4004 Background: Alveltamig (ZG006) is an innovative trispecific T cell engager (Tri-TCE) targeting two distinct DLL3 epitopes on tumor cells and CD3 on T cells (DLL3/DLL3/CD3), designed to bridge tumor cells and T cells, thereby mediating T cell specific killing of tumor cells. Here we conducted a dose optimization study in refractory NEC. Methods: This is a randomized, multicenter, open-label phase 2 study evaluating ZG006 in NEC patients (pts) who failed at least one prior line of therapy. Pts were randomized 1:1 to receive ZG006 at either 10 mg or 30 mg every two weeks, following a priming dose of 1 mg. The primary endpoint is objective response rate (ORR) assessed by IRC per RECIST1.1. Results are reported for 64 pts who received at least one dose of ZG006. Biomarker based efficacy analyses were performed based on a threshold of ≥50% of tumor cells stained at any intensity for DLL3 with an investigational antibody against DLL3 (SP347, Roche Diagnostics). Results: As of Sep. 10, 2025, a total of 64 pts (32 at each dose group) were randomized and received at least one dose of ZG006. The median age was 56 years (range: 25-72), 35 (54.7%) were male. All pts had received ≥1 prior line of systemic therapy, with 65.6% had prior anti-PD-(L)1 treatment. The confirmed ORR in 10 mg and 30 mg groups were 21.9% (7/32) and 37.5% (12/32), respectively; Disease control rate (DCR) were 40.6% (13/32) and 62.5% (20/32), respectively. Among the 19 responders, primary tumor sites included cervix (8), gallbladder (4), stomach (3), rectum (3) and colon (1). Pts with ≥50% DLL3 staining in tumor cells had greater ORR, DCR, and progression-free survival (PFS). The confirmed ORR in 10 mg and 30 mg groups were 33.3% (6/18) and 56.3% (9/16), respectively; DCR were 50.0% (9/18) and 75.0% (12/16), respectively; With a median follow up of 6.4 months, median PFS were 3.02 and 8.41 months, respectively. Median DoR was not yet mature in both groups at data cut-off. Treatment-related adverse events (TRAEs) occurred in all pts. The most frequent events were pyrexia, cytokine release syndrome (CRS) and anaemia. Most CRS were Grade 1-2, with only four grade 3 CRS, resolved with supportive care. TRAEs led to treatment interruption in 15 pts (23.4%) and permanent discontinuation in 2 pts (3.1%, one in each dose group). No grade 5 TRAE. No significant difference was observed in the safety profile between these two dose groups. Conclusions: ZG006 demonstrated a robust and durable response and a manageable safety profile in previously treated NEC pts, with superior efficacy observed at the 30 mg dose. The confirmed ORR of 56.3% and median PFS of 8.41 months in pts with ≥50% DLL3 positive tumor cells are particularly encouraging, and support further development of ZG006 for this patient population at the 30 mg dose. Clinical trial information: NCT06440057 .

8505 Background: RET-fusion positive NSCLC accounts for 1-2% of all lung cancers. Lunbotinib is a next gen brain-penetrant SRI with high potency against RET fusion and mutant proteins ( Zhou et al., 2023; Alonso et al., 2025 ). We report findings from a pivotal phase Ⅱ study in advanced RET-fusion positive NSCLC in China (NCT05265091). An ongoing study is assessing lunbotinib alone or in combination with chemotherapy in Western patients (pts) (NCT05443126). Methods: The phase Ⅱ part enrolled two single-arm cohorts: cohort 1 included pts with prior platinum-based chemotherapy and immunotherapy (pre-treated), and cohort 2 included treatment-naïve pts. All pts received oral lunbotinib 90 mg once daily in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was ORR assessed by an independent review committee (IRC) per RECIST v1.1. Results: As of Oct 29, 2025, 71 pre-treated pts and 92 treatment-naïve pts were enrolled, with median follow-up of 22.6 and 20.7 mos, respectively. Among pre-treated and treatment-naïve pts in full analysis set (FAS), ECOG PS 1 rates were 90% and 80.2%, and metastases involving ≥3 organ sites were observed in 75.7% and 57.1%. IRC-assessed confirmed ORR was 87.1% (95% CI: 77.0-93.9) in pre-treated pts and 81.3% (95% CI: 71.8-88.7) in treatment-naïve pts. mPFS was 27.5 mos and NR, respectively. Among pts with baseline CNS metastases (23 pre-treated, 16 treatment-naïve), ORR was 82.6% and 75.0%, respectively, and 6 pts in each cohort had complete intracranial response. Full efficacy data are in Table. Treatment-related AEs (TRAEs) occurred in 98.8% of pts, the most common were AST (72.4%), ALT (68.1%), anemia (63.2%), urinary retention (45.4%), dry eye (43.6%), and increased blood creatinine (42.9%). Grade ≥ 3 TRAEs observed in 40.5%. Two pts (1.2%) discontinued due to TRAEs. No fatal TRAEs occurred. Conclusions: Lunbotinib demonstrated robust efficacy in pts with advanced RET-fusion positive NSCLC, with high ORR and prolonged PFS in both pre-treated and treatment-naïve populations, and notable intracranial activity. Safety profile was manageable, with no new signals identified. These data support the potential of lunbotinib as a valuable therapeutic option for this population. Clinical trial information: NCT05265091 . Pre-treated pts (Cohort 1) N=71 Treatment-naïve pts (Cohort 2) N=92 Confirmed ORR a /DCR a , % (95% CI) 87.1 (77.0, 93.9)/ 91.4 (82.3, 96.8) 81.3 (71.8, 88.7)/ 92.3 (84.8, 96.9) mDoR a (95% CI), mo 25.7 (14.8, NE) NR (NE, NE) 24-mo DoR rate, % (95% CI) 55.4 (41.1, 67.5) NE mPFS (95% CI), mo 27.5 (16.1, NE) NR (19.4, NE) 24-mo PFS rate, % (95% CI) 52.1 (39.3, 63.5) 59.9 (47.8, 70.0) mOS (95% CI), mo NR (26.1, NE) NR (NE, NE) 24-mo OS rate, % (95% CI) 65.7 (51.5, 76.6) 74.1 (62.1, 82.8) Baseline CNS metastases, n 23 16 ORR, % (95% CI) 82.6 (61.2, 95.0) 75.0 (47.6, 92.7) a In FAS; N was 70 and 91.

Background Programmed death ligand 1 (PD-L1) expression assessed via immunohistochemical analysis of single-site biopsies is standard for guiding immunotherapy in non-small cell lung cancer (NSCLC). However, this approach fails to capture intra- and intertumoral heterogeneity. Purpose To investigate whether gallium 68 (68Ga) NK224 PET/CT enables whole-body assessment of PD-L1 expression and heterogeneity in NSCLC and whether lesion-specific treatment response is associated with PET-defined PD-L1 uptake. Materials and Methods In this prospective study conducted from December 2023 to July 2025, participants with newly diagnosed or recurrent or metastatic NSCLC underwent 68Ga-NK224 PET/CT and PD-L1 immunohistochemical analysis. Tumor uptake of 68Ga-NK224 was quantified using maximum standardized uptake value (SUVmax) from biopsy-plane regions of interest (ROIs) and whole-lesion ROIs. PD-L1 tumor proportion score (TPS) was the reference standard. Intratumoral heterogeneity was assessed using the normalized range of SUVmax, and intertumoral heterogeneity was evaluated using the SUVmax coefficient of variation across lesions. Results This study included 48 participants (median age, 68 years [IQR, 59-75 years]; 31 men). Across 52 lesions, 68Ga-NK224 uptake differed among PD-L1 TPS categories (P < .001), and biopsy-plane SUVmax correlated strongly with TPS (Spearman ρ = 0.80; P < .001). Receiver operating characteristic analysis identified an optimal SUVmax cutoff of 5.6 for discriminating tumors with high PD-L1 expression. Among 12 participants classified as PD-L1 negative via immunohistochemical analysis, five had one or more lesions with SUVmax above the cutoff (15 of 68 lesions). Intratumoral heterogeneity was substantially higher when assessed using whole-lesion ROIs (median normalized range, 1.0) versus biopsy-plane ROIs (median normalized range, 0.4) (P < .001). Intertumoral heterogeneity within individual participants was pronounced (median SUVmax coefficient of variation, 23.6% [IQR, 17.9%-36.7%]). In participants receiving immunotherapy (24 lesions), lesions with partial or complete response (shrinkage ≥30%; median shrinkage, 47.5%) showed greater 68Ga-NK224 uptake than lesions with progressive or stable disease (shrinkage <30%; median shrinkage, 7.4%) (median SUVmax, 5.9 vs 1.9; P = .01). Conclusion 68Ga-NK224 PET/CT enabled whole-body assessment of PD-L1 heterogeneity in NSCLC and revealed lesion-level heterogeneity not captured through biopsy, and uptake was associated with immunotherapy response. Clinical trial registration no. NCT06754345 © The Author(s) 2026. Published by the Radiological Society of North America under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Lopci in this issue.

Soft-tissue sarcomas present a significant clinical challenge owing to their high postoperative recurrence rates and poor responsiveness to radiotherapy and chemotherapy. The insufficient infiltration of immune cells into the tumor microenvironment further limits the efficacy of immunotherapy. Photodynamic therapy (PDT) can induce immunogenic cell death (ICD) in tumor cells by releasing tumor-associated antigens. These antigens can be used to activate dendritic cells (DCs) in vitro and extract DC vesicles. These vesicles can activate T cells in a more effective and specific manner, promoting their maturation and tumor infiltration, thereby achieving effective tumor immunotherapy. After delivering photosensitizers to the tumor site via nanocarriers, the tumor antigens generated in situ by PDT can further enhance tumor accumulation and the anti-tumor immune response of these T cells. Based on this rationale, we developed a cell membrane-based nanoplatform that integrates PDT and T cell activation. Nanoparticles were fabricated by coating indocyanine green-loaded mesoporous polydopamine nanoparticles with a hybrid membrane derived from DCs activated by PDT-released antigens and tumor cells (DTM-MI). In vitro, DTM-MI demonstrated efficient tumor cell targeting and laser irradiation, produced abundant reactive oxygen species (ROS), and induced tumor cell death and release of ICD-related molecules. DTM-MI selectively accumulated in tumors of tumor-bearing mice in vivo Combined with PD-L1 antibody and laser irradiation, DTM-MI significantly inhibited tumor growth while elevating serum levels of immune-related cytokines, confirming anti-tumor immune activation. Lymph nodes showed increased T-cell and CD8 + T-cell populations, and tumor sites exhibited enhanced CD8 + T-cell and cytotoxic T lymphocyte (CTL) infiltration. The dual targeting of tumor cells and T cells by DTM-MI coupled with DC membrane-mediated T-cell activation and homing to PDT-treated regions facilitated potent tumor killing. Laser-triggered immunogenic cell death and antigen release further amplify T cell-mediated anti-tumor immunity, presenting a promising therapeutic approach for sarcomas.

Ferroptosis is regulated cell death due to the accumulation of iron-dependent lipid peroxidation in cells, providing a potential new strategy for anti-tumor therapy. In recent years, more and more studies have begun to explore the interaction between ferroptosis and the tumor microenvironment (TME), especially the relationship between immune cells in the TME and ferroptosis, revealing the role of ferroptosis in tumor immunotherapy. This article summarizes the main metabolic pathways and regulatory mechanisms of ferroptosis, and focuses on the new role of ferroptosis in immune cells in the TME, which may provide new diagnostic, prognostic or therapeutic opportunities for the cooperation of immunotherapy and ferroptosis treatment.

Trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate (ADC) is a promising anticancer agent that has shown remarkable efficacy in several malignancies. However, in lung cancer, two phase 3 trials on TROP2-ADCs in unselected patients with advanced non-small-cell lung cancer (NSCLC) have both failed. Sacituzumab tirumotecan (sac-TMT) is a novel TROP2-directed ADC. Here we report the efficacy and safety of sac-TMT in previously treated, advanced NSCLC with or without activating EGFR mutations from the phase 1/2 KL264-01 and phase 2 SKB264-II-08 studies. Primary endpoint was objective response rate (ORR). KL264-01 enrolled EGFR-wild-type and EGFR-mutant NSCLC (n = 43). Confirmed ORR was 40% (17 of 43; 95% confidence interval (CI), 25-56). Median progression-free survival (PFS) was 6.2 months (95% CI, 5.3-11.3). Post-hoc subgroup analyses found better outcomes in the EGFR-mutant subset (22 of 43, 51%) with a confirmed ORR of 55% (12 of 22) and median PFS of 11.1 months. These findings were independently supported by results from SKB264-II-08, where sac-TMT led to confirmed ORR of 34% (22 of 64; 95% CI, 23-47) and median PFS of 9.3 months (95% CI, 7.6-11.4) in 64 patients with EGFR-mutant NSCLC. For a total of 107 patients receiving sac-TMT, the most common treatment-related adverse events were hematologic toxicities. Diarrhea (4%) and interstitial lung disease (1%) were uncommon. Exploration of potential mechanisms revealed that the presence of EGFR mutation substantially increased the internalization and activity of sac-TMT in vitro. Overall, sac-TMT showed encouraging single-agent activity and manageable tolerability in previously treated, advanced NSCLC with EGFR mutations. Randomized phase 3 trials in treatment-naive and previously treated patients with EGFR-mutant NSCLC are ongoing. ClinicalTrials.gov Identifiers: NCT04152499 , NCT05631262 .

PURPOSE:Ferroptosis is a novel form of iron-dependent programmed cell death that is associated with the progression of various tumors and cancer treatment responses. However, its role in the clinical treatment of lung cancer, particularly in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), remains poorly understood. This study aims to explore the prognostic value of ferroptosis-related genes in lung cancer and establish a reliable predictive model. METHODS:We collected the GSE4573, TCGA-LUAD, and TCGA-LUSC datasets, comprising a total of 1,271 samples and a ferroptosis gene set of 717 genes. Weighted gene coexpression network analysis (WGCNA) was used to identify ferroptosis-related markers, followed by the application of 101 machine learning algorithms combining 10 different approaches to develop a ferroptosis-related signature (FRS) for lung cancer prognosis. RESULTS:The FRS demonstrated superior performance in predicting the survival of lung cancer patients, significantly outperforming traditional TNM and American Joint Committee on Cancer (AJCC) staging systems. External validation using the GSE13213 dataset also confirmed its robustness. Furthermore, the low-risk group exhibited higher immune microenvironment scores, suggesting a more active anti-tumor immune response, while the high-risk group showed elevated cell proliferation, migration, T-cell exclusion, and TIDE scores, indicating a more aggressive tumor phenotype. Additionally, the low-risk group demonstrated higher sensitivity to multiple drugs, including cisplatin, cyclophosphamide, paclitaxel, erlotinib, Niraparib, Rapamycin, Fulvestrant, and Venetoclax, highlighting its potential for guiding personalized treatment strategies. CONCLUSION:The FRS represents a powerful and clinically relevant tool for predicting the survival of lung cancer patients, offering new insights into personalized treatment and therapeutic decision-making.

Ferroptosis is a programmed cell death characterized by iron-dependent lipid peroxidation, which is regulated by various cellular metabolic and signaling pathways. The main regulatory mechanisms of intracellular ferroptosis include the GSH-GPX4 pathway, the FSP1-CoQ10 pathway, the GCH1-BH4 pathway, and the DHODH-CoQH2 system. As the hub of iron metabolism and energy generation, mitochondria have been increasingly implicated in ferroptosis, underscoring their pivotal role in cellular processes. Ferroptosis is a significant mode of cell demise linked to cancer progression. It is expected to combat drug-resistant tumors by triggering iron-mediated cell death. This review delves into the intricate mechanisms governing intracellular ferroptosis, emphasizing the centrality of mitochondria in regulating this process within cancer cells. Furthermore, this review explores the potential and hurdles of targeting ferroptosis as a therapeutic avenue to overcome resistance to cancer treatment.

e16344 Background: Treatment options for patients (pts) with advanced neuroendocrine carcinoma (NEC) are very limited, of which etoposide and cisplatin (EP) is the first-line standard treatment. Combination of immune checkpoint inhibitors with chemotherapy is a potential therapeutic strategy in NEC. This study is designed to evaluate ZG005 (a recombinant humanized anti-PD-1/TIGIT bispecific antibody with dual-targeted blocking effects on PD-1 and TIGIT) plus EP as the first-line therapy in pts with NEC. Methods: This phase 1/2, multiple-centers, dose escalation (Part 1) and expansion (Part 2) study was conducted to evaluate the safety and efficacy of ZG005 in combination with EP as a first-line treatment in the pts with NEC (excluding small cell lung cancer [SCLC]). In Part 1, pts received escalating doses of ZG005 (10 mg/kg or 20 mg/kg) with a fixed dose of EP every three weeks (Q3W). In Part 2, pts were administered ZG005 10 mg/kg + EP, ZG005 20 mg/kg + EP, and placebo + EP, respectively. The primary objective of Part 1 was to evaluate the safety and determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ZG005 + EP. The primary efficacy endpoint of Part 2 was investigator-assessed ORR by RECIST V1.1, while key secondary endpoints included PFS, DOR, DCR, etc. Results: As of Jan 10, 2025, a total of 21 pts were enrolled. The median age was 61 (range 48-70), with 81% male, 100% Ki-67 ≥ 55%, and 66.7% liver metastasis. The most common primary site of the tumor was gastrointestinal (38.1%), and median treatment cycles were 4 (range 2-4). No dose-limiting toxicities (DLT) were observed in Part 1. The most common treatment-related adverse events (TRAEs) were anaemia (23.8%), white blood cell count decreased (14.3%), neutrophil count decreased (14.3%), and alanine aminotransferase increased (14.3%). Three (14.3%) pts experienced Grade ≥3 TRAEs. Serious adverse events (SAEs) occurred in 4 (19.0%) pts, with only immune-mediated enterocolitis (immune-related) being related to the ZG005. Of the 12 efficacy-evaluable pts, 6 (2 on ZG005 10 mg/kg + EP and 4 on ZG005 20 mg/kg + EP) achieved partial responses (PR, 4 confirmed PRs) and 5 pts were stable disease (SDs), with an ORR of 50% and DCR of 91.7%; DOR and mPFS were not reached yet. Conclusions: Combination of ZG005 with chemotherapy was well tolerated and showed encouraging ORR in patients with NEC. This clinical trial is still going on, and updated safety and efficacy will be presented in the future. Clinical trial information: NCT06372626 . Research Sponsor: Suzhou Zelgen Biopharmaceuticals Co., Ltd.

To evaluate the diagnostic accuracy and clinical impact of fibroblast activation protein (FAP)-targeted PET/CT imaging in primary and metastatic breast cancer and compare the results with those of standard-of-care imaging (SCI) and [18F]FDG PET/CT. We prospectively analyzed patients with diagnosed or suspected breast cancer who underwent concomitant FAP-targeted PET/CT (radiotracers including either [68Ga]Ga-FAPI-46 or [18F]FAPI-42) and [18F]FDG PET/CT scans from June 2020 to January 2024 at two medical centers. Breast ultrasound (US) imaging was performed in all treatment-naïve patients as SCI. The SUVmax, tumor-to-background ratio (TBR), lesion detection rate, and tumor-node-metastasis (TNM) classifications between FAP-targeted and [18F]FDG PET/CT were evaluated and compared. Sixty-one female patients (median age, 52 y; range, 28–82 y) were included. Among them, 23 patients underwent evaluation for a definitive diagnosis of suspected breast lesions, 15 underwent initial staging, and 23 were evaluated for the detection of recurrence. The sensitivities of breast US, [18F]FDG, and FAP-targeted PET/CT for detecting primary breast tumors were 82

Abstract Background: TROP2 (trophoblast cell surface antigen 2) is commonly over-expressed in non-small cell lung cancer (NSCLC) and associated with poor prognosis. SKB264 (MK-2870) is a TROP2 ADC developed with a novel linker to conjugate the payload, a belotecan-derivative topoisomerase I inhibitor. The linker is affected by both extracellular pH-sensitive cleavage and intracellular enzymatic cleavage within tumor cells, which leads to efficiently release payload inside tumor cells as well as within tumor microenvironment to exert its anti-tumor effects. Here, we present the updated data from a Phase 2 expansion cohort for patients (pts) with advanced NSCLC. Methods: Pts with previously treated advanced NSCLC were enrolled to receive SKB264 at 5 mg/kg Q2W until disease progression or unacceptable toxicity (KL264-01, NCT04152499). Tumor assessment was performed every 8 weeks per RECIST v1.1 assessed by investigator. Results: As of Nov 22, 2023, 43 NSCLC pts had been enrolled. Median follow-up was 17.2 months (mo). 21 pts with EGFR wild type had received median prior 3 regimens of therapy including anti-PD-1/L1 inhibitors. 22 pts with EGFR mutant had progressed on or after TKI therapy, 50% of whom also failed at least one line of chemotherapy. Updated efficacy results are shown in the Table. Overall, 30 pts (69.8%) experienced Grade ≥3 treatment-related adverse events (TRAEs). The most common Grade ≥3 TRAEs were neutrophil count decreased (34.9%), anemia (30.2%), WBC count decreased (25.6%), stomatitis (9.3%), and rash (7.0%). No TRAEs leading to treatment discontinuation or deaths occurred. No drug-related ILD/pneumonitis was reported. Conclusions: The updated data continues to demonstrate that SKB264 monotherapy delivers promising clinical efficacy with manageable toxicity in pretreated advanced NSCLC pts. A Phase 3 global study of SKB264 in pts with 3L+ EGFR mutant NSCLC (NCT06074588) and a Phase 3 study of SKB264 in China in pts with 2L EGFR mutant NSCLC (NCT05870319) are ongoing. TABLE 1: NAND Table Clinical outcomes by EGFR mutation status Overall (N=43) EGFR mutant (N=22) EGFR wild type Total (N=21) Non-squamous (N=9) Squamous (N=12) ORR*, % 43.6% 60.0% 26.3% 22.2% 30.0% Median DoR, mo (95%CI) 9.3 (3.7, 10.3) 8.7 (3.7, 10.3) 9.6 (3.5, NE) / / Median PFS, mo (95% CI) 7.2 (5.4, 11.3) 11.5 (5.7, 12.9) 5.3 (3.5, 6.2) 5.8 (1.5, 12.1) 5.1 (1.9, 9.3) Median OS, mo (95% CI) 22.6 (13.1, NE) 22.7 (19.7, NE) 14.1 (10.7, NE) 16.2 (5.8, NE) 12.8 (3.5, NE) 12-mo OS rate, % (95% CI) 69.0% (52.7, 80.7) 81.0% (56.9, 92.4) 57.1% (33.8, 74.9) 66.7% (28.2, 87.8) 50.0% (20.8, 73.6) 18-mo OS rate, % (95% CI) 56.5% (40.1, 70.0) 76.2% (51.9, 89.3) 35.9% (16.0, 56.4) 44.4% (13.6, 71.9) 30.0% (7.7, 56.9) *Including confirmed or unconfirmed response. Based on response evaluable pts (≥1 on-study scans) with 4 pts (2 EGFR mutant pts with non-squamous histology and 2 EGFR wild type pts with squamous histology) excluded. Citation Format: Wenfeng Fang, Ying Cheng, Zhendong Chen, Wei Wang, Yongsheng Li, Yongmei Yin, Xingya Li, Huiting Xu, Guohua Yu, Yanjun Mi, Zev A. Wainberg, Jordi Rodon, Xiang Wang, Xian Wang, Xiaoqing Zhang, Xiaoping Jin, Lian Lu, Junyou Ge, Jin Li, Li Zhang. Updated efficacy and safety of anti-TROP2 ADC SKB264 (MK-2870) for previously treated advanced NSCLC in Phase 2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT247.

Background: Some patients with cancer-administered anti-cancer drugs may develop renal lesions with low-level enhancement on follow-up abdominal computed tomography (CT). Objective: To explore the clinical significance of renal lesions with low-level enhancement on CT after exposure to anti-cancer drugs. Methods: Medical records of patients with cancer who developed renal lesions on CT after exposure to anti-cancer drugs were retrospectively reviewed. Renal lesions were scored according to the extent of involvement, CT attenuation values of lesions and normal parenchyma were measured on precontrast CT and three phases of contrast-enhanced CT, and changes in serum creatinine (SCr) from one week before exposure to drugs to one week before and after the appearance of renal lesions were recorded. Results: This study included 54 patients (86 lesions). Lesions were slightly lower density on pre-contrast CT, and less enhancing than normal renal parenchyma, especially in the delayed phase. Lesions were wedge-shaped, and involved the renal pyramid and associated renal cortex, as well as, were single or multiple, and occurred in the unilateral or bilateral kidneys. There were patchy and cord-like shadows of increased density in adjacent perirenal adipose tissue. During follow-up, lesions disappeared in 15 patients and persisted in 39 patients without significant progression. There were significant differences in renal lesions and normal renal parenchyma CT attenuation values in each phase of contrast-enhanced CT. Change in SCr level was significantly positively correlated with lesion score. Conclusion: Renal lesions with low-level enhancement on CT suggest early drug-induced kidney injury. These findings will inform clinical decision-making.

Abstract Background: Overexpression of TROP2 (trophoblast cell surface antigen 2) in advanced gastric cancer is known as a poor prognostic factor. SKB264 (MK-2870) is a TROP2 ADC developed with a novel linker to conjugate the payload, a belotecan-derivative topoisomerase I inhibitor. The linker is affected by both extracellular pH-sensitive cleavage and intracellular enzymatic cleavage within tumor cells, which leads to efficiently release payload inside tumor cells as well as within tumor microenvironment to exert its anti-tumor effects. Here, we report the preliminary results from a Phase 2 expansion cohort in pts with advanced G/GEJ cancer. Methods: Pts with previously treated inoperable advanced G/GEJ adenocarcinoma were enrolled to receive SKB264 monotherapy at 5 mg/kg Q2W until disease progression or unacceptable toxicity in Phase 2 expansion cohort of KL264-01 study (NCT04152499). Pts with heavily pre-treated G/GEJ cancer were enrolled first, and then the cohort was amended to enroll pts with only one prior therapy of chemotherapy and anti-PD-1/L1 therapy. Tumor assessment was performed every 8 weeks per RECIST v1.1 assessed by investigator. Results: At data cutoff date (Nov 22, 2023), a total of 48 pts were enrolled and followed up for at least 9 weeks. 24 pts (50.0%) had received one prior line of therapy (2L), while 24 pts (50.0%) had received ≥ 2 prior lines of therapy (3L+). 40 pts (83.3%) had received prior anti-PD-1/L1 inhibitors. Treatment-related adverse events (TRAEs) of ≥ Grade 3 were reported in 52.1% of pts. The most common ≥ Grade 3 TRAEs (occurred in ≥5% of pts) were anemia (20.8%), neutrophil count decreased (18.8%), WBC decreased (12.5%) and neutropenia (6.3%). TRAEs leading to dose reduction and dose delay occurred in 18.8% and 33.3% of pts, respectively. No TRAEs leading to treatment discontinuation or deaths occurred. No neuropathy or drug-related ILD/pneumonitis was reported. Of 41 response-evaluable pts (defined as ≥ 1 on-study scans), the ORR was 22.0% (9 PRs, 2 pending confirmation) and disease control rate (DCR) was 80.5%. The ORRs in the 2L and 3L+ setting were 27.3% (including 2 pending confirmation) and 15.8%, respectively. Median duration of response (DoR) was 7.5 months (mos). In the subset of 3L+ pts (n=24 including 54.2% of pts with ≥ 4 prior lines of therapy) with more mature follow-up (median follow up of 14.6 mos), median progression free survival (mPFS) was 3.7 mos (95% Cl: 2.6, 5.4); median overall survival (mOS) was 7.6 mos (95% Cl: 5.3, 15.5) with 12-mo OS rate of 32.6%. Conclusions: The preliminary data suggests that pts with heavily pre-treated advanced G/GEJ cancer could achieve durable response and potentially prolonged OS from SKB264 monotherapy, with a manageable safety profile. A Phase 3 global study of SKB264 monotherapy vs SOC in 3L+ G/GEJ adenocarcinoma is being planned. Citation Format: Jordi Rodon, Zev A. Wainberg, Mingjun Zhang, Tianshu Liu, Bo Liu, Guohua Yu, Yongmei Yin, Shuang Zhang, Yanjun Mi, Xingya Li, Xian Wang, Yunpeng Liu, Xiang Wang, Ying Cheng, Xiaoqing Zhang, Yalan Yang, Junyou Ge, Omobolaji O. Akala, Elliot Chartash, Jin Li. Preliminary efficacy and safety results of anti-TROP2 ADC SKB264 (MK-2870) in patients (pts) with previously treated advanced gastric (G) or gastroesophageal junction (GEJ) cancer from a Phase 2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT038.

Polo-like kinase 1 (PLK1) inhibitor NMS-P937 is a targeted therapeutic agent with good preclinical efficacy in various human cancers, and its therapeutic effect on nasopharyngeal carcinoma (NPC) remains to be determined. Here, to explore biological activity of NMS-P937 in NPC, multiple types of NPC cells were utilized. We tested IC50 values, carried out flow cytometry, western blot analysis analysis, immunofluorescence, and constructed subcutaneous xenograft mouse models. We found that treatment with NMS-P937 increased the proportion of G2/M phase NPC cells, where CyclinB1 expression was upregulated and CyclinE1 expression was downregulated. Besides, NMS-P937 treatment-induced NPC cell apoptosis with increased cleavage of PARP and caspase-3. Mechanistically, NMS-P937 treatment led to aberrant mitosis, causing increased reactive oxygen species (ROS) levels. ROS scavenger N-acetylcysteine partially reversed ROS levels induced by NMS-P937. Furthermore, NMS-P937 administration restrained NPC xenografts growth in nude mice. Overall, NMS-P937 suppressed NPC cell proliferation and increased ROS levels, causing cell cycle abnormalities and apoptosis. NMS-P937 holds great promise as a therapeutic agent for treating nasopharyngeal carcinoma.

Supplementary Figure 2 from Apatinib (YN968D1) Reverses Multidrug Resistance by Inhibiting the Efflux Function of Multiple ATP-Binding Cassette Transporters

Supplementary Figure 1 from Apatinib (YN968D1) Reverses Multidrug Resistance by Inhibiting the Efflux Function of Multiple ATP-Binding Cassette Transporters

3007 Background: KL590586 (A400/EP0031) is a potent next-generation selective RET inhibitor (SRI) with activity against acquired resistance mutations to first-generation SRIs, and brain metastases (mets). Here we present preliminary data of the phase Ⅰ part from a phase I/II study (KL400-I/II-01, NCT05265091) in patients (pts) with RET-altered advanced tumors to define safety, pharmacokinetics (PK) and efficacy. Methods: The phase Ⅰ of KL400-I/Ⅱ-01 consisted of dose-escalation (Bayesian Optimal Interval design) and dose-expansion. Primary endpoints were to determine the maximum tolerated dose (MTD) and/or Recommended Phase II Dose. Secondary endpoints included safety, PK, objective response rate (ORR), disease control rate (DCR), and duration of response (DoR) as per RECIST 1.1. Results: As of Dec. 30, 2022, 87 pts with RET-altered tumors were treated at 6 doses levels (10 to 120 mg QD). No DLTs were observed, and MTD was not reached. Incidence of treatment-related adverse events (TRAEs, any grade) was 93.1% (81/87), most (74.7%) were grade 1-2, reversible and included (>25%): AST increase (50.6%), ALT increase (48.3%), creatinine increase (33.3%), bilirubin increase (32.2%), constipation (32.2%) and headache (31%). 24.1% of pts had grade ≥3 TRAEs, the most common (occurring in >2% of pts) were ALP increase (2.3%), GGT increase (2.3%), ileus (2.3%). TRAEs led to dose reduction or treatment discontinuation in 4.6% and 6.9% of pts, respectively. Hypertension, QT interval prolongation, platelets decrease and lymphocytes decrease (leading to 1st gen SRI dose delays and modifications frequently) were rare (<5%) and low-grade. The exposure increased dose-dependently and the mean half-life was found to be 34.1-99.8 h. Clinical responses were observed from 40mg onwards. 69 pts treated at the 40-120mg dose levels (57 NSCLC, 10 MTC, 1 pancreatic cancer, 1 ovarian cancer) were evaluable for efficacy analysis, ORR was 64% (NSCLC, MTC and pancreatic cancer). Most pts (58/69) remained on treatment, with the longest >11 months. The ORR in pts with systemic pretreated NSCLC (median prior treatment: 2, range 1-9, 28% pretreated with anti-PD1/PD-L1 therapy) was 63%(20/32, 1 CR), DCR 91% with median DoR not reached. 9 pts received prior 1st gen SRI, 7 with tumor shrinkage of -10% to -69%, with 3 PR and 4 SD. 11 pts with brain mets (without radiotherapy):4/5 with measurable brain disease had 100%, 100%, 80%, and 47% shrinkage. Overall CNS DCR was 100%.The ORR in treatment naïve NSCLC was 76% (19/25, 1 CR), DCR 92% and median DoR not reached. 3/4 pts with brain mets (without radiotherapy) had complete or partial disappearance of baseline brain lesions. Conclusions: KL590586 was well-tolerated, and associated with robust clinical activity in RET-altered tumors regardless of tumor type, including NSCLC pts with resistance to1st gen SRIs and with CNS mets. Pivotal studies are planned. Clinical trial information: NCT05265091 .

9114 Background: TROP2 (trophoblast cell surface antigen 2) is commonly overexpressed in non-small cell lung cancer (NSCLC) and associated with poor prognosis. SKB264 is a novel anti-TROP2 ADC developed using sulfonyl pyrimidine-CL2A-carbonate linker to conjugate its payload, a belotecan-derivative topoisomerase I inhibitor, to achieve an average Drug-to-antibody Ratio (DAR) of 7.4. The design was to achieve a more effective balance between stability in circulation and release of the ADC payload in tumor cells. Here we report clinical efficacy and safety results of SKB264 in the treatment of patients (pts) with NSCLC from a Phase 2 expansion cohort. TROP2 expression level by immunohistochemistry was assessed retrospectively. Correlation analyses between response and TROP2 level will be provided. Methods: This is a Phase 1/2, multicenter dose-escalation/expansion study in pts with relapsed or refractory locally advanced/metastatic NSCLC and other tumor types (NCT04152499). All NSCLC pts received SKB264 at 5 mg/kg IV Q2W. Tumor assessments based on RECIST 1.1 were performed every 8 weeks by investigators. Results: As of February 9 th , 2023, 43 pts (63% male, 88% ECOG PS 1, median age 58 yrs [44-74]) were enrolled. Median follow-up was 11.5 months (mo; 95% CI, 10.4-12.2). Median treatment duration was 5.7 mo (range, 0.5-14.1). Among 39 response-evaluable pts, the ORR was 44% (17/39, 15 confirmed and 2 pending confirmation), median DoR was 9.3 mo (range, 1.3+ to 11.2+), 6-month DoR rate was 77%. For EGFR wild type subgroup (previously received median 2 lines of therapy including anti-PD-1/L1), the ORR was 26% (5/19), DCR was 89% (17/19), median PFS was 5.3 mo, and 9-month OS rate was 80.4%. For subgroup with TKI resistant EGFR mutant NSCLC (50% also failed at least one line of chemotherapy), the ORR was 60% (12/20), DCR was 100% (20/20), median PFS was 11.1 mo, and 9-month PFS rate was 66.7%. 67.4% (29/43) of pts had Grade ≥ 3 treatment-related adverse events (TRAEs). The most common Grade ≥3 TRAEs (occurred in ≥5% of pts) were neutrophil count decreased (32.6%), anemia (30.2%), white blood cell count (WBC) decreased (23.3%), stomatitis (9.3%), rash (7.0%), and lymphocyte count decreased (7.0%). Grade 4 TRAEs occurred only for neutropenia and WBC decreased. Most of the hematology toxicity occurred within the first two months of treatment and resolved after treatment with granulocyte colony stimulating factor or erythropoietin without blood transfusions. 23.3% (10/43) of the pts experienced dose reduction due to TRAEs. No neuropathy or drug-related ILD/pneumonitis was reported. No TRAEs led to treatment discontinuation or death. Conclusions: SKB264 at 5 mg/kg Q2W demonstrated encouraging anti-tumor activity and manageable safety profile in pts with relapsed or refractory locally advanced/metastatic NSCLC. TRAEs were mainly hematologic. Phase 3 studies of SKB264 in pts with advanced NSCLC have been planned. Clinical trial information: NCT04152499 .