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Updated efficacy and subgroup analysis of first-line serplulimab plus bevacizumab and XELOX versus placebo plus bevacizumab and XELOX in metastatic colorectal cancer: A phase 2/3 study.

170 Background: This is a randomized, double-blind, multicenter phase 2/3 study comparing the efficacy and safety of serplulimab (a novel anti-PD-1 antibody) plus bevacizumab and XELOX chemotherapy vs. placebo plus bevacizumab and XELOX as first-line treatment for metastatic colorectal cancer (mCRC). Our previous presentation at the 2024 ASCO Meeting showed the progression-free survival results. Here we present the updated efficacy and safety findings together with subgroup analysis results after a median follow-up of 31.0 months. Methods: A total of 114 patients with mCRC and no prior systemic therapy were randomized 1:1 (serplulimab arm, n = 57; placebo arm, n = 57) to receive intravenous (IV) serplulimab (300 mg) plus bevacizumab (7.5 mg/kg) and XELOX (IV oxaliplatin [130 mg/m 2 ] and oral capecitabine [1000 mg/m 2 ]) (group A) or placebo plus bevacizumab and XELOX (group B) once every 3 weeks. Stratification factors were PD-L1 expression level, ECOG PS score, and primary tumor site. The primary endpoint was independent radiological review committee (IRRC)-assessed PFS per RECIST 1.1. Secondary endpoints included other efficacy endpoints, safety, pharmacokinetics, biomarker explorations, and quality-of-life assessments. Results: In the phase 2 part, by the data cutoff of June 30, 2024, sustained improvements in PFS (16.6 vs. 10.7 months, stratified HR 0.66, 95% CI 0.37–1.19) and DOR (17.7 vs. 11.3 months, stratified HR 0.45, 95% CI 0.20–0.98) were observed for patients in group A compared to group B in the modified intent-to-treat population (n = 112; two patients in group A did not receive any intended study treatment). 32/55 (58.2%) patients in group A and 35/57 (61.4%) in group B have died. Median overall survival (OS) was 25.6 months in group A and 21.2 months in group B (stratified HR 0.86, 95% CI 0.53–1.42). A trend of PFS and OS benefits was similarly observed for the patients with a microsatellite stable (MSS) status (PFS: 16.8 vs. 10.1 months, stratified HR 0.65, 95% CI 0.33–1.29; OS: 23.5 vs. 20.2 months, stratified HR 0.79, 95% CI 0.45–1.38). 39 (70.9%) patients in group A and 34 (59.6%) in group B had grade ≥3 treatment-related adverse events. Serplulimab/placebo-related serious TRAEs occurred in 13 (23.6%) patients in group A and 14 (24.6%) patients in group B. Conclusions: With a follow-up duration of 31.0 months, improved survival benefits demonstrated with the addition of serplulimab were maintained in the first-line treatment of mCRC patients including those with MSS status alongside a manageable safety profile. The phase 3 part of this study is currently ongoing to further evaluate serplulimab plus bevacizumab and XELOX as a first-line treatment option in mCRC. Clinical trial information: NCT04547166 .

Overall survival (OS) of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with first-line (1L) FOLFIRINOX (FFX): Bridging the gap between the NAPOLI 3 trial and real-world practice.

690 Background: NALIRIFOX (liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin) demonstrated significantly improved OS compared to 1L gemcitabine + nab-paclitaxel in the phase 3 NAPOLI 3 trial (NCT04083235). The median OS (95% CI) in the NALIRIFOX intention-to-treat population (N= 383) was 11.1 (10.0, 12.1) months. However, the relative efficacy of NALIRIFOX versus FFX (irinotecan + 5-fluorouracil/leucovorin + oxaliplatin), another standard of care for 1L treatment of mPDAC, has not been studied. To further contextualize findings from NAPOLI 3 trial, the current study described OS among patients treated with 1L FFX in the real-world setting. Methods: Three cohorts of patients with mPDAC treated with 1L FFX were identified from the Flatiron Health database. The all-comer cohort included all adult patients with mPDAC treated with 1L FFX since January 2014. Among them, the trial-aligned cohort included patients with mPDAC treated with 1L FFX between January 1, 2020 and July 31, 2022 (to align with the time period of NAPOLI 3 trial) who met the eligibility criteria of NAPOLI 3. Finally, a subgroup of patients in the trial-aligned cohort who received modified FFX (mFFX) regimen composed the trial-aligned mFFX cohort. OS was assessed using Kaplan-Meier analysis. Results: The all-comer cohort consisted of 3,271 patients. The trial-aligned cohort included 219 patients, of whom 154 (70%) were treated with mFFX. The distribution of baseline characteristics was similar across three cohorts (Table). The median age of the trial-aligned cohort was 65 years old, with 46% of patients being female, 67% being White, and 47% having ECOG score of 1. The median OS (95% CI) in the all-comer cohort and trial-aligned cohort was 9.0 (8.5, 9.3) months and 9.1 (7.8, 10.9) months, respectively; the median OS (95% CI) was 8.6 (7.3, 10.5) months in the trial-aligned mFFX cohort. Conclusions: NALIRIFOX regimen in the NAPOLI 3 trial showed numerically improved OS compared to FFX, including mFFX, in the real-world setting. Analysis adjusting for baseline characteristics are warranted and will provide further insights for the comparative efficacy of the two regimens. Characteristics of real-world FOLFIRINOX cohorts. All-comer cohort(N=3,271) Trial-aligned cohort(N=219) Trial-aligned mFFX cohort (N=154) Baseline characteristics Age, years, mean (SD) 63.5 (9.0) 64.6 (8.2) 65.1 (8.5) Female, n (%) 1,377 (42.1) 100 (45.7) 68 (44.2) White, n (%) 2,118 (64.8) 146 (66.7) 100 (64.9) ECOG score = 1, n (%) 1,327 (48.9)* 103 (47.0) 77 (50.0) Endpoint Median OS, months (95% CI) 9.0 (8.5, 9.3) 9.1 (7.8, 10.9) 8.6 (7.3, 10.5) Abbreviations: CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; OS, overall survival; SD, standard deviation. *Proportion calculated based on 2,711 patients with ECOG available at baseline.

Two‐dimensional Nanosheets by Liquid Metal Exfoliation (Adv. Mater. 8/2025)

Analysis of serum and urine miRNAs as biomarkers of cancer cachexia in pancreatic cancer.

773 Background: Cancer cachexia (CC), characterized by anorexia, weight loss and skeletal muscle wasting, is a common complication in patients (pts) with pancreatic cancer (PC). The association of CC with treatment-related toxicity and decreased quality of life has been reported. Although CC is believed to result from systemic inflammation and cancer-induced metabolic changes, the underlying mechanisms remain poorly understood. Early diagnosis of CC is particularly challenging, highlighting the need for reliable biomarkers. We analyzed microRNAs (miRNAs) in serum and urine as potential biomarkers for the early detection of CC in PC. Methods: Clinical information, along with serum and urine samples were collected from pts with PC treated at the National Cancer Center Hospital, Tokyo, from March 2022 to March 2024. CC diagnosis according to Fearon et al: (1) ≥5% weight loss in 6 months, (2) ≥2% weight loss in individuals with a BMI of <20 kg/m², or (3) ≥2% weight loss in pts with sarcopenia. In this study, pts were considered to have CC if they met the definition of CC at enrollment or within six months. Serum and urine extracellular vesicle (EV) miRNA profiles were sequenced by NGS and compared by means of counts per million (CPM). Differential expression of miRNAs between pts with and without CC was investigated by DEseq2. Results: Of the 84 enrolled cases, 73 had sufficient sample volume for NGS assay. After excluding 4 cases with low miRNA read counts and 10 cases with unknown CC status, 59 cases were analyzed. CC was present in 41 pts (69%). Patients’ background was as follows (CC/no CC); median age 70 [IQR:62–75]/ 67 [63–69], male 21/9 pts, cStage {I (7/0), II (1/0), III (18/5), IV (15/13)} pts, median BMI (21.7 [IQR:19.6–24.0]/21.8 [20.7–22.4]) kg/m2, respectively. There were 141 common miRNA species between serum and urine samples, 81 miRNAs unique to serum and 33 unique to urine. The correlation between the common miRNAs was moderate (R = 0.60). No significant differences in miRNA expression were observed between pts with and without CC in serum samples. In urine samples, miR-141-5p was significantly downregulated (log2FoldChange = -0.667, padj = 0.0463), while miR-146b-5p was significantly upregulated (log2FoldChange = 1.03, padj = 0.0463) in pts with CC compared to those without. Conclusions: The results of this study suggest that urine is a suitable biofluid for detecting CC in patients with PC, as differentially expressed miRNAs were not observed in serum. However, the mechanism underlying the superiority of urine over serum in detecting CC remains unclear and should be addressed in future studies.

Evaluation of the impact of lymph node ratio on survival in patients with pancreatic cancer undergoing neoadjuvant therapy.

702 Background: Pancreatic cancer continues to have a dismal prognosis despite improvements in surgical care. Resection status and lymph node status continues to be key factors impacting prognosis. There remains significant debate on the utility of increasing nodal harvest in patients undergoing surgery, while others report an improvement in survival. We sought to evaluate the impact of lymph node positivity to lymph nodes resected in patients with pancreatic cancer undergoing resection. Methods: Utilizing the National Cancer Database, we identified patients diagnosed with pancreatic cancer who underwent neoadjuvant chemotherapy (NCT) or neoadjuvant chemoradiation (NCR) followed by resection. We then stratified by nodal status and calculated a LN+/LNR (lymph node resected) ratio. Pearson’s Chi-square test was used to compare categorical variables. Survival analysis was estimated by the Kaplan-Meier method and associated log-rank test. Propensity score matching (PSM) was completed for variables of age, sex, tumor size, LN removed, LN positive, pathogenic T- stage and N-stage, grade, 30- and 90-day mortality, R0 resection, facility volume, response, adjuvant therapy, and LNR. Significance was considered at p-value ≤0.05. Results: We identified 4117 patients with a median age of 65 (25-90). There were 2323 patients who underwent NCT and 1794 who underwent NCR. The median LN resected in the NCT was 18 vs 15 in the NCR, p<0.001. However, there were more LN+ in the NCT vs NCR, 2.1 vs 0.9, p<0.001. The R0 resection rates were lower in the NCT vs NCR 81% vs 86%, p<0.001. Additionally, complete response rates were higher amongst the NCR, 9.2% vs 4.7%, p<0.001. Lymph node ratios were consistently higher in the NCT cohorts among all ratio strata, p<0.001. Patients with pN+ disease had a median and 5-year survival of 26.4mo and 17% compared to their pN- counterparts at 38.8mo and 36%, p<0.001. Patients treated with NCT demonstrating a LNR of 0.01-0.1 had median and 5-year survival of 32.8 and 27%, LNR 0.11-0.4 (25.5mo and 12%), and LNR>0.4 (19.1mo and 10%), p<0.001. Patients treated with NCR demonstrating a LNR of 0.01-0.1 had median and 5-year survival of 29.1 and 21%, LNR 0.11-0.4 (25.8mo and 17%), and LNR>0.4 (21.3mo and 5%), p<0.001. PSM confirmed a higher LNR in the NCT cohort compared to NCR, p<0.001, however survival was also longer in these patients among the LNR 0.01-0.1, and 0.11-0.4, p<0.001. Conclusions: Lymph node status in patients with pancreatic cancer continues to be a significant prognostic indicator of survival. Moreover, lymph node ratio may be a more accurate predicter of survival in patients undergoing neoadjuvant chemotherapy and neoadjuvant chemoradiation.

Association between ex vivo pharmacotyping of patient-derived tumor organoids and personalized therapeutic options for patients with biliary tract cancer.

618 Background: Biliary tract cancers (BTC), including cholangiocarcinomas and gallbladder adenocarcinomas, present significant therapeutic challenges due to limited treatment options and poor prognoses. We report findings from the CLIA-certified PARIS assay, evaluating drug sensitivities of patient-derived tumor organoids (PDTOs) to a panel of oncology drugs. Methods: PDTOs were successfully cultured from 27 out of 46 live tumor samples obtained from 43 BTC patients. The majority of patients presented with advanced metastatic disease (60% stage IV, 13% stage III, 10% stage II, 4.4% stage I, 10% unknown) and had exhausted standard therapeutic options. Each PDTO culture underwent testing against an average of 50 drugs, encompassing chemotherapeutic agents and targeted therapies. Results: Comparative analysis of PDTO drug sensitivities with patients' prior treatment histories revealed non-responsiveness to >80% of drugs associated with clinical progression, including gemcitabine, cisplatin, and targeted therapies for FGFR translocations. In contrast, 100% (26/26) of the samples demonstrated significant sensitivity to one or more targeted agents, particularly inhibitors of EGFR, MEK, ERK, mTOR, PI3K, MDM2, BCL2, and BET families. Despite these shared sensitivities, each individual PDTO culture exhibited unique responses to targeted therapies, highlighting the genetic and phenotypic diversity between BTC patients. Comparison of ex vivo drug sensitivities with tumor genomic profiles validated oncogenic drivers such as HER2 amplification, KRAS and PIK3CA pathogenic mutations, correlating with sensitivities to EGFR/HER2 inhibitors, MEK inhibitors, and PI3K inhibitors, respectively. While mutations in KRAS , BRAF , BRCA1 , BRCA2 , ERBB2 , ERBB3 , or MET are present in less than 8% of cases, their role as biomarkers in BTCs requires further validation. PDTOs offer a promising tool to expedite this validation process. The PARIS assay results guided treatment decisions for five patients with metastatic disease, two of whom maintained treatment for over 4 weeks. Notably, two patients showed clinical benefit with everolimus (5 weeks) and dasatinib (11 weeks), experiencing symptom relief and reduced ascites. Intriguingly, 5 out of 7 PDTOs with FGFR alterations exhibited exceptional PARIS test responses to dasatinib, suggesting potential efficacy linked to FGFR activation. Conclusions: In conclusion, our study demonstrates that ex vivo drug testing of PDTO cultures can inform treatment selection and potentially accelerate drug approvals for BTC, leveraging therapies approved for other cancers. Early integration of such assays in patient management, possibly at diagnosis, holds promise for improving outcomes in this challenging disease.

Multiscale Manufacturing of Recyclable Polyimide Composite Aerogels (Adv. Mater. 5/2025)

Manganese Galvanic Cells Intervene in Tumor Metabolism to Reinforce cGAS‐STING Activation for Bidirectional Synergistic Hydrogen‐Immunotherapy

Abstract The cGAS‐STING pathway is pivotal in initiating antitumor immunity. However, tumor metabolism, particularly glycolysis, negatively regulates the activation of the cGAS‐STING pathway. Herein, Mn galvanic cells (MnG) are prepared via liquid‐phase exfoliation and in situ galvanic replacement to modulate tumor metabolism, thereby enhancing cGAS‐STING activation for bidirectional synergistic H 2 ‐immunotherapy. The obtained MnG can be etched by water, enabling efficient and sustained generation of H 2 gas and Mn 2+ . MnG not only activated and amplified the cGAS‐STING pathway through the sustained release of Mn 2+ but also regulated tumor glucose metabolism to inhibit the expression of three prime repair exonuclease 2 (TREX2), thereby synergistically enhancing the activation of the cGAS‐STING pathway. The injection of MnG into tumors resulted in a robust immune response, thereby providing favorable support for antitumor therapy. Consequently, the combination of MnG with immune checkpoint blockade therapy resulted in significant suppression of both primary tumors and distant tumors. Furthermore, the MnG‐lipiodol dispersion exhibited remarkable efficacy in combination with transarterial embolization (TAE)‐gas‐immunotherapy in a rabbit orthotopic liver tumor model. The present study underscores the significance of employing a metal galvanic cell strategy for enhanced immunotherapy, thereby offering a novel approach for rational design of bioactive materials to augment immunotherapeutic effectiveness.

Trends in early onset colorectal cancer–related mortality among adults in the United States from 1999-2020.

42 Background: Colorectal cancer (CRC) has witnessed a decrease in incidence and mortality in the United States (US) for the past few decades likely due to increased screening and improvements in treatment . Despite the overall burden of CRC has declined and survival has been made for older adults, there is a simultaneous and alarming increase in CRCs diagnosed in individuals younger than 50 years of age. These Early Onset CRC (EOCRC) which now account for roughly 10% of new CRC cases in the US. The purpose of this study was to assess the trends and regional differences in EOCRC-related mortality among adults in the United States. Methods: Death certificates from the CDC WONDER (Centers for Disease Control and Prevention Wide-Ranging OnLine Data for Epidemiologic Research) database were examined from 1999 to 2020 for -related mortality in adults <45 years of age. Age-adjusted mortality rates (AAMRs) per 10,000 persons and annual percent change (APC) were calculated and stratified by year, sex, race/ethnicity, and geographic region. Results: Between 1999 and 2020, 32,850 EOCRC-related deaths occurred among adults 25-44 years. The AAMR increased from 2.1 in 1999 to 2.6 in 2020. Men had consistently higher AAMR than women from 1999 (AAMR men: 2.0 vs women: 1.6) to 2020 (AAMR men: 2.6 vs women: 2.0). Non Hispanic (NH) African Americans had the highest overall AAMR (3.1), followed NH White (2.2), NH Asians (1.6) and Hispanics (AAMR 1.5) Caucasians have had a significant increase in mortality over the past 2 decades ( APC 1.4 (95%Cl 1.1-.7)) whereas the Hispanics have shown an APC of 4 (95% Cl 2.3-5.8 from 2012-2020). AAMR also varied substantially by region (overall AAMR: Midwest 2.1; South: 2.4; West: 1.9; Northeast: 2.0). States in the top 90th percentile of EOCRC-related AAMR were Mississippi, Arkansas, Oklahoma, South Carolina, Alabama West Virginia, Louisiana ,Kentucky and Tennessee which had approximately double the AAMRs compared with states that fell into the lower 10th percentile. Conclusions: EOCRC-related mortality in U.S. adults has been steadily increasing over the past two decades . The highest AAMRs were observed among African American adults and men, and among patients living in the Southern , Midwestern regions and those living in the nonmetropolitan United States. Targeted strategies are needed to prevent and treat EOCRC among older adults to curb increasing levels of EOCRC-related mortality.

Trends in surgery and overall survival in non-metastatic anal cancer: A population-based analysis.

3 Background: The incidence of anal cancer has recently exceeded > 10,000 patients/year in the United States. For non-metastatic squamous cell carcinoma of the anal canal (SCCA), concurrent chemoradiotherapy (CRT) followed by abdominoperineal resection (APR) as salvage surgery for non-responders is a key treatment approach. Over the past two decades, findings from phase III trials (RTOG 98-11 and ACT II) have increased our knowledge about appropriate treatment approaches. ACT II indicated that delayed assessment of tumor response and consideration of APR up until 26 weeks is appropriate, as many patients demonstrate delayed response to treatment. Our analysis examines whether current evidence has influenced real-world clinical practice by analyzing trends in rates of primary APR and overall survival (OS) outcomes. Methods: We conducted a retrospective cohort study using data from the Surveillance, Epidemiology, and End Results (SEER) registry, including patients diagnosed with non-metastatic SCCA between 2004 and 2020. Patients with T0 or T1N0 stage disease were excluded. Descriptive statistics were generated, and chi-square tests were used to compare characteristics between patients who underwent surgery and those who did not. Temporal trends in surgery and radiation therapy were analyzed using the Cochrane-Armitage trend test. Multivariable logistic regression was employed to identify factors associated with surgery uptake, while OS trends were analyzed using Kaplan-Meier and Cox proportional hazard models. Results: A total of 16,718 patients were included, with 33.1% requiring salvage APR following CRT. The proportion of patients requiring surgery significantly declined from 46.6% in 2004 to 31.1% in 2020 (p < 0.001). Factors associated with surgery included younger age, male gender, and non-Hispanic Black race (p < 0.001). Kaplan-Meier analysis revealed significant improvements in OS over the study period (log-rank p = 0.0002), with more recent years (2016-2020) associated with significantly better OS compared to earlier periods (2004-2007, HR = 0.77, p < 0.001). Conclusions: The significant decrease in rates of salvage APR for non-metastatic SCCA likely reflects the global impact of recent phase III trials. Meanwhile, OS rates have been steadily improving. These findings suggest improved overall knowledge regarding treatment strategies and highlight the real-world impact of clinical investigation in non-metastatic squamous cell carcinoma of the anal canal.

EORTC-1203 GITC "INNOVATION": Integration of trastuzumab (T), with or without pertuzumab (P), into perioperative chemotherapy of HER-2 positive stomach cancer: Overall survival results.

LBA331 Background: 10-20% of GC are HER-2 positive. The role of perioperative anti-HER2-directed treatment is yet undefined. Methods: This randomized, open-label phase II-trial investigates the benefit of perioperative chemotherapy (CT) alone or in combination with either T or T and P for HER-2+ gastric (GC) and esophagogastric junction cancer (EGJC). 172 patients (pts) with centrally confirmed, positive HER-2 status and resectable GC or EGJC (UICC TNM stages Ib-III) were included. Pts were randomized in a 1:2:2 ratio to: Arm A (CT alone) (35 pts); Arm B (CT+ T [8mg/kg, followed by 6mg every 3 weeks]) (67 pts); Arm C (CT + T+ P [840mg every 3 weeks]) (70 pts). CT was initially cisplatin (80 mg/m 2 d1) and capecitabine (2 x 1000 mg/m 2 /d d1) for 3 cycles before and after surgery. After publication of FLOT-4 (Al-Batran, Lancet 2019), the protocol was amended. CT changed to four cycles FLOT, with FOLFOX or CAPOX as alternative for pts ineligible for FLOT. In arm B and C, T and P were continued beyond CT at the same dose for a total of 17 cycles. Out of 172 pts randomized, 161 fulfilled all key eligibility criteria and started their allocated treatment (per protocol population). Centrally determined major pathological response rates (mpRR) were 33.3%, 53.3% and 37.9% in Arm A: B: C after amending the protocol while, in contrast, they were 8.3%, 16.7% and 12.5% before (ASCO 2024, abstract 4057). Here, we present progression-free-(PFS) and overall survival (OS) after a median follow-up of 4.3 years. Results: In Arm A: B: C, 63.6%, 64.7%, 50.4% and 51.9%, 61.0%, 47.9% of pts were progression-free at 3 and 5 years. As compared to CT alone, HRs for PFS versus CT+T were 0.88 (90% CI, 0.51 to 1.53) and for CT+T+P 1.40 (90% CI, 0.82 to 2.37). Survival rates at 3 and 5 years in arm A: B: C were 75.6%, 76.9%, 65.2% and 60.5%, 67.5% and 62.6 %. As compared to CT alone, HRs for OS for CT+T and CT+T+P were 0.89 (95% CI, 0.42 to 1.88)) and 1.29 (95% CI, 0.62 to 2.66). For results before and after amendment see table. Conclusions: Non-significant advantages in terms of PFS and OS were observed for the addition of T to CT before, but not after the amendment. CT+T+P was detrimental. These results reflect the challenge of using mpRR as surrogate for survival in the perioperative treatment of GC. Clinical trial information: NCT 02205047 . PFS and OS results before and after amendment. Before amendment: Arm PFS (%) at 3 Years (95% CI) Hazard Ratio (95% CI) OS (%) at 3 Years (95% CI) Hazard Ratio (95% CI) CT(N=14) 57.1(28.4, 78.0) 1.00 78.6(47.3, 92.5) 1.00 CT+T(N=26) 64.2(42.5, 79.5) 0.64(0.24, 1.72) 83.6(62.0, 93.5) 0.77(0.25, 2.44) CT+T+P(N=28) 50.4(30.1, 67.6) 1.18(0.48, 2.93) 68.3(46.3, 82.8) 1.28(0.44, 3.75) After amendment: CT(N=19) 68.4(42.8, 84.4) 1.00 73.3(47.2, 87.9) 1.00 CT+T(N=38) 65.0(47.5, 78.0) 1.12(0.46, 2.75) 72.2(54.3, 84.0) 0.99(0.37, 2.69) CT+T+P(N=36) 50.4 (32.9, 65.7) 1.62(0.67, 3.90) 62.2(42.6, 76.8) 1.30(0.49, 3.48)

Field‐Programmable Topographic‐Morphing Array for General‐Purpose Lab‐on‐a‐Chip Systems (Adv. Mater. 7/2025)

Reversible Nanocomposite by Programming Amorphous Polymer Conformation Under Nanoconfinement

Abstract Nanoconfinements are utilized to program how polymers entangle and disentangle as chain clusters to engineer pseudo bonds with tunable strength, multivalency, and directionality. When amorphous polymers are grafted to nanoparticles that are one magnitude larger in size than individual polymers, programming grafted chain conformations can “synthesize” high‐performance nanocomposites with moduli of ≈25GPa and a circular lifecycle without forming and/or breaking chemical bonds. These nanocomposites dissipate external stresses by disentangling and stretching grafted polymers up to ≈98% of their contour length, analogous to that of folded proteins; use both polymers and nanoparticles for load bearing; and exhibit a non‐linear dependence on composition throughout the microscopic, nanoscopic, and single‐particle levels.

A comparison of real-world outcomes by mismatch repair status in patients with stage II/III rectal cancer in the Netherlands.

260 Background: A subset of rectal tumours (~3–5%) have mismatch repair deficiency (dMMR); the remaining are classified as MMR proficient (pMMR). A recent trial for stage II/III dMMR rectal cancer (RC) showed that 6 months of neoadjuvant treatment with dostarlimab, a programmed cell death protein 1 inhibitor, induced a 100% clinical complete response rate and allowed for organ preservation. Using real-world data from the Netherlands, a dMMR patient cohort was compared to a matched pMMR cohort to assess if clinical outcomes differed, even after matching for baseline characteristics. Methods: Utilizing data from the Netherlands Cancer Registry, this retrospective analysis assessed patients with stage II/III RC treated from 2015–2022 with known MMR status. The dMMR cohort was matched 1:2 to a cohort of pMMR patients on age, year of diagnosis, tumour clinical (cT) stage, and node clinical (cN) stage. Event-free survival (EFS; defined as first occurrence of locoregional failure, distant metastasis, a new primary colorectal tumour, or death from any cause) and overall survival (OS) were compared using Kaplan-Meier methodology and a univariable Cox model. Results: Among the 7939 patients included, 184 (2.3%) had dMMR tumours. After matching and a loss of 8 dMMR patients due to ineligibility, 176 dMMR patients were compared to 363 pMMR patients. Matching successfully removed differences in age, cT, and cN stage; however, dMMR patients continued to have more BRAF mutants (p=0.014), more poorly differentiated tumours (p<0.001) and more variation in histology (p=0.01). dMMR patients had a statistically significant lower risk of experiencing an event (hazard ratio [HR] 0.54 [95% confidence interval (CI) 0.38–0.77], p<0.001), with a 3-year EFS of 79.6% (95% CI 73.7–86.1) compared to pMMR patients (64.7% [95% CI 59.8–70.1]). For OS, there was no significant difference between the dMMR and pMMR cohorts (HR 0.73 [95% CI 0.47–1.16], p=0.181); however, within the small group of patients with an event, OS at 1 year for dMMR patients was 68.4% (95% CI 55.1–84.9) compared to 93.5% (95% CI 89.5–97.7) for pMMR patients (p=0.001). Conclusions: dMMR RC is rare, and tumour characteristics differ from those of patients with pMMR tumours (1). After controlling for clinical stage and age, this study suggests dMMR patients have improved EFS compared to pMMR patients. There is no significant difference in OS between groups but dMMR patients with an event have worse OS than pMMR patients, highlighting an additional need to prevent recurrence of disease within dMMR patients.1. Lunenberg, R et al. Poster presented at ESMO Congress (Presentation 569P), 13-17 Sept 2024, Barcelona, Spain.

SIL-204 siRNA encapsulated in extended release microparticles for the treatment of localized cancer that harbors a KRAS G12x or G13D mutation.

745 Background: In a Phase 2 trial, treatment of non-resectable locally advanced pancreatic cancer (LAPC) patients harboring the KRAS G12D or G12V mutations, with SiG12DLoder combined with chemotherapy resulted in superior median overall survival (OS) of 9.3 months over chemotherapy (not statistically significant) and Objective Response Rate of 55% (35% over the chemotherapy control), when administered once every 3 months (Clinical trial # NCT01676259, ESMO 2023, abstract FPN: 1626). SIL-204 which is a modified version of siRNA siG12D is composed of a 21-base sense and 23-base antisense strands, both chemically modified and linked to a lipid. SIL-204 is encapsulated in biodegradable PLGA microparticles (MP), for direct release and injection into KRAS mutated solid tumors using an endoscopic ultrasound procedure. The strategy of preventing the synthesis of KRAS mutated protein may have an advantage over other approaches targeting KRAS function using small molecules. Methods: Methods are presented in results section. Results: SIL-204 has an increase stability over siG12D.To enhance stability, base modifications and phosphorothiate bonds at cleavage sites were implemented. SIL-204 exhibited a half-life of more than 48 hours in human serum. SIL-204 has robust KRAS silencing . When tested in Hepa1-6 cells transfected with individual human KRAS mutations, SIL-204 effectively silenced the various G12x mutations found in pancreatic cancer (D,V,R,C) at sub-nanomolar concentration (IC50 range=0.19-0.59) as well as G13D (IC50 =0.37). Addition of a hydrophobic tail to a prototype of SIL-204, SIL-101, increased the silencing of KRAS. Using PANC-1 cells (KRAS G12D mutation), lipid conjugation of the siRNA doubled the siRNA’s silencing efficiency in these cells. In addition, release of SIL-204 from the MP was tested in rats and indicates a prolong and sustained release over our intended treatment regimen SIL-204-MP was administered to tumors from human pancreatic tumor cell lines Capan-1 (KRAS G12V mutation and labelled with luciferase) grown in NSG mice and Panc-1 (grown in Athymic Nude mice). Bioluminescence imaging of tumor growth showed that SIL-204-MP significantly reduced Capan-1 tumor growth compared to vehicle controls, p<0.0005. Furthermore, histopathological analyses of tumor center slices from Capan-1 and Panc-1 models showed induction of significant tumor necrosis with SIL-204 compared to vehicle controls. Conclusions: The preclinical results of SIL-204-MP are promising and as the potential to further enhance the anti-tumor effect demonstrated by siG12DLoder in pancreatic patients. SIL-204 is now in toxicology studies as preparation for clinical trials in non-resectable pancreatic cancer.

Frailty assessed by a 10-item index from comprehensive geriatric assessment (FI-CGA-10) versus oncologist-assessed performance status (PS) in older adults with gastrointestinal (GI) cancer.

821 Background: A FI-CGA-10 is a recently developed measure of frailty in the geriatric oncology setting [Oncologist, 26, e1751 (2021)]. Our objective was to compare the multidimensional frailty assessment by FI-CGA-10 with PS assessed by a primary oncologist in older adults with cancer. Methods: This study included 790 older adults with GI cancer who underwent a CGA before cancer treatment decisions at a geriatric oncology service between September 2018 and May 2024, and whose PS was documented in the electronic medical record by a primary oncologist. Fitness and frailty level were evaluated using the FI-CGA-10, which assesses 10 domains: cognition, mood, communication, mobility, balance, nutrition, basic and instrumental activities of daily living, social support, and comorbidity. Deficits in each domain were scored as 0 (no problem), 0.5 (minor problem), and 1.0 (major problem). FI-CGA-10 scores (range 0-1) were calculated by dividing the sum of the scores for each domain by 10 and then categorized as fit (<0.2), pre-frail (0.2–0.35), and frail (>0.35). The strength of the ordinal association between the frailty category and each CGA domain score was assessed using Spearman’s non-parametric correlation coefficient (rho). Results: The median age was 79 years; 60% were male, 62% had GI tract cancer (esophageal, gastric, colorectal), 20% had hepatobiliary cancer, 15% had pancreatic cancer, and 46% had stage 4 disease. Overall (n=790), 25% of patients were fit, 40% were pre-frail, and 35% were frail (Table). Among patients with PS 0-1 (n=633), 30% were classified as fit, 48% as pre-frail, and 22% as frail. Among PS 0-1 patients, Spearman's rho was greater than 0.5 for the association between the frailty category (fit, pre-frail and frail) and cognition, IADL, and mobility domains. In this subcohort (PS 0-1), the proportion of patients with a cognition domain score of 0.5 (mild cognitive impairment) or 1.0 (dementia) was 7%, 30%, and 78% in the fit, pre-frail, and frail groups, respectively; the proportion of those with an IADL domain score of 0.5 (OARS IADL = 12-13) or 1.0 (OARS IADL ≤ 11) was 5%, 46%, and 92%, respectively; the proportion of those with a mobility domain score of 0.5 (0.8 m/s ≤ gait speed < 1.0 m/s) or 1.0 (gait speed < 0.8 m/s) was 45%, 85%, and 98%, respectively. Conclusions: In this study, 70% of older adults with GI cancer whose PS was scored as 0-1 by a primary oncologist were classified as pre-frail or frail when assessed using FI-CGA-10. Among patients with PS 0-1, there were strong correlations between the frailty levels and impairment levels in the cognition, IADL, and mobility domains, indicating that these domains are major contributors to the frailty classification (fit, pre-frail, and frail). All patients (n=790) Fit Pre-frail Frail PS 0 (n=351), n (%) 145 (41) 163 (46) 43 (12) PS 1 (n=282), n (%) 45 (16) 141 (50) 96 (34) PS 2-3 (n=157), n (%) 4 (3) 18 (11) 135 (86)

Performance‐Oriented and Deformation‐Constrained Dual‐topology Metamaterial with High‐Stress Uniformity and Extraordinary Plastic Property (Adv. Mater. 7/2025)

Riveting Nucleation Enabled Long Cycling Life Calcium Metal Anodes

AbstractCalcium metal batteries with high capacity and low cost are promising alternatives to Li‐ion batteries for large‐scale energy storage. However, its development is crucially impeded by the irreversible Ca metal anode, which is highly associated with uncontrollable Ca plating/stripping. Here, we report a new riveting strategy to regulate the nucleation and growth of a Ca metal anode in the 3D structure of a carbon nanotube film (CNF) by introducing in situ‐formed Na metal mediators. Na metal mediators are found to first deposit in the CNF substrate prior to Ca nucleation and subsequently induce dense and uniform Ca plating due to their thermodynamically favorable kinetics. Therefore, even at a high current density of 10 mA cm−2 and a high capacity of 5 mAh cm−2, it realizes the uniform nucleation and growth of dendrite‐free Ca metal. Moreover, an unprecedented cycling life of over 800 cycles is also achieved for Ca metal batteries with a high coulombic efficiency above 98.4%. This work demonstrates the significance of a riveting strategy to enable the superior performance of Ca metal batteries by regulating the plating/stripping behaviors of Ca metal anodes and paves a new way for the development of Ca metal batteries.

Phase II study of FOLFIRI with low-dose irinotecan plus ramucirumab as second-line treatment in Japanese patients with metastatic colorectal cancer (RINDO study).

124 Background: Phase III trials (ML18147, VELOUR, and RAISE trials) of second-line combination therapy with molecular-targeted agents after first-line treatment with bevacizumab (BEV) for metastatic colorectal cancer (mCRC) demonstrated significant improvements in overall survival (OS). In the RAISE trial (irinotecan (IRI) dose: 180 mg/m²), the relative dose intensity (RDI) of IRI was lower (63.8%) and the incidence rates of adverse events leading to discontinuation of cytotoxic agents was higher (48.6%) in the Japanese population compared to all patients. Based on these results, we conducted a prospective trial to evaluate the efficacy and safety of fluorouracil, levofolinate, and IRI (150 mg/m², standard dose in Japan) (FOLFIRI) plus ramucirumab (RAM) as second-line treatment for mCRC in Japanese patients. Methods: On day 1 of each 2-week cycle, patients with unresectable mCRC who were refractory to oxaliplatin and fluoropyrimidine in combination with BEV or anti-epidermal growth factor receptor (EGFR) antibodies as first-line treatment received 8 mg/kg RAM, followed by the FOLFIRI regimen with low-dose IRI (150 mg/m²). The primary endpoint was progression-free survival (PFS), and secondary endpoints were OS, treatment compliance, and safety. We hypothesized an RFS threshold of 4.3 months and expected RFS of 5.7 months based on data from a Japanese subgroup of the RAISE trial. The protocol treatment was considered to be effective if the lower limit of the 95% confidence interval (CI) exceeded the 4.3-month threshold. Results: A total of 62 patients were enrolled from 15 institutions between January 2018 and August 2021. The intent-to-treat and safety populations included 61 and 58 patients, respectively. The cutoff date for the primary analysis was December 2023. Median PFS and OS were 5.9 months (95% CI, 4.8-6.9 months) and 17.0 months (95%CI, 12.0-21.0 months), respectively. Median PFS was 5.7 months (95% CI, 4.4-6.8 months) in patients treated with first-line chemotherapy with BEV and 7.4 months (95% CI, 4.6-11.0 months) in those treated with first-line chemotherapy with anti-EGFR antibodies (hazard ratio [HR], 1.17; 95% CI, 0.64-2.12; p = 0.60), and median OS was 19.8 months (95% CI, 10.4-22.4 months) and 17.5 months (95% CI, 11.5-26.1 months), respectively (HR, 0.96; 95% CI, 0.52-1.78; p = 0.91). The objective response rate and disease control rate were 8.2% and 74%, respectively. Median RDI of IRI, 5-fluorouracil, and RAM were 73.8% (range, 40.3-102.4%), 58.5% (range, 22.8-102.4%), and 80.8% (range, 36.1-102.4%), respectively. The observed Grade ≥3 adverse events included neutropenia (40%), anemia (1.7%), diarrhea (8.6%), fatigue (6.9%), decreased appetite (10%), hypertension (6.9%), and proteinuria (3.4%). Conclusions: FOLFIRI with low-dose IRI plus RAM is a feasible second-line treatment in Japanese patients with mCRC. Clinical trial information: jRCTs041180074 .

Zanzalintinib (XL092) alone or in combination with atezolizumab in patients (pts) with refractory metastatic colorectal cancer (mCRC): Results from an expansion cohort of the phase 1 STELLAR-001 study.

127 Background: VEGFR tyrosine kinase inhibitors (TKIs) in combination with immune checkpoint inhibitors (ICIs) have demonstrated clinical activity in pts with previously treated mCRC, particularly in pts without liver metastases (LM). Zanzalintinib (zanza) is a novel, oral, multitargeted TKI with activity against VEGFR, MET, and TAM kinases. Here, we present results from the randomized expansion cohort of pts with previously treated non-MSI-H/dMMR mCRC receiving zanza ± atezolizumab (atezo) in the phase 1 STELLAR-001 study (NCT03845166). Methods: Adults (aged ≥18 y) with locally advanced or metastatic CRC that was RAS -wildtype, who were refractory/intolerant to prior standard of care (5-FU–based treatment ± targeted therapies) and had an ECOG PS of 0/1, were enrolled. Pts with MSI-high or dMMR CRC, or who had received prior treatment with a PD-L1/PD-1 targeting ICI, regorafenib, and/or TAS-102, were excluded. Pts were randomized 1:1 to receive zanza+atezo (100 mg QD + 1200 mg Q3W) or single-agent zanza (100 mg QD). Objectives were to evaluate median (m)OS, investigator-assessed ORR, and mPFS per RECIST 1.1, and safety. Results: As of May 6, 2024, 107 pts were enrolled (zanza+atezo, n=54; zanza, n=53). In the zanza+atezo/zanza groups, median age was 61/60 years, 39%/51% had an ECOG PS of 1, pts had a median 2.5/3.0 (range, 1–5) prior lines of therapy, and 31%/32% did not have LM. With a median follow-up of 15 months across both arms, the mOS was 14.3 and 11.1 months for zanza+atezo and zanza, respectively (HR 0.75, 95% CI 0.45–1.26), confirmed ORR was 7.4% and 1.9% (all partial responses), mPFS was 4.0 and 3.0 months (HR 0.68, 0.44–1.04), and DCR was 59% and 55%. In pts without LM, mOS was not reached and 12.5 months (HR 0.46, 0.15–1.36) with 6-month survival rates of 88% and 65%, confirmed ORR was 18.0% and 5.9%, mPFS was 8.2 and 3.3 months (HR 0.40, 0.16–1.0), and DCR was 76% and 59%. The most common treatment-related adverse events (TRAEs) were diarrhea (zanza+atezo, 52%; zanza, 49%), nausea (54%, 36%), and decreased appetite (41%, 36%). Grade 3/4 TRAEs occurred in 48% of pts with zanza+atezo and 40% with zanza (Grade 4 in 3.7% and 0); a Grade 5 TRAE occurred in 1 pt (2%) in each group. 89% and 94% of pts had discontinued study treatment. Zanza was discontinued due to TRAEs in 11% and 8% of pts; atezo was discontinued due to TRAEs in 9% (zanza+atezo). Biomarker analysis is ongoing and results will be presented. Conclusions: Clinical activity was observed with zanza both as a single agent and in combination with atezo in this cohort of heavily pretreated pts with mCRC. Greater activity was seen with zanza+atezo versus zanza alone, particularly in pts without LM. Both treatments were generally well tolerated. Evaluation of zanza+atezo versus regorafenib is ongoing in the phase 3 STELLAR-303 study in non-MSI-H/dMMR mCRC (NCT05425940). Clinical trial information: NCT03845166 .