Metastatic Solid Tumors Research Articles

Simulation model of tumor-treating fields

Tumor-treating fields (TTFields) is a novel treatment modality for malignant solid tumors, often employing electric field simulations to analyze the distribution of electric fields on the tumor under different parameters of TTFields. Due to the present difficulties and high costs associated with reproducing or implementing the simulation model construction techniques, this study used readily available open-source software tools to construct a highly accurate, easily implementable finite element simulation model for TTFields. The accuracy of the model is at a level of 1 mm 3. Using this simulation model, the study carried out analyses of different factors, such as tissue electrical parameters and electrode configurations. The results show that factors influncing the distribution of the internal electric field of the tumor include changes in scalp and skull conductivity (with a maximum variation of 21.0% in the treatment field of the tumor), changes in tumor conductivity (with a maximum variation of 157.8% in the treatment field of the tumor), and different electrode positions and combinations (with a maximum variation of 74.2% in the treatment field of the tumor). In summary, the results of this study validate the feasibility and effectiveness of the proposed modeling method, which can provide an important reference for future simulation analyses of TTFields and clinical applications.

Development and validation of a nomogram for predicting 28-day mortality in patients with ischemic stroke.

We aimed to construct a validated nomogram model for predicting short-term (28-day) ischemic stroke mortality among critically ill populations. We collected raw data from the Medical Information Mart for Intensive Care IV database, a comprehensive repository renowned for its depth and breadth in critical care information. Subsequently, a rigorous analytical framework was employed, incorporating a 10-fold cross-validation procedure to ensure robustness and reliability. Leveraging advanced statistical methodologies, specifically the least absolute shrinkage and selection operator regression, variables pertinent to 28-day mortality in ischemic stroke were meticulously screened. Next, binary logistic regression was utilized to establish nomogram, then applied concordance index to evaluate discrimination of the prediction models. Predictive performance of the nomogram was assessed by integrated discrimination improvement (IDI) and net reclassification index (NRI). Additionally, we generated calibration curves to assess calibrating ability. Finally, we evaluated the nomogram's net clinical benefit using decision curve analysis (DCA), in comparison with scoring systems clinically applied under common conditions. A total of 2089 individuals were identified and assigned into training (n = 1443) or validation (n = 646) cohorts. Various identified risk factors, including age, ethnicity, marital status, underlying metastatic solid tumor, Charlson comorbidity index, heart rate, Glasgow coma scale, glucose concentrations, white blood cells, sodium concentrations, potassium concentrations, mechanical ventilation, use of heparin and mannitol, were associated with short-term (28-day) mortality in ischemic stroke individuals. A concordance index of 0.834 was obtained in the training dataset, indicating that our nomogram had good discriminating ability. Results of IDI and NRI in both cohorts proved that our nomogram had positive improvement of predictive performance, compared to other scoring systems. The actual and predicted incidence of mortality showed favorable concordance on calibration curves (P > 0.05). DCA curves revealed that, compared with scoring systems clinically used under common conditions, the constructed nomogram yielded a greater net clinical benefit. Utilizing a comprehensive array of fourteen readily accessible variables, a prognostic nomogram was meticulously formulated and rigorously validated to provide precise prognostication of short-term mortality within the ischemic stroke cohort.

Oncolytic virus V937 in combination with PD-1 blockade therapy to target immunologically quiescent liver and colorectal cancer

V937 is an investigational, genetically unmodified Kuykendall strain of coxsackievirus A21, which has been evaluated in the clinic for advanced solid tumor malignancies. V937 specifically infects and lyses tumor cells that overexpress intercellular adhesion molecule-1 (ICAM-1). Intratumoral V937 as a monotherapy and in combination with anti-PD-1 antibody pembrolizumab has shown clinical response in patients with metastatic melanoma, which overexpresses ICAM-1. Here, we investigate in pre-clinical studies the potential bidirectional cross-talk between hepatocellular carcinomas (HCC) or colorectal carcinomas (CRC) and immune cells when treated with V937 alone or in combination with pembrolizumab. We show that while V937 treatment of tumor cell lines or organoids or peripheral blood mononuclear cells (PBMCs) alone induced a minimal immunological response, V937 treatment of non-contact co-cultures of tumor cell lines or CRC organoids with PBMCs led to robust production of pro-inflammatory cytokines and immune cell activation. In addition, both recombinant interferon-gamma (IFN-γ) and pembrolizumab increased ICAM-1 on tumor cell lines or organoids and, in turn, amplified V937-mediated oncolysis and immunogenicity. These findings provide critical mechanistic insights on the cross-talk between V937-mediated oncolysis and immune responses, demonstrating the therapeutic potential of V937 in combination with PD-1 blockade to treat immunologically quiescent cancers.

Prevalence and factors influencing anemia recovery after intensive care

BackgroundAnemia is associated with adverse outcomes and prolonged hospitalizations in critically ill patients. Regarding the recent adoption of restrictive transfusion protocols in intensive care unit (ICU) management, anemia remains highly prevalent even after ICU discharge. This study aimed to investigate the prevalence of anemia following ICU discharge and factors affecting recovery from anemia. MethodsIn this retrospective cohort study involving 3969 adult ICU survivors, we assessed anemia severity using the National Cancer Institute criteria at six time points: ICU admission, ICU discharge, hospital discharge, and at 3-, 6-, and 12-month post-hospital discharge. In addition, baseline characteristics, including age, sex, comorbidities, and recent iron supplementation or erythropoietin administration, were evaluated. ResultsOur findings revealed an in-hospital mortality rate of 28.6%. The median hospital and ICU stays were 20 and 5 days, respectively, with common comorbidities including hypertension, and diabetes mellitus (DM). Among the patients, the hemoglobin levels of 3967 patients were confirmed at the time of discharge from the ICU, representing 99.95% of the total. The prevalence of anemia persisted post- ICU discharge; less than 30% of patients recovered, whereas 13.6% of them experienced worsening of anemia post-ICU discharge. Factors contributing to anemia severity were female sex, DM, chronic renal failure, malignant solid tumors, and administration of iron supplements. ConclusionsThis study highlighted the need for targeted interventions to manage anemia post-ICU discharge and suggested potential factors that influence recovery from anemia.

CDK5RAP3 is a novel super-enhancer-driven gene activated by master TFs and regulates ER-Phagy in neuroblastoma

Super enhancers (SEs) are genomic regions comprising multiple closely spaced enhancers, typically occupied by a high density of cell-type-specific master transcription factors (TFs) and frequently enriched in key oncogenes in various tumors, including neuroblastoma (NB), one of the most prevalent malignant solid tumors in children originating from the neural crest. Cyclin-dependent kinase 5 regulatory subunit-associated protein 3 (CDK5RAP3) is a newly identified super-enhancer-driven gene regulated by master TFs in NB; however, its function in NB remains unclear. Through an integrated study of publicly available datasets and microarrays, we observed a significantly elevated CDK5RAP3 expression level in NB, associated with poor patient prognosis. Further research demonstrated that CDK5RAP3 promotes the growth of NB cells, both in vitro and in vivo. Mechanistically, defective CDK5RAP3 interfered with the UFMylation system, thereby triggering endoplasmic reticulum (ER) phagy. Additionally, we provide evidence that CDK5RAP3 maintains the stability of MEIS2, a master TF in NB, and in turn, contributes to the high expression of CDK5RAP3. Overall, our findings shed light on the molecular mechanisms by which CDK5RAP3 promotes tumor progression and suggest that its inhibition may represent a novel therapeutic strategy for NB.

Heterogeneous characterization of neutrophilic cells in head and neck cancers.

Neutrophilic cells are among the most abundant immune populations within the head and neck tumor microenvironment (TME) and harbor multiple mechanisms of immunosuppression. Despite these important features, neutrophilic cells may be underrepresented in contemporary studies that aim to comprehensively characterize the immune landscape of the TME due to discrepancies in tissue processing and analysis techniques. Here, we review the role of pathologically activated neutrophilic cells within the TME and pitfalls of various approaches used to study their frequency and function in clinical samples. The literature was identified by searching PubMed for "immune landscape" and "tumor immune microenvironment" in combination with keywords describing solid tumor malignancies. Key publications that assessed the immune composition of solid tumors derived from human specimens were included. The tumor and blood processing methodologies in each study were reviewed in depth and correlated with the reported abundance of neutrophilic cells. Neutrophilic cells do not survive cryopreservation, and many studies fail to identify and study neutrophilic cell populations due to cryopreservation of clinical samples for practical reasons. Additional single-cell transcriptomic studies filter out neutrophilic cells due to low transcriptional counts. This report can help readers critically interpret studies aiming to comprehensively study the immune TME that fail to identify and characterize neutrophilic cells.

Engineered oncolytic bacteria for malignant solid tumor treatment

AbstractBacteria have been explored for their potential in fighting against cancer for decades. Due to their outstanding tumor‐targeting capacity and high biocompatibility, live bacteria can serve as microrobots delivering and producing anti‐tumor agents. In addition, live bacteria have intrinsic immune‐activating functions that aid in the generation of anti‐tumor immunity both systemically and locally in the tumor microenvironment. While bacteria‐based cancer therapy is still facing great challenges, progress in this platform combined with nanobiotechnologies has shown promise in terms of safety and effectiveness. Here, basic development strategies of bacteria‐based delivery systems armed with nanotechnologies, virulence attenuation, and genetic manipulation are summarized and the design of a spatiotemporal selectivity is particularly emphasized. In conclusion, the engineered bacteria platform has a high potentiality in the development of novel cancer therapeutics and holds prospects for future investigation and clinical use.

Effects of immune checkpoint inhibitor associated endocrinopathies on cancer survival.

Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs), of which endocrinopathies are common. We characterized endocrine and non-endocrine irAEs in cancer patients receiving ICIs, identified risk factors for their development and established whether endocrine and non-endocrine irAEs were differentially associated with improved cancer prognosis. Single-center, retrospective cohort study of patients with advanced or metastatic solid tumors receiving at least one ICI treatment cycle (242 men, 151 women, median age 65 years). Main outcome measures were incidence of any irAE during the study period, overall survival and time to treatment failure. Non-endocrine irAEs occurred in 32% and endocrine irAEs in 12% of patients. Primary thyroid dysfunction was the most common endocrine irAE (9.5%) and the majority of endocrinopathies required permanent hormone replacement. Women had an increased risk of developing endocrine irAEs (p = 0.017). The biggest survival advantage occurred in patients who developed both endocrine and non-endocrine irAEs (overall survival: HR 0.16, CI 0.09-0.28). Time to treatment failure was also significantly improved in patients who developed endocrine irAEs (HR 0.49, CI 0.34 - 0.71) or both (HR 0.41, CI 0.25 - 0.64) but not in those who only developed non-endocrine irAEs. Women may have increased risk of endocrine irAEs secondary to ICI treatment. This is the first study to compare the effects of endocrine irAEs with non-endocrine irAEs on survival. Development of endocrine irAEs may confer survival benefit in ICI treatment and future, prospective studies are needed to elucidate this.

A thermoresponsive nanocomposite integrates NIR-II-absorbing small molecule with lonidamine for pyroptosis-promoted synergistic immunotherapy

Photothermal immunotherapy is regarded as the ideal cancer therapeutic modality to against malignant solid tumors; however, its therapeutic benefits are often modest and require improvement. In this study, a thermoresponsive nanoparticle (BTN@LND) composed of a photothermal agent (PTA) and pyroptosis inducer (lonidamine) were developed to enhance immunotherapy applications. Specifically, our “two-step” donor engineering strategy produced the strong NIR-II-absorbing organic small-molecule PTA (BTN) that exhibited high NIR-II photothermal performance (ε1064 = 1.51 × 104 M−1 cm−1, η = 75.8%), and this facilitates the diagnosis and treatment of deep tumor tissue. Moreover, the fabricated thermally responsive lipid nanoplatform based on BTN efficiently delivered lonidamine to the tumor site and achieved spatiotemporal release triggered by the NIR-II photothermal effect. In vitro and in vivo experiments demonstrated that the NIR-II photothermal therapy (PTT)-mediated on-demand release of cargo effectively faciliated tumor cell pyroptosis, thereby intensifying the immunogenic cell death (ICD) process to promote antitumor immunotherapy. As a result, this intelligent component bearing photothermal and chemotherapy can maximally suppress the growth of tumors, thus providing a promising approach for pyroptosis/NIR-II PTT synergistic therapy against tumors.Graphical

Non-primary solid malignancies of breast in needle core biopsy: a clinicopathological analysis of 23 cases

Objective: To investigate the accurate diagnosis and differential diagnosis of non-primary solid malignant tumors in breast needle core biopsy. Methods: Twenty-three cases of breast, axilla or neck lymph nodes pathologically diagnosed as non-primary solid malignant tumors were collected at the First Affiliated Hospital of Nanjing Medical University, Nanjing, China from January 2013 to March 2023. The differential diagnoses and diagnostic features were analyzed, based on combining clinical data, histology, and expression characteristics of biomarkers. Results: All patients were female, with age ranging from 29 to 75 years (average 56 years). The average time from the diagnosis of primary tumor to the current diagnosis was 21 months (0 to 204 months).The primary sites included the ovary (9 cases), the lung (5 cases), the gastrointestinal tract (4 cases), the pancreas, intrahepatic bile duct, thyroid gland, nasal cavity and forearm skin (1 case each). No carcinoma in situ was found in any of the cases. The morphological differences were significant among the tumors, but similar to the primary tumors. The tumors of neuroendocrine and female reproductive tract had great morphological and immunophenotypic overlaps with breast cancer. Metastatic lung cancer cells showed obvious atypia and tumor giant cells. The morphology and immunophenotype of metastatic serous carcinoma of female reproductive system might resemble invasive micropapillary carcinoma of the breast. Metastatic adenocarcinoma of the gastrointestinal tract often had features of mucous secretion. Metastatic neuroendocrine tumors were bland in appearance and morphologically similar to solid papillary carcinoma of breast, but negative for ER. TRPS1 was mostly negative (18/23) and variably positive in ovarian (4/9) and intrahepatic bile duct (1/1) tumors. Conclusions: The diagnosis of breast needle core biopsy specimen should be combined with clinical history, imaging study, and careful examination of histological features, such as presence of in situ component, morphological similarity between the primary and metastatic tumors, and using appropriate markers to differentiate the primary from metastatic tumors.

Abstract CT182: Oncolytic virus CF33-hNIS for the treatment of advanced cancer

Abstract Background: CF33-hNIS is a novel vaccinia virus engineered with the human sodium-iodide symporter (hNIS) gene. CF33-hNIS selectively replicates in tumor cells and promotes anti-tumor immunity. Here, we report results on a first-in-human phase 1 dose escalation study of CF33-hNIS, administered intratumorally (IT) or intravenously (IV) in adult patients with metastatic or advanced solid tumors (MAST). Methods: The MAST study is evaluating the safety of CF33-hNIS administered IT or IV, alone or in combination with pembrolizumab in patients with advanced or metastatic solid tumors with ≥ 2 prior lines of therapy (NCT05346484). CF33-hNIS is administered in 21-day cycles on C1D1 and C1D8, then D1 of each cycle thereafter. Pembrolizumab begins C2D1 for the combination groups and is administered Q3W. The study consists of two parts. Part 1 follows a 3+3 dose escalation scheme independent of each route of CF33-hNIS administration (IT and IV) and for each therapy regimen (monotherapy and combination therapy) with up to 7 dose levels of CF33-hNIS ranging from 8.6x105 to 3.0x109 PFU. Part 2 is a cohort expansion in select indications at the optimal dose. The co-primary endpoints are safety and identification of the recommended phase 2 dose. Secondary endpoints include objective response rate according to RECIST v1.1 and iRECIST, and assessment of viral replication in tumor lesions via Single-Photon Emission Computerized Tomography (SPECT). Results: As of Dec 2023, 36 patients have been treated in Part 1 of the study with a median age of 59 (range 23-81). Twenty-two (61%) patients were heavily pretreated with ≥3 prior lines of systemic therapy, and 14 (39%) received prior treatment with checkpoint blockade. Treatment-related adverse events consisted predominantly of ‘flu-like’ symptoms, such as grade 1/2: fatigue (31%), pyrexia (22%), and chills (14%). No dose-limiting toxicities have occurred. The highest dose treated to date is 1.1x108 PFU by IT and IV delivery; dose escalation continues. In the IT cohorts (14 patients), 7 of 15 (47%) injected lesions had a reduction in tumor burden, three lesions were completely eradicated. Three patients (21%) had an objective response: one complete response by iRECIST in a patient with cholangiocarcinoma; and two partial responses in patients with melanoma by RECIST. In IV cohorts (17 patients), 53% of patients achieved stable disease as their best response. Patients who received prior checkpoint blockade therapy derived clinical benefit with and without pembrolizumab. Viral replication, assessed by SPECT was higher in patients that saw a reduction in tumor burden. Immunological changes in peripheral blood and tumor biopsies will be presented. Conclusions: CF33-hNIS alone or in combination with pembrolizumab is a safe treatment option for advanced cancer patients. Encouraging efficacy has warranted advancement to part 2 of this study with a cohort expansion of patients with cholangiocarcinoma and other tumor types. Citation Format: Daneng Li, Anthony F. Shields, Hirva Mamdani, Patrick Travis, Gavin Wright, Wallace Akerley, Alex Spira, Gregory Daniels, Jaime Merchan, Abhijeet Kumar, Emerson Lim, Colt Egelston, Oscar Flores, Stanley Hamilton, Janet Austria, Amanda Seiz, Sharon Yavrom, Seymour Fein, John Byon, Paul Woodard, Grey A. Wilkinson, Jennifer Leddon. Oncolytic virus CF33-hNIS for the treatment of advanced cancer [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 CT182.

Abstract CT077: An open-label phase 1 study to investigate SGN-CEACAM5C in adults with advanced solid tumors (SGNCEA5C-001, Trial in Progress)

Abstract Background Patients (pts) with recurrent or metastatic solid tumors, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), gastric adenocarcinoma (GC), and pancreatic ductal adenocarcinoma (PDAC), have limited treatment options with short PFS and OS despite recent advances (Bordry 2021; Chakrabarti 2022; Merle 2022). Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is highly expressed across multiple solid tumors, such as CRC, GC, PDAC, and NSCLC. Restricted normal tissue expression and efficient lysosomal trafficking of CEACAM5 highlight its potential as an anticancer target. SGN-CEACAM5C is a novel investigational antibody-drug conjugate (ADC) directed to CEACAM5 composed of the humanized immunoglobulin G (IgG1) anti-CEACAM5 monoclonal antibody tusamitamab chemically conjugated to 8 molecules of the topoisomerase 1 inhibitor 7-aminomethyl-10,11-methylenedioxycamptothecin (AMDCPT). SGN-CEACAM5C selectively binds to CEACAM5 present on the cell surface and is internalized via the endo-lysosomal pathway, with subsequent release of the payload through enzymatic cleavage. Release of the cytotoxic payload induces DNA damage, cell cycle arrest in S phase, and apoptosis in tumor cells. In vitro bystander activity was observed against tumor cells without CEACAM5 surface expression. SGN-CEACAM5C is highly active in multiple patient-derived xenograft models, including CRC, GC, and NSCLC, across various levels of CEACAM5 expression (Baudat 2023; Baudat 2024). These preclinical findings justify evaluation of SGN-CEACAM5C in a clinical trial setting. Methods SGNCEA5C-001 (NCT06131840) is a phase 1, open-label, multicenter study designed to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of SGN-CEACAM5C in adults with select advanced solid tumors. This study consists of dose escalation (Part A), dose and schedule optimization (Part B), and dose expansion (Part C). Eligible pts are adults ≥18 years of age with confirmed metastatic or unresectable solid tumor malignancy, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, an ECOG PS of 0-1, and 1 of the following tumor types: CRC, GC/gastroesophageal junction adenocarcinoma (GEJ), PDAC, NSCLC (squamous/non-squamous), or SCLC. Primary endpoints include incidence of AEs, laboratory abnormalities, dose modifications due to AEs, dose-limiting toxicities, and cumulative safety. Secondary endpoints include estimates of PK parameters, incidence of antidrug antibodies, objective response rate and best response per RECIST v1.1 by investigator, duration of response, PFS, and OS. Safety and antitumor activity endpoints will be summarized using descriptive statistics. Recruitment is ongoing for Part A in North America. Citation Format: Funda Meric-Bernstam, Cesar A. Perez, Nehal Lakhani, Meredith Pelster, Justin Call, Suzanne McGoldrick, Tianhua Wang, Brigitte Demers, Amita Patnaik. An open-label phase 1 study to investigate SGN-CEACAM5C in adults with advanced solid tumors (SGNCEA5C-001, Trial in Progress) [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 CT077.

Abstract CT062: A phase 1 study of tamnorzatinib (ONO-7475), an Axl/Mer dual inhibitor, alone and in combination with nivolumab in patients with advanced or metastatic solid tumors

Abstract Background: Tamnorzatinib (ONO-7475) is an orally active small molecule Axl/Mer dual inhibitor that not only directly acts on cancer cells to suppress their proliferation, but also on immune cells and exerts characteristics of cancer immunotherapy. Methods: We performed a phase 1 study to assess the tolerability, safety, and pharmacokinetics of ONO-7475 alone (Part A) and in combination with nivolumab (NIVO) (Part B) in Japanese patients (pts) with advanced or metastatic solid tumors (NCT03730337). Patients received once-daily ONO-7475 (3-10 mg, orally) as a monotherapy or in combination with NIVO (240 mg, i.v., every 2 weeks). Results: Twelve pts in both Part A and Part B (three each at 3 and 6 mg, and six at 10 mg ONO-7475) received the study treatment. Baseline characteristics, safety, and efficacy outcomes are summarized in the Table. While one of six pts in the Part B 10-mg cohort developed dose-limiting toxicities of grade 4 nephritis, grade 3 colitis, and grade 3 hepatic function abnormal, no others did. In biomarker analyses, activation of T cell function and an increase in T cell number, an increase in inflammatory (M1) macrophages/immunosuppressive (M2) macrophages ratio, and suppression of epithelial-to-mesenchymal transition were observed after treatment. Conclusion: ONO-7475 was tolerated at repeated once-daily oral doses up to 10 mg as a monotherapy and in combination with NIVO in pts with advanced or metastatic solid tumors. TABLE 1. NAND Table. Baseline Characteristics, Safety Outcomes, and Efficacy Outcomes Part A (ONO-7475 alone) N = 12 Part B (ONO-7475 + NIVO) N = 12 Baseline Characteristics Median age, years (range) 63.5 (31–76) 56.0 (39–72) Female, n (%) 8 (66.7) 9 (75.0) ECOG PS, n (%) 0 8 (66.7) 10 (83.3) 1 4 (33.3) 2 (16.7) Safety Outcomes Number of patients with AEs (%) Any grade 11 (91.7) 11 (91.7) Glade ≥3 0 2 (16.7) *2 Number of patients with SAEs (%) 2 (16.7) *1 1 (8.3) *3 *1 Pyrexia and diverticulitis (1 patient each) *2 Grade 4 neutrophil count decreased (1 patient), grade 4 lymphocyte count decreased and nephritis (1 patient each), and grade 3 colitis, enterocolitis infectious, device related infection, anemia, hyperglycemia, and hepatic function abnormal (1 patient) *3 Colitis, hepatic function abnormal, and nephritis Efficacy Outcomes Objective Response Rate, n (%) [95% CI] 0 [0.0, 26.5] 1 (8.3) [0.2, 38.5] Disease Control Rate, n (%) [95% CI] 3 (25.0) [5.5, 57.2] 4 (33.3) [9.9, 65.1] Best Overall Response, n (%) [95% CI] Complete Response 0 [0.0, 26.5] 0 [0.0, 26.5] Partial Response 0 [0.0, 26.5] 1 (8.3) [0.2, 38.5] Stable Disease 3 (25.0) [5.5, 57.2] 3 (25.0) [5.5, 57.2] Progressive Disease 9 (75.0) 5 (41.7) Not Evaluable 0 3 (25.0) Median OS, months [95% CI] 12.21 [4.93, not reached] 16.99 [5.98, not reached] Median PFS, months [95% CI] 1.86 [0.92, 3.84] 2.17 [0.95, 3.78] Citation Format: Yuki Katsuya, Kan Yonemori, Toshio Shimizu, Takafumi Koyama, Sigehisa Kitano, Kazuki Sudo, Shunsuke Kondo, Jun Sato, Hiroaki Hozumi, Noboru Yamamoto. A phase 1 study of tamnorzatinib (ONO-7475), an Axl/Mer dual inhibitor, alone and in combination with nivolumab in patients with advanced or metastatic solid tumors [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 CT062.

Abstract CT289: A phase II study of Tucatinib and Ado-trastuzumab Emtansine (T-DM1) in patients with HER2-positive metastatic solid tumors and metastases to brain (TUCATEMEB)

Abstract Background: HER2 overexpression or amplification is a validated prognostic and predictive biomarker for treatments in several tumor types. The development of brain metastases is an unfortunate and common complication in patients with metastatic cancer and the incidence of brain metastases continues to grow as advances in cancer treatment extend the survival. Unfortunately many of the clinical trials still exclude patients with brain metastases. Tucatinib is a selective small molecule HER2 inibitor that has shown intracranial activity and it is approved with trastuzumab and capecitabine for treatment of patients with breast cancer including with active brain metastases. Tucatinib showed significant preclinical and clinical antitumor activity in combination with other HER2-targeted therapies, including T-DM1 in breast and other cancers. We hypothesize that the combination of tucatinib and T-DM1 will be a safe and effective treatment in HER2-positive (+) metastatic solid tumors that have metastasized to the brain. To test this hypothesis, we are conducting a Phase II Study of Tucatinib and T-DM1 in Patients with HER2+ Metastatic Solid Tumors and Metastases to Brain (TUCATEMEB). Methods: Eligible adult patients with HER2-positive solid tumors and active brain metastases (with at least one untreated brain lesion ≥0.5 cm and <3.0 cm) will be enrolled in the study. HER2 positivity is defined as HER2 overexpression by immunohistochemistry 3+ or 2+ and fluorescence in situ hybridization positive and/or HER2 amplification by in situ hybridization or next-generation sequencing and/or activating ERBB2 mutation. Patients will receive the study treatment in 21-day cycles: Tucatinib 300 mg orally twice daily; T-DM1 3.6 mg/kg intravenously on Day 1. The primary objective is to determine the intracranial antitumor activity of the tucatinib and T-DM1 combination per the modified RECIST in patients with HER2+ metastatic solid tumors and brain metastases. The secondary objectives are to determine the intracranial antitumor activity per the RANO-BM criteria; to evaluate the safety and tolerability, the duration of intracranial response, the overall survival, the progression free survival, the systemic antitumor activity and clinical benefit rate in patients with HER2+ metastatic solid tumors and brain metastases. Exploratory objectives are to assess predictive and pharmacodynamic markers of response and to corelate them with clinical and molecular characteristics. The efficacy endpoint will be monitored using the Bayesian optimal phase 2 BOP2 design and safety and tolerability will be monitored based on Bayesian posterior probability. Restaging brain MRI and systemic scans will be performed every 6 weeks for the first 12 weeks, and every 9 weeks thereafter. The trial opened in May 2023 and is enrolling patients (NCT05673928). Citation Format: Ecaterina E. Dumbrava, Amber M. Kennon, Rashmi K. Murthy, Emma J. Montazari, Hussein Tawbi, Jing Li, Frederick F. Lang, Gisela Sanchez, Jianbo Wang, Isabella C. Glitza, Barbara J. O'Brien, Thomas Beckham, Todd Swanson, Martin C. Tom, Uyen M. Vu, Tanisha T. Darko, Tiantian Cai, Komal Shah, Funda Meric-Bernstam, Jordi Rodon. A phase II study of Tucatinib and Ado-trastuzumab Emtansine (T-DM1) in patients with HER2-positive metastatic solid tumors and metastases to brain (TUCATEMEB) [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 CT289.

Abstract CT132: A Phase I/IIa clinical trial (TranStar101) to evaluate the safety, tolerability and pharmacokinetics of OSEMITAMAB administered as monotherapy or in combination with nivolumab or standard of care in patients with locally advanced or metastatic solid tumors

Abstract Introduction: TST001/osemitamab is a novel, recombinant humanized IgG1 mAb with improved CLDN18.2 binding affinity and enhanced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) and can result in more efficient cytotoxicity of tumors expressing human CLDN18.2 across a broad range of levels including low to medium expression. Methods: This is an open-label, multi-center phase I/IIa first in human (FIH) study of osemitamab administered as monotherapy or in combination with nivolumab or standard of care for patients with locally advanced or metastatic solid tumors. The study includes two parts: Part A (completed), a dose escalation of osemitamab as a monotherapy in solid tumors, osemitamab intravenous infusion at dose from 1mg/kg to 10mg/kg and once every two weeks (Q2W) or once every three weeks (Q3W) were evaluated; Part B (ongoing) includes expansion cohorts of osemitamab in combination with other therapies (cohort A and B). Cohort A includes combination of osemitamab, nivolumab, and mFOLFOX6 as the 1st line treatment for G/GEJ cancer. Cohort B includes osemitamab in combination with nivolumab in advanced pre-treated G/GEJ cancer. Results: As of Nov. 30, 2023, 68 patients have been treated: 38 patients were enrolled in the Part A dose escalation,13 in Part B Cohort A, and 17 in Part B Cohort B. The population (N=68) consisted of 59% males, median age 62 years and 50% with G/GEJ cancer. Doses evaluated are 3 to 10mg/kg Q3W and 1 to 6 mg/kg Q2W in part A. One dose limiting toxicity of Grade 3 infusion related reaction was reported at the 1mg/kg dose Q2W. The MTD was not reached. The recommended phase 2 dose was determined as 6mg/kg Q3W or 4mg/kg Q2W based on the totality of available safety, efficacy, PK/PD data including information from another phase I/II study (TranStar102). The most common TRAEs (occurred in ≥ 20% subjects) were nausea (73.5%), vomiting (48.5%), fatigue (30.9%). TRAE of Grade ≥ 3 across all tested doses (3-10 mg/kg) that occurred in ≥3% of patients included nausea, vomiting, hypoalbuminemia, hypertension, infusion related reaction, and lymphocyte count increased. Within the dose ranges studied, PK exposures increased as dose increased. The mean CLss value of osemitamab ranged from 9.4 to 13.7 mL/day/kg across different dose levels, without a clear dose relationship. Mild accumulation was observed following Q2W and Q3W dosing. Conclusion: Osemitamab as monotherapy or in combination with nivolumab or mFOLFOX plus nivolumab is well tolerated and safe with a PK profile consistent with other studies (TranStar 102 study -NCT04495296). TranStar 101 is currently ongoing. More information will be shared. Clinical trial information: NCT04396821. Study Sponsor: Suzhou Transcenta Therapeutics Co., Ltd. Citation Format: Yelena Janjigian, Anthony Tolcher, Rutika Mehta, Michael Cecchini, Brian Van Tine, Madappa Kundranda, Alese Olatunji, Manish R. Patel, Jordan Berlin, Caio Max Sao Pedro Rocha-Lima, Dulabh Monga, Ben George, Aaron Scott, Zhenzhong Xia, Mohamed Elsafy, Erikca Jones, Zhenling Yao, Chuan Qi, Caroline Germa, Nash Gabrail. A Phase I/IIa clinical trial (TranStar101) to evaluate the safety, tolerability and pharmacokinetics of OSEMITAMAB administered as monotherapy or in combination with nivolumab or standard of care in patients with locally advanced or metastatic solid tumors [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 CT132.

Abstract CT061: Pharmacodynamic analysis from a phase 1/2 study of subasumstat (TAK-981) as single agent in patients (pts) with advanced/refractory metastatic solid tumors

Abstract Background Subasumstat (TAK-981, suba) is a first-in-class innate immunity enhancer that unlocks innate/adaptive immune responses to target tumors through SUMOylation inhibition, which may enhance antitumor activity by restoring endogenous type 1 IFN signaling in immune cells. In the phase 1/2 study (NCT03648372), suba showed dose-dependent upregulation of an IFN-1 gene signature in peripheral blood (PB) and plasma levels of several IFN-1-induced cytokines, and an increase in activated NK, CD8, and CD4 T cells in PB. Here, we report pharmacodynamic data from skin and tumor biopsy samples from this study. Methods In phase 1, 84 pts received suba IV at escalating doses (3-120 mg) twice-weekly (BIW) or once-weekly in 21-day cycles. In phase 2, 25 pts with refractory NSCLC, cervical cancer, or CRC received suba 90 mg BIW. Skin and tumor biopsies were collected at screening and on cycle 1, day 8 (C1D8, skin) or C2D8 (+7 days; tumor). Target engagement (TE) and levels of SUMO2/3-conjugates were assessed using IHC. Immune activation in the tumor microenvironment (TME) was measured by IHC and multiplex IF. Results In skin samples collected 1-3 hours after D8 dosing, suba ≥10 mg demonstrated dose-dependent TE as seen by suba-SUMO adduct formation and dose-dependent SUMO2/3 inhibition at ≥60 mg. Assays of paired tumor samples from pts with CPI-naïve MSS-CRC (90 mg BIW, n=3), cervical cancer (90 mg BIW, n=1), CPI-exposed non-squamous NSCLC (90 mg BIW, n=2), and melanoma (25 mg BIW, n=1) showed robust TE in the post-dose sample, along with SUMO2/3 inhibition or stabilization. Suba’s effects on the TME were assessed through PD-L1 IHC. There was an increase in PD-L1 combined positive score in most on-treatment tumors, consistent with suba’s ability to enhance IFN production, leading to induction of an inflammatory landscape in the TME. Multiplex IF analysis revealed significant CD8+ and CD4+ T cell infiltration in samples from CPI-naïve (cervical cancer) and CPI-exposed (melanoma and NSCLC) pts. In contrast, biopsies obtained from MSS-CRC pts did not exhibit an increase in T cell density, suggesting that “cold” tumors may be less susceptible to suba-mediated immune remodeling. Accordingly, biopsies from pts with cervical cancer and melanoma displayed a significant increase in T cell activation and density of activated CD11c+HLA-DR+ myeloid dendritic cells within the TME, as well as a marked increase in HLA-class I expression. Conclusion Suba-mediated inhibition of SUMOylation led to marked changes in the TME across different indications, supporting the hypothesized immune-activating mechanism of action of the drug. Our findings support continued development of suba in solid tumors. Suba is being evaluated in combination with pembrolizumab in NSCLC, cervical cancer, and melanoma (NCT04381650). Citation Format: Dina Stroopinsky, Slawomir Mandzuik, Daniel Anderson, José-Ángel Hernández-Rivas, Hadeel Assad, Allison Berger, Aleksander Chudnovsky, Qi Dong, Afshin Dowlati, Dejan Juric, Razelle Kurzrock, Iwona Lugowska, Kelly Richter, Jordi Rodón, David Schröder, Siddha Kasar, Anthony Olzanski. Pharmacodynamic analysis from a phase 1/2 study of subasumstat (TAK-981) as single agent in patients (pts) with advanced/refractory metastatic solid tumors [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 CT061.

Abstract CT181: First-in-human phase I of anti-VISTA monoclonal antibody W0180 with and without anti-PD-1 pembrolizumab in patients with locally advanced or metastatic solid tumors

Abstract Background: V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) is an immune checkpoint regulator highly expressed on myeloid cells. VISTA has been shown to maintain tumor microenvironment (TME) in an immunosuppressive state. Its expression is reported as a resistance mechanism to immune checkpoint blockers, making it an attractive target for cancer treatment. Preclinical data showed that VISTA blockade mediates antitumor activity by activating the antitumor immune response and is enhanced in combination with anti-PD-1. W0180 is a humanized, Fc competent, IgG1 antibody targeting VISTA with high affinity. This study investigates W0180 with/without pembrolizumab (pembro) in patients (pts) with solid tumors. Methods: Pts initially received W0180 monotherapy in dose escalation (3.5-600 mg weekly (QW)). Following evaluation of the first 3 dose levels in monotherapy, dose escalation of W0180 (60 to 300 mg QW) in combination with pembro (200 mg Q3W) started in pts treated with prior anti-PD-(L)1. Objectives were to characterize safety and tolerability of W0180, determine RDE and PK/PD on blood and paired tumor biopsies. Results: By October 2023, 33 pts were treated in dose escalation, 24 pts with W0180 monotherapy and 9 pts with W0180 + pembro. Two dose-limiting toxicities were observed, Grade 2 subacute cerebral infarction and Grade 3 infusion related reaction (IRR). Overall, 33 pts experienced ≥1 treatment-emergent AE (TEAE). Most common TEAEs were IRR (32/33), fatigue (14/33), and anemia (11/33). Grade 3/4 TEAEs occurred in 23 pts, neutropenia (6/23) and anemia (6/23) were the most common. There was no treatment-related death. 6 (18%) pts discontinued due to AEs. Following the observation of Grade 3 arterial thromboembolism (n=1) and Grade 2 subacute cerebral infarction (n=1), eligibility criteria were amended to require adequate lipid profile, troponin and exclude pts with history of arterial thrombotic events and current smoking. W0180 PK was nonlinear with a rapid clearance at 3.5-600 mg doses. No objective response was observed but 5 pts had stable disease (SD) lasting for >16 weeks. One pt with appendix cancer treated at 600mg monotherapy had SD for >15 months. One pt with head and neck cancer treated at 300mg in combination had SD for 13 months. Biomarkers data suggested evidence of PD effect with a trend for dose response through sustained increase of proliferative CD8+ T-cells in blood at the highest W0180 exposures and increased density of tumor-infiltrating lymphocytes in 10 out of 16 pts. These changes were independent of tumor VISTA expression level and correlated to high PD-L1 expression (CPS>5) for 4 pts at baseline. Conclusions: Analysis is ongoing to assess the RDE of W0180 + pembro and collect additional evidence of proof of mechanism in pts with solid tumors. NCT04564417 Citation Format: Carlos Gomez-Roca, Stéphane Champiat, Philippe Cassier, David Jegou, Marie Primard, Aurélie Pétain, Geneviève Gueguen-Dorbes, Claire Fabre, Ignacio Melero, Aurélien Marabelle. First-in-human phase I of anti-VISTA monoclonal antibody W0180 with and without anti-PD-1 pembrolizumab in patients with locally advanced or metastatic solid tumors [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 CT181.

Abstract CT099: NGM707 in combination with pembrolizumab in advanced or metastatic solid tumors: Preliminary results from dose escalation

Abstract BACKGROUND: NGM707-IO-101 (NCT04913337) is a Phase 1/2, dose escalation/expansion study evaluating NGM707, a humanized monoclonal antibody that blocks ILT2 and ILT4 receptors, as monotherapy or in combination with pembrolizumab. Here we report data from the combination part of the study. METHODS: Eligible patients (pts) with advanced/metastatic solid tumors were enrolled into escalating dose cohorts of 200-1800 mg NGM707 combined with 200 mg pembrolizumab, administered Q3W iv. Assessment of safety and tolerability and recommended expansion doses for NGM707 in combination with pembrolizumab were the primary objectives of the study. Secondary and exploratory objectives included assessment of pharmacokinetics/receptor occupancy (RO), immunogenicity, biomarkers, and preliminary antitumor activity per RECIST v1.1. RESULTS: As of 06 Nov 2023, 46 pts have been enrolled in the combination escalation at dose levels up to 1800 mg; 5 pts crossed over from monotherapy. Median age 58.5 yrs [28-81]; ECOG PS 0 (19.6%), 1 (80.4%). Pts had received a median of 3 prior therapies (range 1-6) and all pts had metastatic disease. Overall, 20/45 pts had prior exposure to anti-PD1/anti-PD-L1. Treatment-related adverse events (any grade/grade ≥3) occurred in 41.3%/4.4% of pts. The most common treatment-related adverse events were fatigue (17.4%), diarrhea (6.5%), myalgia (4.3%), arthralgia (4.3%), and nausea (4.3%). No dose-limiting toxicities were observed. A maximum tolerated dose was not reached, and the maximum administered dose was 1800 mg NGM707 in combination with 200 mg pembrolizumab. Peripheral immune cells showed dose-dependent RO, with doses ≥ 200 mg maintaining ILT2 and ILT4 RO for the entire dosing interval. PK of NGM707 was typical for monoclonal antibodies, with a half-life of 12.8 days. Gene expression changes associated with myeloid cell and T cell activation were observed in tumor biopsies post-treatment. Of 37 response-evaluable pts, best overall responses to date are PR (confirmed) in 4 pts, SD in 12 pts, representing a DCR of ~43%. Nine pts had reduced target lesion (TL) size with a maximum reduction of 100%. Out of the 4 patients who had PR, 3 patients were pre-treated with anti-PD1/anti-PD-L1. Two subjects with MSS CRC achieved confirmed PR, one of them with TL reduction that allowed subsequent surgical resection of all gross residual disease and confirmed pathological CR with no active tumor cells and ctDNA below detection. CONCLUSIONS: NGM707 in combination with pembrolizumab appears to be safe and well tolerated at all dose levels. In this advanced and metastatic solid tumor cohort, early efficacy signals have been observed. Preliminary evidence of myeloid cell reprogramming was observed in paired tumor biopsies. Trial enrollment for the expansion part of the study is ongoing and updated data will be presented in the future. Citation Format: Judy S. Wang, Manish R. Sharma, William J. Edenfield, Kartik Sehgal, Do-Youn Oh, Yixing Jiang, Joel Michalski, Jeeyun Lee, Hans Hammers, Li-Yuan Bai, Chih-Hung Hsu, Brenda Dampier, Kefei Zhou, Li Yan, Lisa K. Blum, Joanne Sloan-Lancaster, Daniel D. Kaplan, Dhiraj Abhyankar, Hsiao D. Lieu, Vladimir Hanes, Aung Naing. NGM707 in combination with pembrolizumab in advanced or metastatic solid tumors: Preliminary results from dose escalation [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 CT099.

Abstract CT119: Safety and efficacy of HS-10370 in KRAS G12C-mutated solid tumors including non-small cell lung cancer (NSCLC)

Abstract Background: KRAS G12C mutation occurs in ~13% of NSCLC and up to 4% of other solid tumors. HS-10370 is a selective, covalent, orally bioavailable KRAS G12C inhibitor. We conducted a first-in-human phase I trial to evaluate the dose-limiting toxicity (DLT), safety, tolerability, pharmacokinetics, and efficacy of HS-10370 in patients (pts) with advanced solid tumors bearing KRAS G12C mutation. Methods: In a phase I study HS-10370-101 (NCT05367778), patients of advanced or metastatic solid tumors with measurable disease were recruited. HS-10370 monotherapy was given at oral doses of 200~1600 mg QD until disease progression, intolerance, or withdrawal from consent. Rolling 6 was applied as the dose escalation schedule in this phase I dose escalation trial. The primary objectives of the dose escalation part was safety and tolerability. The secondary objectives included pharmacokinetics (PK) profile and efficacy. Results: As of Dec 15th, 2023, 55 patients with advanced solid tumors were enrolled in this study, including 49 patients with KRAS G12C mutation. Of the 49 patients, 43 were with NSCLC, 5 with colon cancer, and 1 with pancreatic cancer. Safety: No dose-limiting toxicity was observed, neither maximum tolerated dose (MTD) been identified. Treatment-emergent adverse events(TEAEs) occurred in 87.3% of the treated patients (48/55), the most common TEAEs (≥10%) were AST increase (29.1%, 16/55), ALT increase (29.1%, 16/55), anemia(27.3%, 15/55) , diarrhea (25.5%, 14/55), weight gain (18.2%, 10/55), decreased appetite (14.5%, 8/55), hypoproteinemia (12.7%,7/55), nausea(12.7%,7/55), fatigue(14.5%, 8/55) and rash (12.7%, 7/55). The TEAEs ≥Grade 3 occurred in 27.3% patients (15/55). TEAEs leading to dose interruptions and dose reductions were reported in 18.2% patients (10/55) and 7.3% patients (4/55), respectively. Efficacy: Of the 49 patients with KRAS G12C mutant status, 24 had partial response (PR) and 20 had stable disease (SD). The confirmed objective response rate (ORR) and disease control rate (DCR) were 49.0% and 89.8% respectively. Objective responses were observed in patients received 400mg QD or above. In patients with KRAS G12C mutant NSCLC who received more than or equal to 400mg daily dose, the confirmed ORR and DCR were 51.2% (21/41) and 95.1% (39/41), respectively. Of the same subpopulation, the median duration of response was not reached (5.4, NA). Meanwhile, the median progression-free-survival (PFS) was 11.3 month (6.1, NA), with the 6-months PFS rate 75% and the 9-months PFS rate 63.6%. Responses were also observed in patients with colon cancer and pancreatic cancer. Conclusions: HS-10370 was well tolerated and showed inspiring antitumor activities in KRAS G12C mutated advanced solid tumors, especially in NSCLC. Citation Format: Xiaorong Dong, Xiangjiao Meng, Yan Zhang, Yan Wang, Jianhua Chen, Liang Han, Qiming Wang, Zhong Lin, Hongying Wei, Siheng Lin, Chuan Li, Qiong Wu. Safety and efficacy of HS-10370 in KRAS G12C-mutated solid tumors including non-small cell lung cancer (NSCLC) [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 CT119.

Abstract CT084: A phase 1 study of LY4101174 (ETx-22), an antibody-drug conjugate targeting nectin-4, in patients with advanced or metastatic urothelial cancer and other solid tumors (trial in progress)

Abstract Background: Nectin-4 is a cell adhesion molecule expressed in multiple tumor types.1 Enfortumab vedotin (EV), an antibody-drug conjugate (ADC) comprising a fully humanized nectin-4 antibody conjugated to the microtubule inhibitor, monomethyl auristatin E (MMAE), is approved for the treatment of advanced urothelial cancer (UC). However, skin toxicity, peripheral neuropathy, and hyperglycemia are clinically significant toxicities with EV. LY4101174 (ETx-22) is a next-generation nectin-4 targeting ADC comprising a humanized IgG1 Fc-silent monoclonal antibody linked to the topoisomerase I inhibitor, exatecan, via a maleimide-ß-glucuronide poly-sarcosine linker with improved stability and a homogeneous drug-antibody ratio (DAR) of 8. Preclinically, LY4101174 has demonstrated robust in vivo efficacy in tumor models across a range of nectin-4 expression levels and in the nectin-4-MMAE ADC treated resistant tumor model.2 Methods: LOXO-ENC-23001 is a global, open-label, multi-center, first-in-human phase 1 study of LY4101174 in patients (pts) with advanced or metastatic solid tumors known to express nectin-4. LY4101174 will be administered intravenously and evaluated initially on either every 2 weeks or 3 weeks schedule. Eligible pts (≥18 years) must have good performance status (ECOG PS 0-1) with metastatic UC, head and neck squamous cell carcinoma, esophageal, pancreatic, prostate, non-small cell lung, cervical, ovarian, or triple-negative breast cancer, and must have received or not be a candidate for available standard therapies. The study will be conducted in 2 phases: phase 1a dose escalation/dose optimization and phase 1b dose expansion. Dose escalation will utilize a Bayesian optimal interval design. Additional pts will be allowed to backfill to previously cleared dose levels that demonstrate therapeutically relevant exposures or direct evidence of clinical activity. The dose-limiting toxicity evaluation period will be 21 or 28 days based on dosing schedules. Phase 1b dose expansion cohorts will enroll pts with selected tumor types: mUC with no prior EV treatment (cohort B1), mUC with prior EV treatment (cohort B2), and other selected non-UC tumors (cohort C). Primary objectives are to determine the recommended phase 2 dose (RP2D) and assess the safety of LY4101174. Key secondary objectives are to evaluate the pharmacokinetic profile, immunogenicity, and antitumor activity of LY4101174 per RECIST v1.1. Nectin-4 expression and other biomarker data will be generated and correlated with clinical activity. 1Challita-Eid PM et al. 2016 Cancer Res 76(10):3003-13. 2Azim H et al. 2023 Mol Cancer Ther 22(12_Suppl):B128. Citation Format: Jonathan Rosenberg, Renaud Sabatier, Armelle Viceneux, Thibault de La Motte Rouge, Stephane Champiat, Loic Lebellec, Philippe Barthélémy, Guru Sonpavde, Xin Gao, Scot Niglio, Tian Zhang, Craig Gedye, Matthew Galsky, Matthew Milowsky, Melissa Reimers, Andrew Weickhardt, Enrique Grande, Daniel E. Castellano, Mehmet Bilen, Amita Patnaik, Robert Zerbib, Minna Balbas, Xiaojian Xu, Kaitlyn Aptaker, Arjun V. Balar, Ahmad H. Awada. A phase 1 study of LY4101174 (ETx-22), an antibody-drug conjugate targeting nectin-4, in patients with advanced or metastatic urothelial cancer and other solid tumors (trial in progress) [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 CT084.