tbuckley/cabot-search huggingface dataset:
Effect of targeting FAK by ifebemtinib and immunogenic cell death of Kras G12C/G12D inhibition on the efficacy of PD1 blockade.
Authors: Baoyuan Zhang, Jiaming Gao, Ran Pang, Ping Zhang, Jingwen Cheng, Natasha Qin, Leo Liu, Zaiqi Wang
Journal: Journal of Clinical Oncology (2024)

e15102 Background: Focal adhesion kinase (FAK) is one major component of focal adhesion complex and is important in regulating cancer cell survival. Previously, we found that a clinical-stage FAK inhibitor, ifebemtinib (aka IN10018) can overcome drug resistance of Kras G12C inhibitors by down regulating the FAK-YAP signaling. Combination of Kras G12Ci and FAKi has demonstrated encouraging efficacy in NSCLC. Here, we reported that targeting Kras G12D by selective Kras G12Di can also be enhanced by ifebemtinib. Further, Kras G12C inhibition plus PD1 blockade has demonstrated clinical benefits in PD-L1 high expression patient population, but ≈30% of patients experienced early disease progression; this might be attributed to loss-of-function of LKB1 and others. Immunogenic cell death (ICD) of Kras inhibition is enhanced by ifebemtinib, ICD reportedly enhances anti-PD1 activity. Thus, Kras inhibition and PD1 blockade plus ifebemtinib may be an ideal combination for patients with Kras G12D. Methods: Cell killing and apoptosis assays were performed to test the combination of Kras G12D inhibition and ifebemtinib. FACs analysis evaluated exposure levels vs. ICD biomarkers. The mice inoculated with CRC GP2D and PDAC PC-07-0013 were used for evaluating the combinational effects of Kras G12Di and ifebemtinib. The tumor bearing mice with Kras G12D mutant/LKB1 loss, NSCLC KPL, and CRC CT26 with knock-in Kras G12C were used for testing the effects of Kras inhibition, ifebemtinib, and PD1 blockade. Results: Ifebemtinib enhances the drug effects of Kras G12D inhibition in vitro and in vivo. The dual regimen of ifebemtinib and Kras inhibition outperformed either monotherapy with significant ICD induction in vitro (calreticulin/GRP94 exposure). The triple regimen of Kras inhibition, FAK inhibition and PD1 blockade exhibited stronger anti-cancer effects compared to the other related therapies, especially in a Kras G12D mutant, LKB1 loss animal model which is intrinsically resistant to PD1 blockade/Kras G12D inhibition. Conclusions: We discovered that targeting FAK by ifebemtinib enhances the anti-cancer effects of Kras G12D inhibition. It promotes ICD by targeting Kras G12D or G12C, further primes the dual regimen of Kras inhibition and ifebemtinib towards a response to anti PD1 therapy. The preclinical results warrant a further evaluation in the clinic.
Sequential combination of sacituzumab govitecan and talazoparib in metastatic triple negative breast cancer (mTNBC): Results from a phase II study.
Authors: Rachel Occhiogrosso Abelman, Laura Spring, Andrzej Niemierko, Elizabeth Abraham, Mary McNeice, Jennifer Goff, Amanda Valenti, Seth Andrew Wander, Steven J. Isakoff, Beverly Moy, Dejan Juric, Neelima Vidula, Adrienne Gropper Waks, Heather Anne Parsons, Leif W. Ellisen, Sara M. Tolaney, Aditya Bardia
Journal: Journal of Clinical Oncology (2024)

1102 Background: The antibody-drug conjugate (ADC) sacituzumab govitecan (SG) has demonstrated improvement in overall survival for patients with metastatic triple negative breast cancer (mTNBC). Despite great interest in enhancing efficacy of ADCs using combination therapy, there are no approved regimens. Preclinical data suggest that SG synergizes with Poly ADP-ribose polymerase inhibitors (PARPi) to induce DNA damage and cell death. Though the phase 1b study demonstrated intolerable myelosuppression with simultaneous dosing, tolerability was improved with sequential administration of SG and the PARPi talazoparib (Bardia AACR 2022). Here we report clinical outcomes from the phase II dose expansion cohort (NCT04039230). Methods: In a single-arm phase II study, adult patients with measurable mTNBC (per ASCO/CAP guidelines) were eligible. Starting dose was SG at 10mg/kg on days 1 and 8 with talazoparib 1mg on days 15-21. Growth factor (G-CSF) prophylaxis was required. The primary endpoint was the confirmed Objective Response Rate (ORR) calculated per RECIST v1.1 and secondary endpoints included progression-free survival (PFS) and overall survival (OS). The Clinical Benefit Rate (CBR) at 6 months was also measured. Results: From June 2021 to March 2023, 26 patients were enrolled. The median age was 54 (range, 35 to 81). Patients received a median of 2 prior therapy lines for metastatic disease (range, 0 to 7). 6/26 patients remain on treatment at time of data cutoff. Median PFS was 6.2 months (95% CI, 3.7 to 12.8), and median OS was 18.0 months (95% CI, 10.7 to not evaluable). The confirmed ORR was 30.1% (95% CI, 14 to 52) and the CBR at 6 months was 53.8% (95% CI, 33 to 73). Serious adverse events (AEs) were seen in 10 (38.5%) of patients; in 7 (26.9%) serious AEs were treatment related. The most common treatment related AEs were anemia (92.3%), neutropenia (88.5%), nausea (84.6%) fatigue (80.7%), and thrombocytopenia (65.3%). Grade ≥3 neutropenia and anemia were seen in 80.7% and 34.6% of cases, respectively. One or more dose reductions were required in 58.0% of patients. One patient with a germline BRCA mutation was treated for 625 days before disease progression. Updated biomarker and survival data will be presented at the meeting. Conclusions: In this single-arm phase II study, SG in combination with talazoparib was feasible and demonstrated preliminary evidence of efficacy. A randomized clinical trial is needed to determine if the SG-PARPi combination is superior to SG monotherapy. Clinical trial information: NCT04039230 .
Exosomal HMGB1 educate PD-L1<sup>+</sup>-tumor associated macrophages via glycometabolic reprogramming to induce lung-tropic metastasis of triple negative breast cancer.
Authors: Wei-xian Chen, Bei Zhu, Tian-cheng Cheng, Jia-hao Wu, Lin Zheng
Journal: Journal of Clinical Oncology (2024)

1090 Background: Lung metastasis occurs in one third of triple negative breast cancer (TNBC), the underlying molecular mechanism remains largely unclear. Mounting evidence suggests that PD-L1 + -tumor associated macrophages (PD-L1 + -TAMs) are closely associated with immune suppression, invasion, and metastasis. Tumor-derived exosomes have been reported to remodel tumor microenvironment and accelerate metastasis through packing and delivering a variety of biologically active molecules. The aim of this study was to investigate whether TNBC-derived exosomes were able to polarize lung macrophages towards PD-L1 + -TAMs and promote a pre-metastatic immunosuppressive niche, therefore discovering the underlying mechanism of lung-tropic metastasis. Methods: Exosomes obtained from EO771 TNBC cell line (EO771/exo) and HC11 normal breast epithelial cell line (HC11/exo) were characterized. Absorption of exosomes by macrophages was observed by confocal microscopy. Mass spectrometry was used to identify the significantly highly expressed HMGB1 protein in EO771/exo, and ligands of HMGB1 on lung macrophages were detected by co-immunoprecipitation. Significance of EO771/exo and HMGB1 in inducing PD-L1 + -TAMs and generating a pre-metastatic immunosuppressive niche were confirmed by both in vitro and in vivo studies. Functions of EO771/exo and HMGB1 on glycolysis and lactate production were evaluated by metabolism assays. Results: EO771/exo could polarize macrophages toward PD-L1 + -TAMs and generate a pre-metastatic immunosuppressive niche. Mass spectrometry, clinical samples, and bioinformatics analysis showed that HMGB1 was significantly expressed in EO771/exo and was involved in cellular communication and metabolism processes. Co-immunoprecipitation and 3-dimensional modeling suggested a strong binding of HMGB1 with Tim-3 ligand on lung macrophages. Macrophages incubated with EO771/exo exhibited an enhanced glycolysis and lactate production. Flow cytometry demonstrated that green fluorescent protein (GFP)-EO771 tumor-bearing mice had more lung micro-metastases than brain and liver. Immunofluorescence and laser confocal microscopy demonstrated that EO771/exo were able to increase lung micro-metastases and escalate PD-L1 expression on lung macrophages. Moreover, elevated PD-L1 + -TAMs and reduced CD3 + CD8 + T lymphocytes were detected in TNBC positive axillary lymph nodes and lung metastasis specimens than TNBC negative axillary lymph nodes. Conclusions: Exosomal HMGB1 from TNBC could target Tim-3 ligand on lung macrophages and accelerate glycolysis and lactate production to induce PD-L1 + -TAMs, thereby suppressing CD3 + CD8 + T lymphocytes immunity and generating a pre-metastasis immune-suppressive niche. Our research would uncover a novel mechanism of lung-tropic metastasis.
Phase I trial of hypoxia-responsive CEA CAR-T cell therapy in patients with heavily pretreated solid tumor via intraperitoneal or intravenous transfusion.
Authors: Hangyu Zhang, Zhi Yang, Xudong Zhu, Jie Li, Yang Gao, Yingzi Zhang, Zhou Tong, Qihan Fu, Xuanwen Bao, Bin Li, Qianzhen Zhang, Junjie Shen, Yi Zheng, Lulu Liu, Peng Zhao, Cheng Qian, Weijia Fang
Journal: Journal of Clinical Oncology (2024)

3514 Background: Chimeric antigen receptor (CAR) T cell therapy has been successful in hematologic malignancies but not in solid tumors. Homing capacity and tumor microenvironment are key issues to limit CAR-T efficacy to solid tumors. Our previous study has shown that hypoxia-responsive CAR-T cells exhibit reduced exhaustion and enhanced efficacy in solid tumors (Cancer Res 2024). Here, we aimed to optimize the administration route by comparing safety and efficacy of our newly established CEA CAR-T through intraperitoneal (I.P.) and intravenous (I.V.) infusions in solid tumor patients who failed to standard therapy. Methods: In this phase I, open-label, dose-escalation clinical trial, eligible patients were CEA positive and relapsed or refractory to at least second-line treatment. CAR-T cells was administered via I.P. or I.V. with dose escalation including low dose of 1-3 x10 6 CAR+/kg and high dose of 4-6 x10 6 CAR+/kg. Adverse events were graded by CTCAE 5.0. Tumor responses were evaluated using RECIST 1.1. Results: Between June 2022 to Jan 2024,40 pts were enrolled and infused CAR-T cells, including 35 CRC pts, 3 GC pts, 1 NSCLC pts and 1 BTC pts. There were 16 pts in the I.P. group and 24 pts in the I.V. group. CRS was observed in 62.5% of the pts at grade 1-2, and no ICANS or treatment related death was reported. Grade 1-2 mucositis was reported in 25% of the patients. Immune-mediated diarrhea and colitis of all grades occurred in 32.5% of the patients, including 17.5% grade 3 events. And 100% of patients experienced grade 3-4 hematologic toxicity. In terms of efficacy, the I.P. group displayed a higher objective response rate (ORR) of 25% (4/16), compared to 8% (2/24) in the I.V. group, alongside a superior disease control rate (DCR) of 88% (14/16) in I.P. compared to 67% (16/24) in I.V. group. Notably, within the high-dose group receiving I.P. infusion, the ORR increased to 28.5%. Moreover, the responded patients in the high-dose group all had sustained tumor remission for more than 5 months, including one patient who had a 76% target lesions regression at six months follow up. CAR-T cells demonstrated robust expansion in both the I.P. and I.V. groups, while no significant difference was found in maximum concentration. Conclusions: The CEA CAR-T cell therapy had acceptable toxicity via I.P. or I.V. infusion. We have observed a promising antitumor potential by I.P. infusion and a prolonged tumor remission in high-dose group. Further investigation is needed to highlight these findings and the corresponding mechanisms. Clinical trial information: NCT05396300 . [Table: see text]
Sweet syndrome in the setting of breast cancer: A literature review.
Authors: Amanda Lee, Awais Paracha, Fahad Hussain, Kayla Dillon, Maha Arshad, Emma Li, Brittany Kwait, Sneha Shrivastava, Nouneh J. Gostanian
Journal: Journal of Clinical Oncology (2024)

e24044 Background: Sweet syndrome (SS) or acute febrile neutrophilic dermatosis typically present as patients with pyrexia, neutrophilia and rash with dermal neutrophilic dominance on biopsy. While the association of SS with malignancy is well-documented, the connection of sweet syndrome and solid tumors especially breast cancers is not explored enough. It is important to understand these associations better understand the disease course of SS in the setting of breast cancer. We aim to examine the different triggers, subtypes of breast cancer associated with SS, and differences in presentation and resolution time. Methods: A literature review from 1/1950-11/2023 was conducted for co-existing diagnoses of BC and SS in the PubMed Database. Search terms included Sweet Syndrome or Acute febrile neutrophilic dermatosis with Breast Cancer with subtypes. Key outcomes included: trigger identification, breast cancer subtypes, and treatment options. Findings were analyzed via a thematic lens. Results: A total of 34 cases of female BC patients with SS were identified with triggers divided into subtypes of surgery (47%), medication (20%), paraneoplastic (20%), and radiation therapy (11%). Depending on the trigger, average time to presentation varied with drug-triggered being the shortest (3.3 months) followed by radiation (8.5 months) while surgery (50 months) and paraneoplastic- associated (57 months) had similar presentation times. Although the time to presentation time for paraneoplastic-associated SS was the longest, 50% of these cases were associated with underlying progression of cancer. Regarding treatment and resolution time, 26 cases of SS resolved after treatment with treatment mainstay including oral (65%) and topical (12%) steroids. Analyzing triggers specific treatment outcomes, drug (2.7 days) and radiation-induced SS (7 days) had shorter average resolution times while paraneoplastic- associated (10.5 days) and surgery-associated SS (18.5 days) had longer resolution times. 5 cases that documented initial relapse or recurrence of SS after initial treatment were associated with paraneoplastic –induced sweet syndrome. On further analysis, among the 15 cases mentioned the BC type associated with SS- the most common breast cancer subtype was invasive ductal carcinoma of the breast (47%) followed by metastatic carcinoma (20%), adenocarcinoma (13%) and invasive lobular carcinoma (6%), canalicular breast carcinoma (6%) and unspecified malignant tumor of the breast (6%) regardless of the trigger mentioned. Conclusions: Oncologists should always consider SS on the differential for BC patients presenting with fever and rash given the varied presentation times depending on type of trigger. Treatment should be started promptly and continued for an adequate amount of time depending on the trigger to better mitigate complications in breast cancer patients.
SCR-A002, a novel FGFR2b-targeting antibody-drug-conjugate for solid tumors.
Authors: Yayuan Fu, Yuanjie Ge, Xiaohui Shao, Qi Deng, Chunlei Xia, Renhong Tang
Journal: Journal of Clinical Oncology (2024)

e15019 Background: FGFR2b (fibroblast growth factor receptor 2 IIIb), a transmembrane tyrosine kinase, is overexpressed in various cancers, including gastric, esophageal, breast, hepatocellular, pancreatic, ovary, uterine, cervical, endometrial, lung, colorectal cancers. Bemarituzumab (FPA144), an afucosylated humanized IgG1 monoclonal antibody targeting FGFR2b with enhanced ADCC activity, showed promising clinical efficacy in phase 2 study of FGFR2b-selected gastric or gastroesophageal junction adenocarcinoma. We have developed a potential first-in-class FGFR2b-targeting ADC (SCR-A002) at IND-enabling status, displaying significantly superior anti-tumor potency compared to Bemarituzumab. Methods: SCR-A002 is comprised of a humanized anti-FGFR2b IgG1 monoclonal antibody conjugated with proprietary TOPO1 inhibitor payload (DAR 8) via a cleavable linker. Anti-FGFR2b antibody was generated by immunization of FGFR2b protein in mice followed by hybridoma technique. Binding activity and cytotoxicity were assessed in FGFR2b+ tumor cell line. And anti-tumor efficacy was evaluated in several CDX and PDX models. Results: SCR-A002 could specifically bind to FGFR2b on cancer cells and be internalized, and the TOPO1 inhibitor could be cleaved intracellularly to kill the cancer cells potently in vitro. After single-dose administration of SCR-A002, tumor regression was achieved in different FGFR2b expression level CDX and PDX models, even with big-size tumor or Bemarituzumab resistance. Conclusions: SCR-A002 showed potent anti-tumor efficacy in preclinical data, which suggest that SCR-A002 is expected to provide a new treatment option as single agent or combo with SoC for patients with FGFR2b-overexpressing solid tumor.
Incidence of cardiotoxicity after high cumulative dose of anthracyclines in adult patients with advanced soft tissue sarcomas: A systematic review and meta-analysis.
Authors: Rachelle Diane Bautista Maravilla, Paula Isabel Gimena Franco, Gale Rizzae Mercado Alcala, John Christopher Agsalud Pilapil, Agnes Evangelista Gorospe, Anna Marie Mangune Pascual-Panganiban
Journal: Journal of Clinical Oncology (2024)

e24004 Background: The risk of anthracycline-related cardiotoxicity increases with cumulative dose, with most available literature based from studies on breast cancer patients. Although soft tissue sarcomas are heterogenous entities, anthracycline-based chemotherapy is considered the most active regimen. This study aims to clarify the incidence of cardiotoxicity among patients with advanced soft tissue sarcomas who receive a high cumulative dose of anthracyclines. Methods: We performed a systematic search across PubMed, Cochrane, Google Scholar, and ASCO and ESMO references. Studies were eligible if they (1) investigated soft tissue sarcoma patients, (2) receiving high cumulative doses of doxorubicin ( &gt; 450mg/m 2 ), lipodox ( &gt; 550mg/m 2 ) or epirubicin ( &gt; 900mg/m 2 ), and (3) reported the incidence of cardiotoxicity (clinical and subclinical). Three authors independently assessed validity of the articles using the Cochrane Tool for randomized trials and the Newcastle-Ottawa scale for cohorts. Pooled analysis was performed using MetaXL with the random effects model. Pooled incidence with 95% CI and heterogeneity (Cochran's Q) were determined. Results: For doxorubicin, 4 studies with 168 patients without pre-existing cardiomyopathy, and a mean age of 47 years were included. At a mean cumulative dose of 651.1mg/m 2 , clinical cardiotoxicity was seen in 2.6% (0.62–5.62%,Q3) while subclinical cardiotoxicity was seen in 23.8%(17.67%-30.53%,Q86). For epirubicin, we included 3 studies with 109 patients, without pre-existing cardiomyopathy, and mean age of 39 years. At a cumulative dose of 1128.33mg/m 2 , clinical cardiotoxicity was seen in 5.3% (1.74–10.38%,Q25), and subclinical cardiotoxicity was seen in 13.4% (7.62%-20.50%,Q37). Conclusions: The incidence of cardiotoxicity in patients with advanced soft tissue sarcomas receiving high cumulative dose of anthracyclines is comparable with existing data on breast, lymphoma and leukemia patients. Subclinical cardiotoxicity is more prominent. Majority of the patients received cardioprotective strategies during their treatment (dexrazoxane or continuous infusions of doxorubicin). Evidence with regard to lipodox is lacking.
Comparison of antitumor efficacy of first-line palbociclib, ribociclib, or abemaciclib in patients with HR+/HER2- aBC: Results of the multicenter, real-world, Italian study PALMARES-2.
Authors: Claudio Vernieri, Leonardo Provenzano, Mario Giuliano, Gianpiero Rizzo, Angela Toss, Marta Piras, Marianna Sirico, Barbara Tagliaferri, Monica Giordano, Daniela Miliziano, Daniele Giulio Generali, Donata Sartori, Alberto Zambelli, Alessandra Gennari, Nicla Maria La Verde, Rebecca Pedersini, Matteo Lambertini, Andrea Botticelli, Giuseppe Curigliano, Maria Vittoria Dieci
Journal: Journal of Clinical Oncology (2024)

1014 Background: The Cyclin Dependent Kinase 4/6 inhibitors (CDK4/6i) Palbociclib, Ribociclib and Abemaciclib in combination with Endocrine Therapy (ET) represent the standard-of-care, 1 st line treatment for patients with Hormone Receptor-positive, Human Epidermal growth factor Receptor 2-negative, advanced Breast Cancer (HR+/HER2- aBC). So far, no large real-world studies have compared the efficacy of the three CDK4/6i in this clinical setting. Methods: The multicenter, population-based study PALMARES-2 evaluated the antitumor efficacy of 1 st line Palbociclib, Ribociclib or Abemaciclib in combination with ET in consecutive HR+/HER2- aBC patients treated in 18 Italian cancer centers between 1 st January 2016 and 1 st September 2023. The primary study endpoint was real-world Progression-Free Survival (rwPFS), as defined as the time interval between ET plus CDK4/6i initiation and disease progression. Multivariate Cox regression model was used to adjust the association between individual CDK4/6i and rwPFS for clinically relevant variables. Results: With a data cut-off date of January 1 st , 2024, we enrolled 1850 patients, 750 (40.6%), 676 (36.5%) and 424 (22.9%) of whom received Palbociclib, Ribociclib and Abemaciclib, respectively. Among 1226 (66.3%) patients with endocrine-sensitive disease, 1087 (89%) received concomitant Aromatase Inhibitors, whereas 441 (70.7%) out of 624 (33.7%) patients with endocrine-resistant disease received concomitant Fulvestrant. Patients treated with Abemaciclib were more likely to have endocrine-resistant disease, liver metastases, lobular tumor histology and lower PgR tumor expression, and less likely to have de novometastatic disease (p&lt;0.001). Median rwPFS in the whole study cohort was 34.9 months (95% CI 32.0-37.4). Abemaciclib and Ribociclib were independently associated with better rwPFS when compared to Palbociclib (Table), whereas Abemaciclib and Ribociclib showed no significantly different efficacy (aHR 0.91, 95% CI 0.70-1.19; p=0.505). Other covariates independently associated with rwPFS are shown (Table). Conclusions: The real-world study PALMARES-2 revealed different antitumor efficacy of individual CDK4/6i in HR+/HER2- aBC patients. Longer follow-up is required to study if Palbociclib, Ribociclib and Abemaciclib are associated with different overall survival. [Table: see text]