bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of immune related adverse events following extended interval dosing of immune checkpoint inhibitors.
Authors: Deviley Jake Anthony , Hayashi-Tanner Yacki , Frankki Susan M , Marinier David E.
Published: June 2023

e14605

Background: Increased use of immune checkpoint inhibitors (ICI) has resulted in a rise in immune related adverse events (irAEs). In 2019, pembrolizumab and nivolumab received approval for extended interval (EI) dosing at 400 mg intravenous (IV) every 6 weeks and 480 mg IV every 4 weeks, respectively, compared to the standard interval (SI) dosing of 200 mg IV every 3 weeks and 240 mg IV every 2 weeks, respectively. Since EI dosing has been implemented, clinicians have hypothesized increased dosing may lead to more irAEs. Mixed results have been published to date with discordant results between studies. The aim of this study was to investigate the incidence and grade of irAEs, including multisystem adverse events (ms irAEs) in SI versus EI dosing in a real-world community-based hospital system in the United States of America. Methods: We performed an Institutional Review Board approved retrospective study of all patients 18 years or older who received SI or EI dosing of pembrolizumab or nivolumab from 2015 through 2021. An irAE was considered connected to the specific dosing group if it was observed after the first date of stated dosing and within 90 days after last dose of such dosing. Statistical analysis included descriptive statistics, Wilcoxon signed-rank test, Fisher’s exact test, and Kaplan-Meier survival analysis and was performed in R version 4.2.2 at a significance level of 0.05. Results: Our study included 458 patients who were 99% white, 59% male, and an average age of 67 years. There were 354 (77%) patients in the SI group and 104 (23%) in the EI group. The overall incidence of irAEs was 32% (146 patients), of which 37% (54 patients) presented at some point with ms irAEs. There was no significant association between dosing group and presence of irAEs (p = 0.087), grade groups 1-2 vs > 3 (p = 0.7), or ms irAEs (p = 0.13). The incidence of irAEs was 34% (120 patients) in the SI group with a distribution of grades 1-2-3-4-5 being 39-62-25-5-1, respectively. The incidence of irAEs was 25% (26 patients) in the EI group with a distribution of grades 1-2-3-4-5 being 18-27-11-1-0, respectively. In the SI group there were 41 (34%) patients with ms irAEs compared to 13 (50%) in the EI group. There was a significant association between dosing groups and overall survival (p < 0.001). Conclusions: Our results lend data to suggest there is indeed no statistically significant risk of increased irAEs with EI dosing. However, there may be a clinically significant trend toward increased ms irAEs in EI dosing that needs further investigation with comparisons of comorbid conditions that increase risk of autoimmune reactions. Of note, the OS in EI dosing group was statistically significant but likely heavily confounded due to patient selection bias, this may also be an avenue for future research to be conducted with a randomized clinical trial.
Effect of hypofractionated radiotherapy, PD-1 immunotherapy, and anti-angiogenic therapy on abscopal responses and the tumor microenvironment.
Authors: Han Guang , Dong Zhiqiang , Li Chunhui , Bi Jianping , Yi Ding , He Hanping , Wei Wei , Pi Guoliang , Li Ying , Li Yanping , Zhang Li , Verma Vivek , Hu Desheng
Published: June 2023

e14609

Background: Hypofractionated radiotherapy (HFRT) of the primary tumor can induce abscopal effects in metastatic cancer, which could be enhanced by adding PD-1 immunotherapy (IO) and low-dose radiotherapy (LDRT) of distant disease. However, this strategy remains with suboptimal efficacy. Translational research has shown that LDRT primarily modulates the immune microenvironment of tumors in the irradiated area, a mechanism shared by anti-angiogenic therapy (AAT). Therefore, this study aimed to compare the efficacy (abscopal responses and cytokine levels in the tumor microenvironment) between HFRT+IO+AAT and HFRT+IO+LDRT. Methods: Bilateral mouse tumor models were divided into seven groups for various treatments (Table 1). After treatment, blood and tumor samples of mice were collected for analysis. We evaluated clinical effects of HFRT+IO+AAT in 4 patients with unirradiated lung metastases in a currently-accruing phase Ib study of stereotactic body radiotherapy (SBRT) plus anlotinib (AAT) with or without toripalimab (PD-1 IO) in driver mutation-negative non-small cell lung cancer (NCT05021328). Results: The results of animal studies are shown in Table 1. HFRT to the primary tumor combined with AAT and IO enhanced the abscopal response in secondary tumor compared to HFRT, HFRT+IO, HFRT+AAT, IO+AAT, as well as HFRT+LDRT+IO. The most noteworthy secondary tumor control was observed in mice receiving HFRT+IO+AAT. The enhanced abscopal responses were associated with increased infiltration of CD8+ effector T cells, increased expression of IFN-γ and levels of TNF-α. From the prospective trial population, 4 unirradiated lung lesions in the HFRT+IO+AAT cohort decreased by an average of 48% in size (n=3 partial response, n=1 stable disease). No grade 3 treatment-related toxicity was observed. Conclusions: HFRT+IO+AAT is a promising therapeutic combination that may optimize abscopal responses, potentially even further than HFRT+LDRT+IO. This new “triple therapy” was safe and efficacious in patients and deserves further study. [Table: see text]
Outcomes for immuno-chemotherapy based treatment in patients with poorly differentiated extrapulmonary neuroendocrine carcinoma.
Authors: Kumar Sakthi , Talabi Toluwalase , Mahmoudieh Mahta , Pennington Daniel , Saboda Kathylynn , Arshad Junaid , Scott Aaron James
Published: June 2023

e14619

Background: Extrapulmonary neuroendocrine carcinoma (EP-NEC) represents a rare collection of neuroendocrine cancers characterized with a poor prognosis and modest treatment benefit similar to small cell lung carcinoma (SCLC). Platinum-based chemotherapy (cisplatin or carboplatin) and etoposide is the preferred 1st line therapy for patients (pts) with metastatic EP-NEC who are not eligible for curative surgery (Frizziero et al. 2019). Studies in pts with advanced SCLC have shown improved progression free survival (PFS) and overall survival (OS) with the addition of atezolizumab, an anti-PD-L1 monoclonal antibody, to induction chemotherapy (4 cycles) versus chemotherapy alone (Horn et al. 2018). Prospective trials investigating immune checkpoint inhibitors such as atezolizumab plus chemotherapy have yet to be published in EP-NEC. Methods: We retrospectively reviewed all registered pts at the Gastrointestinal Medical Oncology Clinic at Banner-University of Arizona Cancer Center who received at least 1 dose of atezolizumab from 1/2017 through 3/2022 (UAIRB00001593). Criteria for pt selection for analysis was based on the following: pts diagnosed with grade III, Ki 67>20%, poorly differentiated, metastatic EP-NEC and treated with ≥ 1 dose of atezolizumab plus chemotherapy as 1st line treatment. Results: Ten pts received atezolizumab based therapy during this timeframe. 6 pts met criteria for analysis and 4 pts were excluded for alternative diagnoses. 4 pts were female, 2 pts were male, and the average age at diagnosis was 63.8 years. The median number of chemotherapy cycles was 7.0 [4-17]. The median number of atezolizumab doses was 7.5 [6-28]. The median PFS was 7 months (95% CI 5-*). The median overall survival (mOS) was 13 months (95% CI 8-*). The mOS since starting atezolizumab was 12 months (95% CI 8-*). [*Upper bound of 95% CI cannot be determined.] Five pts (83%) demonstrated a partial response per RECISTv1.1. All pt tumors were MMR-proficient/MSI-stable and PD-L1 expression was negative in 3 pts (PD-L1 status unavailable for 3 pts). No hospitalizations related to immunotherapy or chemotherapy were observed. The most common adverse events included nausea, diarrhea and fatigue. One immune-mediated adverse event of thyroid dysfunction was observed and successfully medically managed. Conclusions: Our experience with atezolizumab plus chemotherapy for 1st line EP-NEC pts demonstrated efficacy via high response rate and survival rates above historical experience. Continuing chemotherapy beyond the induction phase until maximum clinical response demonstrated tolerability with manageable side effects. Although the scope is limited due to sample size, this data supports further investigation of this combination. There is an ongoing large, randomized, prospective trial investigating this regimen in frontline, metastatic EP-NEC pts ( NCT05058651 ).
Peripheral immunological response to treatment with a novel bifunctional anti-PD-L1/TGFβRII agent in recurrent/metastatic nasopharyngeal carcinoma.
Authors: Kam Ngar Woon , Lau Jeffrey Yan Ho , Dai Wei , Chiang Chi Leung , Che Chi Ming , Lee Victor Ho-Fun , Kwong Dora Lai Wan
Published: June 2023

e14622

Background: Anti-programmed cell death protein-ligand 1 (PD-L1) monotherapy has not shown promising anti-tumor effects in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC) in first-line settings. Consequently, second-generation checkpoint inhibitors via targeting multiple pathways are urgently needed. Bintrafusp alfa (also known as M7824) is one of such agents that targets both the transforming-growth factor beta (TGF-β) and PD-L1 pathways. As T cells are the major immune cell subset responsible for tumor destruction, we focus on the peripheral memory T-cell subsets. Through the evaluation of peripheral biomarker analysis and their correlation with clinical outcomes, we have characterized blood-based dynamic phenotypes that predict responses to M7824 in NPC. Methods: Biomarker analysis was performed as part of a phase II clinical trial (NCT04396886) in patients with treatment-refractory histologically confirmed recurrent NPC (n=32) who received M7824. Peripheral blood samples were obtained at baseline before treatment (D0) and every 2 weeks during treatment. Samples collected at D0 and at time of best response assessment (DR) were analysed using multicolor flow cytometry. Patients with complete/partial response or stable disease for at least 6 months were considered responders (R), those with stable disease less than 6 months or progressive disease were considered non-responders (NR). Results: Peripheral T cells between R (n=10) and NR (n=22) patients were compared. While the overall percentage of memory T-cell subsets was similar in both groups after treatment, R patients displayed a significantly lower amount of prototype cell death receptor, CD95, among terminally differentiated effector memory (TEMRA; CD45RA+CD62L+) T cells (CD45+CD3+and CD45+ CD3+CD4+: p<0.0001; CD45+CD3+CD8+: p=0.0047) (CD95DR/RvsNR) as compared to patient in NR group. Besides, reduced expression of CD95DR on TEMRA CD4 T cells was significantly associated with longer overall survival (OS), regardless of response status (median OS: 16.26 months for patients with lower CD95 levels; median OS: 5.29 months for patients with higher CD95 levels [p < 0.0001]). Notably, we noticed that R patients displayed a lower frequency of CD95-expressing TEMRA at the baseline (CD95D0/Rvs NR) as compared to NR group. Conclusions: The apoptotic response of peripheral blood TEMRA CD4 T cells (CD95DR/R vsNR) may be a useful surrogate biomarker for predicting prognosis to M7824 therapy in NPC. The finding of a lower frequency of CD95D0TEMRA in R patients suggesting that CD95 may potentially act as a biomarker for predicting treatment response as well as reveal a possible target for guiding therapeutic strategy for R/M NPC.[Table: see text]
Neoadjuvant tislelizumab, a PD-1 mAb plus nab-paclitaxel (nab-P) followed by tislelizumab plus epirubicin/cyclophosphamide (EC) for triple-negative breast cancers (TNBC): Interim analysis of clinical response in a phase 2 TREND trial.
Authors: Xu Yingying , Zhang Qiang , Zhu Bo , Wang Mozhi , Yao Litong
Published: June 2023

e14623

Background: Chemo-based immunotherapy improves the prognosis of TNBC. However, the dominant population and optimal chemo-backbone of neoadjuvant immunotherapy remain undefined. Aim of TREND trial was to assess the efficacy and safety of tislelizumab in combination with nab-P and EC (nab-P-EC) in neoadjuvant therapy of TNBC. Methods: In this prospective, single-arm phase 2 clinical study, untreated TNBC patients who have clinically node-positive or at least T2 disease without distant metastasis were eligible. Before surgery, enrolled patients received tislelizumab (200 mg IV Q3W) plus weekly nab-P (100 mg/m² IV Q3W) for 12 weeks, followed by tislelizumab (200 mg IV Q3W) plus epirubicin (75 mg/m² IV Q3W) and cyclophosphamide (600 mg/m² IV Q3W) for the subsequently 12 weeks. The primary endpoint was pCR (ypT0/Tis ypN0) and secondary endpoints was objective response rate (ORR, RECIST v1.1). Combined positive score (CPS) of PD-L1 expression in pre-treatment biopsy samples was tested by PD-L1 IHC 22C3 PharmDx. Single-cell RNA sequencing, single-cell TCR sequencing, mass cytometry by time of flight, whole exome sequencing, RNA-seq and olink-assay were performed on pre- and post-treatment samples from primary tumors, metastatic lymph nodes and peripheral blood. Results: Of 43 enrolled patients from Nov 2020 to Nov 2022, 21 patients completed neoadjuvant therapy and accepted surgery in per protocol set (PPS; median age 48 years; range 25-69 years), and 16 were still on treatment. In PPS, the pCR (ypT0/is ypN0) rate was 71.43% (15/21). For different target lesions, 15 patients achieved ypT0/Tis (pCR rate = 71.43%) and 20 reached ypN0 (pCR rate = 95.24%). When stratified by CPS, pCR (ypT0/is ypN0) rate were 68.4%,72.2% and 76.9% in CPS ≥ 1, CPS ≥ 5 and CPS ≥ 10 subgroups, respectively. The ORR in PPS was 90.48% (n = 19/21, 95% CI: 68.18 - 98.33) and DCR reached 95.24% (n = 20/21, 95% CI: 74.13 - 99.75), including 9 complete response and 10 partial response. Treatment emergent adverse event (TEAE) occurred in 74.4% patients (32/43), of which 69.8% were Immune-related adverse event (irAE) (30/43). Grade ≥ 3 IrAE was 7.0% (3/43) and no treatment-related deaths were found. Conclusions: Combining tislelizumab and neoadjuvant nab-P-EC achieved favorable efficacy in TNBC, supporting that platinum-free regimen was non-inferior as a chemo-backbone. For heterogeneity of efficacy to immunotherapy, metastatic tumors in lymph nodes responded better to tislelizumab than primary tumor, suggesting that node-positive patients were potentially dominant population of neoadjuvant immunotherapy. Further results from the ongoing TREND trial and subsequent analysis of mechanism are urgently awaited. Clinical trial information: ChiCTR2000035262 .
Treg cells and the response to neoadjuvant chemotherapy combined with immunotherapy in resectable esophageal squamous carcinoma.
Authors: Jiang Bo , Yang Xin , Yu Pengyi , Zhang Chu , Li Chunyang , Tang Wenhua , Zhang Junling , Huang Mengli
Published: June 2023

e14626

Background: More and more studies focus on the neoadjuvant chemotherapy combined with immunotherapy (chemo-immunotherapy) in resectable esophageal squamous carcinoma (ESCC). Herein, we aimed to evaluate the efficacy and safety of neoadjuvant programmed cell death protein 1 inhibitors with chemotherapy and explore tumor microenvironment (TME) profiles. Methods: Patients with previously untreated, resectable, stage III ESCC in the third affiliated hospital of Soochow University were enrolled. Each patient received two-four cycles of neoadjuvant chemo-immunotherapy before surgical resection. The TME profiles of formalin-fixed paraffin-embedded tumor samples at baseline were evaluated by multiplex immunofluorescence to discover novel biomarkers of response to neoadjuvant chemo-immunotherapy. Results: Twenty patients were included, all of whom underwent R0 resection. 85% (17/20) of patients underwent 2 cycles of neoadjuvant therapy. TP53 (13/20,65%) was were high-frequency mutated gene, followed by CDKN2A (5/20,25.0%) and PIK3CA (3/20, 15.0%). PD-L1 positive (TPS≥1%) was found in only 3 patients. Postoperative pathological evaluation showed that 18 patients (90.0%) were major pathologic response (MPR), of which 5 patients (28.0%) achieved pathological complete response (pCR). Neoadjuvant therapy has acceptable side effects. TME profiles at baseline showed no significant correlation between PD-L1 and pathological response. The density of Treg cell in the tumor area was significantly lower in pCR patients than in MPR patients (P=0.0302). Conclusions: Neoadjuvant chemo-immunotherapy was well tolerated and was effective therapy for resectable ESCC. Treg cells may serve as potential predictive biomarkers.
Clinical and pathological description of patients with triple negative breast cancer undergoing neoadjuvant chemotherapy and pembrolizumab in a Brazilian cancer center.
Authors: Sousa Isadora Martins de , Marin Comini Ana Carolina Carolina , Borges Italo Barradas e Silva , Tavares Monique Celeste
Published: June 2023

e14632

Background: High-risk early triple-negative breast cancer (TNBC) is frequently associated with early recurrence and high mortality. Studies suggest a sustained clinical benefit in patients with TNBC who have a pathological complete response (PCR) after neoadjuvant chemotherapy (NACT). In TNBC, the combination of cancer immunotherapy based on PD-1/PD-L1 immune checkpoint inhibitors with chemotherapy was effective both in advanced and early setting phase 3 clinical trials, in this last scenario the addition of pembrolizumab to platinum containing NACT resulted in a significant increase of pathological complete response. Methods: We performed a retrospective observational cohort study of patients with early TNBC, stage I-III who received neoadjuvant treatment with chemotherapy based on doxorubicin, cyclophosphamide, paclitaxel and carboplatin associated with pembrolizumab treaties from January 2022 to January 2023, in AC Camargo Cancer Center, São Paulo, Brazil, to evaluate their clinical-pathological characteristics. Results: All 52 patients were women, 60,4% premenopausal, with a median age of 42 years old when diagnosed, 59.6% had comorbidities, most commonly hypertension, and 1.9% had an autoimmune disease. About 16.7% germline mutation in the BRCA 1 and 8.3% in the BRCA 2 gene. Regarding pathological characteristics of the tumor, 98% were invasive ductal carcinoma, 78% with histological grade III, 89.8% had nuclear grade III, 51.1% with score 3 mitoses. There were 56,3% with weak, 35,4% with moderate, and 8,3% with intense Tumor Infiltrating Lymphocytes Stromal (TILS). In 47.1% of cases, the ki67 was greater than 80%. The expression of HER 2 was low in 23,8%. About the clinical stage of the tumor 65.4% were cT2 and 17.3% cT3, being cN0, cN1 and cN2a was 40.4%, 36.5% and 13.5%, respectively and grouped clinical stage 40.45 IIA, 25% IIB and 19.2% IIIA. Treatment-related toxicities 20% patients had immune related toxicities, being the main one 30% endocrinologic and 20% hepatic, being that 36.4% occurring after the second cycle. Due to the toxicities, 22.2% of the patients had their treatment delayed. In terms of treatment, 68.6% had begun with platinum and taxane, and 7.8% received dense dose AC (ACdd). Now, only 42.6% of the patients have completed all NACT and 53.2% are still on treatment. From these, 56.8% had complete clinical response, 2.3% stable disease and and those who have already finished and operated 66.7% complete pathological response. Conclusions: Our cohort is mostly pre-menopausal cT2, cN0, stage IIA. Twenty percent of them had IRT, the most common being endocrine and hepatic, which occurred early after the second cycle, leading to treatment delay in 22.2%. About 8% received ACdd, of the patients who completed the treatment and underwent surgery, 66.7% had a complete pathological response.
Tissue cadherin 17 (CDH17): A favorable prognostic determinant of colorectal cancer using digital image analysis.
Authors: Ng Lui , Sun Stella , Shan Wing Yu , Leung Pauline , Luk John Moon , Foo Dominic Chi-Chung
Published: June 2023

e14651

Background: Colorectal cancer (CRC) is the third most diagnosed malignancy and the second leading cause of cancer-death globally. The identification of robust prognostic markers for risk stratification of CRC would facilitate the accurate selection of high-risk patients for adjuvant therapies, hence improving patients’ survival and quality of living. Cadherin 17 (CDH17) is a validated biomarker for CRC characterized by its overexpression in tumor tissues (Zheng et al., 2021). CDH17 expression in tissue samples can be reliably detected by immunohistochemistry (IHC), which could potentially provide useful information for malignancy monitoring and prognosis. Nevertheless, the implementation of IHC in clinical settings is hindered by the lack of standardized guidelines. In this regard, the present study employed a standardized automated IHC platform and a digitalized sample scoring system to investigate CDH17 tissue expression and examine its clinical prognostic value in CRC. Methods: IHC was performed to assess CDH17 expression on paired tumor and adjacent non-tumor tissues from a cohort of 198 retrospective CRC cases, using the Lic3 antibody and an automated IHC system integrated with AI-digital imaging analysis. The M-score was generated for CDH17 membrane staining according to the formula (1 × % of weakly stained cells + 2 × % moderately stained cells + 3 × % of strongly stained cells)/6. Clinical correlation analysis with TNM, differentiation, and metastasis was determined. The prognostic value of tissue CDH17 was evaluated by Kaplan-Meier curves and Cox regression analyses on patients’ OS and RFS. Comparison of M-score and pathologist visual scoring was made to assess the validity of software-derived IHC scoring. Results: A significantly higher tissue CDH17 level was observed in CRC patients with advanced tumour staging (Early vs. Late stage, p = 0.0493; Mann-Whitney U test) and distant metastasis (p = 0.0188; Mann-Whitney U test). CRC patients with high M-score (M-ScoreHigh; cut-off = 30) were associated with poorer OS and shorter RFS (OS, p = 0.015; RFS, p = 0.018; Log-rank test). Subgroup analysis revealed that M-ScoreHigh in early-stage CRC predicts patients’ disease recurrence of less than 2 years after curative surgery (p = 0.025; Log rank test). Multivariate cox regression analysis showed that CDH17 was an independent prognostic factor for OS (HR = 1.918, 95% CI = 1.001-3.676, p = 0.05). A comparison of software-derived CDH17 M-score with pathologist scoring demonstrated good correlation of 0.7257 (p < 0.0001, n = 36; Pearson correlation). Conclusions: The present study suggests that CDH17 is a potential biomarker of poor prognosis for CRC. Quantification of tissue CDH17 level using a standardized automated IHC platform and digital image analysis could aid in patient stratification which allows efficient treatment strategies for better survival outcomes.
Efficacy of STC-1010, a new allogenic cancer vaccine in colorectal cancer models.
Authors: You Benoit , Tortorelli Corinne , Wang Yan , Peyronnier Arnaud , Bessede Alban , Gongora Céline , Pinteur Benoit , Chalus Lionel , Alzeeb George , Bravetti Paul , Ghiringhelli François
Published: June 2023

e14661

Background: Colorectal cancer (CRC) is the second cause of cancer-related death worldwide. Recent tremendous progresses have installed immunotherapy as a treatment option and opened multiple ways to address therapeutic challenges for MSI or MSS CRC patients. Accordingly, Brenus-Pharma developed a therapeutic cancer vaccine, the STC-1010, basing on the technology by stimulating tumor cells (STC) with physical (irradiation and heat shock) and chemical (via standard-of-care (SoC) chemotherapy) stress, coupled with the haptenization for overexpressing tumor-related antigens. Methods: The mouse version of STC-1010 (mSTC-1010) vaccine prepared using two CRC mouse cell lines (CT26 and CMT93) and one pancreatic cancer mouse cell line (LTPA), previously showed encouraging results in pre-clinical studies on MSS CT26 ‘cold-tumor’ and anti-PD1 resistant MSI MC38 ‘hot-tumor’ murine models. mSTC-1010 associated with immunostimulant (cyclophosphamide and GM-CSF at low doses), combined or not with chemotherapy (FOLFOX or FOLFIRI) led to a significant decrease of tumor volume, a M1-oriented macrophage response (immunohistochemical, iNOS/CD163 > 1), and an increase of T lymphocyte infiltration. Results: We confirmed these proof-of-concept efficacy with the human STC-1010 using three CRC human cell lines (HCT116, HT29 and Lovo). STC-1010 favored ex vivo an immune stimulation on human dendritic cells (DCs) which further primed CD8+ T cells to induce massive apoptosis of CRC cells (versus control). In HT29 in-ovo chicken embryo Chorio-Allantoid Membrane (CAM) assay, STC-1010 significatively increased IL-12, IL-2 and IFN-gamma expression (versus control) (p < 0.02). Results from this immune reactive model showed significant increase of tumor necrosis (p = 0,0267), metastasis regression (-49%), and increase infiltration of CD4+, CD8+ compared to control group. Conclusions: The good tolerability of the STC-1010 vaccine in different models allows to plan a first-in-human phase I/II clinical trial with MSS and MSI-H metastatic CRC (mCRC) patients. A dose-escalation phase Ia (STC-1010 plus immunostimulant, associated to mFOLFOX6 w/o bevacizumab) will be performed with MSS mCRC patients to evaluate the safety and the recommended phase 2 trial dose (RP2D). A subsequent expansion phase IIa part will assess STC-1010 efficiency, associated with SoC in first-line setting for MSS patients, and in second-line setting after immunotherapy for MSI-H, dMMR or Lynch syndrome mCRC patients.
SI-B003 (PD-1/CTLA-4) in patients with advanced solid tumors: A phase I study.
Authors: Wang Yakun , Li Yongsheng , Liu Jiyan , Luo Su-xia , Li Qi , Zou Wen , Wang Zhaoxiang , Peng Yujia , Xiao Sa , Wang Hongwei , Zhu Hai , Olivo Martin Sebastian , Zhu Yi , Shen Lin
Published: June 2023

e14668

Background: Although marketed antibodies against PD-1/L1 or CTLA-4 have been shown to be efficacious in a variety of tumors, the overall response rate (ORR) remains low. SI-B003 is a PD-1/CTLA-4 bispecific antibody. We hypothesized that co-targeting PD-1 and CTLA-4 simultaneously could achieve a better anti-tumor activity due to cooperative binding to exhausted T-cell subsets. Methods: Patients with recurrent or metastatic solid tumors who had failed standard therapy were eligible to participate. SI-B003 was administered intravenously every other week (Q2W) in a four-week cycle. The phase Ia dose escalation consisted of an accelerated titration phase (the first 2 dose levels) and a mTPI-2 with a total of five dose levels: 0.1, 0.3→1.0, 3, 5 and 10 mg/kg. The phase Ib consisted of a dose expansion and indication expansion cohorts with 5, 10 mg/kg Q2W and 7.5mg/kg Q3W. The primary objectives of phase Ia were to assess dose-limiting toxicity (DLT), maximum tolerated dose (MTD) or maximum administration dose (MAD), and treatment emergent adverse events (TEAEs). The primary objectives of phase Ib included safety, tolerability, and identification of the recommended phase 2 dose (RP2D). Results: As of December 31, 2022, 60 patients with solid tumors received SI-B003 at six different dose levels (14 in Ia, 46 in Ib). Median age was 55.5 years. The median PFS (95%CI) was 3.7 (1.6~5.7) months. Among 56 evaluable patients, the objective response rate (ORR) (n/N, 95%CI) was 16.1% (9/56, 7.6~28.3%) and disease control rate (DCR) was 50.0% (28/56). Confirmed ORR, DCR, median duration of response (DoR) and median progression free survival (PFS) were 9.5% (2/21, 1.2~30.4%), 42.9% (9/21), NR and 2.1 (95%CI, 1.4~NA) months in the 5mg/kg Q2W group and 8.3% (2/24, 1.0~27.0%), 62.5% (15/24), 7.1 (95%CI, 1.9~NA) and 5.7 (95%CI, 1.9~8.7) months in 10mg/kg Q2W group respectively. One patient received 7.5mg/kg Q3W had a confirmed response and was still under treatment. Among 21 evaluable patients who had received prior PD-1/L1 treatment, the ORR and DCR were 14.3% (3/21, 3.1~36.3%) and 52.4% (11/21). The mDoR (95%CI) and mPFS (95%CI) were 4.2 (NA) months and 4.1 (1.4, 5.7) months. The most common TRAEs were rash (35%), AST increased (28%), ALT increased (28%). The most common grade ≥3 TRAEs were AST increased (3%). One patient died from an immune-mediated pneumonia. Conclusions: SI-B003 demonstrated a tolerable safety profile and preliminary anti-tumor activity in patients with recurrent or metastatic solid tumors. Anti-tumor effects of SI-B003 were observed in patients who had progressed on prior PD-1/L1 immunotherapy suggesting that SI-B003 may be beneficial for patients who have developed resistance to PD-1/L1 drugs. Clinical trial information: NCT04606472 .
IMM27M, a humanized Fc-engineered anti CTLA-4 antibody, in patients with advanced solid tumors: A phase I dose-escalation study.
Authors: Wang Shusen , Zhang Qingyuan , Gao Quanli , Wu Shikai , Li Enxiao , Li Zhi-hua , Liu Ziquan , Zhao Xiwen , Gao Siman , Lu Qiying , Tian Wenzhi
Published: June 2023

e14670

Background: IMM27M is a humanized Fc-engineered IgG1 CTLA-4 monoclonal antibody with enhanced ADCC. In pre-clinical models, IMM27M could enhance immune responses and promote Treg depletion. The pre-clinical results showed IMM27M induced a significantly stronger anti-tumor activity than ipilimumab and resulted in complete tumor remission even at a low dose. Methods: This study is an open-label, multi-center, phase I dose-escalation study conducted to evaluate the safety, tolerability, maximum tolerated dose/recommended dose for expansion, PK and anti-tumor activity in patients with advanced solid tumors. The study was designed with an accelerated titration followed by a standard 3+3 design. IMM27M (0.1,0.3,1,2,3 mg/kg) was administered as monotherapy on Day 1 of every 3 weeks. Results: As of 30 Dec 2022, the dose has been escalated to 2mg/kg. 11 pts (8 female, 3 male) were enrolled and treated (1 at 0.1 mg/kg, 3 at 0.3 mg/kg, 3 at 1.0 mg/kg, 4 at 2.0 mg/kg), including 3 pts with melanoma, 3 pts with breast carcinoma, 2 pts with RCC, 1 pt with HCC, 1pt with NSCLC and 1 pt with ovarian carcinoma. Median age was 52 years (range 36-72). 9 pts (81.8%) received ≥ 2 lines of previous systemic therapies and 7 pts (63.6%) received previous anti PD-1/PD-L1 treatment. Treatment-related adverse events (TRAEs) occurred in 10 pts (90.9%) to date. Most TRAEs were grade 1 or 2. The most common TRAEs (≥ 10%) of all grades were anaemia (n = 3 [27.3%]), white blood cell count decreased (n = 2 [18.2%]), lymphocyte count decreased (n = 2 [18.2%]), constipation (n = 2 [18.2%]) and rash (n = 2 [18.2%]). Grade ≥3 TRAEs occurred in 2 pts (18.2%): lymphocyte count decreased (G3, n = 1 [9.1%]) and immune-related lung disease (G3, n = 1 [9.1%]). Treatment related SAE patients only occurred in 1 pt (immune-related lung disease, possibly related to treatment), and this patient recovered after clinical treatment. No DLT was observed. No TRAE leading to treatment discontinuation was reported. In 10 response evaluable pts, 3 pts had SD as best response. One pt in 2.0 mg/kg dose cohort had tumor shrinkage of 17% at Week 6, who had metastatic melanoma and received 2 lines of previous treatments including anti PD-1. The treatment of this patient is ongoing. Preliminary PK analysis of IMM27 showed an approximate proportional dose curve and the mean t1/2 was around 11 days. Conclusions: IMM27M monotherapy in general was well-tolerated at the dose level evaluated and preliminarily anti-tumor activity in patients with advanced solid tumors. The dose escalation study of IMM27M in advanced solid tumors is ongoing. Clinical trial information: NCT05235438 .
Safety, tolerability, and pharmacokinetics of HLX26 (an anti-LAG3 antibody) in patients with advanced or metastatic solid tumors or lymphomas.
Authors: Liu Rujiao , Zhang Jian , Chen Yang , Gao Shuiping , Hu Chen , Zhou Liang , Li Hua , Kang Wenying , Zhu Jun
Published: June 2023

e14671

Background: HLX26 is a novel humanized anti-LAG3 monoclonal antibody. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of HLX26 in patients with advanced or metastatic solid tumors or lymphomas. Methods: This was a first-in-class, multicenter, open-label, dose-escalation phase 1 study. Patients with histologically or cytologically confirmed advanced solid tumors or lymphomas who had failed or were not suitable for standard therapies were enrolled and received HLX26 at five dose levels (60, 150, 300, 500, or 800 mg, Q3W) intravenously. This study followed accelerated titration combined with a “3+3” design. HLX26 was given until disease progression with no clinical benefit, 2 years of treatment, experiencing intolerable toxicity, withdrawal of consent, or death, whichever occurred first. The primary endpoints were dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) within DLT observation period, which was 3 weeks after the first dose of HLX26. Secondary endpoints included safety, pharmacokinetic and pharmacodynamic characteristics, preliminary efficacy, immunogenicity, and potential biomarker explorations of HLX26. Results: As of December 22, 2022, 12 patients with stage IV breast (n = 10, 83.3%) or rectum (n = 2, 16.7%) solid tumors were enrolled and received HLX26 at 60 mg (n = 1), 150 mg (n = 1), 300 mg (n = 3), 500 mg (n = 3), or 800 mg (n = 4). The mean age was 57.5 (range 31–73) years. No DLT was reported and the MTD was not determined as of yet. Eleven (91.7%) patients experienced treatment-emergent adverse events (TEAEs), most commonly hypercholesterolemia (41.7%), hypertriglyceridemia (25.0%), and hyperuricemia (25.0%). Most TEAEs were grade 1 (n = 8, 66.7%) and 2 (n = 2, 16.7%). Conclusions: In summary, no new safety signals were observed from 60 mg to 800 mg of HLX26. HLX26 was safe and well tolerated in patients with advanced or metastatic solid tumors. Clinical trial information: NCT05078593 .
The timing of statin initiation on survival outcomes of cancer patients treated with immune checkpoint inhibitors: A retrospective cohort study.
Authors: See Xin Ya , Chiang Cho Hsien , Chiang Cho Han , Chen Yuan-Jen , Chang Yu-Cheng , Wang Shih-Syuan , Peng Chun-Yu , Horng Chuan-Sheng , Hsia Yuanping , Chiang Cho Hung , Peng Cheng-Ming , Shiah Her-Shyong
Published: June 2023

e14672

Background: Concomitant use of statins has been associated with improved survival outcomes in patients treated with immune checkpoint inhibitors (ICIs), but it is unclear if the timing of statin initiation plays a role in patient outcomes. We aimed to investigate the outcomes of patients who were started on a statin before and after initiation of ICI therapy. Methods: We performed a retrospective cohort study at two tertiary referral centers in Taiwan. We collected data on statin use including the timing of statin initiation, basic demographics, underlying comorbidities, and cancer information. We compared the overall survival (OS) and progression-free survival (PFS) between statin and non-statin users using Cox proportional hazard model analysis and Kaplan-Meier Survival analysis. Results: Among 734 patients who received ICIs, 76 patients received statins after ICI initiation, 52 patients received statins before ICI initiation, and 606 were non-statin users. Patients who received statins after ICI had a longer OS (median 37.6 vs. 11.3 vs. 10.3 months, p = 0.01) and PFS (median 10.5 vs. 5.6 vs. 6.3 months, p = 0.02) than patients who received statins before ICI and non-statin users. In Cox proportional hazard analyses, the use of statins after ICI was associated with a lower risk of mortality (HR, 0.65 [95% CI: 0.45-0.94], p = 0.02) or disease progression (HR, 0.71 [95% CI: 0.53-0.95], p = 0.02) compared with non-statin users. On the other hand, the use of statins before ICI was not associated with a lower risk of mortality (HR, 1.46 [95% CI: 0.96-2.22], p = 0.08) or disease progression (HR, 1.22 [95% CI: 0.86-1.73], p = 0.26) compared with non-statin users. These trends were observed in multivariate Cox proportional analyses adjusting for underlying comorbidities, cancer stage, type, and therapy. Conclusions: The use of statins after the initiation of immunotherapy is associated with improved survival outcomes. [Table: see text]
A phase Ia trial to evaluate the safety and efficacy of HB0030, an anti-TIGIT antibody, in patients with advanced solid tumors: Preliminary results.
Authors: Zhou Huan , Li Wei , Xie Jing , Li Hongtao , Zhu Xiangyang , Yang Yongmin , Yang Yang , Zheng Yang , Wang Qiaofeng , Chen Juan , Li Chao , Xu Ruirui , Wang Jingjing , He Yiran
Published: June 2023

e14673

Background: HB0030 is an IgG1 type humanized monoclonalanti-TIGIT antibody. Its heavy chain Fc fragment is wild-type that preserves function for inducting CDC and ADCC effects. Nonclinical data showed that HB0030 has a good affinity for TIGIT and anti-tumor activity. Methods: This is an ongoing single-center, open-label, dose escalation Phase Ia study to mainly evaluate HB0030 safety, antitumor activity and immunogenicity in patients (pts) with advanced solid tumor. HB0030 is administered by IV infusion every 21 days. An accelerated titration method combined the standard 3+3 design was utilized for dose escalation, which of contained 8 dose groups (0.1, 0.3, 1.0, 3.0, 10, 20, 30, 40mg/kg). The tumor assessment evaluated by investigator according to RECIST v1.1. Results: As of Jan 9, 2023, 20 pts (4Male/16Female) with advanced malignant solid tumor have been enrolled and dosed at 0.1mg/kg (n = 1), 0.3mg/kg (n = 3), 1mg/kg (n = 3), 3mg/kg (n = 4), 10mg/kg (n = 3) and 20mg/kg (n = 6). The median age was 56.9 years. All pts had stage IV disease and failed from the anti-tumor standard therapy with a median of 3 lines. The main tumor types included lung(n = 6), breast(n = 3), colorectal(n = 3) and cervical (n = 2) cancer. Total 16 pts have completed at least once tumor assessment. The ORR and DCR were 6.3% (1/16) and 62.5% (10/16), respectively. The best response was a PR with 47% tumor regression pt who was diagnosed non-small cell lung cancer (NSCLC) accompanied with TP53 gene mutation. The pt relapsed with multiple metastasis after radical operation and adjuvant chemotherapy, and failed to systemic chemotherapy combined targeting anti-vascular therapy. He achieved PR with 3 cycles of 20mg/kg HB0030 treatment, and PR status continued at present. A NSCLC pt maintained 24 weeks SD after 3mg/kg HB0030 administration. The most common treatment related adverse events (TRAEs) were lymphopenia (9/20, 45%) and shortened activated partial thromboplastin time (APTT) (6/20,30%). Grade 3 TRAEs occurred in 15% of pts (3/20) which included thrombocytopenia, anemia, syncope and hypertension. There were no Grade 4-5 AEs, serious adverse events (SAEs), dose-limiting toxicity (DLT) and death. The anti-drug antibodies (ADAs) were detected in 2 pts in 20 mg/kg dose group, and not caused by HB0030 therapy because it had existed in baseline. Conclusions: HB0030 showed very well safety in the stage of dose escalation from 0.1 to 20 mg/kg, and potential promising anti-tumor activity above 3mg/kg dose in advanced solid tumors pts, especially in NSCLC. Currently, 30mg/kg and 40mg/kg dose escalation are ongoing. Clinical trial information: NCT05706207 .
Adrenal insufficiency in patients on immune checkpoint inhibitors: An All of Us Data study.
Authors: Olusoji Rahman Adesoji , Eun Yong , Mohamed Salih Rajaa , Osei Noah , Ahluwalia Meena
Published: June 2023

e14675

Background: Immune Checkpoint Inhibitors have revolutionized the management of cancers. Several cases are reported about their adverse effects, which include adrenal insufficiency, a life-threatening irreversible sequela in some patients. Little has been done to evaluate the burden of this adverse effect on cancer patients. This study aimed to measure the incidence rate of adrenal insufficiency in patients on immune checkpoint inhibitors in the United States using the All Of Us database. Methods: In this cross-sectional study, we included participants from the All of Us dataset version 6, which includes data collected between May 6, 2018, and January 1, 2022, who had available Electronic Health Records data (N = 258,188). We defined the cancer cohort as having at least one ICD-9/ICD-10 diagnostic code for cancer. We identified participants in the cancer cohort without or with at least one exposure to immune checkpoint inhibitors nivolumab, pembrolizumab, cemiplimab, ipilimumab, atezolizumab, avelumab, durvalumab, tremelimumab, relatlimab, tremelimumab, pidilizumab. Adrenal insufficiency was defined as having one or more ICD-9/ICD-10 codes for any adrenal insufficiency after treatment with immune checkpoint inhibitors. The calculation for the Relative Risk(RR) was with unconditional maximum likelihood estimation. Results: Among 36,377 individuals diagnosed with cancer, 418 patients had exposure to immune checkpoint inhibitors. 44(10.5%) of the 418 were diagnosed with adrenal insufficiency after exposure to immune checkpoint inhibitors. The relative risk of adrenal insufficiency after the commencement of an immune checkpoint inhibitor is five times that of patients not on immune checkpoint inhibitors. (RR 5.43, 95% CI 4.07-7.25, P < 0.05). Conclusions: Our result suggests a higher incidence of adrenal insufficiency in cancer patients on immune checkpoint inhibitors compared to cancer patients, not on immune checkpoint inhibitors. Future prospective studies will be needed to confirm this finding. Physicians, particularly oncologists and endocrinologists, should have a high index of suspicion for adrenal insufficiency in patients on immune checkpoint inhibitors.
Hemophagocytic lymphohistiocytosis in patients treated with immune checkpoint inhibitors: A pharmacovigilance study from FDA Database.
Authors: Neupane Niraj , Shikhrakar Shreeja , Thapa Sangharsha , Shrestha Asis
Published: June 2023

e14684

Background: Immune checkpoint inhibitors (ICIs) are increasingly used to treat multiple cancers uncovering varieties of immune-related adverse events (irAEs). ICI-related haemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome caused by exaggerated activation of macrophages and cytotoxic T cells resulting in fatal hematological toxicity and multi-organ damage. Methods: We conducted a retrospective analysis of reported cases of HLH in patients treated with checkpoint inhibitors using data from the FDA's Adverse Event Reporting System (FAERS) database from 2018 to 2022. Patients aged 18 or older were included, and cases were classified using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. Results: Of 2,317 patients with HLH reported in the FAERS, 13.6% (315) of patients were reported to receive commonly used ICIs. With nivolumab being 44.93%%, pembrolizumab 35.87%, Ipilimumab 30.43%, and atezolizumab 15.94%. HLH among these ICI use was most commonly reported in males (65.2%) with a median age of 65. Melanoma was the most common cancer reported in this sample population. Out of the reported cases, 26% died, and 72% were males. Death was observed more in combination ICI therapy (40.73%) than in single-agent use (29.04%). Even though the most commonly reported HLH was with Nivolumab, mortality was highest with Atezolizumab use (29.55%). Conclusions: Nearly half of the patients with a diagnosis of HLH received commonly used ICIs, which points towards ICIs being one of the important risk factors for developing HLH. However, several confounders should be considered, like a cancer diagnosis, infection, and antibiotics. Further studies on ICI-induced HLH are necessary to establish its causal relationship.
Intravenous (IV) infusion of T3011, an oncolytic HSV expressing IL-12 and PD-1 antibody, as monotherapy in advanced solid tumors: Preliminary results from an ongoing phase 1/2a study.
Authors: Niu Jiaxin , Barve Minal A. , Spira Alexander I. , Edenfield William Jeffery , Pang Weijia , Fu Wenmin , Lu Yingxin , McKean Meredith
Published: June 2023

e14689

Background: Oncolytic virotherapy has emerged as a promising anticancer treatment. To date, almost all oncolytic viruses (OVs) are delivered via intratumoral (IT) injection, which limits its broad clinical application. Systemic delivery of OVs, a more practical option for patients (pts) without injectable lesions, allows both primary tumor and metastases treated simultaneously. However, due to concerns for immune clearance and the potential cytokine storms, very few studies thus far are conducted using OVs intravenously. T3011 is a genetically modified, next-generation oncolytic HSV-1 expressing IL-12 and PD-1 antibody. Extensive preclinical studies have demonstrated the feasibility, safety and efficacy of T3011 delivered intravenously. Here, we present preliminary results of IV T3011 as a single agent. Methods: In this phase 1/2a, multi-center, open label, dose escalation and expansion study, T3011 was administered intravenously on Days 1, 4, 8 of a 21-day cycle in pts with advanced solid tumors. The primary objective was to evaluate the safety and tolerability of escalating doses of IV T3011, characterize dose limiting toxicities (DLTs) and identify the MTD and RP2D of IV T3011. Phase 1 portion used a 3+3 design in 4 escalating cohorts (1×106, 1×107, 1×108, 3×108 PFU). Pharmacokinetics, immunogenicities and pharmacodynamic profiles were studied in various samples. Results: As of Jan 2023, 10 pts received IV T3011 therapy: 4 in Cohort 1, 3 in Cohort 2, and 3 in Cohort 3. Median number of doses was 8. T3011 was well tolerated with no ≥ Grade 3 treatment-related adverse events (TRAEs) and no DLTs to date. Nausea and infusion-related reaction (including postdose delayed fever, chills, rigors, etc.) were the most common TRAEs. 7 of 10 pts had ≥ 1 tumor assessment, 4 achieved stable disease (SD) by RECIST 1.1 with a disease control rate of 57.1%, 2 had SD for ≥ 6 months. 1 pt had a postdose tumor biopsy revealing T cell activation via transcriptome profiling and gene ontology analysis. T3011 DNA was detected in blood in 9/10 pts at 0.5 hours after the 1st dose and its level was dose-dependent and increased with repeated doses. T3011 DNA clearance was observed at 4-7 days after dosing. Saliva and urine samples from all pts were tested for T3011 DNA, only one was positive with very low DNA copies in a saliva sample at 0.5 h after the 2nd dose from a pt in Cohort 1. Of note, pre-existing HSV-1 IgG had no impact on T3011 activity. Conclusions: IV T3011 monotherapy was well tolerated and safe at the first 3 dose levels, highly unlikely to be transmissible. Preliminary efficacy was encouraging. Our results also suggest T3011 IV treatment could stimulate anti-tumor immunity in the tumor microenvironment. Clinical trial information: NCT04780217 .