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 .

Supplementary Table 1 Final Product Release Criteria for UTAA06 Supplementary Table 2 Representativeness of Study Participants Supplementary Table 3 Baseline Characteristics and Clinical Outcomes of Individual Patients Supplementary Table 4 Characteristics of UTAA06 Products Supplementary Table 5 Serum Tumor Marker Kinetics

Objective:. Despite radical resection, postoperative recurrence of nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs) remains common, particularly among high-risk patients. This study evaluates the adjuvant therapeutic potential of Qizhen Yiliu Formula (QZYL) in a multicenter real-world cohort. Methods:. We retrospectively analyzed patients with NF-PanNETs treated at 5 tertiary centers in China between 2010 and 2022. Patients were divided into QZYL and control groups based on receipt of QZYL as postoperative adjuvant therapy. Baseline differences were adjusted using propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) sensitivity analysis. Three hundred and eighty-five eligible patients were analyzed, with 112 matched pairs. Results:. QZYL treatment was associated with longer recurrence-free survival (RFS) compared with controls (median: 78.0 vs 71.9 months; hazard ratio [HR] = 0.60, P = .027), with higher 24-, 36-, and 60-month RFS rates (90.92% vs 80.36%, 86.14% vs 70.07%, 64.97% vs 55.56%, respectively). Subgroup analyses demonstrated trends favoring QZYL across high-risk strata (Ki-67 index 10%–20%, tumor size ≥4 cm, lymph node metastasis, and pathological invasion), although statistical significance varied between PSM and IPTW analyses. Among patients receiving other adjuvant therapies, QZYL use was associated with improved outcomes (HR = 0.56, P = .070). Safety analysis indicated that QZYL did not increase the overall incidence of adverse events (P = .847) and was associated with a lower incidence among patients receiving other adjuvant therapies (P = .010). Conclusions:. QZYL use was associated with a reduced risk of postoperative recurrence in patients with high-risk NF-PanNET, suggesting its role in postoperative management. Prospective validation is warranted.

PURPOSE:The clinical efficacies of third- or later-line therapies for metastatic colorectal cancer (CRC) are extremely limited. The purpose of this study was to evaluate the safety and efficacy of a chimeric antigen receptor T (CAR T) cell targeting guanylyl cyclase 2C (GUCY2C) that was steadily expressed in all stages of CRC in a phase I study. PATIENTS AND METHODS:This was an open-label, single-center, phase I study, consisting of a 3 + 3 pattern dose-escalation phase and a dose-expansion investigation. Tumor tissues were histologically confirmed positive for GUCY2C expression. Four dose levels were tested in the dose-escalation phase, including 3 × 108 (DL1), 6 × 108 (DL2), 12 × 108 (DL3), and 20 × 108 (DL4) CAR T cells. The primary end points were safety and tolerability within 28 days after the first infusion. RESULTS:In the dose-escalation phase, dose-limiting toxicity was not observed. DL3 was chosen for dose-expansion study. A total of 20 patients with metastatic CRC were infused with GUCY2C CAR T after lymphodepletion, and only one patient (5.0%) showed grade 3 cytokine release syndrome and neurotoxicity. Grade 3 diarrhea occurred in 11 patients (55.0%). Of 19 evaluable patients, the objective response rate (ORR) was 26.3%, with all responding patients in DL3 and DL4 groups. Of 10 patients in the DL3 group, the ORR was 40.0% and the median progression-free survival time (mPFS) was 7.0 months. Among patients showing medium-to-high GUCY2C expression in the DL3 group, the ORR achieved 50.0% and the mPFS was 9.0 months. CONCLUSION:GUCY2C CAR T showed acceptable safety profile and high response rate in patients with third- or later-line CRC, and the clinical efficacy was associated with CAR T dose level.

Supplementary Figure 1 Specificity profiling of the anti-B7-H3 scFv using the Membrane Proteome Array (MPA). Supplementary Figure 2 Study Dose-Escalation Schema. Supplementary Figure 3 Association of Peak CAR-T Cell Expansion (Cmax) with Clinical Outcomes. Supplementary Figure 4 Lymphocyte Reconstitution Dynamics Following UTAA06 Infusion. Supplementary Figure 5 Longitudinal Serum Cytokine Dynamics Following UTAA06 Infusion. Supplementary Figure 6 Association of Cytokine Fold-Change with Clinical Outcomes. Supplementary Figure 7 Host CD8+ Activation and CAR-T Copy Number Kinetics for Individual Patients. Supplementary Figure 8 Longitudinal analysis of NK cell activation and inhibitory markers in patient P10.

Immune checkpoint inhibitor (ICI) plus an anti-angiogenic agent has shown antitumor activity in patients whose disease had progressed on a prior ICI but further evidence across tumor types is needed. This phase 2 trial evaluated the efficacy and safety of surufatinib (anti-angiogenic multi-tyrosine-kinase inhibitor, 250 mg orally, once daily) plus toripalimab (programmed-death-1 [PD-1] inhibitor, 240 mg intravenously, once every three weeks) in adult patients with advanced solid tumors and progression on a PD-1/programmed death ligand 1 inhibitor. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A total of 28 patients were enrolled and received treatment. Two of 27 evaluable patients achieved partial response, for an ORR of 7.4

3536 Background: Proficient mismatch repair/microsatellite stable (pMMR/MSS) metastatic colorectal cancer (mCRC) is largely resistant to immune checkpoint inhibitors, with limited options after standard therapies. IDOV-Safe is a systemically deliverable, vaccinia virus-based oncolytic virotherapy. This phase 1 clinical trial evaluated the safety and preliminary efficacy of intravenous IDOV-Safe combined with toripalimab and fruquintinib in patients with pMMR/MSS mCRC (NCT06380309). Methods: Patients with pMMR/MSS mCRC who had progressed on or were intolerant to ≥2 prior systemic therapies were enrolled. Dose escalation used a 3+3 design across four dose levels (1×10 9 , 3×10 9 , 1×10 10 , and 3×10 10 PFU). In expansion, three combination strategies with immune-target therapy were evaluated: sequential, early, and IO free combinations using fruquintinib with or without toripalimab. Primary endpoints were safety and objective response rate (ORR). Results: Fifty-five patients were enrolled; 80% had received ≥3 prior treatment lines. Dose-limiting toxicities at 1×10 10 PFU led to selection of 1×10 9 and 3×10 9 PFU for expansion. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 62% of patients, most commonly fever, thrombocytopenia, and neutropenia; grade ≥3 immune-related events were infrequent (2%), and no grade ≥3 TRAEs were attributed to fruquintinib. In sequential combination cohorts, objective responses occurred only after initiation of combination therapy. ORR was 33.3% at 1×10 9 PFU (IIA1) and 30.0% at 3×10 9 PFU (IIA2), with disease control rates (DCRs) of 50.0% and 70.0%, respectively. In early combination cohorts, objective responses were observed at 3×10 9 PFU (IIC2; ORR 16.7%), with high DCRs (83.3% in IIC1 and 91.7% in IIC2). The DCR in the IO-free cohort (IID) was 50.0%. Median progression-free survival (mPFS) across five cohorts was 5.4 (IIA1), 8.7 (IIA2), 5.4 (IIC1), 5.5 (IIC2), and 4.6 months (IID). Conclusions: Intravenous IDOV-Safe demonstrated a favorable safety profile and encouraging preliminary antitumor activity when combined with toripalimab and fruquintinib, particularly using a sequential combination strategy in heavily pretreated patients with pMMR/MSS mCRC. Clinical trial information: NCT06380309 . Response to IDOV-safe and immuno-targeted therapy. Response IIA1 1×10 9 IIA2 3×10 9 IIC1 1×10 9 IIC2 3×10 9 IID 3×10 9 Best overall response — n (%) Partial response 2 (33.3) 6 (30.0) 0 2 (16.7) 0 Stable disease (SD) 1 (16.7) 8 (40.0)* 5 (83.3) 9 (75.0) 3 (50.0) Progressive disease 3 (50.0) 5 (25.0) 0 1 (8.3) 2 (33.3) Not evaluable 0 1 (5.0) 1 (16.7) 0 1 (16.7) ORR—Percent (95% CI) 33.3 (4.3, 77.7) 30.0 (11.9, 54.3) 0 16.7 (2.1, 48.4) 0 DCR —Percent (95% CI) 50.0 (11.8, 88.2) 70.0 (45.7, 88.1) 83.3 (35.9, 99.6) 91.7 (61.5, 99.8) 50.0 (11.8, 88.2) *One patient in IIA2 cohort had unconfirmed SD.

PURPOSE:Despite emerging genomic discoveries, few have been translated into practical management strategies for people with gastroenteropancreatic neuroendocrine carcinoma (GEPNEC). This study aims to identify key genes and their potential clinical relevance to improve care for this patient group. METHODS:In the analytical cohort, we reported high-frequency alteration genes, significantly mutated genes, and driver genes and defined their overlap as key genes. Genotypes were identified as Type I/II/III. For further validation, we prospectively recruited eligible patients to build a main cohort, through which we performed univariate/multivariate Cox regression analysis and sketched Kaplan-Meier survival plot. Targetable genes were defined by the OncoKB database. RESULTS:The analytical cohort consisted of 124 patients. The genes most frequently altered were TP53 (78%), RB1 (35%), APC (27%), and KRAS (17%). Key genes were identified as TP53, RB1, APC, and KRAS. The main cohort included 171 patients. We defined the genotype "Type I" (defined as TP53/RB1 co-alterations) as a reference. In midgut/hindgut NEC, we identified a "Type II" subtype characterized by mutations in either APC or KRAS alterations without TP53/RB1 co-alterations. Type II of midgut/hindgut NEC patients had elevated carcinoembryonic antigen (CEA) levels and longer median overall survival (mOS) than others (not reached vs 11.4 months, HR = 0.19[0.08, 0.44], P = .0028). In foregut NEC, we identified "Type III" (either APC/KRAS alterations or TP53/RB1 co-alterations). Type III of foregut NEC patients showed shorter mOS than others (11.6 vs 19.0 months, HR = 1.93[1.13, 3.25], P = .01). Type II patients who received non-platinum/etoposide (EP) chemotherapy had longer first-line progression-free survival (PFS) compared to EP regimen. They also benefited from second-line immunotherapy. Targeted therapy as second-line was also suitable for targetable patients (longer PFS than others: 12.5 vs 3.0 months, HR = 0.40[0.21-0.75], P = .0017). CONCLUSIONS:Our study identified key gene-based genotypes (Type II/III) of distinct GEPNEC patients and yielded their prognosis and therapeutic utility.

Abstract Background: Cadherin-17 (CDH17), belonging to a subclass of the 7D-cadherin superfamily, is a biomarker for gastrointestinal (GI) cancers characterized by its overexpression in multiple GI cancers but controlled expression in normal tissues from healthy adults. CDH17 is therefore considered a possible therapeutic target for GI cancers. DB-1324 is an anti-CDH17 antibody-drug conjugate (ADC) in which a humanized antibody is linked to a proprietary topoisomerase I inhibitor payload via a cleavable tetrapeptide-based linker, with a drug-antibody ratio of approximately 8. Preclinical studies of DB-1324 showed that DB-1324 specifically binds to the CDH17 extracellular domains, with no binding to other cadherin family proteins. It demonstrated antitumor activity in human CDH17-positive murine cancer models and an acceptable safety profile, warranting further clinical development. Methods: This is a global, first-in-human, Phase 1/2 study to assess the safety, tolerability, pharmacokinetics, and antitumor activity of DB-1324 in participants with advanced/unresectable, or metastatic GI tumors (NCT07263594). Eligible participants must have a GI tumor (regardless of CDH17 or other biomarker expression levels) that has relapsed or progressed on or after standard systemic treatments, or is intolerable with standard treatment, or for which no standard treatment is available; have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1; and evidence adequate organ function. Multiple dose levels of DB-1324 will be evaluated to identify the maximum tolerated dose in Phase 1, which includes Dose Escalation, Backfill, and Dose Expansion. Phase 2 will consist of one or more cohorts intended to confirm early signals of efficacy identified in Phase 1. DB-1324 will be administered intravenously as monotherapy until disease progression, loss of clinical benefit, unacceptable toxicity, withdrawal of consent, or loss to follow up. The study plans to enroll approximately 127 participants in Phase 1 Dose Escalation and Backfill parts from locations including but not limited to Australia, United States and China. The study is currently open in multiple centers and is currently recruiting. Citation Format: Lin Shen, Jifang Gong, Jermaine Coward, Rajiv Shinde, Joe Wei, Yanhong Deng, Yanqiao Zhang, Ming Lu, Meili Sun, Sreenivasa Chandana, Davendra Sohal, Ting Zhang, Hua Mu, Yuran Liang, Haiqing Hua, Xiaodong Sun, Yang Qiu, Jiajia Chen, Zhongyuan Zhu. A phase 1/2, first-in-human study of an ADC targeting CDH17 (DB-1324) in participants with advanced/metastatic gastrointestinal tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT086.

Abstract Purpose: The aim of the study was to evaluate the safety, pharmacokinetics, and preliminary clinical activity of UTAA06, an “off-the-shelf” allogeneic B7-H3–targeted chimeric antigen receptor (CAR) Vδ1T-cell therapy, in patients with pretreated, advanced B7-H3–positive solid tumors. Patients and Methods: In this first-in-human, phase I, dose-escalation study (NCT06372236), 10 patients with advanced solid tumors (including gastric, colorectal, hepatocellular, ovarian, and neuroendocrine cancers) were enrolled. Following lymphodepletion chemotherapy (cyclophosphamide and fludarabine), patients received UTAA06 infusion across three dose levels (5 × 108, 8 × 108, or 1 × 109 cells). The primary endpoint was safety. Secondary endpoints included pharmacokinetics and antitumor efficacy. Results: UTAA06 demonstrated a manageable safety profile; no GVHD was observed, and cytokine release syndrome was limited to two transient grade 1 events. A single dose-limiting toxicity (grade 3 pneumonitis) was reported in one patient at the 5 × 108 cell dose level. Although UTAA06 demonstrated signals of biological activity, including transient reductions in serum tumor markers in 50% of patients, no objective response by RECIST v1.1 criteria was observed. Further analysis identified that the limited CAR T-cell persistence was likely driven by subclinical host-versus-graft rejection. Conclusions: This study provides clinical proof of concept for allogeneic B7-H3–targeted CAR-Vδ1T cells as a safe platform with low risk of GVHD and demonstrable biological activity in solid tumors. However, clinical efficacy was constrained by limited cellular persistence caused by host immune rejection. Future strategies are required to enhance the durability and therapeutic potential of this allogeneic approach.

Research on patients with advanced esophageal squamous cell carcinoma (ESCC) who have progressed on immunotherapy remains limited. BL-B01D1 is a first-in-class antibody-drug conjugate consisting of an EGFR-HER3 bispecific antibody bound to a topoisomerase I inhibitor (Ed-04) payload via a cleavable linker. Here, we present safety and efficacy data from a phase 1 study of BL-B01D1, in 82 patients previously treated for ESCC. The primary endpoint was the recommended phase 2 dose. Administered doses were 2.0 (n = 22) and 2.5 (n = 60) mg kg-1 D1D8 infusion every 3 weeks (Q3W). The confirmed objective response rate (cORR) was 29.3% (24 of 82) in all patients and 32.9% (24 of 73) among evaluable patients. For patients dosed at 2.5 mg kg-1, cORR was 39.6% (21 of 53) and disease control rate was 79.2% (42 of 53). In the 2.0 mg kg-1 group, cORR was 15.0% (3 of 20), and the disease control rate was 50.0% (10 of 20). The phase 2 dose was established at 2.5 mg kg-1 D1D8 Q3W. The incidence of G3 treatment-related adverse events at 2.5 mg kg-1 was 63.3%; most common adverse events were anemia (28.3%), leukopenia and thrombocytopenia (18.3%, each), and neutropenia (16.7%). Two cases of ≥G3 interstitial lung disease were observed. Overall, BL-B01D1 demonstrated promising efficacy and manageable safety in patients with metastatic ESCC. A further phase 3 clinical trial has already been initiated. ClinicalTrials.gov registration: NCT05262491 .

Introduction and Objective: Type 2 diabetes mellitus (T2DM) and its complications are associated with alteration of gut bacterial composition, but little is known about the gut virome. Here, we characterized the gut virome alterations in newly diagnosed T2DM with or without diabetic ketosis (DK). Methods: Totally 35 healthy controls, 47 newly diagnosed T2DM patients were enrolled. Among them, 16 patients were accompanied by DK and 31 patients were without DK. We characterized and compared the gut virome. Results: Compared with controls, T2DM patients, especially those with DK, exhibited a significant increase in the diversity of the gut virome and had a visibly altered overall structure.In virus group differential analysis, we found an increase in the relative abundance of Myovirdae in DK patients, compared with controls and T2DM-nonDK. Functional analysis revealed that viral functions related to 6-pyruvoyl tetrohydropterin synthase, GTP cyclohydrolase I, which could modulate tetrahydrobiopterin (BH4) metabolism, were distinguished between DM and control groups. Conclusion: T2DM is characterized by altered gut viral diversity, changes in specific virus species, and disturbance of multiple viral functions. DK may aggravate the changes and disturbance. These findings indicated the role of human virome in elucidating potential mechanisms and providing novel therapeutic strategies for T2DM and DK. M. Lu: None. C. Liu: None. X. Zhang: None. National Natural Science Foundation of China (82100829)

The prognosis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) following metastasis is often poor. The efficacy of 177Lu-DOTATATE therapy and the subgroups that benefit from it remain unclear. Our objective is to characterize the composition of the tumor immune microenvironment in GEP-NETs and to identify predictive biomarkers associated with response and PFS following 177Lu-DOTATATE. Multiplex immunofluorescence (mIF) staining of tumor sections was used to characterize the cellular density and spatial organization of the microenvironment of 50 NET patients. The relationship between baseline immune microenvironment and 177Lu-DOTATATE efficacy or prognosis in 20 177Lu-DOTATATE-treated patients was explored. Patients with GEP-NET exhibited an immunosuppressive microenvironment. The overall response rate (ORR) to 177Lu-DOTATATE therapy was 60

Background:High-grade neuroendocrine neoplasms (NENs) have limited treatment options following first-line platinum-based chemotherapy, often resulting in poor clinical outcomes. Dual immune checkpoint blockade targeting CTLA-4 and PD-1 offers a synergistic approach by enhancing T-cell activation and amplifying anti-tumor immune responses. This study evaluates the efficacy and safety of HBM4003, a novel fully human anti-CTLA-4 monoclonal antibody, in combination with toripalimab, a PD-1 inhibitor, in patients with high-grade, refractory NENs. Methods:This multicenter, open-label, phase II study enrolled patients with neuroendocrine carcinomas (NECs), grade 3 NETs (NETs G3), and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) who had progressed on first-line therapy. Patients received HBM4003 at either 0.3 mg/kg or 0.45 mg/kg in combination with toripalimab (240 mg) every three weeks. The primary endpoint was the objective response rate (ORR). The study was registered on ClinicalTrials.gov (NCT05167071). Findings:Between December 2021 and May 2024, a total of 29 patients were enrolled (NECs, n = 22; NETs G3, n = 3; MiNENs, n = 4). All patients had previously undergone chemotherapy, with 11 receiving ≥2 lines of therapy. Thirteen (13) patients had lung metastasis and 18 had liver metastasis. Patients were assigned to the HBM4003 0.3 mg/kg cohort (n = 13) or the 0.45 mg/kg cohort (n = 16), with 26 patients forming the efficacy analysis set. The overall ORR was 34.6% (95% confidence intervals [CI], 17.2-55.7), and the disease control rate (DCR) was 65.4% (95% CI, 44.3-82.8). Median progression-free survival (PFS) and overall survival (OS) were 4.0 months (95% CI, 1.6-5.1) and 21.8 months (95% CI, 16.7-not estimated [NE]), respectively. For 19 NEC patients in the efficacy analysis set, the ORR and DCR were 36.8% (95% CI, 16.3-61.6) and 68.4% (95% CI, 43.4-87.4), respectively. The median PFS was 4.0 months (95% CI, 1.6-5.4), while the median OS was not reached (95% CI, 13.5-NE). Of the 29 NEN patients receiving at least one dose of study treatment, all patients experienced at least one treatment-related adverse event (TRAE), with 10 (34.5%) experiencing grade ≥3 TRAE and eight (27.6%) experiencing grade ≥3 immune-related adverse events. Interpretation:HBM4003 combined with toripalimab demonstrated promising anti-tumor activity and manageable safety in patients with refractory NENs, supporting further investigation of this combination therapy. Funding:This study was funded by Harbour BioMed (Shanghai) Co. Ltd.

Combining the programmed death-1 inhibitor toripalimab and the angio-immuno kinase inhibitor surufatinib showed preliminary antitumor activity in patients with advanced solid tumors in a phase I study. Here, we report the efficacy and safety of this combination regimen in treatment-naive advanced or metastatic non-small-cell lung cancer (NSCLC) patients with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of 1

Introduction The development of novel, effective and well-tolerated biological strategies to treat primary and secondary CNS lymphoma (CNSL) is a significant priority. We are evaluating tafasitamab, a humanized anti-CD19 monoclonal antibody, as a novel therapeutic for relapsed/refractory (R/R) PCNSL and SCNSL. We hypothesize that tafasitamab may have unique activity given enhanced ADCC as well as potential CNS penetration via perturbation of CD19 expressed on mural cells, a component of the blood-brain barrier. We reported that the tafasitamab/lenalidomide combination induced brain parenchymal regressions in two consecutive cases of relapsed PCNSL and SCNSL, each with disease refractory to methotrexate, lenalidomide and rituximab. (Rauschecker et al., Br J Haematol 2023). One of these responses has been durable, exceeding 3.5 years. Methods This single-arm, open-label, multicenter Phase I/II study (NCT05351593) was designed to assess the safety and preliminary efficacy of tafasitamab plus lenalidomide in R/R PCNSL/SCNSL. The study applies 3+3 dose escalation rules to identify the recommended phase 2 dose (RP2D), analyzing lenalidomide doses of 10mg, 15mg and 20 mg plus standard dose intravenous tafasitamab (12 mg/kg). After the RP2D is identified, the Phase II portion of the study will begin. The primary objective of the Phase II expansion is to evaluate the clinical benefit rate (stable disease or better) via Simon's minimax two-stage design. Results Thus far nine patients (8 PCNSL, 1 SCNSL, all large B-cell lymphoma) have been treated on protocol (4 male/5 female; median age 66, range 59-75). The cohort was exposed to a median of three prior lines of therapy (range 1-6) and four had prior IMiD exposure. Among the 7 PCNSL pts with baseline lymphoma mutational data available, 6 had high risk aberrations, as identified by Geng et al., Blood Advances 2025. The combination of tafasitamab plus lenalidomide has been well-tolerated with only one grade 3 adverse event related to study drugs (febrile neutropenia associated with urinary tract infection) and no evidence of neurotoxicity. The activity of tafasitamab plus lenalidomide has been confirmed thus far in R/R PCNSL/SCNSL, at both 10 mg and 20 mg dose levels, with median of 24 days to best response, and in each compartment within the neuroaxis, resulting in 3 CRs, 4 PRs and one SD. The study drug combination has shown efficacy in three patients whose tumors had progressed on lenalidomide. One patient on study treated with tafasitamab plus lenalidomide at the 10 mg dose level experienced rapid clearance of leptomeningeal lymphoma (confirmed by flow-cytometry and cytology) and partial regression of a brain parenchymal lesion, disease previously refractory to lenalidomide dosed at 15mg/d, intravenous rituximab and high-dose methotrexate. The second patient, with disease refractory to methotrexate, temozolomide, rituximab, etoposide plus cytarabine, ASCT (Thiotepa/BCNU) and lenalidomide, had near complete resolution of a 2.5 cm enhancing cerebellar mass within one month of tafasitamab plus lenalidomide, 15 mg/day. The third patient, treated with tafasitamab plus lenalidomide at 15 mg/day on study, experienced stable disease lasting 6.5 months on study. The durations of complete response in brain parenchyma have thus far exceeded 6 months in two patients, with the longest response, 8 months, exceeding by > 2-fold the response duration in this patient to up-front high-dose methotrexate, temozolomide, and intravenous rituximab. Three patients currently receive tafasitamab/lenalidomide on study. Serial ELISA measurements of IL-10 in CSF were associated with response and resistance. Declines in IL-10 correlated with both clinical responses and radiographic stable disease, whereas increases in IL-10 signaled impending radiographic progression. Conclusions These phase I trial data support the activity and safety of tafasitamab plus lenalidomide in heavily pre-treated, high-risk, R/R PCNSL/SCNSL, including in tumors that had progressed on lenalidomide and rituximab. These preliminary results may indicate an enhanced efficacy and/or synergy of the tafasitamab/lenalidomide combination in the CNSL tumor microenvironment. The combination has been well-tolerated at lenalidomide 10 and 15 mg dose levels and accrual continues at the lenalidomide 20 mg dose level with the aim of determining the RP2D. Supported by the Leukemia and Lymphoma Society.

Background:Patients with advanced extrapulmonary neuroendocrine carcinoma (EP-NEC) usually present with metastatic disease and have a poor prognosis. No standard therapies have been established beyond the first-line platinum-based chemotherapy. This study aims to evaluate the efficacy and safety of nab-paclitaxel plus bevacizumab in patients with previously treated advanced EP-NEC. Methods:This multicenter, single-arm, phase 2 trial was conducted from January 2021 to March 2024 to evaluate the efficacy and safety of nab-paclitaxel plus bevacizumab in patients with advanced EP-NEC who progressed after prior standard-of-care treatments. Patients were assigned to receive nab-paclitaxel of 150 mg/m2 plus bevacizumab of 5 mg/kg intravenously every 2 weeks in a cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall survival (OS). The secondary endpoints included the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), and safety. The study was registered at ClinicalTrials.gov: NCT04705519 (https://clinicaltrials.gov/study/NCT04705519?cond=NCT4705519&rank=1). Findings:A total of 79 patients were enrolled, with 40 patients receiving ≥2 lines of therapy. After a median follow-up of 22.4 (Interquartile Range [IQR] 14.7-42.9) months, the median OS was 12.8 (95% CI, 8.6-17.4) months. The median PFS was 5.3 (95% CI, 4.2-6.6) months. Among 76 patients with assessable best response, the ORR was 55% (42/76, 95% CI 43-67%), and DCR was 87% (66/76, 95% CI 77-94). The median DoR was 5.7 (95% CI, 3.3-7.2) months. Patients with gastric NEC had a numerically higher ORR compared with those with NEC from other sites, but statistical significance was not achieved (26/39, [67%] vs. 16/37, [43%]; P = 0.068); however, no statistically significant difference in PFS (6.6 [95% CI 3.9-7.5] vs. 4.6 [95% CI 2.6-6.3]; P = 0.13) or OS (14.4 [95% CI 7.7-18.4] vs. 10.0 [95% CI 7.2-20.0]; P = 0.76) was observed. Multivariable analyses identified that metastatic organs >2 was the independent factor significantly associated with worse PFS (HR 2.06, 95% CI 1.20-3.56; P = 0.0092) and OS (HR 1.86, 95% CI 1.04-3.30; P = 0.035). Most treatment-related adverse events (TRAEs) (≥10%) of grade ≥3 were neutropenia (28/79, 35%) and leukopenia (15/79, 19%). Interpretation:Patients with metastatic EP-NEC achieved a high response rate and encouraging survival with tolerable toxicity. The combination regimen has the potential to become a valuable treatment option, if further controlled studies confirm its efficacy for patients who have exhausted standard therapies. Funding:This study was partially supported by Qilu Pharmaceutical Co., Ltd. This work is supported by the Beijing Municipal Science & Technology Commission (No. Z231100007223002).