tbuckley/cabot-search huggingface dataset:
Updated safety and efficacy data of combined KRAS G12C inhibitor (glecirasib, JAB-21822) and SHP2 inhibitor (JAB-3312) in patients with <i>KRAS p.G12C</i> mutated solid tumors.
Authors: Jun Zhao, Jian Fang, Yan Yu, Qian Chu, Xiaoyan Li, Jiayan Chen, Zhe Liu, Li Zhang, Lin Wu, Wu Zhuang, XingYa Li, Yanqiu Zhao, Ligang Xing, Lian Liu, Chunmei Bai, Xiaorong Dong, Qibin Song, Pinghua Pan, Xuefeng Fang, Jie Wang
Journal: Journal of Clinical Oncology (2024)

3008 Background: Resistance to KRAS G12C inhibitor in non-small cell lung cancer (NSCLC) can be overcome by SHP2 blockade. This concept was tested in Phase I study of glecirasib combined with JAB-3312 in patients (pts) with KRAS p.G12C mutated tumors. Promising preliminary data of safety and response were reported at the 2023 ESMO (653O). Here, we present the updated safety and efficacy data with treatment response and progression-free survival (PFS) of the combination therapy in front-line NSCLC. Methods: The phase 1/2a study [NCT05288205] evaluated glecirasib plus JAB-3312 in patients with KRAS p.G12C mutated solid tumors. The primary objective of the dose-escalation phase was to assess the safety and tolerability of the combination therapy, and the primary objective of the dose-expansion phase was to assess efficacy. Efficacy endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), PFS by investigator per RECIST1.1 and overall survival. Glecirasib 400 mg or 800 mg daily was combined with various JAB-3312 doses and schedules. Results: As of December 1 st , 2023, 179 pts were enrolled, including 157 with NSCLC, 17 with colorectal cancer, and five with other tumor types. Treatment-related adverse events (TRAE) ≥ grade 3 occurred in 41.9% of all pts. There were no treatment-related deaths. Discontinuation of either glecirasib or JAB-3312 due to TRAE occurred in 7.8% of all pts. The AE profile was unchanged from the last ESMO report. The most common ( &gt; 20%) TRAEs included anemia, ALT/AST increased, hypertriglyceridemia, bilirubin increased, neutropenia/leukopenia, creatine kinase increased, and edema. No overlapped toxicity was observed for this combination therapy. Amongst all pts enrolled, 88 had NSCLC and received the combination therapy as front-line treatment in seven dosing groups. The median follow-up duration was 6.1 (range:0.5-16.7) months. Eighty pts had at least once post-treatment efficacy assessment. The ORR was 72.5% (58/80) and DCR was 96.3% (77/80). In the group of glecirasib 800mg QD + JAB-3312 2mg one week on/one week off, the ORR was 77.8% (21/27) and DCR was 92.6% (25/27). The median PFS was not mature by the data cut-off date. The 6-month and 12-month PFS rate were 67.3% and 53.7%, respectively. Additional safety and efficacy data will be presented at the meeting. Conclusions: Glecirasib plus JAB-3312 has a manageable safety profile and a promising ORR and PFS as a front-line treatment for patients with KRAS p.G12C NSCLC. This combination will be further evaluated in a randomized phase III trial in NSCLC. Clinical trial information: NCT05288205 .
The anti-CD20 antibody-drug conjugates TRS005 in relapse/refractory CD20-positive B-cell non-Hodgkin lymphoma: A multicenter, open-label, single-arm, phase I study.
Authors: Yuankai Shi, Zhiming Li, Yan Qin, Yufu Li, Keshu Zhou, Huilai Zhang, Ling Li, Youchao Jia, Xiangmin Tong, Xinquan Liang, Yongdong Zhang, Kunyan Li, Hui Zhou, Shuling Hou, Zengjun Li, Yuerong Shuang, Peng Liu, Lin Gui
Journal: Journal of Clinical Oncology (2024)

3026 Background: TRS005 is a novel anti-CD20 antibody-drug conjugate targeting CD20 positive tumor cells to deliver MMAE into the cells via receptor-mediated endocytosis. The aim of this study was to evaluate the safety, pharmacokinetics, and anti-tumor activity of TRS005 in relapse/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). Methods: This first-in-human, single arm, multicenter, phase I, dose-escalation and expansion study conducted at 28 hospitals in China. The eligible patient had histologically confirmed CD20 positive B-cell lymphoma and had failed ≥2 prior lines of standard treatment. The dose-escalation phase involved 6 dose cohorts (from 0.1mg/kg to 2.1mg/kg) following a 3+3 design. Patients received TRS005 intravenously on day 1 of each 21-day cycle for 6 cycles. The dose cohort in which partial response (PR) or complete response (CR) was observed entered the dose-expansion phase. The safety, tolerability and efficacy of TRS005 were evaluated every two cycles. The primary endpoints were safety and pharmacokinetics. Secondary endpoints were objective response rate (ORR), disease control rate (DCR) and progression free survival (PFS) assisted by investigators. Results: From Aug 24 th ,2020 to Oct 23 th ,2023, 130 R/R B-cell NHL patients received treatment. The dose limiting toxicity was observed in the first patient in the 2.1mg/kg dose group during the dose-escalation phase. 70 patients had R/R diffuse large B cell lymphoma (DLBCL). Of the 70 R/R DLBCL patients, the median age was 59 (25-83) years, 82.9% of patients were in stage III-IV and 98.6% of patients received at least 2 lines of treatment (except one patient who only received 1 line of previous treatment). Overall, 88.6% of patients experienced all grades adverse events (AEs). Treatment-emergent adverse events (TEAEs) of ≥grade 3 occurred in 65.7% of patients, hematologic TEAEs were the most common. Two patients withdraw the treatment due to TEAEs and no TEAE related death were observed. At the data cutoff date of Nov 17 th , 2023, the median treatment duration was 4 (1-27) cycles. 58 patients were evaluated for efficacy and confirmed ORR was 46.6%, with a DCR of 75.9%. The highest ORR was seen in 1.8mg/kg dose cohort, with an ORR and DCR of 56.7% and 86.7%, respectively. The PFS was 5.6 (95% CI: 4.2-17.4) months and 12-month PFS was 35.1%. Conclusions: TRS005 is well-tolerated and exhibits encouraging anti-tumor efficacy in the treatment of R/R DLBCL. Clinical trial information: NCT05395533 . [Table: see text]
Clinical validation of Northstar Select, a novel liquid biopsy assay for comprehensive genomic profiling of solid tumors.
Authors: Xavier Bower, Jan Wignall, Joyce Zhu, Michael O'Sullivan, Naomi Searle, Lenny Hong, Matthew Gordon Varga, Jason Luong, Esther Lin, Marie Erica Simon, David Tsao, John ten Bosch, Wen Zhou
Journal: Journal of Clinical Oncology (2024)

3072 Background: Comprehensive Genomic Profiling (CGP) liquid biopsy tests are vital tools for oncologists that enable the non-invasive detection of diverse somatic mutations, many of which correspond to targeted therapies, in circulating tumor DNA (ctDNA). However, these tests have less utility when ctDNA signal is low, which is common even in late-stage cancer patients. BillionToOne’s Northstar (NS) Select assay is a novel CGP test that seeks to leverage proprietary technology and novel calling algorithms to address this limitation by achieving higher sensitivity. Methods: Clinical samples for 182 unique patients with stage III or IV solid tumors were obtained via a prospective validation study assessing head-to-head concordance with widely adopted, commercially available ‘comparator’ liquid biopsy CGP assays. The study cohort was recruited from 1 large hospital center and 6 community clinics across the US and was diverse in patient demographics and clinical presentations. Over 15 different cancer types were represented in the cohort, with the majority of patients having either Lung, Breast, Colorectal, or Prostate cancer, all of which are commonly tested using liquid biopsies in the US. Pathogenic (including likely pathogenic) variants called by NS Select and/or the comparator assay were analyzed for concordance. For a subset of samples (N=28), white blood cell-derived genomic DNA was also processed to identify which variants were detected due to clonal hematopoiesis of indeterminate potential (CHIP). Results: In the head-to-head comparison, a large number of variants (N=380) were concordant between the two assays. In addition, NS Select detected 43% (N=147) more pathogenic variants than comparators when controlling for matched coverage regions. The majority of these variants were detected below the reported limit of detection of the comparator assays, but above the limit of detection of NS Select. The rate of CHIP mutations was not significantly different in the variants detected by NS Select (19.0% ± 7.6%) vs. comparators (17.2% ± 9.2%). Finally, the proportion of patients with no pathogenic variants detected was shown to be lower by 45% when using NS Select vs. the comparator assays (20/182 vs. 36/182). Conclusions: NS Select reported clinically useful information about the tumor for most patients. For patients in which ctDNA signal was high, NS Select had very high concordance with comparator tests. Furthermore, additional low-VAF pathogenic mutations identified by NS Select translated to a higher diagnostic yield compared to other CGP assays, and CHIP was ruled out as an explanation for these additional detections. This suggests that some patients with low levels of ctDNA would derive clinical benefit from testing with NS Select due to its high sensitivity.
Performance characteristics of a tissue-agnostic genome-wide methylome enrichment MRD assay for head and neck malignancies.
Authors: Geoffrey Liu, Martha Pienkowski, Shao Hui Huang, Laurie Ailles, Katrina Rey-McIntyre, Jun Min, Yarong Wang, Justin Burgener, Joshua T. Jones, Ben Brown, Junjun Zhang, Owen Hall, Shu Yi Shen, Jeremy B. Provance, Eduardo Sosa, Jing Zhang, Abel Licon, Brian Allen, Anne-Renee Hartman, Daniel D. De Carvalho
Journal: Journal of Clinical Oncology (2024)

3009 Background: Plasma cell-free DNA (cfDNA) tests have emerged as a promising approach for cancer management. cfDNA methylome approaches are well-suited for molecular residual disease (MRD) detection. Here we present data using a tissue-agnostic, genome-wide methylome enrichment platform based on cell-free methylated DNA immunoprecipitation and high throughput sequencing (cfMEDIP-seq) in head and neck cancer (HNC) to predict relapse for purposes of guiding adjuvant therapy after completion of curative-intent treatment and to detect early relapse. Methods: The cohort is comprised of biobanked samples from individuals diagnosed with stage I-IVB human papillomavirus (HPV)-negative and HPV-positive HNC with longitudinal data collection and sampling. The full cohort includes 325 unique patients with 1,155 samples. Samples were split into distinct sets to train and test a classifier consisting of differentially methylated regions. Blood collection time points include at diagnosis, and approximately 3 (landmark), 12 and 24 months after curative intent treatment. 5-10 ng of cfDNA isolated from each plasma sample was used for cfMEDIP-seq. MRD signals were quantified from average normalized counts across informative methylated regions and binarized into a positive (above the threshold) and negative groups. Recurrence-free survival (RFS) was compared for patients who tested positive to those who tested negative at 3 months post-curative treatment (i.e., landmark timepoint) and longitudinally. Results: A total of 196 post-treatment samples from 80 unique patients [stage I (35%), II (15%), III (24%), IV (26%)] were analyzed and correlated with recurrence, in this interim training result. At the landmark timepoint, patients who tested positive showed significantly worse RFS than those who tested negative (Hazard ratio (HR) 9.69; 95% CI, 4.39-21.4, P&lt;0.001). Incorporating serial longitudinal samples, recurrence-free survival was worse in patients who tested positive compared to those that tested negative (HR 14.52; 95% CI, 5.78-36.46, P&lt;0.001). Conclusions: Interim analysis demonstrates that MRD detection with a tissue-agnostic, genome-wide methylome enrichment platform in HNC patients after curative intent treatment correlates strongly with RFS with hazard ratios consistent with tumor-informed assays previously described. Updated analyses from the cohort will be presented at the meeting.
Cold-inducible RNA-binding protein as a context-specific functional mediator of breast cancer metastasis.
Authors: Matthew Dankner, Veronique Ouellet, Jakob Lafon, Rima Ezzeddine, Matthew G Annis, Peter M Siegel
Journal: Journal of Clinical Oncology (2024)

3136 Background: Cold-inducible RNA-binding protein (CIRBP) is a stress-induced mRNA-binding protein associated with clinical outcomes in a variety of human disease states. CIRBP’s role as a prognostic biomarker in breast cancer (BC) has yet to be established. Methods: We describe a clinically annotated tissue micro-array cohort of 1406 hormone receptor positive (HR+) and 281 triple negative primary breast cancers (TNBC) stained by immunohistochemistry (IHC) for CIRBP. Statistical analyses were performed with the Kaplan-Meier estimator, as well as univariate and multivariate Cox proportional-hazards models. Multivariate models incorporated tumor size, lymph node status, grade and CIRBP expression levels. Co-primary endpoints were overall survival (OS) and progression-free survival (PFS). MDA-MB-231 TNBC cells and MDA-MB-361 HR+ cells were used for CIRBP knockout (KO) by CRISPR/Cas9, and subsequent mammary fat pad injections were performed in immunocompromised mice. Results: In N=281 primary TNBCs, high levels of CIRBP expression by IHC was associated with poor prognosis in multivariate analysis (OS: adjusted hazard ratio (aHR) 2.05, 95% confidence interval (CI) 1.24-3.41, P=0.005. PFS: aHR 2.46, 95% CI 1.33-4.57, P=0.004). However, in N=1406 HR+ primary BC, CIRBP expression was correlated with favorable prognosis (OS: aHR 0.927, 95% CI 0.88-0.98, P=0.05. PFS: aHR 0.904, 95% CI 0.85-0.96, P=0.002). CIRBP KO had minimal impact on mammary fat pad primary tumor growth in both MDA-MB-231 and MDA-MB-361 cell models. However, CIRBP KO resulted in the inhibition of efficient spontaneous metastasis to the liver and lungs in TNBC MDA-MB-231 cells but not HR+ MDA-MB-361 cells. Conclusions: CIRBP expression is associated with poor prognosis in TNBC but not HR+ BC patients, a finding validated with CRISPR/Cas9 KO in representative model systems. This finding highlights the prognostic significance of CIRBP in TNBC and suggests differential underlying mRNA targets bound and modulated by CIRBP in TNBC and HR+ BC, respectively.
Phase II study to evaluate safety and efficacy of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, and trastuzumab biosimilar in patients with HER2 mutated advanced solid tumors (KCSG AL20-17).
Authors: Kyoungmin Lee, Kyung-Hun Lee, Dong-Wan Kim, Jeesun Yoon, Wonyoung Choi, Youngjoo Lee, Yoon Ji Choi, Soohyeon Lee, Ju Won Kim, Hyewon Ryu, Dong-Hoe Koo, Yun-Gyoo Lee, Hei-Cheul Jeung, Min-Young Lee, Namsu Lee, Myoung Joo Kang, Ji Eun Lee, Sook Hee Hong, Eun Joo Kang, Inhae Park
Journal: Journal of Clinical Oncology (2024)

3134 Background: Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has single agent clinical activity in HER2 mutated cancer. This open-label single arm phase 2 trial investigated the efficacy and safety of the dual anti-HER2 therapy, neratinib plus trastuzumab in heavily pretreated patients with HER2 mutated solid tumors excluding HER2 amplifications. Methods: Neratinib was administered 240mg p.o. daily with trastuzumab biosimilar (Herzuma) every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST v1.1. Secondary endpoints were duration of response (DoR), progression free survival (PFS), and safety. An exploratory biomarker study was also conducted. Results: Forty patients were enrolled with a median follow-up of 11.08 months (range, 0.39-21.63 months) and a median of 3 (range 1-9) lines of prior systemic therapy. Tumor types included lung (42.5%), colorectal (20%) biliary (12.5%), and breast (7.5%). Sixty percent (60%) of patients (n=24) had HER2 mutation in the kinase domain. Among evaluable patients (n=39), the ORR was 23.1% (CR=0, PR=9) with a median DoR of 11.18 months (95% CI 0-22.63). Median PFS was 3.42 months (95% CI 1.57-5.27) and median overall survival was 9.47 months (95% CI 2.93-16.01). Grade ≥3 adverse events (AEs) occurred in 47.5% of patients (n=19) and diarrhea was the most frequently reported AE (n=10; 25%) followed by bilirubin elevation (n=2; 5%), and anemia (n=2; 5%). Conclusions: In heavily pretreated patients with HER2 mutated solid tumors, neratinib plus trastuzumab showed a moderate response rate, with a durable duration of response. Most AEs were manageable, highlighting the need for prophylactic diarrhea management. Exploratory biomarker results will be presented at the upcoming meeting. Clinical trial information: NCT06083662 .
Safety and efficacy of immune checkpoint inhibitors (ICI) in patients (pts) with pre-existing neurologic autoimmune diseases (NAID) and Parkinson's disease.
Authors: Kylie Fletcher, Amin Nassar, Alexander M. Menzies, Georgina V. Long, Frank Aboubakar Nana, Andrea Malgeri, Alessio Cortellini, Shailee Shah, Jessica Cecile Hassel, So Yeon Kim, Abdul Rafeh Naqash, Pavan Challa, Douglas Buckner Johnson
Journal: Journal of Clinical Oncology (2024)

2653 Background: Patients with pre-existing NAID often flare with ICIs; neurological (neuro) immune related adverse events (irAEs) are often morbid or fatal, and little is known about safety of ICI in pts with NAID and other neuro conditions (e.g. Parkinson’s). Thus, we aimed to determine their safety and efficacy in these contexts. Methods: We retrospectively analyzed 71 pts from 5 institutions receiving ICIs with NAIDs and Parkinson’s disease. NAIDs included multiple sclerosis (MS), myasthenia gravis (MG), inflammatory neuropathy, transverse myelitis, Lambert-Eaton, myotonic dystrophy, and multifocal motor neuropathy. We collected demographics, cancer outcomes, NAID characteristics, and safety outcomes. We used descriptive statistics to analyze treatment outcomes, NAID flares, and irAEs. Results: We collected 71 pts, 40 with NAID and 31 with Parkinson’s. 24 had melanoma, 12 non-small cell lung cancer (NSCLC), 3 small cell lung cancer (SCLC), 6 urothelial/bladder, 4 renal cell carcinoma, and 22 other; 60 had metastatic and 11 had localized disease. Median age at ICI start was 72 years (61% male, 39% female); 8 received combination ICI and 63 received monotherapy. Of 40 pts with NAID, 30% had either NAID flares or neurologic irAEs and 33% experienced other (non-neuro) irAEs (Table). Toxicities were particularly severe in MG; 70% (n=7) had MG flare/neuro irAE, 3 of which were fatal. In addition, 31 had Parkinson’s; of these, 12.9% (n=4) had Parkinson’s flares, 3% (n=1) had neuro-irAEs, and 42% (n=13) had other irAEs. One pt died of grade 5 myocarditis/myositis following combination ICI (Table). 5 MS patients responded to therapy (23%), but none were those with NAID flare/neuro irAE. Both MG patients who had non-neuro irAEs responded to treatment. Conclusions: In this cohort of ICI treated pts with prior neuro disorders, we demonstrated that MG pts have high rates of MG flare/neuro irAEs, hospitalizations, and fatalities, but low response rates. In contrast, other NAID (particularly MS) as well as Parkinson’s appeared to have modest risks of flares/neuro irAEs. Notably, Parkinson’s pts had high rates of non-neuro irAEs and response rates. [Table: see text]
Artificial intelligence (AI) -powered H&amp;E whole-slide image (WSI) analysis of tertiary lymphoid structure (TLS) to predict response to immunotherapy in non-small cell lung cancer (NSCLC).
Authors: Leeseul Kim, Sangwon SHIN, Soo Ick Cho, Wonkyung Jung, Sanghoon Song, Liam IL Young Chung, Chan-Young Ock, Young Kwang Chae
Journal: Journal of Clinical Oncology (2024)

3135 Background: Recent data indicate that immune cells present in the TLS within the tumor microenvironment (TME) could potentially serve as a favorable predictor for immune checkpoint inhibitor (ICI) therapy. To examine this further, AI model was created to provide an assessment of TLS in H&amp;E WSI, and to determine its correlation with survival outcomes of NSCLC patients treated with ICI. Methods: We collected H&amp;E-stained WSI of primary and metastatic tumors and clinical data in a retrospective study of advanced-stage NSCLC patients treated with ICI (with or without chemotherapy) at Northwestern University from May 2015 to November 2022. When evaluating the TLS status in the biopsy specimen collected from the lymph nodes (LNs), TLSs were only considered if they were admixed with tumor cells and located distant from the residual parenchyma, ensuring the exclusion of innate lymphoid follicles. Following the assessment of the presence of TLS by a pathologist, the identical WSIs were evaluated by the AI-powered H&amp;E WSI analyzer. We used Lunit SCOPE IO, an AI-powered H&amp;E WSI analyzer developed using 21,096 H&amp;E stained WSIs, which can segment various classes of tissue area including TLS within the TME. Survival analysis was performed using Kaplan-Meier curves, and differences in survival outcomes among TLS groups were evaluated using the log-rank test. Results: In this analysis, out of a total of 73 patients, 24 (33%) cases were identified as containing TLS (TLS +) by the AI analyzer. In contrast, the pathologist classified 17 (23%) cases as TLS+. The AI model demonstrated an accuracy of 84.9% (with a sensitivity of 88.2% and specificity of 83.9%) in identifying the presence of TLS compared to the pathologist's interpretation. The median value of the proportion of TLS area within TME (TLSP) in samples containing TLS was 0.418% (Q1: 0.228%, Q3: 1.311%). TLSP was not found to be correlated with survival outcomes. The number of clusters of TLS was not found to be correlated with survival outcomes. Conclusions: AI-powered TLS analysis can be potentially utilized as a predictive biomarker of survival outcomes of NSCLC patients treated with ICI. [Table: see text]