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Phase 1, first-in-human (FIH) study evaluating safety and efficacy of ABBV-706: Results from patients with high-grade central nervous system (CNS) tumors.
2041 Background: Patients (pts) with primary high-grade CNS tumors, especially those with glioblastoma (GBM), face poor clinical outcomes (GBM 5yr OS 5–10%). Seizure-related 6 homolog (SEZ6) is overexpressed in many tumor types, including primary CNS tumors. ABBV-706 is a SEZ6-targeting antibody-drug conjugate with topoisomerase 1-inhibitor payload that has shown a manageable safety profile in pts with small cell lung cancer. We present safety and efficacy data from a phase 1, FIH study evaluating ABBV-706 in pts with CNS tumors. Methods: This phase 1, FIH study (NCT05599984) enrolled pts ≥18 years with histologically/cytologically confirmed advanced relapsed/refractory GBM (IDH-wildtype, Grade [G] 4) or astrocytoma (IDH-mutant, G 3/4). Pts had ECOG performance score ≤1, and ≥1 measurable lesion per Response Assessment in Neuro-Oncology (RANO). Pts had prior surgical resection and progressed after receiving standard of care treatment. During dose escalation and expansion, pts received 1.3–3.5 mg/kg and 2.5 mg/kg ABBV-706, respectively. Treatment was every 3 weeks until disease progression or intolerable toxicity. Endpoints included safety and efficacy determined by RANO criteria. Results: As of Sep 27, 2025, 48 pts with primary CNS tumors (GBM, n=41; astrocytoma, n=6; missing indication, n=1) received ABBV-706 (1.3 mg/kg, n=1; 2.5 mg/kg, n=44; 3.0 mg/kg, n=1; 3.5 mg/kg, n=2). Among all pts, median age was 50 years (range 18–78), 58% were male, and the median number of prior lines of therapy was 2 (range 1–5). Median follow-up was 13.7 and 13.2 months for pts with GBM and astrocytoma, respectively. Treatment-related adverse events (TRAEs) were observed in 90% of pts. Most common toxicities were hematological (65%) and gastrointestinal (52%) events. G ≥3 TRAEs were observed in 60% of pts; most commonly anemia (40%). TRAEs led to treatment discontinuation, dose interruption, and dose reduction in 4%, 38%, and 27% of pts, respectively. No G 5 TRAEs were reported. One pt had pneumonitis (2.5 mg/kg, G 2). Among all pts, ORR was 8%, and 2 pts (4%) had a confirmed complete response. Efficacy data for GBM are shown in the Table. SEZ6 IHC expression was similar between GBM pts with (n=4) and without (n=31) an objective response. Conclusions: In pts with previously treated primary CNS tumors, ABBV-706 had a comparable safety profile to that observed in other tumors and showed encouraging antitumor activity. Clinical trial information: NCT05599984 . Efficacy of ABBV-706. a Pts with GBM2.5 mg/kg ABBV-706(n=41) BOR, n (%)CR b PR b SDPD b NE/not assessed 2 (5)4 (10)21 (51)9 (22)5 (12) ORR c , n (%), 95% CI 4 (10), 3–23 CBR, n (%), 95% CI>5 weeks>6 months 26 (63), 47–785 (12), 4–26 Median PFS, months (95% CI)Probability at 9 months, % (95% CI) 2.7 (2.3-5.4)10 (3-24) Median OS, months (95% CI)Probability at 12 months, % (95% CI) 6.4 (5.4–8.3)17 (6–33) a By investigator per RANO. b Including confirmed + preliminary. c Confirmed.
Ultrastable Heterocluster Metal‐Organic Framework Scintillator via Reticular Armoring of Iodocuprate Modules for X‐ray Imaging
ABSTRACT Metal‐organic framework (MOF)‐based scintillators promise advanced X‐ray detection and imaging by virtue of their structural tunability. However, the simultaneous attainment of high radioluminescence efficiency, ultralow detection limits, and extreme environmental robustness remains a formidable challenge. Herein, we report a heterocluster MOF scintillator, designated CuSI‐MPTZ (MPTZ = 2‐mercapto‐4‐(4‐pyridinyl)thiazole), constructed through atomically precise assembly of rigid copper‐sulfydryl clusters ({Cu 6 S 6 }) and emissive copper‐iodide clusters ({Cu 2 I 2 }). This innovative heterocluster design synergistically combines efficient triplet metal‐halide‐to‐ligand charge transfer emission from the Cu‐I clusters with intrinsic framework‐level protection conferred by hydrophobic tert ‐butylthiolate shells and rigid Cu‐S nodes. The resulting material exhibits unprecedented stability, retaining crystalline integrity after prolonged exposure to 1 M HCl, 10 M NaOH, boiling water for one week, and ambient air for over two years. Under X‐ray excitation, CuSI‐MPTZ delivers a high light yield exceeding 37600 photons MeV −1 , an ultralow detection limit of 81.84 nGy s −1 , and a rapid response with minimal afterglow. Large‐area flexible composite screens from CuSI‐MPTZ achieve a spatial resolution of 11.82 lp mm −1 , enabling high‐contrast imaging of complex internal structures. This work establishes a transformative paradigm for stable, high‐performance, lead‐free MOF scintillators, paving the way for practical applications in low‐dose medical diagnostics, security screening, and radiation detection in harsh‐environments.
4‐Methylpyridine‐Mediated Homogenization of Wide‐Bandgap Perovskite Films for Efficient All‐Perovskite Tandem Solar Cells
ABSTRACT Mixed‐halide wide‐bandgap (WBG) perovskites are promising top‑cell materials for multi‐junction photovoltaics owing to their tunable bandgap and excellent photoelectronic properties. However, their solution processing often suffers from mismatched crystallization kinetics between iodine and bromine species, leading to compositional inhomogeneity and limited device performance. Herein, we report a solvent engineering strategy by introducing 4‐methylpyridine (4‐MePy) as a coordinating modulator. 4‐MePy possesses strong coordinating ability and a moderate boiling point. It selectively retards the rapid crystallization of bromine‐rich components by interacting more strongly with lead bromide, thereby homogenizing the halide distribution. The resulting perovskite films exhibit low defect density, reduced lattice strain, and uniform composition and morphology. These improvements suppress carrier recombination and increase the halide migration barrier. Consequently, single‐junction WBG cells with a bandgap of 1.77 eV achieve a champion power conversion efficiency (PCE) of 20.68% and a high open‑circuit voltage ( V OC ) of 1.35 V. When integrated into all‐perovskite tandem solar cells, this strategy delivers PCEs of 29.70% (certified 29.17%) on 0.05 cm 2 and 29.00% on 1 cm 2 devices.
Non‐Invasive Brain Targeted Delivery of Cannabidiol for Alleviating Neuroinflammatory Disease
ABSTRACT Chronic neuroinflammation is a known etiopathogenic factor in neurodegenerative disease. While cannabidiol (CBD) has demonstrated anti‐inflammatory effects, unfavorable pharmacokinetics and poor blood‐brain barrier (BBB) permeability lead to low brain exposure. Here, we greatly improve the efficacy of CBD to treat neuroinflammation by incorporating CBD in a BBB‐permeable glucose nanoparticle (GNPs) that by design also incorporates tissue‐targeting moieties and uses reactive oxygen species responsive polymer to selectively target neuroinflammatory lesions. We achieved a high drug concentration over 20 times higher than naked cargo and demonstrate potent therapeutic effects in two mouse models of neuroinflammatory disease. Mechanistically, disease amelioration resulted from repolarizing microglia from the neurotoxic M1 to the neuroprotective M2 phenotype, leading to neuronal cell regeneration by enhanced secretion of brain derived neurotropic and anti‐inflammatory factors. Our approach for brain targeted CBD delivery may provide a versatile platform for treating other CNS disorders characterized by neuroinflammation.
Real-world clinical characteristics and outcomes of gastroesophageal cancer treated at a tertiary academic center (2021–2025).
e16085 Background: Gastroesophageal cancer (GEC) remains an aggressive malignancy with high mortality despite therapeutic advances. Real-world outcomes often differ from clinical trial data due to comorbidities, sequencing variability, and access barriers. We characterized contemporary real-world GEC patients treated at a high-volume academic center and evaluated selected clinical and treatment-associated outcomes. Methods: We conducted a retrospective cohort study of adults with GEC at Siteman Cancer Center (2021–2025). Outcomes included stage at diagnosis (stage I–III vs IV), overall survival (OS), and recurrence. OS was summarized using Kaplan–Meier. Additional analyses: (1) association of Esophageal Squamous Cell Carcinoma (ESCC) with underweight at diagnosis (BMI < 18.5) using logistic regression and (2) an exploratory comparative analysis among stage I–III patients, comparing definitive chemotherapy + radiation (CRT) versus trimodality (CRT→surgery) using a 6-month landmark Cox model adjusted for stage and age. Results: Among 220 patients, the mean age was 65.3 years; 77.7% were male; 87.7% White, and 10.9% Black. Stage at diagnosis was stage I 5.0%, stage II–III 38.2%, and stage IV 44.5%. Biomarker availability varied: PD-L1 positive 38.6%, HER2 positive 20.5%, MMR deficient 3.6%, and CLDN18.2 positive 4.5%. Treatments included chemotherapy 86.4%, radiation 49.1%, immunotherapy 50.5%, and surgery 30.0%. At cutoff, recurrence was 13.2% and vital status was 48.6% alive, 32.7% deceased, and 18.6% loss to follow-up. In adjusted stage IV models, Black race and female sex were not associated with stage IV [aOR 1.31 (95% CI 0.46–3.80; p = 0.618) and aOR 1.09 (95% CI 0.49–2.42; p = 0.832) respectively] while older age was associated with lower odds of stage IV [aOR 0.95 (95% CI 0.92–0.98; p < 0.001)]. Median follow-up was 12.0 months. ESCC was associated with underweight at diagnosis (unadjusted OR 10.34 [95% CI 3.19–39.84], p = 0.00020; adjusted OR 6.81 [1.92–27.76], p = 0.0039). In stage I–III CRT patients (N = 59), trimodality versus CRT-only was not associated with significantly different OS in a 6-month landmark model (adjusted HR 0.54 [0.14–2.01], p = 0.355). Conclusions: In this real-world GEC cohort, nearly half of the patients presented with stage IV disease, underscoring persistent gaps in early detection and referral. ESCC was strongly associated with underweight at diagnosis, even after adjustment, supporting the need for early nutritional risk screening and supportive care integration. Our small landmark analysis did not show an OS difference between trimodality and CRT alone, likely reflecting limited power and selection in a real-world setting. These findings support prioritizing multimodality and biomarker-directed approaches when feasible while also targeting modifiable factors to improve real-world GEC outcomes.
Regorafenib vs. apatinib: An indirect treatment comparison in the treatment of advanced gastric cancer.
e16082 Background: Advanced gastric cancer has a poor prognosis with limited treatment options. The mainstay of treatment is chemotherapy with targeted therapy (HER2, VEGF pathway) and immunotherapy added to it based on markers. Although, the objective response rate is 40 to 60% and disease control rate is 60 to 70%, median overall survival continues to be < 2 years or possibly lower in patients with poor performance status. Tyrosine kinase inhibitors which target the VEGF pathway have been shown to improve overall survival and progression free survival in these patients. No head-to-head comparison has been performed between these agents in this patient population. Methods: Data pertaining to the INTEGRATE IIA (regorafenib vs. best supportive care) and NCT01512745 (apatinib vs. best supportive care) clinical trials was analyzed. INTEGRATE IIA was a phase 3 randomized double-blind placebo controlled clinical trial with 2:1 randomization and NCT01512745 was a phase 3 randomized double-blind placebo controlled clinical trial with 2:1 randomization. In both studies patients had failed > 2 prior therapies. The best supportive care arm was used as the common comparator. Patient population characteristics were compared along with treatment adverse events. Hazard ratios for overall survival and progression free survival were compared using the Bucher method for indirect treatment comparison. Upper and lower limits of the 95% confidence intervals were calculated. Results: Indirect treatment comparison of regorafenib and apatinib shows a hazard ratio of 0.99 for overall survival and a hazard ratio of 1.19 for progression free survival. However, these results are not statistically significant: 95% confidence interval for overall survival was 0.69 to 1.41 and 95% confidence interval for progression free survival was 0.8 to 1.79. Results are tabulated below. Although, > 2/3rds of the patients in the INTEGRATE IIA clinical trial were from Asia, baseline characteristics could not be appropriately matched as the NCT01512745 clinical trial was conducted in China. These results suggest that apatinib and regorafenib have similar efficacy but apatinib may show slightly better progression free survival. These results are pertinent as apatinib is better tolerated than regorafenib due to a better side effect profile. Conclusions: Apatinib and regorafenib appear to have similar efficacy in terms of overall survival and progression free survival. Apatinib has a better side effect profile and may be considered as a preferred alternative to regorafenib. Direct comparison of these two agents, possibly with a lower dose of regorafenib may be considered for a future clinical trial. Regorafenib vs. Best Supportive Care (INTEGRATE IIA) Apatinib vs. Best Supportive Care (NCT01512745) Indirect Treatment Comparison OS 0.7 (0.56 – 0.87) 0.709 (0.537 – 0.937) 0.99 (0.69 - 1.41) PFS 0.53 (0.4 to 0.7) 0.444 (0.331 – 0.595) 1.19 (0.8 - 1.79)
Using IPOS to trigger advance care planning in outpatient palliative oncology: A multicenter real-world study.
12052 Background: Advance care planning (ACP) is central to high-quality palliative oncology care; however, in Brazil, ACP is not routinely integrated into clinical practice, making timely patient identification challenging. Patient-reported outcomes, such as the Integrated Palliative Outcome Scale (IPOS), may support earlier and more structured ACP discussions. This study evaluated whether IPOS, alone or combined with functional status and follow-up time, can identify patients undergoing ACP in outpatient palliative oncology. Methods: This multicenter, observational study used real-world data from a national Brazilian program across eight states. Adult patients with cancer who completed the IPOS at program entry were included. Functional status was assessed using the Palliative Performance Scale (PPS). ACP was defined as documented initiation during follow-up. Logistic regression models evaluated associations between IPOS domains, PPS, and ACP, adjusting for follow-up time. Discrimination was assessed using receiver operating characteristic (ROC) curves based on predicted probabilities from the final model. Results: A total of 1,301 patients were included (median age 68 years; SD 15.4), of whom 61.4% were female. The most common cancer types were gastrointestinal (30.3%), breast (16.6%), genitourinary (12.3%), and lung (11.9%). ACP was initiated in 32.1% of patients during follow-up. Median baseline IPOS total score was 22 (SD 10.1) and median PPS at entry was 70 (SD 15.7). Median follow-up time was 11.3 weeks (SD 20.2). Baseline IPOS total score did not discriminate ACP initiation (AUC 0.48), while functional status showed modest inverse discrimination (AUC 0.59). Time in palliative care demonstrated higher standalone discrimination (AUC 0.64). A multivariable model combining functional status, selected IPOS symptom and psychosocial domains, and follow-up time significantly improved discrimination for ACP (AUC 0.66; 95% CI 0.63-0.69). Conclusions: IPOS total score alone does not function as a screening tool for ACP initiation. However, when combined with functional status and longitudinal exposure to palliative care, IPOS symptom and psychosocial domains meaningfully improve identification of patients undergoing ACP. These findings support the use of IPOS as a structured clinical trigger to guide timely ACP discussions in outpatient palliative oncology.
Post-progression treatment strategies and immunotherapy rechallenge sensitivity following chemoradiation and consolidation durvalumab in unresectable stage III NSCLC: The POST-PACIFIC study.
8048 Background: Durvalumab consolidation after platinum-based chemoradiotherapy (CRT) is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). However, optimal treatment strategies after progression remain undefined, and data guiding post-durvalumab strategies, including immunotherapy rechallenge, are limited. Methods: This global retrospective multicenter study included patients with unresectable stage III NSCLC treated with concurrent or sequential CRT who progressed after ≥1 dose of durvalumab consolidation. Survival outcomes were assessed using Kaplan-Meier and Cox methods. Immunotherapy sensitivity was defined by time from durvalumab initiation to progression: refractory (< 12 months) or sensitive (≥12 months) and correlated with outcomes after immunotherapy rechallenge. Results: Among 319 patients, median age was 66.5 years; 54.2% were male, and 96.7% had ECOG PS 0-1. Concurrent CRT was delivered in 96.5% (median RT dose 60 Gy). Median follow-up was 62.2 months. Progression pattern included locoregional recurrence in 34.8% and distant relapse in 65.2%. Of 293 patients receiving a first subsequent therapy (FST), chemotherapy (CT) ± VEGF inhibition was most common (31.7%), followed by local ablative therapy (LAT, 30.7%), immunotherapy ± CT (18.4%), targeted therapy (TT, 10.9%), and durvalumab beyond progression (BP) ± LAT (6.5%). When comparing FST, immunotherapy rechallenge demonstrated superiority over CT. Compared with CT ± VEGF inhibition, immunotherapy ± CT was associated with a higher objective response rate (ORR: 40.7% vs. 16.9%, p < 0.01) and significantly improved progression-free survival (mPFS2: 8.48 vs. 4.14 months; HR 0.41, p < 0.01) and overall survival (mOS2: 23.7 vs. 12.2 months; HR 0.41, p < 0.01), findings confirmed in multivariable analyses. Patients with actionable oncogenic drivers or indolent, focal relapses achieved the most favorable outcomes with TT or durvalumab BP ± LAT, respectively, reflecting a disease biology amenable to highly effective systemic or localized interventions. Among patients who received immunotherapy rechallenge, those relapsing ≥12 months after durvalumab initiation experienced higher ORR and numerically longer PFS and OS. Additionally, upfront rechallenge was independently associated with superior survival in multivariable models (PFS aHR: 0.51, p < 0.01; OS aHR: 0.46, p < 0.01) and with higher ORR (41.5% vs. 17.6%, p = 0.04), compared with later-line rechallenge. Conclusions: Post-PACIFIC treatment approaches are heterogeneous, but immunotherapy-based strategies provide superior efficacy over CT alone. Patients with prolonged benefit from durvalumab (≥12 months) retain immune sensitivity and derive the greatest benefit from immunotherapy rechallenge, particularly as FST.
Vaccination patterns among patients receiving ICIs: A practice-informing implementation analysis.
e22673 Background: Vaccination is recommended for patients receiving immune checkpoint inhibitors (ICI), yet historically low vaccination rates in patients with cancer receiving cytotoxic therapy have raised concern about uptake during treatment. Emerging data suggest that vaccination during ICI therapy may confer survival benefits beyond infection prevention. We hypothesized that ICI-treated patients exhibit strong vaccine engagement but incomplete adherence to ASCO guidelines, highlighting a clinically actionable opportunity to improve preventive care. Methods: A registry-validated retrospective cohort study in a large integrated healthcare system identified patients treated with ICI between 2018-2024 and a propensity-matched cohort of healthcare-active patients without cancer to contextualize baseline vaccination rates. Vaccination status was captured from the medical record and verified against the California Immunization Registry. Uptake of ASCO-recommended vaccines was evaluated and temporally classified relative to ICI therapy. Vaccination rates and dosing patterns were compared between ICI-treated patients and matched controls. Descriptive statistics and group comparisons used chi-square, Fisher’s exact and Wilcoxon rank-sum tests. Results: In a cohort of 1859 ICI-treated patients, 75.6% were partially vaccinated in alignment with guidelines, 13.8% were fully vaccinated, and 10.7% had no documented vaccine. When compared to a matched cohort, overall vaccination rates were similar. COVID-19 vaccination rates were high and comparable between ICI-treated patients and controls (87.1% vs 85.5% p = NS), though consistent with national trends, rates declined from 2021-2024 in both groups. Notably, 59.0% of ICI-treated patients received at least one ASCO-recommended vaccine within 100 days of ICI initiation. In multivariable analysis adjusting for age and sex, older age and male sex were associated with higher odds of receiving a vaccine within 100 days of ICI initiation (age: aOR 1.01/year, 95%CI 1.01-1.02; male sex: aOR 1.09, 95%CI 1.01-1.47). Across vaccine types, pneumococcal, Tdap/Td and zoster vaccines demonstrated the lowest uptake (unvaccinated: 56.2%, 64.2%, 65.9%, respectively) and offer greatest opportunity for targeted intervention. Conclusions: Vaccination engagement among patients receiving ICI is high within a large healthcare system and is comparable with historically reported rates in patients receiving cytotoxic therapy. Vaccination rates were comparable to matched non-cancer controls, though most patients remained incompletely vaccinated according to guidelines, particularly for pneumococcal, Tdap/Td and zoster vaccines. This work highlights an opportunity to build on existing engagement by integrating systematic vaccination assessment and delivery into routine ICI care to further strengthen guideline-concordant preventive care.
Integrated multi-omics profiling of pulmonary signet ring cell adenocarcinoma to reveal diagnostic markers, immune subtypes, and therapeutic vulnerabilities.
e20026 Background: Pulmonary signet ring cell adenocarcinoma (PSRCA) is a rare, aggressive subset of lung adenocarcinoma with a dismal prognosis. Its molecular characteristics remain poorly defined, leading to a lack of specific biomarkers and evidence-based therapeutic strategies. Methods: We conducted an integrated multi-omics analysis on formalin-fixed paraffin-embedded tumor samples from 39 treatment-naïve Chinese PSRCA patients—the largest cohort reported to date. Analyses included whole exome sequencing (WES), RNA sequencing (RNA-seq), and multiplex immunohistochemistry (mIHC) for deep profiling of the tumor immune microenvironment (TIME). Genomic alterations, transcriptomic signatures, and immune cell compositions were characterized. Differentially expressed genes (DEGs) were identified using edgeR and Mann-Whitney U test. TIME phenotypes were derived via unsupervised clustering of mIHC data. Results: WES revealed recurrent mutations in mucin family genes and distinct genome-wide copy number alterations. Transcriptomic analysis identified 121 uniquely downregulated and 94 uniquely upregulated genes in PSRCA. From these, five novel diagnostic markers were validated, effectively distinguishing PSRCA from lung adenocarcinoma, squamous cell carcinoma, and gastric signet ring cell carcinoma. TIME analysis classified tumors into three phenotypes: “Inflamed” (immune-hot), “Desert” (immune-cold), and “Hybrid”. The Inflamed phenotype showed a trend toward better response to anti-PD-1 therapy. Notably, EML4::ALK fusions were detected in 34.78% of patients with fusion data. All three ALK-fusion positive patients with the Hybrid TIME phenotype exhibited marked radiological responses to tyrosine kinase inhibitors (TKIs: crizotinib, lorlatinib, alectinib). Conclusions: This first comprehensive multi-omics study of PSRCA defines its distinct molecular landscape, proposes novel diagnostic biomarkers, and establishes a clinically relevant immune subtyping framework. The high frequency of ALK fusions and their association with TKI response in Hybrid TIME tumors provide a strong rationale for routine molecular profiling and precision therapy in this aggressive malignancy. Clinical trial information: NCT07207278 .
Socioeconomic and spatial inequities in U.S. county-level breast cancer mortality, 2018–2023: A Bayesian hierarchical spatial analysis.
e23112 Background: Despite advances in screening and treatment, breast cancer mortality remains uneven across U.S. counties. Understanding how social, economic, and geographic factors shape these disparities is essential for designing equitable cancer-control strategies. Methods: County-level breast cancer mortality data (2018–2023) from CDC WONDER were linked with socioeconomic indicators from the PLACES and American Community Survey datasets. A Bayesian hierarchical Poisson model with a Besag–York–Mollié 2 (BYM2) spatial prior was estimated using Integrated Nested Laplace Approximation (INLA). Predictors included poverty, education, percentage of Black women ≥ 55 years, uninsured women ≥ 55 years, mammography screening, facility density, and metropolitan status, scaled for comparability. Model adequacy was evaluated using the Deviance Information Criterion (DIC), Watanabe–Akaike Information Criterion (WAIC), and Conditional Predictive Ordinates (CPO). Results: Higher poverty (Rate Ratio [RR] = 1.03, 95% CrI: 1.01–1.05), proportion of black women aged ≥ 55 years (RR = 1.05, 1.04–1.06), and higher uninsured rates (RR = 1.21, 1.19–1.22) were associated with elevated mortality. Higher educational attainment (RR = 0.94, 0.94–0.95), mammography screening (RR = 0.99, 0.99–1.00), and metropolitan residence (RR = 0.97, 0.95–0.99) were protective. Residual spatial dependence was modest (φ ≈ 0.06), with clusters mainly in the Southeast and Midwest. Conclusions: Socioeconomic disadvantage, insurance gaps, and racial composition remain key drivers of geographic variation in U.S. breast cancer mortality. Reducing these upstream determinants and improving screening access in persistently high-risk regions may meaningfully reduce county-level disparities.
Immunotherapy-based total neoadjuvant therapy with or without short-course radiotherapy for locally advanced rectal cancer: Preliminary results of TORCH-iTNT.
3644 Background: In patients with proficient mismatch repair (pMMR) locally advanced rectal cancer (LARC), the integration of PD-1 inhibitor into total neoadjuvant chemoradiotherapy (iTNT) has demonstrated promising potential to enhance complete response (CR) rates and facilitate organ preservation. However, the combined use of radiotherapy and surgical intervention frequently leads to increased functional impairment relative to either modality administered independently. Concurrently, the combination of chemotherapy and PD-1 inhibitor has been shown to promote tumor downstaging, thereby enabling sphincter-preserving surgery while mitigating radiation-induced injury. This trial evaluates oncological efficacy and functional outcomes of two iTNT regimens: CAPOX plus PD-1 inhibitor with or without SCRT in neoadjuvant treatment of pMMR LARC patients. Methods: The TORCH-iTNT trial (NCT06281405) is a prospective, multicenter, randomized phase II study involving 192 patients with pMMR LARC (T3-4/N+M0). Participants were randomized into Group A (6 cycles of CAPOX plus toripalimab) or Group B (SCRT [25Gy/5Fx] followed by 6 cycles of CAPOX plus toripalimab). Patients achieving clinical complete response (cCR) were offered a watch-and-wait (W&W) strategy, while those without cCR were advised to undergo surgery. Group A patients with positive circumferential margins received adjuvant chemoradiotherapy. The primary endpoint was CR rate (pathological complete response [pCR] plus cCR). Secondary endpoints included organ preservation rate, anorectal function, adverse effects, and survival outcomes. Results: By December 31, 2025, 192 patients were enrolled, with 137 completing treatment (Group A: 65; Group B: 72). Baseline characteristics were balanced, with 97.1% (133/137) exhibiting at least one high-risk feature: lower tumor location (≤5cm), cT4, cN2, MRF+, or EMVI+. In Group A, 5 patients achieved cCR and adopted W&W, compared to 22 in Group B. Of the 54 and 49 patients in Group A and B who underwent surgery, pCR was observed in 19 (35.2%) and 22 (44.9%) cases, respectively. Five non-cCR patients in Group A declined surgery or were still undergoing treatment. Disease progression occurred in one patient per group. The overall CR rates were 36.9% (24/65) in Group A and 61.1% (44/72) in Group B. The most frequent grade 3-4 toxicity was thrombocytopenia (Group A: 12.3%; Group B: 12.5%). Conclusions: This study is the first comparative analysis of two iTNT regimens in LARC. Unprecedentedly, neoadjuvant CAPOX plus PD-1 inhibitor achieved a promising CR rate in pMMR LARC, and this CR rate can be further enhanced with the addition of SCRT prior to immunochemotherapy. Further follow-up is necessary to assess long-term efficacy and functional endpoints. Clinical trial information: NCT06281405 .
A phase Ib/II clinical study of adebrelimab in combination with capecitabine and oxaliplatin for previously untreated patients with advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma.
e16065 Background: Immune checkpoint inhibitors (ICIs) have dramatically improved survival in various tumor types by preventing the inhibition of T cells by tumor cells. Adebrelimab is a PD-L1 monoclonal antibody using lgG4 subtype immunoglobulin with superior antitumor activity and safety profile. We conducted this study to investigate whether the addition of adebrelimab to capecitabine and oxaliplatin would further improve clinical outcomes. Methods: This multicenter, single-arm, prospective trial was conducted across 8 academic institutions in China (NCT06776770). Eligible patients were advanced or metastatic gastric cancer/gastroesophageal junction adenocarcinoma with no prior systemic therapy for metastatic disease. The Phase Ib study used a 3+3 design to determine the recommended Phase II dose (RP2D) of adebrelimab with eight 21-day cycles of oxaliplatin (130 mg/m², d1) and capecitabine (1,000 mg/m², twice daily on days 1 to 14, followed by a 7-day rest period). The Phase II trial evaluated efficacy and safety at the RP2D. The primary endpoint was objective response rate (ORR), targeting an improvement from 35% to 55%. Results: From 2024 to 2026, the study had a median follow-up duration of 7.7 months, which did not reach the expected progression-free survival (PFS) time. A total of 15 patients were enrolled during this period, including 3 in the Phase Ib dose-escalation cohort and 12 who have been enrolled to date in the Phase Ⅱ dose-expansion cohort. No dose-limiting toxicities (DLT) were observed during the Phase Ib dose escalation (10 mg/kg to 1200 mg); based on the Phase Ib results, the recommended Phase II dose (RP2D) of adebrelimab was established as 1200 mg Q3W. Common drug-related AEs included hematological toxicities (neutropenia, leukopenia, thrombocytopenia, anemia) and hepatic dysfunction. All were chemotherapy-related with no irAEs observed; all were well controlled with standard interventions, no new AEs or treatment-related deaths reported. Among the Phase Ib cohort, 3 patients were evaluable for efficacy with an objective response rate (ORR) of 66.7%, and 10 patients in the Phase Ⅱ cohort were evaluable for efficacy with an ORR of 60.0%. Conclusions: The results inform clinical decision-making for patients on first-line adebrelimab plus capecitabine and oxaliplatin for advanced gastric cancer. Clinical trial information: NCT06776770 . Variables Adebrelimab 10 mg/kg (N=3) Adebrelimab 20 mg/kg or 1200 mg (N=12) All (N=15) Median Age (years, range) 54(42~57） 61(43~75) 60(42~75) Males 2 7 9 ECOG PS 0/1 3/0 9/3 12/3 PD-L1 CPS < 1 /≥ 1 /≥ 5 0/3/2 1/10/4 1/13/6 Liver metastasis YES/NO 0/3 3/9 3/12 Peritoneal metastasis YES/NO 3/0 7/3 10/3 BOR per RECIST 1.1 CR/PR/SD/PD/NE 0/2/1/0/0 0/6/3/1/2 0/8/4/1/2 ORR/DCR 67%/100% 60%/90% 61%/92%
Evaluation of Gemini Pro for primary site prediction in a real-world blinded cohort of 465 patients.
e15002 Background: Artificial intelligence (AI) integration in oncology has transitioned from experimental use to routine clinical practice. Large Language Models (LLMs), such as Gemini Pro, are increasingly used for real-time decision support and molecular interpretation. This study evaluates Gemini Pro’s ability to identify the primary tumor site—defined by histopathology—using only genomic alterations, age, and sex. Methods: We performed a blinded, retrospective analysis of 465 evaluable Next-Generation Sequencing (NGS) cases, including 356 tissue biopsies and 109 liquid biopsies, generated via comprehensive hybrid-capture sequencing. Gemini Pro was queried using a standardized zero-shot prompt to provide three ranked primary tumor site predictions with confidence levels (Very High, High, Moderate, Low) and molecular justification based on lineage-specific genomic features. No supervised training or model fine-tuning was performed. Performance was assessed using Top-1 and Top-3 accuracy. Pearson’s Chi-square tests compared subgroups, and multivariate logistic regression calculated adjusted odds ratios (aOR) with 95% confidence intervals (CI). Results: Gemini Pro achieved a Top-1 accuracy of 50.1% (233/465; 95% CI: 45.6–54.6%) and a Top-3 accuracy of 68.4% (318/465; 95% CI: 64.2–72.6%). Model-assigned confidence was the strongest predictor of correctness: “Very High” predictions achieved 81.6% accuracy (102/125) with an aOR of 9.46 (95% CI: 5.82–15.38; p < .001) versus Moderate/Low confidence. Performance was strongest in common tumor lineages, including Breast (74.6%, 53/71) and Colorectal (72.8%, 43/59), where genomic anchors such as GATA3 and APC are prevalent. Accuracy was lower in rare or genomically complex tumors, particularly sarcomas (< 20%), which frequently exhibited non-specific copy number alterations. No significant difference was observed between tissue (54.6%) and liquid biopsies (42.9%; p = .174). Discordant cases commonly reflected a “neuroendocrine trap,” with TP53/RB1-deficient tumors misclassified as small cell lung cancer regardless of origin. Conclusions: In this blinded evaluation, Gemini Pro demonstrated moderate accuracy as a genomic-based tumor-origin classifier, supporting its role as a diagnostic adjunct rather than a replacement for histopathology. High-confidence predictions increased reliability and may guide targeted immunohistochemical confirmation within established diagnostic workflows. Category Variable Top-1 Accuracy (%) Adjusted Odds Ratio (OR) p-value Global Performance Full Study Cohort 50.1% -- -- Top-3 Prediction Rate 68.4% -- -- Model Confidence Very High 81.6% 9.46 < 0.001 High 63.0% 2.60 < 0.001 Moderate / Low 27.8% Reference -- High-Accuracy Lineages Breast 74.6% 7.92 < 0.001 Colorectal 72.8% 4.89 < 0.001 Lung 58.8% 3.06 < 0.001 Specimen Type Tissue Biopsy 54.6% 1.38 0.174 (NS) Liquid Biopsy (ctDNA) 42.9% Reference --
Digital oncology navigation based on ePROs: Effects on acute healthcare utilization and cost savings in a middle-income country setting.
11111 Background: Oncologic treatment is associated with a high clinical and economic burden. Traditional patient navigation models often lack real-time symptom monitoring, increasing the risk of clinical deterioration. Digital navigation models incorporating ePROs have emerged as a promising strategy to address this gap. However, evidence on their implementation in low- and middle-income settings remains limited. This study aimed to assess the healthcare utilization and economic impact of an ePRO-based digital oncology navigation program in a real-world Brazilian healthcare setting. Methods: We conducted a prospective, single-arm, before-and-after study between February and November 2025 at a private healthcare provider in southern Brazil. Adult patients (pts) with any cancer type undergoing intravenous chemotherapy and/or immunotherapy were enrolled in a digital oncology navigation program integrating app-based ePRO monitoring, automated symptom triage, and proactive nurse-led follow-up. The primary outcome was estimated cost avoidance (from the healthcare provider perspective), calculated as the difference between pre- and post-implementation costs associated with acute healthcare utilization (hospitalizations and emergency room [ER] visits). Secondary outcomes included hospitalization and ER utilization rates, patterns of digital health service use (program adherence and daily and overall volume of symptom reports), and the clinical profile of pts who required hospitalization. Descriptive statistics were applied. Results: A total of 55 pts were included. The mean age was 54 years, and 63.5% were female. Breast cancer (25.5%; n = 14), non-Hodgkin lymphoma (12.7%; n = 7), and lung cancer (10.9%; n = 6) were the most frequent tumor types. Most pts had stage II–III disease (63.9%) and were receiving chemotherapy (54.8%). Hospitalization rates decreased from 29% to 22% after program implementation, while ER utilization declined from 80% to 35%. Patient adherence was high (90.8%), with consistent engagement in symptom reporting throughout follow-up (600 total symptom reports; mean of 5.4 daily reports). Most reported symptoms were managed remotely by the nursing team (95%), with minimal need for physician escalation. Among pts who required hospitalization, lung cancer was the most frequent primary tumor (50.1%). The estimated total cost avoidance was R$332,769 (≈US$66,500), corresponding to a mean saving of R$6,050 (≈US$1,210) per pt. Avoided hospitalizations accounted for most of the economic benefit. Conclusions: Implementation of an ePRO-driven digital oncology navigation program may reduce acute healthcare utilization and meaningful short-term cost avoidance in a real-world healthcare setting. These findings support the integration of digital symptom monitoring as scalable, cost-saving strategie in oncological care delivery.
Perioperative outcomes and early survival after curative-intent non–small cell lung cancer (NSCLC) resection in a Colombian tertiary center.
e20106 Background: Real-world data on perioperative quality indicators and outcomes after curative-intent NSCLC resection in Latin America remain limited. Regional evidence is needed to assess surgical performance and compare outcomes with international benchmarks. Methods: We conducted a retrospective cohort study of adults undergoing oncologic lung resection with curative intent at Fundación Santa Fe de Bogotá (2018–2025). Kaplan–Meier (KM) estimated 12- and 24-month event rates. OS and DFS were analyzed with log-rank and Cox models (≤2 covariates), and TTR with cumulative incidence functions and Fine– Gray models. Results: A total of 81 patients were included, with 68.8% staged as I–II and 23.8% as stage III. Minimally invasive and open approaches were used in 88.0% and 12.0% of patients, respectively. R0 resection occurred in 71 patients (87.7%). Median length of stay was 5 days (IQR 4–7). At 30 days, conversion occurred in 3.7% of cases, any complication in 7.4%, unplanned readmission in 7.4%, and mortality was 0%. Survival and recurrence outcomes were analyzed in 78 patients. After a median follow-up of 20.7 months (95% CI 15.5–29.9), median survival was not reached. OS, DFS, and TTR event-free were 95.1%/86.2%, 85.7%/75.9%, and 87.4%/79.6% at 12/24 months. Compared with stages I–II, stage III was associated with a nonsignificant reduction in OS (HR 3.69, 95% CI 0.88–15.37) and with significantly worse DFS (HR 11.05, 95% CI 2.94–41.54) and higher TTR (SHR 12.40, 95% CI 3.04–50.56). Surgical margins were not significantly associated with DFS (HR 1.48, 95% CI 0.32–6.85) or TTR (SHR 2.36, 95% CI 0.70–7.96). Conclusions: In this Colombian NSCLC surgical cohort, perioperative outcomes met STS/ESTS benchmarks. Pathologic stage III was the main predictor of DFS and TTR, while margins were not significant. These real-world Latin American data support stage-adapted postoperative surveillance and the feasibility of high-quality curative-intent NSCLC surgery. Quality indicators vs international benchmarks. Indicator Cohort (n=81) International Benchmark (Institution/Source) Intraoperative conversion 3 (3.7%) <10% (STS GTSD/VATS studies) Intraoperative complication 2 (2.5%) <3-5% (STS GTSD) R0 resection 71 (87.7%) >85% minimum target (NCCN/IASLC/CoC; STS 87%) 30-day SSI 4 (4.9%) <5% (STS GTSD) Any 30-day complication 6 (7.4%) <9.1% (STS GTSD) Unplanned 30-day readmission 6 (7.4%) <10% post-pulmonary resection (STS studies) 30-day mortality 0 (0%) <2% (STS GTSD) Hospital length of stay (median [IQR]) 5 [4-7] days (n=72) Median 5-7 days (ESTS/Europe; STS) ESTS: European Society of Thoracic Surgeons; GTSD: General Thoracic Surgery Database; IASLC: International Association for the Study of Lung Cancer; SSI: surgical site infection; NCCN: National Comprehensive Cancer Network; STS: Society of Thoracic Surgeons; VATS: Video-Assisted Thoracoscopic Surgery.
Safety and efficacy of a novel PD-L1/4-1BB bispecific antibody QLF31907 in previously-treated patients with advanced melanoma: Results from a phase 2 study.
2527 Background: QLF31907, a bispecific antibody that simultaneously block PD-1/L1 immunosuppressive pathway on cancer cells and conditionally activate 4-1BB co-stimulatory pathway on tumor-specific T cells, was designed to restrict 4-1BB agonism to the tumor microenvironment, which might overcome resistance to PD-(L)1 inhibitor and reduce hepatoxicity as traditional 4-1BB monoclonal antibodies reported. Although immunotherapy (IO) has revolutionized the treatment of melanoma, a significant proportion of patients (pts), particularly those with mucosal and acral subtypes, either fail to respond initially or experience disease relapse after treatment. Here, we present results of QLF31907 in previously-treated pts with advanced melanoma, including IO-exposed. Methods: This phase 2 trial was comprised of safety observation stage and efficacy expansion stage. Pts with unresectable locally advanced or metastatic melanoma who failed, were intolerable to, or refused standard treatment were recruited and administered QLF31907 via intravenous infusion from 5 mg/kg to 20 mg/kg every 2 weeks (Q2W) or 3 weeks (Q3W). The primary endpoints were dose-limiting toxicity (DLT) and safety in safety observation stage, and was objective response rate (ORR) per RECIST v1.1 assessed by investigator in efficacy expansion stage. Results: As of Dec 31, 2025, 59 pts were enrolled (median age: 57.0 years; male: 47.5%; ECOG PS of 1: 42.4%; stage IV: 93.2%). The mucosal subtype accounted for the most (40.7%), followed by acral (33.9%), cutaneous (non-acral; 18.6%) and primary unknown (6.8%). Median prior lines of therapies were 2.0 (range, 1–5). Fifty-five (93.2%) pts received prior immunotherapy, including 50 (87.7%) pts received prior anti-PD-1/PD-L1 agents. No DLT occurred. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 34 (57.6%) pts. The most common grade ≥3 TEAEs (≥10%) were liver injury (18.6%), neutrophil count decreased (15.3%), anemia (13.6%), white blood cell count decreased (11.9%). In 57 efficacy-evaluable pts, seven had partial response. The ORR and disease control rate (DCR) was 12.3% (95% confidence interval [CI], 5.1%-23.7%) and 56.1% (95% CI, 42.4%-69.3%), respectively. The median progression-free survival, duration of response, and overall survival was 2.6 months (95% CI, 1.6-3.7), 5.8 months (95% CI, 2.3-not evaluable [NE]), and 15.3 months (95% CI, 11.6-NE), respectively. Conclusions: QLF31907 showed potential anti-tumor activity and acceptable safety profile in heavily-treated pts with advanced melanoma, including IO-exposed pts. These results warrant validation in further clinical trials. Clinical trial information: NCT05823246 .
Real-world analysis of CRS and ICANS following tarlatamab and its association with survival in patients with SCLC.
e23440 Background: Tarlatamab, a DLL3-targeted bispecific T-cell engager (BITE), is approved for small cell lung cancer (SCLC) in second line and later settings. We aimed to evaluate real-world data regarding cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), their association with overall survival (OS), and post-progression management. Methods: A retrospective cohort study was conducted using the TriNetX Global Network (May 2024–December 2025). Patients with SCLC treated with tarlatamab were identified. CRS, ICANS and presence of baseline central nervous system (CNS) metastasis were identified via ICD-10-CM codes. Survival outcomes were compared using log-rank tests and Cox proportional hazards models. Subsequent treatment patterns and median time to next treatment (TTNT) were also analyzed. Results: We identified 643 patients with SCLC treated with tarlatamab (Mean age 66 ± 10 years; range 22–88; 47.9% female; 76.3% White, 7.1% Black). Overall, 314 patients (48.8%) comprised the toxicity cohort, having developed CRS and/or ICANS of any grade. Amongst those who experienced toxicity, 159 (50.6%) had CRS only, 50 (15.9%) had ICANS only, and 96 (30.6%) experienced both toxicities. Tocilizumab was utilized in 118 (37.6%) of the toxicity cohort (median time to administration: 1 day). Baseline CNS disease was balanced between the no-toxicity (n = 126; 38%) and toxicity (n = 124; 39%) cohorts. Survival analysis demonstrated significantly superior outcomes in patients without CRS or ICANS (Log-rank p < 0.0001). The no-toxicity cohort (n = 329) demonstrated a significantly lower risk of death (HR: 0.498; 95% CI: 0.368–0.675; p < 0.0001) with a 9-month survival probability of 69.1% for the no-toxicity cohort compared to 49.7% for the toxicity cohort. Following tarlatamab discontinuation, 38.1% of the total cohort initiated subsequent therapy with the most frequent agents including lurbinectedin (15.4%) and topotecan (7.1%), with a median TTNT of 98 days (IQR: 62–145). Conclusions: In this real-world analysis of SCLC patients treated with tarlatamab, CRS or ICANS was documented in around half of the study population with a higher incidence of ICANS compared to clinical trials. Occurrence of this toxicity was associated with worse overall survival and this observation warrants further study. Subsequent therapies after tarlatamab discontinuation reflected contemporary treatment patterns in this setting. Safety and survival tarlatamab in SCLC. Category Metric Value Safety Incidence of CRS or ICANS CRS alone ICANS alone CRS + ICANS 314 (48.8%) 159 (50.6%) 50 (15.9%) 96 (30.6%) Tocilizumab Utilization Rate 118/314 (37.6%) Survival 9-Month & 12-Month Survival (No-Tox) 69.1%, 64.4% 9-Month Survival & 12-Month (Tox Group) 49.7%, 41.7% Hazard Ratio (No-Tox vs. Tox) 0.498 (95% CI: 0.360–0.646); 0.487 (95% CI: 0.362-0.655) Log-Rank P-value < 0.0001
Real-world factors associated with early combination therapy initiation in metastatic hormone-sensitive prostate cancer.
e13722 Background: Combination systemic therapy (CST) improves survival in patients with metastatic hormone-sensitive prostate cancer, but this approach remains underutilized. In our study, we examined in an academic practice factors associated with a non-CST approach to further explore opportunities to address this important care gap. Methods: We conducted a retrospective study of patients with newly diagnosed mHSPC treated within the Mount Sinai Health System through 2025. The primary outcome was receipt of CST within 3 months of metastatic diagnosis, and secondary outcome is CST at 6 months. Sociodemographic and clinical characteristics were analyzed using univariable and multivariable logistic regression models were to identify factors associated with early treatment intensification. Results: Among 205 patients with newly diagnosed mHSPC, 136 (66.3%) received combination therapy within 3 months of diagnosis, and 148 (72.2%) received treatment intensification within 6 months. Baseline sociodemographic and clinical characteristics were similar between groups. In multivariable analysis, African American patients were significantly less likely to receive early combination therapy compared with non-Hispanic White patients (OR 0.37, 95% CI 0.14 to 0.97; P = 0.048). Higher PSA at diagnosis was independently associated with increased odds of early combination therapy (OR 1.34 per 1 unit increase in log(PSA + 1), 95% CI 1.08 to 1.68; P = 0.009). Medicaid insurance demonstrated a trend toward higher odds of early combination therapy compared with commercial insurance, though this did not reach statistical significance after adjustment (OR 3.62, 95% CI 1.02 to 15.37; P = 0.058). No significant associations were observed for age, primary language, distance from the treatment facility, ECOG performance status, Gleason Grade Group, or metastatic burden. Conclusions: In this real-world cohort study from a large urban academic health system, African American race was independently associated with a lower likelihood of early CST, while higher PSA at diagnosis was associated with a higher likelihood. Differences in insurance payor may play a role as well. These findings highlight the critical need to address these disparities in mHSPC. Multivariable model: combination therapy within 3 months. Variable Adjusted OR (95% CI) P value African American vs White 0.37 (0.14–0.97) 0.048 Hispanic vs White 0.61 (0.20–1.92) 0.395 Medicaid vs Commercial 3.62 (1.02–15.37) 0.058 Spanish vs English 3.16 (0.73–17.08) 0.141 Outside NYC vs Within NYC 2.20 (0.72–7.77) 0.186 Age (per year), per 1-year increase 1.00 (0.96–1.04) 0.940 PSA (log[PSA+1]), per 1-unit increase 1.34 (1.08–1.68) 0.009 ECOG ≥2 vs 0–1 0.83 (0.31–2.29) 0.714 Gleason Grade Group 3–5 vs 1–2 2.04 (0.56–7.38) 0.272 High vs Low metastatic burden 1.15 (0.47–2.88) 0.758 Adjusted for sociodemographic and baseline disease factors.
A real-world data platform for comparative analysis of treatment patterns, costs, and cost-effectiveness among ALK TKIs in advanced NSCLC.
e20688 Background: Real-world evidence (RWE) directly comparing Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors (ALK TKIs) is crucial for optimizing treatment strategies and healthcare resource allocation in advanced non-small cell lung cancer (aNSCLC). This study leverages a comprehensive medical insurance database to establish an RWE platform capable of comparing clinical outcomes, healthcare resource utilization (HCRU), and economic impact across multiple ALK TKIs. Methods: We conducted a retrospective cohort analysis using the Beijing Medical Insurance Database (01/2019-02/2025). Patients with aNSCLC initiating first-line ALK TKI therapy (Alectinib, Lorlatinib, Crizotinib, Ensartinib, Ceritinib, Brigatinib) were included. For each agent, we extracted real-world metrics on HCRU, direct medical costs, treatment duration, and sequencing patterns. These data were used to populate a partitioned survival model for cost-effectiveness analysis (CEA). Using Alectinib vs. Lorlatinib as a proof-of-concept pairwise comparison, the CEA calculated lifetime costs (2025 CNY), quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER), with a 5% discount rate. The model inputs were derived from the real-world cohort. The framework supports future head-to-head comparisons among other TKI pairs. Results: The cohort included 862 eligible patients. RWE revealed significant variations across TKIs in median duration of therapy (Alectinib: 569 days; Lorlatinib: 388 days; Crizotinib: 252 days), annual HCRU, and cost structures. Alectinib was associated with lower average annual non-drug direct medical costs, resulting in a saving of ¥8,657 compared to Lorlatinib. In the proof-of-concept CEA (Alectinib vs. Lorlatinib), Alectinib provided more QALYs (4.74 vs. 4.53) at a higher total cost (¥859,738 vs. ¥853,019), yielding an ICER of ¥31,471 per QALY gained, which is below the 1x GDP per capita threshold (¥95,749). The economic outcome was driven by Alectinib's longer treatment duration and associated utility benefit, alongside its lower real-world progressed disease phase costs (¥2,721 vs. ¥4,275 per cycle) compared to Lorlatinib, which offset differences in progression-free phase costs. Conclusions: This study establishes a robust RWE platform using real-world costs and resource use data that enables comparative effectiveness and economic evaluations among all ALK TKIs. The proof-of-concept analysis demonstrates that Alectinib is a cost-effective option compared to Lorlatinib from a Chinese payer perspective, supported by its clinical benefits and favorable cost structure, including lower non-drug medical costs. The developed framework supports future head-to-head comparisons for other TKI pairs, providing critical evidence to inform clinical decision-making and optimize aNSCLC care.