PD-L1 Inhibitors In Patients Research Articles

Impact of senescence cell signature in patients with non-small cell carcinoma and melanoma receiving PD-L1/PD-1 inhibitors

Tumor cell senescence plays a crucial role in tumor immunity. We investigated whether the senescent cell signature (SCS) could predict prognosis in non-small cell carcinoma (NSCLC) and melanoma datasets treated with PD-L1/PD-1 inhibitors. Patients with high SCS expression exhibited elevated levels of interferon-gamma and T cell-inflamed signatures in three lung adenocarcinomas (LUAD), two squamous cell carcinoma (LUSC) and three melanoma datasets. The high SCS group was associated with PD-L1-related pathways such as IL6/JAK/STAT3 and TNF-alpha signaling via NF-kB in LUAD, LUSC, and melanoma datasets. A positive correlation was observed between several immune checkpoint markers and the SCS, indicating an immunosuppressive state in LUAD, LUSC and melanoma datasets. In patients treated with PD-1/PD-L1 inhibitors, a higher SCS was associated with a better prognosis, and a positive correlation between SCS and PD-L1 was observed in six independent NSCLC and three independent melanoma datasets. We used the LASSO Cox regression model to build a risk model focusing on the SCS genes that particularly predict prognosis. We confirmed that the model accurately predicts prognosis. However, the senescent immunohistochemical markers p16 and p21 could predict the response to PD-1/PD-L1 inhibitors in patients with LUSC and melanoma but not in patients with LUAD. SCS could serve as a valuable biomarker to complement PD-L1 expression in patients receiving PD-L1/PD-1 inhibitors.

Development and validation of a nomogram to predicting the efficacy of PD-1/PD-L1 inhibitors in patients with nasopharyngeal carcinoma

PurposeWith the treatment of nasopharyngeal carcinoma (NPC) by PD-1/PD-L1 inhibitors used widely in clinic, it becomes very necessary to anticipate whether patients would benefit from it. We aimed to develop a nomogram to evaluate the efficacy of anti-PD-1/PD-L1 in NPC patients.MethodsTotally 160 NPC patients were enrolled in the study. Patients were measured before the first PD-1/PD-L1 inhibitors treatment and after 8–12 weeks of immunotherapy by radiological examinations to estimate the effect. The least absolute shrinkage and selection operator (LASSO) logistic regression was used to screen hematological markers and establish a predictive model. The nomogram was internally validated by bootstrap resampling and externally validated. Performance of the model was evaluated using concordance index, calibration curve, decision curve analysis and receiver operation characteristic curve.ResultsPatients involved were randomly split into training cohort ang validation cohort. Based on Lasso logistic regression, systemic immune-inflammation index (SII) and ALT to AST ratio (LSR) were selected to establish a predictive model. The C-index of training cohort and validating cohort was 0.745 and 0.760. The calibration curves and decision curves showed the precise predictive ability of this nomogram. The benefit of the model showed in decision curve was better than TNM stage. The area under the curve (AUC) value of training cohort and validation cohort was 0.745 and 0.878, respectively.ConclusionThe predictive model helped evaluating efficacy with high accuracy in NPC patients treated with PD-1/PD-L1 inhibitors.

Patients with Advanced or Metastasised Non-Small-Cell Lung Cancer with Viscum album L. Therapy in Addition to PD-1/PD-L1 Blockade: A Real-World Data Study.

Immunotherapy with PD-1/PD-L1 inhibitors has significantly improved the survival rates of patients with metastatic non-small-cell lung cancer (NSCLC). Results of a real-world data study investigating add-on VA (Viscum album L.) to chemotherapy have shown an association with the improved overall survival of patients with NSCLC. We sought to investigate whether the addition of VA to PD-1/PD-L1 inhibitors in patients with advanced or metastasised NSCLC would have an additional survival benefit. In the present real-world data study, we enrolled patients from the accredited national registry, Network Oncology, with advanced or metastasised NSCLC. The reporting of data was performed in accordance with the ESMO-GROW criteria for the optimal reporting of oncological real-world evidence (RWE) studies. Overall survival was compared between patients receiving PD-1/PD-L1 inhibitor therapy (control, CTRL group) versus the combination of anti-PD-1/PD-L1 therapy and VA (combination, COMB group). An adjusted multivariate Cox proportional hazard analysis was performed to investigate variables associated with survival. From 31 July 2015 to 9 May 2023, 415 patients with a median age of 68 years and a male/female ratio of 1.2 were treated with anti-PD-1/PD-L1 therapy with or without add-on VA. Survival analyses included 222 (53.5%) patients within the CRTL group and 193 (46.5%) in the COMB group. Patients in the COMB group revealed a median survival of 13.8 months and patients in the CRTL group a median survival of 6.8 months (adjusted hazard ratio, aHR: 0.60, 95% CI: 0.43-0.85, p = 0.004) after adjustment for age, gender, tumour stage, BMI, ECOG status, oncological treatment, and PD-L1 tumour proportion score. A reduction in the adjusted hazard of death by 56% was seen with the addition of VA (aHR 0.44, 95% CI: 0.26-0.74, p = 0.002) in patients with PD-L1-positive tumours (tumour proportion score > 1%) treated with first-line anti-PD-1/PD-L1 therapy. Our findings suggest that add-on VA correlates with improved survival in patients with advanced or metastasised NSCLC who were treated with PD-1/PD-L1 inhibitors irrespective of age, gender, tumour stage, or oncological treatment. The underlying mechanisms may include the synergistic modulation of the immune response. A limitation of this study is the observational non-randomised study design, which only allows limited conclusions to be drawn and prospective randomised trials are warranted.

Neoadjuvant PD-1/PD-L1 combined with CTLA-4 inhibitors for solid malignancies: a systematic review and meta-analysis

BackgroundThe effectiveness and safety of neoadjuvant PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors is controversial. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors as neoadjuvant therapy for malignant solid tumors.MethodsThis study has been registered with the number CRD42023407275 on PROSPERO. Systematic searches were conducted in PubMed, Embase, Web of Science and Cochrane Library databases until March 17, 2023. In addition, manual searches were performed. The inclusion criteria encompassed randomized controlled trials (RCTs) that assessed the utilization of neoadjuvant PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors PD-1/PD-L1 inhibitors for patients with solid malignancies. The Cochrane Collaboration's tool for assessing risk of bias in randomized trials (ROB1) were used. Risk ratios (RRs), hazared ratios (HRs) and their respective 95% confidence intervals were calculated using Stata17.0 MP and Review Manager 5.4 software.ResultsA total of 2780 records were identified, and ultimately 10 studies involving 273 patients were included. The meta-analysis showed that the addition of CTLA-4 inhibitors to PD-1/PD-L1 inhibitors did not demonstrate a significant effect on overall response rate, main pathological response, pathological complete response, surgical resection, radical resection, overall survival, progression-free survival, recurrence-free survival, grade 3–4 adverse events, all-cause mortality, and completed treatment (P > 0.05). However, further subgroup analysis indicated that the combination of PD-1 with CTLA-4 inhibitors significantly increased the occurrence of grade 3–4 adverse events in patients (P < 0.05).ConclusionsAs neoadjuvant therapy for malignant solid tumors, the addition of CTLA-4 inhibitors to PD-1/PD-L1 inhibitors does not appear to enhance efficacy.Moreover, there is a potential increase in the risk of grade 3–4 adverse events associated with this combination. However, it is important to note that the studies included in this analysis suffer from limitations such as small samples and single-center designs, which are inherent constrains with the available published literature. Further research involving large-sample and multicenter RCTs are warranted to obtain more reliable results.

EP13.05-04 Real-world Efficacy of PD-1/PD-L1 Inhibitors in Patients with Advanced Pulmonary Neuroendocrine Carcinoma

EP13.05-04 Real-world Efficacy of PD-1/PD-L1 Inhibitors in Patients with Advanced Pulmonary Neuroendocrine Carcinoma

A novel [89Zr]-anti-PD-1-PET-CT to assess response to PD-1/PD-L1 blockade in lung cancer.

Harnessing the anti-tumor immune system response by targeting the program cell death protein (PD-1) and program cell death ligand protein (PD-L1) axis has been a major breakthrough in non-small cell lung cancer (NSCLC) therapy. Nonetheless, conventional imaging tools cannot accurately assess response in immunotherapy-treated patients. Using a lung cancer syngeneic mouse model responder to immunotherapy, we aimed to demonstrate that [89Zr]-anti-PD-1 immuno-PET is a safe and feasible imaging modality to assess the response to PD-1/PD-L1 blockade in NSCLC. A syngeneic mouse model responder to anti-PD-1 therapy was used. Tumor growth and response to PD-1 blockade were monitored by conventional 2-deoxy-2-[18F]fluoro-D-glucose ([18F]-FDG) PET scans. Additionally, tumor lymphocyte infiltration was analyzed by the use of an [89Zr]-labeled anti-PD-1 antibody and measured as 89Zr tumor uptake. Conventional [18F]-FDG-PET scans failed to detect the antitumor activity exerted by anti-PD-1 therapy. However, [89Zr]-anti-PD-1 uptake was substantially higher in mice that responded to PD-1 blockade. The analysis of tumor-infiltrating immune cell populations and interleukins demonstrated an increased anti-tumor effect elicited by activation of effector immune cells in PD-1-responder mice. Interestingly, a positive correlation between [89Zr]-anti-PD-1 uptake and the proportion of tumor-infiltrating lymphocytes (TILs) was found (Cor = 0.8; p = 0.001). Our data may support the clinical implementation of immuno-PET as a promising novel imaging tool to predict and assess the response of PD-1/PD-L1 inhibitors in patients with NSCLC.

The efficacy and safety of anti-PD-1/PD-L1 in treatment of glioma: a single-arm meta-analysis.

This meta-analysis aimed to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors in patients with glioma. PubMed, EMBASE, Web of Science, and the Cochrane library were searched from inception to January 2023 without language restriction. Primary outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). The risk of bias was assessed by subgroup analysis, sensitivity analysis, and publication bias, including funnel plot, Egger's test, and Begg's test. A total of 20 studies involving 2,321 patients were included in this meta-analysis. In the analysis of the included phase III clinical trials, the forest plot showed that PD-1/PD-L1 inhibitors did not improve the OS (HR=1.15, 95% CI: 1.03-1.29, P=0.02, I2 = 14%) and PFS (HR=1.43, 95% CI: 1.03-1.99, P=0.03, I2 = 87%). In the single-arm analysis, the forest plot demonstrated that the 6-month OS was 71% (95% CI: 57%-83%, I2 = 92%), 1-year OS was 43% (95% CI: 33%-54%, I2 = 93%), and the 2-year OS was 27% (95% CI: 13%-44%, I2 = 97%). The pooled estimate of the median OS was 8.85 months (95% CI: 7.33-10.36, I2 = 91%). Furthermore, the result indicated that the 6-month PFS was 28% (95% CI: 18%-40%, I2 = 95%), 1-year PFS was 15% (95% CI: 8%-23%, I2 = 92%), and the 18-month PFS was 10% (95% CI: 3%-20%, I2 = 93%). The pooled estimate of the median PFS was 3.72 months (95% CI: 2.44-5.00, I2 = 99%). For ORR, the pooled estimate of ORR was 10% (95% CI: 2%-20%, I2 = 88%). We further analyzed the incidence of PD-1/PD-L1 inhibitor-related AEs, and the pooled incidence of AEs was 70% (95% CI: 58%-81%, I2 = 94%). The incidence of AEs ≥ grade 3 was 19% (95% CI: 11%-30%, I2 = 94%). The funnel plot for the median PFS and median OS was symmetric with no significant differences in Egger's test and Begg's test. The sensitivity analysis revealed that our results were stable and reliable. The results of this meta-analysis suggest that anti-PD-1/PD-L1 therapy is relatively safe but could not prolong survival in glioma. More randomized controlled trials are needed to confirm our results. https://www.crd.york.ac.uk/prospero/, identifier CRD42023396057.

Anti-PD-1 antibodies, a novel treatment option for advanced chemoresistant pulmonary lymphoepithelioma carcinoma.

Pulmonary lymphoepithelioma-like carcinoma (LELC) exhibits a unique immune microenvironment, including high PD-L1 expression and abundant infiltrating-immune cells. However, the availability of PD-1/PD-L1 inhibitors in patients with LELC is still not determined. A total of 36 cases of pulmonary LELC treated with PD-1/PD-L1 inhibitors were reviewed, including 10 cases from our institute and 26 cases included from the literature. The Kaplan-Meier method and log-rank test were utilized to analyze the survival outcomes of LELC patients receiving immunotherapy, and the factors related to immunotherapy response were further examined. Of the 10 patients from our institute, the median age was 53.5 years, adrenal glands and distant lymph nodes were the most common metastatic sites, and 4 of 8 (50%) patients had a PD-L1 TPS ≥50%. The median progression-free survival and overall survival in patients from our institute and from the literature were 11.6 and 27.3 months, 17.2 months and not reached, respectively. In all 36 patients, the objective response rate was as high as 57.6%. Patients with higher PD-L1 expression were more likely to have a tumor response, but the association of PD-L1 expression with survival time remains to be determined. PD-1/PD-L1 inhibitors in patients with pulmonary LELC demonstrated a promising efficacy in retrospective cohorts, and deserve further validation in prospective studies administrating in front-line setting.

Envafolimab – first PD-1/PD-L1 antibody to be administered by subcutaneous injection for microsatellite instability-high or deficient mismatch repair advanced solid tumors

ABSTRACT Introduction Programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors mobilize and activate the anti-tumor activity of the immune system by blocking the inhibitory effects of the PD-1/PD-L1 signaling pathway in T cells. Several anti-PD-1 or -PD-L1 monoclonal antibodies have been approved for the treatment of advanced solid tumors. However, most of immune checkpoint inhibitors (ICIs) are administered via intravenous infusion, which is inconvenient and leads to unsatisfactory patient compliance in the treatment process. Therefore, subcutaneous envafolimab is a potential treatment modality for advanced solid tumors. Area covered A phase I clinical trial showed that the safety and pharmacokinetic profiles of envafolimab were similar to those of other traditional antibodies. Additionally, clinical findings from a phase II trial revealed that envafolimab monotherapy exhibited satisfactory clinical therapeutic effects and no significant adverse events in patients with microsatellite instability-high/deficient mismatch Repair (MSI-H/dMMR) solid tumors who failed at least one line of prior systemic therapy. Expert opinion Subcutaneous envafolimab may serve as a more convenient and acceptable treatment modality than those approved PD-1/PD-L1 inhibitors for patients with an advanced solid tumor, which may revolutionize the modes of immunotherapy in the future.

Safety and Efficacy of PD-1/PD-L1 Inhibitors in Cancer Patients With Preexisting Autoantibodies.

BackgroundProgrammed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors therapy is now a routine scheme in cancers. However, the effect of preexisting autoantibodies on the safety and efficacy of PD-1/PD-L1 inhibitors in cancer patients is not well understood.MethodsThe present retrospective cohort study evaluated the safety and efficacy of PD-1/PD-L1 inhibitors in patients with preexisting autoantibodies. Patients who received PD-1/PD-L1 inhibitors in the Department of Medical Oncology, Peking Union Medical College Hospital between November 2017 and August 2021 were reviewed.Results67 (37.9%) of the 177 patients, 27 (20.3%) of the 133 patients, and 16 (11.0%) of 146 patients who received PD-1/PD-L1 inhibitors were positive for ANA, anti-Ro52, and antithyroid antibodies, respectively. Preexisting ANA and anti-Ro52 antibody were not associated with the increased risk of immune-related adverse events (irAEs), while thyroid dysfunction was more frequent in patients with positive antithyroid antibody (75.0% versus 13.8%, p < 0.001). The median progression-free survival (PFS, 13.1 versus 7.0 months, p = 0.015) was significantly longer in the ANA-positive patients, while the median overall survival (OS, 14.5 versus 21.8 months, p = 0.67) did not differ significantly between the ANA-positive and ANA-negative groups. Moreover, the preexisting anti-Ro52 and antithyroid antibodies were not significantly associated with PFS and OS.ConclusionsThe presence of ANA and anti-Ro52 antibody were not associated with a higher risk of irAEs, whereas patients positive for antithyroid antibody should monitor closely immune-related thyroid dysfunction. Preexisting ANA might be a predictor of longer PFS, while anti-Ro52 and antithyroid antibodies had no significant effect on survival outcomes in patients receiving PD-1/PD-L1 inhibitors therapy.

Clinical benefits of PD-1/PD-L1 inhibitors in patients with metastatic colorectal cancer: a systematic review and meta-analysis

BackgroundImmunotherapy for colorectal cancer has developed rapidly in the past decade. Many high-quality clinical trials examining the application of PD-1/PD-L1 inhibitors in patients with metastatic colorectal cancer (mCRC) have been conducted in recent years. However, the clinical benefits, including the efficacy and safety of these treatments against mCRC, remain controversial. Hence, we conducted this meta-analysis on the clinical benefits of PD-1/PD-L1 inhibitors in patients with mCRC.MethodsWe searched online databases including MEDLINE, Embase, Cochrane Library, and Web of Science, from inception to January 4, 2021. The outcomes related to efficacy and safety were extracted and analyzed. Subgroup analyses were conducted according to the categories of dMMR-MSI-H (tumors with mismatch repair deficiency and high levels of microsatellite instability) ≥ 5% vs. dMMR-MSI-H < 5%, monotherapy vs. combination therapy, PD-1 inhibitors vs. PD-L1 inhibitors, and nivolumab vs. pembrolizumab.ResultsFourteen studies including 1129 subjects were included in our systematic review. The overall complete response (CR), partial response (PR), stable disease (SD), and progression of disease (PD) rates were 0.01 (95% CI 0.00–0.04), 0.04 (95% CI 0.05–0.26), 0.27 (95% CI 0.22–0.32), and 0.44 (95% CI 0.30–0.58), respectively. The overall objective response rate (ORR) and disease control rate (DCR) were 0.16 (95%CI 0.06–0.31) and 0.50 (95%CI 0.35–0.65), respectively. The overall rate of adverse events (AEs) and severe adverse responses (SAEs) were 0.84 (95% CI 0.72–0.92) and 0.30 (95% CI 0.20–0.41), respectively. The ORRs of the dMMR-MSI-H ≥ 5% and dMMR-MSI-H < 5% subgroups were 0.40 (95% CI 0.30–0.51) and 0.04 (95% CI 0.00–0.09), respectively.ConclusionsPD-1/PD-L1 inhibitors produced encouraging clinical benefits including the response rate in the treatment of dMMR-MSI-H mCRC. They actually have been influenced by the present state of mCRC therapy including pMMR-MSI-L mCRC. Nevertheless, additional multi-center prospective studies are still expected.Trial registrationWe have registered this study in the International Prospective Register of Systematic Reviews (PROSPERO), and the registration number is CRD42021249601.

Efficacy of PD-1/L1 inhibitors inbrain metastases of non-small-cell lung cancer: pooled analysis from seven randomized controlled trials.

Background: The efficacy of PD-1 or PD-L1 inhibitors in patients with brain metastases of non-small-cell lung cancer (BM-NSCLC) is inconclusive. Materials & methods: An electronic search was performed. Randomized controlled trialsRCTs that compared the efficacy of PD-1- or PD-L1-inhibitor-based regimens with non-PD-1/L1 inhibitor regimens in patients with NSCLC and reported the data of subgroup patients with brain metastases were eligible for inclusion. The hazard ratios (HRs) for progression-free survival and overall survivalwere pooled in BM-NSCLC. Results: Seven RCTs with 472 BM-NSCLC cases are included. The pooled HRs indicated that PD-1 or PD-L1 inhibitor-based regimens reduced risk of disease progression by44% and reduced risk of death of BM-NSCLC patients by29% compared with non-PD-1/L1 inhibitor regimens. Conclusion: This meta-analysis indicates that PD-1 or PD-L1 inhibitors can reduce risk ofboth disease progression and death of patients with brain metastases of NSCLC, who have been pretreated with local therapies and/or are asymptomatic for the brain lesions.

Efficacy of PD-1/PD-L1 inhibitors in patients with non-small cell lung cancer and brain metastases: A real-world retrospective study in China.

BackgroundThere is only limited knowledge of the treatment responses and clinical outcomes of immune checkpoint inhibitors (ICIs) in driver gene‐negative non‐small cell lung cancer (NSCLC) patients with brain metastases (BM). This study aims to assess the efficacy of immunotherapy in these patients in a real world setting.MethodsNSCLC‐BM patients without driver gene mutations who received ICIs were retrospectively identified between July 2017 and December 2019. The primary observation endpoint was intracranial objective response rate (iORR), and secondary objectives were objective response rate (ORR), intracranial and systemic progression‐free survival (iPFS, PFS), and overall survival (OS).ResultsWe reviewed 1578 patients with lung cancer and BM. According to the exclusion criteria, 41 patients were finally enrolled. Among these 41 patients, iORR was 36.6% (95% confidence interval [CI] = 21.2%–52.0%), whereas iPFS was 6.8 (95% CI = 3.32–10.35) months. Additionally, ORR, PFS, and OS were 24.4% (95% CI = 10.7%–38.1%), 6.2 (95% CI = 4.57–7.83) months and 13.7 (95% CI = 11.20–16.26) months, respectively. ICIs combined with concurrent radiotherapy group exhibited preferred iORR (p = 0.030) compared with no radiotherapy group, and ICIs plus chemotherapy showed improved OS (p = 0.024) compared to ICI monotherapy. Moreover, the lines of ICI treatment ≥2 (p = 0.005) and derived neutrophil‐to‐lymphocyte ratio (dNLR) ≥3 (p = 0.010) were independently negative factors for OS.ConclusionIn NSCLC‐BMs patients lacking driver genes, ICIs exhibited an effective drug regime. A combination of ICIs with concurrent radiotherapy showed a better intracranial response, whereas ICIs plus chemotherapy were associated with superior OS.

Clinical Response to Immunotherapy Targeting Programmed Cell Death Receptor 1/Programmed Cell Death Ligand 1 in Patients With Treatment-Resistant Microsatellite Stable Colorectal Cancer With and Without Liver Metastases

Microsatellite stable (MSS) metastatic colorectal cancer has been historically characterized as resistant to immunotherapy. Recent studies have demonstrated limited clinical activity of programmed cell death receptor 1/programmed death ligand 1 (PD-1/PD-L1) targeting in MSS metastatic colorectal cancer. The association of metastatic disease in the liver with treatment response has not been fully investigated. To investigate the association of liver metastases with response to PD-1/PD-L1-targeting therapy in MSS metastatic colorectal cancer. This single-center retrospective cohort study evaluated clinical responses to PD-1- or PD-L1-targeting therapy, with or without other investigational agents, in patients with MSS metastatic colorectal cancer and disease progression after standard of care therapy from January 1, 2014, to December 31, 2020. Objective response rate (ORR) and progression-free survival (PFS), measured from initiation of PD-1/PD-L1-targeting therapy. Ninety-five patients with MSS metastatic colorectal cancer were identified (54 men [56.8%]; median age, 55 [interquartile range (IQR), 49-64] years). The overall ORR was 8.4% (8 of 95 patients). Eight of 41 patients without liver metastases achieved an ORR of 19.5%, and no response was observed in 54 patients with liver metastases. The disease control rate was 58.5% (24 of 41) in patients without liver metastasis and 1.9% (1 of 54) in patients with liver metastasis. Patients without liver metastases at the time of PD-1/PD-L1-targeting treatment had a superior median PFS compared with patients with liver metastases (4.0 [IQR, 2.0-7.5] vs 1.5 [IQR, 1.0-2.0] months; P < .001). In addition, median PFS was 5.5 (IQR, 2.0-11.5) months for patients without any prior or current liver involvement at the time of PD-1/PD-L1-targeting treatment initiation. Using a multivariate Cox regression model correcting for Eastern Cooperative Oncology Group status, primary tumor location, RAS and BRAF status, tumor mutation burden, and metastatic sites, liver metastases was the variable with the most significant association with faster progression after PD-1/PD-L1 treatment inhibition (hazard ratio, 7.00; 95% CI, 3.18-15.42; P < .001). Findings of this cohort study suggest that patients with MSS metastatic colorectal cancer and without liver metastases may derive clinical benefits from checkpoint inhibitors, whereas the presence of liver metastases was associated with resistance. Further prospective studies are needed to investigate PD-1/PD-L1 inhibitors in patients with MSS metastatic colorectal cancer without liver metastases.

Immune-Related Adverse Events and Their Association With the Effectiveness of PD-1/PD-L1 Inhibitors in Non-Small Cell Lung Cancer: A Real-World Study From China

BackgroundProgrammed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors are increasingly used in China, but no real-world data are available about the immune-related adverse events (irAEs). This real-world retrospective study aimed to assess the safety and effectiveness of PD-1/PD-L1 inhibitors in patients with non-small cell lung cancer (NSCLC) and to analyze the association between irAEs and effectiveness.MethodsThis was a retrospective study of the clinical data of patients with NSCLC treated with PD-1/PD-L1 inhibitors from August 2016 to November 2019 at Beijing Cancer Hospital. The patients were divided into the irAE or non-irAE groups. Overall adverse events, the impact of irAE on tumor response, and the association of irAEs with effectiveness were evaluated.ResultsOne hundred and ninety-one patients were included, including 70 (36.6%) patients in the irAE group and 121 (63.4%) patients in the non-irAE group. AE, grades 3–5 AEs, and irAE occurred in 107 (56.0%), 24 (12.6%), and 70 (36.6%) of the patients, respectively. The objective response rate (ORR) and disease control rate (DCR) were higher in the irAE group compared with the non-irAE group (42.0% vs. 25.8%, P=0.038; 91.9% vs. 70.8%, P=0.002). Multivariable analyses identified that irAE were associated with progression-free survival (HR=0.62, 95%CI: 0.43–0.91; P=0.015), but not with overall survival (HR=0.76, 95%CI: 0.44–1.28; P=0.299).ConclusionIn NSCLC treated with PD-1/PD-L1 inhibitors, patients with irAEs showed improved effectiveness over patients without irAEs. Future studies of anti-PD-1/PD-L1 immunotherapy should explore this association and the underlying biological mechanisms of efficacy.

Efficacies of programmed cell death 1 ligand 1 blockade in non-small cell lung cancer patients with acquired resistance to prior programmed cell death 1 inhibitor and development of diabetic ketoacidosis caused by two different etiologies: a retrospective case series.

The programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis is vital for immune resistance during tumor development, while PD-L1 inhibitors can also inhibit the PD-L1/B7-1 (CD80) interaction, indicating one of the molecular differences between PD-1 and PD-L1 inhibitors. However, the clinical benefits of PD-L1 inhibitors in patients previously treated with PD-1 inhibitors remain unknown. In this study, we retrospectively analyzed the clinical data of eight patients with non-small cell lung cancer who received the PD-L1 inhibitor atezolizumab and previously treated with the PD-1 inhibitor nivolumab. The median progression-free survival was 2.1 months (1.8-18.7 months), and 4 of 8 patients achieved at least stable disease. In two of these patients, atezolizumab treatment resulted in longer progression-free survival (PFS) compared with that of nivolumab. Conversely, one patient exhibited grade 4 diabetic ketoacidosis (DKA) within 2 weeks after the initial administration of atezolizumab. Another patient had developed type 1 diabetes mellitus (T1DM) during the prior nivolumab treatment and then developed DKA due to an infection after the initiation of atezolizumab. Both of them had high-risk human leukocyte antigen-DR/DQ types relevant to T1DM. These results demonstrate the potential efficacy of PD-L1 inhibitors to some tumors that have acquired resistance to PD-1 inhibitors and suggest that appropriate managements are required for not only a newly onset of T1DM but also blood glucose control after the development of T1DM during a reiteration of the PD-1/PD-L1 blockade.

Pembrolizumab and other immune checkpoint inhibitors in locally advanced or metastatic Merkel Cell Carcinoma: safety and efficacy

ABSTRACT Introduction Merkel Cell Carcinoma (MCC) is a rare aggressive skin cancer, mostly affecting elderly patients. Until recently, patients with advanced disease were treated with cytotoxic chemotherapies despite rapid chemoresistance and high toxicity. As with other cancers, immune checkpoint inhibitors (CPI), including pembrolizumab, allow durable responses with a manageable safety profile in these patients. Areas covered This review describes the rationale for using PD-1/PD-L1 inhibitors in MCC, as well as efficacy and safety results from the three open-label trials investigating pembrolizumab or other PD-1/PD-L1 inhibitors in patients with advanced MCC. Real-life experience and predictive pre-treatment biomarkers are discussed to assess which patients are likely to be candidates for such strategies. Ongoing fields of research include the use of CPI in the adjuvant or neoadjuvant setting and combined strategies in refractory patients. Expert Opinion: CPI have become the standard of care for frontline treatment in patients with advanced MCC. Earlier introduction of CPI in the disease course, including neo-adjuvant and adjuvant settings, is likely to improve the outcomes further. Given the rarity of this cancer, we still need to harmonize efforts in order to conduct large-scale trials and efficiently identify best optimal care.

The relative and absolute benefit of programmed death receptor-1 vs programmed death ligand 1 therapy in advanced non-small-cell lung cancer: A systematic review and meta-analysis

IntroductionProgrammed death receptor-1 (PD-1) and its ligand (PD-L1) inhibitors have shown promising results in treating advanced non-small-cell lung cancer (NSCLC). Our objective was to compare the relative and absolute benefits between PD-1 and PD-L1 inhibitors in advanced NSCLC. Materials and methodsPubMed, EMBASE and the Cochrane Library were searched up to Dec 1, 2019, for randomized controlled trials of PD-1/PD-L1 inhibitors that had available overall survival (OS) data in NSCLC. Random-effects models were used to calculate the pooled estimates. ResultsTwenty-three randomized controlled trials (15,797 patients) of PD-1/PD-L1 inhibitors were included in the analysis. PD-1 inhibitors significantly extended OS compared with standard of care therapy (difference in means, 4.80 months, 95% CI 3.41–6.18; HR 0.72, 95% CI 0.66–0.78; P < 0.01 for both). PD-L1 inhibitors also significantly improved OS compared with standard of care therapy (difference in means, 2.59 months 95% CI 1.47–3.71; HR 0.83, 95% CI 0.79–0.88; P < 0.01 for both). More importantly, PD-1 inhibitors had significantly higher OS than PD-L1 inhibitors (difference in means, P = 0.015; HR, P = 0.006). The same increased OS benefit was observed in patients with PD-L1 ≥1% (P = 0.035) and PD-L1 <1% (P = 0.007). However, OS did not differ between PD-1 and PD-L1 inhibitors in patients with an EGFR mutation-positive status (P = 0.724) and who were never smokers (P = 0.999). ConclusionsPD-1 inhibitors showed superior relative and absolute OS benefits compared with PD-L1 inhibitors in the treatment of advanced NSCLC. These findings have implications for treatment selection in current clinical practice and future study design.

The association between STK11/LKB1 and/or KEAP1 mutations and response to PD-1/PD-L1 inhibitors in patients with advanced non-small cell lung cancer (NSCLC).

e21538 Background: Advanced non-small cell lung cancer (NSCLC) patients with tumors harboring STK11/LKB1 or KEAP1 mutations have inferior treatment outcomes when treated with PD-1/PD-L1 blockade, regardless of KRAS status, PD-L1 score, or TMB score (Skoulidis et al, Cancer Discovery 2018, ASCO abstract 102, 2019). Methods: Retrospective clinical databases from Indiana University and Karmanos Cancer Institute were queried to identify patients from 2008-2019 with advanced NSCLC treated with PD-1/PD-L1 monotherapy (group A) or concurrent chemotherapy + PD-1/PD-L1 inhibitors (group B) whose tumors harbored STK11/LKB1 and/or KEAP1 mutations. Patients were characterized by best response, progression of disease (PD) or non-PD (complete response (CR) + partial response (PR) + stable disease (SD)). Patient and disease characteristics, response, and duration of response (&gt; vs. &lt; 6 months) were recorded. Results: A total of 77 patients met the above criteria (55 in group A, 22 in group B). 52 of 55 patients in group A received prior chemo. Patient and disease characteristics and outcomes are summarized in the table. Conclusions: STK11/LKB1 and/or KEAP1 mutations are independent of PD-L1/TMB status, although most patients had PD-L1 of &lt;1%. Nearly ½ of patients with STK11/LKB1 and/or KEAP1 mutations achieve at least SD with PD-1/PD-L1 inhibitor monotherapy and more than 50% of those with non-PD maintain that response status for &gt; 6 mos. The frequency and duration of non-PD in this population is higher in patients receiving chemotherapy + PD-1/PD-L1 concomitantly. [Table: see text]

Effectiveness of PD-1/PD-L1 inhibitors in the treatment of lung cancer: Brightness and challenge

Immune checkpoint inhibitors (ICIs), especially inhibitors of the PD-1/PD-L1 axis, have significantly affected the outcomes of patients with lung cancer. Nivolumab and pembrolizumab have been approved as PD-1 blocking antibodies, whereas atezolizumab, avelumab, and durvalumab are approved as PD-L1 blocking antibodies by the United States Food and Drug Administration. However, which patient may benefit the most and how to identify patients at risk of primary or acquired resistance has not been completely defined. Meanwhile, close attention has been paid to the ongoing international and domestic clinical trials in Chinese patients with lung cancer. This review aimed to provide deep insight into the effectiveness of PD-1/PD-L1 inhibitors in patients with lung cancer, including the current settings for varied disease status, the predictive biomarkers, the resistance to ICIs, and the ongoing clinical trials in Chinese patients.