Cancer research最新文献

{"title":"Abstract CT057: Evaluation of tumor associated P30-peptide antigen (ETAPA): Safety and immunogenicity in a phase 1b trial in glioblastoma","authors":"Kelly Hotchkiss, Pamela Norberg, Evan Buckley, Katayoun Ayasoufi, Stevie Threatt, Justin T. Low, Madison L. Shoaf, Melody Goldston, Kristen Batich, Margaret O. Johnson, Smita Nair, Kent Weinhold, Henry S. Friedman, John H. Sampson, David M. Ashley, Annick Desjardins, Mustafa Khasraw","doi":"10.1158/1538-7445.am2025-ct057","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-ct057","url":null,"abstract":"We developed a novel peptide-based vaccine, P30-EPS, which combines the universal class II-binding P30 epitope derived from tetanus toxoid with HLA-A2:01 class I peptides from tumor-associated antigens (TAAs) EphA2, CMV pp65, and survivin. Administered with poly-ICLC as an adjuvant, this vaccine induces inflammatory cytokines such as IFN-γ, TNF-α, and IL-6 to enhance antigen presentation and CD8+ T-cell activation, while the tetanus toxoid-derived P30 peptide serves as a helper epitope to amplify CD4+ T-cell responses and boost overall immunogenicity. This vaccine is specifically designed to enhance CD4 T cell engagement and boost immune responses against antigens commonly expressed by glioblastoma cells. The phase 1b ETAPA trial (NCT05283109) is enrolling both CMV- and CMV+ patients with newly diagnosed, unmethylated GBM to evaluate the safety and immunogenicity of P30-EPS. Patients receive seven doses of the vaccine following standard radiation therapy and concomitant temozolomide treatment, with an escalating peptide dose. A “3+3” dose-escalation strategy with 300 μg and 400 µg per peptide was used to assess dose-limiting toxicities (DLT) following vaccination with P30-EPS. Patients were observed for DLT from vaccine 1 until 30 days after vaccine 5. Primary outcomes include safety, while secondary objectives focus on peripheral blood immune responses, specifically TAA-specific T cell activity assessed by IFNγ ELISPOT and polyfunctional flow cytometry, alongside survival metrics. P30-EPS vaccination at both dose levels (n=12) was well-tolerated in CMV+ and CMV- patients with no serious adverse events (SAEs) or DLTs, all reported adverse events were mild (grade 1-2). Enrollment continues at the 400 μg dose. Four of the initial six patients had increased vaccine specific immune activation by ELISPOT at vaccine 5 compared to baseline. Interestingly, increased IFN-γ response was not dependent on patient HLA A2:01 type. Furthermore, patients which developed vaccine specific immunity had higher baseline B cell percentages. Comprehensive data from flow cytometry and scRNA VDJ TCR sequencing of B and T cell receptors in PBMCs, collected both pre- and post-vaccination will be presented, this data will inform subsequent steps in clinical development. Citation Format: Kelly Hotchkiss, Pamela Norberg, Evan Buckley, Katayoun Ayasoufi, Stevie Threatt, Justin T. Low, Madison L. Shoaf, Melody Goldston, Kristen Batich, Margaret O. Johnson, Smita Nair, Kent Weinhold, Henry S. Friedman, John H. Sampson, David M. Ashley, Annick Desjardins, Mustafa Khasraw. Evaluation of tumor associated P30-peptide antigen (ETAPA): Safety and immunogenicity in a phase 1b trial in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr CT057.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"69 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB291: Monitoring and targeting therapy resistance mediating neuroendocrine trans-differentiation in breast cancer via the neurod1/ncam axis","authors":"Roberto Würth, Tasneem Cheytan, Paul Schwerd-Kleine, Ewgenija Gutjahr, Martin Sprick, Andreas Trumpp","doi":"10.1158/1538-7445.am2025-lb291","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb291","url":null,"abstract":"Neuroendocrine breast carcinoma (NEBC) is a rare, aggressive subtype of breast cancer known for its high resistance to therapies. Unlike prostate, pulmonary, or gastroenteropancreatic tumors where neuroendocrine trans-differentiation (NED) is recognized as a key driver of intra-tumoral heterogeneity and treatment resistance, NEBC remain poorly characterized. Its rarity, combined with its emergence predominantly as a relapse-associated therapy escape mechanism, presents significant challenges for research and clinical management. Neuroendocrine transdifferentiation underscores the remarkable plasticity of cancer cells under therapeutic pressure. The absence of robust patient-derived NEBC models further hampers progress in understanding this resistant state and developing effective interventions. In addition, beyond synaptophysin detection through histopathological analysis, there are limited actionable biomarkers to clinically detect or monitor NEBC appearance post-treatment.To investigate neuroendocrine-mediated resistance, we leveraged our recently developed Circulating Tumor Cell (CTC)-organoid platform and established unique patient-derived organoid (PDO) models that faithfully mirror the key features of NEBC, including its intra-tumoral heterogeneity and multidrug resistance. Through comparative analysis of matched epithelial and neuroendocrine PDOs derived from distinct sites of the same patient tumor, we uncovered distinct molecular and genetic profiles that offer valuable insights into NEBC biology and resistance mechanisms. While both cell types shared some genetic alterations (e.g., ERBB2 and MYCN amplification, TP53 loss), NEBC cells exhibited unique additional genomic rearrangements and downregulated ERBB2 expression. Multi-omics data integration allowed us to identify the transcription factor NEUROD1 as a key driver of neuroendocrine reprogramming. Moreover, our findings indicate that the NEUROD1 downstream target neural cell adhesion molecule (NCAM) serves as a potential biomarker for stratifying NEBC patients, detectable through NCAM-expressing CTCs in liquid biopsies. Additionally, a comprehensive drug screen revealed that NEBC cells are particularly sensitive to CDK4/6 and FGFR inhibitors. Collectively, by integrating NCAM expression on circulating CTCs analysis, we introduce a novel diagnostic tool possibly enabling early and longitudinal detection of treatment resistant NED cells. Our preclinical data also identified promising novel therapeutic avenues, such as CDK4/6 inhibition, which should be further explored for the management of the complex disease state of neuroendocrine breast cancer.1 Würth, R., et al. Circulating tumor cell plasticity determines breast cancer therapy resistance via neuregulin 1-HER3 signaling (2025). Nature Cancer, Jan 3. doi: 10.1038/s43018-024-00882-2 Citation Format: Roberto Würth, Tasneem Cheytan, Paul Schwerd-Kleine, Ewgenija Gutjahr, Martin Sprick, Andreas Trumpp. Monitoring and targeting therapy ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"3 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract CT099: BRIGHT-2 final analysis: A phase III trial of bireociclib plus fulvestrant as second-line endocrine therapy for patients with advanced HR+/HER2-breast cancer","authors":"Jiayu Wang, Qingyuan Zhang, Huiping Li, Zhongsheng Tong, Quchang Ouyang, Huihui Li, Yuee Teng, Biyun Wang, Tao Sun, Jingfen Wang, Wei Li, Zhaofeng Niu, Hongsheng Li, Chang Gong, Li Wang, Fei Liu, Xianghui Duan, Qiuli Wang, Binghe Xu","doi":"10.1158/1538-7445.am2025-ct099","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-ct099","url":null,"abstract":"Background: At the BRIGHT-2 (NCT05077449) interim analysis, bireociclib (a novel selective CDK4/6 inhibitor) plus fulvestrant significantly improved progression-free survival (PFS) with a tolerable safety profile as second-line therapy for HR+/HER2- advanced breast cancer (ABC) patients (pts). Herein, we report the final analysis after 11-month of additional follow-up. Method: Eligible pts with HR+/HER2- ABC who have progressed on or after previous endocrine therapy were randomized 2:1 to receive bireociclib (360 mg po bid) or placebo with fulvestrant (500 mg im, d1, d15 for cycle1, d1 for the subquent cycles) on each 28-day cycle. Pts were stratified by endocrine resistance (primary vs secondary) and visceral metastases (yes vs no). The primary endpoint was investigator-assessed PFS per RECIST v1.1. A post hoc analysis was conducted to assess the impact of protocol-allowed dose reductions (120 mg decrements) on PFS in bireociclib plus fulvestrant (BF) group. Results: 305 eligible female pts were enrolled to receive BF (n = 204) or placebo plus fulvestrant (F, n = 101). 209 (68.5%) pts had visceral metastases, 78 (25.6%) pts with primary endocrine resistance and 73 (23.9%) pts had received chemotherapy for advanced disease. At data cutoff (Feb. 22, 2024), with a median follow-up of 18.99 months (mo), the investigator-assessed stratified median PFS (mPFS) was 14.69 mo (95% CI, 11.07-20.21) in BF group vs 7.33 mo (95% CI, 5.49-11.04) in F group (HR, 0.542; 95% CI, 0.399-0.735; p<0.0001). The mPFS assessed by blinded independent central review (BICR) was 17.51 mo (95% CI, 13.83-23.06) in BF group vs 7.29 mo (95% CI, 5.49-9.46) in F group (HR, 0.462; 95% CI, 0.333-0.642; p<0.0001). Improvement in PFS with BF treatment was consistent across all prespecified subgroups. HR for pts with bone-only metastases was 0.184; 95% CI, 0.063-0.541. For pts who didn't receive chemotherapy in advanced disease, the mPFS for the BF group and F group were 17.28 mo and 7.69 mo, respectively (HR, 0.559; 95% CI, 0.387-0.807). The overall survival data was yet immature, with a trend of survival benefit in BF group (HR, 0.762; 95% CI, 0.476-1.218; p=0.5221). The most common treatment-emergent adverse events (TEAEs) were hematologic toxicity and diarrhea and comparable to previously reported profiles. No new safety signal was observed. 86 pts (42.2%) received bireociclib dose reduction due to TEAEs in BF group. The mPFS was 14.52 mo (95% CI, 11.07 to NR) vs 14.75 mo (95% CI, 10.87 to NR) for pts with or without bireociclib dose reduction respectively, p=0.5758. Conclusions: Bireociclib plus fulvestrant exhibited superior efficacy and manageable tolerability as second-line endocrine therapy for HR+/HER2- ABC after prolonged follow-up, with benefits across different subgroups and clinically appropriate dose reductions not compromising efficacy. Citation Format: Jiayu Wang, Qingyuan Zhang, Huiping Li, Zhongsheng Tong, Quchang Ouyang, Huihui Li, Yuee Teng, Biyun Wa","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"75 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB458: Osimertinib treatment drives expression of TROP2, and combination treatment with datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate, enhances its efficacy in PDX models of EGFR mutant non small-cell lung cancer","authors":"Matthew J. Martin, Alex Koers, Fernando Calero, Sara Talbot, Adina Hughes, Lukasz Magiera, Lucy Ireland, Nicolas Floc'h","doi":"10.1158/1538-7445.am2025-lb458","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb458","url":null,"abstract":"Osimertinib is a 3rd generation EGFR tyrosine kinase inhibitor with proven efficacy in the first-line advanced or metastatic EGFR-mutant (EGFRm) non-small cell lung cancer setting. Despite clinical benefit, most patients become refractory to drug, highlighting the need for combination strategies to maximize the duration of response. To understand the signaling changes induced by prolonged osimertinib treatment we characterised the mRNA expression of cell surface markers by RNAseq. We found that acute and prolonged osimertinib treatment leads to significant upregulation of TACSTD2, the transcript encoding the TROP2 protein. We further found that levels of TROP2 protein on the cell surface were increased by prolonged osimertinib treatment, but returned to baseline upon drug cessation, both in vitro and in vivo. Moreover, single-cell RNAseq analysis of osimertinib-treated tumours showed a specific cell subpopulation that upregulated TACSTD2 expression, which was eliminated when xenograft-bearing animals were treated with the combination of osimertinib and the TROP2-directed antibody-drug conjugate (ADC) Dato-DXd. Critically, we found that in vivo Dato-DXd/osimertinib combination treatment showed improved in vivo efficacy over osimertinib monotherapy in 4 out of 9 EGFRm patient-derived xenograft (PDX) models. Expanding these studies to PDX models derived from osimertinib-resistant patients showed superior efficacy of the combination compared to either agent alone, in 3 out of 4 models. Taken together these preclinical data highlight the ability for long-term osimertinib treatment to enhance TROP2 expression and demonstrate the potential utility of a novel combination treatment strategy with a TROP2-targeting ADC. Citation Format: Matthew J. Martin, Alex Koers, Fernando Calero, Sara Talbot, Adina Hughes, Lukasz Magiera, Lucy Ireland, Nicolas Floc'h. Osimertinib treatment drives expression of TROP2, and combination treatment with datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate, enhances its efficacy in PDX models of EGFR mutant non small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr LB458.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"2 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract CT079: Pharmacodynamic (PD) and exploratory biomarker (BM) analysis of the PRMT5 inhibitor BMS-986504 in patients (pts) with advanced solid tumors with homozygous MTAP deletion (MTAP-del)","authors":"Jordi Rodón, Tyler Simpson, Ben George, Pasi A. Jänne, Kathryn C. Arbour, Konstantinos Leventakos, Kyriakos P. Papadopoulos, Melissa L. Johnson, Alexander I. Spira, Cesar A. Perez, Hani M. Babiker, Richard Zuniga, Candace L. Haddox, Tapsi Kumar, Yidi Qin, Wen-Chi Chou, Peter Olson, Kenna Anderes, Alice Wozniak, Curtis Chin, Ming Lei, Jason T. Henry","doi":"10.1158/1538-7445.am2025-ct079","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-ct079","url":null,"abstract":"Background: Effective treatments (Tx) are needed for MTAP-del cancers (10-15% of all cancers). BMS-986504 (formerly MRTX1719) is a potential first-in-class MTA-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor that selectively binds to the PRMT5-MTA complex, a synthetic lethal target in MTAP-del but not MTAP-wild-type cells. In the first-in-human phase 1/2 CA240-0007 study, BMS-986504 was well tolerated and showed clinical activity in heavily pretreated pts across multiple advanced solid tumors with homozygous MTAP-del. Here, we report results of exploratory PD analyses of PRMT5 inhibition with BMS-986504 in CA240-0007. Methods: Pts with advanced, unresectable or metastatic solid tumors with homozygous MTAP-del received BMS-986504 (50 to 800 mg) in 3-wk cycles. Symmetric dimethylarginine (SDMA) and intron retention are known PD BMs of PRMT5 inhibition. Therefore, PD effects of BMS-986504 were assessed via changes in plasma and tumor SDMA levels (mass spec and IHC), intron retention, and gene expression (RNASeq) based on samples collected at baseline (BL) and cycle 2 day 1 (C2D1). Additional analyses correlating efficacy outcomes with PD results and select mutations at BL were performed in clinically evaluable pts as of 19-SEP-24. Results: Robust PD modulation of the PRMT5 pathway was observed with BMS-986504. Among pts with matched samples (n = 63), median plasma SDMA levels were reduced by 56% from BL (122.6 ng/mL) to C2D1 (53.8 ng/mL). There were dose-dependent reductions in median plasma SDMA with the greatest reductions at 400 mg QD (59.7% [n = 20]), 400 mg BID (61.9% [n = 9]) and 600 mg QD (59.1% [n = 14]). These PD effects were corroborated in the tumor. Median tumor SDMA levels decreased from an HScore of 285 at BL to 0 at C2D1. Consistent with the SDMA decreases, increased intron retention was observed in 9/11 pts with matched samples. BMS-986504 led to downregulation of several gene pathways including DNA repair and mitotic spindle formation, and MYC and E2F targets, as assessed by RNASeq. There was no significant change in expression of MAT2A, PRMT5, or other PRMT genes, suggesting a lack of compensation for PRMT5 inhibition through these genes. Responses were observed with BMS-986504 across EGFR, KRAS, and TP53 mutation subgroups. Additional correlative analyses among BMs and efficacy outcomes will be presented. Conclusions: BMS-986504 demonstrated robust PD effects across multiple doses and solid tumors which is consistent with the proposed mechanism of action. There was a trend of increasing plasma SDMA reduction across doses, with the greatest reductions observed at 400 mg QD and above. Together these results support further investigation of BMS-986504 at 400 mg QD and higher doses as a potential first-in-class synthetic lethal Tx option in pts with advanced solid tumors with MTAP-del. Citation Format: Jordi Rodón, Tyler Simpson, Ben George, Pasi A. Jänne, Kathryn C. Arbour, Konstantinos Leventakos, Kyriakos P. Papa","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"29 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract CT073: A first-in-human study of oral TNO155 (batoprotafib) alone and in combination with EGF816 (nazartinib) in adult patients with advanced solid tumors","authors":"Chia-Chi Lin, Helena Yu, Dong-Wan Kim, Daniel Tan, Dae Ho Lee, Maria Jove Casulleras, N Steeghs, Fredericus Eskens, Ahmad A. Tarhini, Melissa Johnson, Irene Brana, Giuseppe Curigliano, Lillian Siu, Aitana Calvo Ferrandiz, Geoffrey Shapiro, Victor Moreno Garcia, Hironobu Minami, Martin Klumpp, Helen Evans, Thomas Hengelage, Suresh B. Lakshminarayana, John Ritz, Xin Yang, David Kodack, Christopher Straub, Pruthvi Desireddy, Susan Moody, Pilar Garrido","doi":"10.1158/1538-7445.am2025-ct073","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-ct073","url":null,"abstract":"Background: TNO155 (batoprotafib), a selective, allosteric, oral inhibitor of SHP2, showed anti-tumor efficacy in preclinical cancer models. SHP2 transduces signals from activated receptor tyrosine kinases to downstream pathways including MAPK. EGF816 (nazartinib), an EGFR inhibitor, targets specific mutations in the EGFR gene commonly found in non-small cell lung cancer (NSCLC). Here, we present results from the first-in-human study of TNO155 single agent (SA), and in combination with nazartinib, in adult patients (pts) with advanced solid tumors. Methods: CTNO155X2101 (NCT03114319) is an ongoing, dose escalation/expansion (ESC/EXP) trial consisting of two arms: A) TNO155 SA and B) TNO155 with nazartinib. Primary objective is to assess safety and identify dosing regimen(s) for future study. Secondary objectives include pharmacokinetics, pharmacodynamics, and preliminary efficacy. Arm A included pts with advanced solid tumors in ESC and pts with advanced RAS/BRAF WT solid malignancies (Group 1), KRAS G12C-mutant NSCLC (Group 2), and NRAS/BRAF WT cutaneous melanoma (Group 3) in EXP; Arm B included pts with advanced NSCLC with an EGFR TKI-sensitizing mutation. Arm B EXP required progression on osimertinib as the most recent prior therapy. Results: As of 1-Aug-2024, 227 pts were treated (Arm A: ESC; n=141; EXP; n=42; Arm B; ESC; n=29; EXP; n=15), and 224 (98.6%) pts had discontinued study treatment, mainly due to progressive disease. Arm A ESC cohorts were previously reported (Brana et al. 2021). The recommended dose for expansion (RDE) was declared as 60 mg QD 2 weeks on/1 week off (2/1). Arm B ESC pts were treated with TNO155 20-60 mg QD 2/1 with nazartinib 100-150 mg QD continuous (cont). The RDE was declared as TNO155 40 mg QD 2/1 plus nazartinib 100 mg QD cont. Dose-limiting toxicities were reported in 2 pts, both on TNO155 60 mg QD 2/1 + nazartinib 100 mg QD cont (grade 4 decreased platelet count and grade 3 diarrhea). At the corresponding RDEs, the most common adverse events (>30%), regardless of relationship, reported in Arm A pts (n=55) were peripheral edema and anemia, and in Arm B pts (n=22) were diarrhea, thrombocytopenia, peripheral edema, anemia, and increased creatine phosphokinase.Plasma concentrations on day 14 of TNO155 and nazartinib administered in combination were within the range observed when administered at the same doses as SAs. Best overall response per RECIST v1.1 in Arm A EXP was stable disease (SD) in 5/15 pts (33%) in group 1, 1/12 pts (8.3%) in group 2, and 7/15 pts (46.7%) in group 3 and in Arm B EXP was SD in 3/15 pts (20%). Median duration of SD was 4.4 months in Arm A EXP, and 5.5 months in Arm B EXP.At the RDEs a reduction in tumor DUSP6 expression of >50% from baseline was observed in 9/12 pts in Arm A, and in 2/2 pts in Arm B. Conclusions: TNO155 shows acceptable safety as a SA and with nazartinib and demonstrates evidence of MAPK pathway suppression in tumors. Citation Format: Chia-Chi Lin, Helena","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"78 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract CT185: Trispecific EGFR x cMET x VEGF antibody, TAVO412, has clinical responses in esophageal and lung cancers","authors":"Mark Chiu, Wei Zhang, Yanjiao Yu, Helen Jiang, Chao Han","doi":"10.1158/1538-7445.am2025-ct185","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-ct185","url":null,"abstract":"Background: Abnormal EGFR signaling, increased cMET activation, and VEGF-induced angiogenesis are responsible for the growth and metastasis of many difficult to treat solid tumors. TAVO412 is a humanized multi-specific antibody with two distinct anti-EGFR nanobody-like domains, an anti-cMET Fab arm, and an anti-VEGF ScFv domain. In addition, the Fc domain allows for the heterodimerization, antibody-like pharmacokinetic profile, and additional mutations that enhance the Fc effector functions. TAVO412 had strong in vivo tumor growth inhibition in the preclinical models of NSCLC, gastrointestinal and esophageal cancers, PDAC, TNBC, and other solid tumor models. TAVO412 also had strong tumor growth inhibition as demonstrated against NSCLC patient derived xenograft (PDX) models with various mutant EGFR and cMet genotypes. Stronger activities were also demonstrated when TAVO412 was in combination with docetaxel, TKIs, and with radiotherapy. Methods: The clinical study (TAVOTEK412-CN001) is a two-part, open-label, non-randomized, Phase I study to determine the safety and tolerability, to define the MTD/RP2D, and to assess the preliminary efficacy of TAVO412 in patients with advanced or metastatic solid tumors who progressed on prior standard-of-care therapies (Clinical trial NCT06761651). Part 1 of the study is a dose escalation by a standard 3+3 design, mainly for safety and tolerability with 5 dose cohorts up to 1500 mg. Part 2 of the study is an extension of the study in about 100 patients based on the preliminary information obtained in Part 1 regarding dose levels, type of tumor showing preliminary efficacy signals, and genetic makeup. At the time of this abstract, 25 patients with a variety of solid tumors have been enrolled in Part 1 dose escalation. Since no DLT have been observed and MTD has not been reached, an additional dose level at 1750 mg will be tested. Meanwhile, the safety and efficacy signals are being enhanced by the backfill of patients to the safe and potential efficacious dose cohorts starting Q1 2025. The Part 2 of the study is expected to start in Q4 2025. Keywords: trispecific antibody, EGFR, cMET, VEGF, gastrointestinal cancers, lung cancersEthics approval: “This study was approved by CRADL-Suzhou’s Ethics Board; approval number P202302160002.NMPA IND Approval number 2023LP01660; Henan Cancer Hospital Ethics Board approval number 2023-314-003 Citation Format: Mark Chiu, Wei Zhang, Yanjiao Yu, Helen Jiang, Chao Han. Trispecific EGFR x cMET x VEGF antibody, TAVO412, has clinical responses in esophageal and lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr CT185.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"2 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB259: Development of a CTC based assay to characterize MAOA expression in metastatic prostate cancer","authors":"Daniel Bsteh, Caelin Brenninkmeijer, Hyun O. Choi, Seok Hee Jang, Chun-Peng Liao, David B. Agus, Amir Goldkorn, Mitchell E. Gross","doi":"10.1158/1538-7445.am2025-lb259","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb259","url":null,"abstract":"Background: Monoamine oxidase A (MAOA) is best known for its role in neurotransmitter regulation and as the target for MAO inhibitors used as first-generation antidepressants. MAOA expression is associated with poor outcomes and treatment resistance in many cancers. In prostate cancer, MAOA over-expression is associated with high histologic Gleason grade and resistance to androgen-targeting and cytotoxic agents. MAO inhibitors have demonstrated anti-cancer activity in many laboratory studies and in a clinical trial with non-metastatic prostate cancer patients (NCT02217709). Here, we developed and explored the potential clinical utility of a novel assay quantifying MAOA expression in circulating tumor cells (CTCs) from metastatic prostate cancer patients utilizing the RareCyte platform. Methods: Nucleated cells were prepared from whole blood samples collected at various timepoints using the AccuCyte system. The CyteFinder automated immunofluorescent imaging system was used to identify CTCs (CK+/EpCAM+, CD45-) stained with a custom MAOA Rareplex staining assay on a Leica BOND RXm automated ICC stainer. Single-cell MAOA protein level expression, measured as mean fluorescent intensity (MFI), was evaluated in all CTC+ samples. MFI threshold for MAOA+ cells was established to maximize detection accuracy using spike-in controls of MAOA positive (LNCaP) versus MAOA negative (PC3) cells. Clinical data was passively collected from the medical record. Subjects were classified as either castrate-sensitive or castrate-resistant prostate cancer (CSPC or CRPC) based on standard clinical criteria. All data analysis was performed using relevant libraries in R. Results: 79 samples were collected at various treatment timepoints from 46 subjects (CSPC=25, CRPC = 21) with metastatic prostate cancer: age (mean ± SD) 73.5 ±-8.8 years; PSA 30.3 ± 116 ng/dl; metastatic to bone 83% (n=38), lymph nodes 28% (n=13); and other visceral sites 22% (n=10). MAOA+ CTCs were observed in 45% (n=18/40) of CRPC samples versus 10% (n=4/39) of CSPC samples (p<0.05, Fisher’s exact test). Cox proportional hazard analysis revealed that the presence of MAOA+ CTCs in CRPC patients at baseline was associated with poor overall survival (HR: 4.50, 95%CI: 1.25-16.2; p<0.05). Conclusions: A CTC-based assay was developed and used to explore MAOA expression in a pilot cohort of patients with metastatic prostate cancer. We observed significantly increased MAOA expression in CRPC versus CSPC and worse overall survival in MAOA+CTC+ CRPC patients. These data suggest potential clinical utility for a CTC-based MAOA assay, which merits additional validation in expanded patient cohorts. Citation Format: Daniel Bsteh, Caelin Brenninkmeijer, Hyun O. Choi, Seok Hee Jang, Chun-Peng Liao, David B. Agus, Amir Goldkorn, Mitchell E. Gross. Development of a CTC based assay to characterize MAOA expression in metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer R","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"140 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB216: Exploration of optimal synergistic treatment strategies of postoperative radiotherapy and immunotherapy in early-stage breast cancer","authors":"Qingyao Shang, Hanyu Wang, Meishuo Ouyang, Fei Ma, Jennifer K. Plichta, Samantha M. Thomas, Youwen He, Xin Wang, Sheng Luo","doi":"10.1158/1538-7445.am2025-lb216","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb216","url":null,"abstract":"Background: The synergistic effects of radiotherapy (RT) and immunotherapy (IT) in cancer treatment have been increasingly recognized. However, the optimal sequencing and dosing of RT and IT remain unclear for breast cancer patients. This study aims to identify the best synergistic strategy of postoperative RT and IT for early-stage breast cancer. Method: Using the National Cancer Database, HER2-negative early-stage breast cancer patients who underwent surgery followed by RT and IT were selected. Patients were stratified into either RT-first (RI group) or IT-first (IR group) sequences. Propensity score methods were used to balance baseline characteristics. Kaplan-Meier survival analysis and weighted log-rank test evaluated overall survival. Subgroup analyses were conducted. To verify the hypothesis that tumor burden may influence the choice of optimal sequencing, stage IV inoperable patients with higher tumor burden were additionally screened for survival analysis. Results: A total of 3813 patients were included (RI group: 923 (24.2%); IR group: 2890 (75.8%)). Patients in the IR group showed significantly improved survival (p < 0.001). Patients who received adjuvant chemotherapy had improved survival with the IT-first sequence (p<0.001); however, for patients who did not receive adjuvant chemotherapy, there was no difference in survival between the two sequences (p=0.21). Additionally, the conventional RT fractionation regimen combined with the IT-first sequence was associated with better outcomes (p < 0.001), whereas there was no significant difference in outcomes between sequences under the hypofractionated regimen (p=0.20). For patients with stage IV breast cancer, there were no significant difference between the two sequencing (p=0.34). Discussion: Recent studies have shown that RT can remodel tumor microenvironment and damage tumor cells to release tumor-specific antigens, which are more significant in advanced stage patients with high tumor burdens. However, in postoperative early-stage breast cancer patients, a low tumor burden may limit these mechanisms. On the other hand, initiating IT first may reshape the immune microenvironment, thus enabling RT to exert a stronger abscopal effect. This may explain why patients in the IR group showed a better prognosis. Therefore, the optimal RT-IT synergy strategy should consider tumor burden, adjuvant therapies, and RT regimens, since conventional RT fractionation may yield better outcomes. Conclusion: This study found that IT followed by RT may be a better synergistic sequencing for patients with early-stage breast cancer who undergo upfront surgery, especially those receiving adjuvant chemotherapy. Moreover, conventional RT fractionation may be associated with better outcomes. Tumor burden may influence the choice of the optimal strategy, highlighting the need for personalized treatment. Citation Format: Qingyao Shang, Hanyu Wang, Meishuo Ouyang, Fei Ma, Jennifer K. Plichta, S","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"75 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract CT248: Using adaptive design elements to respond to regulatory changes and emerging data in a phase 1-2 study of OR502 - A best-in-class antibody targeting leukocyte immunoglobulin-like receptor B2 (LILRB2)","authors":"David Sommerhalder, Mohamad Salkeni, Andrae Vandross, Nenad Sarapa, Myriam N. Bouchlaka, Kamal Puri, Lesley Skingley, Mike Yefimenko, Alice Bexon, Shiraj Sen","doi":"10.1158/1538-7445.am2025-ct248","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-ct248","url":null,"abstract":"Background: OR502 is a best-in-class LILRB2 antagonist antibody with strong pre-clinical evidence of efficacy, now confirmed by durable clinical monotherapy responses. OR502 prevents LILRB2-mediated immunosuppression of myeloid cells by blocking LILBR2 binding to human leukocyte antigen-class I proteins. It potentiates Th1-like innate immune responses, rescues T-cells from M2c macrophage-mediated immune suppression and restores T-cell proliferation and effector functions. OR502 reduces and prevents immunosuppressive phenotype of existing and new tumor-associated macrophages. Combination with anti-PD-1 amplifies activity in M2c/T-cell coculture. Durable responses were seen in patients with mucosal melanoma, non-small cell lung cancer (NSCLC) and dedifferentiated liposarcoma in phase 1. Dose escalation is now complete and this abstract focuses on the study design to support dose selection. FDA’s Project Optimus has changed the requirements for oncology drugs to progress to later phase trials. It is essential to explore dose-response and identify the minimal effective dose in a randomized fashion to gain regulatory approval for further clinical development. Methods: Study OR502-101 [NCT06090266] was designed to comply with Project Optimus. The dose escalation component was completed in ∼40 subjects consisting of two arms: A1 (IV OR502 100, 200, 400, 800 and 1600 mg, once every 3 weeks [Q3W]) and A2 (IV OR502 3QW with standard dose cemiplimab). The OR502 dose selected for the second part of the study is 800 mg Q3W based on safety, efficacy, pharmacokinetics (PK) and receptor occupancy (RO). As dose escalation concluded, despite strong efficacy signals, we realized it was premature to move to randomized dose-finding. Following FDA interactions, we decided that objective efficacy rather than pharmacodynamic signals should be confirmed prior to initiating two-dose expansion cohorts. The protocol’s adaptive elements, combined with Safety Committee oversight, facilitated design modification without amendments. Consequently, two new mini-expansion cohorts of 10 to 20 subjects are recruiting. Subjects with cutaneous melanoma will receive IV OR502 800 mg 3QW and subjects with NSCLC will receive IV OR502 800 mg 3QW + cemiplimab. All subjects must have disease which has progressed following ≥12 weeks of prior PD-(L)1-based therapy and ≥ 2 lines of treatment. The primary objective of the mini-expansion cohorts is to confirm efficacy signal in the chosen indications. Study endpoints including adverse events, PK and RO will also be reported. Twenty subjects per cohort provide greater statistical confidence to continue development. In a challenging regulatory environment, this study design using adaptive elements provides the flexibility needed to ensure the rapid progress of drug development. Citation Format: David Sommerhalder, Mohamad Salkeni, Andrae Vandross, Nenad Sarapa, Myriam N. Bouchlaka, Kamal Puri, Lesley Skingley, Mike Yefimenko, Alice Bexon, Shiraj Se","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"29 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}