PD1/PD-L1 blockade in clear cell renal cell carcinoma: mechanistic insights, clinical efficacy, and future perspectives.

The advent of PD1/PD-L1 inhibitors has significantly transformed the therapeutic landscape for clear cell renal cell carcinoma (ccRCC). This review provides an in-depth analysis of the biological functions and regulatory mechanisms of PD1 and PD-L1 in ccRCC, emphasizing their role in tumor immune evasion. We comprehensively evaluate the clinical efficacy and safety profiles of PD1/PD-L1 inhibitors, such as Nivolumab and Pembrolizumab, through a critical examination of recent clinical trial data. Furthermore, we discuss the challenges posed by resistance mechanisms to these therapies and potential strategies to overcome them. We also explores the synergistic potential of combination therapies, integrating PD1/PD-L1 inhibitors with other immunotherapies, targeted therapies, and conventional modalities such as chemotherapy and radiotherapy. In addition, we examine emerging predictive biomarkers for response to PD1/PD-L1 blockade and biomarkers indicative of resistance, providing a foundation for personalized therapeutic approaches. Finally, we outline future research directions, highlighting the need for novel therapeutic strategies, deeper mechanistic insights, and the development of individualized treatment regimens. Our work summarizes the latest knowledge and progress in this field, aiming to provide a valuable reference for improving clinical efficacy and guiding future research on the application of PD1/PD-L1 inhibitors in ccRCC.

Cumulative incidence and risk factors of brain metastases in metastatic non-small cell lung cancer without baseline brain metastasis: Pooled analysis of individualized patient data from IMpower130, IMpower131, and IMpower150.

BACKGROUND: The objective of this study was to explore the abilities of atezolizumab plus chemotherapy in preventing brain metastases (BMs) among metastatic non-small cell lung cancer (NSCLC) without initial BMs, as well as the risk factors of BMs. METHODS: Individual patient data from three trials involving first-line atezolizumab for metastatic NSCLC (IMpower130, IMpower131, and IMpower150) were pooled. Among patients without baseline BMs and without epidermal growth factor receptor (EGFR) and/or anaplastic lymphoma kinase (ALK) mutations, those receiving atezolizumab + chemotherapy ± bevacizumab were classified as the atezolizumab plus chemotherapy group and those receiving placebo + chemotherapy ± bevacizumab were classified as the chemotherapy group. The cumulative incidences of BM (CI-BMs) between the two groups were compared. Other factors associated with the CI-BM were analyzed by Cox regression analyses. RESULTS: With a median follow-up of 17.6 months (range, 0.03-33.64 months), 74 (3.1%) of the 2380 enrolled patients developed BMs, including 50 (3.1%) and 24 (3.0%) in the atezolizumab plus chemotherapy group (n = 1589) and the chemotherapy group (n = 791), respectively. The CI-BMs at 6, 12, and 24 months were 1.7%, 2.8%, and 3.3%, respectively. After taking competing risk events into account, there was no significant difference in the CI-BMs between the two groups (p = .888). Nevertheless, the use of bevacizumab and the histology of nonsquamous NSCLC were found to be independently associated with the risk of BMs. CONCLUSIONS: In patients with metastatic EGFR/ALK wild-type NSCLC without baseline BMs, adding atezolizumab in the first-line treatment might not reduce the CI-BM. However, the administration of bevacizumab may reduce the risk of BMs.

Oligo-residual disease in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer: incidence, pattern of failure, and clinical value of local consolidative therapy.

OBJECTIVES: To investigate the feasibility and potential clinical value of local consolidative therapy (LCT) in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: PD-1/PD-L1 inhibitor-treated metastatic NSCLC patients with measurable disease in three academic centers were screened and those with adequate follow-up were included. Oligo-residual disease (ORD) was defined as residual tumors limited to three organs and five lesions evaluated at the best response among patients with partial response or stable disease after PD-1/PD-L1 inhibitors. Oligometastatic and multiple-metastatic disease (OMD/MMD) were similarly classified at baseline. Locoregional interventions, administered after effective treatment of PD-1/PD-L1 inhibitors and before initial disease progression, were defined as LCT. Patterns of initial progressive disease (PD) were classified as involving only residual sites (RP), only new sites (NP), or a combination of both (BP). RESULTS: Among the 698 patients included, ORD was documented in 73 (47.1%) of 155 patients with baseline OMD and 60 (11.0%) of 543 patients with baseline MMD. With a median follow-up of 31.0 (range, 6.0-53.0) months, 108 patients with ORD developed initial PD, with RP, NP, and BP occurring in 51 (47%), 23 (21.3%), and 34 (31.5%), respectively. Among the 133 patients with ORD, those receiving LCT (n = 43) had longer progression-free survival (HR = 0.58, 95% CI 0.40-0.85, p = 0.01) and overall survival (HR = 0.49, 95% CI 0.30-0.79, p < 0.0001). CONCLUSION: ORD occurs with a clinically relevant frequency among PD-1/PD-L1 inhibitor-treated metastatic NSCLC patients and LCT may provide extra survival benefits in those with ORD.

Possibility of PD-1/PD-L1 Inhibitors for the Treatment of Patients with Chronic Hepatitis B Infection.

BACKGROUND: Chronic hepatitis B (CHB) infection is still a major global public health problem, with nearly two billion patients. Although current antiviral drugs can inhibit viral replication and reduce hepatitis B virus (HBV) related complications, it is difficult to achieve clinical endpoints due to drug resistance. SUMMARY: Immune checkpoint inhibitors (ICIs) are an important strategy to reverse T-cell exhaustion, and rebuilding an effective functional T-cell response is a promising immunomodulatory approach for CHB patients. However, ICIs may lead to viral reactivation or immune-related adverse effects. There are still many controversies in the application of ICIs in treating patients with CHB. KEY MESSAGES: This article reviews the research progress of ICIs in CHB infection and related issues. The goal of this paper was to summarize the possible impact of new therapies for CHB with the aim of reducing potential clinical risks.

Lipid alterations play a role in the integration of PD-1/PD-L1 inhibitors and anlotinib for the treatment of advanced non-small-cell lung cancer.

BACKGROUND: Studies have shown that integrating anlotinib with programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors enhances survival rates among progressive non-small-cell lung cancer (NSCLC) patients lacking driver mutations. However, not all individuals experience clinical benefits from this therapy. As a result, it is critical to investigate the factors that contribute to the inconsistent response of patients. Recent investigations have emphasized the importance of lipid metabolic reprogramming in the development and progression of NSCLC. METHODS: The objective of this investigation was to examine the correlation between lipid variations and observed treatment outcomes in advanced NSCLC patients who were administered PD-1/PD-L1 inhibitors alongside anlotinib. A cohort composed of 30 individuals diagnosed with advanced NSCLC without any driver mutations was divided into three distinct groups based on the clinical response to the combination treatment, namely, a group exhibiting partial responses, a group manifesting progressive disease, and a group demonstrating stable disease. The lipid composition of patients in these groups was assessed both before and after treatment. RESULTS: Significant differences in lipid composition among the three groups were observed. Further analysis revealed 19 differential lipids, including 2 phosphatidylglycerols and 17 phosphoinositides. CONCLUSION: This preliminary study aimed to explore the specific impact of anlotinib in combination with PD-1/PD-L1 inhibitors on lipid metabolism in patients with advanced NSCLC. By investigating the effects of using both anlotinib and PD-1/PD-L1 inhibitors, this study enhances our understanding of lipid metabolism in lung cancer treatment. The findings from this research provide valuable insights into potential therapeutic approaches and the identification of new therapeutic biomarkers.

Identification of novel PD-1/PD-L1 small molecule inhibitors: virtual screening, synthesis and in vitro characterisation.

The PD-1/PD-L1 pathway is considered as one of the most promising immune checkpoints in tumour immunotherapy. However, researchers are faced with the inherent limitations of antibodies, driving them to pursue PD-L1 small molecule inhibitors. Virtual screening followed by experimental validation is a proven approach to discover active compounds. In this study, we employed multistage virtual screening methods to screen multiple compound databases to predict new PD-1/PD-L1 ligands. 35 compounds were proposed by combined analysis of fitness scores, interaction pattern and MM-GBSA binding affinities. Enzymatic assay confirmed that 10 out of 35 ligands were potential PD-L1 inhibitors, with inhibitory rate higher than 50% at the concentration of 30 µM. Among them, ZDS20 was identified as the most effective inhibitor with low micromolar activity (IC50 = 3.27 µM). Altogether, ZDS20 carrying novel scaffold was identified and could serve as a lead for the development of new classes of PD-L1 inhibitors.

Roles of cancer-associated fibroblasts (CAFs) in anti- PD-1/PD-L1 immunotherapy for solid cancers.

In recent years, breakthroughs have been made in tumor immunotherapy. However, tumor immunotherapy, particularly anti-PD-1/PD-L1 immune checkpoint inhibitors, is effective in only a small percentage of patients in solid cancer. How to improve the efficiency of cancer immunotherapy is an urgent problem to be solved. As we all know, the state of the tumor microenvironment (TME) is an essential factor affecting the effectiveness of tumor immunotherapy, and the cancer-associated fibroblasts (CAFs) in TME have attracted much attention in recent years. As one of the main components of TME, CAFs interact with cancer cells and immune cells by secreting cytokines and vesicles, participating in ECM remodeling, and finally affecting the immune response process. With the in-depth study of CAFs heterogeneity, new strategies are provided for finding targets of combination immunotherapy and predicting immune efficacy. In this review, we focus on the role of CAFs in the solid cancer immune microenvironment, and then further elaborate on the potential mechanisms and pathways of CAFs influencing anti-PD-1/PD-L1 immunotherapy. In addition, we summarize the potential clinical application value of CAFs-related targets and markers in solid cancers.

The 27-gene IO score is associated with efficacy of PD-1/L1 inhibitors independent of FGFR expression in a real-world metastatic urothelial carcinoma cohort.

Multiple targeted therapeutics have been approved by the FDA for mUC, including immune checkpoint inhibitors (ICIs) and more recently targeted agents for both FGFR and Nectin-4. FGFR3-aberrant and Nectin-4 expressing cells have been associated with an immunosuppressed phenotype. Given that less than half of all patients respond to these agents as monotherapies and less than 20% are eligible to receive salvage therapy, effective personalized treatment plans are critical. Typical biomarkers for ICIs such as PD-L1 and TMB have not been definitive in mUC, yet a biomarker-driven optimization of first-line therapy and subsequent sequencing have the potential to achieve higher and more durable response rates. The IO score is a 27-gene tumor immune microenvironment (TIME) classifier that has been associated with the clinical benefits of ICIs in multiple cancer types, including mUC. This study demonstrates that the IO score was associated with both progression-free survival (PFS) and overall survival (OS) in a real-world cohort of mUC patients treated with ICIs. Furthermore, the IO score was independent of and provided information incremental to TMB. Interestingly, the IO score predicted benefit in patients with high FGFR expression, despite conflicting data regarding response rates among the FGFR aberrant population. Taken together, these results demonstrate that the IO score assessment of the TIME is associated with a clinical benefit from ICI therapy and that this novel biomarker may inform therapeutic sequencing decisions in mUC, potentially improving outcomes for this notoriously difficult-to-treat disease.

Comparative efficacy and safety of PD-1/PD-L1 inhibitors in triple negative breast cancer: a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Triple-Negative Breast Cancer (TNBC) is a lethal subtype of breast cancer with limited treatment options. The purpose of this Network Meta-Analysis (NMA) is to compare the efficacy and safety of inhibitors of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in treating TNBC. METHODS: Our search strategy was used in six databases: PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature database, Embase, Scopus, and Web of Science up to November 2nd, 2022, as well as a thorough search in the most used trial registries. We included phase II and III randomized controlled trials that looked at the efficacy of PD-1/PD-L1 inhibitors in the treatment of TNBC and reported either Overall Survival (OS), Progression-Free Survival (PFS), or pathological Complete Response (pCR). The risk of bias was assessed utilizing Cochrane's risk of bias 2 tool, and the statistical analysis was performed using a frequentist contrast-based method for NMA by employing standard pairwise meta-analysis applying random effects model. RESULTS: 12 trials (5324 patients) were included in our NMA including seven phase III trials. Pembrolizumab in a neoadjuvant setting achieved a pooled OS of 0.82 (95% Confidence Interval (CI) 0.65 to 1.03), a PFS of 0.82 (95% CI 0.71 to 0.94) and a pCR 2.79 (95% CI 1.07 to 7.24) compared to Atezolizumab's OS of 0.92 (95% CI 0.74 to 1.15), PFS of 0.82 (95% CI 0.69 to 0.97), and pCR of 1.94 (95% CI 0.86 to 4.37). Atezolizumab had less grade ≥ 3 adverse events (OR 1.48, 95% CI 0.90 to 2.42) than Pembrolizumab (OR 1.90, 95% CI 1.08 to 3.33) in the neoadjuvant setting. CONCLUSIONS: PD-1/PD-L1 inhibitors exhibited varying efficacy in terms of OS, PFS, and pCR. They were associated with an increase in immune-related adverse effects. When used early in the course of TNBC, PD-1/PD-L1 inhibitors exert their maximum benefit. Durvalumab as a maintenance treatment instead of chemotherapy has shown promising outcomes. Future studies should focus on PD-L1 expression status and TNBC subtypes, since these factors may contribute to the design of individualized TNBC therapy regimens. Systematic review registration PROSPERO Identifier: CRD42022380712.

Identification on surrogating overall survival with progression-free survival of first-line immunochemotherapy in advanced esophageal squamous cell carcinoma-an exploration of surrogate endpoint.

BACKGROUND: Overall survival (OS) is the gold standard to assess novel therapeutics to treat cancer. However, to identify early efficacy and speed up drug approval, trials have used progression-free survival (PFS) as a surrogate endpoint (SE). Herein, we aimed to examine if PFS could function as an OS surrogate in advanced Esophageal Squamous Cell Carcinoma (ESCC) treated with first-line immunochemotherapy. METHODS: Two hundred ninety-two advanced ESCC patients treated using inhibitors of PD-1/PD-L1 + chemotherapy or chemotherapy alone were collected. In addition, six phase III randomized clinical trials were eligible for inclusion. Bayesian normal-induced-copula-estimation model in retrospective patient data and regression analysis in the published trial data were used to determine the PFS-OS correlation. RESULTS: PFS correlated moderately with OS in the retrospective cohort (Kendall's Tau = 0.684, τ = 0.436). In trial-level, treatments effects for PFS correlated weakly with those for OS in intention-to-treat population (R2 = 0.436, adj.R2 = 0.249, P > 0.05) and in PD-L1-enriched population (R2 = 0.072). In arm-level, median PFS also correlated weakly with median OS. Moreover, analysis of the retrospective cohort demonstrated that the annual death risk after progression in the continued immunotherapy group was considerably lower than that in the discontinued group. CONCLUSION: In trials of anti-PD-1 agents to treat advanced ESCC, the current results provide only weak support for PFS as an OS surrogate; OS cannot be substituted completely by PFS in these cases. The results also suggest that qualified patients with advanced ESCC might benefit from continuous immunotherapy beyond progression to achieve a decreased risk of death.

The sound and surprise: overlapping meta-analyses on the topic of safety and efficacy of PD-1 and PD-L1 inhibitors in the treatment of non-small cell lung cancer.

PURPOSE: To analyze the characteristics of overlapping meta-analyses based on randomized controlled trials (RCTs) which reported PD-1/PD-L1 inhibitors in non-small cell cancer (NSCLC). METHODS: Meta-analyses were identified from English and Chinese databases until January 1, 2022. Differences in characteristics of overlapping meta-analyses that conducted in China and other countries were compared to assess their publication propensity. The corrected covered area (CCA) and coverage of relevant RCTs were analyzed for subtopics according to detailed intervention types. The waste and redundancy of evidence were assessed in the case of PD-1/PD-L1 inhibitor monotherapy for second-line treatment for NSCLC. RESULTS: Fifty-nine meta-analyses published in English and 17 meta-analyses published in Chinese reporting 26 RCTs were identified. Fifty-three (69.74%) meta-analyses were conducted in China. The overlapping meta-analyses in China were more likely to be from hospitals, supported by government funding, integrate first and second-line therapies. Five of the six subtopics had overlapping meta-analyses according to specific types of interventions. The CCA of overlapping meta-analyses ranged from 33.33 to 63.19%, and the coverage of relevant RCTs ranged from 63.64 to 100%. All the conclusions of overlapping meta-analyses have been consistent in the subtopic of PD-1/PD-L1 inhibitor monotherapy for second-line treatment since 2017. CONCLUSION: Overlapping meta-analyses of PD-1/PD-L1 inhibitors in NSCLC hints that meta-analyses under this topic probably exist serious redundancy. Future research should focus on prospective registration of protocols for systematic reviews/meta-analyses, scientific designed PICO, and cumulative meta-analysis to reduce redundant and wasted studies. Journals should strengthen the requirement for reviewing previously published evidence in manuscript review.

Progress in programmed cell death-1/programmed cell death-ligand 1 pathway inhibitors and binding mode analysis.

Programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) plays an important role in negative regulating immunity. The search for effective PD-1/PD-L1 inhibitors has been at the cutting-edge of academic and industrial medicinal chemistry, leading to the emergence of 16 clinical candidate drugs and the launch of six monoclonal antibodies (mAbs) drugs. However, due to the unclear mechanism of the interaction between drugs and substances in vivo, the screening of preclinical drugs often takes a long time. In order to shorten the time of drug development as much as possible, the binding mode analysis that can simulate the interaction between drugs and substances in vivo at the molecular level can significantly shorten the drug development process. This paper reviews the mechanism of PD-1/PD-L1 signaling pathway at the molecular level, as well as the research progress and obstacles of inhibitors. Besides, we analyzed the binding mode of recently reported PD-1/PD-L1 inhibitors with PD-1 or PD-L1 protein in detail in order to provide ideas for the development of PD-1/PD-L1 inhibitors.

Risk of Immune-Related Pneumonitis with PD-1/PD-L1 Inhibitors in Different Cancer Types and Treatment Regimens: A Systematic Review and Meta-Analysis of 22 Randomized Controlled Trials.

BACKGROUND: Pneumonitis, the specific toxicity associated with PD-1/PD-L1 inhibitors, is severe and potentially life-threatening, and its incidence and severity are poorly understood among different tumor types or treatment methods. This meta-analysis was performed to compare the incidence and severity of pneumonitis among different tumor types and treatment regimens. METHODS: MEDLINE and Embase were retrieved until September 2021. Meta-analysis of the risk of pneumonitis was calculated using a fixed-effect model. Pooled analysis of the incidence of pneumonitis in different tumor types was performed using a metaprop function. RESULTS: Twenty two randomized controlled trials (RCTs) (n = 10,700) were included for pool analysis, and eighteen RCTs (n = 8,852) were eligible for meta-analysis. For all-grade pneumonitis, the risk of the combination therapy (PD-1/PD-L1 plus CTLA-4 inhibitor) was 3.62 times significantly higher than that of monotherapy, and 4.06 and 1.78 times significantly higher than that of chemotherapy and placebo than monotherapy. The incidence of pneumonitis was not significantly different between PD-1/PD-L1 inhibitor versus ipilimumab or between low doses versus high doses. For high-grade (grade ≥3) pneumonitis, the risk in PD-1/PD-L1 inhibitors alone was 3.62 times significantly higher than chemotherapy. No significant difference was found in the incidence of pneumonitis between combination versus monotherapy, monotherapy versus placebo, combination versus ipilimumab alone, monotherapy versus ipilimumab alone, or low doses versus high doses. CONCLUSIONS: Compared with chemotherapy, PD-1/PD-L1 inhibitor monotherapy may cause more treatment-related pneumonitis. Increasing the dose of PD-1/PD-L1 inhibitor does not significantly increase the incidence of pneumonitis. Compared with the monotherapy, combination therapy does not increase the incidence of pneumonitis significantly.

Discovery of 4-phenylindolines containing a (5-cyanopyridin-3-yl)methoxy moiety as potent inhibitors of the PD-1/PD-L1 interaction.

With the great success of anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) monoclonal antibodies in clinical applications, blocking the PD-1/PD-L1 pathway has become the most compelling strategy in the field of tumor immunotherapy. In this study, a novel series of 4-phenylindolines containing a (5-cyanopyridin-3-yl)methoxy moiety were developed, and their structure-activity relationships were preliminarily discussed. Among them, compounds M17 and M23 exhibited the most potent ability to disrupt the PD-1/PD-L1 interaction, demonstrating IC50 values of 60.1 nM and 53.2 nM, respectively. The binding mode of M23 was further explored by molecular docking analysis with dimeric PD-L1. Therefore, M17 and M23 are promising lead compounds for developing potent inhibitors of the PD-1/PD-L1 axis.

Efficacy and safety of PD-1/PD-L1 inhibitors in triple-negative breast cancer: a systematic review and meta-analysis.

OBJECTIVE: Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis that seriously threatens women's health. There is still a lack of effective therapeutic targets for TNBC treatment. We conducted a meta-analysis to evaluate the efficacy and safety of programmed cell death protein 1 (PD-1)/programmed death protein ligand 1 (PD-L1) inhibitors in combination with chemotherapy for TNBC patients. METHODS: We searched PubMed, EMBASE, Cochrane Library, and Web of Science for randomized controlled trials (RCTs) related to PD-1/PD-L1 inhibitors combined with chemotherapy. Literature conforming to the research content was identified according to the inclusion and exclusion criteria. The endpoints of efficacy were pathological complete response (pCR), event-free survival (EFS), progression-free survival (PFS), and overall survival (OS). Safety outcomes included adverse events (AEs) of any grade, AEs of grade ≥3, serious AEs, and the incidence of various AEs. We obtained odds ratios (OR), hazard ratio (HR), and 95% confidence interval (CI) for the included studies. Data analysis was performed using Review Manager software (version 5.3). RESULTS: A total of 4468 patients from eight RCTs were analyzed. PD-1/PD-L1 inhibitors in combination with chemotherapy significantly improved pCR (OR, 1.59; 95% CI, 1.28 - 1.98, p < 0.0001), EFS (HR, 0.66; 95% CI, 0.48 - 0.91, p = 0.01), and OS (HR, 0.72; 95% CI, 0.52 - 0.99, p = 0.05) in patients with TNBC compared to chemotherapy alone or placebo in combination with chemotherapy. Furthermore, we found that the pCR rate was almost identical in the PD-L1 positive group (OR, 1.65; 95% CI, 1.26 - 2.16, p = 0.0002) and the PD-L1 negative group (OR, 1.56; 95% CI, 1.04 - 2.33, p = 0.03). Among patients with advanced-stage TNBC, PFS (HR, 0.82; 95% CI, 0.74 - 0.90, p < 0.0001) was longer in the combination therapy group than in the chemotherapy group. There were no statistically significant differences between the experimental and control groups in OS (HR, 1.03; 95% CI, 0.74 - 1.42, p = 0.87). In terms of safety, we found that the combination therapy group had a significantly higher incidence of hyperthyroidism in patients with early and advanced TNBC (OR, 5.76; 95% CI, 2.38 - 13.95, p = 0.0001) (OR, 7.86; 95% CI, 2.65 - 23.29, p = 0.0002). CONCLUSIONS: The combination of PD-1/PD-L1 inhibitors and chemotherapy could improve the survival and prognosis of patients with early and advanced TNBC. Combination treatment may be harmful to the thyroid; therefore, active surveillance and regular follow-up are necessary during treatment.

Molecular hybridization used to design and synthesize neo-tanshinlactone derivatives as PD-1/PD-L1 inhibitors.

Four series of molecular hybrids (37 final products) of neo-tanshinlactone, a natural product extracted from Salvia miltiorrhiza Bunge, and known PD-1/PD-L1 interaction inhibitors were prepared as possible chemotherapeutic agents against triple negative breast cancer. Screening using a homogenous time-resolved fluorescence method resulted in three lead compounds (MZ52 IC50 74 ± 4 nM; MZ58 IC50 134 ± 17 nM; MZ61 IC50 225 ± 19 nM). With less T cell cytotoxicity and effects in activating CD8+ T cells in a T cell proliferation assay and a functionality experiment, MZ58 was selected as the best candidate for animal experiments. MZ58 exhibited antitumor effects in a subcutaneous transplantation tumor model as well as effects in reducing T cell exhaustion. In conclusion, after in vivo and in vitro experiments, we successfully acquired an effective candidate (MZ58) showing antitumor effects with low cytotoxicity toward T cells as well as the ability to activate CD8+ T cells and reduce T cell exhaustion.

Quality of life in patients with non-small cell lung cancer treated with PD-1/PD-L1 inhibitors: a systematic review and meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have dramatically prolonged survival in non-small cell lung cancer (NSCLC) patients, but little research had focused on its impact on quality of life (QoL). The purpose of our study was to compare the QoL in patients with NSCLC treated with programmed cell death protein-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors versus chemotherapy. METHODS: We searched for randomized controlled trials utilizing the Quality of Life Questionnaire Core 30 items (QLQ-C30) and the EuroQol Five Dimensions Questionnaire-3L (EQ-5D-3L) to assess the QoL of NSCLC treated with PD-1/PD-L1 inhibitors versus chemotherapy. We collected hazard ratios (HRs) for the time from baseline to the first clinically significant deterioration (TTD) and effect size as the difference in mean change between and within treatment groups in patients' reported outcomes (PROs). (PROSPERO registration number: CRD42022296680). RESULTS: In the five trials reported by QLQ-C30, TTD was longer in PD-1/PD-L1 inhibitors compared with control groups (HR = 0.86; 95% CI = 0.76, 0.97; P = 0.013), with similar results in terms of physical function, role function, and pain. The difference in mean change between the PD-1/PD-L1 inhibitors group and the chemotherapy group in QLQ-C30 and EQ-5D VAS was 3.64 (95% CI = 1.62, 5.66; P = 0.001) and 4.74 (95% CI = 2.65, 6.83; P = 0.001), which supported PD-1/PD-L1 inhibitors. However, for the EQ-5D utility index, there was no statistically significant difference between the two groups, with a mean change difference of 0.03 (95% CI = -0.01, 0.07; P = 0.094). The mean change from baseline to follow-up in PD-1/PD-L1 inhibitors group was 2.57 (95% CI = 0.43, 4.71; P = 0.019), and chemotherapy group was -1.31 (95% CI = -3.71, 1.09; P = 0.284), correspondingly. The subgroup analysis showed that no difference was observed between open-label and double-blind trials in patients treated with chemotherapy or PD-1/PD-L1 inhibitors. CONCLUSION: In conclusion, PD-1/PD-L1 inhibitors could improve the QoL of patients with NSCLC compared to chemotherapy and reduce unfavorable symptoms during treatment.

PD-1/PD-L1 inhibitor monotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck: a meta-analysis.

PURPOSE: To evaluate the efficacy and safety of programmed cell death-1/programmed cell death-ligand 1 inhibitor monotherapy compared to the standard of care in the first-line setting for recurrent or metastatic head and neck squamous cell carcinoma. MATERIALS AND METHODS: The PubMed, Embase, and Cochrane Library databases were searched for relevant randomized controlled trials. The clinical outcomes of overall survival, progression-free survival, objective response rates, and grade 3 or higher adverse events were analyzed using Stata SE 15 software with a significance level set to 0.05. RESULTS: We identified four randomized controlled trials (1 nivolumab, 2 pembrolizumab, and 1 durvalumab), including a total of 2474 patients. The results of the meta-analysis showed pooled hazard ratios of overall and progression-free survival for programmed cell death-1/programmed cell death-ligand 1 inhibitor monotherapy of 0.82 (95% CI: 0.73-0.91, p < 0.001) and 0.96 (95%CI: 0.84-1.07, p < 0.001) and pooled odds ratios of objective response rates and grade 3 or higher adverse events of 1.04 (95%CI: 0.46-2.37; p = 0.926) and 0.28 (95%CI: 0.22-0.35, p < 0.001), respectively. Subgroup analysis showed that inhibitors for both programmed cell death-1 (nivolumab and pembrolizumab) and programmed cell death-ligand 1 (durvalumab) were associated with significantly longer overall survival (HR = 0.80, 95% CI: 0.70-0.90, p < 0.001 and HR = 0.88, 95%CI: 0.70-1.06, p < 0.001, respectively). CONCLUSIONS: Programmed cell death-1/programmed cell death-ligand 1 inhibitor monotherapy showed more clinical benefit versus the standard of care in patients with recurrent or metastatic head and neck squamous cell carcinoma, with an acceptable safety profile.

Safety and Efficacy of Cetuximab-Based Salvage Chemotherapy After Checkpoint Inhibitors in Head and Neck Cancer.

BACKGROUND: There are still few data on the activity and safety of cetuximab-based salvage chemotherapy after immunotherapy (SCAI) in patients with squamous cell cancer of the head and neck (SCCHN). MATERIALS AND METHODS: This was a retrospective study of patients with SCCHN who received cetuximab-based SCAI after programmed cell death protein 1 or programmed cell death ligand 1(PD[L]1) inhibitors. Overall response rate (ORR) and disease control rate (DCR) with SCAI and with last chemotherapy before immunotherapy (LCBI) by RECIST 1.1, percentage change from baseline in target lesions (PCTL), progression-free survival (PFS), overall survival (OS), treatment compliance, and toxicity were evaluated. RESULTS: Between March 2016 and November 2019, 23 patients were identified. SCAI consisted of cetuximab-based combinations (3-weekly cisplatin-5FU-cetuximab [n = 2], weekly paclitaxel-cetuximab [n = 17], weekly cisplatin-cetuximab [n = 2], weekly carboplatin-paclitaxel-cetuximab [n = 2]). ORR was 56.5% (11 partial response, 2 complete response). DCR was 78.3%. Among 13 objective responders, median best PCTL was -53.5% (range, -30% to -100%). Median OS and PFS were 12 months and 6 months, respectively. In 10 patients receiving LCBI, ORR to LCBI was 40%, whereas ORR to SCAI achieved 60%. In LCBI-treated patients, median PFS with LCBI was 8 months and median PFS and OS with SCAI were 7 months and 12 months, respectively. Reduced dose intensity of the chemotherapy and cetuximab components occurred in 82.6% and 52.2% of the patients. Grade 1 or 2 adverse events (AEs) occurred in all patients. Grade 3 or 4 AEs developed in 65%, being grade 3 in all of them except in one patient (grade 4 neutropenia). There were no treatment-related deaths. CONCLUSION: Cetuximab-based salvage chemotherapy after PD(L)1 inhibitors associated with high response rates and deep tumor reductions with a manageable safety profile. Subsequent lines of therapy may explain the long survival achieved in our series. These results invite to design studies to elucidate the best therapeutic sequence in patients with SCCHN in the immunotherapy era. IMPLICATIONS FOR PRACTICE: Cetuximab-based salvage chemotherapy (SCAI) achieved high response rates in patients with recurrent/metastatic squamous cell cancer of the head and neck (SCCHN) after progression to PD-1/PD-L1 inhibitors. Objective response rate was higher than and progression-free survival was comparable to that of chemotherapy administered before immunotherapy (IO). In most patients, SCAI consisted of weekly, well-tolerated regimens. These observations have implications for current practice because of the limited evidence to date in SCCHN and the scant therapeutic options in this disease and invite to elucidate which may be the best treatment sequence for patients with head and neck cancer in the IO era.

The Inconsistent and Inadequate Reporting Of Immune-Related Adverse Events in PD-1/PD-L1 Inhibitors: A Systematic Review of Randomized Controlled Clinical Trials.

BACKGROUND: Immune-related adverse events (irAEs) are of great interest and importance in clinical practice, and many deficiencies and controversies have been noted in the reporting of irAEs. Herein, we aimed to evaluate the current status of irAE reporting in randomized controlled clinical trials (RCTs) of PD-1/PD-L1 inhibitors and to attempt to explain and solve the current pitfalls associated with this reporting. MATERIALS AND METHODS: We conducted a systematic review across multiple databases, including PubMed, Web of Science, Embase, and the Cochrane Library. The RCTs that compared PD-1/PD-L1 inhibitors with standard treatments were included. The Harms extension of the Consolidated Standards of Reporting Trials (CONSORT) was used to evaluate the completeness of irAE reporting. RESULTS: A total of 44 articles and 23,759 patients were included in the analysis. The terminology of the irAEs changed over time (p = .01) and was different among immune checkpoint inhibitors (ICIs) (p = .005). Twenty-two of the studies provided a definition of irAE, but only four of them concretely addressed this definition. The incidence of any grade of irAEs ranged from 16.9% to 96%, whereas grade 3-4 irAE ranged from 2% to 23%. The RCTs with combined therapy exhibited a higher incidence of grade 3-4 irAEs (p = .012). Thirty-two studies reported irAEs in the control arms, whereas seven studies reported irAEs only in the experimental arms. Respiratory, endocrine, and gastrointestinal disorders were the most commonly reported irAEs. IrAEs were generally neglected in the introduction or conclusion sections in all of the study reviews and were never subjected to subgroup analyses. Moreover, withdrawals due to severe irAEs, as well as clarifications of the irAE collection methods, were also poorly reported. RCTs using combination therapies in the experimental arms were associated with a higher reporting quality (p = .032). However, the completeness of the reporting did not improve over the last 5 years (p = .076). CONCLUSION: The reporting of irAEs was inadequate, and there are still inconsistencies and controversies in the reporting of irAEs. In the future, authors should be encouraged to adhere to the Harms extension of the CONSORT statement. IMPLICATIONS FOR PRACTICE: PD-1/PD-L1 inhibitors profoundly changed the landscape of cancer treatment, and thousands of randomized controlled clinical trials (RCTs) were active or completed over the past decade. However, different from chemotherapy or targeted therapy, the profile of immune-related adverse effects (irAE) was unique. An understanding of irAEs is developed mainly from clinical trials; however, inconsistencies and controversies between trials were noted. This study primarily reviewed the evolution of irAE terminology and definitions and evaluated the reporting quality of each RCT. It was found that RCTs using combined immunotherapy were associated with higher quality of irAE reporting. This article identifies the controversies and deficiencies in current irAE reporting and provides possible explanations and suggestions for these inadequacies.