Human IgG1 Monoclonal Antibody Research Articles

Adopting adalimumab combined surgery in the management of moderate to severe hidradenitis suppurativa: Experience from a single medical center in southern Taiwan.

Hidradenitis suppurativa (HS) is a chronic inflammatory disorder primarily affecting the intertriginous and anogenital regions. Guidelines recommend various treatments for HS, including biologic agents like adalimumab for moderate to severe cases. Adalimumab is a type of human monoclonal IgG1 antibody designed to target tumor necrosis factor α. Recent studies have shown the effectiveness of adalimumab, either alone or combined with surgery, in managing HS. We retrospectively analyzed the medical chart of HS patients in a southern Taiwan medical center from 2019 to 2022 and investigated clinical features and treatment response. The institutional review board at Chang Gung Medical Foundation granted approval for the study. We primarily focused on moderate to severely affected patients. One hundred and two clinically diagnosed HS patients participated, with a male-to-female ratio of 2:1 and an average age of 31.8 at diagnosis. Among them, 41.2% were in Hurley stage III and 32.4% in stage II. Nineteen patients received excision with pre-surgical adalimumab; their average age at diagnosis was 31.1, with a gender ratio of 5.3:1. Surgery was most common on the buttocks (68%), axillae (21%), and groin (10%). Excision patients were primarily in advanced stages (Hurley III 94.7%, II 5.3%) with high body mass index. Adalimumab and surgery combined yielded a 68.4% improvement rate, while 15.8% remained stable and 15.8% did not respond as expected. In addition, smoking and obesity were prevalent among patients. Adalimumab showed promising results in moderate to severe HS, with significant improvement observed in our cases. The combination of adalimumab and surgery appeared effective in advanced HS patients with larger involved areas and more tunnels. No severe adverse events were reported. However, our study was limited by its retrospective nature and the lack of a control group. Despite these limitations, our study revealed the benefits of integrating adalimumab with suitable surgical procedures in managing patients experiencing moderate to severe HS in real-world scenarios.

Advances in Understanding and Managing Alzheimer's Disease: From Pathophysiology to Innovative Therapeutic Strategies.

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by the presence of amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles, leading to cognitive and physical decline. Representing the majority of dementia cases, AD poses a significant burden on healthcare systems globally, with onset typically occurring after the age of 65. While most cases are sporadic, about 10% exhibit autosomal forms associated with specific gene mutations. Neurofibrillary tangles and Aβ plaques formed by misfolded tau proteins and Aβ peptides contribute to neuronal damage and cognitive impairment. Currently, approved drugs, such as acetylcholinesterase inhibitors and N-methyl D-aspartate receptor agonists, offer only partial symptomatic relief without altering disease progression. A promising development is using lecanemab, a humanized IgG1 monoclonal antibody, as an immune therapeutic approach. Lecanemab demonstrates selectivity for polymorphic Aβ variants and binds to large soluble Aβ aggregates, providing a potential avenue for targeted treatment. This shift in understanding the role of the adaptive immune response in AD pathogenesis opens new possibilities for therapeutic interventions aiming to address the disease's intricate mechanisms. This review aims to summarize recent advancements in understanding Alzheimer's disease pathology and innovative therapeutic approaches, providing valuable insights for both researchers and clinicians.

Pharmacokinetics of Briquilimab as a Conditioning Agent for Hematopoietic Stem Cell Transplantation in Patients With Severe Combined Immunodeficiency, Myelodysplastic Syndrome, or Acute Myeloid Leukemia

For successful engraftment of donor hematopoietic stem cells (HSC), conditioning with chemotherapy and/or radiation prior to hematopoietic cell transplantation (HCT) has been required to open marrow niche space and minimize the risk of immune rejection. Briquilimab, a humanized IgG1 monoclonal antibody that blocks the interaction between the c-Kit receptor and stem cell factor on various C-Kit expressing tissues including HSC, is a potential nonmyeloablative conditioning agent in clinical development for patients with severe combined immunodeficiency (SCID), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). This study aimed to characterize pharmacokinetics (PK) and develop a population PK model of briquilimab after single intravenous infusions of 4 different doses in patients with SCID, MDS, or AML receiving HCT. The PK data was collected from 2 different studies: JAS-BMT-CP-001 and JSP-CP-003. JAS-BMT-CP-001 is a phase 1/2 open-label study of briquilimab as a conditioning agent prior to allogenic HCT in SCID patients. The participants received single intravenous infusions of 0.1, 0.3, 0.6, or 1.0 mg/kg. JSP-CP-003 was a phase 1a/b open-label study of briquilimab in combination with a standard conditioning regimen of low dose total body irradiation and fludarabine in MDS or AML subjects undergoing HCT. The participants received a single intravenous dose of 0.6 mg/kg briquilimab. In both studies, briquilimab PK samples were obtained at pre-treatment, 5 minutes post-end of infusion, 4- and 24-hours post-start of infusion, any time between 2 days and 30 days postinfusion, and on the day of HCT prior to donor cell infusion.The population PK model was developed using the PK data from these 2 clinical studies, and the effect of participants’ baseline characteristics on the briquilimab PK was evaluated. PK simulations were performed using the developed PK model to calculate the time to reach target concentrations for HCT. A total of 49 participants (21 SCID adult and pediatric participants with a median age of 12 yr and 28 MDS/AML adult participants with a median age of 70 yr) were included in the PK analysis. A 2-compartment model with combined linear and non-linear elimination best described the PK of briquilimab. Body weight was determined as the sole covariate of the PK parameters among the explored covariates. For a typical subject with a body weight 70 kg, the estimated parameters for clearance, maximum metabolic rate of Michaelis Menten elimination, Michaelis Menten constant, central volume, peripheral volume, and intercompartmental clearance were 17.6 mL/h, 51,434.8 ng/h, 71.5 ng/mL, 3444.0 mL, 1613.3 mL, and 21.2 mL/h, respectively. The median time to reach target concentrations of 500, 1000, and 2000 ng/mL after a single dose of 0.6 mg/kg was calculated as 12.3, 10.4, and 7.7 days, respectively. The PK of intravenous briquilimab was characterized in subjects with SCID, MDS, or AML receiving HCT, and a population PK model was developed to estimate briquilimab clearance to use as a guide to the timing of donor cell infusion post-briquilimab. Body weight was identified as a significant covariate on elimination and volume of distribution of briquilimab.

Safety and efficacy of burosumab in improving phosphate metabolism, bone health, and quality of life in adolescents with X-linked hypophosphatemic rickets

Background and objectiveX-linked hypophosphatemic rickets (XLH) is due to loss-of-function mutations in the phosphate-regulating endopeptidase homologue on the X chromosome (PHEX) that lead to increased fibroblast growth factor 23 (FGF23) production. FGF23 excess causes renal phosphate wasting and insufficient 1,25-dihydroxyvitamin D (1,25(OH)2D) synthesis with reduced intestinal phosphate absorption, ultimately resulting in chronic hypophosphatemia.Children with XLH show typical skeletal lesions of rickets, deformities of the lower limbs, stunted growth with disproportionate short stature, bone pain, and physical dysfunctions.Burosumab, a fully human IgG1 monoclonal antibody that binds to FGF23 to inhibit its activity, is more effective to improve the biochemical and clinical signs of XLH than conventional treatment with phosphate supplements and vitamin D active metabolites. Data on adolescents with XLH during the transition period to young adulthood are few.In this prospective case series, we aimed to assess safety and efficacy of burosumab in adolescents with XLH who discontinued long-term conventional therapy. MethodsFive Caucasian adolescents (4 males, 1 female; mean age 15.4 ± 1.5 years) with XLH were recruited and switched from conventional treatment to burosumab (0.8–1.2 mg/kg, s. c. QW2). Burosumab was continued for 12–48 months and, once discontinued, patients were followed-up for 6–12 months. In all patients, serum calcium, phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), and 1,25(OH)2D levels, and renal tubular reabsorption of phosphate (TmP/GFR) values were assessed at entry and during burosumab. Intact FGF23 plasma levels were measured at entry. Patient-reported outcomes (PROs) were assessed at entry and every 3–6 months to evaluate the impact of low extremity pain, stiffness, and difficulties performing daily activities. ResultsAt entry, all patients showed hypophosphatemia, increased intact FGF23 levels, reduced TmP/GFR, insufficient 1,25(OH)2D levels, and in four out of five increased ALP levels. Two patients had radiological signs of rickets. During burosumab, all patients showed a significant increase in serum phosphate and 1,25(OH)2D levels, and in TmP/GFR values (P < 0.05 - P < 0.0001). Serum ALP levels significantly declined (P < 0.05) to normal values. No changes of serum calcium and PTH levels (PNS) were found during burosumab. PROs significantly improved (P < 0.02 - P < 0.0001) in all patients. Four patients discontinued burosumab when they turned 18 or 19, whereas one continued the treatment since he was still younger than 18 during the study period. Four patients who suspended burosumab showed a rapid decline in serum phosphate and 1,25(OH)2D levels and in TmP/GFR values; serum ALP levels increased, and PROs progressively worsened with a significant reduction in quality of life. These consequences were not observed in the patient who continued burosumab treatment. DiscussionOur data showed that conventional treatment improved only in part the signs and symptoms of XLH. Burosumab was well tolerated and was effective in improving phosphate metabolism, bone health, and PROs. All the benefits of burosumab were lost after its discontinuation. These results suggested that continuing burosumab is required to achieve and maintain the clinical benefits of the treatment during the transition to young adulthood in patients with XLH.

A phase 2 study of spartalizumab (PDR001) among patients with recurrent or metastatic esophageal squamous cell carcinoma (KCSG HN18-17, K-MASTER project 12)

ABSTRACT Spartalizumab (PDR001) is a humanized IgG4 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We conducted a single-arm, phase 2 trial to investigate the efficacy and safety of spartalizumab in patients with refractory esophageal squamous cell carcinoma (ESCC). Patients with histologically confirmed ESCC who experienced disease progression after platinum-based chemotherapy received 300 mg of intravenous spartalizumab every three weeks until disease progression or occurrence of unacceptable toxicity. The primary endpoint was centrally assessed objective response according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Adverse events were closely monitored throughout the study. From March 2020 through April 2021, 44 patients with ESCC were enrolled. Of the 44 patients, the objective response rate was 20.5% (95% confidence interval: 8.5–32.4). With a median follow-up of 10.9 months, median progression-free survival and overall survival were 3.2 months and 11.2 months, respectively. In addition, the median duration of response was 24.7 months. The most common grade 3 or 4 adverse event was grade 3 dysphagia (eight [18%] patients). Biomarker analyses explored programmed cell death ligand 1 and CD20 as potential predictive markers for PD-1 blockade. Spartalizumab showed promising activity with a manageable safety profile, indicating its potential as a new treatment option for patients with refractory ESCC. Trial registration The trial was registered at ClinicalTrials.gov under the identifier NCT03785496.

Safety, pharmacokinetics and pharmacodynamics of SHR-1703, an innovative long-acting anti-interleukin-5 monoclonal antibody, in healthy subjects: a randomized, double-blind, dose-escalation, placebo-controlled phase I study

ABSTRACT Objective SHR-1703 is a novel humanized IgG1 monoclonal antibody with high IL-5 affinity and prolonged half-life, aiming to control eosinophil-related diseases. The study intended to evaluate pharmacokinetics, pharmacodynamics, immunogenicity, safety, and tolerability of SHR-1703 in healthy subjects. Methods A single-center, randomized, double-blind, placebo-controlled, single-dose escalation phase I study was conducted. 42 subjects were allocated to sequentially receive single subcutaneous injection of 20, 75, 150, 300, and 400 mg SHR-1703 or placebo. Results After administration, SHR-1703 was slowly absorbed with median Tmax ranging from 8.5 to 24.5 days. Mean t1/2 in 150 to 400 mg doses was 86 to 100 days. Cmax and AUC increased in nearly dose-proportional pattern over range of 75 to 400 mg SHR-1703. After receiving SHR-1703, peripheral blood eosinophils (EOS) greatly decreased from baseline, which showed no significant change from baseline in placebo group. Magnitude and duration of reduction of EOS rose with increased dosing of SHR-1703. In 400 mg dose, remarkable efficacy of reducing EOS maintained up to approximately 6 months post single administration. Moreover, SHR-1703 exhibited low immunogenicity (2.9%), favorable safety, and tolerability in healthy subjects. Conclusion Pharmacokinetics, pharmacodynamics, immunogenicity, safety, and tolerability of SHR-1703 support further clinical development of SHR-1703 in eosinophil-associated diseases. Clinical Trial registration The study was registered on the ClinicalTrials.gov (identifier: NCT04480762).

A phase I/II study of KD6001, a novel fully human anti-CTLA4 IgG1 monoclonal antibody, in combination with toripalimab in patients with advanced melanoma.

9527 Background: Anti-CTLA4 and anti-PD-1 immunotherapies have changed the treatment landscape of patients (pts) with advanced or metastatic melanoma. However, there is still a need to develop an anti-CTLA-4 antibody with further improved safety and efficacy profile. KD6001, a novel fully human anti-CTLA4 IgG1 monoclonal antibody that exhibits immunomodulatory effects, enhances T-cell-mediated anti-tumor immune response, and shows preliminary anti-tumor activity as monotherapy in a FIH phase I trial in pts with advanced solid tumors. Here we report a new study result of KD6001 in combination with toripalimab, an anti-PD-1 monoclonal antibody, in pts with advanced melanoma (KD6001CT02). Methods: KD6001CT02 is a phase I/II study conducted in advanced melanoma. This study consists of dose escalation and dose expansion phases. The primary objective is to evaluate the safety and tolerability of KD6001 in combination with toripalimab and determine the MTD/RP2D. The secondary objectives are to measure antitumor activity, immunogenicity, and pharmacokinetics (PK). Results: As of 15 Dec 2023, 29 pts with melanoma were enrolled (dose escalation n=6 and dose expansion n=23), including 9 (31.0%) acral, 9 (31.0%) nonacral cutaneous, 8 (27.6%) mucosal, and 3 (10.3%) unknown primary subtypes. 18 of them had no brain metastases. The median age was 56 yrs (range 41-78 yrs). The majority of pts previously received anti-PD-1/L1 therapy (16/29, 55.2%) and 27.6% of them received ≥3 lines of therapy. No dose-limiting toxicity or ≥Gr 3 adverse events (AEs) were reported in the dose escalation phase. The study did not reach MTD. 26 (89.7%) pts had treatment-related adverse events (TRAEs), with ≥Gr 3 TRAEs occurring in 3 (10.3%) pts and were well manageable. All other TRAEs were Gr 1 or 2. There were no death events due to TRAEs. No novel safety signals were seen other than the previously reported safety profile of treatment with a combined inhibition of CTLA-4 and PD-1. At data cutoff, among 13 efficacy-evaluable pts without brain metastases, the unconfirmed and confirmed objective response rates (ORR) were 38.5% and 23.1%, respectively. The disease control rate (DCR) was 76.9%. Among 3 pts with confirmed partial response (PR) , 2 pts were mucosal melanoma and 1 patient was nonacral cutaneous melanoma. Among 7 pts who received KD6001 as the ≥2 line treatment and all failed anti-PD-1/L1 therapy, the unconfirmed and confirmed ORR were 57.1% and 42.9%, respectively. DCR was 85.7%. The median PFS and OS were not reached. Conclusions: KD6001 in combination with toripalimab for treatment of advanced melanoma was safe, well-tolerated and showed anti-tumor activity in pts with advanced melanoma. Preliminary analysis indicates that KD6001 combined with toripalimab is efficacious in pts who have progressed after previous anti-PD-1/L1 therapy and in pts with mucosal melanoma. Clinical trial information: NCT05723432 .

A phase Ib study of JMT103, a receptor activator of NF-kB ligand (RANKL) antibody, in patients (pts) with bone metastases from solid tumors.

e15190 Background: JMT103 is a human IgG4 monoclonal antibody against RANKL and blocks the RANK signaling in osteoclasts, thus suppressing bone resorption. This phase Ib study aims to demonstrate the activity of JMT103 in bone metastases patients with solid tumors. Methods: In this randomized, multi-center, open-label, phase Ib study, adult pts with bone metastases from solid tumors were enrolled and randomized at a 1:1:1 ratio to receive JMT103 subcutaneously at 120mg every 4 weeks (Q4W, Cohort 1), 120mg every 8 weeks (Q8W, Cohort 2) and 180mg Q8W (Cohort 3) up to 49 weeks. The primary endpoint was the percent change from baseline to week 13 in creatinine-adjusted urinary N-telopeptide (uNTx/Cr). Secondary endpoints included safety, anti-drug antibodies (ADA) positivity, the percentage of patients who experienced on-study skeletal-related events (SREs), and ≥ 2-point decreases in pain with Brief Pain Inventory – Short Form. Results: At database lock (Mar. 31, 2023), 295 pts were enrolled; 293 were treated with JMT103 and eligible for efficacy and safety evaluation (96 pts in Cohort 1, 97 pts in Cohort 2, and 100 pts in Cohort 3). The median age was 58 years (Interquartile range [IQR] 51, 66), and the primary tumor types were mainly breast (145, 50%) and prostate cancer (44, 15%). At week 13, the median (IQR) percent change in uNTx/Cr was - 80% (- 93%, - 50%) in Cohort 1, - 73% (- 94%, - 34%) in Cohort 2, and - 76% (- 92%, - 40%) in Cohort 3, respectively. The incidence of SREs in the three cohorts was 3%, 6%, and 7%, respectively. Among the 33 pts in Cohort 1, 35 pts in Cohort 2, and 37 pts in Cohort 3 with baseline pain scores ≥ 2, 61% in Cohort 1, 46% in Cohort 2, and 54% in Cohort 3 experienced ≥ 2-point decreases in pain at the first post-treatment visit (Day 15). For ADA analysis, only 1 (1%) pt in Cohort 2 with a negative result at baseline tested positive after treatment. The table shows the overall summary of the safety profile. Most of TRAEs were low in grade and resolved quickly. The most common TRAEs (any grade) were hypocalcemia (68, 23%), hypophosphatemia (67, 23%), and increased aspartate transaminase (35, 12%). Among the 40 cases of grade-5 TEAE, only 1 was reported as a TRAE (pneumonia); the rest were unrelated to JMT103. Conclusions: Our study demonstrated a promising efficacy of JMT103 in reducing bone metabolism biomarker and a good safety profile with low immunogenicity. Clinical trial information: NCT04630522 . [Table: see text]

SCR-A002, a novel FGFR2b-targeting antibody-drug-conjugate for solid tumors.

e15019 Background: FGFR2b (fibroblast growth factor receptor 2 IIIb), a transmembrane tyrosine kinase, is overexpressed in various cancers, including gastric, esophageal, breast, hepatocellular, pancreatic, ovary, uterine, cervical, endometrial, lung, colorectal cancers. Bemarituzumab (FPA144), an afucosylated humanized IgG1 monoclonal antibody targeting FGFR2b with enhanced ADCC activity, showed promising clinical efficacy in phase 2 study of FGFR2b-selected gastric or gastroesophageal junction adenocarcinoma. We have developed a potential first-in-class FGFR2b-targeting ADC (SCR-A002) at IND-enabling status, displaying significantly superior anti-tumor potency compared to Bemarituzumab. Methods: SCR-A002 is comprised of a humanized anti-FGFR2b IgG1 monoclonal antibody conjugated with proprietary TOPO1 inhibitor payload (DAR 8) via a cleavable linker. Anti-FGFR2b antibody was generated by immunization of FGFR2b protein in mice followed by hybridoma technique. Binding activity and cytotoxicity were assessed in FGFR2b+ tumor cell line. And anti-tumor efficacy was evaluated in several CDX and PDX models. Results: SCR-A002 could specifically bind to FGFR2b on cancer cells and be internalized, and the TOPO1 inhibitor could be cleaved intracellularly to kill the cancer cells potently in vitro. After single-dose administration of SCR-A002, tumor regression was achieved in different FGFR2b expression level CDX and PDX models, even with big-size tumor or Bemarituzumab resistance. Conclusions: SCR-A002 showed potent anti-tumor efficacy in preclinical data, which suggest that SCR-A002 is expected to provide a new treatment option as single agent or combo with SoC for patients with FGFR2b-overexpressing solid tumor.

Anti-TNFR2 monoclonal antibody LBL-019 in patients with advanced malignant tumors: A phase I, first-in-human, open-label, multicenter, dose escalation Study.

e14580 Background: LBL-019 is a humanized monoclonal IgG1 antibody against TNF receptor 2 (TNFR2). It specifically binds to TNFR2 with high affinity, co-stimulates TNFR2 in Fc crosslinking-dependent manner, results in activation of NF-κB signaling and T cell activation and expansion, promoting antitumor immunity. Here we report the preliminary safety and efficacy of LBL-019 in patients with advanced malignant tumors. Methods: This is a phase Ⅰ, open-label, multicenter, dose-escalation study to evaluate the safety, tolerability, and PK of LBL-019 in patients with advanced solid tumors that progressed after standard systemic therapy. The dose escalation phase consists of 7 dose cohorts of LBL-019 at 0.2, 0.8, 3, 10, 15, 20, and 30 mg/kg (iv Q2W), using accelerated titration design (first dose) followed by 3+3 design. The primary endpoints were tolerability and safety. The second objectives were pharmacokinetics, pharmacodynamics, and preliminary efficacy (per RECIST 1.1). Results: As of January 02, 2024, 26 patients [17 (65.4%) male, median age 57 years (range:27, 72), 22 (84.6%) ECOG score of 1] were treated in phase Ⅰ. Tumor types include 7 (26.9%) hepatocellular carcinoma (HCC), 4 (15.4%) melanoma, and 15 (57.7%) other tumors. 19 (73%) previously received anti-PD(L)-1 treatment. During the study, no DLT was observed, and the MTD was not reached. The median follow-up was 12.2 months (95%CI: 7.5, 15.9). 19 patients (73.1%) experienced TRAEs of all grades, with 2 (7.7%) having grade ≥3 TRAEs. The most common TRAEs (≥10%) included lipase increased (19.2%), anaemia (19.2%), aspartate aminotransferase increased (15.4%), pruritus (11.5%), rash (11.5%). Treatment interruption and permanent discontinuation due to TEAEs occurred in 12 (46.2%) and 1 (3.8%) patient, respectively. Thirteen patients (50.0%) experienced SAEs, and one of SAE was related to treatment. Out of 23 who underwent efficacy evaluation, 1 patient with HCC achieved PR, and 7 patients achieved SD. The patient with PR and 6 patients with SD received prior immunotherapy, the ORR and DCR were 4.3% and 34.8%, respectively. The DoR in the patient with PR has exceeded 10 months. Conclusions: LBL-019 is well tolerable and has demonstrated preliminary efficacy in patients with advanced malignant tumors. Clinical trial information: NCT05223231 .

Adverse events of patients treated with antibody-drug conjugates in phase 1 clinical trials at the Royal Marsden Drug Development Unit from 2014 to 2024.

e15020 Background: Antibody-drug conjugates (ADCs) are designed to improve therapeutic indices of cytotoxic agents. Nevertheless, they may induce unexpected toxicities not observed with parent payloads. This study aimed to characterize the adverse events (AEs) seen in patients treated with ADCs in Phase 1 trials at The Royal Marsden Drug Development Unit (DDU). Methods: This is a retrospective cohort analysis of consecutive patients who received at least one dose of an ADC in a phase I trial from January 2014 to January 2024 at The Royal Marsden DDU. Descriptive statistics of patient characteristics, ADCs, and treatment-related AEs were performed. Univariate and multivariate logistic regression will be utilized to assess correlations among patient and ADC characteristics and adverse events. P values of &lt; 0.05 will be considered significant. Results: A total of 131 patients who participated in twelve ADC trials were included. The median age of participants was 63 years (range: 31-84) and 61% were females. Patients received a median of three prior lines of systemic treatment. The most common type of ADC target, antibody, linker and payload were receptor tyrosine kinase (51%), humanized IgG monoclonal antibody (69%), valine-citrulline (VC) cleavable linker (85%), and a tubulin-binding payload (59%), respectively. Most patients received an ADC dose of 1-3 mg/kg (76%) with each cycle given once every 3 weeks (64%). The median number of cycles was 3 with an average treatment duration of 63 days. Within the cohort, 89% of patients developed any grade AE and 17% experienced grade 3 or higher AEs. The major treatment-related AEs were fatigue (48%), nausea/vomiting (27%), ocular toxicity (26%), neuropathy (26%), skin rash (20%) and pneumonitis (8%). The median time to first onset of treatment-related adverse events were 37 days for ocular toxicity, 46 days for pneumonitis, and 54 days for neuropathy. ADC-related AEs led to treatment interruptions (51%), dose reductions (13%), and treatment discontinuations (28%). Two treatment-related grade 5 events occurred. The objective response rate was 18%, with 1 complete response and 22 partial responses. Conclusions: Despite being designed to minimize side effects, ADCs were associated with significant toxicities, including unexpected adverse events unrelated to target, antibodies or the payloads, limiting their therapeutic indices. Further analysis of the relationship between different components of the wide range of ADCs and AEs are warranted to better understand the potential mechanisms of ADC toxicity.

A phase Ib/II study of an anti-CD137 agonist antibody ADG106 in combination with weekly paclitaxel and dose-dense doxorubicin/cyclophosphamide.

e14507 Background: ADG106 is a fully human agonistic anti-CD137 IgG4 monoclonal antibody which modulates the tumor microenvironment and has demonstrated increased efficacy when added to chemotherapy in preclinical models. We studied the combination of ADG106 with chemotherapy. Methods: We conducted a phase Ib trial in patients with advanced solid tumors to determine the recommended phase 2 dose (RP2D) of ADG106 + weekly P (paclitaxel 80mg/m2) or ddAC (doxorubicin 60mg/m2, cyclophosphamide 600mg/m2 Q2W with pegfilgrastim), followed by a phase II trial of neoadjuvant ADG106 + weekly Px12→ADG106 + ddACx4→surgery in stage I-III HER2 negative breast cancer patients. In phase Ib, one dose of single agent ADG106 was administered followed 2 weeks later by ADG106 + ddAC (Cohort 1) or ADG106 + weekly P (Cohort 2). Dose levels (DL) of ADG106 were 50mg (DL-1), 100mg (DL1), 200mg (DL2). Serial tumor biopsies were performed at baseline, after single agent ADG106 and at disease progression in phase I, and at baseline, after single agent ADG106, after cycle 1 ADG106 + P, and at surgery in phase II for translational studies. Results: 11 patients were enrolled into Phase Ib with median 3 (range 2-11) prior lines of palliative systemic therapy. ADG106 + ddAC (n=2 at DL1) was deemed intolerable with 1 patient experiencing G4 neutropenia and the other G3 infection; thus ADG106 was not added to ddAC in phase II. No DLTs were observed in all patients receiving ADG106 + P (n=6 at DL1; n=3 at DL2); ADG106 RP2D was declared at 200mg + P. In this cohort, the most common all-grade AEs were neutropenia (n=6), peripheral neuropathy (n=6) and fatigue (n=6); significant ≥G3 AEs were infection (n=2) and G3 neutropenia (n=6). 5/11 (45%) patients in phase I achieved clinical benefit (CBR; PR=2, SD=3) which is clinically meaningful as 9/11 (82%) had prior taxane exposure. 18 of the planned 30 patients have been enrolled into Phase II (ADG106+weekly P→ddACx4→surgery); 10 have completed study treatment and 5 have undergone surgery. While on ADG106 + P, 4 patients experienced G3 adverse events (AEs): neutropenia (n=3), hypophosphatemia (n=1), fever (n=1). Most common G1-2 AEs were ALT elevation (n=4), acneiform rash (n=3) and peripheral neuropathy (n=3). While on ddAC alone, all AEs were low grade except for 1 patient who had G3 pneumonitis from Pneumocystis Jiroveci Pneumonia. 26 sets of matched tumor biopsies have been collected (9 in phase I; 17 in phase II) and will be tested for a panel of 40 markers by multiplex IHC, including CD137, PD-L1, and CD3/4/8. Conclusions: ADG106 when combined with ddAC exacerbates neutropenia and is not tolerable despite prophylactic pegfilgrastim. The RP2D of ADG106 in combination with P is 200mg and is safe and tolerable; manageable G3 neutropenia was the most common AE. There are no new safety signals thus far in Phase II. Further efficacy analyses and studies on tumor immune markers are ongoing. Clinical trial information: NCT05275777 .

ESG401, a trophoblast cell-surface antigen 2 (TROP2) antibody drug conjugate (ADC), for the treatment of first-line metastatic triple negative breast cancer (mTNBC).

e13132 Background: ESG401, a novel ADC comprising a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to the Topoisomerase I Inhibitor SN-38, with the Drug-Antibody Ratio at 8, by a stable cleavable linker, exhibited preliminary efficacy and tolerability in the Phase Ia trial (Ma, ASCO 2023). This report summarizes current results from the first-line mTNBC cohort of the Phase Ib trial. Methods: Patients (pts) aged ≥18 years with confirmed local advanced/unresectable or metastatic TNBC, without prior metastatic treatment, received ESG401 (16 mg/kg IV on Day 1,8, and 15, with a 28-day cycle) until unacceptable toxicity, progressive disease, or consent withdrawal. Results: As of the cutoff date (Jan 30th, 2024), 23 pts in the cohort received ≥1 dose of ESG401. Median age was 52 years (range: 33-73), 34.8% were ECOG 0, 26.1% were de novo stage IV, 73.9% had visceral disease (8.7% brain, 34.8% liver, 52.2% lung), 43.5% received radiotherapy, and 73.9% received chemotherapy (73.9% Taxanes, 69.6% Anthracycline, 4.3% Platinum)as prior treatments for early-stage disease. Among 14 Efficacy Evaluable (EE) pts, the ORR was 78.6%, including one (7.1%) patient who achieved a complete response. DCR was 100%, and CBR was 85.7%. Eight pts (57.1%) achieved confirmed Partial Response (PR). As of the cutoff date, 14 pts (63.6%) remained on treatment, with the longest on-treatment duration being 8.0 mons. Two (2) pts in this cohort had brain metastases. One pt achieved a complete intracranial response, and the overall response evaluation was PR. The evaluation time for the other pt has not yet been reached. Across the entire Phase Ia/1b trials, including 15 EE pts with brain metastases, the best overall intracranial response rate was 33%, with an intracranial disease control rate of 73%. The response of the intracranial tumor lesion is correlated with the response of the non-CNS lesion. The safety profile of ESG401 remained consistent with previous reports, showing no new or unexpected safety signals. The most common TRAEs were leukopenia (65.2%), neutropenia (69.6%), anemia (43.5%), fatigue (21.7%), nausea (43.5%), and vomiting (34.8%). The most common TRAEs≥ Grade 3 were neutropenia (43.5%). There was no ≥ Grade 3 diarrhea. No interstitial lung disease (ILD) has been reported so far for the entire PhIa/b trials containing 139 pts. Conclusions: ESG401 demonstrates promising antitumor activity in the first-line mTNBC pts, with efficacy comparable to the combination therapy reported by the BEGONIA Study. Additionally, the efficacy of ESG401 in brain metas in the first-line mTNBC pts is in alignment with our previous observations made in the late-line mTNBC and HR+/HER2- BC pts. These results warrant further clinical investigation of ESG401. Clinical trial information: NCT04892342 .

A first-in-human, phase I, dose-escalation study to evaluate pharmacokinetics, safety, and tolerability of KD6001, a novel anti-CTLA-4 monoclonal antibody (mAb) in patients with advanced solid tumors.

e14501 Background: KD6001, a novel fully human anti-CTLA4 IgG1 monoclonal antibody, exhibits immunomodulatory effects, enhances T-cell-mediated antitumor immune response and shows promising activity in preclinical models of solid tumors. Here we present the pharmacokinetics, safety and tolerability data from the phase 1 study of KD6001 (NCT05230290) in patients with advanced solid tumors. Methods: patients were enrolled in a 3+3 dose escalation phase 1 study with the following pre-defined KD6001 cohorts: 0.2mg/kg, 1mg/kg, 3mg/kg or 6mg/kg, every 2 weeks via intravenous infusion for 4 cycles. The primary objective was to evaluate the safety and tolerability of KD6001 and determine the MTD/RP2D. The secondary objectives were to measure antitumor activity, immunogenicity and pharmacokinetics (PK). All AEs are graded using NCI CTCAE v5.0. Efficacy assessments are per RECIST 1.1. Blood samples are obtained for pharmacokinetics (PK) and for immunogenicity assessments, measured by the development of anti-drug antibodies. Results: The study had been completed. Thirteen pts with melanoma had been enrolled and treated at 0.2 mg/kg (n = 1), 1mg/kg (n = 3), 3 mg/kg (n = 6) and 6mg/kg (n = 3) at Beijing Cancer Hospital. The average age was 57.2 years (range 34-68). Baseline ECOG scores were 0 (n = 5), 1(n = 8) with all pts. Seven pts (53.85%) received ≥ 2 lines of previous systemic therapies and 12 pts (92.31%) received previous PD-1/PD-L1 treatment. KD6001 was well-tolerated with no dose-limiting toxicities (DLTs) observed, nor was the MTD reached at the highest doses administered. All the thirteen pts had at least one adverse event during treatment, and eleven of them (84.62%) had Treatment Related Adverse Events (TRAEs), most of which were Grades 1-2. There were no permanent drug discontinuation or deaths due to adverse events. Pharmacokinetic analysis indicated a linear correlate between the drug exposure (Cmax, AUC0-t and AUC0-inf) and study drug dosages evaluated. The geometric mean T1/2 was 10 days (CV%: 31%). The peak concentration and exposure level increased proportionally to dose from 0.2mg/kg to 6 mg/kg. No anti-drug antibodies were detected in any of the patient’s serum samples. Clinical efficacy was observed in 12 evaluable pts: 3 patients at 3mg/kg had a stable disease (SD) and 1 patient at 3mg/kg had a confirmed partial response (PR). The ORR of the 3mg/kg dose group was 16.7% (1/6), the DCR was 66.67% (4/6). The median PFS was 109 days and the median OS was not reached. Conclusions: KD6001 showed promising antitumor activity and a tolerable safety profile in patients with advanced solid tumors. Hence, 3mg/kg was selected as the RP2D. Clinical trial information: NCT05230290 .

Phase 1 study of anti–immunoglobulin-like transcript 3 (ILT3) monoclonal antibody MK-0482 + pembrolizumab + gemcitabine + nab-paclitaxel (Gem/Nab-P) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC).

4139 Background: Standard first-line treatment of mPDAC includes Gem/Nab-P doublet therapy, which typically results in an ORR of 23%-35%, a median PFS of 5-6 mo, and a median OS of 7-10 mo. ILT3 is an inhibitory receptor expressed on monocytic myeloid cells, including tolerogenic dendritic cells and myeloid-derived suppressor cells. MK-0482 is a novel humanized IgG4 monoclonal antibody targeting ILT3. ILT3 inhibition with MK-0482 has the potential to relieve immunosuppression within the tumor microenvironment. In the expansion cohort of the first-in-human phase 1 study MK-0482-001 (NCT03918278), the combination of MK-0482 + pembrolizumab + Gem/Nab-P was evaluated in pts with treatment-naive mPDAC. The safety and efficacy data from this cohort are presented. Methods: Pts aged ≥18 y with previously untreated mPDAC, measurable disease per RECIST v1.1, and an ECOG PS of 0 or 1 received MK-0482 750 mg Q3W + pembrolizumab 200 mg Q3W IV for ≤35 cycles + Gem/Nab-P (gemcitabine 1000 mg/m2; nab-paclitaxel 125 mg/m2) on days 1, 8, and 15 Q4W until PD or treatment discontinuation. The primary end point was safety. Secondary end points were ORR, DCR (CR + PR + SD), and DOR by investigator assessment per RECIST v1.1. Exploratory end points included PFS per RECIST v1.1 and OS. Results: A total of 37 pts were enrolled and received study treatment. At data cutoff (Oct 3, 2023), median follow-up was 13 mo (range 8.9-18.9). Median age was 65 y (range, 39-77). Most pts were male (54%), had an ECOG PS 1 (65%), and had ≥3 sites of metastasis (54%). Any-cause adverse events (AEs) occurred in all pts and treatment-related AEs (TRAEs) occurred in 36 pts (97%). Grade 3 or 4 TRAEs occurred in 27 pts (73%); the most frequent (≥10%) were decreased neutrophil count (27%), anemia (19%), and neutropenia (19%). No deaths due to TRAEs occurred. Immune-mediated AEs occurred in 12 pts (32%); the most frequent (≥10%) was hypothyroidism (11%). Grade 3 immune-mediated AEs occurred in 5 pts (14%; hepatitis, n = 2; severe skin reactions, n = 2; colitis, n = 1); no grade 4 or 5 events occurred. Confirmed ORR was 43% (16/37; 95% CI, 27.1-60.5), DCR was 84% (31/37; 68.0-93.8), and median DOR was 8.5 mo (range, 3.7-17.8+). Median PFS was 8.5 mo (95% CI, 5.7-12.3) and median OS was 15.6 mo (10.5-22.1); 12-mo PFS and OS rates were 35% and 60%, respectively. Biomarker data will be included in the presentation. Conclusions: MK-0482 + pembrolizumab + Gem/Nab-P showed a manageable AE profile in patients with treatment-naive mPDAC, which was generally consistent with the combined safety profiles of pembrolizumab-based immunotherapy and Gem/Nab-P, respectively. The 4-drug combination showed increased clinical efficacy compared with that historically observed for chemotherapy regimens. Further evaluation is needed to confirm the clinical activities observed. Clinical trial information: NCT03918278 .

EVOLVE-HNSCC: A global phase 3 study of volrustomig as sequential therapy for unresected locally advanced head and neck squamous cell carcinoma (LA-HNSCC) following definitive concurrent chemoradiotherapy (cCRT).

TPS6120 Background: Currently there are no approved maintenance therapies for patients (pts) with unresected LA-HNSCC following definitive cCRT. The PD-1 inhibitors pembrolizumab and nivolumab are licensed for treatment of pts with recurrent or metastatic HNSCC who have progressed on or after a platinum-based therapy. Dual inhibition of CTLA-4 and PD-L1 is approved in solid tumors including renal cell carcinoma (RCC), NSCLC, and melanoma, and has shown a numerical trend towards improved survival in first-line pts with recurrent/metastatic HNSCC whose tumors express PD-L1. Volrustomig (MEDI5752) is a monovalent, PD-1/CTLA-4 bispecific, humanized IgG1 monoclonal antibody engineered to specifically inhibit PD-1, with increased CTLA-4 blockade on PD-1+ activated T cells compared to PD-1– resting peripheral T cells. In a first-in-human phase 1/2 study (NCT03530397), volrustomig monotherapy showed promising efficacy with acceptable tolerability in advanced clear cell RCC and in combination with chemotherapy in advanced NSCLC. The phase 3, randomized, open-label, multicenter, eVOLVE-HNSCC study will evaluate the efficacy and safety of sequential therapy with volrustomig compared with observation in pts with unresected LA-HNSCC who have not progressed after receiving definitive cCRT (NCT06129864). Methods: Key eligibility criteria include histologically or cytologically confirmed, unresected LA-HNSCC with no evidence of metastatic disease, i.e. AJCC 8th edition (TNM staging system) stage IVA/B cancers of the hypopharynx, oral cavity, larynx or HPV-negative oropharynx, or stage III HPV-positive oropharynx cancer; age ≥18 years; WHO/ECOG performance score of 0 or 1; and adequate organ and bone marrow function. Key exclusion criteria include requiring further treatment with curative intent after definitive cCRT, resected LA-HNSCC, recurrent/metastatic disease, and &gt;1 primary tumor. Following initial screening and definitive cCRT (cisplatin or carboplatin + paclitaxel or carboplatin + 5-FU, plus concomitant radiotherapy), approximately 1145 pts whose disease has not progressed within 12 weeks of the last dose of cCRT will be randomized 1:1 to Arm A or B. Arm A will receive volrustomig intravenously every 3 weeks for a maximum of 12 months or 18 cycles, or until RECIST v1.1-defined radiological progressive disease (PD) or unacceptable toxicity. Arm B will undergo observation for a maximum of 12 months or until PD. The primary endpoint is PFS in pts with PD-L1-expressing tumors. Secondary endpoints include PFS in all randomized pts, OS in pts with PD-L1-expressing tumors and in all randomized pts, PFS2, safety, patient-reported outcomes, pharmacokinetics, and immunogenicity. Exploratory biomarker analyses will also be conducted. Enrollment began in December 2023. Clinical trial information: NCT06129864 .

GEMINI-Gastric: A phase 2 study of novel treatment combinations in patients with locally advanced unresectable or metastatic gastric cancers.

TPS4182 Background: A large proportion of patients (pts) with gastric cancer present with locally advanced or metastatic disease, which is linked with poor survival. Platinum- and fluoropyrimidine-based doublet chemotherapy (CTx) remains the standard of care in advanced gastric cancers. Based on recent clinical data, immuno-oncology (IO) agents plus CTx can improve overall survival (OS) in pts with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma who have human epidermal growth factor receptor 2 negative/low expression (HER2–) and have not been previously treated for advanced/metastatic disease. GEMINI-Gastric (NCT05702229) is a phase 2, open-label, multidrug, multicenter, master protocol study designed to assess the efficacy, safety, tolerability, pharmacokinetics (PK), and immunogenicity of multiple novel IO + CTx combination therapies in this setting. Methods: Adults (≥18 years) with previously untreated HER2– locally advanced unresectable, or metastatic gastric or GEJ adenocarcinoma are eligible. Pts should have measurable target disease per RECIST v1.1 and an ECOG performance status of 0–1. The GEMINI-Gastric design allows assessment of multiple novel agents plus CTx in different substudies (Table). Novel agents include: volrustomig, an anti-PD-1/CTLA-4 bispecific humanized IgG1 monoclonal antibody (mAb); rilvegostomig, an anti-PD-1/TIGIT bispecific humanized IgG1 mAb; AZD0901, a claudin18.2-targeted antibody-drug conjugate; and AZD7789, an anti-PD-1/TIM-3 bispecific mAb. Co-primary endpoints are objective response rate and progression-free survival (PFS) at 6 months by investigator assessment per RECIST v1.1. Secondary endpoints include safety, duration of response, PFS, OS, PK, and immunogenicity. Sample sizes have been selected to provide adequate precision for the primary endpoints. The study is currently recruiting at sites in the US, Europe, and Asia. Clinical trial information: NCT05702229 . [Table: see text]

A phase 1, first-in-human study of CUSP06, a cadherin-6 (CDH6) -directed antibody-drug conjugate, in patients with platinum-refractory/resistant ovarian cancer and other advanced solid tumors.

TPS3166 Background: Cadherin-6 (CDH6) is a transmembrane glycoprotein involved in cancer metastasis and invasion expressed in various tumor types including ovarian cancer (OC), renal cell carcinoma (RCC), papillary thyroid cancer, cholangiocarcinoma, hepatocellular cancer, glioma, uterine serous carcinoma and non-small cell lung cancer. CUSP06 is an antibody-drug conjugate composed of a human IgG1 monoclonal antibody against CDH6 conjugated with a protease-cleavable linker, T1000, to exatecan, a topoisomerase I inhibitor payload. In preclinical studies, CUSP06 showed CDH6-dependent cell growth inhibition in ovarian cancer cell lines. High CDH6-expressing ovarian and renal CDX and PDX models demonstrated tumor regression after treatment with CUSP06, as did low CDH6-expressing PDX models of other solid tumors. Methods: This is a Phase 1a/1b, open-label, multicenter dose escalation and expansion study to evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), recommended Phase 2 dose (RP2D), and preliminary efficacy of CUSP06 in patients with platinum-refractory/resistant ovarian cancer (PRROC), advanced RCC and other advanced CDH6-positive solid tumors. Patients with advanced solid tumors previously treated with standard of care systemic therapy, or for whom no standard therapy is available are eligible for enrollment. Prescreening for CDH6 expression will be required for those patients with solid tumors other than PRROC or RCC. CUSP06 will be administered intravenously every 21 days. Phase 1a will follow a standard 3+3 dose escalation design. Phase 1a also includes up to 3 dose enrichment cohorts at doses that have demonstrated safety, each with a maximum of 18 patients, to generate additional safety, PK, PD, and preliminary efficacy data to support an optimized dose for expansion. Phase 1b consists of several dose expansion cohorts including PRROC, RCC, and other CDH6-positive solid tumors, to be enrolled according to Simon's 2-stage design. Mandatory pre- and on-study biopsies in dose expansion cohorts will support a robust exploratory biomarker plan that may include correlation of CDH6 levels with response, and other RNA and protein markers of sensitivity and resistance. The study is currently enrolling in Phase 1a dose-escalation. Clinical trial information: NCT06234423 .

GEMINI-Hepatobiliary: A phase 2 study of novel first-line immuno-oncology-based treatments in patients with advanced hepatobiliary cancers.

TPS4187 Background: Although targeted therapies and immuno-oncology (IO)-based regimens have improved overall survival (OS) in advanced hepatobiliary carcinomas, long-term survival rates remain unsatisfactory. Early-phase studies have demonstrated the efficacy of volrustomig (volru; anti-PD-1/CTLA-4 bispecific humanized IgG1 monoclonal antibody [mAb]) in patients (pts) with non-small-cell lung cancer (NSCLC) and renal cell carcinoma, and of rilvegostomig (rilve; anti-PD-1/TIGIT bispecific humanized IgG1 mAb) in pts with NSCLC, along with manageable safety profiles. GEMINI-Hepatobiliary (NCT05775159) is a phase 2, open-label, multidrug, multicenter, master protocol study designed to evaluate the preliminary efficacy and safety of novel IO bispecific mAbs as monotherapy or in combination with standard of care anticancer agents in pts with advanced hepatocellular carcinoma (HCC) and biliary tract cancer (BTC). Methods: The GEMINI-Hepatobiliary platform design permits separate independent substudies (Table). Substudy 1 includes treatment-naïve adults (≥18 years) with histologically confirmed advanced HCC not eligible for locoregional therapy, Barcelona Clinic Liver Cancer Stage B/C, Child-Pugh class A 5–6, and an ECOG performance status (PS) of 0–1. Pts will be treated with volru as monotherapy or in combination with bevacizumab or lenvatinib. Primary endpoints for Substudy 1 are safety and objective response rate (ORR) per RECIST v1.1 by investigator’s assessment. Substudy 2 includes treatment-naïve adults with locally advanced or metastatic, histologically confirmed BTC and an ECOG PS of 0–1. Pts will be treated with gemcitabine + cisplatin with either rilve or volru. Primary endpoints for Substudy 2 are safety and progression-free survival (PFS) per RECIST v1.1 by investigator’s assessment. Secondary endpoints for both substudies include duration of response, disease control rate, ORR, PFS, OS, pharmacokinetics, and immunogenicity. While there are no formal statistical comparisons or hypothesis testing, sample sizes were selected to provide adequate precision for the primary endpoints. The study is currently recruiting at sites in the US, Asia, and Europe. GEMINI-Hepatobiliary master protocol design. Clinical trial information: NCT05775159 . [Table: see text]

Abstract PO1-20-13: TROPION-Breast04: A phase 3 study of neoadjuvant datopotamab deruxtecan (Dato-DXd) + durvalumab followed by adjuvant durvalumab vs the standard of care in treatment-naive early-stage triple negative or HR-low/HER2– breast cancer

Abstract Background: The current standard of care for patients (pts) with treatment-naive Stage II–III triple-negative breast cancer (TNBC) is neoadjuvant pembrolizumab + anthracycline/taxane/platinum-based chemotherapy followed by surgery and adjuvant pembrolizumab monotherapy. However, among pts who received the combination of pembrolizumab and chemotherapy in the KEYNOTE-522 trial (NCT03036488), 28% ultimately discontinued therapy due to treatment-related adverse events, and 37% had residual disease at the time of surgery, which was associated with poor outcomes. Consequently, there remains an unmet need to develop a treatment approach that improves pathologic complete response (pCR) rates and long-term survival while reducing chemotherapy-associated toxicity in pts with early-stage TNBC. Dato-DXd is a TROP2-directed antibody-drug conjugate that consists of a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to a potent topoisomerase I (Topo-I) inhibitor via a plasma stable tetrapeptide-based tumor-selective cleavable linker. Dato-DXd monotherapy has demonstrated a manageable safety profile and encouraging preliminary efficacy in pts with metastatic TNBC in the Phase 1 TROPION-PanTumor01 study (NCT03401385), with a confirmed objective response rate (ORR) of 32% in all pts and 44% in Topo-I inhibitor-naive pts with measurable disease at baseline. The combination of Dato-DXd with durvalumab has demonstrated durable responses in unresectable locally advanced or metastatic TNBC in the Phase 1b/2 BEGONIA study (NCT03742102), with an ORR of 79%, median duration of response of 15.5 months and median progression-free survival of 13.8 months. The ongoing Phase 3 TROPION-Breast03 trial (NCT05629585) is evaluating Dato-DXd ± durvalumab versus standard-of-care therapy as adjuvant treatment in pts with Stage I–III TNBC with residual invasive disease at the time of surgery after neoadjuvant treatment. The TROPION-Breast04 trial aims to determine if improved efficacy and safety can be achieved with neoadjuvant Dato-DXd + durvalumab followed by adjuvant durvalumab, compared with the pembrolizumab-based standard of care regimen in pts with previously untreated TNBC or hormone receptor-low (estrogen and/or progesterone receptor 1% to &amp;lt;10%; neither hormone receptor may be ≥10%)/HER2-negative (HR-low/HER2–) breast cancer. Trial design: TROPION-Breast04 (NCT06112379) is an ongoing Phase 3, 2-arm, parallel-group, randomized, open-label, multicenter, global trial. Approximately 1728 adults (aged ≥18 years) with previously untreated histologically confirmed Stage II–III unilateral or bilateral primary invasive TNBC or HR-low/HER2– breast cancer per AJCC edition 8 as assessed by the investigator, and an ECOG PS of 0 or 1, will be randomized 1:1 into one of two arms: neoadjuvant Dato-DXd + durvalumab followed by adjuvant durvalumab-based therapy, or neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab-based therapy (full treatment details are provided in the Table). Randomization will be stratified by lymph node status, tumor stage, HR status, and geographic region. Pts with distant disease and any prior surgery, radiotherapy, or systemic anticancer therapy will be excluded from the study. The primary endpoints are pCR and event-free survival. The key secondary endpoint is overall survival; others are distant disease-free survival, patient reported outcomes, pharmacokinetics, immunogenicity, and safety/tolerability. TROPION-Breast04 opened for enrolment in November 2023. Citation Format: Heather McArthur, Sara Tolaney, Sibylle Loibl, Rebecca Dent, Peter Schmid, Jamil Asselah, Erwei Song, Naoki Niikura. TROPION-Breast04: A phase 3 study of neoadjuvant datopotamab deruxtecan (Dato-DXd) + durvalumab followed by adjuvant durvalumab vs the standard of care in treatment-naive early-stage triple negative or HR-low/HER2– breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-20-13.