This study evaluated the effectiveness and safety of tislelizumab plus lenvatinib (TL group) and tislelizumab monotherapy (T group) in patients with stage C hepatocellular carcinoma (HCC) according to the Barcelona Clinic Liver Cancer (BCLC) staging system after lenvatinib failure, and it analyzed the factors influencing the effectiveness of TL as a second-line treatment. This retrospective analysis involved 51 patients treated at a single center between January 2019 and July 2023. Survival outcomes and tumor responses were compared between the TL and T monotherapy groups. Prognostic factors for overall survival (OS) and progression-free survival (PFS) were identified using Cox proportional hazard regression models. Among patients with BCLC stage C advanced HCC who experienced lenvatinib treatment failure, median PFS was significantly longer in the TL group than in the T group (6.8 months vs. 4.5 months, p = 0.003), and OS was notably extended in the TL group (14.0 months vs. 10.4 months, p = 0.012). Although the disease control rate (64% vs. 53.8%, p = 0.461) and objective response rate (20% vs. 7.7%, p = 0.202) were numerically higher in the TL group, these differences did not reach significance. Child-Pugh B liver function and tislelizumab monotherapy were independent prognostic factors for poor OS, whereas only tislelizumab monotherapy was an independent prognostic factor for poor PFS, Child-Pugh B was not a prognostic factor for PFS. Subgroup analysis demonstrated the OS benefit of tislelizumab plus lenvatinib in patients with Child-Pugh A liver function (14.0 months vs. 12.0 months, p = 0.013) but not in those with Child-Pugh B liver function (7.7 months vs. 6.1 months, p = 0.225). In the TL group, the most frequent treatment-related adverse events (AEs) were hand-foot skin reaction (32%), hypertension (28%), diarrhea (32%), and hypothyroidism (20%). Grade 3 or higher AEs occurred in 24% of patients in the TL group, and hand-foot skin reaction and diarrhea were the most frequent grade 3 or higher AEs. The incidence of AEs was comparable between the two groups. As a second-line treatment, the combination of tislelizumab and lenvatinib was well tolerated and associated with improved OS and PFS versus tislelizumab alone for patients with advanced HCC, particularly in those with Child-Pugh A liver function.

The current standard treatment for advanced and metastatic esophageal squamous cell carcinoma (ESCC) involves a combination of immunotherapy and chemotherapy, but paclitaxel's hormone preconditioning can reduce immune response and effectiveness. Polymeric micellar paclitaxel (Pm-Pac), a nanoformulation, bypasses this issue, enhancing tumor permeability and retention. While Pm-Pac has shown promise in non-small cell lung cancer, its efficacy in ESCC is yet to be established.

This is a prospective phase II trial involving untreated stage IV ESCC receiving two cycles of Pm-Pac, cisplatin, and tislelizumab. If no disease progression was observed, they received two additional cycles followed by a year of tislelizumab maintenance. Each 3-week cycle consisted of Pm-Pac (230 mg/m2), cisplatin (70 mg/m2), and tislelizumab (200 mg) on Day 1. The main objective was ORR. Secondary endpoints encompassed OS, PFS, DCR, and safety.

Between September 1, 2022, and June 30, 2024, 23 patients were included in the study. The median follow-up period was 14.8 months. The ORR stood at 69.6% (95% CI: 0.45-0.84) with a DCR of 100% (95% CI: 0.86-1.00). Out of the patients, 2 experienced complete responses, 14 had partial responses, and 7 maintained stable diseases. The mPFS was 10.8 months (95% CI: 0.26-0.632). The 1-year OS rate was 69.6% (95% CI: 49.1-84.4). Notably, no grade 3 or higher treatment-related adverse events or treatment-linked fatalities were reported.

The combination of Pm-Pac, cisplatin, and tislelizumab as an initial therapy for advanced ESCC is safe and effective and should be tested on a larger scale in the future.

Chinese Clinical Trial Registry: ChiCTR2400088576.

Pancreatic ductal adenocarcinoma (PDAC) is a gastrointestinal tumor with high morbidity and mortality. Despite advances in diagnostic and therapeutic modalities, the outcome and prognosis of PDAC remain poor. Most patients have locally advanced disease (30%-35%) or distant metastases (50%-55%) at the time of diagnosis. The treatment of unresectable pancreatic ductal adenocarcinoma (UR-PDAC) remains an urgent problem. In this study, we report that a patient with UR-PDAC underwent significant tumor shrinkage after PD-1 inhibitor combination chemotherapy, and obtained R0 (pathologically negative margin) resection and long-term survival.

A 51-year-old woman was diagnosed with pancreatic cancer (stage III). She underwent 3 cycles of preoperative neoadjuvant therapy (NAT) with programmed cell death protein 1 (PD-1) antibody in combination with chemotherapy and the tumor shrank from 4.0 × 3.3 cm to 0.9 cm without significant adverse effects. The patient underwent conversion surgery (CS) and achieved R0 resection, and no tumor cells remained as confirmed by pathology.

PD-1 antibody combination chemotherapy regimens have significant efficacy and do not add additional side effects in UR-PDAC patients, heralding advances in UR-PDAC treatment. We may have a way to give UR-PDAC patients access to curative treatment and long-term survival. This case of UR-PDAC patient with PD-L1-negative and microsatellite stability (MSS) gives us a more comprehensive understanding of the treatment options of immune-combination chemotherapy.

Plant-made PD1-Fc fusions engineered for optimized glycosylation and Fc-receptor engagement are highly efficient in blocking PD1/PDL1 interactions and can be cost-effective alternatives to antibody-based immune checkpoint inhibitors. Immune checkpoint inhibitors (ICIs) are antibodies to receptors that have pivotal roles during T-cell activation processes. The programmed cell death 1 (PD1) can be regarded as the primary immune checkpoint and antibodies targeting PD1 or its ligand PDL1 have revolutionized immunotherapy of cancer. However, the majority of patients fail to respond, and treatment resistance as well as immune-related adverse events are commonly associated with this therapy. Alternatives to antibody-based ICIs targeting the PD1 pathway may bear the potential to overcome some of these shortcomings. Here, we have used a plant expression platform based on the tobacco relative Nicotiana benthamiana to generate immunoglobulin fusion proteins harboring the wild type or an affinity-enhanced PD1 ectodomain. We have exploited the versatility of our system to generate variants that differed regarding their glycosylation profile as well as their capability to engage Fc-receptors. Unlike its wild-type counterpart, the affinity-enhanced versions showed strongly augmented capabilities to engage PDL1 in both protein- and cell-based assays. Moreover, in contrast with clinical antibodies, their binding is not affected by the glycosylation status of PDL1. Importantly, we could demonstrate that the plant-made PD1 fusion proteins are highly efficient in blocking inhibitory PD1 signaling in a T cell reporter assay. Taken together, our study highlights the utility of our plant-based protein expression platform to generate biologics with therapeutic potential. Targeting PDL1 with plant derived affinity-enhanced PD1 immunoglobulin fusion proteins may reduce overstimulation associated with antibody-based therapies while retaining favorable features of ICIs such as long serum half-life.

Molecularly targeted therapies and immunotherapy are increasingly being employed in the treatment of aggressive, recurrent thyroid cancer. Evidence from several studies indicates that a significant proportion of tumor patients derive limited benefit from immunotherapy as a monotherapy, with vascular abnormalities in solid tumors contributing to immune evasion. Numerous studies, both domestic and international, have assessed the efficacy of combining immune checkpoint inhibitors with antiangiogenic agents across various tumor types. These studies suggest that such combination therapies are effective in controlling disease progression and extending survival, among other outcomes. Nevertheless, further research is warranted to substantiate these findings and optimize treatment protocols.

This study aims to describe a patient diagnosed with anaplastic thyroid carcinoma (ATC) combined with primary squamous cell carcinoma of the thyroid (PSCCT) and concurrent thyroid abscess. The patient experienced local recurrence and metastasis following surgical intervention, radiotherapy, and chemotherapy, and was found to be PD-1 negative. Disease progression was effectively controlled through combination therapy with anlotinib and tislelizumab. Additionally, a comprehensive review of the relevant literature was conducted.

The patient exhibited disease recurrence 8 months postoperatively, notwithstanding the administration of adjuvant radiotherapy and chemotherapy. The local recurrent mass demonstrated minimal reduction following 4 cycles of targeted therapy with anlotinib. However, subsequent treatment with a combination of anlotinib and tislelizumab resulted in a substantial reduction of the neck mass and enlarged cervical lymph nodes after 12 cycles. The patient tolerated the combination therapy well, experiencing no significant adverse effects aside from pronounced fatigue. Thus, the combination therapy with anlotinib and tislelizumab proved effective in controlling the disease.

The management of postoperative recurrence of ATC-PSCCT presents significant challenges, as recurrent tumors typically demonstrate increased aggressiveness and resistance to pharmacological interventions, necessitating multimodal therapeutic approaches. Tislelizumab, an immune checkpoint inhibitor, may facilitate immune-mediated tumor clearance through the activation of various immune cells, including natural killer cells and macrophages. Despite the patient's PD-1 negativity, the combination of anlotinib and tislelizumab may exert synergistic effects through distinct mechanisms, thereby potentially enhancing therapeutic efficacy. The integration of a multi-targeted tyrosine kinase inhibitor within this combination therapy regimen warrants further investigation.

Treatment with cadonilimab and chemotherapy has shown promise as a first-line treatment for gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. However, its application in neoadjuvant settings has not yet been documented.

This multicenter, phase 2 trial (ChiCTR2200066893) was conducted at four hospitals across China. Treatment-naive patients with locally advanced G/GEJ adenocarcinoma (cT3/4, N+, M0) and who were human epidermal growth factor receptor 2 negative received 3-cycle or 4-cycle neoadjuvant treatment of cadonilimab plus FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) chemotherapy, followed by gastrectomy and 4-cycle adjuvant FLOT chemotherapy. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints included major pathological response (MPR), overall response rate (ORR), disease control rate (DCR), R0 resection rate, downstaging rate, and safety.

Between December 23, 2022, and December 15, 2023, 32 of 38 patients completed the scheduled treatment, achieving an R0 resection rate of 100% (32/32). The pCR rate was 21.1% (8/38, 90% confidence interval [CI]: 9.7-32.4), and the MPR rate was 44.7% (17/38, 90% CI: 30.9-58.5). Radiological evaluations were available for 28 of 38 patients by blinded independent central review. The ORR was 60.7% (17/28, 90% CI: 44.7-76.7), and the DCR was 100.0% (28/28, 90% CI: 100.0-100.0). Tumor downstaging occurred in 71.9% of patients (23/32), with consistent efficacy across all populations observed in the subgroup analysis. Grade 3 adverse events occurred in 31.6% of patients without severe safety issues.

Neoadjuvant cadonilimab plus FLOT chemotherapy treatment exhibits promising efficacy with manageable toxicities in locally advanced G/GEJ adenocarcinoma, providing preliminary evidence for further investigation.

This study was funded by Akeso Biopharma.

Background/Objectives: Finotonlimab (SCTI10A) is a humanized anti-PD-1 antibody tested in Phase III trials for several solid tumor types. Methods: This study characterized the in vitro and in vivo efficacy, Fc-mediated effector function, and non-clinical PK/PD properties of finotonlimab. Results: The results demonstrated that finotonlimab is effective in stimulating human T cell function in vitro and exhibits marked antitumor efficacy in vivo using both PD-1-humanized and PBMC-reconstructed mouse models. Additionally, finotonlimab exhibited minimal impact on the activation of effector cells via Fc receptor-dependent pathways, potentially facilitating PD-1+ T cell killing. In cynomolgus monkeys, finotonlimab exhibited a nonlinear pharmacokinetic (PK) profile in a dose-dependent manner, and a receptor occupancy rate of approximately 90% was observed at 168 h following a single administration of 1 mg/kg. Finotonlimab's PK profile (especially Cmax) was better than that of marketed antibodies. Following a 13-week successive administration of finotonlimab, a pharmacodynamic analysis revealed that a sustained mean receptor occupancy of PD-1 molecules on circulating T cells remained at or above 93% for up to 8 weeks, even at a dose of 3 mg/kg, and that there were higher antibody accumulations in different dose groups. Conclusions: Taken together, the preclinical findings are promising and provide the groundwork for evaluating the efficacy and pharmacodynamic characteristics of finotonlimab in clinical trials.

Upper tract urothelial carcinoma (UTUC) is a rare subset of urothelial cancers with poor prognosis. No consensus exists on the benefit of adjuvant immunotherapy for patients with UTUCs after nephroureterectomy with curative intent and the existing studies are limited. Herein, this study aimed to evaluate the effectiveness and safety of adjuvant treatment of tislelizumab with or without chemotherapy in patients with high-risk UTUC.

A retrospective study was conducted on 63 patients with high-risk UTUC who received tislelizumab with or without gemcitabine-cisplatin (GC) chemotherapy regimen after surgery between January 2020 and December 2022. Data on demographic and clinical characteristics, surgical, outcomes, prognostic factors, and safety were collected and analyzed.

Among the 63 patients with high-risk UTUC, the median age was 66 years (interquartile range 57-72), with 33 (52%) being male. The majority of patients with staged pT3 (44%) and pN0 (78%) disease. Fifty-one patients (81%) received tislelizumab plus GC chemotherapy, and 12 (19%) were treated with tislelizumab monotherapy. After the median follow-up of 26 months (range 1-47), 49 (78%) patients achieved stable disease. The 2-year disease-free survival (DFS) and 2-year overall survival were 78.68% (95% CI: 60.02-87.07%) and 81.40% (95% CI: 68.76-89.31%), respectively. The cycles of GC chemotherapy were independent prognostic factors for survival, with higher DFS (hazard ratio = 0.68, 95% CI, 0.50-0.93; p = 0.016) observed in the subgroup undergoing ≥ 3 cycles versus < 3 cycles of GC chemotherapy. Fifty-eight patients (92%) experienced at least one treatment-related adverse event (TRAE), with grade 3-4 TRAEs occurring in 13%. The most common grade 3-4 TRAEs were decreased white blood cells, thrombocytopenia, and ulcers.

The study demonstrates promising clinical benefits and a manageable safety profile of the tislelizumab-based adjuvant regimen for patients with high-risk UTUC. This suggests that adjuvant immunotherapy represents a potential therapeutic strategy for this population.

Pulmonary sarcomatoid carcinoma (PSC) is a scarce pathologic type of lung cancer of non-small cell lung cancer (NSCLC) that exhibits resistance to conventional chemotherapy and radiotherapy, resulting in a poor prognosis. Herein, a 67-year-old man was admitted to the hospital in January 2022 with a diagnosis of PSC for over 6 months and a newly discovered brain metastasis for 4 days. He had previously undergone two unsuccessful chemotherapy regimens: bevacizumab combined with pemetrexed and loplatin, and albumin-bound paclitaxel combined with loplatin. Radiotherapy was performed for the brain and skull metastases, followed by treatment with tislelizumab combined with anlotinib, a programmed cell death protein 1 (PD-1) inhibitor with anti angiogenic drug, respectfully. The patient initially received nine cycles of treatment with tislelizumab and anlotinib, resulting in a significant shrinkage of the lung tumor. Subsequently, anlotinib was discontinued due to bleeding in the brain metastasis, and the patient received two additional cycles of tislelizumab. Following improvement in the hemorrhage from brain metastasis, the patient received two cycles of treatment with tislelizumab and anlotinib. Treatment was subsequently interrupted for 1 month due to the coronavirus disease 2019 (COVID-19) pandemic, which then resumed with two additional cycles of tislelizumab and anlotinib. Finally, the patient refused to continue treatment due to the progression of the brain metastasis and economic conditions, despite the stable condition. At this point, the patient has achieved over a year of progression-free survival, with overall survival exceeding 39 months. This case illustrates the efficacy and safety of combining antitumor immunotherapy with anlotinib, a targeted anti-angiogenic therapy.

Treatment guidelines recommend neoadjuvant or adjuvant chemotherapy, with or without immune checkpoint inhibitors, for resectable non-small-cell lung cancer (NSCLC). We report the interim results for the phase 3 RATIONALE-315 study, which aimed to investigate perioperative tislelizumab for the treatment of resectable NSCLC.

RATIONALE-315 is a randomised, double-blind, placebo-controlled phase 3 trial conducted at 50 sites (hospitals or academic research centres) in China. Patients (aged ≥18 years) with untreated stage II-IIIA squamous or non-squamous NSCLC were randomly assigned (1:1) to neoadjuvant tislelizumab 200 mg or placebo intravenously every 3 weeks, plus platinum-based doublet chemotherapy followed by surgery and adjuvant tislelizumab 400 mg or placebo every 6 weeks. Dual primary endpoints were major pathological response rate and event-free survival, analysed by intention to treat. Safety was also assessed in all patients who received at least one dose of study treatment. RATIONALE-315 is registered with ClinicalTrials.gov, NCT04379635, and is active but not recruiting.

Between June 8, 2020, and Aug 31, 2022, 453 patients were assigned to tislelizumab (n=226) or placebo (n=227). The median age of patients was 62·0 years (IQR 56·0-67·0). 410 (91%) of 453 patients were male and 43 (9%) were female. As of Aug 21, 2023 (data cutoff for the interim analysis of event-free survival), median duration of follow-up was 22·0 months (IQR 15·5-28·0). Tislelizumab significantly improved event-free survival versus placebo (stratified hazard ratio 0·56 [95% CI 0·40-0·79]; one-sided p=0·0003). The major pathological response rate was significantly higher in the tislelizumab group (56% [95% CI 50-63]) than in the placebo group (15% [11-20]; difference 41% [33-49]; one-sided p<0·0001). Grade 3 or worse adverse events and serious treatment-related adverse events occurred in 163 (72%) of 226 patients and 35 (15%) of 226 patients, respectively, in the tislelizumab group, and in 150 (66%) and 18 (8%) patients, respectively, in the placebo group. The most common grade 3 or worse treatment-related adverse event was decreased neutrophil count (138 [61%] of 226 in the tislelizumab group vs 134 [59%] of 226 in the placebo group). 31 (14%) of 226 patients in the tislelizumab group and 45 (20%) of 227 patients in the placebo group died during the study.

Perioperative tislelizumab plus neoadjuvant chemotherapy showed a clinically meaningful and statistically significant improvement in efficacy and a manageable safety profile compared with neoadjuvant chemotherapy in patients with resectable stage II-IIIA NSCLC.

BeiGene.

Extranodal natural killer/T-cell lymphoma (ENKTCL) is almost always fatal after the failure of asparaginase. This phase II study aimed to investigate the efficacy and safety of tislelizumab combined with gemcitabine and oxaliplatin (Tisle-GemOx) in patients with ENKTCL failing asparaginase.

Eligible patients received Tisle-GemOx as initial induction for 6-8 cycles at 21-day intervals. Responders continued tislelizumab maintenance every two months for two years. The primary endpoint was the best complete response rate (CRR).

As of September 2023, 32 patients were enrolled in our study. Among the 30 efficacy-evaluable patients, the best CRR was 60 %, meeting the primary efficacy endpoint. With a median follow-up of 22.6 months, the median progression-free survival (PFS) was 7.4 months and the 1-year PFS rate was 46.4 %. Subgroup analyses showed that shorter PFS was associated with previous lines of chemotherapy ≥ 2 (P = 0.034) and concomitant hemophagocytic lymphohistiocytosis (P = 0.040). Pseudo-progression was observed in three patients (10 %). The most common grade ≥ 3 toxicities were lymphopenia (25 %) and anemia (15.6 %).

Tisle-GemOx exhibits promising anti-tumor activity and manageable toxicities as a salvage therapy for ENKTCL failing asparaginase. Further long-term follow-up is necessary to evaluate the durability of the response with tislelizumab maintenance in this patient population.

PD-1 has emerged as a central inhibitory checkpoint receptor in maintaining immune homeostasis and as a target in cancer immunotherapies. However, targeting PD-1 for the treatment of autoimmune diseases has been more challenging. We recently showed in a phase 2a trial that PD-1 could be stimulated with the PD-1 agonist antibody peresolimab to treat rheumatoid arthritis. Here, we demonstrate that PD-1 antibodies can elicit agonism and inhibit T cell activation by co-localization of PD-1 with the T cell receptor via Fcγ receptor (FcγR) engagement. Three PD-1 agonist antibodies with different antigen binding domains, including the clinically validated PD-1 blocking antibody pembrolizumab, suppressed T cell activation to a similar degree; this finding suggests that a specific PD-1-binding epitope is not required for PD-1 agonism. We next explored whether antibody-mediated clustering was an important driver of inhibition of T cell activation; however, we found that a monovalent PD-1 antibody was not inferior to a conventional bivalent antibody in its ability to suppress T cell activation. Importantly, we found that affinity to PD-1 correlated positively with inhibition of T cell activation, with higher affinity antibodies exhibiting higher levels of inhibition. Using a series of human Fc mutants with altered affinities to various FcγRs, we dissected the contributions of FcγRs and found that multiple FcγRs rather than a single receptor contribute to agonist activity. Our work reveals an important role for FcγR binding in the activity of PD-1 antibodies, which has implications for optimizing both PD-1 agonist and antagonist antibodies.

Tislelizumab combined with chemotherapy has shown significant clinical benefits in improving overall survival compared to chemotherapy alone for patients with extensive-stage small-cell lung cancer (ES-SCLC).

This study aimed to evaluate the cost-effectiveness of tislelizumab plus chemotherapy versus standard chemotherapy as a first-line treatment for ES-SCLC from the US payer perspective and the perspective of the Chinese healthcare system.

We conducted an economic evaluation using a Markov state-transition model, reflecting the US payer perspective and the perspective of the Chinese healthcare system. Baseline patient characteristics and essential clinical data were obtained from the RATIONALE-312 trial. The costs and utilities were derived from open-access databases and published literature. The primary outcomes measured included quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER), incremental net health benefit (INHB), and incremental net monetary benefit (INMB). Uncertainties in the model were addressed by probabilistic sensitivity analysis (PSA) and one-way sensitivity analysis (OWSA).

In the base-case analysis, the addition of tislelizumab to chemotherapy provided an incremental gain of 0.16 QALYs at an additional cost of $7430.73, resulting in an ICER of $46,132.33 per QALY. Although above the willingness-to-pay (WTP) threshold of China of $38,042.49 per QALY, the cost-effectiveness was marginal, with an INHB of - 0.03 QALYs and an INMB of $- 1303.06. In the US, despite a slightly higher effectiveness gain of 0.28 QALYs, the increased cost of $45,157.35 resulted in an unfavorable ICER of $163,885.06 per QALY, exceeding the US WTP threshold of $150,000.00. PSA showed probabilities of cost-effectiveness of tislelizumab plus chemotherapy at 17.18% in China and 40.41% in the US.

Tislelizumab combined with chemotherapy was not a cost-effective first-line treatment option for ES-SCLC in China or the US; however, the margin of cost-effectiveness was narrow.

LAG-3 is a member of the immunoglobulin superfamily expressed on activated T cells, but also on other immune cells. It has significant homology to CD4. Both molecules have four extracellular Ig-like domains with similar structural motifs but the sequence identity between LAG-3 and CD4 is low. Furthermore, unlike CD4 LAG-3 restrains T cell responses and antibodies targeting this receptor are emerging drugs in cancer immunotherapy. A combination of LAG-3 and PD-1 antibodies has already been approved for the treatment of metastatic melanoma. Despite this success, its biology is still not well understood. Here we summarize the current knowledge on expression, ligands, and function of LAG-3. We point to the differences between LAG-3 and other inhibitory immune checkpoints and describe obstacles to study the role of this receptor in T cell activation processes. Finally, we discuss future directions for scientific efforts to come to a more complete understanding of the biology of this eminent immune checkpoint.

The efficacy of tislelizumab plus chemotherapy in improving progression-free survival (PFS) and overall survival (OS) in unresectable gastric or gastroesophageal junction cancer (GC/GEJC) has recently been emphasized. This study compared the cost-effectiveness of tislelizumab plus chemotherapy versus placebo plus chemotherapy for the United States (US) and Chinese populations.

Using data from the RATIONALE-305 phase 3 trial, a Markov model was developed to analyze quality-adjusted life years (QALYs), incremental cost-effectiveness ratios (ICERs), incremental net health benefits (INHBs), and incremental net monetary benefits (INMBs). The health state utilities and direct medical costs were obtained from the relevant literature and local cost databases. The model uncertainty was evaluated using sensitivity analyses.

In the base-case analysis, the addition of tislelizumab to chemotherapy yielded an ICER of $37,768.48 per QALY in China, slightly below the willingness-to-pay (WTP) threshold of $38,042.49 per QALY, showing marginal cost-effectiveness with an INHB of 0.05 QALYs and an INMB of $1,852.49. Subgroup analyses revealed ICERs of $23,853.52 for patients with a PD-L1 TAP score ≥ 5% (TAP ≥ 5%). In the US, the ICER was $502,786.22 per QALY in the intent-to-treat (ITT) and $321,395.28 per QALY in the TAP ≥ 5% subgroup, exceeding the US WTP threshold of $150,000.00.

In China, tislelizumab plus chemotherapy is a cost-effective first-line therapy for unresectable GC/GEJC in both ITT and TAP ≥ 5% subgroups. In the US, tislelizumab plus chemotherapy is not cost-effective.

To evaluate the effectiveness and safety of low-dose gemcitabine and metronomic capecitabine in combination with tislelizumab for patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) who have previously received other anti-PD-1 therapies.

This retrospective, observational study included patients with RM-NPC who had prior treatment with anti-PD-1 therapy and subsequently received tislelizumab along with low-dose gemcitabine and metronomic capecitabine between March 2019 and August 2023. Progression-free survival (PFS) was estimated using the Kaplan-Meier method.

Among 25 eligible patients, 8 (20%) achieved a complete response (CR). The objective response rate (ORR) was 68%, and the disease control rate (DCR) was 80%. The 1-year PFS rate was 78%. All patients experienced treatment-related adverse events, which were all grade 1 or 2.

The combination of tislelizumab with low-dose gemcitabine and metronomic capecitabine demonstrated promising antitumor effectiveness in RM-NPC patients who had failed previous anti-PD-1 therapy, with a manageable safety profile.

The development of checkpoint antibodies for cancer therapy has been guided by the principle of blocking T cell inhibitory signals. Recognition of the role of the Fc domain in therapeutic activities, through the depletion of immunosuppressive populations and myeloid cell activation, prompts a shift toward the development of optimized Fc-engineered checkpoint antibodies.

The Fc region of antibodies is vital for most of their physiological functions, many of which are engaged through binding to a range of Fc receptors. However, these same interactions are not always helpful or wanted when therapeutic antibodies are directed against self-antigens, and can sometimes cause catastrophic adverse reactions. Over the past 40 years, there have been intensive efforts to "silence" unwanted binding to Fc-gamma receptors, resulting in at least 45 different variants which have entered clinical trials. One of the best known is "LALA" (L234A/L235A). However, neither this, nor most of the other variants in clinical use are completely silenced, and in addition, the biophysical properties of many of them are compromised. I review the development of different variants to see what we can learn from their biological properties and use in the clinic. With the rise of powerful new uses of antibody therapy such as bispecific T-cell engagers, antibody-drug conjugates, and checkpoint inhibitors, it is increasingly important to optimize the Fc region as well as the antibody binding site in order to achieve the best combination of safety and efficacy.

Hepatocellular carcinoma (HCC) patients with macrovascular invasion (MVI) have dismal prognosis and there are no standard perioperative therapies. This phase 2 trial (ChiCTR2000036385) aimed to investigate the activity and safety of perioperative tislelizumab plus intensity modulated radiotherapy (IMRT) for resectable HCC with MVI. Thirty treatment-naïve patients with MVI received 3 cycles of tislelizumab intravenously (200 mg, every three weeks) and concurrent IMRT (45 Gray in 15 fractions). Primary endpoints were the overall response rate (ORR) and overall survival (OS). Secondary endpoints were the proportion of patients with a complete or major pathological response (pCR or MPR), recurrence-free survival (RFS) and safety. Of patients enrolled, 15 (50%) underwent curative surgery followed by adjuvant tislelizumab. The ORR was 30.0% (90% CI 16.6%-46.5%) and the median OS was 18.7 months. Of the 15 patients underwent surgical resection, 10 (66.7%) achieved pCR or MPR and 8 (53.3%) remained recurrence-free. The median RFS were not reached with a median follow-up of 21.77 months (95% CI 12.50-31.03) post-surgery. 4 (13.3%) patients experienced grade 3 treatment-related adverse events. The most common events were thrombocytopenia, leukopenia, and anemia. The trial has met the pre-specified endpoints, and these results support further studies of perioperative immunotherapy plus radiotherapy in HCC.

Prolgolimab is a recombinant IgG1-based anti-PD-1 antibody, whose properties were improved by the introduction of the LALA mutation, and which has demonstrated high efficacy in patients with metastatic melanoma. This paper presents the results of comparative preclinical studies of antigen-binding and effector functions involving prolgolimab and conventional IgG4 antibodies, nivolumab and pembrolizumab. None of the studied antibodies had undesirable antibody-dependent cellular cytotoxicity activity. Prolgolimab has shown higher PD-1 receptor occupancy and T-cell activation, but lower propensity to activate antibody-dependent cellular phagocytosis as compared to nivolumab and pembrolizumab. An in vivo study in mice inoculated with CT26.wt cancer cells showed that tumor growth inhibition was 16% for pembrolizumab and 56% for prolgolimab. This study warrants clinical comparison of IgG1- and IgG4-based anti-PD-1 antibodies.

The purpose of this study was to report an updated, final analysis with longer follow-up for the open-label phase III RATIONALE-304 study of first-line tislelizumab plus chemotherapy versus chemotherapy alone for advanced nonsquamous non-small-cell lung cancer (nsq-NSCLC).

Patients with histologically confirmed stage IIIB/IV nsq-NSCLC were randomized (2 : 1) to 4-6 cycles of tislelizumab plus platinum-based chemotherapy and pemetrexed every 3 weeks, followed by maintenance tislelizumab and pemetrexed, or platinum-based chemotherapy and pemetrexed alone every 3 weeks followed by maintenance pemetrexed. The primary endpoint was independent review committee (IRC)-assessed progression-free survival (PFSIRC). Overall survival (OS), safety, and tolerability were secondary endpoints.

Overall, 334 patients were randomized (tislelizumab plus chemotherapy: n = 223; chemotherapy: n = 111). At final analysis (median follow-up 16.1 months), safety/tolerability profiles in both arms were consistent with the interim analysis. Tislelizumab plus chemotherapy continued to demonstrate prolongation of PFSIRC versus chemotherapy alone {stratified hazard ratio (HR) 0.63 [95% confidence interval (CI) 0.47-0.86]; median PFSIRC 9.8 months (95% CI 8.9-11.7 months) versus 7.6 months (95% CI 5.6-8.0 months), respectively}. OS stratified HR for tislelizumab plus chemotherapy versus chemotherapy was 0.90 (95% CI 0.63-1.28), with median OS of 21.4 months (95% CI 17.7 months-not estimable) versus 21.3 months (95% CI 15.6 months-not estimable), respectively. At a subsequent ad hoc analysis (median follow-up 19.3 months), OS HR between arms was 0.85 (95% CI 0.63-1.14); when adjusted for crossover using the two-stage method, the OS HR was 0.68 (95% CI 0.48-0.96).

After longer follow-up, first-line tislelizumab plus chemotherapy continued to demonstrate a manageable safety profile and a favorable PFS benefit over chemotherapy alone in patients with advanced/metastatic nsq-NSCLC.

Programmed death 1 blockade (tislelizumab) has been approved for metastatic urothelial carcinoma but not as part of neoadjuvant therapy for muscle-invasive bladder cancer (MIBC). In this multicenter single-arm trial (ChiCTR2000037670), 65 participants with cT2-4aN0M0 MIBC received neoadjuvant gemcitabine-cisplatin plus tislelizumab; 57 of them underwent radical cystectomy (RC). The primary endpoint of pathologic complete response (pCR) rate was 50.9% (29/57, 95% confidence interval (CI) 37.3-64.4%) and the pathologic downstaging (secondary endpoint) rate was 75.4% (43/57, 95% CI 62.2-85.9%) in participants undergoing RC. Genomic and transcriptomic analyses revealed three MIBC molecular subtypes (S): S1 (immune-desert) with activated cell-cycle pathway, S2 (immune-excluded) with activated transforming growth factor-β pathway and S3 (immune-inflamed) with upregulated interferon-α and interferon-γ response. Post hoc analysis showed pCR rates of 16% (3/19, S1), 77% (10/13, S2) and 80% (12/15, S3) (P = 0.006). In conclusion, neoadjuvant gemcitabine-cisplatin plus tislelizumab for MIBC was compatible with an enhanced pCR rate.

First-line tislelizumab plus chemotherapy significantly improved progression-free survival (PFS) versus chemotherapy alone in advanced squamous non-small-cell lung cancer (sq-NSCLC) at the interim analysis of the phase III RATIONALE-307 trial. We present the final analysis of this trial.

Patients with treatment-naive, stage IIIB/IV, sq-NSCLC were randomized (1 : 1: 1) to 21-day cycles of i.v.: tislelizumab plus paclitaxel and carboplatin (arm A); tislelizumab plus nab-paclitaxel and carboplatin (arm B); or paclitaxel and carboplatin (arm C). The primary endpoint was independent review committee-assessed PFS; overall survival was a secondary endpoint.

In total, 360 patients were randomized; 355 received treatment. At the final analysis (median study follow-up: 16.7 months), tislelizumab plus chemotherapy had a manageable safety profile, consistent with that at the interim analysis. Improvement in PFS was maintained for arms A and B versus C {hazard ratio (HR) 0.45 [95% confidence interval (CI) 0.33-0.62] and 0.43 (95% CI 0.31-0.60), respectively}. Overall survival HRs for arms A and B versus C were 0.68 (95% CI 0.46-1.01) and 0.75 (95% CI 0.50-1.12), respectively.

The RATIONALE-307 final analysis demonstrated superior clinical benefit with addition of tislelizumab to chemotherapy, and a manageable safety profile, as first-line treatment of advanced sq-NSCLC.

Sitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MER), VEGFR-2, KIT, and MET. SAFFRON-104 (NCT03941873) was a multicohort phase Ib/II study investigating sitravatinib with/without tislelizumab, an anti-programmed cell death protein 1 (PD-1) antibody, in patients with advanced hepatocellular carcinoma (HCC) or gastric cancer/gastroesophageal junction cancer (GC/GEJC).

Eligible patients had histologically/cytologically confirmed advanced HCC or GC/GEJC. Phase I determined the recommended phase II dose (RP2D) of sitravatinib with/without tislelizumab. Phase II evaluated sitravatinib monotherapy in patients with pretreated HCC, and sitravatinib plus tislelizumab in anti-PD-(L)1-naïve or -treated HCC and anti-PD-(L)1-naïve GC/GEJC. Primary endpoints were safety/tolerability (phase I) and objective response rate (ORR) (phase II).

At data cutoff (March 31, 2023), 111 patients were enrolled; 102 were efficacy-evaluable (median study follow-up 9.1 months [range: 0.7-36.9]). The RP2D of sitravatinib was determined as 120 mg orally once daily. In patients receiving sitravatinib monotherapy and sitravatinib in combination with tislelizumab, grade ≥ 3 treatment-related adverse events occurred in 14 (51.9%) and 42 (50.0%) patients, respectively. The ORR was 25% (95% confidence interval [CI]: 8.7-49.1) in patients with pretreated HCC receiving sitravatinib monotherapy. In patients receiving sitravatinib with tislelizumab, the ORR was 11.5% (95% CI 2.4-30.2) with anti-PD-(L)1-naïve HCC, 9.5% (95% CI 1.2-30.4) with anti-PD-(L)1-treated HCC, and 16.1% (95% CI 5.5-33.7) in patients with anti-PD-(L)1-naïve GC/GEJC.

Sitravatinib with/without tislelizumab was generally well tolerated and showed preliminary antitumor activity in patients with advanced HCC and GC/GEJC.

This study evaluated health-related quality of life (HRQoL) in the RATIONALE-309 (NCT03924986) intent-to-treat (ITT) population and in a subgroup of patients with liver metastases.

Patients were randomized 1:1 to tislelizumab + chemotherapy or placebo + chemotherapy. As the secondary endpoint, HRQoL was evaluated using seven selected scores from the EORTC QLQ-C30 and QLQ Head and Neck Cancer module (QLQ-H&N35).

Of 263 randomized patients in the ITT population (tislelizumab + chemotherapy n = 131, placebo + chemotherapy n = 132), 43% had liver metastases (tislelizumab + chemotherapy n = 56; placebo + chemotherapy n = 57). No differences in change in selected scores on the QLQ-C30 from baseline to cycle 4 or cycle 8 were observed for the ITT or liver metastases subgroup. No differences in selected QLQ-H&N35 scores were observed between the arms from baseline to cycle 4. In the ITT population and the liver metastases subgroup, a greater reduction from baseline to cycle 8 was observed in the tislelizumab + chemotherapy arm than the placebo + chemotherapy arm in QLQ-H&N35 pain score. At cycle 8 in the liver metastases subgroup, the tislelizumab + chemotherapy arm experienced greater improvement in the QLQ-H&N35 senses problems score than the placebo + chemotherapy arm. Differences in time to deterioration between arms were not observed.

The current findings, along with improved survival and favorable safety, suggests that tislelizumab + chemotherapy represents a potential first-line treatment for recurrent or metastatic nasopharyngeal cancer.

Despite the success of immunotherapies for melanoma in recent years, there remains a significant proportion of patients who do not yet derive benefit from available treatments. Immunotherapies currently licensed for clinical use target the adaptive immune system, focussing on Tcell interactions and functions. However, the most prevalent immune cells within the tumor microenvironment (TME) of melanoma are macrophages, a diverse immune cell subset displaying high plasticity, to which no current therapies are yet directly targeted. Macrophages have been shown not only to activate the adaptive immune response, and enhance cancer cell killing, but, when influenced by factors within the TME of melanoma, these cells also promote melanoma tumorigenesis and metastasis.

We present a review of the most up-to-date literatureavailable on PubMed, focussing on studies from within the last 10 years. We also include data from ongoing and recent clinical trials targeting macrophages in melanoma listed on clinicaltrials.gov.

Understanding the multifaceted role of macrophages in melanoma, including their interactions with immune and cancer cells, the influence of current therapies on macrophage phenotype and functions and how macrophages could be targeted with novel treatment approaches, are all critical for improving outcomes for patients with melanoma.

The RATIONALE-306 study revealed that patients with advanced or metastatic oesophageal squamous cell carcinoma (OSCC) could benefit from treatment with tislelizumab plus chemotherapy. This study aimed to evaluate the cost-effectiveness of tislelizumab plus chemotherapy for treating OSCC from the perspective of the Chinese healthcare system. Partitioned survival model estimated the cost-effectiveness of tislelizumab plus chemotherapy compared with chemotherapy alone for treating OSCC using RATIONALE-306 data. Costs and utilities were obtained from local databases and published studies. Costs, quality-adjusted life-years (QALYs), life-years, incremental cost-effectiveness ratios (ICER), incremental net health benefits (INHB), and incremental net monetary benefits (INMB) were outcomes. Price simulation were conducted at the willingness-to-pay (WTP) threshold. Sensitivity and subgroup analyses were performed to assess model robustness. Compared with chemotherapy alone, tislelizumab plus chemotherapy yielded an ICER of USD 27,896/QALY, gained an additional 0.414 QALYs and 0.751 life-years, and increased the cost by USD 11,560. Probabilistic sensitivity analysis revealed that tislelizumab plus chemotherapy was cost-effective at the WTP of USD 38,258/QALY with probability of 94.43%. When the price in China was less than USD 3.714 per mg, the price simulation results indicated that tislelizumab plus chemotherapy was cost-effective at a WTP threshold of USD 38,258. Tislelizumab plus chemotherapy yielded an INHB of 0.112 QALYs and an INMB of USD 4,279 compared with chemotherapy alone at a WTP threshold of USD 38,258. Based on the sensitivity analyses, the above results were stable. A general trend was observed for subgroups with better survival benefits related to a higher probability of cost-effectiveness. From the Chinese healthcare perspective, tislelizumab plus chemotherapy is more cost-effective than chemotherapy alone as a first-line therapy for OSCC. These findings can help clinicians make optimal clinical decisions and assist decision-makers in evaluating the cost-effectiveness of tislelizumab in clinical practice.

Sinonasal squamous cell carcinoma (SNSCC) is the most common, high-aggressive sinonasal malignancies that have remained relatively stable poor outcomes over the past decade. As a first-line treatment for SNSCC, surgery plus adjuvant radiotherapy is recommended. However, complete surgical resection may not be appropriate due to the proximity of the nasal cavity and sinuses to key structures such as orbit or intracranial. Currently, immune checkpoint inhibitors (ICIs) have been established as one of the first-line therapies for many solid tumors with unresectable stage. However, evidence on the efficacy of ICIs in sinonasal malignancy is scarce and no ICIs are approved for use in SNSCC up to day. In this report, we report a case of a 64-year-old man with SNSCC treated by multi-protocol exploration. The patient achieved pathological complete response (pCR) after receiving two cycles of Docetaxel and cisplatin combined with tislelizumab. To the best of our knowledge, this is the first case of SNSCC treated with tislelizumab that achieved pCR. This case offers real-world evidence that chemotherapy plus immunotherapy is a promising treatment for SNSCC.

Despite adequate transurethral resection of the bladder tumor (TURBT) followed by intravesical bacillus-calmette guérin (BCG), high-risk non-muscle-invasive bladder cancer (HR-NMIBC) is associated with high rates of recurrence and progression. Immune checkpoint inhibitors can improve antitumor activity in bladder cancer, but relevant evidence in HR-NMIBC is limited. Thus, we evaluated the efficacy and safety of the tislelizumab-based combination regimen in HR-NMIBC.

A retrospective study included 21 patients diagnosed with HR-NMIBC between July 2020 and September 2022. All patients underwent TURBT followed by combination regimens of tislelizumab plus BCG with or without gemcitabine/cisplatin (GC) chemotherapy. Clinical Data on demographics and characteristics, treatment information, outcomes, and safety were collected and analyzed.

Among the 21 patients with HR-NMIBC, the median age was 63 years (range 39-85), with the majority of patients with stage T1 (16/21, 76.19%). The median treatment of tislelizumab was 5 cycles (range 1-12) and the median number of BCG instillations was 12 times (range 2-19). Of the 21 patients, 15 (71.43%) received combination chemotherapy with GC, with a median treatment of 2 cycles (range 0-7); others did not. Overall, after the median follow-up of 25 months (range 7-31), the estimated 2-year bladder recurrence-free survival rate was 78.64% (95% confidence intervals [CIs], 50.79-91.83%), 2-year cystectomy-free survival rate was 83.00% (95% CI 53.53-94.59%), and 2-year disease-free survival rate was 73.39% (95% CI 46.14-88.36%). Sixteen stage T1 patients achieved a distant metastasis-free survival rate of 95.45% (95% CI 71.87-99.34%) at 2 years. Fourteen (66.67%) patients experienced at least one treatment related-AEs (TRAEs), with 9.52% (2/21) of grade 3-4. Grade ≥ 3 TRAEs were hypophysitis (1/21, 4.76%) and myasthenia (1/21, 4.76%). No treatment-related deaths were observed.

The study demonstrated promising clinical benefits and a manageable safety profile of tislelizumab-based combination regimen as a bladder-sparing treatment of HR-NMIBC.

OX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies, including a clinically relevant monoclonal antibody (mAb) (GSK3174998) and evaluated how isotype can alter those mechanisms with the aim to develop improved antibodies for use in rational combination treatments for cancer.

Anti-mOX40 and anti-hOX40 mAbs were evaluated in a number of in vivo models, including an OT-I adoptive transfer immunization model in hOX40 knock-in (KI) mice and syngeneic tumor models. The impact of FcγR engagement was evaluated in hOX40 KI mice deficient for Fc gamma receptors (FcγR). Additionally, combination studies using anti-mouse programmed cell death protein-1 (mPD-1) were assessed. In vitro experiments using peripheral blood mononuclear cells (PBMCs) examining possible anti-hOX40 mAb mechanisms of action were also performed.

Isotype variants of the clinically relevant mAb GSK3174998 showed immunomodulatory effects that differed in mechanism; mIgG1 mediated direct T-cell agonism while mIgG2a acted indirectly, likely through depletion of regulatory T cells (Tregs) via activating FcγRs. In both the OT-I and EG.7-OVA models, hIgG1 was the most effective human isotype, capable of acting both directly and through Treg depletion. The anti-hOX40 hIgG1 synergized with anti-mPD-1 to improve therapeutic outcomes in the EG.7-OVA model. Finally, in vitro assays with human peripheral blood mononuclear cells (hPBMCs), anti-hOX40 hIgG1 also showed the potential for T-cell stimulation and Treg depletion.

These findings underline the importance of understanding the role of isotype in the mechanism of action of therapeutic mAbs. As an hIgG1, the anti-hOX40 mAb can elicit multiple mechanisms of action that could aid or hinder therapeutic outcomes, dependent on the microenvironment. This should be considered when designing potential combinatorial partners and their FcγR requirements to achieve maximal benefit and improvement of patient outcomes.