Tislelizumab In Patients Research Articles

Phase II study of sitravatinib in combination with tislelizumab in patients with advanced biliary tract cancer who have failed to at least 1 prior systemic treatment.

4018 Background: In first line of advanced biliary tract cancer (BTC), immune-checkpoint inhibitor (ICI) in combination with cytotoxic chemotherapy is now standard of care supported by TOPAZ-1 and KN-966 studies. With this landscape, new drug development using ICI in second or later line setting is urgent unmet medical needs area. Anti-angiogenic agent induced improved anti-tumor immune responses by increasing tumor antigen presentation and promoting lymphocyte infiltration and migration. Methods: This study is an open-label, phase 2 trial to investigate the efficacy of sitravatinib and tislelizumab (PD1 inhibitor) combination treatment for 2L advanced BTC. Patients who received prior ICI could be enrolled. All patients received sitravatinib 120mg orally once daily in combination with tislelizumab 200mg intravenously once every 3 weeks until disease progression, unacceptable toxicity. The primary endpoint was disease control rate (DCR), with key secondary endpoints including overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Tissue biopsies were conducted three times in total: screening, the first response evaluation, and disease progression. Blood samples were collected every cycles. (NCT04727996) Results: A total of 43 patients were enrolled. Data-cut off was on July 31, 2023. Median follow-up was 10.5months (95% Confidence interval (CI), 7.03-15.6). 9 patients had received prior ICI. This study met primary endpoint as a DCR of 65.1% in all population. ORR was 20.5% in unselected per-protocol population, and PFS was 4.93 months (95% CI, 3.10-8.87). OS was 10.3months (95% CI, 6.67-18.2). Similar efficacy was observed regardless of prior ICI exposure. The most common treatment-related adverse events (AEs) were sitravatinib-related; hand-foot syndrome (any grade 60.5%, grade 3/4 0%), hypertension (any grade 34.9%, grade 3/4 11.6%). Immune-related AEs (irAEs) were 46.5%, with most irAEs being grade 1-2. In exploratory analysis, patients with homologous recombination deficiency (HRD) detected by baseline tissue NGS (frequency 18.5%) showed higher ORR (60% vs 13.6%), longer PFS (not reached vs 4.87 months) and OS (21.1 vs 8.57 months) than patients without HRD. HRD detected by circulating tumor DNA had a complementary role for patient selection. RNA sequencing showed upregulation in inflammatory signal and downregulation in angiogenesis signal between screening and on-treatment tumor tissue. Responders showed higher inflammatory signaling at baseline and on-treatment tumor tissue compared to non-responders. Conclusions: Sitravatinib/tiselizumab combination as 2L therapy in patients with advanced BTC demonstrated meaningful efficacy and an acceptable safety profile. Especially, patient selection using HRD biomarker might be a promising strategy in this setting. Clinical trial information: NCT04727996 .

Selinexor combined with tislelizumab in patients with relapsed or refractory extranodal NK/T-cell lymphoma (R/R ENKTL): Results of dose escalation of cohort C, from a multicenter, single-arm, phase I/II study (TOUCH).

7065 Background: ENKTL is a rare subtype of mature T and NK/T cell lymphoma presenting features of highly aggressive clinical course and association with EBV infection.The prognosis remains poor for R/R ENKTL patients (pts) with treatment failure of L-Aspariginase (L-Asp) based regimens, highlighting the need for novel approaches. Monotherapy of tislelizumab (Tis) showed preliminary clinical activity in R/R ENKTL. Selinexor (Sel), a novel XPO1 inhibitor, has demonstrated preclinical synergistic effects when combined with PD-1 antibody. The TOUCH study (NCT04425070) includes three cohorts investigating the combination of Sel with chemotherapy (ICE or GEMOX) or Tis in R/R ENKTL. Methods: Cohort C was designed to evaluate the safety, tolerability, preliminary efficacy of Sel plus Tis in R/R ENKTL. Pts who received at least one prior treatment containing L-Asp were enrolled. In the escalation stage, a 3+3 design was implemented to determine the RP2D of Sel. The starting dose of Sel was 40 mg QW, followed by 60 mg QW (dose level 2), administered orally on Days 1, 8, and 15 of each 21-day cycle. Tis was administered at a fixed dose of 200 mg every 3 weeks on Day 1. DLTs were assessed during the first cycle. Efficacy was evaluated per Lyric 2016. Results: As of 25 Dec 2023, 12 R/R ENKTL pts were enrolled in the escalation stage [Sel 40mg (n=3); Sel 60mg (n=9)]. At study entry, the median age was 52 years (range 32-65); Five males and 7 females; 6 (50.0%) had stage III/IV disease; Seven (58.3%) pts had PINK score ≥2 and 6 (50.0%) pts were circular EBV-DNA positive. The median number of prior treatment lines was 2.5 (range 1-5); Ten (83.3%) pts were refractory to their last-line therapy. Eleven pts had prior exposure to PD-1/PD-L1 antibodies, including 7 pts who had received prior Tis. No DLT was observed and MTD was not reached. The most common TEAEs were asthenia (83.3%), neutropenia (83.3%), nausea/vomiting (58.3%), decreased appetite, weight loss, anemia, thrombocytopenia (50.0%, respectively), lymphocytopenia (41.7%), pneumonia, AST increased and proteinuria (33.3%, respectively). Only 1 pt experienced an irAE with thyroiditis. Seven pts (58.3%) had Grade≥3 TEAEs. TESAEs occurred in 3 pts (25%) with only 1 (sepsis) considered treatment related. No pt discontinued or died due to TEAEs. Among 11 efficacy evaluable patients, ORR was 72.7% (8/11), and CR rate was 36.4% (4/11). Of 7 Tis exposed pts, 2 achieved CR and 3 achieved PR. At a median follow-up of 6.8 months (range 5.5-12.6), the median PFS, DOR and OS were 6.1 months, 4.7 months, and not reached (6-month OS rate 90.9%), respectively. The RP2D of Sel in Cohort C was determined to be 60mg QW. Conclusions: Selinexor plus tislelizumab showed tolerable safety profile and encouraging response rate in R/R ENKTL. Expansion stage of Cohort C is ongoing. Clinical trial information: NCT04425070 .

Abstract CT189: A first-in-human, phase 1a, dose-escalation study of BGB-10188, a phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, + tislelizumab (anti-PD-1) in patients with solid tumors

Abstract Background: PI3Kδ inhibition hampers regulatory T-cell proliferation and function, potentially optimizing CD8+ T-cell activation for antitumor immunity in solid tumors. BGB-10188, a novel PI3Kδ inhibitor, showed high selectivity, potency, and an improved safety profile vs other PI3Kδ inhibitors in preclinical studies. Here, we present the results of BGB-10188 + tislelizumab in patients with solid tumors from the phase 1a dose-escalation part (Part D) of an open-label, multicenter, 5-part phase 1/2 study (NCT04282018). Methods: Eligible patients were aged ≥18 years with ECOG PS of 0 or 1 and had previously treated unresectable locally advanced or metastatic solid tumors. BGB-10188 was given orally once daily (QD) at 6 dose levels (20, 40, 80, 160, 320, and 540 mg). Tislelizumab 200 mg IV was given on Day 8 of the 28-day Cycle 1 and Day 1 of all subsequent 21-day cycles. Primary objectives were to assess the safety and tolerability of BGB-10188 + tislelizumab. Select secondary/exploratory objectives were to evaluate preliminary antitumor activity, pharmacokinetics, and pharmacodynamics. Results: As of August 30, 2023, 44 patients were treated with BGB-10188 + tislelizumab (median follow-up: 4.65 months; 3 patients remain on treatment). The median age was 61 years. Patients had a median of 2 prior lines of therapy (range, 1-11) and 97.7% of patients had metastatic disease at study entry. 84.1% (37 of 44) of patients had ≥1 adverse event (AE) related to either study drug. 81.8% (36) of patients had ≥1 BGB-10188-related AE, of which the most common (≥10%) were nausea (22.7%, n=10), decreased appetite (18.2%, n=8), fatigue (18.2%, n=8), alanine aminotransferase (ALT) increased (13.6%, n=6), aspartate aminotransferase (AST) increased (11.4%, n=5), and rash (11.4%, n=5). Two patients discontinued study drug treatment due to BGB-10188-related AEs. Three dose-limiting toxicities for BGB-10188 + tislelizumab were observed: grade (Gr) 5 pneumonia and Gr 5 intracranial hemorrhage at 160 mg, Gr 3 ALT/AST increase at 320 mg, and Gr 3 rash at 540 mg. Maximum tolerated dose was not reached. The confirmed objective response rate was 9.1% (4 of 44) and the disease control rate was 31.8% (14 of 44). The plasma exposure to BGB-10188 exhibited a dose-dependent increase across a range of 20 mg to 540 mg. The peak concentration of BGB-10188 typically occurred ~2 hours post dose. Additionally, the mean half-life was observed to be between 8 hours and 13 hours across dosages. Peripheral p-AKT inhibition increased with dose, suggesting valid target engagement of BGB-10188, and reached a plateau at ~84%. Conclusions: BGB-10188 + tislelizumab showed preliminary antitumor activity and was generally safe and tolerable across doses in this heavily pretreated population of patients with solid tumors. BGB-10188 + tislelizumab will be further evaluated in dose expansion (Part E). Citation Format: Rasha Cosman, Elizabeth Ahern, Jie Li, Hui K. Gan, Yu Chen, Bo Gao, Yongsheng Wang, Xiyan Mu, Huan Cheng, Yanrong Qian, Heather Zhang, Ke Cao. A first-in-human, phase 1a, dose-escalation study of BGB-10188, a phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, + tislelizumab (anti-PD-1) in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT189.

Clinical dose rationale of tislelizumab in patients with solid or hematological advanced tumors.

Tislelizumab, an anti-programmed cell death protein 1 monoclonal antibody, has demonstrated improved survival benefits over standard of care for multiple cancer indications. We present the clinical rationale and data supporting tislelizumab dose recommendation in patients with advanced tumors. The phase I, first-in-human, dose-finding BGB-A317-001 study (data cutoff [DCO]: August 2017) examined the following tislelizumab dosing regimens: 0.5-10 mg/kg every 2 weeks (q2w), 2-5 mg/kg q2w or q3w, and 200 mg q3w. Similar objective response rates (ORRs) were reported in the 2 and 5 mg/kg q2w or q3w cohorts. Safety outcomes (grade ≥3 adverse events [AEs], AEs leading to dose modification/discontinuation, immune-mediated AEs, and infusion-related reactions) were generally comparable across the dosing range examined. These results, alongside the convenience of a fixed q3w dose, formed the basis of choosing 200 mg q3w as the recommended dosing regimen for further clinical use. Pooled exposure-response (E-R) analyses by logistic regression using data from study BGB-A317-001 (DCO: August 2020) and three additional phase I/II studies (DCOs: 2018-2020) showed no statistically significant correlation between tislelizumab pharmacokinetic exposure and ORR across multiple solid tumor types or classical Hodgkin's lymphoma, nor was exposure associated with any of the safety end points evaluated over the dose range tested. Hence, tislelizumab showed a relatively flat E-R relationship. Overall, the totality of data, including efficacy, safety, and E-R analyses, together with the relative convenience of a fixed q3w dose, provided clinical rationale for the recommended dosing regimen of tislelizumab 200 mg q3w for multiple cancer indications.

WUTSUP-02-II-Neo-Dis-Tis: Investigating the efficacy and safety of neoadjuvant tislelizumab plus disitamab vedotin with adjuvant tislelizumab in upper urinary tract carcinoma—A phase II multi-center study.

TPS718 Background: Upper tract urothelial carcinoma (UTUC) and urothelial bladder cancer (UBC) are frequently referred to as “disparate twins” despite their common tissue origin. They exhibit varying biological behaviors, prognostic outcomes, and responses to treatment. It is crucial to conduct dedicated clinical trials for UTUC as a separate entity rather than relying solely on UBC study results, giving that UTUC lags in evidence quantity and quality compared to UBC. Despite the superior outcomes of neoadjuvant treatment over adjuvant treatment in UBC trials, the currently available evidence for neoadjuvant therapy of UTUC remains limited in quantity and diversity, as the largest trial, POUT, is focused on adjuvant therapy. Additionally, the limited number of neoadjuvant trials for UTUC primarily utilize chemotherapy-based regimens, with little investigation into combination therapies. Of note, UTUC patients frequently have impaired renal functions, making a chemotherapy-independent approach a desirable alternative. On the other hand, given the short duration of neoadjuvant therapy, a combination therapy strategy appears to be necessary, especially with the increasing interest in immune therapy maintenance after surgery. Tislelizumab has demonstrated efficacy in patients with advanced or metastatic urothelial carcinoma. Disitamab Vedotin, a HER2-targeting antibody-drug conjugate (ADC), has demonstrated robust clinical efficacy in metastatic urothelial carcinoma patients with HER2 2+ or 3+ expression. Disitamab Vedotin in combination with PD-1 immunotherapy has shown remarkable results in locally advanced or metastatic urothelial carcinoma, regardless of HER2 expression, indicative of a synergistic effect between ADC and PD-1 immunotherapy. In this study, we aim to conduct a prospective phase II trial to investigate the efficacy and safety of neoadjuvant tislelizumab plus Disitamab Vedotin followed by adjuvant tislelizumab in patients with high-risk UTUC. Methods: This multi-center phase II trial aims to enroll 45 patients with histologically confirmed UTUC at clinical stage cT2-4N0M0 or cT1-4N1-2M0. Neoadjuvant therapy includes 4 cycles of Tislelizumab (200mg for each 3-week cycle) in combination with Disitamab Vedotin (2.0mg/kg for each 3-week cycle). Radical nephroureterectomy (including bladder cuff resection and regional lymph node dissection if indicated) will be performed if there is no obvious contraindication within 3-6 weeks after the final neoadjuvant therapy administration. Postoperative adjuvant treatment with 8 cycles of tislelizumab will be provided. The primary endpoint is pathological complete response rate. Secondary endpoints include overall survival, local recurrence free survival, distant metastasis free survival, FACT–G. Clinical trial information: ChiCTR2300067836 .

A real-world evaluation of tislelizumab in patients with head and neck cancer.

Various studies support the use of programmed cell death protein 1 (PD-1) blockades, also known as immune checkpoint inhibitors (ICIs), to treat head and neck cancer (HNC). Tislelizumab is a humanised immunoglobulin G4 (IgG4) monoclonal antibody with a high affinity and specificity for PD-1. However, the "real-world" clinical evidence of tislelizumab for HNC is limited. In this study, the medical records of 39 patients with head and neck squamous cell carcinoma (HNSCC) or nasopharyngeal carcinoma (NPC) who received tislelizumab between January 2021 and March 2022 were reviewed retrospectively. Tislelizumab was administered to 15 patients during neoadjuvant therapy (Group 1), five patients during adjuvant therapy (Group 2), 14 patients during consolidation therapy (Group 3), and five patients during salvage therapy (Group 4). The Kaplan-Meier method was used to calculate progression-free survival (PFS) and overall survival (OS). The median age of enrolled patients was 55 (range, 28-83) years. The median follow-up time was 27.1, 26.1, 28.6, and 20.9 months for Groups 1, 2, 3, and 4, respectively. The mean PFS and OS of Groups 1, 2, 3, and 4 were 21.5 and 22.8; 24.1 and 24.2; 26.9 and 28.1; and 13.9 and 17.1 months, respectively. In Groups 1 and 4, the objective response rate (ORR) was 86.7% and 60%, respectively. Meanwhile, except for one (2.6%) patient with grade 4 enteritis, the other observed non-haematological adverse events (AEs) were ≤ grade 2. Tislelizumab demonstrated promising efficacy and tolerability in patients with HNSCC or NPC in a real-world setting, consistent with previous reports.

Cost-effectiveness analysis of the tislelizumab versus docetaxel for advanced or metastatic non-small-cell lung cancer in China.

Tislelizumab is the first PD-1 inhibitor in China to demonstrate superior efficacy in second-line or third-line treatment of patients with advanced or metastatic non-small-cell lung cancer (NSCLC). This study aimed to evaluate the cost-effectiveness of tislelizumab compared to docetaxel from a Chinese healthcare system perspective. A dynamic Markov model was developed to evaluate the cost-effectiveness of tislelizumab in comparison to docetaxel in second or third-line treatment. The efficacy data utilized in the model were derived from the RATIONALE-303 clinical trial, while cost and utility values were obtained from the drug data service platform and published studies. The primary outcomes of the model encompassed quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). One-way sensitivity analysis and probabilistic sensitivity analysis were conducted to validate the robustness of the base case analysis results. The tislelizumab group demonstrated a cost increase of CNY 117,473 and a gain of 0.58 QALYs compared to the docetaxel group, resulting in an ICER value of CNY 202,927 per QALY gained. The administration of tislelizumab in patients with advanced or metastatic NSCLC not only extends the progression-free survival (PFS) and overall survival (OS). Moreover, this treatment demonstrates a favorable cost-effectiveness profile across the Chinese population.

77P A single-arm trial of BACE plus tislelizumab in patients with NSCLC: Updated analysis

77P A single-arm trial of BACE plus tislelizumab in patients with NSCLC: Updated analysis

89P Hepatic arterial infusion chemotherapy sequential transarterial embolization combined with lenvatinib and tislelizumab in patients with high-risk unresectable hepatocellular carcinoma: A single arm phase II trial

89P Hepatic arterial infusion chemotherapy sequential transarterial embolization combined with lenvatinib and tislelizumab in patients with high-risk unresectable hepatocellular carcinoma: A single arm phase II trial

Combination of Mitoxantrone Hydrochloride Liposome with Tislelizumab in Patients with Relapsed or Refractory NK/T Cell Lymphoma: A Phase Ib/Ⅱ Clinical Trial

Background : Extranodal NK/T cell lymphoma (ENKTL) is a highly aggressive malignancy associated with Epstein-Barr virus (EBV) infection, and remains a high unmet clinical need for improving prognosis. Mitoxantrone hydrochloride liposome (PLM60) is a nano-drug that has been approved as the first treatment option for relapsed/refractory (r/r) PTCL, and has shown certain efficacy and safety in a pivotal phase Ⅱ study. Tislelizumab is a humanized immunoglobulin G4 variant monoclonal antibody against PD-1. This trial aims to investigate the safety and efficacy of combining PLM60 with tislelizumab in patients (pts) with r/r ENKTL. Methods: Pts with r/r ENKTL were recruited in this ongoing, prospective, multicenter, open-label phase Ib/Ⅱ study (NCT05464433). Phase Ib was 3+3 design with two dose levels of PLM60 (d1, 16 mg/m 2 and 20 mg/m 2) plus tislelizumab 200 mg (d1, Q4W) induction therapy for up to 6 cycles, then tislelizumab 200 mg (Q3W) to continue maintenance therapy until disease progression, discontinuation, withdrawal or one year of therapy (including induction therapy period). Phase II was a dose expansion at the recommended phase II dose (RP2D). The primary endpoints were to assess the tolerability (i.e. dose-limiting toxicity (DLT)) and explore RP2D of PLM60 in phase Ib, and the objective response rate (ORR) of phase II. Secondary endpoints were complete response (CR) rate, ORR, disease control rate (DCR) and safety of phase Ib, and DCR, progression-free survival (PFS), overall survival (OS) and safety of phase II. Results: At data cut-off on 11 July 2023, 13 eligible pts were enrolled (phase Ib, n=6 and phase II, n=7). 6 pts of phase Ib were evaluable for response with a median age of 29.5 (range, 22-47) years, and 5 pts (83.3%) were ECOG 1. 3 pts (50.0%) had advanced stage III or IV (Ann Arbor). No DLT occurred at 16 mg/m 2 and 20 mg/m 2in phase Ib study. RP2D was PLM60 20 mg/m 2 plus tislelizumab 200 mg. The CR rate, ORR and DCR were 33.3% (2/6, 95% CI 4.3%-77.7%), 100.0% (6/6, 95% CI 54.1%-100.0%) and 100.0% (6/6, 95% CI 54.1%-100.0%), respectively. At data cutoff, the phase II study is being enrolled. Overall, the 11 pts evaluated in phase Ib and phase II had an ORR of 81.8% (9/11) (Figure 1). Furthermore, a decrease in EBV viral load was observed during treatment with PLM60 and tislelizumab except for one pt who experienced viral load rebounded and disease progression after 3 cycles of therapy (Figure 2). With a median follow-up of 2.1 (range, 1.0-5.6) months currently, the median PFS and OS will be reported after long-term follow-up. Treatment-related adverse events (TRAEs) of any grade occurred in all 13 enrolled pts, in which 7 (53.8%) pts were grade 3/4. The common grade 3/4 TRAEs were leucopenia (38.5%), neutropenia (30.8%), lymphocyte count decreased (30.8%), thrombocytopenia (7.7%), alanine aminotransferase increased (7.7%) and diarrhea (7.7%). Three patients had treatment delayed because of AEs. Moreover, no adverse cardiac events occurred during this study. Conclusions: PLM60 plus tislelizumab proves an encouraging efficacy in r/r ENKTL pts with manageable safety profiles.

IMM01 Plus Tislelizumab in Prior Anti-PD-1 Failed Classic Hodgkin Lymphoma: An Open Label, Multicenter, Phase 2 Study (IMM01-04) Evaluating Safety As Well As Preliminary Anti-Tumor Activity

Background: IMM01, a recombinant SIRPa-Fc fusion protein, can activate macrophages to enhance anti-tumor activity by blocking CD47-SIRPa interaction. IMM01 showed unique property of weak human erythrocyte conjugation in preclinical studies, and low incidence of anemia in early clinical trials with no need for a priming dose. IMM01 plus tislelizumab has the potential to augment both innate and adaptive anti-tumor immune responses. Methods: IMM01 at a dose of 2.0mg/kg was administered once a week and tislelizumab (200mg) was administered once every 3 weeks. 2.0mg/kg of IMM01 was determined as RP2D when combo with tislelizumab in patients with advanced solid tumors (e.g. SCLC, NSCLC, HNSCC). The primary objective of this phase 2 study was to evaluate the preliminary anti-tumor activity as well as safety of IMM01 plus tislelizumab in patients with classic Hodgkin lymphoma (cHL) who have failed prior check point inhibitor treatment. A total of 32 patients are planned to be enrolled in this phase 2 study according to pre-plan statistical assumption. Adverse events (AEs) were reported according to CTCAE v5.0. The anti-tumor activity was assessed according to the Lugano 2014 criteria. Results: As of 19 Jul 2023, 20 cHL patients (median age: 34 years, range: 23-73 years) who have failed prior anti-PD-1 treatment were enrolled, 18 patients were relapsed on anti-PD1, and 2 patients were anti-PD1 refractory. 18 (90%) patients received 3 or more prior lines of therapy. All patients had Ann Arbor stage III-IV disease. Among total 14 evaluable patients, 2 patients achieved complete response (CR), 7 patients achieved partial response (PR). The objective response rate (ORR) and disease control rate (DCR) were 64.3% and 100%, respectively. Among the responders, 5 patients failed prior tislelizumab. As of 7 Jul 2023, for all 20 treated patients, treatment-related adverse events (TRAEs) of any grade occurred in 18 (90.0%) patients. The most frequent TRAEs (≥ 20%) were platelet count decreased (50.0%), lymphocyte count decreased (35.0%), anemia (30.0%), white blood count decreased (30.0%), neutrophil count decreased (25.0%) and Gamma-glutamyl transferase increased (20.0%). Most TRAEs were grade 1-2. TRAEs of grade ≥3 occurred in 7 (35%) patients, including lymphocyte count decreased (30.0%), platelet count decreased (10.0%), neutrophil count decreased (5.0%) and white blood count decreased (5.0%). 1 patient had treatment related SAE (platelet count decreased, grade 3) and recovered without bleeding. There was no reported hemolytic anemia or hemolysis in any of the patients. No TRAEs leading to drug discontinuation or death. Conclusions: IMM01-04 showed a robust anti-tumor effectivity with a well-tolerated safety profile in prior anti-PD-1 failed classical Hodgkin Lymphoma patients. The phase 2 study is ongoing.

AdvanTIG-105: a phase I dose escalation study of the anti-TIGIT monoclonal antibody ociperlimab in combination with tislelizumab in patients with advanced solid tumors

BackgroundOciperlimab, a novel, humanized monoclonal antibody (mAb), binds to T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) with high affinity and specificity. Tislelizumab is an anti-programmed cell...

719TiP A phase I/Ib study of the Werner (WRN) helicase inhibitor HRO761 as single agent and in combination with irinotecan or tislelizumab in patients with microsatellite instability-high (MSIhi) or mismatch repair deficient (dMMR) advanced solid tumors

719TiP A phase I/Ib study of the Werner (WRN) helicase inhibitor HRO761 as single agent and in combination with irinotecan or tislelizumab in patients with microsatellite instability-high (MSIhi) or mismatch repair deficient (dMMR) advanced solid tumors

Tislelizumab monotherapy for the treatment of recurrent/metastatic head and neck squamous cell carcinoma

Objective:The aim of this retrospective study is to evaluate the safety and efficacy of tislelizumab in patients with recurrent/metastatic head and neck squamous cell carcinoma. Methods:Six patients with recurrent/metastatic head and neck squamous cell carcinoma who received tislelizumab monotherapy in our hospital from 2018 to 2020 were retrospectively analyzed. The information of sex, age, TNM stage, efficacy, and adverse reactions were collected. All patients were recruited from the RATIONALE 102 study. The primary end point was the objective response rate, and other end points included progression-free survival and overall survival. We performed tumor immune-related gene sequencing and transcriptome sequencing analysis on the tumor tissues of the patient, and used bioinformatics methods to enrich immune cells and analyze signaling pathways. All analyses were performed using R 4.1. 0 software, SPSS Statistics 24.0 software and GraphPad Prism 8. Results:As of May 31, 2020, the median follow-up time was 26.35 months. The objective response rate with tislelizumab was 50.0%, the median progression-free survival was 6.44 months, and the estimated median survival was 20.07 months. The incidence of grade 3 or higher adverse reactions was 66.7%, including hyponatremia, hypokalemia, hypercalcemia, etc. The expression of macrophage, Treg and neutrophil-related genes are higher in immune-sensitive patients, and the signaling pathways of the intestinal immune network for IgA production, graft versus host disease and autoimmune thyroid disease are significantly activated. Conclusion:Tislelizumab was found to be controllable and tolerable in patients with recurrent/metastatic head and neck squamous cell carcinoma. The response to tislelizumab is related to immune cell infiltration and activation of immune-related signaling pathways.

Pamiparib in combination with tislelizumab in patients with advanced solid tumours: results from the dose-expansion stage of a multicentre, open-label, phase I trial

BackgroundThe aim of this study was to investigate the antitumour activity, safety, and tolerability of pamiparib plus tislelizumab in patients with previously treated advanced solid tumours.MethodsIn this study, patients were enrolled into eight arms by tumour type. All received pamiparib 40 mg orally twice daily plus tislelizumab 200 mg intravenously every 3 weeks. The primary endpoint was objective response rate (ORR), assessed by the investigator per Response Evaluation Criteria in Solid Tumours v1.1. Secondary endpoints included duration of response (DoR), safety, and tolerability.ResultsOverall, 180 patients were enrolled. In the overall population, the ORR was 20.0% (range: 0–47.4 across study arms), with median DoR of 17.1 months (95% confidence interval [CI]: 6.2, not estimable [NE]). The highest ORR was observed in the triple-negative breast cancer (TNBC) arm (patients with BRCA1/2 mutations and/or homologous recombination deficiency) (ORR: 47.4%; median DoR: 17.1 months [95% CI: 3.0, NE]). Treatment-emergent adverse events (TEAEs) of ≥Grade 3 occurred in 61.7% of patients. Serious TEAEs occurred in 50.0% of patients.ConclusionsPamiparib plus tislelizumab showed a variable level of antitumour activity in patients with advanced solid tumours, with the highest ORR in TNBC and was associated with a manageable safety profile.Clinical trial registrationClinicalTrial.gov: NCT02660034.

Regorafenib plus tislelizumab for patients with metastatic colorectal cancer: A real-world study.

e15589 Background: Regorafenib improves progression-free survival (PFS) and overall survival (OS) in patients with refractory metastatic colorectal cancer (mCRC). As a multikinase inhibitor, regorafenib could regulate the immune microenvironment. We aimed to evaluate the efficacy and safety of regorafenib plus tislelizumab in patients with mCRC in a real-world setting. Methods: We retrospectively analyzed the efficacy and safety of patients with mCRC who received at least one cycle of regorafenib plus tislelizumab between Mar 10, 2021 and Dec 18, 2022 in the Affiliated Hospital of Jiangnan University. 33 patients were received regorafenib (80mg, po, qd, d1-21) every 4 weeks and tislelizumab (200mg, iv) every 3 weeks, until disease progression, intolerable toxicities, or physician/patient withdrawal. The safety and efficacy were assessed by investigators per CTCAE v5.0 and RECIST v1.1, respectively. Results: A total of 33 mCRC patients (19 male vs. 14 female, 5 second-line recipients vs. 20 third-line recipients vs. 7 fourth-line recipients vs. 1 unknown, average age of 62.6 years) were enrolled. Most patients had left-sided cancer (63.6%), liver metastases and lung metastases both occurred in 19 patients (57.6%). With a median follow-up of 6.77 months (range 0- 21.6), the objective response rate (ORR) and disease control rate (DCR) were 15.2% and 100%, with a median PFS of 12.97 months (95% CI, 9.07-NA). The median OS was 19.83 months (95%CI, 7.66-32.01). There was no significant difference in OS between patients with and without liver metastases, the mOS was 19.8 months (95%CI, 9.53-NA) vs. not reached (NR); P = 0.368. The incidence of grade 3/4 adverse events was 24.2%, the most common TRAEs of grade ≥3 were anemia (9.1%) and hyperbilirubinemia (9.1%). No new safety signals were identified. Conclusions: The combination of regorafenib and tislelizumab had a manageable safety profile and promising efficacy in mCRC patients. And this combined therapy needs further prospective studies to verify the outcomes.

IMM01 plus tislelizumab in patients with advanced solid tumors and lymphoma: An open-label, multicenter, phase 1b/2 dose escalation and expansion study (IMM01-04).

2600 Background: IMM01, a recombinant SIRPα-Fc fusion protein, can activate macrophages to enhance anti-tumor activity by blocking CD47-SIRPα interaction. Based on preclinical results, IMM01 showed unique property of weak human erythrocyte conjugation. IMM01 plus tislelizumab has the potential to augment both innate and adaptive anti-tumor immune responses. Methods: This study included the phase 1b dose escalation part and the phase 2 dose expansion part. The dose escalation part was conducted with a standard 3+3 design to evaluate the safety, MTD/RP2D and anti-tumor activity in patients with advanced solid tumors. IMM01 (1.0, 1.5, 2.0 mg/kg) was administered once a week and tislelizumab (200mg) was administered once every 3 weeks. The results of the dose escalation part were reported here. Results: As of 26 Dec 2022, 14 pts were enrolled in the dose escalation part, including 5 NSCLC, 2 SCLC, 2 ESCC, 2 CRC, 1 HCC, 1 melanoma and 1 cervical carcinoma. Median age was 61 years (range 49-70). Median of prior therapies was 4 (range 1-10), and 13 pts (92.9%) received previous anti PD-1/L1 treatment. Treatment-related adverse events (TRAEs) occurred in 14 pts (100.0%) to date. Most TRAEs were grade 1-2. The most common TRAEs (≥10%) of all grades were anaemia (85.7%), platelet count decreased (28.6%), asthenia (28.6%), white blood cell count decreased (21.4%), lymphocyte count decreased (21.4%), IRR (21.4%), proteinuria (21.4%), gamma-glutamyltransferase increased (14.3%), white blood cell count increased (14.3%), blood creatine phosphokinase MB increased (14.3%), neutrophil count decreased (14.3%), neutrophil count increased (14.3%), hypoalbuminaemia (14.3%) and hyponatraemia (14.3%). The Grade 3-4 TRAEs were lymphocyte count decreased (21.4%), white blood cell count decreased (14.3%), platelet count decreased (14.3%), blood creatine phosphokinase MB increased (7.1%), blood pressure increased (7.1%) and anaemia (7.1%). No DLT occurred. No TRAE leading to treatment discontinuation was reported. 2 pts (14.3%) had treatment related SAE (2 platelet count decreased), they recovered without platelet transfusion and no bleeding occurred. In 14 pts, 1 pt had confirmed PR and 3 pts had SD. One heavily pre-treated NSCLC pt in the 2.0 mg/kg dose cohort had confirmed PR at Week 12, who was resistant to anti PD-1. One NSCLC pt in 1.5 mg/kg dose cohort and 2 pts (1 SCLC, 1 CRC) in 2.0 mg/kg dose cohort had SD. The treatments of these four pts are ongoing. Conclusions: Up to 2mg/kg IMM01 plus tislelizumab is well tolerated. The RP2D of IMM01 was determined as 2mg/kg, this was the highest IMM01 dose evaluated in human as a single agent. IMM01 plus tislelizumab showed preliminarily anti-tumor activity in patients with advanced solid tumors. The dose expansion part in advanced solid tumors and lymphoma is ongoing. Clinical trial information: chictr20220791 .

Neoadjuvant tislelizumab plus nab-paclitaxel and carboplatin followed by adjuvant tislelizumab in patients with early triple-negative breast cancer.

602 Background: Triple-negative breast cancer (TNBC) is the subtype with the least favorable outcomes. However, TNBC is associated with higher immune cell abundance than other subtypes, making it a good candidate for immunotherapy. Neoadjuvant chemotherapy is the preferred treatment approach for early TNBC. Emerging evidence shows that additional immune checkpoint inhibitors (ICI) in neoadjuvant therapy significantly increases pathological complete response (pCR) and event-free survival in early TNBC. Treatment regimens of paclitaxel and carboplatin (TP) is class I recommendation for TNBC neoadjuvant therapy, the application of ICI with TP regimens is worth exploring. Methods: In this multicenter, open-label, phase II study, patients with untreated, histologically confirmed TNBC in stage II-III (per AJCC 8th edition) were enrolled. Patients received six cycles of neoadjuvant therapy with tislelizumab at 200 mg once every 3 weeks plus nab-paclitaxel (125 mg/m2 on days 1 and 8) and carboplatin (at a dose based on an area under the concentration 2 on days 1 and 8) every 3 weeks. Patients who either completed or discontinued the neoadjuvant treatment would undergo definitive surgery. After surgery, the patients received adjuvant tislelizumab every 3 weeks for up to 12 cycles. The primary endpoint was the rate of pCR (ypT0/Tis ypN0). The secondary endpoints included 1-, 2-, 3-year event free survival rates and overall survival rates. Based on the Simon’s Two-Stage design, if > 13 of 32 patients achieved pCR, the enrollment would proceed to full accrual of 62 patients as planned. If > 29 of 62 patients achieved pCR, we would deem the study to have met the primary endpoint. Results: From Mar 2021 to Jan 2022, 32 patients were enrolled; 18 of them achieved pCR, and therefore the study proceeded to complete the enrollment of 62 patients. At the data cut-off of Oct 13, 2022, 62 patients were enrolled, among which 50 patients received neoadjuvant treatment and underwent definitive surgery. The median age was 50 years. 36 (72.0%) patients had stage II breast cancer at diagnosis. 31 of the 50 patients achieved pCR (ypT0/Tis ypN0), and the pCR rate was 62.0% (95% CI, 47.2-75.4). Patients with immune cell PD-L1 expression ≥10% had numerically higher pCR rate (81.8% vs 53.6%) than those with PD-L1 expression ≥1%. All 50 (100%) patients reported any grade of neoadjuvant treatment-related adverse events (TRAEs). Grade ≥3 TRAEs occurred in 27 (54%) patients. The rate of immune-related adverse events (irAEs) was 34% (17/50), with the common occurring (10%) irAE of hypothyroidism (n = 8, 16%). 2 (4.9%) patients experienced grade ≥3 irAEs. Severe adverse events were reported in 5 (10%) patients. Conclusions: The study has met its primary endpoint. Tislelizumab plus nab-paclitaxel and carboplatin achieved a higher pCR and was generally well tolerated in the neoadjuvant treatment of early TNBC. Clinical trial information: ChiCTR2100041675 .

Safety and efficacy of tislelizumab plus chemotherapy versus chemotherapy alone as neoadjuvant treatment for patients with locally advanced gastric cancer: real-world experience with a consecutive patient cohort.

Immunotherapy plus chemotherapy has recently been applied in the neoadjuvant treatment for locally advanced gastric cancer (LAGC), while its superiority over neoadjuvant chemotherapy (NACT) alone remains to be explored. This study explored the safety and efficacy of NACT plus tislelizumab in patients with LAGC. The data on patients with LAGC who received NACT combined with radical gastrectomy and NACT plus tislelizumab followed by radical gastrectomy was retrospectively collected. Clinicopathological characteristics of the two groups were compared. A total of 119 and 50 patients with gastric cancer treated with NACT and NACT plus tislelizumab, respectively, were enrolled. No significant difference was found between the baseline data of the two groups. The operative time (210.5 ± 70.4min vs. 237.6 ± 68.4min, P=0.732), intraoperative blood loss (157.8 ± 75.9ml vs. 149.1 ± 92.5ml, P=0.609), and number of dissected lymph nodes (24.7 ± 9.3 vs. 28.1 ± 10.3, P=0.195) was not statistically different between the two groups. In comparison to the NACT plus tislelizumab group, the R0 resection rate (100% vs. 89.9%, P=0.019) and pathologic complete response rate (26.0% vs. 3.4%, P<0.001) were significantly lower in the NACT group. The postoperative complication rates were 24.4% and 26.0% in the NACT and NACT plus tislelizumab groups with no significant difference (P=0.823). In subgroup analysis, tumor regression grade (TRG) (TRG 3: 72.3% vs. 23.5%, P<0.001) and ypN stage (stages 2-3: 46.8% vs. 5.9%, P=0.003) in the NACT group were significantly higher compared with the NACT plus tislelizumab group in esophagogastric junction carcinoma. Compared with the S-1 and oxaliplatin (SOX) or 5-fluorouracil, folinic acid, and oxaliplatin (FOLFOX) NACT regimen, NACT plus tislelizumab significantly improved the efficacy and R0 resection rate of LAGC without increasing the incidence of perioperative complications, particularly in esophagogastric junction carcinoma.

Zanubrutinib, Alone and in Combination With Tislelizumab, for the Treatment of Richter Transformation of Chronic Lymphocytic Leukemia.

Zanubrutinib, Alone and in Combination With Tislelizumab, for the Treatment of Richter Transformation of Chronic Lymphocytic Leukemia.