tbuckley/cabot-search huggingface dataset:
Cardiovascular complications associated with asciminib use: A retrospective analysis.
Authors: Saloni Savani, Arpita Pawa, Himil Mahadevia, Samip R. Master
Journal: Journal of Clinical Oncology (2024)

6563 Background: Asciminib, a newly developed drug, has shown promising results in the treatment of several diseases. It is a cellular tyrosine kinase inhibitor (TKI) that specifically targets ABL myristoyl pocket (STAMP) inhibitor, responsible for the malignant growth and proliferation of leukemia cells in chronic myeloid leukemia (CML) patients, assuring a positive treatment of CML. However, as with all medications, there are possible side effects that must be carefully monitored. In comparison to Ponatinib (tyrosine kinase inhibitor) which is extensively used to treat CML and exhibits a cardiovascular risk profile, cardiovascular side effects with the use of Asciminib are rarely reported in literature, prompting its use in patients at a higher risk of these events. Through this study, we aim to highlight the cardiovascular complications associated with the use of Asciminib by integrating patient experience and clinical research. Methods: A publicly available FDA Adverse Events Reporting System (FAERS) database was utilized to review cardiovascular events associated with the use of Asciminib in patients with Chronic Myeloid leukemia (CML) between 2018-2023. Cardiovascular events such as coronary artery disease (CAD), peripheral arterial disease (PAD), and cerebrovascular accidents (CVA) were reviewed. The study focused only on adverse events reported by healthcare providers and observed in adults (above 18 years old). Results: We identified a total of 563 adverse events pertaining to the use of Asciminib in patients with CML. Of which, 63 were cardiovascular events, contributing to 11.2% of the total adverse events. Out of the reported cardiovascular side effects, 29 (46%) were due to CAD, 6 (9.5%) were due to PAD, and 28 (44.45%) were due to CVA. The mortality rate amongst patients who experienced cardiovascular side effects was 11%. Moreover, cardiovascular events contributed to 7% of all mortality associated with the use of Asciminib, with CAD contributing to most of the deaths. Conclusions: It is imperative to consider the potential of cardiovascular events in patients initiated on Asciminib. This study emphasizes the importance of using patient records and medical research to obtain complete information. Patients with underlying risk factors for the development of cardiovascular diseases should be thoroughly evaluated before drug initiation. The minimum threshold for drug discontinuation should be considered in patients with suspected heart disease.
Therapeutic activity of a new KRAS<sup>G12C</sup> inhibitor JMKX001899 in brain metastases: Preclinical models of KRAS<sup>G12C</sup>-mutant non-small cell lung cancer.
Authors: Danming He, Jie Wang, Yixiang Zhu, Jia Zhong, Hua Bai
Journal: Journal of Clinical Oncology (2024)

8630 Background: Development of therapies targeting KRAS have transformed KRAS from undruggable to druggable. However, patients with KRAS G12C -mutant non-small cell lung cancer (NSCLC) with brain metastasis (BM) have a poor prognosis. JMKX001899, a new potent oral small-molecule KRAS G12C inhibitor, irreversibly and selectively binds KRAS G12C , locking it in its inactive state. Its antitumor activity in the intracranial is unclear. Methods: In order to verify the activity of new KRAS G12C inhibitor JMKX001899 in KRAS G12C -mutant NSCLC with BM, murine models were employed for investigating the efficacy. 5-6 weeks old female Balb/c nude mice were implanted intracranially with H358-Luc and H23-Luc cells. Baseline bioluminescent imaging (BLI) was used to monitor the tumor burden and total flux was calculated by Living Image. Ten days after implantation, oral once-daily dosing of vehicle, sotorasib (AMG510) at 100 mg/kg, 30 mg/kg and JMKX001899 at 100 mg/kg, 30 mg/kg, 10 mg/kg was started and continued for 21 days. The tumor burden was monitored by BLI weekly. The mice were weighed per 3 days. Results: At the 30mg/kg and 100mg/kg dose level, the mean cerebrospinal fluid (CSF)-to-unbound plasma ratios (K p,uu ) was 0.18-0.50, which determined JMKX001899 CSF exposure was sufficient to mediate regression tumors in experimental BM models. In mice bearing intracranial xenografts of H358-Luc and H23-Luc, oral JMKX001899 100mg/kg once daily treatment for 21 days resulted in significant inhibition of brain tumor growth revealed by BLI, compared with vehicle and AMG510. H358-Luc xenografts responded particularly well to the JMKX001899 treatment, showed by the ratio of 14 days and 0 days total bioluminescence flux (vehicle vs. AMG510 100mg/kg vs. JMKX001899 100mg/kg, 0.85 vs. 0.89 vs. 0.01, p &lt; 0.05). In addition, JMKX001899 at 100mg/kg once daily demonstrated an increase in over survival. JMKX001899 100 mg/kg once daily treatment was well tolerated with minimal sign of overt toxicity or animal weight loss. Conclusions: The preclinical models in vivo suggest the new KRAS G12C inhibitor JMKX001899 penetrates the central nervous system and show great inhibition of KRAS G12C -mutant NSCLC with BM, which demonstrates therapeutic activity of JMKX001899 in BM. These data support further development of JMKX001899 in patients with KRAS G12C -mutant NSCLC with BM.
Clinical impact of the rapid genomic screening platform for non-small cell lung cancer in Asia-Pacific (LC-SCRUM-AP).
Authors: Shigeki Umemura, Chih-Hsi Kuo, Virote Sriuranpong, Muthukkumaran Thiagarajan, Charuwan Akewanlop, Yuri Murata, Yuji Shibata, Methaneethorn Prae, Tatsuya Ikeda, Kaori Egami, Genevieve Chase, Christer Svedman, Takashi Seto, Hiroki Izumi, Shingo Matsumoto, Koichi Goto
Journal: Journal of Clinical Oncology (2024)

8637 Background: In 2013, a lung cancer genomic screening project (LC-SCRUM-Asia) started in Japan and expanded to other Asia-Pacific countries in October 2022 (LC-SCRUM-AP). The objective of this study is to clarify the characteristics of genomic profile in Asia-Pacific countries outside of Japan and to elucidate the clinical significance of rapid genomic screening. Methods: To shorten the turnaround time (TAT), a central laboratory was set in each participating country. Samples are analyzed by a multi-gene PCR assay and a rapid next-generation sequencing assay. Clinical, pathological and genomic data are stocked as a clinical-genomic database in each participating country, which is combined with Japanese database and the integrated clinical-genomic database of the Asia-Pacific region was established. Results: A multi-gene PCR assay data was available in 7879 samples from 4 Asia-Pacific countries (Taiwan/Thailand/Malaysia/Japan = 126/65/30/7658 pts). The rates of driver alterations in never-smokers with non-squamous histology were similar in the 4 Asia-Pacific countries: 83%, 80%, 89% and 75% in Taiwan, Thailand, Malaysia, and Japan, respectively. The pattern of genomic profile was also similar among these 4 countries. The median TAT was 4 days and 5 days in Japanese cohort and Taiwan/Thailand/Malaysia cohort, respectively. In Taiwan/Thailand/Malaysia cohort (n = 221), the genomic analysis successful rate was 99.5%. The rates of genomic alterations detected: EGFR (35%) of which ex20ins (6%), KRAS (10%) of which G12C (4%), ALK fusions (6%), ROS1 fusions (4%), RETfusions (0.5%), HER2ex20ins (4%), MET ex14skip (3%), BRAF V600E (1.5%), and NTRK3 fusions (0.5%). Oncogenic driver alterations were detected in 149 pts, of which 102 (68%) pts received targeted therapies approved in each country. 14 patients were enrolled into clinical trials of the investigational drugs, of which 5 were for targeting rare driver alterations. Conclusions: LC-SCRUM-AP is the first international genomic screening platform established in the Asia-Pacific region, which enables the efficient detection of rare driver alterations with a short TAT, contributing to the high implementation rate of targeted therapies. The similar pattern of genomic profile in the 4 Asia-Pacific countries indicates the utility of this screening platform as the basis for the clinical trials for NSCLC with rare driver alterations. We plan to further expand the number of institutions and participating countries.
Alcohol-associated liver disease: Emerging therapeutic strategies
Authors: Benjamin H. Mullish, Mark R. Thursz
Journal: Hepatology (2024)

The large and growing burden of alcohol-associated liver disease—and the considerable burden of morbidity and mortality associated with it—has been a drive toward ongoing research into novel strategies for its treatment, with a particular focus upon alcohol-associated hepatitis (AH). Management of alcohol-use disorder forms the central pillar of alcohol-associated liver disease care, with evidence-based psychological and pharmacological approaches being well established, and certain models demonstrating improved clinical outcomes when hepatology and addiction services are co-located. Corticosteroids have previously been used somewhat indiscriminately in patients with severe AH, but effective tools now exist to assess early response (and limit futile ongoing exposure). Techniques to predict risk of corticosteroid-related infection are also available, although current clinical strategies to mitigate this risk are limited. A variety of novel therapeutic approaches to AH are at different phases of trials and evidence gathering, with some of the most promising signals related to cytokine manipulation, epigenetic modulation, and targeting of the gut microbiota (ie, by means of fecal microbiota transplant). While remaining an ongoing source of debate, early liver transplant in severe AH has grown in interest and acceptability over the past decade as evidence supporting its efficacy builds, in the process challenging paradigms about mandatory pretransplant sobriety periods. However, uncertainty remains regarding the optimal selection criteria, and whether liver transplant has a role for only a highly limited proportion of patients with AH or more widespread application. This review aims to provide an overview of this fast-moving field.
Characterization of DNA damage repair (DDR) alterations and the tumor immune microenvironment (TIME) in advanced non-small cell lung cancer (NSCLC).
Authors: Kamya Sankar, Jacob Mercer, Ellen B. Jaeger, Jen Godden, Jonathan David Berkman, Edward Williams, Michael A. Thompson, Shetal Arvind Patel, Karen L. Reckamp, Frank Weinberg
Journal: Journal of Clinical Oncology (2024)

8603 Background: Exploiting the DDR pathway with synthetic lethality agents such as PARP inhibitors has been clinically validated in several cancers. In NSCLC, novel agents leveraging defects in the DDR pathway are being studied alone and in combination with checkpoint inhibitors. To expand on combination approaches and inform biomarker selected strategies, we analyzed DDR alteration prevalence and impact on the TIME in metastatic NSCLC. Methods: We retrospectively analyzed de-identified next-generation sequencing data from patients (pts) with metastatic NSCLC in the Tempus Database. Tumors were sequenced with the Tempus xT DNA and xR RNA assays. DDR pathway genes were defined as previously described (PMID 29617664). Pts were stratified based on the presence (DDRmt) or absence (DDRwt) of a pathogenic somatic alteration or copy number deletion in a DDR pathway gene. The associations of DDR alteration with immune cell infiltration predicted from gene expression patterns, PD-L1 from IHC, TMB (TMB-H, &gt;10 mut/Mb), and microsatellite instability (MSI) were examined. Wilcoxon rank-sum and Pearson’s Chi-squared/Fisher's exact tests were used to assess statistical significance (p&lt;0.05, q&lt;0.05 for false discovery rate correction for multiple testing). Results: Across 14,127 samples, 5,255 (37%) were DDRmt and 8,872 (63%) were DDRwt. The median age at diagnosis was 67 (IQR 60-74). Current/former smokers (83%; n=10,445) had a higher prevalence of DDRmt (86% vs. 82%; p&lt;0.001). The most prevalent DDRmt was SMARCA4 (18%), followed by PTEN (13%), BRCA2 (11%), ATM (9.0%), ERCC3 (6.6%), PMS2 (6.0%), and MUTYH (5.1%). TMB-H was more common (18% [n=931] vs. 11% [n=1001]; p&lt;0.001) and median TMB was higher (5.4 vs. 4.6; p&lt;0.001) in DDRmt pts compared to DDRwt. MSI-H was more prevalent in the DDRmt group (1.1% [n=57] vs. &lt;0.1% [n=7]; p&lt;0.001), while PD-L1 positivity was similar in DDRmt and DDRwt pts (55% [n=1918] vs. 58% [n=3314]; p=0.071). Compared to DDRwt, pts with DDRmt exhibited modest changes in immune cell infiltration patterns (Table). Conclusions: In this large, real-world cohort of pts with metastatic NSCLC, DDRmt was associated with distinct TIME patterns including high TMB, MSI-H, and modest changes in immune cell infiltrates. These findings warrant further studies to understand how DDR pathway alterations mediate changes in the TIME to inform novel combinatorial immunotherapeutic approaches in NSCLC.[Table: see text]
A multi-center cohort study Examining risk factors for central nervous system metastases (CNSm) in patients with stage III non-small cell lung cancer (NSCLC) treated with definitive chemoradiation (ChemoRT) followed by durvalumab (Durva).
Authors: John Sharp, Philip Young, Songzhu Zhao, Sandip Pravin Patel, Lai Wei, Mingjia Li, Jeremy Brownstein, Karl Haglund, Joshua David Palmer, Raju R. Raval, Peter G. Shields, Kai He, Jacob Kaufman, Regan Michelle Memmott, Asrar Alahmadi, David Paul Carbone, Gregory Alan Otterson, Carolyn J. Presley, Ryan D. Gentzler, Dwight Hall Owen
Journal: Journal of Clinical Oncology (2024)

8076 Background: In the PACIFIC trial, 6.3% of patients with unresectable stage III NSCLC receiving durva after chemoRT developed CNSm. In a single center study, we previously reported real-world incidence of CNSm is higher at 19.8%. Risk factors for development of CNSm post-durva are incompletely understood. Methods: We conducted a multi-center retrospective study of patients with unresectable stage III NSCLC treated with durva after chemoRT from 2018 to 2022 with no CNSm on baseline brain MRI to assess for incidence of CNSm. Patient characteristics were compared between cohorts with and without CNSm to assess for risk factors for CNSm using Fisher’s exact test for categorical variables and two-sample t-test or Wilcoxon Mann-Whitney U-test for continuous variables. Overall survival was compared using log-rank test. Results: Of 193 patients in our study, 32 (16.6%) developed CNSm with median time to CNSm of 6.4 mo (IQR 4.5 - 13.7). Twenty-five (78%) had CNSm within one year. Patients with CNSm had a longer interval between baseline brain MRI and start of durva (median 3.7 mo vs 3.3 mo, p=0.02) and received fewer doses of durva compared to those without CNSm (median 7 vs 12, p=0.03). As some patients received Q2 week and others Q4 week durva, we also compared median durva treatment duration, which was consistent (3.7 mo vs 8.3 mo, p=0.02). There was no association between CNSm and age, sex, histology, T/N stage, PDL1 status, or chemoRT regimen (Table). Patients with CNSm had shorter median survival (19.6 mo vs 36.4 mo, p=0.008). Conclusions: Real-world incidence of CNSm is higher than that seen in PACIFIC. Patients with CNSm received less durva, likely due to early disease progression, and had longer intervals between baseline brain MRI and starting durva. Minimizing treatment delays may improve outcomes. Further research is needed to understand optimal surveillance strategies for CNSm in this patient population. [Table: see text]
Safety and efficacy of ifebemtinib (IN10018) combined with D-1553 in non-small-cell lung cancer (NSCLC) with KRAS G12C mutation: Results from a phase Ib/II study.
Authors: Zhengbo Song, XingYa Li, Rongbo Lin, Yuan Yuan, Huaqiu Shi, Ying Liu, Yongzhong Luo, Tangfeng Lv, Yiping Zhang, Yinxin Zhu, Zaiqi Wang
Journal: Journal of Clinical Oncology (2024)

8605 Background: KRAS G12C mutation is present in about 12-14% of NSCLC population. Ifebemtinib (IN10018) is a highly potent and selective oral inhibitor of focal adhesion kinase (FAK). D-1553 (garsorasib) is a novel oral and potent KRAS G12C inhibitor. Preclinical data showed that ifebemtinib in combination with KRAS G12C inhibitors had synergistic anti-cancer effect in multiple KRAS G12C mutant cancer models. This study is to evaluate the safety and antitumor activity of ifebemtinib combined with D-1553 in solid tumors with KRAS G12C mutation. Here we report the preliminary data from phase II part of front-line NSCLCs with KRAS G12C mutation. Methods: Locally advanced or metastatic NSCLC subjects without prior systemic anti-cancer therapy were enrolled. Subjects were required to have KRAS G12C mutation in tumor tissues. All subjects were assigned to the recommended phase II dose (RP2D) of ifebemtinib (100mg qd) + D-1553 (600mg bid). Results: As of 31 January 2024, 33 front-line NSCLC subjects with KRAS G12C mutation were enrolled and received the combination therapy. Median age was 65yrs (range 58, 83), 93.9% were male, and 81.8% had stage IV metastatic disease. Median study follow-up (FU) was 2.2 months (range 1.1, 9.2). The safety profile of the combination therapy is comparable to each single agent without additive toxicities. No ifebemtinib- or D-1553-related death was reported. Four subjects (12.1%) had ifebemtinib-related SAEs (diarrhea, enteritis, oedema peripheral and proteinuria) as assessed by investigators, and all SAEs were also considered D-1553 related. Six subjects (18.1%) had ≥ Grade 3 ifebemtinib-related AEs as assessed by investigators, and all were also D-1553 related AEs. The majority of ifebemtinib-related AEs were CTCAE Grade 1 or 2. There was no event leading to study treatment discontinuation. We have observed continuing tumor shrinkage in almost all subjects who had at least 2 tumor assessments. Among 16 subjects with ≥ 3 months FU, preliminary efficacy found that 14 had best overall response of partial response (PR) including 12 confirmed PRs and 2 unconfirmed but still in treatment, 1 had stable disease (SD), and 1 had progressive disease (PD). The overall response rate (ORR) was 87.5% (95%CI: 56.6, 96.2), and disease control rate (DCR) was 93.8% (95%CI: 63.6, 98.5). The median duration of response (DOR), median progression-free survival (PFS) and overall survival (OS) have not been reached. Conclusions: The combination of ifebemtinib and D-1553, as a dual-oral regimen, showed promising antitumor activity and manageable safety profile in KRAS G12C mutant front-line NSCLC population. Long term follow-up is needed to assess the potential of such novel combo. Clinical trial information: NCT06166836 ; NCT05379946 .
Safety and efficacy of osimertinib plus consolidative stereotactic ablative radiation (SABR) in advanced EGFR mutant non-small cell lung cancer (NSCLC): Results from a multi-center phase II trial.
Authors: Sawsan Rashdan, Sagus Sampath, Puneeth Iyengar, Jonathan Dowell, Chul Ahn, Kenneth D. Westover, Yuanyuan Zhang, Suzanne Cole, Erminia Massarelli, Arya Amini, Marianna Koczywas, David E Gerber
Journal: Journal of Clinical Oncology (2024)

8518 Background: Despite high response rates to EGFR inhibitors, patients with advanced EGFR mutant NSCLC generally experience disease progression within two years (osimertinib median PFS 18.9 months, median OS 38.6 months). We sought to determine whether administration of SABR to residual sites of disease at the time of expected best response to EGFR inhibition could prolong disease control. Methods: This was a multi-center single-arm phase 2 study. Eligible patients had advanced EGFR mutant (exon 19 or 21) NSCLC not restricted by number, site, or size of metastases; ECOG 0-2; no prior treatment with EGFR inhibitors or immune checkpoint inhibitors; and no history of interstitial lung disease. Patients with stable or responding disease after 8 weeks of osimertinib received SABR to persisting lesions, followed by continued osimertinib until progression or intolerance. At subsequent progression, patients could receive further SABR and continue osimertinib if deemed clinically feasible and appropriate. The primary endpoint was progression-free survival (PFS); secondary endpoints included duration on osimertinib, toxicity, and overall survival (OS). Results: A total of 43 patients (32 women, 11 men) were enrolled and initiated osimertinib, of whom 29 (67%) received SABR. Reasons SABR was not administered included inadequate response (9%), insufficient residual disease (19%), and other (5%). At a median follow-up of 35.7 months (95% CI, 28.8, 37.6), 42 evaluable patients had a median PFS of 32.6 months and a median OS of 45.7 months. The median duration of osimertinib was 31.5 months. Grade ≥3 toxicities included one incidence each (2%) of the following: pain at the site of radiation, paronychia, liver enzyme elevation, fatigue, hyponatremia, diarrhea, and pneumonitis. Conclusions: Osimertinib plus consolidative SABR appears to provide a PFS and OS benefit when considered against historical data with osimertinib alone. This treatment strategy may offer a well-tolerated and practical approach to improving outcomes for patients with advanced EGFR mutant NSCLC. Clinical trial information: NCT03667820 .
ARTEMIS-001: Data from a phase 1a/b study of HS-20093 in patients with relapsed small cell lung cancer (SCLC).
Authors: Jie Wang, Jianchun Duan, Yuping Sun, Ligang Xing, Liang Han, Qiming Wang, Lin Wu, Jianhua Chen, Ping Lu, Wei Guo, Haiying Wang, Baogang Liu, Zhiye Zhang, Junhong Zhang, Jianying Huang, Huaqiu Shi, Haiyu Yang, Guoping Zhang, Fangling Ning, Weiliang Zhu
Journal: Journal of Clinical Oncology (2024)

8093 Background: SCLC is characterized by a high rate of proliferation and poor prognosis, and new therapies are urgently needed. B7-H3 is highly expressed in SCLC. HS-20093, a B7-H3-targeted antibody-drug conjugate (ADC), demonstrated antitumor activity in advanced solid tumors in the dose escalation part of ARTEMIS-001 study (Jie Wang et al., JCO, 2023) (NCT05276609). Here, we present results on the efficacy and safety of the expansion doses in patients (pts) with SCLC from phase 1a/b. Methods: ARTEMIS-001 study consisted of dose escalation (1a) and expansion (1b) part. Pts were treated with doses of 1.0 to 16.0 mg/kg HS-20093 every 3 weeks in dose escalation, and were treated with doses at 8.0 mg/kg and 10.0 mg/kg randomly in dose expansion. Pts with SCLC were required to have received prior platinum-based standard therapy. B7-H3 expression was retrospectively evaluated by IHC. Results: As of data cutoff November 30 th 2023, a total of 56 pts with extensive stage SCLC (ES-SCLC) were enrolled and received ≥1 dose of HS-20093 with doses at 8.0 mg/kg (n=31) or 10.0 mg/kg (n=25). Median prior lines of therapy was 2.0 (range: 1-6). All pts received platinum plus etoposide and 73.2% (41/56) received immunotherapy. Safety profile was consistent with previous reports. The most common grade≥3 treatment-related adverse events (≧10%) were neutropenia, leukopenia, lymphopenia, thrombocytopenia and anemia. Out of 56 pts, 52 pts were efficacy evaluable (8.0 mg/kg: 31 pts; 10.0 mg/kg: 21 pts). HS-20093 showed encouraging efficacy in relapsed ES-SCLC (Table). Tumor shrinkage in target lesions occurred in 96.2% (50/52) pts with a post-baseline scan. Deep response defined as tumor shrinkage ≥50% was obtained in 44.2% (23/52) pts. Median overall survival has not yet reached. Responses were observed regardless of B7-H3 expression. Pharmacokinetic (PK) showed approximately dose-proportional increase in exposure with a half-life of 3-7 days. PK profiles of total antibody and ADC were similar and exposure to payload was considerably low. Conclusions: HS-20093 demonstrated promising antitumor activity and manageable safety in pts with previously-treated SCLC. Phase 3 study is planned to compare the efficacy and safety of HS-20093 with standard-of-care chemotherapy in relapsed SCLC. Clinical trial information: NCT05276609 . [Table: see text]