tbuckley/cabot-search huggingface dataset:
Preliminary results from a FIH, open-label phase 1 study with BMC128, a rationally designed live bacterial consortium, in combination with nivolumab.
Authors: Ruth Perets, Shiri Meshner, Osnat Tirosh, Shiri Eshar, Alona Metz-Breiner, Sheerli Kruger Ben-Shabat, Hila Ben-Yehuda, Elran Haber, Meital Cohen-Asis, Corinne Maurice-Dror, Yehuda Ringel, Roy Holland, Yelena Shirman, Talia Shentzer kutiel
Journal: Journal of Clinical Oncology (2024)

8631 Background: Immune-Checkpoint inhibitors (ICI) have transformed the treatment of solid tumors, specifically in cutaneous melanoma, clear cell renal cell carcinoma (ccRCC) and non-small cell lung cancer (NSCLC). Despite these advances, resistance to ICI eventually occurs in many patients. Recent reports have found that patients showing poor response to ICI are characterized by a reduced gut microbiome diversity, suggesting that the gut microbiome might affect immune activation by ICI. BMC128 is a live bacterial consortium of 4 bacterial strains designed to induce anti-tumor immune function when given in conjunction with ICI. These strains were identified by analyzing microbiome data obtained from NSCLC and ccRCC patients presenting varied responses to ICI, using a proprietary computational discovery platform enabling high-resolution functional microbiome analysis. In pre-clinical studies, treatment with BMC128 potentiated the efficacy of ICI in breast cancer and melanoma mouse models, reducing tumor volume, increasing the number of responders, and demonstrating an increase in infiltrating immunocytes: CD4, CD8 and NK cells. The aim of this study was to assess the safety and tolerability of BMC128 in combination with nivolumab. Methods: 12 patients with ccRCC, cutaneous melanoma and NSCLC-adenocarcinoma (EGFR/ALK wild-type) (6, 1 and 5 patients, respectively), who previously progressed on PD1/PDL-1 inhibitors were recruited to this FIH open label phase 1 study. Patients were treated with a daily oral dose of BMC128 4*10 8 live cells/ strain in combination with nivolumab 480mg q4weeks. The study treatment consisted of 4 stages: depletion with antibiotics, induction with BMC128 monotherapy, combination treatment, and nivolumab monotherapy. Results: No SAEs related to BMC128 were reported throughout the duration of the study. Two patients exhibited minor AEs that were potentially associated with BMC128. At the current time point, 4 out ofthe first 8 patients in the study showed SD and sustained benefit beyond the first imaging timepoint, following the combination treatment. Altogether demonstrating clinical benefit for a total of 16 weeks (2 patients), 24 weeks (1 patient), and 68 weeks (1 patient). Conclusions: BMC128 has demonstrated an excellent safety profile and preliminary beneficial clinical effect. A phase 2 study to investigate the efficacy of BMC128 is planned to be initiated in late 2024. Clinical trial information: NCT05354102 .
Integration of circulating tumor DNA and metabolic parameters for outcome prediction in unresectable locally advanced non-small cell lung cancer.
Authors: Leilei Wu, Zhenshan Zhang, Xiaojiang Sun, Yujie Yan, Chenxue Jiang, Yaoyao Zhu, Xu Yaping
Journal: Journal of Clinical Oncology (2024)

8080 Background: An effective biomarker to direct precise consolidation treatment after CRT is still lacking. Circulating tumor DNA (ctDNA) molecular residual disease (MRD) following curative-intent treatment strongly predicts recurrence in multiple tumor types, but whether further treatment can improve outcomes in patients with MRD remains unclear. Hereby, we applied CAPP-Seq ctDNA analysis to plasma samples collected before and after definitive chemoradiotherapy (CRT) or radiotherapy (RT) in unresectable LA-NSCLC. Methods: A total of 62 unresectable LA-NSCLC patients were prospectively enrolled, providing 62 baseline and 49 post-definitive CRT/RT plasma samples. All patients underwent a PET/CT scan at baseline and 33 patients received a mid-treatment PET/CT scan upon reaching a RT dose of 40Gy/20f during therapy. These 33 patients were randomly assigned to either receive or not receive adaptive dose-escalated RT. A group of patients who received immune checkpoint inhibitor (ICI) consolidation after CRT/RT was compared with patients who were ctDNA-/high △TMTV post-treatment. Results: ctDNA was detected at baseline in 44 (71.0%) patients. Pre-treatment ctDNA concentration was significantly correlated with TMTV (p = 0.004) and TLG (p = 0.010). Baseline ctDNA detection and concentration were not able to differentiate patients with varying treatment responses or predict survival. However, patients with undetectable ctDNA and low TMTV exhibited significantly better PFS (p = 0.024). One month after completing CRT or RT, ctDNA was detected in 25 (47.2%) patients. While the concentration of circulating free DNA (cfDNA) remained relatively stable (p = 0.652), both the mean ctDNA Variant Allele Frequency (VAF) (p = 0.002) and ctDNA concentration (p = 0.043) showed a significant decrease. Patients with undetectable ctDNA post-treatment exhibited significantly longer PFS and OS. A lower ∆TMTV was significantly associated with longer PFS and OS. Compared to the non-response group, the response group exhibited significantly lower change in △SUVmax (p = 0.024), with a trend towards lower change in TMTV, although not significant (p = 0.064). Compared with the matched 30 patient receiving ICI consolidation, those with negative ctDNA and high △TMTV after CRT demonstrated significantly better PFS (p = 0.042) and OS (p = 0.039). Conclusions: Baseline ctDNA combined with TMTV can enhance the predictive ability for survival. Post-CRT ctDNA and △TMTV possess strong prognostic capabilities. Patients who are ctDNA- and with high △TMTV may be exempt from ICI consolidation therapy.
ICARUS-LUNG01: A phase 2 study of datopotomab deruxtecan (Dato-DXd) in patients with previously treated advanced non-small cell lung cancer (NSCLC), with sequential tissue biopsies and biomarkers analysis to predict treatment outcome.
Authors: David Planchard, Nathalie Cozic, Marie Wislez, Christos Chouaid, Hubert Curcio, Sophie Cousin, Celine Mascaux, Jacques Cadranel, Margaux Geier, Maria Rosa Ghigna, Ghada Nachabeh, Ricardo F. Zwirtes, Rachel Chiaverelli, Rasha Cheikh-Hussin, Noemie Corcos, Fernanda Mosele, Fabrice Andre, Guillaume Montagnac, Barbara Pistilli
Journal: Journal of Clinical Oncology (2024)

8501 Background: Few treatments with limited benefit are currently available after failure of targeted therapies, immunotherapy and platinum-based chemotherapy in patients (pts) with advanced NSCLC. Dato-DXd is an antibody-drug conjugate (ADC) composed of a TROP-2-directed monoclonal antibody linked to a topoisomerase I inhibitor via a peptide cleavable linker. In the phase 3 TROPION-Lung01 study, Dato-DXd demonstrated a statistically significant improvement of PFS over docetaxel in previously treated pts with advanced NSCLC. Here we report the results of ICARUS-Lung01 (NCT04940325), a multi-center, single-arm, phase 2 study evaluating activity, safety, and biomarkers of response/resistance to Dato-DXd in pretreated pts with advanced NSCLC. Methods: Intravenous Dato-DXd 6 mg/kg was given every 21 days to pts with advanced NSCLC, ECOG 0/1, who progressed on 1-3 lines of therapy (including actionable genomic alteration (AGA)-specific therapy if indicated). All pts underwent fresh tumor tissue biopsies at baseline, on-treatment (week 3 or 6) and end of treatment. Primary endpoint: investigator-assessed confirmed objective response rate (ORR). A set of translational analyses was performed to determine biomarkers associated with response/resistance, including TROP2 tumor membrane expression, TROP2-dynamics and spatial distribution (by AI-digital pathology), genomics, transcriptomic, spatial proteomics (by imaging mass cytometry) and CTCs. Results: A total of 100 pts received ≥1 dose: median age 60 years (26-83); 62% males, 89% smokers, 82% non-squamous (NSQ) histology, 23% AGA, median number of prior therapy lines 2 (1-5). At data cut-off (Dec 04, 2023), 92% discontinued therapy, 92 % had disease event, 67% died. Median treatment duration was 2.8 months (mos) (95%CI, 2.1-4.8), median follow-up 19.4 mos (95%CI, 18.2-20.4). Efficacy and safety results are shown in the table. Conclusions: In this heavily pretreated population, Dato-DXd showed similar efficacy and safety results to those reported in TROPION-Lung01. Patients with NSQ appeared to derive the greatest benefit. Translational analyses to determine biomarkers associated with response and/or resistance will be presented. Clinical trial information: NCT04940325 . [Table: see text]
Analysis of hematology-oncology fellowship match outcomes (2007-2022) and cross-subspecialty comparisons: A retrospective cohort study.
Authors: Sushrut Ingawale, Vaidarshi Abbagoni, Abhiroop Verma, David Regelmann, Praveen Kollipara
Journal: Journal of Clinical Oncology (2024)

9044 Background: The four most sought-after fellowships following Internal Medicine, by volume, are: Hematology-Oncology (HO), Cardiovascular (CV), Gastroenterology (GI), and Pulmonology-Critical Care (PC). This analysis assesses the trends in match outcomes for HO compared to other fellowships, including subset National Residency Match Program (NRMP) outcomes based on applicant types [United States (US) and non-US medical graduates (MDs)]. Methods: This retrospective cohort study analyzes applicants who applied to HO, CV, GI, or PC fellowships for 2007-2022. The analysis is based on publicly available NRMP data for this time. Metrics analyzed include: number of applicants per position, number and type of applicants, number and type of successfully matched applicants, and, corresponding match rates (MR) within each subspecialty. Using the chi-square test, this analysis compared match outcomes between different applicant types. Results: Out of total 55,604 applicants, the distribution across subspecialties was as follows: HO (12,006), CV (19,950), GI (11,693), and PC (11,955). Despite the apparent differences in the total number of applicants for different subspecialties, the number of applicants per position was not statistically significantly different, and decreased from 2007 to 2022 for all subspecialties except PC (+6.7%). As the number of applicants increased, the number of available positions also increased to a substantially higher degree. In 2008, MR ranged from 50-64% across subspecialties, gradually increasing over the years, with HO achieving the highest MR at 73.5% in 2022, compared to PC at 60.7%. USMD graduates consistently had higher MRs compared to non-USMDs (p&lt;0.001) across all subspecialties. Despite this persistent gap over the study's duration, this difference progressively narrowed across all subspecialties, with HO representing the lowest difference (22.1%) and GI the highest (37.2%) in match rates for 2022. Conclusions: The HO fellowship exhibited the highest match rates, closely followed by CV. The proportional increase in HO, CV and GI positions in response to the growing applicants has led to a reduction in the applicants per position, unlike in PC. HO fellowship consistently stands out with the lowest MR disparity among USMDs and non-USMDs. This may represent successful efforts towards equity, diversity and inclusion among programs. [Table: see text]
Molecular profiling across histologies in lung cancer: Time to change WHO nomenclature?
Authors: Alessandro Russo, Manana Javey, Matthew Hiemenz, Benjamin G Kaplan, Stephanie J. Yaung, Richard S.P. Huang, Christian Diego Rolfo
Journal: Journal of Clinical Oncology (2024)

8532 Background: Biomarker testing is essential for optimal therapeutic management of Non-Small lung Cancer (NSCLC). However, a not negligible percentage of patients (pts) is not tested in clinical practice for all the relevant actionable biomarkers. Biomarker testing is recommended in lung adenocarcinoma (LUAD), while in tumors with other histologies it is reserved when clinical features indicate a higher probability of an oncogenic driver. Histopathology report and biomarker testing are usually performed sequentially, which is time consuming and delays patient care. Herein we determined the distribution of actionable biomarkers across NSCLC histotypes and other clinic-demographic characteristics. Methods: This is an observational retrospective analysis on histologically confirmed NSCLC cases tested between 2014-2022 using FoundationOne/FoundationOneCDx assay. Histopathologies of all cases were centrally reviewed and confirmed by Board Certified Anatomic Pathologists. Results: 82,328 NSCLC pts were included. Actionable genomic alterations (GA) were found in 35.1% of the cases (Table). LUAD and adenosquamous (ASC) were more commonly associated with actionable GA (45.8% and 40.9%, respectively) as compared with sarcomatoid (29.1%), not otherwise specified (NOS) (27.6%), large cell (LCC) (21.1%), and squamous cell (LUSC) (6.5%) histologies. Sarcomatoid histology had the highest METex14 skipping mutations (muts) frequency (9.9% vs. 2.4% in LUAD). Tumor mutational burden (TMB) ≥10 Mut/Mb was associated with histology (50.9% in LCC, 40.8% in NOS, 39.1% in LUSC, and 36.3% in sarcomatoid vs. 31.2% in LUAD and 29.2% in ASC). Pts with actionable GA usually had a low TMB (80.9%). A significant correlation (p&lt;0.005) between age and actionable GA was reported for BRAF/ ERBB2 muts, ALK/RET/ROS1 rearrangements (RE), and MET amplification. EGFR actionable muts and KRASG12C were more commonly observed in females, whereas no significant correlation between sex and other GA was observed. Finally, genetic ancestry analyses revealed a strong correlation between EGFR actionable muts and South/East Asian and American ancestries, but not for other GA. Conclusions: This is the largest NSCLC dataset analyzed for biomarker distribution across histologies, age, sex and genetic ancestry. This dataset confirms sufficient enough biomarker prevalence across LUAD and ASC carcinoma to be included in WHO nomenclature for lung tumors, and provides reassurance that cases with NOS, LCC and sarcomatoid histologies must be considered for biomarker workup. [Table: see text]
Association of human leukocyte antigen (HLA) status with immune checkpoint inhibitor (ICI) pneumonitis in patients with non-small cell lung cancer (NSCLC).
Authors: Molly SC Li, Alvin HK Cheung, Zeta Mui, Chit Chow, Yat Ming Lau, Kit Yee Wong, Wei Kang, Ka Fai To, Tony S. K. Mok
Journal: Journal of Clinical Oncology (2024)

8620 Background: Pneumonitis is a potentially serious complication occurring in 5-20% of lung cancer patients receiving ICI. The genetic risk factors for ICI pneumonitis are unclear. Given the association between HLA genetic variants and autoimmune diseases, we hypothesized that certain HLA genetic variants are associated with risk of ICI pneumonitis. Methods: Patients with advanced EGFR/ ALK wild type, PD-L1 tumor proportion score ≥50% NSCLC who received ICI were enrolled from year 2019 to 2022. Germline HLA typing was performed on buccal swab specimens using the Alltype Fastplex assay. Clinicopathological characteristics, treatment courses and survival outcomes were retrospectively collated. The primary endpoint was the correlation of common HLA variants (present in &gt;30% of subjects) to the risk of ICI pneumonitis. Results: 42 patients (all Chinese, 36 male, 33 current/former smokers) were enrolled. Median age was 71 years old (range 51-91). 34, 6, 1 and 1 patients had adenocarcinoma, NSCLC not otherwise specified, squamous cell carcinoma and large cell neuroendocrine carcinoma respectively. Majority (33/42, 79%) received pembrolizumab monotherapy while 9 (21%) patients received pembrolizumab plus chemotherapy. Median follow up time was 27.8 months. At data cutoff, 28 (67%) patients received ICI for more than 1 year and 10 (24%) patients stopped ICI after completion of 2-year course of treatment. Seven (17%) patients developed pneumonitis, of which 3 were grade 2 and 4 were grade 3 in severity. Median time to development of pneumonitis was 6.9 months (range 0.3-25.2). Demographic characteristics were similar between patients who did or did not experience pneumonitis. In the entire cohort, twenty-two (52%) patients harbored the class II DPB1*02 allele. This allele was significantly associated with development of ICI pneumonitis. All 7 patients who had ICI pneumonitis harbored the DPB1*02 allele. The incidence of pneumonitis in patients harboring the DPB1*02 allele was 32% compared to 0% in those without this allele (p=0.009). Patients who experienced pneumonitis had worse survival rates than those without (p=0.03), but expression of DPB1*02 allele was not associated with inferior survival outcomes. Conclusions: Our results suggested that expression of DPB1*02 allele may be associated with development of ICI pneumonitis. A larger case-control study is ongoing to validate this association. [Table: see text]
Real-world treatment patterns and outcomes in US patients (pts) with advanced non-small cell lung cancer (NSCLC) after platinum-based chemotherapy (PBC) and anti–PD-(L)1 treatment.
Authors: Vamsidhar Velcheti, Julia Moore, Huifen Wang, Xinmei Zhu, Yevgeniy Samyshkin, Thomas Ward, Alena Christensen, Caitlyn Solem
Journal: Journal of Clinical Oncology (2024)

8627 Background: Effective treatment options for advanced or metastatic NSCLC are limited, especially for pts who progress after treatment with PBC and an anti–programmed cell death 1 protein (PD-1) or ligand 1 (PD-L1) regimen. Examining real-world treatment patterns and long-term outcomes, we report on progression-free survival (PFS) and overall survival (OS) in pts with NSCLC who previously received PBC and anti–PD-(L)1 regimens. Methods: This study used the nationwide Flatiron Health electronic health record–derived deidentified database. Pts included in the analysis were ≥18 years old with an initial diagnosis of advanced or metastatic NSCLC and an ECOG PS of 0 or 1 who had received prior PBC and anti–PD-(L)1 therapy in 1 (in combination) or 2 (in sequence) lines and had initiated ≥1 subsequent line of treatment between 2018 and 2023; the start date of subsequent treatment (defined as the index regimen) was the index date. Pts were followed up until death or last available data through Mar 31, 2023. Pt characteristics, treatment patterns, and outcomes were analyzed for the overall pt group and according to initial treatment cohort (cohort 1: first-line [1L] PBC plus anti–PD-(L)1; cohort 2a: 1L PBC and second-line [2L] anti–PD-(L)1; or cohort 2b: 1L anti-PD-(L)1 and 2L PBC). PFS and OS were estimated using Kaplan-Meier methods. Results: Of 1793 pts, most were in cohort 1 (73.5%), with fewer pts in cohorts 2a (22.5%) and 2b (4.1%). The majority of pts in cohort 2b had PD-L1 ≥50% (n = 57, 78.1%), while the percentage was lower in cohorts 1 (n = 262, 19.9%) and 2a (n = 72, 17.9%). Most pts (n = 1626, 90.7%) had stage IV disease. Median time from advanced diagnosis to index date was 10.5 months (range, 1.1-103.8); median follow-up from index date was 7.8 months (range, 0.0-65.0). A broad range of treatments were used after PBC and anti–PD-(L)1 regimens; among all pts, the most common were docetaxel + ramucirumab and docetaxel monotherapy. Among all pts, median PFS and OS from the time of starting these index regimens were 5.29 and 11.20 months, respectively; PFS and OS were similar across cohorts. Conclusions: A broad range of subsequent treatments were used following PBC and anti–PD-(L)1 regimens, most commonly docetaxel with or without ramucirumab. Short median PFS and OS underscore a significant unmet need among pts previously treated with PBC and anti–PD-(L)1. [Table: see text]
A phase Ib/IIa trial to evaluate the safety and efficacy of PM8002, a bispecific antibody targeting PD-L1 and VEGF-A, as a monotherapy in patients with advanced NSCLC.
Authors: Chunjiao Wu, Dongqing Lv, Jiuwei Cui, Zhen Wang, Hui Zhao, Huaxin Duan, Ping Duan, Yongmei Yin, Yueyin Pan, Fu-Nan Liu, Chuize Kong, Jian Zhang, Yongsheng Li, Xinpeng Han, Baogang Liu, Lijie He, Zhiquan Qin, Tao Wu, Mei Ji, Ying Cheng
Journal: Journal of Clinical Oncology (2024)

8533 Background: The combination of immune checkpoint inhibitors with chemotherapy has become the first-line treatment for advanced non-squamous NSCLC with negative driver genes, but not for driver gene-positive tumors. PM8002 is a bispecific antibody targeting both PD-L1 and VEGF-A. Previous published data indicated that PM8002 has a tolerable safety profile and potential anti-tumor activity in a variety of solid tumors (SITC2022 abstract #725 and ASCO2023 abstract #2536). Here, we report results of PM8002 in advanced NSCLC patients in an ongoing Phase Ib/IIa trial. Methods: Patients with previously untreated advanced non-squamous NSCLC (EGFR/ALK wild-type and PD-L1+; Cohort 6), advanced non-squamous with EGFR mutations who had failed prior EGFR-TKI treatment (Cohort 7), or EGFR/ALK wild-type who had failed anti-PD-1/L1 therapy and platinum-based chemotherapy regiments (NSCLC IO- and PBC-treated) were enrolled into a Phase I/IIa trial. All patients received PM8002 until observations of unacceptable toxicity, disease progression, or consent withdrawal. Tumor responses were evaluated every 6 weeks. The primary endpoint was objective response rate (ORR), with disease control rate (DCR), progression-free survival (PFS), and safety, as secondary endpoints. Results: As of Dec 20, 2023, 61 patients with advanced NSCLC were enrolled and had at least one tumor assessment. Among 61 evaluable patients 16 partial response (PR) and 32 stable diseases (SD) were observed (all cohorts; see individual cohorts in the table below). Any-grade treatment-related adverse events (TRAEs) occurred in 85.2% patients (52/61) with those ≥ Grade 3 at 18% (11/61). Immune-related AEs (irAEs) occurred in 37.7% patients (23/61). Serious adverse events (SAEs) and treatment-related SAEs were observed in 23% (14/61) and 9.8% (6/61) of patients, respectively. The most common TRAEs (≥15%) were hypertension, hypothyroidism, proteinuria, hypoalbuminemia, hypocalcemia, aspartate aminotransferase increase, and lactate dehydrogenase increase. 8.2% (5/61) of patients discontinued PM8002 due to TRAEs. Conclusions: PM8002 showed preliminary antitumor activity and acceptable safety in patients with advanced NSCLC. Monotherapy and combination trials with chemotherapy for different indications are still ongoing. Clinical trial information: NCT05918445 . [Table: see text]