tbuckley/cabot-search huggingface dataset:
Efficacy and safety of envafolimab plus lenvatinib combined with TACE in initially unresectable hepatocellular carcinoma: An open-label, single-arm, phase II study.
Authors: Xueli Bai, Yiwen Chen, Junlei Zhang, Wendi Hu, Xiang Li, Yan Shen, Min Zhang, Jian Wu, Shunliang Gao, Jun Yu, Risheng Que, Yun Zhang, Fuchun Yang, Weiliang Xia, Aibin Zhang, Xiaofeng Tang, Tingbo Liang
Journal: Journal of Clinical Oncology (2024)

4108 Background: TACE-based conversion therapies are warranted for over 70% of patients with intermediate-advanced unresectable hepatocellular carcinoma (uHCC). This study aimed to investigate the efficacy and safety of envafolimab plus lenvatinib and TACE as conversion therapy in uHCC. Methods: This is an open-label, prospective, single-arm, phase II study. Eligible patients with uHCC (Barcelona Clinic Liver Cancer Stage B or C) were consecutively enrolled. Patients will receive envafolimab subcutaneously (300 mg, Q3W) and Lenvatinib orally daily (12 mg/day (body weight ≥ 60 kg) or 8 mg/day (&lt;60 kg)) during TACE sessions. TACE will be conducted every 6 weeks on demand according to investigators’ evaluation, mainly based on the proportion of viable tumors. The primary endpoint was the objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version1.1 (RECIST 1.1). Secondary endpoints were disease control rate (DCR) and duration of response (DoR) per RECIST 1.1 and mRECIST, progression-free survival (PFS), overall survival (OS), and safety. Results: Between February 2022 and July 2022, 38 patients were enrolled and included for primary efficacy and safety analysis. As of December 13, 2023, the median follow-up of 16.9 months (95CI, 6.7 to 24.2). The ORR and DCR were 47.4% (95%CI, 31.0% to 64.2%) and 78.9% (95%CI, 62.7% to 90.5%) per RECIST 1.1, respectively (with ORR and DCR of both 78.9% per mRECIST). The median PFS (mPFS) was 8.78 months (95CI, 5.23 to not avaliable (NA)), and the median OS (mOS) was immature with 1-year OS of 88.9%. The median DoR assessed per RECIST 1.1 was 6.7 months (7.7 months per mRECIST). Of 38 patients, 17 patients were assessed as successful conversion with a conversion success rate of 44.7%. Sixteen patients underwent surgery with the R0 resection rate of 100%, the pathological complete response (pCR) rate of 31.3%, and major pathological response (MPR) rate of 56.3%. Of 38 patients, overall incidences of AEs of any grade was 97.4%. Grade ≥3 treatment-related adverse events (TRAEs) were observed in 20 (52.6%) patients, which mainly included increased AST (34.2%), increased ALT (18.4%), and decreased platelet count (15.8%). No treatment-related death occurred. Conclusions: Envafolimab combined with lenvatinib and TACE yielded promising survival outcomes and conversion rate with a manageable safety profile in uHCC, representing a potential and feasible conversion therapy regimen for this population. Clinical trial information: NCT05213221 .
SARS-CoV-2 inflammation durably imprints memory CD4 T cells
Authors: Sophie L. Gray-Gaillard, Sabrina M. Solis, Han M. Chen, Clarice Monteiro, Grace Ciabattoni, Marie I. Samanovic, Amber R. Cornelius, Tijaana Williams, Emilie Geesey, Miguel Rodriguez, Mila Brum Ortigoza, Ellie N. Ivanova, Sergei B. Koralov, Mark J. Mulligan, Ramin Sedaghat Herati
Journal: Science Immunology (2024)

Memory CD4 T cells are critical to human immunity, yet it is unclear whether viral inflammation during memory formation has long-term consequences. Here, we compared transcriptional and epigenetic landscapes of Spike (S)-specific memory CD4 T cells in 24 individuals whose first exposure to S was via SARS-CoV-2 infection or mRNA vaccination. Nearly 2 years after memory formation, S-specific CD4 T cells established by infection remained enriched for transcripts related to cytotoxicity and for interferon-stimulated genes, likely because of a chromatin accessibility landscape altered by inflammation. Moreover, S-specific CD4 T cells primed by infection had reduced proliferative capacity in vitro relative to vaccine-primed cells. Furthermore, the transcriptional state of S-specific memory CD4 T cells was minimally altered by booster immunization and/or breakthrough infection. Thus, infection-associated inflammation durably imprints CD4 T cell memory, which affects the function of these cells and may have consequences for long-term immunity.
MAIT cells monitor intestinal dysbiosis and contribute to host protection during colitis
Authors: Yara El Morr, Mariela Fürstenheim, Martin Mestdagh, Katarzyna Franciszkiewicz, Marion Salou, Claire Morvan, Thierry Dupré, Alexey Vorobev, Bakhos Jneid, Virginie Premel, Aurélie Darbois, Laetitia Perrin, Stanislas Mondot, Ludovic Colombeau, Hélène Bugaut, Anastasia du Halgouet, Sophie Richon, Emanuele Procopio, Mathieu Maurin, Catherine Philippe, Raphael Rodriguez, Olivier Lantz, François Legoux
Journal: Science Immunology (2024)

Intestinal inflammation shifts microbiota composition and metabolism. How the host monitors and responds to such changes remains unclear. Here, we describe a protective mechanism by which mucosal-associated invariant T (MAIT) cells detect microbiota metabolites produced upon intestinal inflammation and promote tissue repair. At steady state, MAIT ligands derived from the riboflavin biosynthesis pathway were produced by aerotolerant bacteria residing in the colonic mucosa. Experimental colitis triggered luminal expansion of riboflavin-producing bacteria, leading to increased production of MAIT ligands. Modulation of intestinal oxygen levels suggested a role for oxygen in inducing MAIT ligand production. MAIT ligands produced in the colon rapidly crossed the intestinal barrier and activated MAIT cells, which expressed tissue-repair genes and produced barrier-promoting mediators during colitis. Mice lacking MAIT cells were more susceptible to colitis and colitis-driven colorectal cancer. Thus, MAIT cells are sensitive to a bacterial metabolic pathway indicative of intestinal inflammation.
Impact of CTNNB1 alterations on outcomes in patients with hepatocellular carcinoma (HCC).
Authors: Jonathan Pai, Yasmine Baca, Rituparna Ganguly, Mehmet Akce, Sandra Algaze, Lydia D. Chow, Ani Misirian, Diana L. Hanna, Heinz-Josef Lenz, John Marshall, Syma Iqbal, Rachna T. Shroff, Mitesh J. Borad, Anthony B. El-Khoueiry
Journal: Journal of Clinical Oncology (2024)

4106 Background: The WNT/beta catenin (CTNNB1) pathway plays an integral role in the development of HCC. CTNNB1 has been implicated in HCC progression, metastasis, and drug resistance. We examined associations between CTNNB1 mutations and mRNA expression and clinical outcomes in a real-world cohort of patients with HCC. Methods: 1652 HCC tumors were tested at Caris Life Sciences (Phoenix, AZ) and analyzed with Whole Transcriptome Sequencing (WTS; Illumina Novaseq), Whole Exome Sequencing (NovaSeq,WES) and NextGen DNA sequencing (NextSeq, 592 genes). mRNA expression (transcripts per million) was further stratified into top (Q4) and bottom quartiles (Q1). Kaplan Meier estimates were calculated for overall survival (OS) in the molecularly defined cohorts and estimated from time of tissue collection to last contact. Significance was determined to be p &lt;0.05. Chi-square and Mann-Whitney tests determined molecular differences between subgroups and adjusted for multiple comparisons (q&lt;0.05). Results: Pathogenic CTNNB1 mutations were present in 32% of HCC and mutation status was not associated with CTNNB1 expression level. Pts whose tumors had lower CTNNB1 expression had significantly improved OS, 17.9 vs 12.4 months, Q1 vs Q4, HR 0.72, CI: 0.58-0.89 p=0.002. This association remained significant in patients who received first-line IO (Q1 vs Q4: OS 16.7 vs 10.6 mo, HR 0.54, CI: 0.32-0.94, p=0.025) or TKI (Q1 vs Q4: OS 27.1 vs 17.6 mo, HR 0.60, CI: 0.38-0.94, p=0.025). Low CTNNB1-expressing tumors (Q1) had more frequent ARID1A mutations (15% vs 8%); less frequent TP53 mutations (31% vs 42%); lower VEGFA, EPHB4, EPHA2, HIF1A, TGFB1/2/3 expression, lower MAPK activation and lower T-cell inflamed scores vs Q4 tumors (all q &lt; 0.05). All tumors were MSS. CTNNB1 mutation status (MT vs WT) did not impact survival (OS 17.6 vs 15.3 mo, CTNNB1-MT vs CTNNB1-WT, HR 1.05, CI: 0.91-1.20, p=0.55). Similarly, CTNNB1 mutation status (MT vs WT) did not impact OS in pts treated with IO (19.8 vs 19.6 mo, HR 0.99, p=0.94) or TKI (23.0 vs 22.0 mo, HR 0.86, p=0.33). Conclusions: CTNNB1 mRNA expression, but not CTNNB1 mutation status, is associated with survival in HCC. Patients whose tumors had lower CTNNB1 expression appeared to derive more benefit from immune checkpoint inhibitors and TKI therapy in first line. CTNNB1 expression is associated with DNA repair, immune, neuronal and angiogenic pathways which may pave the way for potential therapeutic opportunities. Further studies are needed to prospectively evaluate CTNNB1 as a biomarker for treatment selection in HCC.
Overall survival results from the phase 2 NIVOFGFR2 study of first-line nivolumab plus CAPOX in patients with FGFR2-positive, PD-L1-positive metastatic gastric cancer.
Authors: Ilya Tsimafeyeu, Gunel Musayeva, Mahmudova Samira, Nana Otkhozoria, Bahadur Abbasov, Alisher Kahharov
Journal: Journal of Clinical Oncology (2024)

4042 Background: The interim analysis of the NIVOFGFR2 phase 2 study showed a 1-year PFS rate of 30.4% in patients with FGFR2-positive, PD-L1-positive metastatic gastric cancer treated with the combination of nivolumab and CAPOX in the first-line setting (GI ASCO 2024). Here, we present data on overall survival (OS) and second-line PFS (PFS2). Methods: In this single-arm, multi-center, phase 2 study, eligible patients had metastatic untreated HER2-negative gastric adenocarcinoma, and their PD-L1 expression (CPS≥5; DAKO 28-8) and FGFR2 status (moderate (2+) and strong (3+) membranous staining in more than 1% of tumor cells; Abсam EPR24075-418) were centrally confirmed by IHC. Patients were treated with nivolumab 360 mg in combination with capecitabine and oxaliplatin every 3 weeks till disease progression or unacceptable toxicity. Following progression, the planned treatment regimen included ramucirumab at a dose of 8 mg/kg with paclitaxel. The primary endpoint was the 1-year PFS rate and secondary endpoints included median PFS, PFS2, OS, objective response rate (ORR), and the Grade ≥3 adverse events (AEs) rate. Results: Twenty-three patients were enrolled (median age 61 years, men 74%, Caucasian 91%, ECOG PS 1-2 78%, organs with ≥2 metastases 78%; CPS (5-9) 22%, (≥10) 78%, previous surgery 61%, adjuvant/neoadjuvant therapy 17%, time to metastatic disease &lt;1 year 48%). Two (8.7%) patients remain on first-line therapy, 19 (82.6%) have received second-line ramucirumab and paclitaxel, and 10 (43.5%) have received 3 or more lines of therapy. The median follow-up for OS was 17.3 months, with 7 patients still alive. We present the updated efficacy and toxicity results (Table). Conclusions: Despite the modest efficacy of nivolumab with CAPOX in the first-line setting, a favorable median OS was observed, possibly attributable to the incorporation of ramucirumab with paclitaxel in the second-line treatment of FGFR2-positive, PD-L1-positive metastatic gastric cancer. Clinical trial information: NCT05859477 . [Table: see text]
Camrelizumab plus rivoceranib vs sorafenib as first-line therapy for unresectable hepatocellular carcinoma (uHCC): Final overall survival analysis of the phase 3 CARES-310 study.
Authors: Arndt Vogel, Stephen Lam Chan, Zhenggang Ren, Yuxian Bai, Shanzhi Gu, Xiaoyan Lin, Zhendong Chen, Weidong Jia, Yongdong Jin, Yabing Guo, Xiaohua Hu, Alexander Valerievich Sultanbaev, Monika Pazgan-Simon, Margaryta Pisetska, Tsz Keung Nip, Haisong Zhang, Jinghua Du, Ann-Lii Cheng, Ahmed Omar Kaseb, Shukui Qin
Journal: Journal of Clinical Oncology (2024)

4110 Background: The phase 3 CARES-310 trial is the first to demonstrate significant progression-free survival (PFS) and overall survival (OS) benefits with immunotherapy plus an anti-angiogenic tyrosine kinase inhibitor (TKI) over standard TKI as first-line treatment for uHCC. In the primary analysis of PFS (data cut-off [DCO], May. 10, 2021) and interim analysis of OS (DCO, Feb. 8, 2022), significant improvements were observed with camrelizumab (C; anti-PD-1 antibody) + rivoceranib (R; VEGFR2-TKI) vs. sorafenib (S). Here, we report updated data at the final analysis (FA), after an additional follow-up of ~16 mo. Methods: In this international, randomized, open-label, phase 3 trial, 543 patients with uHCC who had not previously received systemic treatment were randomized 1:1 to receive either C (200 mg, iv, q2w) + R (250 mg, po, qd) or S (400 mg, po, bid). As of Jun.14, 2023, 351 (65%) deaths occurred, and a protocol-specified FA was performed. Results: 272 patients were allocated to C+R and 271 to S. At DCO of FA, median follow-up was 22.1 mo in C+R group and 14.9 mo in S group. After end of study treatment, 36% of patients in C+R group and 42% in S group received subsequent targeted therapy; 17% and 36% received immunotherapy, respectively. Median OS was significantly prolonged with C+R vs . S (23.8 mo [95% CI 20.6-27.2] vs. 15.2 mo [95% CI 13.2-18.5]; hazard ratio (HR) 0.64 [95% CI 0.52-0.79]; 1-sided p &lt;0.0001). OS rate with C+R vs.S was 49.0% vs. 36.2% at 24 mo, and 37.7% vs. 24.8% at 36 mo. OS benefits with C+R was generally consistent across subgroups, regardless of geographical region, race, and aetiology. Benefits in PFS, objective response rate (ORR) and duration of response (DoR) with C+R were also sustained after prolonged follow-up (Table). Safety data aligned with the interim OS analysis, with no new signals noted. Conclusions: At the protocol-specified FA, C+R continued to show clinically meaningful survival improvement compared with S, with manageable safety. The extended follow-up further confirmed the favorable benefit-to-risk profile of C+R, supporting it as a new first-line treatment option for uHCC. Clinical trial information: NCT03764293 . [Table: see text]
Nivolumab (NIVO) + chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 4-year follow-up of CheckMate 649.
Authors: Elena Elimova, Kohei Shitara, Markus H. Moehler, Jaffer A. Ajani, Lin Shen, Marcelo Garrido, Carlos Gallardo, Lucjan S. Wyrwicz, Kensei Yamaguchi, James M. Cleary, Ricardo Elias Bruges Maya, Michalis Karamouzis, Tomasz Skoczylas, Arinilda Bragagnoli, Tianshu Liu, Mustapha Tehfe, Kynan Feeney, Rui Wang, Raheel Nathani, Yelena Y. Janjigian
Journal: Journal of Clinical Oncology (2024)

4040 Background: NIVO + chemo demonstrated superior overall survival (OS) and clinically meaningful progression-free survival (PFS) benefit vs chemo and an acceptable safety profile in previously untreated, advanced non-HER2+ GC/GEJC/EAC, leading to approvals in many countries. NIVO + chemo continued to demonstrate clinically meaningful improvement in efficacy at 2 and 3-yr follow-ups. We present 4-yr follow-up results for NIVO + chemo vs chemo from CheckMate 649. Methods: Adults with previously untreated, unresectable advanced, or metastatic GC/GEJC/EAC were enrolled, regardless of programmed death ligand 1 (PD-L1) expression. HER2+ patients (pts) were excluded. Randomized pts received NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were OS and PFS by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: 1581 pts were randomized to NIVO + chemo or chemo. At the 48-month (mo) minimum follow-up, NIVO + chemo continued to demonstrate OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts (Table). OS benefit with NIVO + chemo was observed in most prespecified subgroups. Objective response rates (ORR) were higher and responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts (Table). In the exploratory analysis of OS by response at the 18-week landmark timepoint, there were numerically more pts achieving response with NIVO + chemo vs chemo, and median OS (95% CI) with NIVO + chemo was numerically longer in responders vs non-responders both in pts with PD-L1 CPS ≥ 5 (20.5 [17.5–25.0] vs 14.0 [11.6–15.7]) and all randomized pts (19.4 [17.5–21.7] vs 13.1 [11.6–14.4]). No new safety signals were identified, consistent with the 3-yr follow-up. Conclusions: NIVO + chemo is the first PD-1 inhibitor/chemo combination to demonstrate long-term efficacy and acceptable safety after 4 yrs of follow up in previously untreated advanced GC/GEJC/EAC. These results are consistent with earlier follow-ups, further supporting NIVO + chemo as a standard 1L treatment in these pts. Clinical trial information: NCT02872116 . [Table: see text]
Bone metastases and skeletal related events in patients with gastrointestinal neuroendocrine tumors.
Authors: Paula Bruges, Ian Schonman, Marianna Zahurak, Daniel A. Laheru, Jin He, Fabian McCartney Johnston, Jonathan Greer, Lilja Solnes, Ana De Jesus-Acosta
Journal: Journal of Clinical Oncology (2024)

4126 Background: The clinical implications and management of bone metastases in patients (pts) with gastrointestinal neuroendocrine tumors (GI-NETs) is poorly characterized. In this study we investigated the frequency of bone metastases and skeletal-related events (SRE) in pts with GI-NETs. Methods: Retrospective review of ptswith GI-NETs seen at our institution between 2010-2022. We collected clinicopathologic data including tumor primary site, tumor differentiation, grade using Ki-67 labeling index (G1, G2, or G3), time of diagnosis of metastatic GI-NET, and development of bone metastases (synchronous or metachronous). Diagnosis of metastatic bone disease was assessed by contrast imaging (CT, MRI) and/or functional imaging studies (FDG or DOTATATE PET). SRE were defined as bone pain, spinal cord compression, pathological fracture or tumor-related hypercalcemia. Bone directed therapy was defined as use of bisphosphonates, radiation therapy, and surgical intervention. Results: We identified a total of 865 pts with metastatic GI-NETs. Of these, 122 pts (14%) had evidence of bone metastases. In pts with bone metastases, median age was 60 y/o and 72 pts (59%) were male. Primary tumor sites included pancreas (n=52, 47%), small bowel (n=50, 45%), rectum (n=4, 4%), colon (n=3, 3%), and gallbladder (n=1, 1%). Tumors were G1 (n=31, 28%), G2 (n=51, 47%), G3 (n=27, 25%). The majority of pts had well-differentiated tumors (n=103, 84%). Imaging for initial diagnosis of bone metastasis included PET (n=65, 53%), MRI (n=29, 24%), and CT (n=28, 23%). Synchronous metastases occurred in 34 pts (28%). Metachronous bone metastasis occurred in 88 pts (72%) with a median time to developing bone metastasis of 38 months. SRE occurred in 46 pts (38%), with 36 pts (30%) experiencing bone pain, 5 pts (4%) experiencing pathological fracture, 5 pts (4%) experiencing spinal cord compression, and 2 pts (2%) experiencing hypercalcemia. Thirty-six pts (30%) received bone-directed therapy, including bisphosphonates (n=25, 20%), radiation (n=19, 16%), or surgical intervention (n=4, 3%). Median overall survival (OS) was 83.3 months. Factors associated with increased probability of SRE included younger age, non-white race, low tumor grade, synchronous presentation, and poorly differentiated tumor. Risk factors for decreased OS included male gender, intermediate or high-grade disease, and spinal cord involvement. Bisphosphonate therapy was the most frequently used bone-directed treatment (n=25, 20%). Conclusions: Bone metastases occurred in 14% of pts with GI-NETs and SRE occurred in 38% of these pts. SRE were more likely to occur in pts with synchronous metastatic bone disease, intermediate/high grade tumors or poorly differentiated tumors. Further studies evaluating interventions to decrease SRE and impact in quality of life in pts with GI-NETs are warranted.
Utilization of tumor-informed circulating tumor DNA in detecting minimal residual disease and guiding adjuvant therapy in liver cancer.
Authors: De-Zhen Guo, Shi-Yu Zhang, Zhu-Jun Gu, Shuang-Tao Zhou, Da-Wei Jin, Shuang Yang, Jia Fan, Jian Zhou, Xin-Rong Yang
Journal: Journal of Clinical Oncology (2024)

4125 Background: Hepatocellular carcinoma (HCC), a prevalent malignancy and a leading cause of cancer-related mortality, often exhibits a grim prognosis due to recurrence post-surgical treatment. Minimal residual disease (MRD) is deemed a crucial factor contributing to early relapse following radical surgery. Previous studies have indicated that circulating tumor DNA (ctDNA) may serve as a promising biomarker for evaluating MRD in various cancers. However, its applicability in liver cancer remains unclear. Methods: We prospective included 136 patients during 2019 to 2021 who underwent curative-intention surgery for HCC in Zhongshan hospital. Plasma samples (n=625) were collected prior to surgery, 1-month post-surgery, and during subsequent surveillance. Patient-specific somatic mutations were identified through whole-exome sequencing of tumor tissue. For each patient, 16 patient-specific somatic mutations were selected and employed to assess ctDNA through ultra-deep sequencing of plasma DNA. Results: The median follow-up period was 24 months. At the last follow-up, 45 (33.1%) patients relapsed. The preoperative ctDNA concentration was elevated in patients who experienced tumor relapse after surgical treatment compared to those didn’t relapse (median: 125 vs.8.4 mean tumor molecules/mL, P&lt;0.001). Most of patients (80.9%) demonstrated a significant decrease in ctDNA concentration to negative levels after curative surgery. Those maintaining a positive postoperative ctDNA status faced a higher recurrence risk (HR=11.5, P&lt;0.001). Throughout longitudinal follow-up, positive longitudinal ctDNA (positive in any point) was significantly associated with a higher recurrence risk (HR=69.3, P&lt;0.001). The area under the curve of longitudinal ctDNA for predicting recurrence was 0.956, boasting a sensitivity of 93.3% and specificity of 97.8%. The median interval from the first positive longitudinal ctDNA to clinical recurrence confirmed by imaging test was 4 months. The predictive performance of longitudinal ctDNA for recurrence surpassed that of alpha-fetoprotein (0.956 vs. 0.680, P&lt;0.001). Patients with positive longitudinal ctDNA experienced benefits from adjuvant therapy (HR=0.4, P=0.019). Moreover, a decrease or stability of ctDNA after adjuvant therapy indicated treatment response and delayed clinical relapse (HR=0.3, P=0.00012). Conclusions: Tumor-informed ctDNA proves to be a reliable indicator for MRD detection after surgical treatment for HCC, enabling the prediction and anticipation of recurrence before clinical manifestation. It plays a crucial role in guiding the application of adjuvant therapy and assessing treatment efficacy, thereby facilitating postoperative management and enhancing the precision of medical interventions.