bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of IBI110 in combination with sintilimab in first-line advanced HER2-negative gastric cancer or gastroesophageal junction cancer: Updated results from a phase Ib study.
Authors: Mao Chenyu , Qian Jiong , Gao Yuan , Liu Ying , Zhang Tao , Cui Jiuwei , Chen Yuling , Chen Haonan , Zhao Li , Wang Hongli , Xu Nong 
Published: June 2023

2576 Background: Sintilimab plus oxaliplatin and capecitabine (XELOX) has become the standard of care in patients (pts) with untreated advanced, recurrent, or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ AC) in China. Dual inhibition of PD-1 and lymphocyte-activation gene 3 (LAG-3) may further improve anti-tumor effect. The preliminary safety and efficacy data of IBI110 plus sintilimab and XELOX in pts with first-line G/GEJ AC were previously presented (Chenyu Mao et al. ASCO 2022). Here, we presented updated safety and efficacy results of this study. Methods: This phase Ib study enrolled patients with previously untreated, unresectable, locally advanced or recurrent/metastatic HER2-negative GC/GEJ AC. Pts received IBI110 200mg IV Q3W and sintilimab 200mg IV Q3W plus XELOX (oxaliplatin 130 mg/m2 Q3W and capecitabine 1000mg mg/m2/time twice daily [BID]) until disease progression, unacceptable toxicity or death. The primary objectives were to evaluate the safety, tolerability, and efficacy of the combination therapy per RECIST v1.1. Results: As of data cutoff January 9th 2023, 17 pts were assessed as evaluable (median age: 61 years; ECOG PS=1: 14 pts; all gastric cancer). All pts (17/17, 100%) experienced treatment-related adverse events (TRAEs) of any grade, and the most commonly TRAEs were neutrophil count decreased (64.7%), white blood cell count decreased (52.9%), platelet count decreased (52.9%). Grade ≥ 3 TRAEs occurred in 11 pts (64.7%), the most frequent grade ≥ 3 TRAEs were consistent with TRAEs of any grade. Investigator-assessed immune-mediated adverse events (irAEs) occurred in 10 pts (58.8%). Grade ≥ 3 irAEs occurred in 3 pts (17.6%), all led to discontinuation. No treatment-related death occurred. As data cutoff, among 17 efficacy-evaluable pts, the unconfirmed and confirmed objective response rate (ORR) were 88.2% (95% CI, 63.6-98.5) and 64.7% (95% CI, 38.3-85.8), respectively. The disease control rate (DCR) was 94.1% (95% CI, 71.3-99.9). With a median follow up of 13.1 months (95% CI, 7.1-NC), the median duration of response (DoR) and progression-free survival (PFS) were 11.6 months (95% CI, 2.5-14.4) and 12.9 months (95% CI, 3.8-15.8), respectively. The median overall survival (OS) was not reached, and the 12-months OS rate was 70.6% (95% CI, 43.1-86.6). Conclusions: IBI110 in combination with sintilimab and XELOX demonstrated manageable safety and encouraging efficacy results in patients with first-line gastric adenocarcinoma. This is the first positive trial to show clinical benefits of a LAG3 plus PD-1 inhibitor combined with chemotherapy for this population. Clinical trial information: NCT04085185 .
Efficacy and safety of IBI110 in combination with sintilimab and lenvatinib in first-line of advanced hepatocellular carcinoma: Preliminary results from a phase Ib study.
Authors: Liu Ming , Wang Kun , Bao Quan , Wang Hongwei , Jin Kemin , Liu Wei , Luo Jia , Xu Nong , Zhang Tao , Xia Yongxiang , Shao Guoliang , Liu Baorui , Shen Jie , Chen Haonan , Long Sixiang , Chen Yuling , Zhao Li , Wang Hongli , Xing Baocai 
Published: June 2023

2577 Background: Sintilimab plus bevacizumab has been approved as first-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC). Dual inhibition of PD-1 and lymphocyte-activation gene 3 (LAG-3) may improve anti-tumor effect synergistically. IBI110 plus sintilimab has shown preliminary antitumor activity in advance solid tumors. This phase Ib cohort study evaluated the efficacy, tolerability, and safety of IBI110 in combination with sintilimab and lenvatinib as first-line treatment in pts with advanced HCC. Methods: This phase Ib study enrolled pts with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment. Patients received IBI110 200mg IV Q3W and sintilimab 200mg IV Q3W, in combination with lenvatinib (weight <60kg: 8mg, weight ≥60 kg: 12mg) orally administered once daily, until disease progression, unacceptable toxicity or death. The primary objective was to evaluate the safety, tolerability, and efficacy of the combination therapy per RECIST v1.1. Results: As the data cutoff date on January 9th 2023, 28 pts were enrolled (median age: 59 years; ECOG PS=0: 6 pts; stage C per Barcelona Clinic Liver Cancer [BCLC]: 13 pts). All 28 pts were included for safety analysis. Treatment-related adverse events (TRAEs) of any grade occurred in 27 pts (96.4%) and the most frequent TRAEs included hypertension (50%), hypothyroidism (42.9%), neutrophil count decreased (39.3%). Grade ≥ 3 TRAEs occurred in 16 pts (57.1%) and grade ≥3 irAEs occurred in 4 (14.3%) pts. Two (7.1%, 2/28) pts experienced TRAE leading to drug discontinuation. One pt experienced investigator-assessed treatment related death. As of data cutoff, for 27 pts with at least one efficacy evaluation, the objective response rate (ORR) was 29.6% (95% CI, 13.8-50.2). The disease control rate (DCR) was 85.2% (95% CI, 66.3-95.8), and 11 pts were still in treatment. With a median follow up of 12.2 months (95%CI, 11.0-12.6), the median progression-free survival (PFS) was 9.9 months (95%CI, 5.7-NC) and the 9-month PFS rate was 54.5% (95%CI, 33.8-71.2). The median overall survival (OS) was not reached. Conclusions: In this phase Ib study, IBI110 in combination with sintilimab and lenvatinib as first line therapy demonstrated robust response and survival benefit with manageable safety profile in patients with advanced hepatocellular carcinoma. This combination therapy need to be further explored in this population. Clinical trial information: NCT04085185 .
Safety and efficacy of HB0025, an anti-PD-1/VEGF bispecific antibody fusion protein, in patients with advanced solid tumors: Preliminary results from an FIH trial.
Authors: Du Yiqun , Zhang Jian , Sun Meili , Wen Qing , Zheng Yawen , Tolcher Anthony W. , Sommerhalder David , Wang Zhen , Li Xiumin , Gao Zhenyuan , Zhou Huan , Liu Lian , Wang Benjie , Zhu Xiangyang , Yang Yongmin , Yang Yang , Li Chao , Li Jiangfeng 
Published: June 2023

2589 Background: HB0025 is a recombinant humanized anti-PD-L1 monoclonal antibody-VEGFR1 fusion Protein. Nonclinical data both in vitro and vivo have shown high-affinity binding to both targets as well as the inhibition of tumor growth in animal models. Here, we present preliminary safety and efficacy data from a dose escalation phase I study of HB0025. Methods: Eligible patients(pts) were ≥18 years old (ECOG PS 0–1) who had advanced solid tumors (NSCLC, gynecological tumors, digestive system tumors, etc.) and failed standard treatment. This phase 1 dose escalation includes accelerated titration (0.01, 0.03, 0.1 and 0.3mg/kg) and conventional 3+3 dose escalation (1.0, 3.0, 6.0, 10, 12, 20, and 30.0 mg/kg). HB0025 is administered intravenously every 14 days (Q2W). Objectives include evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and antitumor activity. Adverse events (AEs) were reported with CTCAE v5.0 and DLTs were evaluated within a 28-day window. Results: As of Aug 30th 2022, 30 pts including 8 male and 22 female from Caucasian and Mongoloid have received HB0025 at doses of 0.01 mg/kg (n=1), 0.03 mg/kg (n=2), 0.1 mg/kg (n=1), 0.3 mg/kg (n=1),1.0 mg/kg (n=3), 3.0 mg/kg (n=7), 6.0mg/kg (n=7), 10.0 mg/kg (n=5), and 12.0mg/kg (n=3) Q2W. Overall, the median age was 55 years and the median lines of previous treatment was four. Of the 22 evaluable pts dosed at ≥ 3 mg/kg Q2W, the ORR was 9.1% (2/22) and the disease control rate (DCR) was 50% [11/22]. Among the 2 responders, a CR (colorectal ca) pt whose prior therapy was no immune checkpoint inhibitor (ICI) or bevacizumab have continued more than 36 weeks; and a PR (NSCLC) pt with duration more than 18 weeks whose tumor was 60.2% regression and prior ICI failure. Till the date of submission, the therapy was continuing for the CR and PR pts. Treatment-related adverse events (TRAEs) occurred in 83.3% of pts. The grade 3 TRAEs occurred in 20% [6/30] and treatment-related SAEs occurred in 13.3% [4/30]. One DLT occurred in the 12.0mg/kg cohort. No death occurred related to HB0025. TRAEs leading to treatment discontinuation occurred in 13.3% of pts [4/30]. The most frequent TRAEs were hypertriglyceridemia (23.3%), hypercholesterolemia (23.3%), anemia (16.7%), alanine aminotransferase increase (16.7%), and proteinuria (13.3%). Conclusions: HB0025 shows manageable safety and promising anti-tumor activity in pts with various solid tumors. To better characterize the risk-benefit profile, HB0025 is currently enrolled at 20.0 mg/kg Q2W and is being explored at doses 10 mg/kg in expansion cohorts. The future data, including PK, PD and ADA will be presented. Clinical trial information: NCT04678908 .
Partial tumor irradiation plus pembrolizumab in treating large advanced solid tumor metastases.
Authors: Korpics Mark Charles , Onderdonk Benjamin Ernst , Dadey Rebekah E , Hara Jared H , Karapetyan Lilit , Zha Yuanyuan , Karrison Theodore , Olson Adam C. , Fleming Gini F. , Weichselbaum Ralph R. , Bao Riyue , Chmura Steven J. , Luke Jason J. 
Published: June 2023

2593 Background: We previously demonstrated the safety of stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) in patients with advanced solid tumors. This phase 1 clinical trial was expanded to study the safety of partial tumor irradiation (partial-Rx). We assessed irradiated local failure (LF) and clinical outcomes with correlations to biomarkers including CD8-T-cell radiomics score (RS) and circulating cytokines. Methods: Patients received SBRT to 2-4 metastases and pembrolizumab ≤7 days after SBRT. Tumors <65cc received the full radiation dose (complete-Rx), whereas tumors > 65cc received partial-Rx. Landmark analysis was used to assess the relationship between tumor response and overall survival (OS). Multivariable analysis was performed for RS and circulating cytokines. Results: In the combined (expansion plus original) cohort, 97 patients (219 metastases) were analyzed and received SBRT+P. Forty-six (47%) patients received >1 partial-Rx treatment. There were 7 (7.2%) dose-limiting toxicities (DLTs). 1-year LF was 7.6% overall, and 13.3% and 5.4% for partial-Rx and complete-Rx tumors, respectively (hazard ratio 2.32, 95% confidence interval: 0.90-5.97, p = 0.08). The overall, unirradiated, and irradiated objective response rate was 22%, 12%, and 34%, respectively. Irradiated tumor response to SBRT+P was associated with prolonged OS; 1-year OS was 71% (responders), 42% (mixed-responders), and 0% (non-responders) (p < 0.01). High-RS was significantly associated with improved LF, progression-free survival (PFS), and OS. Elevated circulating IL-8 was independently associated with inferior PFS and OS. Conclusions: SBRT+P is safe in patients with large, advanced solid tumors. Additional studies are warranted to assess non-inferiority of complete versus partial irradiation of tumors in the setting of immunotherapy. Clinical trial information: NCT02608385 .
Immune checkpoint inhibitor in high-risk oral potentially malignant disorders (IMPEDE study): An interim analysis on safety.
Authors: Alberti Andrea , Romani Chiara , Paderno Alberto , Battocchio Simonetta , Ardighieri Laura , D'Ambrosio Consuelo , Pellini Raul , Peretti Giorgio , Cossu Rocca Maria , Ansarin Mohssen , Boscolo Rizzo Paolo , Azzi Lorenzo , Lodi Giovanni , Gervasoni Carlo , Vecchio Stefania , Bardellini Elena , Majorana Alessandra , Piazza Cesare , Facchetti Fabio , Bossi Paolo 
Published: June 2023

2595 Background: Oral Potentially Malignant Disorders (OPMD) represent the most common oral precancerous condition, with a variable risk of malignant transformation. The most effective biomarker in predicting malignant transformation risk is loss of heterozygosity (LOH). Patients (pts) carrying OPMD with LOH at 3p14 and/or 9p21 plus LOH at another locus have an expected 3-year risk of developing oral cancer of 35%. This chromosomal profile is found in about 30% of OPMD. IMPEDE is a phase II, open-label, single-arm trial designed to evaluate the efficacy of PD-L1 inhibitor avelumab in reverting cancer transformation risk in OPMD with LOH. In this analysis, we report the first safety results, while data about treatment activity need longer follow up. Methods: During the screening period, pts undergo OPMD biopsy. If pathological diagnosis of dysplasia is confirmed, LOH valuation is performed and in case of positivity of this biomarker, subjects receive a short course of immunotherapy with avelumab 800 mg every 2 weeks for 4 total administrations. Follow-up after last avelumab dose is performed monthly and adverse event data are collected at every visit. Six months after treatment start, surgery and LOH re-assessment are performed. Results: Between November 2020 and December 2022, 49 pts were screened in 8 Italian centers. Of these, 16 pts (33%) had a LOH and 12 received the treatment (3 males, median age 65.5 years, range 49-81). Nine out of 12 treated patients had a previous oral cancer. After a median follow up of 14 months, 39 adverse events (AE) of any grade were reported, of these 18 were considered as immune related AEs (irAE). The most frequent AEs was grade 1 (G1) oral pain (4/12 pts), managed with local painkillers. Only three G2 irAEs were reported, namely amylase/lipase increase, psoriasis and fever. No grade 3-4 AEs were described, and no patient had to stop immunotherapy because of toxicities. Local excision after immunotherapy was not delayed by any treatment toxicities. Conclusions: This is the first trial with immunotherapy in an enriched population of OPMD selected according to LOH. First results support the feasibility of this approach, showing that immunotherapy with avelumab is safe and does not compromise subsequent local surgery. Clinical trial information: NCT04504552 .
Phase 1B study of avelumab and whole brain radiotherapy (WBRT) in patients with leptomeningeal disease (LMD) from epithelial carcinomas: Final results and molecular analyses with single cell RNA sequencing.
Authors: Pina Yolanda , Chen Ann , Arrington John , Macaulay Robert J , Tran Nam D. , Liu James K , Mokhtari Sepideh , Li Jiannong , Law Vincent , Sahebjam Solmaz , Ahmed Kamran A. , Creelan Ben C. , Gray Jhanelle Elaine , Evernden Brittany , Khushalani Nikhil I. , Smalley Inna , Vogelbaum Michael A. , Yu Michael , Smalley Keiran , Forsyth Peter A. J. 
Published: June 2023

2598 Background: Leptomeningeal disease (LMD) from epithelial cancer has a dismal prognosis with median overall survival (OS) of 3-4 months (mo) using PD-1 axis blocking therapy. Preclinical studies showed that this combination promotes antigen presentation within the CSF compartment, increases BBB permeability and increases ingress of activated T cells into the meninges/CSF space. In an open-label phase IB trial, we tested the safety and efficacy of Avelumab in combination with WBRT in patients with LMD (NCT0371768). Methods: Patients received concurrent Avelumab 800 mg IV q2 weeks for up to 5 cycles (until PD or unacceptable toxicity) with WBRT 3000 cGy in 10 daily fractions. Primary endpoints were safety/DLTs and 3-month OS. Secondary endpoints included CSF T-cell transcriptome trajectory i.e., single cell RNA sequencing (scRNAseq). Patients with prior PD-1/PD-L1/CTLA-4/CD137 targeting therapy within 6 mo were excluded. Results: 15 patients were enrolled with disease sites that included breast (8), lung (4), nasopharyngeal (1), ovary (1), and pancreas (1). Patients were 87% female, median age 59 range 32-82. One patient did not complete WBRT. Two of 15 patients had grade 3/4 immune-related AEs (i.e., hypoadrenalism, hypothyroidism, lymphopenia); 5 patients had treatment-related <grade 3 AEs, including hypoadrenalism, anemia, diarrhea, hypothyroidism, lymphopenia, thrombocytopenia, leukopenia). There were no grade 5 toxicities. Median follow up was 3.7 mo (range, 0.9-36.8 mo; 95% CI 1.3-14.7 mo). The median follow-up time for survival analyses of the study was 19.8 mo. Ten out of 15 patients (66.7%) were alive at 3 mo. Median OS was 10.5 (95% CI 1.2 - 19.8 mo). 1-year OS was 44% (95% CI: 19-68%). Median PFS was 4.3 mo (95% CI, 0.9-15.2 mo), Fig. 3B. Two patients remain alive and clinically well. ScRNAseq analyses are underway; signatures correlated with outcomes in short versus long term survivors. Conclusions: The combination of Avelumab and WBRT is safe, well tolerated, and demonstrates encouraging activity in patients with LMD with an OS that is longer than other published series. Multiple platform interrogation of CSF will be used to explore mechanisms of LMD response and resistance. Functional studies of scRNAseq and short versus long term survivors should be further explored. Clinical trial information: NCT03719768 .
DURTRERAD: A phase II open-label study evaluating feasibility and efficacy of durvalumab (D) and durvalumab plus tremelimumab (DT) in combination with radiotherapy (RT) in non-resectable locally advanced HPV-negative head and neck squamous cell carcinoma (LA-HNSCC).
Authors: Keilholz Ulrich , Gauler Thomas Christoph , Stromberger Carmen , Kofla Grzegorz , de Wit Maike , Mette Ramona , Burock Susen , Klinghammer Konrad Friedrich 
Published: June 2023

2611 Background: Concurrent platinum-based chemo-RT is the standard treatment for LA-HNSCC, despite of limited efficacy in poor-risk patients and long-term toxicity. Targeting PD-L1 with D has activity in recurrent/metastatic (RM)-HNSCC, and the combination with the CTLA4 targeting agent T was considered to augment the immunotherapy efficacy of a chemotherapy-free regimen. Thus DURTRERAD was designed as a randomized two-arm phase II study to investigate, whether D or DT combined with RT was feasible in the patient population and a 1-year progression free survival rate of 50% was reached. Methods: The phase II study planned to enroll 60 patients in each treatment arm. Key selection criteria were patients with advanced HPV negative unresectable HNSCC planned for definitive radiotherapy. Treatments: First dose of immunotherapy 14 days prior to start of RT (70Gy over 7 weeks). D (1500mg q 3 weeks x 13) or DT (D: 1500mg q 3 weeks x 13 + T: 4 x 75 mg in weeks 5,9,13,17). Planned treatment duration was 51 weeks in both arms. Treatment was considered feasible in case of <10% treatment discontinuations. An interim analysis for feasibility was planned after treatment of 6 patients per arm and a futility analysis was performed after treatment of 18 patients, resulting in premature closure of the trial. Results: Patient accrual in 4 centers in Germany from 9/2018 - 9/2020. The interim feasibility analysis of DT revealed that 5/6 patients stopped treatment due to 1 grade 5 and 1 grade 4 immune related AE and 3 non-immune related AEs, respectively. Thus, the DT arm was prematurely terminated, and only the D monotherapy arm continued. Futility analysis of D monotherapy: One of 12 patients stopped treatment due to immune related toxicity, and 7 patients experienced disease progression on treatment or died within the first year. The median PFS was 39 weeks, the 1 year PFS rate was 42%. Conclusions: Even though D was previously proven as an active agent in RM-HNSCC, and there DT was not associated with increased toxicity, DT in combination with RT was not feasible in our poor prognostic, vulnerable patient cohort of HPV negative LA-HNSCC. D monotherapy in combination with RT was well tolerated, but revealed a low level of efficacy, when administered in the trial schedule, starting 2 weeks prior to RT. Similar to results in lung cancer, start of immunotherapy after completion of radiotherapy may be of interest. Clinical trial information: NCT03624231 .
MyTACTIC: Afficacy and safety of atezolizumab (atezo) + chemotherapy (chemo) in patients (pts) with advanced unresectable/metastatic solid tumors with high tumor mutational burden (TMB-H) or high microsatellite instability (MSI-H)/deficient mismatch repair (dMMR).
Authors: Spigel David R. , Hussein Maen A. , Zuniga Richard , Mahadevan Daruka , Winn Robert , Darbonne Walter C. , Yoo Bongin , Kim Young , Whitehead Zach , Vanderwalde Ari M. 
Published: June 2023

2612 Background: MyTACTIC (NCT04632992) is a phase II, non-randomized, multi-arm basket study evaluating targeted therapies as single agents or combinations in pts with advanced solid tumors with specific biomarkers. We present the efficacy and safety of arm E from MyTACTIC: atezo + chemo in pts whose tumors have TMB-H and/or MSI-H/dMMR. Methods: Enrolled pts were ≥18 years old, with histologically/cytologically confirmed advanced unresectable/metastatic solid tumors with TMB-H (TMB≥10 mut/Mb) and/or MSI-H/dMMR and ECOG PS ≤2; those with symptomatic/actively progressing CNS metastases were excluded. Pts received intravenous atezo 1200 mg every 21 days and physician’s choice chemo (docetaxel; paclitaxel; capecitabine) until progressive disease (PD), toxicity or death. Primary endpoint: investigator-assessed confirmed objective response rate (cORR). Secondary endpoints included disease control rate (DCR; confirmed complete response [CR] + partial response [PR] + stable disease [SD] or non-CR/non-PD for ≥70 days), duration of response (DOR), progression-free survival (PFS) and safety. Results: At data cutoff (May 16, 2022), 25 pts with 10 tumor types had received atezo + chemo. Median age was 69 years (range 37–83), 88% of pts had ECOG PS ≤1 and 20 pts with metastatic disease had a median of 1 prior line of therapy (range 1–4). Twenty-three pts had TMB-H (2 missing), 7 had MSI-H and 7 had dMMR (12 missing); 7 pts had TMB-H and MSI-H/dMMR. cORR was 28.0% (7/25; 95% CI 12.1–49.4), including 1 CR (colon cancer) and 6 PRs. Responses were observed in 6/10 tumor types studied. cORR was 12.5% in pts with TMB-H alone (2/16) and 71.4% (5/7) in pts with TMB-H and MSI-H/dMMR. DCR was 32.0% (8/25; 95% CI 14.9–53.5). Median DOR and median PFS were 7.4 months (95% CI 7.4–not estimable) and 3.9 months (95% CI 2.2–8.4), respectively. The safety profile of atezo + chemo was consistent with previous reports for this combination. The most common treatment-related adverse events (TRAEs) were diarrhea (60%) and fatigue (32%). Grade 3/4 TRAEs occurred in 32% of pts and there were no serious or grade 5 TRAEs. Conclusions: In this small cohort, treatment with atezo + chemo demonstrated clinical activity in pts with advanced solid tumors with TMB-H and/or MSI-H/dMMR. Responses were observed in different tumor types and were numerically higher in pts whose tumors had both biomarkers vs those with TMB-H alone. Further analyses with a larger cohort and longer follow-up will be required to confirm these results. Clinical trial information: NCT04632992 . [Table: see text]