tbuckley/cabot-search huggingface dataset:
Longitudinal stereotactic injections of oncolytic immunoactivating rQNestin34.5v.2 (CAN-3110) with concomitant biopsies for “-omic” analyses in recurrent glioblastoma (GBM).
Authors: David A. Reardon
Journal: Journal of Clinical Oncology (2024)

TPS2097 Background: Glioblastoma (GBM), the most common primary malignant brain tumor remains incurable. Numerous clinical trials of highly promising treatment modalities have not met efficacy objectives to support regulatory approval. One limitation in trial evaluation has been the lack of tumor sampled at various timepoints during therapy to allow analyses of the treatment’s effect. Sequential biopsies have not been pursued due to possible morbidity, relative surgical inaccessibility of GBM within the brain, and quality and quantity of stereotactic biopsies to permit detailed analyses. We hypothesized that the convergence of modern neurosurgical techniques and imaging with sophisticated “omics” analyses would overcome these limitations. Methods: A multi-institutional phase 1 clinical trial was started in recurrent GBM (rGBM) patients treated with up to 6 stereotactic administrations of the oncolytic immunotherapy, rQNestin34.5v.2 (CAN-3110) (Ling et al. Nature, 2023) over 4 months (day 0, 15, 30, 60, 90 and 120) with concomitant multisector biopsies. Two cohorts of 1 x10 8 pfu per injection and 1 x 10 9 pfus per injection of rQnestin34.5v.2 are planned for a total of 6 patients per cohort using a Bayesian optimal interval (BOIN) design for dose escalation. Before each injection, multiregional sector biopsies of rGBM are undertaken and the biopsies are processed for “-omic” analyses, including single cell RNA sequencing, proteomics/phosphoproteomic/immunopeptidomics, metabolomics, spatial transcriptomics and cell profiles as well as other technologies. In addition, concomitant CSF and blood analyses are performed at the same time to longitudinally correlate biofluid markers with the treated rGBM tissues. So far, 6 patients have accrued, completing cohort 1 without experiencing DLT or SAE from the injected oncolytic rQNestin34.5v.2 and/or the multiple longitudinal procedures. A total of 316 longitudinal core biopsies were obtained from all 6 patients across the planned timepoints. The biopsies have been successfully processed for ongoing longitudinal scientific “-omic” data for the first 2 patients. Cohort 2 is scheduled to start enrollment in the spring of 2024 (NCT03152318). This abstract is submitted on behalf of the Break Through Cancer Accelerating Glioblastoma Therapies Team Lab (breakthroughcancer.org). Clinical trial information: NCT03152318 .
A phase II, multicenter, prospective study of sacituzumab govitecan in recurrent glioblastoma.
Authors: William Kelly, Christine Cordova, Brian D. Vaillant, Henriette Balinda, Joel Michalek, Andrea Gilbert, John Floyd, Andrew J. Brenner
Journal: Journal of Clinical Oncology (2024)

TPS2094 Background: Despite decades of research, glioblastoma (GBM) remains the most common and aggressive primary brain malignancy. GBM has been shown to express trophoblast cell-surface antigen 2 (Trop2) and this expression corelates with proliferation rate, micro vessel density, histological grade and clinical survival 1,2 . Antibody drug conjugates (ADC) targeting cell surface receptors have been recently shown to produce intracranial response rates of 25-44%% 3-5 . Sacituzumab Govitecan (SG) consists of an ADC targeting Trop2 attached via linker to a chemotherapy payload, SN-38. In 2020, it received FDA approved for the treatment of metastatic triple-negative breast cancer followed by HR+/HER2- metastatic breast cancer in 2023. Methods: This is a multi-center, open-label, prospective, single-arm phase 2 study using a 2-stage adaptive Bayesian design. Patients with GBM (IDH wild-type), recurrent following standard-of-care chemoradiation, received SG at 10mg/kg IV on days 1 and 8 of a 21 day cycle. Patients were assessed by RANO and CTCAE v5. The primary endpoint was progression-free survival of patients on SG as compared to a historical control of lomustine monotherapy. Enrollment was conducted at UT Health Science Center in San Antonio, Cleveland Clinic and Texas Oncology in Austin. A total of 23 patients have been screened with 3 screen failures and 20 patients enrolled. The study has now entered interim analysis. Trial Registration: This trial (NCT04559230) is enrolled at Clinical Trials.gov as “Sacituzumab Govitecan in Recurrent Glioblastoma”: https://clinicaltrials.gov/study/NCT04559230 Funding: WK and AB have received contracted funding from Gilead. Additional support provided by an NCI Cancer Center Support Grant (P30CA016672) and an Early Clinical Investigator Award through CPRIT (RP210164). References: 1. Ning, S., et al., TROP2 expression and its correlation with tumor proliferation and angiogenesis in human gliomas. Neurol Sci, 2013. 34(10): p. 1745-50; 2. Harvard, B.I.o.M.a., Broad Institute TCGA Genome Data Analysis Center (2016): Correlation between mRNA expression and clinical features; 3.Fabi, A., et al., T-DM1 and brain metastases: Clinical outcome in HER2-positive metastatic breast cancer. Breast, 2018.41: p. 137-143; 4. Jacot, W., et al., Efficacy and safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive breast cancer with brain metastases. Breast Cancer Res Treat, 2016. 157(2): p. 307-318. Clinical trial information: NCT04559230 .
Effect of biocompatible snowman-like tumor-targeting dimer nanoparticles on delivery efficiency and anti-tumor therapy.
Authors: Chanqi Ye, Ruyin Chen, Qiong Li, Shuaishuai Xu, Jian Ruan
Journal: Journal of Clinical Oncology (2024)

e16347 Background: Chemotherapy is indispensable for the systematic treatment of aggressive malignancies, such as pancreatic ductal adenocarcinoma (PDAC), while delivery vehicles are essential for improving delivery efficiency and enhancing anti-tumor therapy. Methods: We design and synthesize tumor-targeting PLA/shellac-FA dimer nanoparticles (NPs). Paclitaxel (PTX) and curcumin (CUR) are co-loaded in PLA/shellac-FA dimer NPs. In vitro, we apply CCK8 assay to investigate the cell uptake of different particle shape. In vivo, different shape of PLA/shellac-FA dimer NPs are injected to mice model with tumor to investigate their delivery performance and anti-tumor effect. Meanwhile, we apply the flow analysis to explore the effect of different shape of PLA/shellac-FA dimer NPs on tumor microenvironment (TME). Results: In vitro tests demonstrate cell uptake performance is optimized by tuning the particle shape to be snowman-like. In vivo tests confirm improved delivery efficiency and enhanced anti-tumor therapy of snowman-like PLA/shellac-FA dimer NPs. Besides, PTX + CUR-loaded snowman-like PLA/shellac-FA dimer NPs could effectively reduce the proportion of tumor-associated macrophages (TAMs) in lymphocytes and reshape the M1/M2 polarization into an anti-tumor type. Meanwhile, the dimer NPs could enhance the infiltration of cytotoxic T lymphocytes (CTLs), thus activating the immune response in the TME. Conclusions: The results suggest that snowman-like PLA/shellac-FA dimer NPs with a sharp shape can effectively improve the delivery efficiency and enhance the anti-tumor therapy, being a promising system for clinical applications.
Liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin as a first line treatment for the management of metastatic pancreatic adenocarcinoma: A budget impact analysis from a U.S. payer perspective.
Authors: George P. Kim, Theo Holland, Caity Patrick, Megan Lewis, Paul Cockrum, Alexandra Eddy
Journal: Journal of Clinical Oncology (2024)

e16339 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) stands as the predominant pancreatic cancer type, affecting approximately 60,000 individuals in the United States (US) annually and nearly 500,000 globally. The prognosis for mPDAC is poor, with fewer than 20% of diagnosed individuals surviving beyond one year, and just 2.9% surpassing five-years. A phase 3 trial, NAPOLI-3, demonstrated statistically significant improved efficacy outcomes for NALIRIFOX compared with nab-paclitaxel + gemcitabine (Gem-Abraxane) as a first-line (1L) therapy for the treatment of mPDAC. NALIRIFOX showed an overall survival of 11.1 months compared with 9.2 months with Gem-Abraxane, and a significant improvement in progression free survival of 7.4 months compared with 5.6 months. In light of these efficacy outcomes, the objective of this analysis was to estimate the budget impact of adding NALIRIFOX for 1L treatment to a US health plan formulary over a one-year time horizon. Methods: The model estimated the difference in total costs and resource use between a current scenario without NALIRIFOX and a proposed scenario with NALIRIFOX. The eligible population was calculated using published prevalence and incidence data and applied to a hypothetical population plan of 1 million members (includes both commercial and Medicare insurance). NALIRIFOX was compared to the current standard of care (SoC) treatments with the highest market shares; FOLFIRINOX, Gem-Abraxane and Gemcitabine monotherapy, in the first year after marketing authorization. The following costs were included: acquisition, administration, resource monitoring utilization, adverse events (AE) and granulocyte-colony stimulating factor (G-CSF). Baseline characteristics, treatment duration and adverse events for NALIRIFOX and Gem-Abraxane were taken from NAPOLI-3 and published literature for other regimens. Results are presented in terms of the incremental budget impact (BI) and per member per month (PMPM) cost. One-way sensitivity analysis was performed. Results: For a plan of 1 million members, an estimated 132 individuals were eligible for 1L treatment for mPDAC. The PMPM budget impact was &lt; $0.01. NALIRIFOX demonstrated notable cost savings, with reductions of 13.6%, 7.7%, and 1.1% observed in the G-CSF, AEs, and resource monitoring cost categories, respectively. Results were most sensitive to the treatment duration of NALIRIFOX. Conclusions: The model results indicate that the budget impact of NALIRIFOX may be minimal from a US health plan perspective. Given the poor prognosis of mPDAC, NALIRIFOX presents itself as an important new first line treatment option for people living with an aggressive and hard to treat cancer.
Differentiating pancreatic cancer via cfDNA levels in liquid biopsies.
Authors: Romualdas Riauka, Rita Kupcinskaite-Noreikiene, Ingrida Grabauskyte, Giedrius Barauskas, Antanas Gulbinas, Vakare Gruodyte, Aldona Jasukaitiene, Povilas Ignatavicius
Journal: Journal of Clinical Oncology (2024)

e16344 Background: Pancreatic cancer remains an aggressive and highly lethal disease, exhibiting an overall 5-year survival rate of merely 10%, among the lowest compared to other oncological conditions. The absence of early and effective diagnostic tools hampers the management of pancreatic cancer (PC) patients, leading to compromised quality of life and treatment outcomes. Liquid biopsies, a relatively novel diagnostic method, enable non-invasive sampling of tumor materials. Specific genetic information, particularly changes in circulating free DNA (cfDNA) levels, is believed to forecast poorer tumor differentiation, a more aggressive disease course, faster relapse, and potential use as an early cancer diagnostic marker or for evaluating treatment efficacy. Methods: This study was approved by the Kaunas Regional Bioethics Committee (Approval ID: BE-2-31). Patients with newly diagnosed and histologically confirmed PC, without prior treatment and patients with chronic pancreatitis (control group), admitted to the Department of Surgery at Lithuanian University of Health Sciences Hospital, Kaunas Clinics, between September 2022 and November 2023 were included in this study. Blood samples were obtained from the patients before any treatment procedures commenced. cfDNA was extracted from the collected blood using the QIAmp Circulating Nucleic Acid Kit (Qiagen). The concentration and quality of the extracted cfDNA were determined using the Qubit™ 1X dsDNA High Sensitivity (HS) and Broad Range (BR) Assay Kits (ThermoFisher Scientific, Inc., Waltham, MA, USA). Results: Throughout the study period, 55 patients were included (47 with PC and 8 with chronic pancreatitis). cfDNA levels exhibited significant elevation in PC patients compared to those with chronic pancreatitis (p = 0.037; median (minimum – maximum): 46.5 ng/ml (4 – 768) vs 21.9 ng/ml (8.56 – 138.4) accordingly). The determined cut-off value for cfDNA levels distinguishing PC from chronic pancreatitis was 23.65 ng/ml (Area Under the Curve (AUC) = 0.73, sensitivity = 0.851, specificity = 0.625. Nevertheless, no distinctions in cfDNA levels were noted concerning tumor localization, size, differentiation, spread, or survival rates. Conclusions: Liquid biopsies and alterations in cfDNA levels could aid in distinguishing pancreatic cancer from benign inflammatory diseases like chronic pancreatitis. Nonetheless, further studies and experiments are necessary for comprehensive validation.
I-SPY2 Endocrine Optimization Pilot (EOP): Neoadjuvant amcenestrant +/- abemaciclib +/- letrozole in molecularly selected patients (pts) with HR+ HER2- stage 2/3 breast cancer (BC).
Authors: Amy Jo Chien, Rita A. Mukhtar, Karthik Giridhar, Olufunmilayo I. Olopade, Kevin Kalinsky, Christos Vaklavas, Anthony D. Elias, Mei Wei, Matthew P. Goetz, Laura van 't Veer, Silver Alkhafaji, Hope S. Rugo, Nan Chen, W. Fraser Fraser Symmans, Alexander D. Borowsky, Lamorna Brown Swigart, Natsuko Onishi, Douglas Yee, Nola Hylton, Laura Esserman
Journal: Journal of Clinical Oncology (2024)

601 Background: EOP is an I-SPY2 neoadjuvant sub-study designed to test the tolerability and impact of novel endocrine-based strategies in stage 2/3 BC pts predicted to have lower benefit from chemotherapy. Amcenestrant (A) is an oral selective estrogen receptor degrader (SERD) with activity in hormone receptor positive (HR+) HER2- metastatic BC. Methods: EOP eligibility included pts screened for the main I-SPY2 trial with HR+ HER2-, MammaPrint (MP) low risk Stage 2/3 BC. Pts with MP High risk tumor signatures were eligible if clinically node-negative (cN-). Pts were stratified by SET index and menopausal status. Pts were randomized to 3 arms: A 200 mg qd (A), A + abemaciclib 150 mg bid (AA), A + letrozole 2.5 mg qd (AL). Premenopausal pts received concurrent ovarian function suppression. Treatment was for 6 mos followed by surgery. Baseline (BL) and 3-wk biopsies were performed. Breast MRIs were conducted at BL (T0), 3 wks (T1), 12 wks (T2), 6 mos (T3). The primary endpoint was feasibility, defined as &gt;75% of pts completing &gt;75% study therapy. Results: Between May 2021 and Aug 2022, 74 pts were randomized: 31 A, 21 AA, 22 AL. Median age 50 years, 54% premenopausal, 38% clinically node-positive (cN+). 41% pts had ductal, 38% lobular, 11% mixed ductal/lobular histology. Mean BL tumor Ki67 (central testing) was 16.9%, 88% MP low, 76% SET index Hi. Pt and tumor characteristics were balanced across the 3 arms. Treatment in all 3 arms was feasible with 95% of pts completing &gt;75% study therapy. Most common AEs include grade 1-2 hot flashes (69%) and fatigue (66%). Grade 3 AEs include neutropenia (2 pts) and diarrhea (1 pt) in AA. Table summarizes key response endpoints, which were similar between pre- and postmenopausal pts. Of 28 cN+ pts, 2 (7%) were pathologically node-negative (pN-). Mean MRI Functional Tumor Volume (cc) change between T0-&gt;T1, T1-&gt;T2, T2-&gt;T3, T0-&gt;T3 was -6.06 (-34.2%), -3.55 (-29.2%), -0.829 (-20.1%), -11.3 (-68.4%), respectively, similar across arms (p=0.396).ctDNA was detected in 10/59 (17%) pts at T0. ctDNA became undetectable in 6 pts, decreased in 4 pts, and went from ctDNA undetectable at baseline to detectable at T3 in 2 pts. Conclusions: Six months of neoadjuvant endocrine therapy (NET) with the oral SERD amcenestrant is feasible, well-tolerated, and demonstrates anti-proliferative and anti-tumor activity in pre- and postmenopausal pts. NET provides a rich platform for biomarker discovery and investigating response to endocrine therapy. Clinical trial information: NCT01042379 . [Table: see text]
Clinical outcomes and efficacy of HER2-targeted therapy in breast cancer with uncommon in situ hybridization (ISH) patterns or discordant immunohistochemistry (IHC).
Authors: Qianchen Zhang, Jincong Q. Freeman, Fangyuan Zhao, Nan Chen, Rita Nanda, Dezheng Huo, Frederick Matthew Howard
Journal: Journal of Clinical Oncology (2024)

604 Background: HER2-targeted therapy (Tx) improves outcomes in HER2+ breast cancer, but efficacy in patients (pts) with discordant IHC/ISH results, or with ASCO/CAP Group 2–4 ISH results (representing mono/polysomy and borderline positivity), remains uncertain. We sought to characterize the epidemiology and response to HER2-directed Tx in these subgroups. Methods: This retrospective cohort study included pts from the National Cancer Database diagnosed in 2013 - 2020. Cases were classified as HER2+, HER2–, discordant ISH/IHC, or HER2+ with ISH Group 2 (HER2/CEP17 ratio ≥ 2, HER2 copy number [CN] &lt; 4), 3 (ratio &lt; 2, CN &gt; 6), or 4 (ratio &lt; 2, CN ≥ 4 and &lt; 6) per the 2023 ASCO/CAP guidelines. In pts receiving neoadjuvant chemotherapy (NAC) with HER2-targeted Tx, odds ratio (OR) for pathologic complete response (pCR) was calculated adjusting for age, comorbidity, stage, and hormone receptor expression, for HER2+ subgroups relative to HER2– cases; pCR rate was also compared between pts who did vs. did not receive HER2-targeted Tx. Adjusted hazard ratio (HR) for overall survival (OS) in Stage IV pts was calculated relative to HER2– cases, and as a function of receipt of HER2-targeted Tx. Results: We identified 1,105,890 cases for inclusion (mean age, 62 years; median follow-up, 43 months). Of HER2 IHC 3+ cases with dual probe ISH testing (n=6808), 9.4%, 4.2%, 2.7%, and 8.2% had ISH results classified as ASCO/CAP Group 5 (i.e. discordant negative), 4, 3, and 2, respectively. Of HER2 IHC 0 or 1+ cases with dual probe ISH (n=47,817), 2.4% had discordant positive Group 1 ISH results. Among 148,099 pts receiving NAC, HER2+ and Group 2 IHC 3+ treated with HER2-targeted Tx had higher pCR rates than HER2– cases (Table), with no pCR improvement seen in Group 3/4 ISH or discordant ISH/IHC cases. Few pts in HER2+ subgroups did not receive HER2-directed Tx, but improved pCR with HER2-targeted Tx was seen in HER2+ cases with a trend toward improvement in Group 2 ISH cases. Similarly, OS was superior in Stage IV HER2+ (HR 0.49, 95% confidence interval [CI] 0.45 - 0.53) and Group 2/IHC 3+ cases (HR 0.29, 95% CI 0.10 – 0.77) receiving HER2-targeted Tx relative to HER2– cases. Conclusions: HER2+ cases with ASCO/CAP Group 3/4 ISH results, as well as pts with discordant ISH/IHC have inferior outcomes with HER2-targeted Tx, and alternative treatment strategies for these pts incorporating agents approved for HER2– disease should be considered. [Table: see text]
The predictive value of the mature B cell signature in early Her2-positive breast cancer treated with neoadjuvant therapy.
Authors: Po-Han Lin, Chiao Lo, Sung-Hsin Kuo, Chiun-Sheng Huang
Journal: Journal of Clinical Oncology (2024)

606 Background: Neoadjuvant therapy (NAT) by combining polychemotherapy and HER2-targeted drugs has become the golden standard treatment for patients with early-stage Her2-positive breast cancer. Pathologic complete response (pCR) is a surrogate marker that predicts a favorable prognosis. Tumor infiltration lymphocytes (TILs) and immune profiling had been reported as a biomarker associated with the pCR. There are several types of immune cells such as monocytes, T and B cell; however, it’s uncertain which kind of immune cells and immune profile play the most important role to predict the pCR in Her2-positive breast cancer. Methods: We enrolled 188 breast cancer patients who were diagnosed of having stage I-III Her2-positive breast cancer. All patients received taxane in combination with Her2-targeted therapies. We performed RNA sequencing on the breast cancer samples which were collected before treatment. Immunohistochemical staining of immune markers were done, too. Results: 103 patients were treated with trastuzumab-based NAT and 85 patients were treated with dual-blockade (trastuzumab plus pertuzumab) based NAT. Among the clinical and tumor characteristics, high expression of Her2 and low expression of ESR1 were associated with the pCR (both p &lt;0.01). Dual blockade therapy tended towards pCR, but lacked statistical significance. For the microenvironment, we deconvoluted the immune cells from the RNA-seq data to measure the cell populations. The proportion of immune cells was correlated to the TILs that was measured from the pathology slides (p&lt;0.01). Both the TILs and the immune cell amounts from the RNA-seq were significantly associated with the pCR (both p&lt;0.01). By the deconvoluted cell types, higher abundance of B cells was significantly associated with the pCR, compared to lower B cell amount (p&lt;0.001). The total T cells, CD8 T cells and monocytes were trended to the pCR but not statistical significance. We then subgroup B cells into the mature B populations which express immunoglobulin genes and immature B populations which express RAG-1 gene without immunoglobulin. We found that only the mature B cells predicted the pCR and immature B cell didn’t. Multivariate logistic regression analysis adjusted for ESR1 expression, Her2 expression and dual blockade therapy, only the mature B cell independently predicted the pCR (odds ratio, 2.63; 95%CI, 1.34-5.16; p = 0.005). The total TILs by pathology slide and other immune cell types didn’t. In addition to pCR, the mature B cells were independently related to the superior recurrence-free survival by the multivariate Cox regression model after adjusting the ESR1 expression, Her2 expression, dual blockade therapy, TIL and immune cell types (hazard ratio, 0.32 ;95% CI, 0.11-0.98; p=0.047). Conclusions: Our result suggested that the mature B cell signature was more strongly associated with the pCR and recurrence-free survival than TILs.