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A phase II trial of a novel induction regimen: Polymeric micellar paclitaxel plus cisplatin for locally advanced head and neck squamous cell carcinoma.
e18067 Background: Induction chemotherapy with the TPF regimen is recommended by international guidelines for locally advanced head and neck squamous cell carcinoma. However, its significant toxicities lead to generally poor patient tolerance, limiting its widespread clinical application, particularly among elderly or medically unfit patients. By encapsulating paclitaxel within micelles, pm-Pac enhanced permeability and retention effect, thereby improving pharmacokinetics and tumor-targeted delivery. This study evaluated the efficacy and safety of induction therapy with polymeric micellar paclitaxel plus cisplatin in LA-SCCHN, aiming to determine whether its pharmacologic advantages translate into clinical benefit. Methods: According to clinical trail the Eligible patients were stage III to IVB HNSCC received polymeric micellar paclitaxel 230 mg/m² (Day 1) plus cisplatin 70 mg/m² (Day 1–2) every three weeks for 2–4 cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), safety, adverse events (AEs), and completion of subsequent definitive therapy. Results: Thirty patients were enrolled (median age, 66 years), including five HPV-positive cases (16.7%). After induction therapy, 5 patients achieved complete response (CR) and 11 achieved partial response (PR), yielding an ORR of 53.3% and a DCR of 93.3%. ORR reached 80% in HPV-positive patients versus 48% in HPV-negative/unknown patients. Common AEs included myalgia/limb pain (60%), neutropenia (26.7%), and bone marrow suppression (33.3%). Grade ≥3 AEs were mainly hematologic; no solvent-related hypersensitivity reactions occurred. Conclusions: Polymeric micellar paclitaxel plus cisplatin demonstrated promising antitumor activity, high disease control, and favorable tolerability in patients with LA-SCCHN, particularly among elderly or TPF-intolerant individuals. Clinical trial information: ChiCTR2500110591. Variable Number (n=30) Percentage (%) Age, years Median 66 (range 35–77) — <65 12 40.0 ≥65 18 60.0 Sex Male 23 76.7 Female 7 23.3 Primary Tumor Site Hypopharynx 9 30.0 Larynx 8 26.7 Oropharynx 6 20.0 Oral cavity 4 13.3 Other* 3 10.0 Clinical Stage II 2 6.7 III 13 43.3 IVA 14 46.7 IVB 1 3.3 HPV Status Positive 5 16.7 Negative/Unknown 25 83.3 Response Number (n=30) Percentage (%) Complete response (CR) 5 16.7 Partial response (PR) 11 36.6 Stable disease (SD) 12 40.0 Progressive disease (PD) 1 3.3 ORR (CR + PR) 16 53.3 DCR (CR + PR + SD) 28 93.3 Adverse Event All Grades Grade 3–4 Hematologic toxicity Bone marrow suppression 10 (33.3%) 6 (20.0%) Neutropenia 8 (26.7%) 5 (16.7%) Thrombocytopenia 2 (6.6%) 0 Febrile neutropenia 1 (3.3%) 1 (3.3%) Non-hematologic toxicity Limb pain / myalgia 18 (60.0%) 0 Gastrointestinal reactions (nausea/vomiting) 7 (27.3%) 0 Serious adverse events Pulmonary embolism 2 (6.7%) 2 (6.7%)
Intralesional PD-1 blockade for oral cancer prevention: First-in-class phase 1 trial.
10517 Background: Oral premalignant lesions affect 5% of the global population with transformation rates of 1-8% in mild-moderate dysplasia and up to 36% in severe dysplasia. Current management via surgical excision yields 30-40% recurrence despite negative margins, with cumulative functional morbidity. We hypothesized intralesional delivery would achieve immune remodeling while eliminating systemic exposure. Methods: We conducted a phase 1, open-label, dose-escalation trial of intralesional nivolumab in patients with histologically confirmed oral epithelial dysplasia ( NCT05327270 ). Twenty-nine patients received 10 mg or 20 mg intralesional nivolumab every three weeks for four cycles. Primary endpoints were safety and tolerability; secondary endpoints included lesion response, progression to carcinoma, pharmacokinetics, spatial immune profiling, and, uniquely for this population, prospective patient-reported outcomes (PROs). Results: No dose-limiting toxicities occurred; 94% of adverse events were grade 1-2 with no systemic immune-related toxicities. Plasma nivolumab concentrations remained 10-fold below IV dosing without accumulation. Lesion area decreased 60% across cohorts with 41% histologic downgrading. Twelve-month cancer-free survival was 75.8%; all progression events were detected early and surgically salvageable. We performed the first prospective longitudinal analysis of PROs in oral premalignancy. High study completion (86%) and adherence rates, despite significant travel burden, coupled with stable or improved quality-of-life scores (specifically pain and swallowing), indicate that repeated intralesional injections are a feasible, non-toxic approach associated with no functional adversity. Unlike surgical standards that degrade function, this strategy preserved patient quality-of-life. Mechanistic analyses using spatial transcriptomics and multiplexed immunofluorescence revealed immune activation exclusively in treated lesions: increased CD4+ and CD8+ T cell infiltration, enriched CCR7+ activated dendritic cells, elevated CD103+ tissue-resident CD8+ T cells, and formation of higher-order immune assemblies. Untreated non-index lesions from the same patients showed no immune changes, definitively demonstrating anatomically restricted immune activation. PBMC profiling confirmed absence of systemic immune response. Conclusions: This first-in-class trial demonstrates intralesional PD-1 blockade safely reprograms premalignant tissue immunity without systemic toxicity, establishing lesion-directed checkpoint inhibition as a viable cancer interception strategy. These findings have established the foundation for a randomized, placebo-controlled Phase 2 trial currently enrolling at MD Anderson Cancer Center (NCT06561087) and support broader applicability to accessible other epithelial precancers including cervical and anal. Clinical trial information: NCT05327270 .
Thematic game intervention as a novel psychosocial support to reduce sedation needs and anxiety in pediatric neuro-oncology patients during radiotherapy: A prospective cohort study (2020–2025).
10011 Background: Pediatric neuro-oncology patients undergoing radiotherapy frequently require sedation/anesthesia due to severe anxiety (mYPAS >15 in >80% cases) and treatment non-compliance. Conventional psychosocial interventions show limited efficacy in reducing sedation dependence, which incurs costs and clinical risks (e.g., respiratory depression). Methods: A prospective cohort study (2020–2025) of 246 children (3–5 years) receiving varied radiotherapy regimens (average course: ~30 fractions). Non-randomized allocation with propensity score matching for age, tumor stage, and sedation history: 1. Intervention group (n=122): Structured game-based intervention ("Radiation Warrior Training Camp"). 2. Control group (n=124): Standard psychological support. Primary outcomes: mYPAS anxiety scores, sedation/analgesia usage, treatment compliance, and cost savings (calculated at ¥376/session). Results: Sedation avoidance rate : 0% in intervention group vs. 41.1% in controls (OR=0.08, 95% CI [0.03–0.22], p<0.001). mYPAS score (median): 8.5 [6.8–3] vs. 17.1 [14.2–19.8] (β=-7.9, [-9.5,-6.3], p<0.001). Cost savings: ¥5,512/patient (derived from 82% relative sedation reduction × 30 fractions ×¥376/session). Treatment duration deviation reduced by 29% (p=0.011).Key Findings: 1. 92% of intervention patients completed radiotherapy without sedation. 2. Dose-dependent efficacy: Anxiety reduction correlated with gameplay duration (r=-0.71). 3. Developmental gradient: 5-year-olds achieved 9.2-point mYPAS reduction vs. 6.5-point in younger children. Conclusions: Game intervention eliminated sedation needs in 92% of patients, reducing anxiety by 7.9 mYPAS points and yielding ¥5,512/patient cost savings. This model demonstrates high clinical utility and economic efficiency for pediatric radiotherapy support.
Cancer-related fatigue research at the National Institutes of Health (NIH) from 2015-2024.
e24059 Background: Cancer-related fatigue (CRF) is a highly prevalent symptom in cancer patients, significantly impacting quality of life. CRF can result from both cancer and its treatment. There is a strong need for improved management of CRF, as well as a deeper understanding of its underlying mechanisms. In this portfolio analysis, we provide an overview of NIH-funded research over 10 years and discuss areas for growth. Methods: We queried the NIH iSearch database for grants funded by NIH between 2015 and 2024, using a keyword search, and screened results to select for studies that characterize, prevent, measure, or treat CRF. We extracted data on grant characteristics, study design, study samples, and outcomes. We also retrieved information from ClinicalTrials.gov. Results: Our initial search identified 737 grants; further screening resulted in 170 CRF grants. The majority of these studies were funded by the National Cancer Institute (70%). Studies focused largely on clinical patient populations (99%), with only two utilizing animal models. Among the clinical studies, breast cancer (42%), hematologic cancer (21%) and prostate cancer (14%) patients were the most represented patient populations. Sixteen percent of studies were agnostic to cancer diagnosis. Ten percent of the studies focused on patients with advanced cancers. Nearly an equal number of grants studied CRF in pediatric patients (9%) and older adults (8%). Most of the clinical studies were interventional studies (67%), followed by longitudinal studies (24%). CRF was measured through patient-reported outcomes in most studies (97%); several studies also used performance-based measures (4%). Interventional studies primarily focused on lifestyle interventions (80%), followed by devices (12%) and pharmacological interventions (8%). Common lifestyle interventions included exercise (29%), behavioral therapy (22%), or psychological, physical, or combined approaches (15%). Only 3% of the studies focused on diet as an intervention. Forty-seven studies were listed as completed. Among those, 51% had publications with trial results; 9 studies (19%) reported the intervention had a significant effect on CRF measurements, while 8 (24%) studies reported negative findings regarding CRF. Conclusions: Our analysis demonstrates that NIH has invested in many clinical studies related to CRF over 10 years. However, few have examined the underlying mechanisms of CRF in preclinical models. Among the interventional studies, lifestyle interventions, such as exercise, are well-represented in this portfolio analysis. In contrast, there are very few studies focusing on pharmacological agents for CRF. This could be attributed to the need for more mechanistic studies in CRF. Finally, while many of these studies are still ongoing, several studies reported positive findings from their clinical trials, which could be considered for future Phase 3 trials.
Predicting pathological complete response based on multi-time point <sup>18</sup> F-FAPI PET/CT in locally advanced rectal cancer.
e15649 Background: Accurate prediction of pathological complete response (pCR) following neoadjuvant short-course radiotherapy (SCRT) combined with immunotherapy and chemotherapy in locally advanced rectal cancer (LARC) remains challenging. Methods: This prospective, exploratory single-center study (identifier: NCT06608537) enrolled 49 LARC patients treated with neoadjuvant SCRT plus PD-1 inhibitor and CAPOX. All patients underwent baseline and preoperative 18 F-FDG and 18 F-FAPI PET/CT, with pre-operative 18 F-FAPI PET acquired via a dynamic, multi-time-point protocol (30, 60, 90, 120 min post-injection). Histopathological analysis of baseline biopsies quantified tertiary lymphoid structures (TLS), immune cell densities, cancer-associated fibroblast (CAF) markers, and tumor microenvironment phenotypes. A pCR predictive model was developed by integrating PET semi-quantitative parameters with histopathological features via LASSO regression, followed by multivariable logistic regression. The model’s performance was rigorously assessed using repeated nested cross-validation. Results: The pCR rate was 49.0% (24/49). Multi-time-point 18 FFAPI PET imaging revealed distinct kinetic profiles between responders and non-responders, providing superior predictive value compared to other FAPI or FDG parameters. Histopathologically, the presence of pretreatment intratumoral tertiary lymphoid structures (iTLS) was significantly associated with pCR. An integrative multivariable model, incorporating preoperative 18 F-FAPI TIMR at 30 min post-injection, RI 34 18 F-FAPI TIMR, CD20 + B-cell density and iTLS number, achieved a robust predictive performance with a mean AUC of 0.874 (95% CI: 0.858–0.890). Exploratory mechanistic studies identified CAF-derived TGFβ as a key suppressor of TLS formation, linking stromal biology to treatment response. Conclusions: Integrating preoperative 18 F-FAPI PET with immune-stromal histopathology offers a novel, non-invasive strategy for predicting pCR in LARC. This multimodal approach outperforms anatomic imaging and tumor cell-targeted molecular imaging, providing a clinically translatable framework to personalize treatment selection and support organ-preservation strategies. Clinical trial information: NCT06608537 .
Genetic correlation and causal associations between metabolic traits and lung cancer risk.
10599 Background: Lung cancer is the leading cause of cancer-related mortality worldwide. We evaluated whether associations between metabolic traits and lung cancer risk reflect shared genetic susceptibility or causal effects of metabolic dysregulation. Methods: GWAS summary statistics from European-ancestry participants were obtained for lung cancer (TRICL–ILCCO; n = 29,266 cases, 56,450 controls), body mass index (BMI; GIANT; n = 681,275), blood lipids, triglycerides (TG), high-density lipoprotein cholesterol (HDL), and low-density lipoprotein cholesterol (LDL), from the Global Lipids Genetics Consortium (GLGC; n = 1,320,016), and type 2 diabetes (T2D; T2DGGI; n = 242,283 cases, 1,569,734, controls). Genome-wide genetic correlations were estimated using LD score regression. Two-sample Mendelian randomization analyses were conducted with lung cancer as the outcome using inverse-variance weighted models, with weighted median, MR-Egger, and weighted mode sensitivity analyses. Heterogeneity and pleiotropy were assessed using Cochran’s Q, MR-Egger intercept, and MR-PRESSO. Results: Lung cancer demonstrated significant positive genetic correlations (r g ) with BMI (r g = 0.16, P = 1.0 × 10⁻⁴), TG (r g = 0.14, P = 3.0 × 10⁻⁴), and T2D (r g = 0.09, P = 0.017), and a significant inverse correlation with HDL (r g = −0.14, P = 2.4 × 10⁻⁵). No significant genetic correlation was observed for LDL. In MR analyses, genetically predicted BMI was associated with increased lung cancer risk (475 SNPs; IVW β = 0.23, SE = 0.05, P = 2.0 × 10⁻⁶; OR = 1.26, 95% CI 1.14–1.38), and remained statistically significant after outlier correction (β = 0.21, P = 7.2 × 10⁻⁶), with no evidence of distortion. In contrast, no supporting evidence of causal associations between lung cancer risk and genetically predicted HDL, TG, LDL, or T2D liability across primary and sensitivity estimators (all P > 0.05). Cochran’s Q tests indicated heterogeneity across genetic instruments; however, MR-Egger intercept tests did not provide evidence of directional horizontal pleiotropy. Conclusions: These findings suggest that metabolic health, particularly obesity, may play a clinically meaningful role in lung cancer risk assessment. Considering obesity alongside established smoking-related determinants may enhance lung cancer prevention efforts.
Tislelizumab combined with bevacizumab and trifluridine/tipiracil as third-line or later therapy for metastatic colorectal cancer (mCRC) : A real-world study.
e15554 Background: Microsatellite stable (MSS) patients (pts) account for 95% of metastatic colorectal cancer (mCRC) cases and respond poorly to immunotherapy (IO). IOs + anti-angiogenic agents have shown promising preclinical antitumor activity. This real-world study evaluated the efficacy and safety of bevacizumab plus trifluridine/tipiracil and tislelizumab in late-line MSS metastatic colorectal cancer (mCRC), and assess benefit in patients with liver metastases. Methods: This single-center, prospective real-world study enrolled mCRC patients (ECOG PS 0/1) progressing after ≥2 prior therapies. They received trifluridine/tipiracil (35 mg/m² BID, days 1-5 & 8-12/28-day cycle), bevacizumab (5 mg/kg, days 1 & 15), and tislelizumab (200 mg, day 1/21-day cycle). The primary endpoint was progression-free survival (PFS). The secondary outcomes included overall survival (OS) and the objective response rate (ORR) per RECIST 1.1. Results: As of Jan.23, 2026, 35 evaluable patients were included. The median PFS was 7.95 months (95% CI: 5.26–12.02), with 1-year and 2-year PFS rates of 35.4%, and 16.1%, respectively. The ORR was 17.1% (6/35; 3 with liver metastases) and the DCR was 77.1%. Median OS was 16.56 months (95% CI: 10.94–24.71), with survival rates of 62.9% at 1 year, and 36.4% at 2 years. Outcomes differed by metastasis status: in patients with liver metastases (n = 21), median PFS was 5.88 months (95% CI: 4.83–10.32) and median OS of 13.27 months (95% CI: 8.21–22.60). In those without liver metastases (n = 14), median PFS(13.14 months ,95% CI: 2.43–18.17) and OS (22.95 months, 95% CI:6.34–NR) were significantly longer. Grade ≥3 treatment-related adverse events occurred in 57.1% of patients, primarily neutropenia (40.0%). Immune-related adverse events (all grade 1-2) were observed in 34.3% of patients, without increased hepatotoxicity in the liver metastasis subgroup. Early grade 3 neutropenia and decreased neutrophil-to-lymphocyte ratio (NLR) were noted in 8/10 patients with OS > 2 years. Conclusions: This combination shows promising activity and manageable safety in late-line MSS mCRC. Patients without liver metastases had significantly longer PFS and OS. Early NLR reduction may predict better outcomes. Clinical trial information: NCT05314101 .
Oncologic impact of prophylactic oophorectomy in colorectal cancer surgery: A systematic review and meta-analysis.
e15536 Background: The evidence supporting routine prophylactic oophorectomy (PO) during colorectal cancer surgery remains limited and heterogeneous, and there is no consensus regarding routine PO for colorectal patients. We performed a systematic review and meta-analysis to evaluate whether PO provides oncological benefit in patients undergoing surgery for colorectal cancer. Methods: We searched PubMed, Embase, and Cochrane Library for studies comparing PO with ovarian preservation during colorectal cancer surgery. Overall (OS) and disease-free survival (DFS) were analyzed using hazard ratios (HRs), while categorical and continuous outcomes were assessed using risk ratios (RRs) and mean differences (MDs), respectively. Primary outcomes were OS and DFS. Secondary outcomes included perioperative and oncologic endpoints. We considered a 95% confidence interval (CI), and a p-value < 0.05 was statistically significant using Review Manager (RevMan) version 5.4.1. Results: Seven studies (four randomized controlled trials and three cohort studies) including 1,270 patients undergoing oncologic colorectal resection were analyzed. Overall, 445 patients (35.0%) underwent prophylactic oophorectomy; the mean age was 62.5 ± 9.4 years, and 92.1% of patients in the prophylactic oophorectomy group were postmenopausal. On pooled analysis, prophylactic oophorectomy was not associated with improvements in OS (HR 1.17; 95% CI, 0.78–1.75; p = 0.45; I² = 61%) or DFS (HR 1.29; 95% CI, 0.98–1.69; p = 0.07; I² = 11%), nor with differences in local recurrence (RR 1.32; 95% CI, 0.74–2.36; p = 0.35; I² = 77%), postoperative complications (RR 0.90; 95% CI, 0.65–1.26; p = 0.55; I² = 60%), or operative time (MD 6.57 minutes; 95% CI, −22.77 to 35.91; p = 0.66; I² = 93%). In a leave-one-out sensitivity analysis excluding the study incorporating cytoreductive surgery (CRS), prophylactic oophorectomy was associated with fewer postoperative complications (RR 0.82; 95% CI, 0.68–0.98; p = 0.03; I² = 8%). Conclusions: In this systematic review and meta-analysis, PO during colorectal cancer surgery was not associated with improvements in OS or DFS, nor with reductions in local recurrence or operative time compared with ovarian preservation. Overall complication rates were similar between groups; however, sensitivity analysis excluding the CRS study suggested a lower complication rate with PO. Taken together, these findings do not support routine as standard practice, indicating that PO should only be reserved for selected cases.
Upfront surgery versus neoadjuvant chemotherapy in resectable pancreatic adenocarcinoma.
e16472 Background: There is no clear consensus regarding treatment sequence for resectable pancreatic ductal adenocarcinoma (PDAC). Upfront resection followed by adjuvant chemotherapy and neoadjuvant therapy are two acceptable treatment options. We compared outcomes of upfront surgery followed by adjuvant chemotherapy versus neoadjuvant chemotherapy followed by surgery using retrospectively collected data at our stand-alone cancer center. Methods: We analyzed a total of 240 resectable patients with PDAC who were retrospectively enrolled in an institutional REDCap database from 2017-2024. After excluding patients who underwent palliation (n = 34) and those whose surgeries were performed outside the institution (n = 13), 193 patients were included. Patients were categorized into two groups: upfront resection (UR, n = 91) and neoadjuvant chemotherapy followed by resection (NAC, n = 102). Clinicopathologic variables, perioperative outcomes, and overall survival were compared. Kaplan–Meier survival analysis and Cox proportional hazards modeling were used to evaluate survival differences and identify independent prognostic factors. Results: 193 patients were included in the study. 91 (47.2%) underwent upfront resection and 102 (52.8%) were treated with neoadjuvant chemotherapy. Median overall survival was 38.8 months in the upfront resection population versus 22.5 months for patients in the neoadjuvant cohort (log-rank p = 0.064). On multivariate Cox proportional hazards analysis for overall survival, higher baseline CA19-9 (HR 1.047, 95% CI 1.004-1.092; p = 0.033) and greater Charlson-Deyo comorbidity burden (p = 0.030) were independently associated with worse survival whereas association with treatment sequence was not statistically significant (p = 0.087). In the neoadjuvant cohort, 31 patients (30.4%) did not undergo surgical resection due to disease progression, decline in performance status, patient refusal, or loss to follow-up. Conclusions: In patients with resectable PDAC at a stand-alone cancer center, both upfront surgery and neoadjuvant chemotherapy are acceptable treatment options. Evaluation of early recurrence in a subgroup of patients receiving upfront surgery suggests more careful consideration of treatment sequence may benefit outcomes. Attrition in the neoadjuvant cohort suggests potential opportunities to improve selection or implement targeted interventions to facilitate patient navigation through complex multidisciplinary therapy. Multivariate cox models - overall survival. Multivariate Cox Models - Overall Survival HR 2.50% 97.50% Overall P-Value Charlson-Deyo Comorbidity Total Score 1 0.7141 0.4386 1.163 0.02965 2-3 1.573 0.9868 2.506 4+ 1.605 0.5621 4.585 Baseline CA19-9 1.047 1.004 1.0924 0.03266
OncoSEGUE: Transforming cancer care delivery through a decentralized, community-integrated oncology model in Southern Portugal.
e13536 Background: Geographic dispersion, limited oncology capacity, and heavy dependence on medical transport pose major barriers to cancer care in the Algarve, Portugal. To address increasing incidence and long travel times, OncoSEGUE was established as a decentralized, community-integrated oncology program delivering consultations, systemic treatments, and supportive care directly within primary care centers across five municipalities. Methods: A mobile multidisciplinary team (oncologist, nurse, pharmacist, phlebotomist) conducted weekly or biweekly sessions in Lagos, Aljezur, Vila do Bispo, Monchique, and Silves. Eligible patients included those in follow-up or receiving oral, IV, or palliative treatment. Clinical activity, transport-related expenditures, and patient-reported experience were collected from SONHO v2 and structured questionnaires. Results: From September 2024 to September 2025, the program delivered 1,290 medical consultations, 596 nursing consultations, 779 pharmaceutical consultations, 603 treatment sessions, and 1,172 blood tests. These represented 33–41% of the Oncology Service’s overall activity increase. Transport expenditures fell by >50% (~€500,000). Patients reported marked improvements in convenience, reduced fatigue, shorter travel times (>4h to <1h), and fewer work absences. Over 85% rated overall satisfaction as “very high”; qualitative comments emphasized improved well-being, continuity, and trust. No compromise in treatment quality was identified. Conclusions: OncoSEGUE demonstrates that a decentralized oncology program can substantially improve access, efficiency, and patient experience while releasing hospital capacity and reducing system costs. Expansion to survivorship clinics, primary-care triage, broader blood-draw capacity, and palliative-care integration is planned.
Health-related quality of life (HRQOL) in the phase 3 trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III deficient DNA mismatch repair (dMMR) colon cancer (Alliance A021502, ATOMIC).
3626 Background: For patients (pts) with dMMR stage III colon cancer, the addition of atezolizumab (atezo) to adjuvant 5-fluorouracil, leucovorin plus oxaliplatin (mFOLFOX6) significantly improved disease-free survival in ATOMIC (NCT02912559). Here we present HRQOL data. Methods: Pts with surgically resected stage III dMMR colon cancer were randomized (1:1) to receive mFOLFOX6 + atezo (840 mg IV q2 weeks) for 12 cycles (6 months [mo]) followed by atezo monotherapy for 13 cycles (12 mo total) versus mFOLFOX6 for 12 cycles. HRQOL was an exploratory endpoint measured using the FACT-C (includes FACT-G), FACT/GOG-NTX, EQ5D-5L, and PRO-CTCAE. Optional participation was by paper surveys at trial registration, prior to treatment cycles 4 and 7, and at 6, 12, and 36 mo after registration. Mean changes from baseline (BL) were compared between treatment arms using general linear mixed models (negative mean changes indicate worsening). At 6 mo, a two-sided 95% confidence interval excluding a difference of 1.9 points (FACT/GOG-NTX) and 6 points (FACT-C Trial Outcome Index [TOI]) favoring the mFOLFOX6 arm would indicate non-inferiority of the addition of atezo. Rates of side effect bother (FACT-G item GP5) and pt-reported adverse events (AEs) by PRO-CTCAE (composite scores, baseline adjusted) were compared using Fisher’s exact tests. Results: Of 712 randomized pts, 581 (285 atezo+mFOLFOX6; 296 mFOLFOX6) consented to participate in the survey. Pts completed 2398/3021 (79%) of expected surveys across all time points (1218/1489 [82%] atezo+mFOLFOX6; 1180/1532 [77%] mFOLFOX6). The difference in mean changes from BL between arms indicated non-inferiority of the addition of atezo at 6 mo (table); differences remained small at 12 and 36 mo. No significant differences in mean changes from BL between arms were found at 6, 12, or 36 mo for any scale. At 6 mo, 16% vs 20% of pts in each arm reported at least “quite a bit” of side effect bother (p=0.34), favoring atezo. Across cycles, atezo was associated with higher rates of pt-reported itchy skin (62% vs 48%), cough (53% vs 43%), and shortness of breath (51% vs 41%) [all p<0.05]. Conclusions: Addition of atezo to mFOLFOX6 slightly increases pt-reported AEs, but its effect on HRQOL is minimal and not clinically meaningful. Results support tolerability of atezo+mFOLFOX6 as standard of care adjuvant treatment for pts with dMMR stage III colon cancer. Support: UG1CA189823, U10CA180821, U10CA180882; Genentech, a member of the Roche group; https://acknowledgments.alliancefound.org. Clinical trial information: NCT02912559 . Scale Mo Mean change from BL – atezo+mFOLFOX6 Mean change from BL – mFOLFOX6 Diff (95% CI) FACT/GOG-NTX 6 -10.0 -10.6 0.6 (-0.8, 2.1) 12 -8.0 -9.4 1.4 (-0.2, 2.9) 36 -7.2 -6.9 -0.4 (-2.1, 1.4) FACT-C TOI 6 -4.1 -2.5 -1.6 (-3.7, 0.6) 12 2.1 1.8 0.3 (-1.9, 2.6) 36 0.7 1.8 -1.1 (-3.7, 1.5)
Antibody-mediated targeting of secretory protein SCUBE3 for cancer treatment.
e15098 Background: In the landscape of cancer treatment, chemotherapy is the common treatment option for TNBC. However, resistance and tumor relapse remain the major obstacles hindering the effectiveness of chemotherapeutic agents in cancer patients. Therefore, the development of new therapeutics, especially targeted approaches like antibody-based therapies, holds immense significance. This study aims to identify and test the role of secretory protein/s that may support the growth and progression of TNBC cells. Additionally, it seeks to determine if targeting these secretory proteins with antibodies can provide a novel therapeutic approach for TNBC patients. Our study identified secretory protein SCUBE3 as a critical factor that promotes survival and therapy resistance of TNBC cells. Importantly, using antibody-development platform, our study presents a novel therapeutic approach targeting SCUBE3 using anti-SCUBE3 monoclonal antibody, offering new hope for TNBC patients with limited treatment options. Methods: High-throughput loss of function genomic screen was performed on TNBC cells in the presence or absence of doxorubicin to screen the oncoprotein. Mouse models was used to study the effect of SCUBE3 in shaping tumor immune microenvironment. Hybridoma culture was used to generate anti-SCUBE3 monoclonal antibodies. Screening of antibody producing clone was done based on ELISA, colony formation assay. Therapeutic efficacy of antibodies was evaluated in tumor xenograft models. Results: SCUBE3 functions extracellularly by engaging cell-surface receptors EGFR, CALR, and TGFβRI/II thereby activating FOXR2 and c-Myc signaling to promote pro-growth signals in cancer cell. SCUBE3-FOXR2 axis creates an immunosuppressive tumor microenvironment by facilitating recruitment of the Myc-DNMT1 repressor complex to the transcription regulator IRF1, thereby inhibiting antigen presentation. Anti-SCUBE3 antibody engineered with LALAPG mutation in the heavy chain showed enhanced specificity and efficacy. The antibody has shown high therapeutic potential across various cancer types in preclinical models, including breast and ovarian cancer patient-derived xenografts without any cytotoxic effects to major organs. This discovery support clinical development of anti-SCUBE3 antibody therapy as a therapeutic adjuvant for cancers characterized by hyperactive SCUBE3-associated signaling pathways. Conclusions: This study will set the stage for a new paradigm of treating TNBCs by inhibiting SCUBE3 activity. Our study is first to identify SCUBE3 as a novel ligand of EGFR1 and CALR mut . Notably, our study shows that SCUBE3 promotes pro-tumorigenic signaling cascade while inhibiting anti-tumor immunity to promote TNBC growth and render them resistant to therapy. Importantly, we provide compelling evidence that antibody targeting SCUBE3 may serve as a potent therapeutic for treating cancer with overexpressed SCUBE3.
Phase I study of liposomal irinotecan plus fruquintinib as third- or later-line therapy for metastatic colorectal cancer.
e15571 Background: Despite advances in therapeutic strategies, patients (pts) with metastatic colorectal cancer (mCRC) have limited options for third- or later-line (≥ 3L) therapies. Previous studies have demonstrated that fruquintinib combined with chemotherapy exhibits favorable anti-tumor activity. Liposomal irinotecan (naI-IRI), a modified formulation of irinotecan, has undefined safety and efficacy profile in mCRC pts with prior irinotecan exposure. This study aimed to investigate the maximum tolerated dose (MTD) and preliminary efficacy of naI-IRI combined with fruquintinib in the ≥ 3L treatment of mCRC pts who have failed prior irinotecan-based therapy. Methods: Unresectable advanced colorectal cancer patients who have failed ≥ 2L of standard chemotherapy and prior irinotecan-based regimens were enrolled. This phase I study adopted a 3+3 dose-escalation design plus expansion cohorts at the recommended dose. Eligible pts received naI-IRI at one of three predefined dose levels (50, 60 and 70 mg/m 2 ) on day 1 and 15, in combination with a fixed oral dose of fruquintinib (4mg/d) administered using a 3-week on/1-week off schedule every 4 weeks. The primary endpoint was MTD determination. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and dose-limiting toxicities (DLT). Results: As of Oct 2025, 12 pts were enrolled. The median age was 63 years [range: 50-74], 75.0% were male, and 83.3% had an ECOG performance status of 1. 8 pts (66.7%) had ≥2 metastatic sites; the predominant metastatic locations were the lungs (66.7%), liver (50.0%), lymph nodes (41.7%) and peritoneum (25.0%). During dose escalation, no DLT was detected in the naI-IRI 50 mg/m 2 dose cohort. Two DLTs (grade 3 diarrhea and grade 3 febrile neutropenia) occurred in the 60 mg/m² cohort. Therefore, the MTD was determined to be 50 mg/m 2 . Subsequently, 6 pts were enrolled in the dose expansion cohort. Among the 50 mg/m² naI-IRI cohort (n = 9), ORR was 33.3% and DCR was 77.8%. mPFS was 6.30 months (95% CI, 4.90-not reached [NR]). Treatment-emergent adverse events (TEAEs) occurred in all 12 (100%) pts. Among them, 6 pts (50.0%) experienced grade 3 AEs, including diarrhea (25.0%), febrile neutropenia (8.3%), neutropenia (8.3%), anemia (8.3%), and hand-foot syndrome (8.3%); all these events resolved following symptomatic treatment. No grade 4-5 events occurred. Conclusions: The MTD of naI-IRI (on day 1 and 15) combined with fruquintinib (3-week on / 1-week off) every 4 weeks was 50 mg/m 2 . Furthermore, this phase I study demonstrated that the combination regimen exhibited an acceptable safety profile and promising efficacy in pts with mCRC who progressed on ≥ 2L of standard therapies and failed irinotecan-based treatment. Collectively, these findings warrant further investigation of this regimen in mCRC pts. Clinical trial information: ChiCTR2400092084.
Immunotherapy and the sequence relative to survival outcomes in SCLC: Analysis of the National Cancer Database.
e20123 Background: Small-cell lung cancer (SCLC) remains an aggressive malignancy with limited therapeutic progress over the past decades. It remains unclear how the sequence of immunotherapy influences overall survival (OS)in SCLC, we performed a population-based analysis using the National Cancer Database (NCDB) to evaluate its association with survival. Methods: Patients with SCLC diagnosed in the NCDB from 2016 to 2021 were identified to evaluate the impact of immunotherapy on OS. Among patients with ES-SCLC, we conducted subsequent analyses to clarify the relationship between the sequence of immunotherapy and OS in the context of chemotherapy and chemoradiotherapy (CRT). Results: Among 69,820 eligible patients, 9,242 received CRT+immuno, and 11,755 received Chemo+immuno. In the overall population, adding immunotherapy to chemotherapy or CRT was associated with modestly improved survival. In ES-SCLC, immunotherapy was consistently associated with longer survival in both the Chemo and CRT cohort, while addition of immunotherapy didn’t confer benefit in LS-SCLC. Within the ES-SCLC Chemo+immuno cohort, altering the initiated immunotherapy interval (0–90 days) didn’t show any meaningful difference in survival. By contrast, in CRT+immuno cohort, survival showed benefit in a time-dependent pattern: patients who initiated immunotherapy within 4-7 days after CRT had the survival trend, which was consistent with the proposed immune activation window. Conclusions: This real-world analysis suggests that immunotherapy was associated with longer survival in ES-SCLC, CRT+immuno is associated with improved OS with a more obvious survival benefit when ICIs are initiated within 4-7 days after CRT. These findings hint the potential importance of immunotherapy sequence and warrant further prospective validation.
Validation of electronic phenotyping algorithms for prostate cancer in All of Us and their impact on genetic association studies.
1619 Background: The All of Us Research Program enables large scale population-based genetic association studies of cancer. All of Us does not contain cancer registry data, risking misclassification of cancer diagnosis. Thus, validated electronic phenotyping algorithms for cancer diagnoses are needed. We sought to develop and validate prostate cancer (PCa) phenotyping algorithms in All of Us , and assess the impact of different algorithms on gene-cancer associations. Methods: We conducted a cross-sectional analysis of All of Us male participants aged ≥50 years with structured electronic health record (EHR), personal health history survey, and whole genome sequencing (WGS) data (Duke IRB Pro00119057). Using self-report of PCa history as the gold standard, we developed and evaluated two electronic phenotyping algorithms: (1) two PCa diagnosis codes; or (2) two PCa diagnosis codes plus evidence of PCa treatment with radical prostatectomy, radiotherapy, or androgen deprivation. For each algorithm, we computed positive predictive value (PPV), and negative predictive value (NPV) with 95% confidence intervals (CI). Using each algorithm, we conducted genetic association studies between PCa and rare pathogenic variants (RPVs) in PCa predisposition genes ( ATM, BRCA1, BRCA2, HOXB13 G84E) among male participants with structured EHR and WGS data. Included RPVs had pathogenic/likely pathogenic designation in ClinVar with at least two stars. Gene-based odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression, adjusting for age and top 5 principal components. Results: We included 21,883 males in the validation study of PCa phenotyping algorithms, 3,961 (18.1%) of whom reported a personal history of prostate cancer. Algorithm 1 demonstrated a PPV of 0.897 (95% CI 0.885 – 0.907) and NPV of 0.927 (95% CI 0.923 – 0.931). Algorithm 2 demonstrated a PPV of 0.927 (95% CI 0.910 – 0.942) and NPV of 0.864 (95% CI 0.860 – 0.869). In the study of gene-PCa associations, 94,446 male participants were included, except for HOXB13 G84E (n = 59,915), which was limited to those of European ancestry. Associations between RPVs in PCa predisposition genes and PCa diagnoses using the two algorithms are shown in the Table. Conclusions: The inclusion of PCa treatment improves the PPV of PCa electronic phenotyping algorithms. PCa phenotyping definitions influence the results of downstream genetic association studies, and highlight the need for accurate and validated electronic phenotyping algorithms when using All of Us . Gene OR a (Algorithm 1 b ) 95% CI c (Algorithm 1) OR (Algorithm 2 d ) 95% CI (Algorithm 2) ATM 2.10 1.47 - 2.92 2.68 1.67 - 4.08 BRCA1 1.11 0.73 - 1.61 1.16 0.61 - 1.98 BRCA2 2.14 1.53 - 2.92 3.11 2.04 - 4.56 HOXB13 G84E 3.88 2.75 - 5.39 3.31 1.98 - 5.22 a OR = odds ratio. b Two prostate cancer diagnosis codes. c CI = confidence interval. d Two prostate cancer diagnosis codes plus treatment.
Racial and regional disparities in prostate cancer–associated dementia mortality in the United States, 1999–2020: A CDC WONDER analysis.
e17023 Background: As prostate cancer (PC) survival improves, age-related comorbidities, including dementia, increasingly contribute to mortality among affected individuals. However, national patterns and disparities in prostate cancer and dementia related mortality remain poorly characterized. Our study aims to use a publicly available database to evaluate disparities in PC and dementia-related mortality by region of the United States (U.S.) and race, between 1999 and 2020. Methods: We conducted a retrospective, population-based analysis using the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) Multiple Cause of Death database from 1999 to 2020. We extracted data for U.S. adults from 1999 to 2023 who died with prostate cancer (ICD-10: C61) and dementia (ICD-10: F03) as a contributing cause. Age-adjusted mortality rates (AAMRs) were standardized to the 2000 U.S. population. Demographic data, including the census region, race, and year of death, were collected. Age-adjusted mortality rates (AAMRs) were calculated per 100,000 population. Analyses were conducted using R version 4.1.1. Results: A total of 43,441 individuals died with prostate cancer and dementia between 1999 and 2020. Of those, 6561 (15.1%) were Black or African American, 36,477 (84%) were White, and 403 (0.9%) were Asian or Pacific Islander. Prostate cancer and dementia combined caused an overall AAMR of 0.65 (CI 0.55, 0.73) between 1999 and 2020. The AAMR for the Northwest region was 0.60 (CI 0.51, 0.70). The AAMR for the Midwest region was 0.70 (CI 0.61, 0.79). The AAMR for the South region was 0.66 (CI 0.58, 0.73). The AAMR was 0.60 (CI 0.49, 0.68) for the Western Region. When classifying data by race, the overall AAMR for Black or African American persons was 1.15 (CI 0.92, 1.42), White persons had an AAMR of 0.56 (CI 0.50, 0.62), and Asian and Pacific Islander persons had an AAMR of 0.3 (CI 0.16, 0.45). Over time, the AAMR increased in all four regions when comparing the year 1999 to the year 2020. The AAMR increased over time for White and Black or African American persons, comparing the year 1999 to the year 2020, but decreased in Asian or Pacific Islander persons, comparing the year 1999 to the year 2020. Conclusions: Between 1999 and 2020, the Midwest and South had higher AAMRs from prostate cancer and dementia than patients in the Northeast or West regions of the United States. Regarding racial differences, Black or African American persons experienced higher AAMRs than their White or Asian and Pacific Islander counterparts. Our findings call for better public health awareness and care for those with prostate cancer and dementia.
The influence of timing: A retrospective analysis of short-course TKI induction and survival outcomes in refractory MSS colorectal cancer.
e15573 Background: The concurrent use of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) has shown limited efficacy in microsatellite stable (MSS) colorectal cancer (CRC). This limitation likely arises from an unprimed, "cold" tumor microenvironment (TME). Recent evidence suggests that TKI-induced vascular normalization creates a transient “window of opportunity” for immune activation. We hypothesized that a sequential approach, TKI induction followed by ICIs, might outperform concurrent administration by effectively remodeling the TME. Methods: In this retrospective cohort study, 78 patients with refractory advanced CRC treated at Harbin Medical University Cancer Hospital (Jan 2019–Apr 2024) were enrolled. Patients were categorized into a Sequential Group (n = 33, initial TKI induction followed by ICIs) or a Combination Group (n = 45, concurrent TKI and ICIs). To minimize immortal time bias, patients in the Sequential Group had to survive the induction period. The primary endpoint was overall survival (OS), while secondary endpoints included progression-free survival (PFS) and safety. Results: The sequential regimen demonstrated significantly improved survival outcomes compared to the concurrent regimen. Median OS was notably longer in the Sequential Group compared to the Combination Group (18.9 vs. 11.2 months; HR = 0.50, P = 0.0029). Likewise, median PFS significantly favored the Sequential Group (10.0 vs. 3.0 months; HR = 0.30, P < 0.0001). Subgroup analysis revealed that a shorter induction duration (≤ 2 months) provided superior PFS compared to longer induction ( > 2 months) (10.0 vs. 6.3 months; P = 0.049), highlighting the transient nature of the vascular normalization window. Additionally, the sequential approach exhibited a favorable safety profile, with numerically fewer Grade 3–4 adverse events, particularly hypertension (3.0% vs. 11.1%, P = 0.485) and gastrointestinal reactions (0% vs. 8.9%, P = 1.000), likely due to reduced overlapping toxicities. Conclusions: Our study provides the first clinical evidence that “timing matters” in combination therapy for MSS CRC. Short-course TKI induction (≤ 2 months) significantly improves survival compared to concurrent therapy. This benefit likely arises from effectively utilizing the vascular normalization window to prime the TME. Thus, a step-wise therapeutic approach emerges as a promising and less toxic treatment paradigm, challenging the conventional belief that earlier combination therapies are superior.
HIGHLIGHT 1: A randomized, placebo-controlled, double-blind, phase 3 clinical study to investigate the efficacy and safety of fezolinetant for treatment of moderate to severe vasomotor symptoms (hot flashes) in women with stage 0 to 3 hormone receptor–positive breast cancer who are receiving adjuvant endocrine therapy.
TPS642 Background: Breast cancer is the most common cause of death due to malignant neoplasms in women globally. Adjuvant endocrine therapy, e.g., tamoxifen and aromatase inhibitors, can lead to premature menopause and vasomotor symptoms (VMS). Fezolinetant is a non-hormonal neurokinin 3 receptor antagonist that is an approved treatment option for moderate to severe VMS due to menopause in multiple regions worldwide, including North America, Europe, Asia, and Australia, at a dose of 45 mg once daily. The pathophysiology of VMS in women undergoing cancer treatment is not fully elucidated but is hypothesized to have similar etiology to VMS associated with menopause, i.e., rapid decline of estrogen. Methods: This global, double-blind, placebo-controlled phase 3 study (HIGHLIGHT 1 [NCT06440967]) was designed to assess efficacy and safety of fezolinetant 45 mg once daily in moderate to severe VMS associated with tamoxifen or aromatase inhibitors for hormone receptor-positive breast cancer from stage 0 (cancer cells have not spread to nearby tissue) to stage 3+ (cancer has spread from breast to lymph nodes near the breast or the chest wall). HIGHLIGHT 1 comprises screening (28 days), treatment (52 weeks), follow-up (3 weeks after final treatment), and extension follow-up (until week 104). Eligible participants will be randomized 1:1 to fezolinetant 45 mg or placebo and stratified by adjuvant endocrine therapy and prior chemotherapy. Participants will record their VMS daily on an electronic diary. The study is currently recruiting. Participants are women (target enrollment n = 540; 382 enrolled as of 24 Nov) ≥18 years with ≥7 moderate to severe VMS episodes/day receiving hormone therapy for stage 0-3 hormone receptor-positive breast cancer. Key exclusions: history/current malignancy other than hormone receptor-positive breast cancer (stage 0 to 3) or basal cell carcinoma. Co-primary endpoints: mean change from baseline to week 4 and 12 in frequency and severity of moderate to severe VMS. Key secondary endpoints: mean change from baseline to week 12 in MENQOL VMS domain score and PROMIS Total Score Sleep Disturbance–Short Form 8b. Co-primary endpoints and key secondary endpoints will be analyzed using mixed models for repeated measures. Treatment-emergent adverse events (TEAEs) assess fezolinetant safety and tolerability. The DMC last reviewed the study in November 2025 and suggested that the study continue as planned. Clinical trial information: NCT06440967 .
Using ML to predict rapid progression for patients (pts) with HR+/HER2- metastatic breast cancer (mBC) treated with frontline (1L) CDK 4/6 inhibitors (CDK 4/6i).
1025 Background: CDK4/6i ± aromatase inhibitors is a preferred tx for pts with HR+/HER2- mBC in the 1L setting. While a subset of pts experience rapid progression on standard tx, addressing the unmet need remains challenging due to difficult pt identification. While multimodal data have predicted fast progressors in prior work, routinely collected electronic health record (EHR) variables may be more practical for clinical trial design and enrichment use cases. Thus, we performed a feasibility assessment to determine if EHR data can adequately predict fast progressors. Methods: Models were trained on pts in the Flatiron Health Research Database with 1L CDK4/6i start on February 3, 2015, or later and an event ≤12 months (mos) or follow-up ≥12 mos after tx start. Fast progression was defined as real-world progression or death ≤12 mos after tx start. Baseline demographics, clinical characteristics, and laboratory/vital signs were used to train a logistic regression (LR) and a full-feature XGBoost (XGB) model. A feature-reduced XGB model was also developed by sequentially removing least important features until area under the curve (AUC) declined. Hyperparameters were optimized by grid search. Performance was evaluated via AUC, with feature importance assessed via LR coefficients and SHapley Additive exPlanations. Test-set analyses included rwPFS comparisons between predicted fast progressor (pFPs) and predicted non-fast progressors (pNFPs) using Kaplan-Meier methods. Results: Among 10,811 included pts, 3,782 were identified as fast progressors, split 80/20 for train/test datasets. The 3 models had comparable performance for predicting fast progression and effectively stratified pts into risk groups (Table). LR and XGB models used 48 and 76 features, respectively, while a feature-selected XGB model retained 30 features with minimal performance loss. Top LR predictors included advanced age, BRCA/ESR1/AKT positivity, and de novo stage IV disease. Important XGB features were consistent across models and emphasized continuous measures, including shorter time to metastatic diagnosis, greater metastatic burden, elevated AST and alkaline phosphatase, and bone-only metastases. Conclusions: While these models are not optimized as point-of-care clinical risk scores, their ability to identify high- and low-risk groups using scalable, routinely captured variables highlights their potential utility for clinical trial design, enrichment strategies, and cohort stratification. These findings establish a real-world benchmark and support the feasibility of practical, EHR-only approaches to rapid progression prediction. Model AUC pFP rwPFS, median (95% CI), mos pNFP rwPFS, median (95% CI) mos LR 0.67 10.8 (9.8–12.4) 25.6 (23.3–27.9) XGB 0.67 10.8 (9.8–12.4) 25.4 (22.9–27.3) XGB (feature selected) 0.66 11.3 (10.2–13.2) 25.6 (23.0–27.9)
External validation of a deep learning CT biomarker to predict first-line immune checkpoint inhibitor monotherapy-associated survival in PD-L1–high metastatic non–small cell lung cancer.
2534 Background: Immune checkpoint inhibitor (ICI) monotherapy is a standard first-line treatment for patients with metastatic non–small cell lung cancer (mNSCLC) with high PD-L1 expression. However, 60% of patients treated with ICI monotherapy progress within 1 year of treatment. Imaging-based biomarkers from routine pretreatment computed tomography (CT) scans may provide a noninvasive approach to refine patient selection and guide treatment decisions. Methods: Enhanced CT Response Score (eCTRS v0.0.2; Sako et al, JCO CCI, 2024) is an imaging-based biomarker that stratifies patient survival among mNSCLC patients receiving ICI monotherapy. eCTRS is derived from pre-treatment CT scans, using deep-learning extracted imaging features, lesion features, and clinical variables of age and sex. eCTRS was previously trained on a diverse, real-world multi-institutional dataset of 1,058 mNSCLC patients. This retrospective study externally validated eCTRS using a deidentified, EHR-derived longitudinal database with imaging from Flatiron Health. Patients with PD-L1–high (PD-L1 tumor proportion score ≥ 50%) mNSCLC without actionable mutations who received first-line ICI monotherapy and had imaging from 12 weeks before to 2 weeks after treatment start were included. Patients were stratified into eCTRS High and eCTRS Low groups using a pre-determined threshold. Survival analyses were conducted by an external, independent group. Kaplan-Meier and Cox proportional hazards analyses evaluated progression-free survival (PFS) and overall survival (OS) stratification. PFS was derived from RECIST 1.1 assessments by a centralized multi-reader radiologist adjudication process, and OS was defined as time from treatment start to death by any cause. Results: 205 patients met all inclusion criteria (median age 72 years, 48% female, 20% non-White). Eighty (39%) patients were classified as eCTRS Low and 125 (61%) as eCTRS High. PFS was improved among eCTRS High patients (Hazard Ratio [HR], 0.71; 95% CI, 0.51–1.00; p=0.048), with median PFS of 231 (95% CI: 133, 350) days versus 88 (95% CI: 57, 179) days in eCTRS Low patients. eCTRS High patients demonstrated significantly improved OS (HR, 0.56; 95% CI, 0.39–0.80; p=0.001), with median OS of 484 (95% CI: 361, NA) days for eCTRS High, versus 155 (95% CI: 75, 295) days for eCTRS Low. Conclusions: A deep learning–based imaging biomarker derived from routinely acquired pretreatment CT imaging identified survival benefit in patients with PD-L1–high metastatic NSCLC treated with first-line ICI monotherapy. These findings suggest that imaging-based biomarkers may serve as complementary, noninvasive tools to identify patients most likely to derive benefit from ICI monotherapy and to support risk-adapted treatment strategies.