tbuckley/cabot-search huggingface dataset:
Preliminary results from a phase I expansion study of ZG005, a bispecific antibody targeting TIGIT and PD-1, as monotherapy in patients with advanced solid tumors.
Authors: Shukui Qin, Ying Cheng, Qiming Wang, Shuxia Cheng, Xiaoli Chai, Lihua Wu, Yan Yu, Jianhua Shi, Xiumin Li, Lianlian Fan, Jin Xia, Yisheng Huang, Yinghua Ji, Zhixiang Zhuang, Lei Yang, Ou Jiang, Qinhong Zheng, Sihai Liao, Shanyong Yi, Huangyang Ye
Journal: Journal of Clinical Oncology (2024)

2611 Background: ZG005, a PD-1 and TIGIT dual-specific antibody, is a promising immunotherapy for tumors as blocking these two pathways could synergistically activate T cells and enhance the anti-tumor activity of NK cells. Partial results from the dose-escalation stage of this first-in-human (FIH) study were revealed at ASCO 2023, and here we present the preliminary results from the dose-expansion stage. Methods: After a dose-escalation stage, patients (subjects) with solid advanced tumors were enrolled into this dose-expansion stage. Subjects in each cohort were randomized 1:1 to receive ZG005 treatment of either RP2D from the dose-escalation stage (10 mg/kg Q3W or 20 mg/kg Q3W) by intravenous infusion. Efficacy was assessed primarily according to RECIST v1.1. Results: The dose-escalation stage was completed with 32 subjects enrolled and the dose-expansion stage is currently ongoing. As of December 25, 2023, a total of 68 subjects were treated with ZG005 as monotherapy, including 33 males (median age 60) and 35 females (median age 58), wherein 33 had received PD-1/PD-L1 inhibitors before enrollment. Three subjects with either pancreatic neuroendocrine cancer, intrahepatic cholangiocarcinoma, or cervical cancer were treated for more than 20 cycles. The subject with cervical cancer maintained PR status for more than 35 weeks. A total of 1 CR, 6 PR, and 28 SD cases were reported from the 57 efficacy evaluable subjects, among them 1 CR, 5 PRs, and 8 SDs from the 17 subjects with cervical cancer. A total of 43 TRAEs (43/68, 63.2%) were reported, of which 6 were ≥ grade 3, including 2 liver function abnormalities, 1 elevated γ-glutamyl- transferase, 1 unknown death, 1 hypertriglyceridemia and lipase elevation, and 1 elevation in both aspartate aminotransferase and blood bilirubin. SAEs occurred in 19 subjects, 3 events were related to ZG005, including 2 liver function abnormalities (1 was a DLT event), and 1 unknown death. The death event occurred in one female, who received only one dose of ZG005, and the cause of her death was most likely due to poor underlying condition. The C max and AUC increased approximately in dose proportion. Conclusions: ZG005 has demonstrated a tolerable safety profile and encouraging anti-tumor activity during the FIH study. Expansion cohorts in specific advanced solid tumors are underway to warrant further development. Clinical trial information: CTR20220021.
Efficacy and safety of combination therapy with binimetinib, encorafenib, and cetuximab for <i>BRAF</i> non-V600E mutated metastatic colorectal cancer: Results from a phase 2 BIG BANG trial (EPOC1703).
Authors: Daisuke Kotani, Hideaki Bando, Hiroya Taniguchi, Toshiki Masuishi, Taito Esaki, Yu Sunakawa, Yoshito Komatsu, Eiji Shinozaki, Taroh Satoh, Tomohiro Nishina, Yoshiaki Nakamura, Yuichi Mikamoto, Masashi Wakabayashi, Akihiro Sato, Shogo Nomura, Hiromichi Ebi, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2024)

3585 Background: BRAF mutations which are found in 8-12% of metastatic colorectal cancer (mCRC) can be classified into three groups; Class 1 and 2 tumors do not respond to anti-EGFR antibody therapy because of the RAS independent activity, while previous studies suggested potential anti-tumor activity of anti-EGFR antibody for class 3 tumor. Combination therapy with binimetinib, encorafenib, and cetuximab showed the substantial efficacy for BRAF V600E mutated mCRC in the BEACON CRC trial, however, the clinical activity of these triplet therapy for BRAF non-V600E mutated mCRC is unknown. Here, we conducted a multicenter phase 2 trial to assess the efficacy and safety of combination therapy with binimetinib, encorafenib, and cetuximab in patients with BRAF non-V600E mutated mCRC. Methods: We enrolled patients with RAS wild-type and BRAF non-V600E mutated mCRC, refractory or intolerant to at least one fluoropyrimidine-based chemotherapy, and no prior history of anti-EGFR antibody (primary analysis cohort) or refractory to prior anti-EGFR antibody (anti-EGFR antibody refractory cohort). Enrolled patients receive binimetinib (45 mg BID), encorafenib (300 mg QD), and cetuximab (initially 400 mg/m2 and subsequently 250 mg/m2, weekly) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed confirmed objective response rate (ORR) in the primary analysis cohort with sample size of 21 patients. Results: Between May 2018 and March 2023, 12 and 20 patients were enrolled in the primary analysis cohort and the anti-EGFR antibody refractory cohort, respectively (same order in the following abstract). 7 and 19 patients had a history of ≥ 2 lines of previous chemotherapy, respectively. The most frequent mutation overall was BRAF D594G (n=14, 43.8%). There were each 2 responders in both cohorts, resulting in 16.7% (95%CI, 2.1-48.4%) and 10.0% (95%CI, 1.2-31.7%) of confirmed ORR, respectively. Among 7 patients harboring class 1 or 2 tumors in both cohorts combined, there were 2 responders (ORR 28.6%). Median progression-free survival was 3.3 months and 3.0 months, respectively. Grade 3 or higher adverse events occurred in 4 and 10 patients, respectively, and no new safety signals were identified. Conclusions: The combination therapy with binimetinib, encorafenib, and cetuximab showed modest efficacy for BRAF non-V600E mutated mCRC, with a manageable safety profile, although there was not enough statistical power due to slow accrual. Circulating-tumor DNA analyses at the timepoint of before and after treatment are ongoing. Clinical trial information: UMIN000031857. [Table: see text]
Characteristics of patients (pts) with disease relapse despite absence of molecular residual disease (MRD) after resection of colorectal oligometastases (CRM): Implications from PRECISION study.
Authors: Shin Kobayashi, Takeshi Takamoto, Akio Shiomi, Amane Takahashi, Manabu Shiozawa, Yasuhiro Shimizu, Yoshinori Kagawa, Daisuke Nobuoka, Junichiro Yamauchi, Takeshi Kato, Eiji Oki, Akinobu Taketomi, Yu Takahahshi, Soichiro Natsume, Takefumi Niguma, Satoru Kani, Yoshiaki Nakamura
Journal: Journal of Clinical Oncology (2024)

3602 Background: Detection of MRD after curative-intent resection of CRM is prognostic for disease relapse and may guide decisions regarding adjuvant chemotherapy (ACT). However, some pts without MRD detected immediately after resection may also experience disease relapse. We explored the features of pts enrolled in a prospective multicenter study with disease relapse who did and did not have post-resection MRD. Methods: Pts with previously untreated resectable CRM scheduled for surgery were prospectively enrolled between March 2021 and October 2022. Pretreatment genomic alterations were assessed in circulating tumor DNA (ctDNA) by Guardant360, while MRD was assessed 4 weeks after resection with a methylation-based ctDNA MRD assay (Guardant Reveal). Characteristics of pts who were MRD negative but relapsed later were analyzed. Results: Of 118 eligible pts enrolled, pretreatment ctDNA was detected in 99 (84%), 62 (53%) of whom had poor genomic profile, defined as a mutation in BRAF, RAS, PIK3CA, and/or SMAD4. Of 110 pts who underwent surgery, postoperative MRD was detected in 35 (32%). With a median follow-up time of 11.0 months (m), 37 pts recurred, of whom 14 were MRD negative and 23 MRD positive. MRD negative pts were more likely to develop lung metastases (64.3% vs. 30.4%, p=0.09) but less likely to have liver metastases (21.4% vs. 60.9%, p=0.03). Median recurrence-free survival (RFS) of MRD-negative relapsed pts was longer than that of MRD positive pts (8.6 m vs. 3.5 m; hazard ratio [HR], 0.28 [95% CI, 0.13-0.58]). Among MRD-negative pts with recurrence, risk factors most associated with recurrence were a history of lymph node metastases (LNM) (odds ratio [OR], 6.20 [95% CI, 1.28-30.1]) and poor pre-operative genomic profile (OR, 3.85 [95% CI, 1.08-13.70]). Among all resected pts, LNM (HR, 2.55 [95% CI, 1.10–5.89]), poor genomic profile (HR, 2.97 [95% CI, 1.29–6.85]), and MRD positivity (HR, 6.36 [95% CI, 2.96–13.64]) were significantly associated with shorter RFS in multivariate analyses. Conclusions: Pts with a history of LNM or poor pre-operative genomic profile were at risk of recurrence despite the absence of MRD after curative-intent resection of CRM. Clinical trial information: UMIN000042490.
Emerging Therapies for the Management of Human Epidermal Growth Factor Receptor 2–/<i>ERBB2</i>-Altered Advanced Biliary Tract Cancers
Authors: Emily L. Zeme, Katherine Van Loon, Robin K. Kelley, John D. Gordan
Journal: Journal of Clinical Oncology (2024)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology , to patients seen in their own clinical practice.
Perioperative PD-1 antibody tislelizumab plus chemotherapy for locally advanced gastro-oesophageal junction cancer: A prospective, nonrandomized, open-label, phase II trial.
Authors: Run-Cong Nie, Ya Ding, Shu-Qiang Yuan, Yuan-fang Li, Wei Wang, Yongming Chen, Muyan Cai, Xiao-wei Sun, Desheng Weng, Dandan Li, Jingjing Zhao, Xiaojiang Chen, Yuanxiang Guan, Luo Ma, Haibo Qiu, Zhi-wei Zhou, Xiao-Shi Zhang, Ying-bo Chen
Journal: Journal of Clinical Oncology (2024)

4083 Background: The combination of PD-1 antibody and chemotherapy was shown to be effective in advanced gastric cancer, but has not yet been comprehensively investigated in locally advanced patients, especially in the context of adenocarcinoma of gastro-oesophageal junction (GEJ). In this study, we conducted a prospective, nonrandomized, open-label phase II trial to evaluate the effectiveness of adding PD-1 antibody to perioperative chemotherapy in patients with locally advanced resectable GEJ cancer. Methods: In this nonrandomized, open-label, phase II study, patients with resectable GEJ adenocarcinoma clinically staged as cT3-4aNanyM0 or cT1-2N+M0 were allocated three preoperative and five postoperative 3-week cycles of PD-1 antibody tislelizumab plus SOX (S-1 and oxaliplatin) regimen. The primary endpoint was major pathological response (MPR) rate. The secondary endpoints were pathological complete response (pCR), pathological complete /moderate regression rate (TRG 0/1), R0 resection rate, recurrence-free survival, event-free survival, overall survival, treatment safety and quality of life. The trial is registered at Chinese Clinical Trial Registry, identifier: ChiCTR2200058732. Results: Between Oct 2022 and June 2023, 32 patients were enrolled and assessed using intention-to-treat analysis. The median age was 60 years (range: 28-74 years), and 53.1% (17/32) patients were Siewert III type. All patients received at least one cycle of assigned preoperative treatment, and 96.9% (31/32) patients completed three cycles of assigned preoperative tislelizumab and SOX. R0 resection rate was 96.9% (31/32). The MPR rate was 37.5% (12/32, 95% CI: 21.1%-56.3%) and the pCR rate was 28.1% (9/32, 95% CI: 13.7%-46.7%). The surgical morbidity was 12.5% (4/32), and no 30-day mortality was observed. In the preoperative and postoperative treatment period, treatment-related grade 3-4 adverse events was 9.4% (3/32). At the date of 6 th Feb 2024, three (9.4%) patients occurred recurrence. Conclusions: This is the first prospective study that focus on the perioperative immunotherapy in patients with resectable GEJ adenocarcinoma. Perioperative PD-1 antibody tislelizumab plus chemotherapy demonstrated a significantly improved pathological regression and might be a promising option for patients with locally advanced resectable GEJ adenocarcinoma. Clinical trial information: ChiCTR2200058732.
Efficacy and safety of LM-108, an anti-CCR8 monoclonal antibody, in combination with an anti-PD-1 antibody in patients with gastric cancer: Results from phase 1/2 studies.
Authors: Jifang Gong, Chang Liu, Jun Yao, Junli Xue, Jing Dai, Yinghua Ji, Ben Markman, Alison Hiong, Xiuli Yang, Rusen Zhao, Yi Zheng, Qingshan Li, Jun Wu, Minal A. Barve, Mihitha Hashara Ariyapperuma, Gary Edward Richardson, Xia Qin, Crystal Ying Qin, Lin Shen
Journal: Journal of Clinical Oncology (2024)

2504 Background: Targeting tumor-infiltrating regulatory T cells (Tregs) is a potential approach to overcome immunotherapy resistance in the treatment of cancers. LM-108 is a novel Fc-optimized, anti-CCR8 monoclonal antibody that selectively depletes tumor-infiltrating Tregs. Here we report a pooled analysis of results from 3 phase 1/2 studies (NCT05199753; NCT05255484; NCT05518045) to evaluate the efficacy and safety of LM-108 in combination with anti-PD-1 therapy in patients with gastric cancer. Methods: Eligible patients with gastric cancer treated with LM-108 in combination with an anti-PD-1 antibody were included in the analysis. Patients received intravenous LM-108 at dose levels of 3 mg/kg Q2W, 6 mg/kg Q3W, or 10 mg/kg Q3W plus an anti-PD-1 antibody (intravenous pembrolizumab 200 mg Q3W or 400 mg Q6W or toripalimab 240 mg Q3W). The primary endpoint was investigator-assessed ORR per RECIST v1.1. The secondary endpoints included safety, other efficacy outcomes, and biomarkers analysis. Data cutoff date for the pooled analysis was December 25, 2023. Results: Forty-eight patients with gastric cancer (median age: 60.5 years; male: 72.9%) from China, USA, and Australia were treated ≥ 1 dose of LM-108 in combination with pembrolizumab or toripalimab. Most (n = 47, 97.9%) patients had received at least 1 prior anticancer treatment, and 43 (89.6%) had received prior anti-PD-1 therapy. Treatment-related adverse events (TRAEs) occurred in 39 (81.3%) patients, in which the most common events (≥15%) were alanine transaminase increased (25.0%), aspartate transaminase increased (22.9%), white blood cell decreased (22.9%), anemia (16.7%). Grade ≥ 3 TRAEs occurred in 18 (37.5%) patients, the most common events (≥ 4%) were anemia (8.3%), lipase increased (4.2%), rash (4.2%), and lymphocyte count decreased (4.2%). Among 36 efficacy-evaluable patients across all regimens, ORR was 36.1% (95% CI 20.8%–53.8%) and DCR was 72.2% (95% CI 54.8%–85.8%). The median PFS was 6.53 months (95% CI 2.96–NA). Among 11 patients whose disease had progressed on first-line treatment, ORR was 63.6% (95% CI 30.8%–89.1%) and DCR was 81.8% (95% CI 48.2%–97.7%). Of the 11 patients who progressed on first-line treatment, 8 had high CCR8 expression. Among these 8 patients, ORR was 87.5% and DCR was 100%, with 1 CR, 6 PR, and 1 SD observed. Conclusions: LM-108 in combination with an anti-PD-1 antibody showed promising antitumor activity in patients with gastric cancer that was resistance to anti-PD-1 therapy. The combination therapy was well tolerated. These results support further evaluation of LM-108 in CCR8 positive gastric cancer. Clinical trial information: NCT05199753 ; NCT05255484 ; NCT05518045 .
Efficacy of EpCAM CAR-T IMC001 in advanced gastric cancers.
Authors: Tianhang Luo, Weijia Fang, Zhengmao Lu, Chuchu Tong, Hangyu Zhang, Guoqiang Ai, Suqiong Wang, Ruidong Hao, Minmin Sun
Journal: Journal of Clinical Oncology (2024)

4043 Background: EpCAM is highly expressed in various cancer types of the GI system and serves as a promising prognostic/predictive marker and therapeutic target. IMC001 is an autologous EpCAM-targeting CAR-T cell exhibited promising anti-tumor activity in preclinical studies. The specificity of the extracellular humanized scFv of IMC001 was confirmed by membrane proteome array. Patient derived organoids study and murine GLP study indicated a favorable safety profile of IMC001. Previous IIT data showed promising safety and efficacy. Here we present updated clinical data with longer follow up and more pts treated in the expansion recommended dose of 1 million (M) CAR-T cells/kg. Methods: This first-in-human, open-label trial followed a 3+3 design with IMC001 monotherapy dose escalation of 0.3 (n=3), 1 (n=3) or 3 (n=3) M/kg after lymphodepletion chemotherapy, 2 additional pts had been enrolled at dose-expansion (1M/kg). Eligible patients were those with EpCAM-positive (expression ≥1+ staining intensity in ≥10% tumor cells) advanced gastric cancers who had failed or not tolerated at least 2 lines of chemotherapy and were ECOG 0 or 1. The objective was to assess the safety, PK/PD profile and preliminary efficacy of IMC001. Results: As of Dec 30, 2023, 11 pts were infused with IMC001, 10 with evaluable efficacy are included in the efficacy analysis. The median time from diagnosis to enroll was 17.0 months (range 6.9-31.2). All pts were in stage IV, with more than 2 lines previous chemotherapy (1 pt failed 1 st line and refused a 2 nd line treatment), all had metastasis and 72.7% (8/11) had 2 or more metastasis organs. CAR T-cell expansion was observed in most pts; the median Cmax was 547, 500 and 9540 copies/μg gDNA in the 0.3, 1, and 3M/kg dose groups respectively, median Tmax was 7 days (7-28), with a persistence of IMC001 range from 4 to 12 weeks. Significant elevations of serum levels of cytokines were observed in most patients. Three out of 10 evaluable pts achieved PR response and 6 remained SD, with a DCR of 90%. For the recommended dose of 1M/kg, 2 out of 5 pts had PR (ORR 40%), including 1 pt underwent successful radical gastrectomy around W27 after IMC001 infusion and remained survival for more than 81 wks. The other PR pt had a tumor reduction of 48% at W16. The other 2 SD pts had an OS of 55 wks and 43 wks. Patients were well tolerated with no unexpected safety signals were observed at the recommended dose. Conclusions: This phase I study in advanced gastric cancer resulted in durable response with a favorable safety and efficacy profile especially for the recommended dose of 1M/kg, demonstrate a promising of EpCAM CAR-T therapy in advanced GC pts. Further expanding of this dose with larger patient population and longer follow-up shall bring the hope to this unmet medical need. Clinical trial information: ChiCTR2100047129.
Xanthelasma Palpebrarum is Not Associated with Dyslipidemia or Cardiovascular Disease: A Case Control Study
Authors: Yael Lustig-Barzelay, Noa Kapelushnik, Inbal Goldshtein, Ari Leshno, Shlomo Segev, Guy J. Ben-Simon, Daphna Landau-Prat
Journal: Ophthalmology (2024)
Routine, prospective DPYD genotyping guided dose-individualisation for patients receiving fluoropyrimidines: Implementation, prevalence and patient safety outcomes from a multi-institutional clinical trial.
Authors: Mark Nalder, Tivya Kulasegaran, Ben Lundie, Rick Woods, Melissa A. Eastgate, David Wyld, Matthew E. Burge
Journal: Journal of Clinical Oncology (2024)

12121 Background: Prospective data regarding the prevalence of DPYD variant alleles and the impact of genotype guided dosing on safety and efficacy of fluoropyrimidines (FP) remains limited. We assessed the feasibility and safety impact of routine, prospective, DPYD genotype guided FP dosing. Methods: Adult patients (&gt;18 years), commencing FP for the first time were enrolled. Sanger PCR sequencing was designed to target DPYD variants NM_000110.4:c.1905+1G&gt;A (DPYD*2A), NM_000110.4:c.1679T&gt;G (DPYD*13), NM_000110.4:c.1236G&gt;A and NM_000110.4:c.2846A&gt;T. Dose reductions were implemented as per current international pharmacogenomic guidelines. Gr3/4 toxicity, dose reductions/delays and hospital admissions were reviewed for the first 60 days after commencement. For comparison purposes, a retrospective review of patients receiving FP without testing in a prior year was completed. Results: Between July 2021 – May 2023, 334 patients were enrolled for testing. 95% ECOG 0-1. 57% curative treatment intent. Mean time from phlebotomy to result 6.9 days (range 2-15). Clinician/patient acceptance was high (&gt;95% of eligible patients starting FP were enrolled). 20 (6.0%) variant DPYD allele carriers were detected. 11 heterozygous for c.1236G&gt;A, 5 heterozygous for C.1905+1G&gt;A, 3 heterozygous for c.2846A&gt;T and 1 homozygous for c.1236G&gt;A. 295 of patients tested proceeded to receive FP. 62% received Infusional-FP, 38% Capecitabine. 39 patients commenced treatment prior to DPYD result being available (treating clinician decision). Dose modification recommendations were followed in all but two patients. 24% experienced FP related Grade 3/4 toxicity within 60 days. (23% DPYD wild type, 37% DPYD variant) versus 35% in the retrospective cohort. 16% had FP related dose delays (16% DPYD wild type, 12% DPYD variant) versus 25% retrospective cohort. 14% had FP related dose reductions (13% DPYD wild type, 25% DPYD variant) versus 12% retrospective cohort. 13% had FP related hospital admissions (13% DPYD wild type, 19% DPYD variant) versus 17% retrospective cohort. 1 death in the DPYD wild type cohort was deemed potentially related to FP. Conclusions: Prospective DPYD genotype guided dosing was feasible in clinical practice, with prevalence of variant alleles comparable to published literature. There was a modest reduction in risk of FP related severe toxicity, dose delays, and hospital admissions with DPYD guided dosing compared to a historical, untested cohort. Clinical trial information: ACTRN12621001117808.
VALIDATION OF THE ENCEPHALITIS CRITERIA IN ADULTS WITH A SUSPECTED CENTRAL NERVOUS SYSTEM INFECTION: AN UPDATED SCORE
Authors: Steven L. Staal, Sabine E. Olie, Diederik van de Beek, Matthijs C. Brouwer
Journal: Journal of Infection (2024)

We aimed to validate and refine the encephalitis criteria proposed by the International Encephalitis Consortium in a cohort of adults initially suspected of a central nervous system (CNS) infection.
Lung-MAP Next-Generation Sequencing Analysis of Advanced Squamous Cell Lung Cancers (SWOG S1400)
Authors: David Kozono, Xing Hua, Michael C Wu, Khaled A Tolba, Saiama N Waqar, Konstantin H Dragnev, Haiying Cheng, Fred R Hirsch, Philip C Mack, Jhanelle E Gray, Karen Kelly, Hossein Borghaei, Roy S Herbst, David R Gandara, Mary W Redman
Journal: Journal of Thoracic Oncology (2024)
Poised for Innovation
Authors: Roslyn B. Mannon, Flavio G. Vincenti
Journal: Journal of the American Society of Nephrology (2024)

1Department of Internal Medicine, Division of Nephrology, University of Nebraska Medical Center, Omaha, NE 2Department of Medicine and Surgery, University of California at San Francisco, San Francisco aAddress correspondence to: Roslyn B Mannon, MD, 983040 Nebraska Medical Center, MSB 5569, Omaha, NE 68198-3040, [email protected]