tbuckley/cabot-search huggingface dataset:
Presence of molecular residual disease after pathologic complete response among patients with inflammatory breast cancer.
Authors: Jennifer H. Chen, Salyna Meas, Vanessa N. Sarli, Negar Koupaei, Joshua Upshaw, Dhruvajyoti Roy, Vicente Valero, Wendy A. Woodward, Anthony Lucci
Journal: Journal of Clinical Oncology (2024)

3044 Background: Inflammatory breast cancer (IBC) is known to recur more frequently than non-IBC after pathologic complete response (pCR). The presence of circulating tumor cells (CTCs), a marker of molecular residual disease (MRD), has been associated with higher likelihood of metastasis. We sought to characterize CTCs and its relationship with pCR in IBC patients. Methods: Patients diagnosed with IBC were enrolled in a prospective registry from 2005-2022. Serial blood draws were performed before, during, and after neoadjuvant systemic therapy (NST), and 6-months and 1-year post-surgery. CTCs were enumerated using CellSearch™. Patients with ≥ 1 CTC at any timepoint in the post-operative period were included in the positive CTC cohort. T-tests, one-way ANOVA, and chi-squared tests were used to compare differences between groups. Kaplan-Meier analysis was used for survival outcomes. Results: A total of 112 patients were included. The median age of diagnosis was 50.5 years (IQR 17) and BMI was 29.3 kg/m 2 (IQR 11.3). Patients were predominantly White (85, 75.9%) with clinical stage IIIB-C (94, 84.9%), node-positive (107, 95.5%), and HER2-negative (66, 59.0%) disease. Almost all patients (109, 97.3%) received trimodality therapy – NST, modified radical mastectomy, and adjuvant radiation. At a median follow-up period of 7.1 years (95% CI: 4.7-9.4), the overall survival (OS) rate was 72.3%. Baseline CTC positivity rate was 61.8% (42/68). More than half of the patients (61, 54.5%) had a positive CTC at some point in the post-operative surveillance period. Among the 39 patients who achieved pCR (34.8%), 15 (38.5%) had positive CTCs during follow-up. There were no differences in age, BMI, menopause status, clinical stage, nodal status, grade, presence of LVI, and number of lymph nodes (LNs) removed by CTC status. However, patients with positive CTCs had a significantly higher number of positive LNs at resection (p = 0.01), were more likely to be HER2-negative (p = 0.001), and were less likely to achieve pCR (p = 0.01). Triple negative disease (p &lt; 0.0001), lack of pCR (p = 0.006), and positive CTCs (0.007) were associated with poor prognosis. When pCR was combined with CTC status, patients with positive CTCs demonstrated significantly worse survival, despite having achieved pCR, compared to those with pCR and negative CTC status (5-year OS: 35.0% vs. 83.1%, respectively, p = 0.016). Conclusions: A high proportion of IBC patients who achieved pCR had MRD, as demonstrated by persistent CTCs. CTCs portended worse prognosis in patients with IBC, even after pCR. Future incorporation of longitudinal CTC monitoring may be helpful in identifying patients at risk for relapse despite having achieved a pCR. [Table: see text]
The FIPO23 trial: First-in-human phase I/II study of XON7 in advanced solids tumors.
Authors: Jaafar Bennouna, Françoise Shneiker, Jean Yves BLAY, Ahmad Awada, Firas Bassissi, Raffaele Ratta, Jean-Pierre Delord
Journal: Journal of Clinical Oncology (2024)

TPS2673 Background: XON7 is a first-in-class glyco-humanized polyclonal antibody (GH-pAb) targeting selectively multiple tumor-associated antigens. XON7 induces tumor cell apoptosis and promotes the elimination of tumor cells by immune effector cells through CDC (Complement Dependent Cytotoxicity) and ADCP (Antibody-Dependent Cell Phagocytosis). XON7 demonstrated anti-tumor efficacy in mice xenograft models with human solid tumors such as colon, prostate, lung and triple negative breast cancers. Safety pharmacology and toxicology studies in non-human primates demonstrated an acceptable safety profile for XON7. Taken together, these preclinical data support the initiation of human trials in patients with advanced solid tumors. Methods: First-in-patient, multicenter, open-label, two phases (dose-escalation (ESC) followed by dose expansion (EXP)) study of XON7 single agent, in patients with relapsed refractory, locally advanced or metastatic solid tumors without standard available treatments ( NCT06154291). Key eligibility criteria include disease progression after ≤ 4 lines of therapy; age &gt; 18 years; ECOG performance status ≤2; adequate organ functions; no known CNS involvement. All advanced or metastatic tumor types except glioblastoma, can be included during ESC. Primary endpoints: safety, tolerability and determination of MTD/RP2D. Secondary endpoints: pharmacokinetics (PK), pharmacodynamics, immunogenicity and preliminary anti-tumor activity (RECIST 1.1). AEs graded according to CTCAE 5.0. In the ESC part, XON7 is administered as 60-min intravenous infusion every 2 weeks according to an escalating schedule of doses from 1.5 to 20 mg/kg for up to 12, 28-day cycles. Dose escalation/de-escalation is based on the Bayesian Optimal Interval (BOIN) design, up to 45 pts are planned. At the recommended dose, up to 7 EXP cohorts (30 pts each) defined according to the primary tumor site are planned. Bayesian sequential monitoring will be used. Patient recruitment is planned or ongoing at 25 sites worldwide. Results: As of Feb 3 rd , 2024, 3 pts are enrolled in the first dose cohort and have received XON7 at dose 1,5 mg/kg Q2W for the first 28-days cycle. Conclusions Accrual is ongoing in this first-in-human trial of XON7. Clinical trial information: NCT06154291 .
Association of <i>KRAS</i> G12D vs. G12V circulating tumor DNA variant allele fraction and real-world overall survival in metastatic non-small cell lung and colorectal cancers.
Authors: Jacob Edward Till, Leslie A Bucheit, Nicole Zhang, Keelia M. Clemens, Erica L. Carpenter
Journal: Journal of Clinical Oncology (2024)

3041 Background: We previously reported KRAS G12D but not G12V variant allele fraction (VAF), as measured in circulating tumor DNA (ctDNA), was associated with overall survival (OS) in metastatic treatment-naïve pancreatic cancer (mPDAC). However, this has not been examined in other RAS-driven cancers. Here we assessed association of real-world OS (rwOS) with KRAS G12D and G12V VAF in metastatic colorectal cancer (mCRC) and non-small cell lung cancer (mNSCLC). Methods: We queriedGuardantINFORM, a real-world evidence database of aggregated commercial payer health claims and de-identified results from Guardant360 (G360) ctDNA testing from 2014 to 2023, to identify mNSCLC/mCRC patients who were treatment-naive and had KRAS G12D or G12V mutations identified &lt; 30 days prior to first-line therapy initiation. Those with co-occurring KRAS alterations, KRAS amplifications, and/or MSI-H were excluded. Outcomes were assessed as above vs. below median VAF and stratified by treatment type. The Cox regression model was run for continuous VAF, adjusting for age, gender, summary comorbidity score [Elixhauser Comorbidity Index (ECI)], and year of G360. Results: For mCRC, KRAS VAF above median was significantly associated with shorter rwOS for both G12D and G12V (Table 1); subgroup analysis of the predominant standard-of-care chemotherapy, FOLFOX, showed similar findings. For mNSCLC, KRAS VAF above median was associated with shorter rwOS for G12V, but not G12D (Table). Subgroup analysis by first-line treatment type revealed this association to be similar for chemotherapy-containing regimens but not immunotherapy (IO) alone. Conclusions: While a variant-specific association of KRAS VAF with rwOS was observed in mNSCLC overall (G12V associated, G12D not), above vs below median VAF was not associated with rwOS for the subset of patients receiving IO only. In contrast, for mCRC both G12D and G12V VAF were associated with rwOS, including for the subset of patients who received chemotherapy. These data suggest a complex interplay between KRAS variant, ctDNA shedding, first-line treatment, and OS that will be important in the interpretation of the prognostic implications of ctDNA-identified KRAS alterations. [Table: see text]
A phase Ia/Ib, non-randomized, open-label, dose escalation and expansion trial of the B7-H6/CD3 T-cell engager BI 765049 with or without ezabenlimab in Asian patients with advanced solid tumors.
Authors: Toshihiko Doi, Noboru Yamamoto, Shigehisa Kitano, Robert Latek, Jianrui Hou, Yuko Tanaka
Journal: Journal of Clinical Oncology (2024)

TPS2669 Background: Bispecific T-cell engagers represent a promising therapeutic approach for patients with solid tumors; however, these agents require an appropriate target antigen. B7-H6 is an encouraging target as it is expressed on multiple solid tumors but shows only limited expression on normal tissue (1). BI 765049 is a novel immunoglobulin G (IgG)-like T-cell engager designed to simultaneously bind B7-H6-expressing tumor cells and CD3 on T-cells resulting in the formation of a cytolytic synapse that triggers apoptosis of the tumor cells. Methods: NCT06091930 is a Phase I, non-randomized, open-label, multi-center, dose escalation and expansion trial that aims to assess the safety and tolerability of BI 765049 alone or in combination with programmed cell death protein 1 inhibitor ezabenlimab, in patients with advanced or unresectable gastric cancer, colorectal cancer (CRC), pancreatic ductal adenocarcinoma, hepatocellular cancer, head and neck squamous cell carcinoma, or non-small cell lung cancer. Patients must have progressed on, or be ineligible for, standard therapies. Key inclusion criteria include confirmed B7-H6 expression (central pathology review) except in CRC; ≥1 evaluable target lesion outside of the central nervous system (Response Evaluation Criteria in Solid Tumors [RECIST] v1.1); and Eastern Cooperative Oncology Group performance status 0/1. Patients with prior B7-H6-targeted treatment are ineligible. The study is divided into four parts: dose escalation and expansion of BI 765049 monotherapy (Parts I and II, respectively), and in combination with ezabenlimab (Parts III and IV, respectively). BI 765049 dose escalation will be guided by a Bayesian logistic regression model with overdose control. Treatment will continue until progressive disease or discontinuation for other reasons, or for up to 36 months. The primary endpoint for Parts I and III is the occurrence of dose-limiting toxicities; and for Parts II and IV it is objective response (OR; determined by the investigator; RECIST v1.1). The secondary endpoints for Parts I and III are pharmacokinetic (PK) parameters and OR (RECIST v1.1); and for Parts II and IV secondary endpoints are progression-free survival, duration of response, disease control, PK measurements, and OR (immunotherapy RECIST [iRECIST]). 1. Zhang W, et al. Clin Cancer Res 2022;28(23):5190–5201. Clinical trial information: NCT06091930 .
A phase 1 trial of TSC-100 and TSC-101, engineered T cell therapies that target minor histocompatibility antigens to eliminate residual disease after hematopoietic cell transplantation.
Authors: Monzr M. Al Malki, Alla Keyzner, Hyung C. Suh, Uday R. Popat, Saar Gill, Yi-Bin Albert Chen, Melhem M. Solh, Lohith Gowda, Erica Buonomo, Yun Wang, Jim Murray, Gavin MacBeath, Debora Barton, Shrikanta Chattopadhyay, Ran Reshef
Journal: Journal of Clinical Oncology (2024)

TPS2678 Background: Engineered T cell therapies such as CAR-T cell therapies have transformed the treatment of B-cell but not non-B cell hematologic malignancies. Allogeneic hematopoietic cell transplantation (HCT) remains the best curative option for hematologic malignancies but ~40% of patients relapse post-HCT with up to 90% mortality due to residual disease post-HCT. A potential solution is targeting minor histocompatibility antigens (MiHAs) that are homogenously expressed on all hematopoietic cells and are genetically mismatched between donors and patients undergoing HCT. These mismatches enable engineered T cells to selectively eliminate residual patient hematopoietic cells, normal or malignant, leaving donor cells untouched. TScan has developed allogeneic donor derived T-cell products TSC-100 and TSC-101, targeting MiHAs HA-1 and HA-2 respectively, both presented on HLA-A*02:01. By choosing HCT patients who are HLA-A*02:01 positive (&gt;98% of whom are either HA-1 or HA-2 positive) and donors who are either HLA-A*02:01 or MiHA negative, TSC-100 or TSC-101 can potentially eliminate all residual patient-derived hematopoietic cells after HCT, to prevent disease relapse. Methods: Study NCT05473910 is a multi-center, multi-arm, non-randomized controlled Phase 1 umbrella study evaluating the feasibility, safety and preliminary efficacy of TSC-100 and TSC-101. Inclusion criteria include adults with AML, MDS or ALL eligible for reduced intensity conditioning-based haploidentical donor transplantation from HLA or MiHA mismatched donors. HLA-A*02:01-positive patients undergo HA-1/ HA-2 testing and are assigned to either TSC-100 or TSC-101 treatment arms in addition to HCT. HLA-A*02:01-negative patients in the control arm receive HCT alone. Upon count recovery after HCT, patients in treatment arms receive either TSC-100 or TSC-101, administered as single or two doses. Primary endpoints include adverse event profiles and dose limiting toxicities. Secondary endpoints include relapse rates, disease-free survival and overall survival. Exploratory endpoints include surrogates of efficacy such as donor chimerism rates and kinetics and minimal residual disease (MRD) rates. Donor chimerism is measured by standard STR-based and novel high-sensitivity NGS-based assays to quantify residual patient-derived hematopoietic cells. MRD is measured before and after HCT using flow cytometry and NGS. Together, these assays measure elimination of residual patient hematopoietic cells, malignant or normal, and could provide early evidence of biological activity. Clinical trial information: NCT05473910 .
9MW2821, a nectin-4 antibody-drug conjugate (ADC), in patients with advanced solid tumor: Results from a phase 1/2a study.
Authors: Jian Zhang, Rujiao Liu, Shuiping Gao, Huijuan Yang, Jian Chen, Fang Yuan, Jiyan Liu, Hongqian Guo, Shun Zhang, XingYa Li, Xin Yao, Ming Bai, Hualei Bu, Yinyin Li, Changlu Hu, Xiumin Li, Zhen Wang, ShanBing Wang, Hanmei Lou, Zhe Feng
Journal: Journal of Clinical Oncology (2024)

3013 Background: 9MW2821 is a monoclonal ADC that delivers monomethyl auristatin E to cells expressing Nectin-4. Nectin-4 is an adhesion molecule that highly expressed in variety of solid tumors, especially urothelial cancer (UC), cervical cancer (CC), esophageal cancer (EC) and breast cancer. Here we report the updated safety and efficacy data of 9MW2821. Methods: 9MW2821 was administered by intravenous infusion at doses of 0.33-1.5mg/kg on days 1, 8 and 15 of each 28-day cycle. The study included dose escalation, dose expansion and cohort expansion period which included UC, CC, EC, triple negative breast cancer (TNBC) and other Nectin-4 positive solid tumors that progressed after ≥1 systemic treatments (Tx). Primary objectives were assessment of safety and preliminary efficacy. Results: As of Jan 15, 2024, 260 patients (pts) were enrolled with doses ranging from 0.33 to 1.5mg/kg. Only 1 out of 6 pts in 1.5mg/kg group had dose limiting toxicity (grade 4 neutropenia lasted more than 5 days). The maximum tolerated dose was not reached up to 1.5mg/kg and the RP2D was selected as 1.25mg/kg for tolerance. 240 pts were enrolled at dose of 1.25mg/kg. The most common TRAEs of 1.25mg/kg dose group (≥20%, all grade/≥5%, ≥G3) were white blood cell (WBC) count decreased (50.8%, 23.3%), neutrophil count decreased (46.3%, 27.9%), anemia (43.8%, 8.3%), aspartate aminotransferase increased (42.1%, 2.9%), alanine aminotransferase increased (35.4%, 2.1%), asthenia (32.1%, 2.9%), rash (30.0%, 5.0%), decreased appetite (28.8%, 1.3%), nausea (26.7%, 0%), hyperglycemia (25.4%, 2.1%), platelet count decreased (24.2%, 4.6%), alopecia (24.2%, 0%), hypoaesthesia (22.5%, 1.7%), constipation (21.3%, 0%), vomiting (20.9%, 1.3%), hypertriglyceridemia (20.4%, 2.1%), gamma-glutamyltransferase increased (15.8%, 5.4%). Among 190 pts treated with 9MW2821 at 1.25mg/kg or above and reached tumor assessment, objective response rate (ORR) and disease control rate (DCR) was 35.3% and 78.4%, respectively. 37 UC pts, 45 CC pts, 27 EC pts and 16 TNBC pts were enrolled at 1.25mg/kg and evaluable for tumor assessment. Median prior lines of Tx were 2 (range, 1-4). All UC, 51% CC and 93% EC pts progressed after platinum-based chemotherapy and immune checkpoint inhibitors, respectively. Objective responses were also observed in pts with other solid tumor types. Conclusions: The data indicated encouraging efficacy of 9MW2821 in advanced UC, CC, EC and TNBC. 9MW2821 is the first Nectin-4 targeting ADC showed antitumor activity in patients with CC, EC and TNBC. The safety profile showed adequate tolerability. Clinical trial information: NCT05216965 . [Table: see text]
A phase I trial of intratumoral STX-001: A novel self-replicating mRNA expressing IL-12 alone or with pembrolizumab in advanced solid tumors.
Authors: Jason J. Luke, Laura Carpin Kennedy, Neil Sankar, Alexander M. Menzies, Alexander Christopher Jonathan van Akkooi, Maria Gonzalez, Julie Urban, Mini Gill, Cynthia M. Atkins, Julian Quiñones, Brian Miller, Alison A. Duhamel, Ryan T. Sowell, Prashant R Nambiar, Tasuku Kitada, Sarina A. Piha-Paul, Kamalesh Sankhala, Georgina V. Long
Journal: Journal of Clinical Oncology (2024)

TPS2696 Background: STX-001 is a multi-mechanistic lipid nanoparticle encapsulated synthetic self-replicating mRNA, engineered to express the IL-12 cytokine for an extended duration when administered intratumorally. A murine surrogate of STX-001 induces deep durable responses in multiple preclinical solid tumor models. This Phase 1 open-label, multi-center first-in-human dose-escalation trial evaluates the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of STX-001 alone, or in combination with pembrolizumab in patients with treatment refractory advanced cancers. Methods: Approximately 30 adults ≥18 years of age with histologically confirmed advanced solid tumors that are refractory to standard treatments will be enrolled. The study will consist of two arms, an STX-001 monotherapy arm and an STX-001 + pembrolizumab combination arm, enrolling approximately 15 patients each. Key eligibility criteria include ECOG status 0 or 1, a tumor lesion amendable to injection, and confirmed prior disease progression. STX-001 will be administered every 3 weeks (q3w) for 3 doses and then every 6 weeks (q6w) for a further 3 doses. Tumor biopsies will be obtained at baseline and after the first STX-001 administration. Primary endpoints will include safety and maximum tolerated dose (MTD), with secondary endpoints encompassing pharmacokinetics and preliminary efficacy as measured by RECIST 1.1. To determine the MTD, this study will employ the Bayesian optimal interval (BOIN) design, with the 3 + 3 design run-in and a recommended phase 2 dose (RP2D) will be determined. Tumor response will be assessed using RECIST 1.1 criteria. Exploratory pharmacodynamic analyses will assess tumor-infiltrating lymphocytes and STX-001 mRNA in baseline and on-treatment biopsies, evaluate inflammatory cytokine profiles in plasma, determine immune activation in circulating immune cells, and measure circulating tumor DNA (ctDNA) for molecular response assessment. Clinical trial information: NCT06249048 .
Survival analysis of brain metastases secondary to breast cancer: A single-center experience.
Authors: Brie Chun, Emmanuella Oyogoa, Andy Kaempf, Julia Levy, Thalia Padilla Lazos, Teyhana Rounsavill, Mai-Loan Nguyen, Fiona Stefanik, Victoria Eichten, Tana Kornachuk, Jessica Duong, Shaun M. Goodyear, Alexandra Dos Santos Zimmer
Journal: Journal of Clinical Oncology (2024)

e13111 Background: Brain metastasis (BM) contributes to substantial morbidity and mortality for breast cancer (BCa) patients (pts). Advances in systemic therapies have improved survival following BM diagnosis; however, other factors such as age, timing of BM development, and molecular features may also affect outcomes. Here we characterize the overall survival (OS) of pts with BM secondary to BCa treated at our institution with the aim of identifying predictors that can used to improve treatment and management. Methods: In an electronic medical record of “brain metastasis” and “breast cancer”, we identified pts aged &gt;18 years treated between 2015 and 2022. All cases were manually reviewed by ≥2 reviewers. Cases with second metastatic (met) solid tumors, hematologic malignancies, or insufficient data were excluded. Only cases with intraparenchymal and/or leptomeningeal disease attributed to met BCa were included. Kaplan-Meier estimation and Cox regression were applied to OS. Results: Of 344 cases reviewed, 229 (1 male) were appropriate for inclusion. The median age at BM diagnosis (dx) was 58 years. 28% underwent surgical resection and 81% received radiation treatment for BM. With a median follow-up of 5 years, 82% of pts died and median OS (mOS) following BM dx was 14 months (95% CI: 9-19). Among 208 pts without de novo BM, time to BM development (mTBM) from primary BCa varied by subtype: mTBM (IQR) HR+HER2- of 6.4 years (3.9-10.5), HR+HER2+ of 3.5 years (2.0-9.1), HR-HER2+ of 2.1 years (1.2-3.1), TNBC of 2.4 years (1.1-4.9). mOS varied by BCa subtype (table, log-rank p=0.029). 41 cases had de novo met disease (met dx ≤2 months of BCa dx) with 21 (9%) having de novo BM. HER2+ BCa and shorter mTBM were associated with longer mOS (table). Pts with BM dx in 2 nd or later met relapse vs. earlier BM (de novo or 1 st met relapse), OS HR was 1.67 (95% CI: 1.24-2.25; p=0.001). OS did not vary by age at BM diagnosis. Conclusions: Our findings build on prior work showing differential BM survival by subtype. We observe significantly shorter post-BM survival among pts who develop BM after a second or later line of met treatment. Ongoing work will expand our database and explore molecular features of resected brain tumors. [Table: see text]