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A randomized phase II dose optimization study for alveltamig (ZG006), a trispecific T-cell engager targeting DLL3/DLL3/CD3, as monotherapy in patients with refractory neuroendocrine carcinoma (ZG006-003).
4004 Background: Alveltamig (ZG006) is an innovative trispecific T cell engager (Tri-TCE) targeting two distinct DLL3 epitopes on tumor cells and CD3 on T cells (DLL3/DLL3/CD3), designed to bridge tumor cells and T cells, thereby mediating T cell specific killing of tumor cells. Here we conducted a dose optimization study in refractory NEC. Methods: This is a randomized, multicenter, open-label phase 2 study evaluating ZG006 in NEC patients (pts) who failed at least one prior line of therapy. Pts were randomized 1:1 to receive ZG006 at either 10 mg or 30 mg every two weeks, following a priming dose of 1 mg. The primary endpoint is objective response rate (ORR) assessed by IRC per RECIST1.1. Results are reported for 64 pts who received at least one dose of ZG006. Biomarker based efficacy analyses were performed based on a threshold of ≥50% of tumor cells stained at any intensity for DLL3 with an investigational antibody against DLL3 (SP347, Roche Diagnostics). Results: As of Sep. 10, 2025, a total of 64 pts (32 at each dose group) were randomized and received at least one dose of ZG006. The median age was 56 years (range: 25-72), 35 (54.7%) were male. All pts had received ≥1 prior line of systemic therapy, with 65.6% had prior anti-PD-(L)1 treatment. The confirmed ORR in 10 mg and 30 mg groups were 21.9% (7/32) and 37.5% (12/32), respectively; Disease control rate (DCR) were 40.6% (13/32) and 62.5% (20/32), respectively. Among the 19 responders, primary tumor sites included cervix (8), gallbladder (4), stomach (3), rectum (3) and colon (1). Pts with ≥50% DLL3 staining in tumor cells had greater ORR, DCR, and progression-free survival (PFS). The confirmed ORR in 10 mg and 30 mg groups were 33.3% (6/18) and 56.3% (9/16), respectively; DCR were 50.0% (9/18) and 75.0% (12/16), respectively; With a median follow up of 6.4 months, median PFS were 3.02 and 8.41 months, respectively. Median DoR was not yet mature in both groups at data cut-off. Treatment-related adverse events (TRAEs) occurred in all pts. The most frequent events were pyrexia, cytokine release syndrome (CRS) and anaemia. Most CRS were Grade 1-2, with only four grade 3 CRS, resolved with supportive care. TRAEs led to treatment interruption in 15 pts (23.4%) and permanent discontinuation in 2 pts (3.1%, one in each dose group). No grade 5 TRAE. No significant difference was observed in the safety profile between these two dose groups. Conclusions: ZG006 demonstrated a robust and durable response and a manageable safety profile in previously treated NEC pts, with superior efficacy observed at the 30 mg dose. The confirmed ORR of 56.3% and median PFS of 8.41 months in pts with ≥50% DLL3 positive tumor cells are particularly encouraging, and support further development of ZG006 for this patient population at the 30 mg dose. Clinical trial information: NCT06440057 .
Surgical management of locally advanced pancreatic cancer with arterial resections and reconstructions in elderly patients: Short- and long-term comparative outcomes.
e16425 Background: Pancreatic cancer predominantly affects older adults, with peak incidence in the seventh and eighth decades of life. Locally advanced pancreatic cancer (LAPC) frequently presents with arterial involvement, historically limiting resectability. Advanced age further complicates treatment decisions, as concerns regarding operative risk, tolerance of complex vascular reconstruction, and perioperative morbidity have contributed to reluctance to pursue curative-intent resection in elderly patients. Consequently, older patients with arterial involvement are often excluded from surgical consideration despite potential oncologic benefit. We evaluated short- and long-term outcomes of pancreatectomy with arterial resection and reconstruction in elderly versus younger patients. Methods: We retrospectively analyzed 53 patients undergoing pancreatectomy for LAPC requiring arterial resection between December 2002 and September 2025 across two institutional series. Outcomes included margin status, length of stay (LOS), 90-day mortality, disease-free survival (DFS), overall survival (OS), OS from diagnosis, and Kaplan–Meier survival estimates stratified by age (≥70 vs < 70 years). Results: Among 53 patients, 20 were aged ≥70 years and 33 were < 70 years. Median age was 78 years (range 71–87) in elderly patients and 59 years (range 43–69) in younger patients. Median LOS was longer in elderly patients (12 days, range 4–53) compared with younger patients (8 days, range 5–24). Rates of margin-negative resection were comparable (R0: 85% in ≥70 vs 88% in < 70). Ninety-day mortality was higher in elderly patients (25.0% vs 6.1%). Median postoperative OS was 8.5 months (range 1–135) in elderly patients and 11 months (range 2–141) in younger patients; median DFS was 5 months (range 0–40) and 8 months (range 0–141), respectively. Median OS from diagnosis was 11 months (range 1–138) in the ≥70 cohort and 18 months (range 8–143) in the < 70 cohort. Two-year OS rates were similar (25.0% vs 27.3%), while 5-year OS was 5% in elderly patients and 12% in younger patients. Kaplan–Meier curves overlapped beyond the early postoperative period. Conclusions: In selected patients with LAPC, pancreatectomy with arterial resection and reconstruction can achieve meaningful long-term survival in elderly patients despite higher early postoperative risk. Advanced age alone should not preclude consideration of curative-intent resection within experienced multidisciplinary programs.
Ripretinib as preoperative therapy in patients with potentially resectable advanced gastrointestinal stromal tumors after imatinib failure: Final analysis of a prospective, multicenter study.
11537 Background: Cytoreductive surgery may improve outcomes in patients with locally advanced or metastatic gastrointestinal stromal tumors (GIST) after progression on imatinib. Ripretinib has shown a high objective response rate (ORR) and a favorable safety profile in advanced GIST, suggesting its potential for tumor downstaging and enabling surgical intervention. This study evaluated the efficacy and safety of ripretinib as preoperative therapy in patients with imatinib-resistant, potentially resectable advanced GIST. Methods: This single-arm, multicenter, exploratory study (NCT05132738) enrolled patients with imatinib-resistant, locally advanced or recurrent metastatic GIST who met the following criteria: 1) ≤5 evaluable lesions on CT/MRI; 2) resection deemed high-risk by multidisciplinary team (MDT) assessment (meeting one of the following): a) The maximum diameter of a single lesion is ≥10 cm; b) Organ function damage surgery is required; c) Multiple organ resection surgery is required. Patients received ripretinib 150 mg once daily (QD) up to 6 months before surgery. The primary endpoint was the no evidence of disease rate (NED Rate). Secondary endpoints included the R0/R1 resection rate, surgery rate, and ORR. Results: As of January 2026, 20 patients were enrolled, with a median age of 58 years (range: 31-74). The most common primary tumor site was the small intestine (70%). The median sum of target lesion diameters was 10.8 cm (range: 3.2-33.7). The median duration of preoperative ripretinib was 5 months (range: 2-6). The median best percentage change in the sum of target lesion diameters was -20.5% (range: -47.2% to +56.0%). 8 patients (40.0%) achieved a partial response (PR) and 10 patients (50.0%) had stable disease (SD). Median time to response was 2.0 months (range: 2.0-6.0). 70% (14/20) of patients underwent surgery and the NED rate was 92.9% (13/14). Of the 13 patients who achieved R0 resection, 8 (61.5%) have maintained NED to date. Only 1 patient experienced intestinal fistula as a surgical complication, which was unrelated to ripretinib treatment. After surgery, 6 patients continued ripretinib therapy, while 3 switched to imatinib therapy and 5 switched to sunitinib therapy. With a median follow-up of 20.4 months (range: 8.1–47.6), the median overall survival (OS) was immature. Conclusions: These findings demonstrate that preoperative ripretinib effectively reduced tumor burden in patients with imatinib-resistant, potentially resectable advanced GIST, and facilitated successful surgery intervention. Notably, the approach achieved a high NED rate and a low surgical complication rate, supporting ripretinib as a safe and effective preoperative treatment option. Clinical trial information: NCT05132738 .
The SURVIVE study: Re-evaluating follow-up in early breast cancer.
TPS658 Background: For decades, international guidelines unanimously recommended limiting routine follow-up in early breast cancer (EBC) to clinical exams and breast imaging, to detect potentially curable local relapse early. Additionally, guidelines explicitly advise against screening for distant recurrence in asymptomatic patients, as there remains no survival benefit in patients with earlier detected metastatic disease to date, at the cost of quality of life (1). However, as most of this data was published over 30 years ago, a re-evaluation of EBC follow-up strategies is urgently needed, considering numerous novel treatment options for both EBC and metastatic breast cancer patients. Methods: Study Design: The SURVIVE study is a prospective, multicenter, randomized controlled trial investigating a liquid-biopsy based follow-up in intermediate- to high-risk EBC patients. 3.500 EBC patients after completion of primary therapy (surgery, chemo- or radiotherapy) are randomized 1:1 to either standard or liquid-biopsy guided (intensified) follow-up. All patients receive guideline-based follow-up procedures. Additionally, blood samples are taken every 3 months (years 1–3), later every 6 months (years 4–5). While samples from patients in the standard-arm are biobanked, samples from the interventional arm are analyzed longitudinally for tumor markers (CA 27.29, CEA, CA 125, Tosoh Bioscience), CTCs (CellSearch, Menarini), and ctDNA (RaDaR, Neogenomics). The detection of abnormalities via liquid biopsy leads to staging examinations. For patients with confirmed recurrence, treatment hereafter follows national guidelines. The detection of true molecular relapse (positive liquid biopsy without clinical evidence of recurrence) leads to further monitoring within the SURVIVE protocol and creates the unique opportunity for treatment-intervention studies, such as SURVIVE HERoes (NCT06643585). Endpoints: The two co-primary endpoints are overall survival (OS) and the lead time, measured as the time from positive biomarker to positive imaging in the interventional arm. Secondary endpoints include breast cancer-specific survival, quality of life, and biomarker performance. Recruitment: As of January 2026, recruitment is active in 98 study centers in Germany. Currently, nearly 2,400 patients have been randomized since December 2022. Conclusion: The SURVIVE study is a long-anticipated study assessing whether intensified follow-up, guided by liquid biopsy, leads to earlier detection of recurrence and improved overall survival in EBC. NCT05658172. Funding: German Federal Ministry of Education and Research (BMBF), NeoGenomics, Menarini Silicon Biosystems, Tosoh Bioscience. Bibliography: Moschetti I, Cinquini M, Lambertini M, Levaggi A, Liberati A. Follow-up strategies for women treated for early breast cancer. Cochrane Database Syst Rev. 2016;CD001768. Clinical trial information: NCT05658172 .
Characterizing the prevalence of antibody-drug conjugated–induced nausea and vomiting (ADCINV) in patients with cancer.
e24052 Background: Antibody-drug conjugates (ADC) have emerged as an important part of systemic treatment across disease sites. To date, there is no robust pooled prevalence estimate of nausea and vomiting induced by ADCs. Establishing such estimates is essential to determine if ADC-induced nausea and vomiting (ADCINV) represents a clinically significant problem warranting further research into antiemetic prophylaxis, where there is no current standard approach to date. Our aim is to characterize the prevalence and variation of ADCINV in the literature. Methods: A systematic review of Medline, Embase, Cochrane CENTRAL and Web of Science was conducted from database inception until September 24, 2025. Both clinical trials and real-world studies reporting nausea and/or vomiting in patients receiving ADCs for cancer were included. Pooled prevalence of nausea/vomiting, and severe nausea/vomiting (CTCAE grade 3+) were calculated using a random effects model weighted by study size. Subgroup analysis was conducted by ADC. Meta-regression was conducted by age and sex. Quality assessment was conducted. Type I error was set at 0.05. Results: Among 4,669 screened records, 209 studies comprising 15,493 patients were included. Mean study size was 74 patients; 53% were female. Most studies were non-randomized interventional trials (84%); only 5% were randomized trials, and 11% were real-world cohort studies. 39% of patients experienced nausea (95%CI 36–42%) and 26% experienced vomiting (95%CI 23–29%). Severe nausea occurred in 1% (95%CI 0–1%) and severe vomiting in 1% (95%CI 0–2%). Antiemetic prophylaxis was not routinely used across studies and there was significant heterogeneity in antiemetic regimens when used. Higher nausea rates were observed with patritumab deruxtecan (59%), trastuzumab deruxtecan (55%), sacituzumab govitecan (51%), and brentuximab vedotin (47%), while lower rates were seen with disitamab vedotin (28%), telisotuzumab vedotin (22%), rovalpituzumab tesirine (19%), and belantamab mafodotin (6%). Meta-regression demonstrated that increasing age was independently associated with lower nausea risk, with a 12% relative decrease per 10-year age increase (10-year OR=0.89 (95%CI 0.83-0.95, p<0.001)), but no difference in vomiting risk. Female sex showed a non-significant trend toward higher nausea risk (OR=1.00 (0.99-1.01, p=0.072)) but no differences in vomiting risk. Conclusions: ADCINV is prevalent adverse effect, affecting every one in three patients with no standard prophylactic regimen to date. Severe nausea and vomiting rates remain relatively low. Younger patients, females and specific ADCs may be at higher risk. ADCINV should be recognized as a clinically relevant adverse effect, supporting the need for ADC-specific emetogenic classification and prospective evaluation of antiemetic prophylaxis strategies.
[ <sup>18</sup> F] F-NYM124 for safety, imaging, and dosimetry in patients with indeterminate renal masses.
e16513 Background: With limitations of conventional imaging and biopsy, accurate, non-invasive techniques to detect in patients with primary and metastatic clear cell renal cell carcinoma (ccRCC) remain an unmet need. Carbonic anhydrase IX (CAIX) is a tumour antigen highly expressed in ccRCC. NYM124 is a new-generation CAIX targeting small molecule that can be labeled with 1 8 F. Here, [ 18 F] F-NYM124 imaging characteristics, dosimetry, and safety were assessed in 2 patients with ccRCC. Methods: Patients with indeterminate renal masses underwent whole-body PET/CT at 1 h, 3 h, and 5 h after [ 18 F] F-NYM124 administration, and patients also had 18 F-FDG PET/CT. Determination of tumor lesions was based on SUV max and SUV mean . Regions of interest were drawn on PET/CT images over critical organs and tumor lesions to generate time–activity curves, calculate tumor-to-background ratios per time point, and assess radioactivity residence times. Dosimetry assessments were based on time–activity curves and time-integrated activity coefficients to determine effective dose and absorbed dose per organ. Safety and tolerability were assessed up to 7 d after [ 18 F] F-NYM124 administration. Results: The administered [ 18 F] F-NYM124 activities were 9.4 mCi and 8.4 mCi. Tumor uptake was observed at all time points (1-5 h). One hour was chosen as the optimal time point. Across 4 lesions, the SUV max at 1 h after administration ranged from 25.3 to 211.5 (Mean±SD, 90.5±83.2), which was significantly higher than that of 18 F-FDG (2.8±1.4). The tumor-to-background-pool ratio was also higher (8.7±4.3 vs. 1.4±0.2). Intensive uptake was noted in the stomach, kidney, and pancreas, with SUV max of 44.2, 21.9 and 14.6, respectively. Substantial uptake was also noted in the intestine, whereas the brain did not show significant tracer accumulation, and mild uptake was observed in the choroid plexus. The investigators also found mild symmetrical uptake in the epididymis, which is consistent with physiological CAIX expression in this organ. OLINDA dosimetry estimates were calculated for 14 organs. Those with the highest mean absorbed doses included the kidney (0.104 mGy/MBq), pancreas (0.083 mGy/MBq) and stomach wall (0.062 mGy/MBq) with a mean whole-body effective dose of 0.018 mSv/MBq. Absorbed doses in the brain, thyroid and red marrow were low. The total-body residence times of radioactivity measured in the two patients after 18 F-NYM124 administration were 2.1 h and 2.4 h, demonstrating rapid systemic clearance of the tracer. No clinically significant toxicity was observed. Conclusions: Taken together with its reassuring dosimetry profile, [ 18 F] F-NYM124 showed exceptional tumor uptake in patients with clear cell renal cell carcinoma, with high tumor-to-background ratios and no significant adverse events, suggesting potential diagnostic and patient selection applications.
Cumulative toxicity assessed by area-under-the-curve (AUC) in targeted therapy versus chemotherapy for advanced <i>EGFR</i> -mutant NSCLC.
12141 Background: Current adverse event (AE) reporting standards emphasize peak toxicity, which may inadequately capture the cumulative burden of persistent low-grade AEs characteristic of targeted therapies. We conducted a post-hoc analysis of the LUX-Lung 3 trial to compare longitudinal toxicity patterns of targeted therapy and chemotherapy over time. Methods: This post-hoc analysis used individual, de-identified patient-level data from the phase III LUX-Lung3 clinical trial comparing afatinib with platinum-based chemotherapy as first-line treatment for advanced EGFR-mutant NSCLC, accessed through Vivli. Select treatment-related AEs were evaluated longitudinally by grade. Cumulative toxicity burden was quantified using the area-under-the-curve (AUC) of AE grade prevalence over time. Pearson correlation was used to assess temporal trends in AUC. Results: A total of 340 patients had evaluable AE data, including 229 (67%) treated with afatinib and 111 (33%) treated with chemotherapy. The median onset of grade 1-2 AEs generally occurred earlier with chemotherapy than afatinib. The median onset of chemotherapy-related fatigue was 4 days and nausea 2 days, whereas median onset of afatinib-related diarrhea was 4 days, rash 8 days, and paronychia 37 days. Longitudinal AUC analysis (Table 1) demonstrated a significant improvement in grade 1-2 chemotherapy-related nausea (p=0.003) and stomatitis (p=0.05), and a trend towards improvement in fatigue (p=0.2) by 12-months. In contrast, grade 1-2 afatinib-related rash (p=0.4) and diarrhea (p=0.99), remained stable, while paronychia increased over time (p=0.004). For grade 3+ AEs, the AUC improved over time for both the chemotherapy (p=0.04) and afatinib (p=0.02) groups. Conclusions: Assessment of time to onset and longitudinal AUC reveal distinct temporal AE patterns for targeted therapy and chemotherapy. Longitudinal toxicity reporting is feasible and highlights the sustained burden of chronic AEs associated with targeted therapies that are clinically meaningful yet underrepresented by conventional peak toxicity reporting. Cumulative toxicity of afatinib and chemotherapy was quantified using the area under the curve of grade 1-2 adverse events prevalence at landmark time points.* Adverse event Month 1 Month 3 Month 6 Month 12 Pearson’s coefficient p-value Afatinib (%) Rash 0.24 0.39 0.44 0.45 0.24 0.4 Diarrhea 0.30 0.44 0.47 0.45 -0.002 0.99 Paronychia 0.02 0.20 0.32 0.39 0.74 0.004 Chemotherapy (%) Fatigue 0.05 0.09 0.09 0.07 -0.36 0.2 Nausea 0.07 0.17 0.17 0.10 -0.60 0.03 Stomatitis 0.02 0.02 0.02 0.01 -0.56 0.05 *Trends were assessed using Pearson’s correlation coefficient and corresponding p-value.
Implementation of a telephone genetic screening program in breast cancer survivorship in the Bronx: A health care delivery quality improvement project.
e22632 Background: Hereditary screening and testing can identify individuals with a personal or family history harboring genetic variants that increase cancer risk, empowering personalized prevention and targeted treatment. While current national guidelines have increased accessibility of genetic screening, past guidelines limited opportunity at time of diagnosis. This study established a genetic testing initiative as part of a breast cancer (BC) survivorship program to evaluate interest, attitudes, and the current landscape of genetic testing among BC survivors. Methods: This study involved retrospective chart review and telephone survey. Charts of patients (pts) at the Montefiore Einstein Comprehensive Cancer Center BC survivorship program in 2023 were reviewed to determine uptake of genetic testing. All pts were at least 5 years from diagnosis. Pts without prior testing were then contacted for telephone survey. Pts expressing interest were referred for genetic counseling and testing. Results: Of 551 pts seen, 239 (41.4%) were previously referred for genetic counseling, 202 (84.5%) completed genetic testing, and 15 (7.43%) were found to have a pathogenic/likely pathogenic (P/LP) variant [ BRCA1 (5), BRCA2 (3), RAD51C (1), MRE11A (1), SMARC4 (1), ATM (2), MUTYH (2)]. Of 312 pts with no prior genetic testing, 268 were outreached by telephone for survey. 140 were reached (55.2%), and 96 (68.6%) agreed to survey. 71 (74.0%) of those surveyed expressed interest in and were referred for genetic testing. In unsolicited remarks, 6 pts cited interest based on personal or familial risk management. Reasons for declining included distrust of phone calls (10), no interest (9), burden of prior cancer diagnosis/testing (4), other medical concerns (4). 33 patients have completed testing to date: 4 patients with P/LP variants (12.1%): MUTYH (1), TP53 (1), RAD51C (1), ATM (1); 9 patients with variants of uncertain significance (VUS) (27.3%), 20 patients (60.6%) tested negative. 11 patients are awaiting genetic counseling, 2 patients are awaiting blood draw for genetic testing, and 25 patients either declined counseling/testing or missed appointment. Conclusions: Continued genetic screening after BC diagnosis and treatment improves management of survivors and families, and the majority of survivors expressed interest in genetic testing. Identifying four P/LP variants among these survivors, including in a high penetrance gene, is informative and potentially life-saving. We found a numerically higher percentage of survivors with P/LP variants compared with those tested closer to BC diagnosis. Some pts declined to participate citing distrust of phone calls, preferring clinician screening at follow-up visits. This initiative will inform breast cancer care delivery, and can also be expanded to other malignancies, such as prostate and endometrial cancer.
Real-world outcomes of lifileucel in advanced melanoma: A single-institution experience.
9552 Background: Lifileucel (Amtagvi), an autologous tumor-infiltrating lymphocyte (TIL) therapy, was FDA approval for unresectable or metastatic melanoma after progression on systemic therapy based on clinical trial data. However, real-world data describing early outcomes with lifileucel remain limited. Methods: We retrospectively reviewed a prospectively maintained database of patients with unresectable/metastatic melanoma who progressed on immune checkpoint inhibitors (and BRAF ± MEK therapy if applicable) and received lifileucel per standard protocol at a single institution April 2024–January 2026. Eligible patients received an in-specification TIL product and had evaluable imaging ≥12 weeks post-infusion unless progression was detected sooner. Responses were assessed per RECIST v1.1. Endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and grade ≥3 treatment-related adverse events (TRAEs), excluding lymphodepletion-related cytopenias. Time-to-event endpoints were estimated using Kaplan–Meier methods. Results: Of 38 patients who underwent surgical TIL harvest, 32 (84%) received lifileucel, including 5 via the Expanded Access Program due to out-of-specification product. Among 27 patients receiving in-specification lifileucel, 20 had evaluable imaging and were included in the analysis. Patients received a mean of 2.2 prior therapies, and 35% had acral lentiginous or mucosal melanoma. All patients had Stage IV disease, including liver (40%) and brain (30%) metastases. 55% received bridging therapy after surgery prior to infusion. Median follow-up was 5.7 months (range, 0.9–16.9). ORR was 30% (3 CR, 3 PR), and DCR was 45%. Among responders, 67% (4/6) have ongoing response and median DoR was not reached. Median PFS was 3.5 months (95% CI, 2.1–5.3) and median OS was 6.1 months, with 6- and 12-month OS rates of 51% and 44%, respectively. Non-cytopenic grade ≥3 TRAEs occurred in 55%. Conclusions: In this early real-world experience, lifileucel demonstrated encouraging antitumor activity with ongoing responses in heavily pretreated patients despite high-risk features such as elevated LDH and liver and brain metastases. Additional studies and longer follow-up are warranted to optimize patient selection and define durability of benefit and survival outcomes. Baseline patient characteristics and safety outcomes. Characteristic/Outcome Overall (N=20) Age, median (range), y 62 (38-80) Male sex, n (%) 12 (60) Acral lentiginous/mucosal subtype, n (%) 7 (35) BRAF V600E mutation, n (%) 4 (20) LDH level > ULN, No. (%) 5 (25) Liver Metastases, No (%) 8 (40) Brain Metastases, No (%) 6 (30) Prior systemic therapies, mean (range) 2.2 (1-5) Patients with grade ≥3 non-hematologic TRAEs, n (%) 11 (55)
Developing an integrated survivorship checklist for LMIC: Feasibility and results from a tertiary care center.
e24135 Background: Survivorship clinics are vital for identifying health and quality-of-life issues among cancer survivors (CS). However, these clinics are a novelty in LMIC, with little structural anatomy and a sketchy referral system. We developed a comprehensive survivorship checklist to identify major survivorship issues and ensure streamlined multidisciplinary referrals in a single visit. Methods: Our survivorship clinic was established in September 2025. A structured checklist covering demographic details, physical and psychosocial issues, financial toxicity and unmet needs in CS was created, using validated scoring scales in alignment with the NCCN survivorship guidelines across 26 domains. Data was collected by a trained psychological counsellor, and all patients were referred based on their prioritising needs. Results: 85 CS were evaluated.68.2% were males, and 66.2% were post-treatment completion. Among those on active treatment, 35.29% received multimodality treatment. Head and neck cancers (35.2%) and breast cancer (11.8%) were the most common diagnoses. Mean time since diagnosis was 25.89 months.33.2% patients admitted having a history of substance abuse (tobacco 24.5%). The mean scores were NCCN distress scale (3.76), GAD 7 (4.16) and PHQ 9(5.38). Fertility concerns were noted in 12.9%, and sexual health issues in 29.6%. The average fatigue score was 3.55; the mean sleep duration was 6.18 hours, with 22.55 % reporting poor sleep quality.75.3% patients were engaged in some form of physical activity ( 45.3% exercising daily). Peripheral neuropathy (37.64%) and generalised weakness (34.11%) were the most common physical symptoms reported.27.11% of breast cancer patients had lymphoedema. Mean WHO-5 well-being index scoring was 67.27%. All patients were referred to the primary treating physicians with the physical/psychosocial issues highlighted. Referrals include psychology (69.4%), physical rehabilitation (26.6%), endocrinology (21.7%), psychiatry/De-addiction (18.8%), sleep clinic (14%), assisted reproduction (11.8%) and pain services (9.4%). All patients reported mild to moderate financial toxicity using the COST FACIT scale, mainly due to accommodation (78.8%) and travel (69.4%). Impact of cancer on life perspective was the most common unmet need(31.7%). All patients received non-pharmacological interventions like yoga, dietician consult and counselling. Conclusions: This checklist helped us identify physical, emotional, and social problems in CS and ensured timely referral to the concerned specialist in a single visit. Although completing the form was initially time-consuming, the process became smoother with regular use and staff familiarity. With further validation and long-term follow-up, this checklist has the potential to become a practical, low-cost model for strengthening survivorship care in LMIC.
Comparative analysis of adjuvant chemoradiotherapy vs. tegafur/gimeracil/oteracil monotherapy vs. observation alone in gastric cancer patients after gastrectomy plus D2 lymph node dissection: A single-center 15-year retrospective study.
e16096 Background: The surgical management of gastric cancer in lymph nodes dissection (LND) differ between Eastern and Western countries. Western countries typically practice D0 to D1 LND followed by postoperative chemoradiotherapy (CCRT). In contrast, East Asian countries treat extensive D2 LND as the standard, followed by adjuvant chemotherapy, which confers to 5-10% relapse-free and overall survival benefit in the long-term. It remains unclear whether chemoradiotherapy was superior adjuvant chemotherapy in gastric cancer patients who received gastrectomy plus D2 LND. Previous studies had led to inconsistent result. Regarding the comparison of adjuvant CCRT versus gastrectomy plus D2 LND alone, retrospective studies may not be conclusive and are limited by unadjusted selection biases. From August 2008 to December 2023, our institution treated 600 patients with gastric cancer who underwent gastrectomy with D2 LND. We identified and categorized 348 patients into adjuvant CCRT (etoposide/leucovorin/fluorouracil, ELF) group, adjuvant chemotherapy (tegafur/gimeracil/oteracil, TS-1) group, and surgery alone group. We aims to compare the overall survival (OS), relapse-free survival (RFS), and pattern of failure (POF) between the treatment groups in a single institution. Methods: We analyze the impacts of three modalities on survival outcome by Cox proportional hazard model. The variables include type of adjuvant treatment, age, sex, BMI, pathological stage, degree of differentiation, involved lymph node ratio, stomach site, and type of surgery. As a comparison, we perform propensity score matching (PSM) and calculate the hazard ratio for either two of three groups and have another three cohorts, which are chemo-radiotherapy vs. Observation, Chemo-radiotherapy vs. TS-1, and TS-1 vs. Observation. Results: Both CCRT with ELF regimen and TS-1 offers RFS and OS benefits in locally advanced gastric patients after gastrectomy plus D2 LND as compared to observation alone. TS-1 monotherapy has a trend better than CCRT in terms of RFS and OS. Local and regional relapse are not significantly decreased in CCRT group as compared to TS-1 group. Conclusions: CCRT with ELF regimen confers RFS and OS benefit in locally advanced gastric cancer patient after gastrectomy plus D2 LND. CCRT is not superior to TS-1 in terms of survival outcome or loco-regional control. Failure pattern after each adjuvant modality. Local Regional Distant Total Adjuvant_Tx Surgery alone 4 (3.3%) 18 (14.8%) 22 (18.0%) 122 CCRT 8 (6.3%) 40 (31.3%) 24 (18.8%) 128 TS-1 9 (9.2%) 20 (20.4%) 13 (13.3%) 98 P value 0.1865 0.0064 0.5114 348 CCRT is not superior to TS-1 or surgery alone in terms of local or regional control.
A randomized, non-comparative, multicenter phase II trial of neoadjuvant becotatug vedotin alone or combined with immune checkpoint inhibitors (penpulimab/ivonescimab) in resectable locally advanced head and neck squamous cell carcinoma.
TPS6135 Background: The efficacy and safety of neoadjuvant therapy for resectable locally advanced head and neck squamous cell carcinoma (LAHNSCC) remain uncertain, and optimal treatment protocols needs further explored. Epidermal growth factor receptor (EGFR) is overexpressed in 90% of head and neck squamous cell cancers (HNSCC) and plays a critical role in tumor proliferation and survival. Antibody drug conjugates (ADCs) represent an emerging class of cancer therapeutics that combines several mechanisms of action to improve efficacy and reduce the systemic toxicity. Becotatug Vedotin is a novel ADC molecule of an anti-EGFR humanized immunoglobulin G1 (IgG1) monoclonal antibody conjugated with monomethyl auristatin E via a valine-citrulline linker. Studies have shown that combining immunotherapy with an Anti-EGFR monoclonal antibody may produces a synergistic anti-tumor effect. This study aims to assess the efficacy and safety of neoadjuvant Becotatug Vedotin, alone or in combination with immune checkpoint inhibitors Penpulimab, an anti-PD-1 monoclonal antibody, or Ivonescimab, a bispecific anti-PD-1/VEGF-A antibody, in patients with resectable LAHNSCC. Methods: This is a randomized, non-comparative, multicenter phase II clinical trial. Key eligible patients aged 18–70 years with previously untreated, pathologically confirmed LAHNSCC (oral, laryngeal, hypopharyngeal, and oropharyngeal carcinoma), resectable and ECOG 0–1 will be enrolled. Main exclusions include active autoimmune diseases, use of immunosuppressive drugs, or systemic corticosteroids. Patients will be allocated to 3 cohorts, and all will receive three preoperative cycles of Becotatug Vedotin(2.3 mg/kg, ivgtt, Q3W) with or without immune checkpoint inhibitors: Cohort 1 (monotherapy); Cohort 2 (combined with Penpulimab, 200 mg, ivgtt, Q3W); Cohort 3 (combined with Ivonescimab, 10 mg/kg, ivgtt, Q3W). Surgery will be scheduled 2 to 4 weeks after the completion of neoadjuvant therapy, followed by adjuvant radiotherapy or chemoradiotherapy based on risk factors. Subjects in Cohorts 2 and 3 will continue immune checkpoint inhibitor therapy for 14 cycles following the completion of radiotherapy. Dose adjustments are permitted based on toxicity. The primary endpoint is Pathologic Complete Response (PCR).Secondary endpoints include major Pathological Response (MPR), objective Response Rate (ORR), 1-year Event-Free Survival (EFS) Rate, 2-year Overall Survival (OS) Rate, treatment-related safety, and predictive biomarkers. Research Sponsor: Lepu Biopharma Co., Ltd. Clinical trial information: NCT07381075 .
From plenary to practice: A large language model (LLM)–based thematic analysis of landmark clinical trial discussions and factors influencing their real-world adoption.
1583 Background: Landmark trials define standard-of-care (SOC), yet the translation of trial evidence into routine practice remains poorly characterized. LLMs enable the systematic extraction of nuanced clinical discourse from unstructured EHR data previously infeasible at scale. We performed an LLM-based thematic analysis of past ASCO Plenary Session (PS) trial discussions to better understand the nature of shared decision-making in routine care and characterize themes influencing SOC adoption. Methods: We designed a retrospective study of clinician-documented discussions with patients about PS trials presented at ASCO Annual Meetings 2021-2025. 2 trials (negative study; non-therapeutic trial) were excluded. Patient records from the Flatiron Health Database with mention of a relevant trial/NCT number within 2 years of presentation were selected. We prompted an LLM (Claude 4.5 Sonnet) to summarize documentation of clinician-patient trial discussions and extract: 1) context of discussion, 2) clinician sentiment toward trial (positive, neutral, negative) and 3) documented receipt of trial therapy (yes/no; if no, reason why not). To characterize the gap in SOC adoption, a thematic analysis was performed using a multi-model consensus approach (Gemini 2.5pro, GPT-4o, Claude 4.5 Sonnet) to identify EHR-documented discussion themes associated with trial treatment omission. LLMs provided supporting evidence for all answers; a human-in-the-loop approach was used to verify concordance between LLM-extracted themes and expert clinical interpretation. LLMs were hosted on Flatiron Health private servers and HIPAA compliant. Results: The study included 8650 patients and 21 trials discussed across 15 cancer types. Common discussion topics were: efficacy (78%), eligibility (78%), patient education (63%), and toxicity (28%). Clinician sentiment across studies was favorable (47%-93% positive), yet real-world trial therapy initiation occurred in only 64% of cases. Main themes associated with trial treatment omission were: clinical factors (biomarker ineligibility, comorbidities), systemic barriers (insurance, transportation, incarceration), and patient preferences (prioritizing quality of life, preserving life roles). Conclusions: This is the largest thematic analysis of clinician-patient trial discussions to date. We uncovered rich qualitative insights into how clinicians engage in shared decision-making with their patients, balancing positive evidence and sentiment with practical and patient-centered factors that define individualized care. Novel LLM methods can transform clinician-patient narratives into actionable evidence to mitigate disparities and optimize real-world SOC adoption. Future work will examine thematic differences by cancer type and prevalence and correlate findings with outcomes.
Phase II study of multidisciplinary therapy combined with pembrolizumab for patients with synchronous oligometastatic non-small cell lung cancer: TRAP-OLIGO study (WJOG11118L).
8571 Background: Several clinical trials have demonstrated that local ablative therapy (LAT) to all lesions, including primary site, may provide a survival benefit for patients with oligometastatic non-small cell lung cancer (NSCLC). However, few studies have evaluated the efficacy of integrating immune checkpoint inhibitors with chemotherapy and LAT. This study aimed to evaluate the efficacy of multimodal therapy combining platinum-doublet chemotherapy plus pembrolizumab followed by LAT to all sites of disease in patients with synchronous oligometastatic NSCLC. Methods: This multicenter, single-arm, phase II trial enrolled treatment-naive patients with stage IV NSCLC and three or fewer metastatic lesions. Patients received 4 cycles of induction therapy consisting of pembrolizumab plus platinum-doublet chemotherapy. Patients then received LAT to all residual lesions, followed by maintenance therapy with pembrolizumab. The primary endpoint was the 24-month progression-free survival (PFS) rate from the initiation of LAT. Secondary endpoints included safety, response to induction therapy, PFS, overall survival (OS), and the proportion of patients who underwent LAT. The threshold and expected 24-month PFS rates were set at 25% and 60%, respectively, with a one-sided alpha of 0.025 and 80% power. Results: Between October 30, 2020, and August 12, 2022, 30 patients were enrolled. At enrollment, seven patients had one metastasis (23.3%), 14 had two (46.7%), and 9 had three (30%). Twenty-three patients (76.7%) received LAT to all residual disease sites. The 24-month PFS rate from the initiation of LAT was 56.5% (95% CI, 34.3–79.8%). The median PFS from the initiation of LAT was 25.8 months (95% CI, 11.7–not reached). The OS rates at 24 and 36 months from the initiation of LAT were 78.0% (95% CI, 55.0–90.2%) and 61.6% (95% CI, 37.2–78.9%), respectively. During the LAT phase, grade 3/4 adverse events occurred in 3 patients (13.0%). No treatment-related deaths were observed. Conclusions: The TRAP-OLIGO study met its primary endpoint with the lower limit of the 95% CI exceeding the threshold, demonstrating that multimodal therapy combining platinum-based chemotherapy plus pembrolizumab and LAT provides favorable efficacy for patients with synchronous oligometastatic NSCLC. These findings suggest that this integrated approach is a promising treatment strategy for this population. Trial registration: Japan Registry of Clinical Trials, jRCTs041200046. Clinical trial information: jRCTs041200046 .
Precise Modulation of Excited‐State Energy Flow via Consecutive Twisted Intramolecular Charge Transfer (ConTICT) for Autophagy‐Blocking Photothermal Therapy
ABSTRACT The efficacy of photothermal therapy is fundamentally governed by the efficiency of non‐radiative decay; however, current organic photothermal agents are severely limited by competitive energy flow pathways and sluggish excited‐state decay kinetics. These dual bottlenecks prevent the maximization of heat generation per absorbed photon. To overcome these barriers, we designed energy barriers that divert energy from both radiative decay and triplet‐state transfer toward non‐radiative heat generation, thereby enhancing efficiency. Furthermore, by employing a consecutive twisted intramolecular charge transfer (ConTICT) mechanism, we accelerate the cycle rate of non‐radiative relaxation. The long‐wavelength, high‐efficiency photothermal molecule Cy‐CF 3 undergoes ConTICT cycling 112 times per 10 ns, achieving a multiple photothermal cycle efficiency of 66.8%, thus addressing the challenge of slow return to the ground state. This holistic design strategy enables Cy‐CF 3 to achieve a high photothermal conversion efficiency of 87.4% under low‐power irradiation (300 mW cm −2 ). Furthermore, it induces disruption of lysosomal structures, and blocks autophagy processes. Upon encapsulation into liposomes, the photothermal agent exhibits specific tumor site targeting, enables fluorescence/photothermal/photoacoustic trimodal deep‐tissue imaging, and delivers robust in vivo antitumor therapeutic efficacy. This work presents a generalizable molecular strategy for precisely manipulating quantum energy flow to construct next‐generation phototheranostics.
Self‐Regulated Gradient Hydrogel Electrolyte with Ultrafast Ion Channels for Robust Zinc‐Ion Batteries
ABSTRACT Hydrogel electrolytes are crucial for advancing safe and flexible aqueous zinc‐ion batteries. However, conventional homogeneous hydrogels suffer a trade‐off between fast Zn 2+ transport and stable Zn/electrolyte interfaces. Herein, we report a surface energy‐driven self‐regulated gradient hydrogel electrolyte (SRG‐HE) that resolves this conflict via a spatially modulated polymer network. The SRG‐HE shows dense layers at the Zn/SRG‐HE interfaces provide robust passivation, while a low‐density bulk supports rapid Zn 2+ diffusion. During in situ polymerization, amphiphilic Triton X‐100 induces spontaneous component migration and surface enrichment, forming a symmetric surface–bulk–surface gradient. The dense surface layers suppress free‐water activity to stabilize interfaces, whereas the hydrated bulk delivers high ionic conductivity (97.7 mS cm − 1 ). Polar groups in SRG‐HE further immobilize OTf − , enabling selective Zn 2+ transport with a high transference number of 0.88. Consequently, Zn||Zn cells cycle stably for 1365 h at 4 mA cm − 2 with uniform (002)‐textured deposition. When paired with V 2 O 5 cathodes, the full cells maintain a reversible capacity of 234 mAh g − 1 after 2000 cycles at 1000 mA g − 1 , achieving near 100% Coulombic efficiency. Even under mechanical deformation, SRG‐HE‐based pouch cells retain functionality, underscoring their potential for durable, high‐performance energy storage systems.
Functional Indium Vacancies in Indium Phosphors Chalcogenides
ABSTRACT Layered Indium phosphorus trichalcogenides (In 4/3 P 2 X 6 ) have received significant attention due to their ordered indium vacancies and stacking‐dependent properties, enabling applications in electronics, catalysis, and energy storage. However, the vacancy‐governed stacking polytypes and atomic structures in In 4/3 P 2 X 6 remain elusive. Moreover, the facile reconstruction of the indium vacancies upon external stimulus makes their direct visualization challenging. Here, a low‐dose aberration‐corrected scanning transmission electron microscopy (STEM), four‐dimensional STEM (4D‐STEM) techniques, and density functional theory (DFT) are employed to systematically explore the atomic structure of In 4/3 P 2 X 6 and the magnetic properties of doped In 4/3 P 2 X 6 . The indium vacancies with glide‐reflection symmetric ordering in In 4/3 P 2 X 6 are resolved at the atomic scale, driving armchair‐type interlayer gliding with an unconventional step in In 4/3 P 2 Se 6 and zigzag‐type gliding in In 4/3 P 2 S 6 , yielding ABC and nearly‐ABC stacking polytypes, respectively. DFT calculations reveal that both gliding modes are energetically favorable, with their distinctions arising from the ligand‐modulated interlayer charge distributions. Besides, filling the indium vacancies with magnetic dopants induces tunable magnetic ordering in In 4/3 P 2 X 6 , and also drives a structural transition to an MPX 3 ‐like phase and a non‐magnetic paramagnetic (PM)−FM transition. This study sheds light on vacancy‐governed structure in In 4/3 P 2 X 6 and highlights it as an excellent matrix for designing novel functional 2D magnets via doping engineering.
Global trends in leukemia-related disability-adjusted life years and mortality across socio-demographic index regions, 1980–2023.
e18516 Background: Leukemia remains a substantial contributor to global morbidity and mortality, with marked variation in burden across socioeconomic settings. This study aimed to evaluate long-term temporal trends in leukemia-related disability-adjusted life years (DALYs) and age-standardized death rates (ASDR) across countries stratified by Socio-demographic Index (SDI) levels, and to quantify changes over time using annual average percent change (AAPC). Methods: Leukemia burden data were obtained from the Global Burden of Disease (GBD) study, covering the period from 1980 to 2023 for ASDR and from 1990 to 2023 for DALYs. Countries were grouped into low, low-middle, middle, and high-middle SDI categories according to GBD classifications. Age-standardized DALYs and death rates per 100,000 population were analyzed using Joinpoint regression to estimate AAPC with corresponding 95% confidence intervals. Statistical significance was defined as a p value < 0.05. Results: From 1990 to 2023, leukemia-related DALYs demonstrated a consistent downward trend across all SDI categories, with the highest burden persistently observed in high-middle SDI regions. DALYs in this group declined markedly from 297.99 in 1990 to 155.92 in 2023 (AAPC: –1.95; 95% CI: –2.06 to –1.84; p < 0.000001). Middle SDI regions experienced the next highest rates, decreasing from 233.44 to 168.40 over the same period (AAPC: –0.97; 95% CI: –1.12 to –0.82; p < 0.000001). Low-middle SDI countries followed a similar pattern, with DALYs dropping from 162.68 in 1990 to 118.12 in 2023 (AAPC: –0.97; 95% CI: –1.10 to –0.84; p < 0.000001). The lowest DALY levels were observed in low SDI regions, though these still decreased significantly from 189.89 to 144.12 (AAPC: –0.85; 95% CI: –0.94 to –0.75; p < 0.000001). A parallel decline was noted in ASDR trends. From 1980 to 2023, high-middle SDI regions demonstrated the most substantial reduction in leukemia-related ASDR, decreasing from 6.57 to 3.61 (AAPC: –1.39; 95% CI: –1.48 to –1.29; p < 0.000001). Middle SDI regions showed a moderate decrease from 5.13 to 3.88 (AAPC: –0.61; 95% CI: –0.69 to –0.53; p < 0.000001), while low-middle SDI regions showed a comparable reduction from 3.67 to 2.88 (AAPC: –0.54; 95% CI: –0.66 to –0.41; p < 0.000001). Low SDI regions exhibited the smallest but still statistically significant decline, with ASDR decreasing from 4.03 to 3.36 (AAPC: –0.42; 95% CI: –0.50 to –0.34; p < 0.000001). Conclusions: Leukemia related ASDR and DALYs have declined across all SDI categories over the past decades, with the greatest improvements observed in higher-SDI regions. Despite this progress, lower-SDI countries continue to exhibit slower reductions and intermittent periods of increase. These disparities highlight the ongoing need for targeted investments in early diagnosis, treatment access, and health-system strengthening in resource-limited settings.
Impact of physical exercise on psychological status and evaluation of exercise discussions during oncology consultations in Syria.
e13621 Background: Physical activity (PA) is a key component of supportive cancer care and is associated with improved psychological well-being. However, exercise participation and exercise-related communication during oncology consultations remains poorly characterized, particularly in resource-limited settings. Methods: A cross-sectional study was conducted between November and December 2025 at Ibn Al-Nafees Hospital and Al-Bairouni Hospital, the national cancer center in Syria. Data were collected using a structured questionnaire assessing sociodemographic and clinical characteristics, consultation duration at diagnosis, and leisure-time PA using the Godin Leisure Score Index (LSI). Psychological distress was evaluated using the Patient Health Questionnaire-2 (PHQ-2) and Generalized Anxiety Disorder-2 (GAD-2). Adherence to American College of Sports Medicine (ACSM) guidelines was defined as ≥ 90 minutes/week of aerobic exercise and ≥ 2 resistance training sessions/week. Results: A total of 325 patients were included (mean age, 52.5 years; 66.8% female). Consultation time at diagnosis was notably brief: 18.7% of patients reported consultations lasting < 5 minutes, and 39.6% lasted 5–10 minutes. Physical inactivity was highly prevalent; 93.8% of participants had an LSI < 24, and only 0.6% met ACSM guidelines. In a logistic regression analysis, higher leisure-time physical activity was independently associated with a reduced risk of depressive symptoms (OR, 2.95; 95% CI, 1.10–7.91; p = 0.031) after adjusting for potential confounders. While 60.6% of patients preferred oncologist-initiated exercise discussions, exercise was not discussed in 69.8% of consultations, and oncologist-initiated discussion occurred in only 25.5%. Similarly, 80% of patients preferred oncologist-initiated discussions regarding psychological issues; however, such discussions occurred in only 42.2% of consultations, and over half (53.5%) reported that these issues were not discussed at all. Although 63% of patients preferred oncologist assessment and reinforcement of exercise, only 23.7% reported that their activity was assessed, 27.4% received advice, and 27.1% received reinforcement. Referral to exercise services was rare (1.8%), despite 39.1% of patients expressing a preference for referral. Conclusions: Among patients with cancer, short consultation times and marked physical inactivity coexist with significant gaps in exercise counseling and referral. These findings underscore a critical need to integrate structured, time-efficient exercise assessment and counseling into routine oncology care to address both physical and psychological health.
Serum HER2 level as a predictor of treatment efficacy and prognosis in advanced breast cancer patients treated with trastuzumab deruxtecan (T-DXd).
1039 Background: No validated liquid biopsy biomarker currently exists to predict the efficacy of trastuzumab deruxtecan (T-DXd) in advanced breast cancer (aBC). Consequently, the role of serum HER2 (sHER2) in this setting remains unclear. This study aimed to determine whether baseline levels and early on-treatment dynamics of sHER2 are associated with progression-free survival (PFS) and objective response rate (ORR) in aBC patients receiving T-DXd. Methods: We analyzed 43 aBC patients treated with T-DXd who had baseline sHER2 data available. As the established 15 ng/mL cut-off was not associated with PFS in our preliminary analysis, the optimal baseline sHER2 cut-off for predicting PFS was determined using the maximally selected log-rank statistics method. Patients were stratified by this cut-off, and a multivariable Cox model adjusted for clinicopathological factors was used to evaluate the independent prognostic value of baseline serum HER2. In a subgroup of 20 patients, serum HER2 changes after two treatment cycles were assessed for association with efficacy outcomes. Results: Using the maximally selected log-rank statistics method, 10.94 ng/mL was identified as the optimal predictive cut-off, with PFS differing significantly between groups defined by this threshold (P=0.015). Multivariable Cox analysis confirmed that a baseline sHER2 level ≥10.94 ng/mL was an independent protective factor for longer PFS (Hazard Ratio [HR] = 0.129, 95% Confidence Interval [CI]: 0.019-0.875, P=0.038), corresponding to an approximately 87.1% reduction in disease progression risk. This predictive value was independent of primary tumor HER2 status, metastatic burden, and liver metastasis. Primary tumor HER2 status itself was not a significant prognostic factor in the model (P=0.530). Regarding ORR, no statistically significant difference was found between high and low sHER2 groups using the 10.94 ng/mL cut-off (P=0.392). In the 20-patient subgroup, early on-treatment sHER2 dynamics showed no significant association with PFS (P=0.455) or ORR (P=0.256). Conclusions: In aBC patients treated with T-DXd, a baseline serum HER2 level ≥10.94 ng/mL is a strong and independent predictive biomarker for PFS, with prognostic value potentially surpassing primary tumor HER2 status. This newly identified cut-off may help to better select patients who are most likely to benefit from T-DXd therapy using a convenient liquid biopsy approach. Clinical trial information: NCT06492447 .