelerate these gains.

Intensity-modulated proton therapy versus intensity-modulated photon radiotherapy for locally advanced HPV-positive oropharyngeal squamous cell carcinoma: A systematic review and meta-analysis.

e18060 Background: Intensity-modulated proton therapy (IMPT) has been gaining popularity as a method of treating locally advanced HPV positive oropharyngeal squamous cell carcinoma (OPSCC) due to the ability to reduce the amount of normal tissue that is exposed to radiation but whether or not it will result in better clinical outcomes when compared to intensity-modulated photon radiotherapy (IMRT), is still unknown. We performed a meta-analysis to evaluate the effects of IMPT on both cancer related toxicities and outcomes in comparison to IMRT for patients diagnosed with locally advanced HPV positive OPSCC. Methods: We evaluated all comparative studies that examined the use of IMPT vs. IMRT in stage III-IV HPV positive OPSCC. Using random-effects models, we estimated pooled relative risks (RRs) with 95% CIs for each study's measure of association. The primary outcomes of interest were: weight loss; gastrostomy tube insertion; xerostomia; dysphagia; mucositis; fatigue; locoregional recurrence; and OS. Statistical heterogeneity was assessed via I². Results: In total, there were 4 studies that involved 912 patients. As per these studies, a greater number of patients experienced clinically relevant weight loss when receiving IMPT than when receiving IMRT (RR 1.63, 95% CI 1.17–2.27; p= .004; I²= 0%). Additionally, a comparison of six studies which included a total of 1143 patients indicated that gastrostomy tubes are inserted more often after IMPT (RR 2.9, 95% CI 1.8 – 4.6; p&lt;.00001; I²= 0%). No statistically or clinically significant differences were found regarding other side effects from treatments. In terms of cancer recurrence, there was a greater rate of loco-regional recurrence for those patients who received IMPT as compared to IMRT (RR 1.58, 95% CI 1.26- 1.97; p&lt; .0001; I²= 0%) in three studies which included a total of 592 patients. However, no statistical difference in overall survival was identified between IMPT and IMRT (RR 1.06, 95% CI 0.87- 1.29; p=.56), even though there was significant variability (I²= 87%) in three studies which included a total of 747 patients. Conclusions: In locally advanced HPV positive OPSCC, there were no differences in toxicity profiles from IMPT compared to IMRT, and there were increased rates of weight loss, gastrostomy tube placement, and locoregional recurrence from IMPT compared to IMRT, without any observed survival advantage. This highlights the need for future prospective randomized trials to clarify the role of IMPT in the management of locally advanced HPV positive OPSCC.

Phase I/II study of AZD6750, a CD8-guided interleukin-2 agent, alone and in combination with other anti-cancer agents in participants with advanced or metastatic solid tumors.

TPS2666 Background: Interleukin-2 (IL-2) has antitumor activity through stimulation of proliferation and differentiation of cytotoxic T lymphocytes, but toxicity due to systemic immune system activation limits its clinical use. AZD6750 comprises two CD8 human IgG1 binding domains and two IL-2 mutein domains and uses cis-guiding to deliver IL-2 mutein preferentially to CD8+ T cells, with the goal of increasing antitumor activity while limiting toxicity. It has high affinity for CD8α and the CD122/CD132 IL-2R complex, and reduced affinity for CD25 (IL-2Rα). In preclinical studies, AZD6750 has been shown to cause preferential proliferation of CD8+ T cells without increasing cytokine release from peripheral blood mononuclear cells; improve antigen-specific tumor cytolysis; increase IFN-γ secretion, a sign of productive responses in tumor-infiltrating lymphocytes; and inhibit growth of a tumor model in vivo. We describe the design of a phase I/II trial of AZD6750 in patients with metastatic solid tumors (NCT07115043). Methods: This first-in-human, open-label, phase I/II, multicenter clinical trial is evaluating AZD6750 as monotherapy (Module 1, dose escalation) and combined with rilvegostomig (Module 2) in patients with selected locally advanced or metastatic solid tumors. All patients must have ECOG performance status of 0/1 and ≥1 measurable lesion per RECIST v1.1. In Module 1, patients must have received prior standard-of-care therapy and have a tumor type for which immune checkpoint inhibitors are known to be effective or in which IL-2 potentially has benefit. Dose escalation starts with an accelerated titration design and switches to a modified toxicity probability interval-2 (MTPI-2) design after the first 2 dose cohorts or earlier sign of grade ≥2 toxicity. Module 2 will enroll patients with stage IV NSCLC who have either received ≥1 line of therapy in the metastatic setting (including targeted therapy if actionable mutations are present) (Module 2A, dose escalation) or are metastatic treatment naïve and have tumor PD-L1 expression ≥1% (Modules 2A and 2B). Patients who have autoimmune or inflammatory disorders within 3 years of study or toxicity that led to discontinuation of prior immunotherapy are not eligible for Module 2. In Module 2A, dose escalation will use MTPI-2. Module 2B will be a dose expansion module. The primary endpoints of Modules 1 and 2A are the incidence of adverse events (AEs), serious AEs, and dose-limiting toxicities, which will be used to determine the maximum tolerated dose/recommended phase 2 dose. In Module 2B (dose expansion), the primary endpoint will be preliminary antitumor activity. Secondary endpoints include pharmacodynamics (PD-L1), immunogenicity (anti-drug antibodies), and pharmacokinetics. The study is actively recruiting globally, with 3 patients enrolled as of December 2025. Clinical trial information: NCT07115043 .