Programmed Death Ligand-1 Inhibitors Research Articles

Clinical implications of the interaction between PD-1/PD-L1 and PI3K/AKT/mTOR pathway in progression and treatment of non-small cell lung cancer.

The discovery of immune checkpoints has been well known to provide novel clues for cancer treatments. Immunotherapy against the programmed cell death protein-1 (PD-1) /programmed death-ligand-1 (PD-L1), one of the most popular auxiliary treatments in recent years, has been applied in various tumor treatments, including non-small cell lung cancer (NSCLC). However, inevitable issues such as side effects and drug resistance emerge following the use of immune checkpoint inhibitors. The PI3K/AKT/mTOR pathway may participate in the regulation of PD-L1 expression. Abnormal PI3K/AKT/mTOR pathway activation results in increased PD-L1 protein translation, whereas PD-L1 overexpression can activate the PI3K/AKT/mTOR pathway inversely. Via downstream proteins, including 4E-BP1, STAT3, NF-κB, c-MYC, and AMPK in aberrant energy status, the PI3K/AKT/mTOR pathway can regulate PD-L1 post-transcription and translation. Besides, the regulation of the PI3K pathway by the PD-1/PD-L1 axis involves both tumor cells and the tumor immune microenvironment. Inhibitors targeting the PD-1/PD-L1 have been successfully applied in the treatment of gastrointestinal cancer and breast cancer. Meanwhile, drug resistance from alternative pathway activation also evidently affects clinical progress. To achieve a better therapeutic effect and quality of survival, the combination of multiple treatment modalities presents great research value. Here we reviewed the interaction between PD-1/PD-L1 and PI3K/AKT/mTOR pathway in the progression and treatment of NSCLC and summarized its clinical implications. The intracellular interactions between PD-1/PD-L1 and the PI3K/AKT/mTOR pathway indicate that PD-1/PD-L1 inhibitors have a wide range of potential applications. And we presented the mechanism for combining therapy with monoclonal antibody PD-1/PD-L1 and PI3K/AKT/mTOR inhibitors in this review, to broaden the therapies for NSCLC.

Effect of Systemic or Intraperitoneal Administration of Anti-PD-1 Antibody for Peritoneal Metastases from Gastric Cancer.

Programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) blockade therapy is widely used for the treatment of patients with metastatic gastric cancer (GC). However, it is unclear how PD-1 antibodies affect the local immunity related to the growth of peritoneal metastases (PM). The clinical efficacy of PD-1/PD-L1 inhibitors against PM from GC has not been clearly determined. We established a highly metastatic subclone of murine GC cells to the peritoneum, YTN16P, by in vivo selection and evaluated the effects of intravenous (IV) or intraperitoneal (IP) administration of anti-PD-1 antibody on PM in immunocompetent mice model. Phenotypes of immune cells in the spleen and peritoneal metastatic lesions were determined with flow cytometry and immunohistochemistry. IP inoculation of YTN16P (1×106) resulted in multiple mesenteric metastases after 3 weeks. IV and IP administration of anti-PD-1mAb reduced the number of metastases to the mesentery by 30~40% compared with isotype controls. However, no differences were observed depending on the route of administration. Although splenocyte phenotypes were not altered, the densities of CD8(+) T cells in peritoneal tumors were significantly increased, whereas those of Gr-1(+) myeloid derived suppressor cells (MDSC) were significantly reduced in mice treated with anti-PD-1 mAb. PD-1 blockade therapy remodels the cellular immune composition of peritoneal tumors, which can partially suppress the PM from GC regardless of the route of administration. Adding anti-PD-1 antibody to chemotherapeutic regimens may enhance their anti-tumor effects against PM, which can lead to the prolongation of survival of patients with GC with peritoneal involvement.

Comparative Analysis of Predictive Biomarkers for PD-1/PD-L1 Inhibitors in Cancers: Developments and Challenges.

Simple SummaryThe development of immune checkpoint inhibitors (ICIs) has greatly changed the treatment landscape of multiple malignancies. However, the wide administration of ICIs is mainly obstructed by the low response rate and several life-threatening adverse events. Thus, there is an urgent need to identify sets of biomarkers to predict which patients will respond to ICIs. In this review, we discuss the recently investigated molecular and clinical determinants of ICI response, from the aspects of tumor features, clinical features, as well as tumor microenvironment.Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) have dramatically changed the landscape of cancer therapy. Both remarkable and durable responses have been observed in patients with melanoma, non-small-cell lung cancer (NSCLC), and other malignancies. However, the PD-1/PD-L1 blockade has demonstrated meaningful clinical responses and benefits in only a subset of patients. In addition, several severe and life-threatening adverse events were observed in these patients. Therefore, the identification of predictive biomarkers is urgently needed to select patients who are more likely to benefit from ICI therapy. PD-L1 expression level is the most commonly used biomarker in clinical practice for PD-1/PD-L1 inhibitors. However, negative PD-L1 expression cannot reliably exclude a response to a PD-1/PD-L1 blockade. Other factors, such as tumor microenvironment and other tumor genomic signatures, appear to impact the response to ICIs. In this review, we examine emerging data for novel biomarkers that may have a predictive value for optimizing the benefit from anti-PD-1/PD-L1 immunotherapy.

Sex-Based Clinical Outcome in Advanced NSCLC Patients Undergoing PD-1/PD-L1 Inhibitor Therapy-A Retrospective Bi-Centric Cohort Study.

Simple SummaryRetrospective analyses suggest that men treated with immune-checkpoint inhibitor (ICI) monotherapy for non-small cell lung cancer (NSCLC) have better outcomes than women. However, female patients have more favorable responses when chemotherapy (CHT) is given together with ICI. We aimed to explore the clinical impact of such sex differences in two cohorts, receiving ICI monotherapy or ICI-CHT combination, respectively. We found no significant difference in outcomes between men and women treated with either therapeutic regimen. However, known predictive factors for ICI response such as the expression of programmed-death ligand 1 (PD-L1) on tumor cells or patient performance status had significant implications for men rather than for women. Our results warrant increased research efforts to clarify sex-specific differences in anti-tumor immune response mechanisms and in the efficacy of ICI therapies, especially in women. Men with non-small cell lung cancer (NSCLC) have a more favorable response to immune-checkpoint inhibitor (ICI) monotherapy, while women especially benefit from ICI-chemotherapy (CHT) combinations. To elucidate such sex differences in clinical practice, we retrospectively analyzed two cohorts treated with either ICI monotherapy (n = 228) or ICI-CHT combination treatment (n = 80) for advanced NSCLC. Kaplan–Meier analyses were used to calculate progression-free (PFS) and overall survival (OS), influencing variables were evaluated using Cox-regression analyses. No significant sex differences for PFS/OS could be detected in either cohort. Men receiving ICI monotherapy had a statistically significant independent impact on PFS by Eastern Cooperative Oncology Group performance status (ECOG) ≥2 (hazard ratio (HR) 1.90, 95% confidence interval (CI): 1.10–3.29, p = 0.021), higher C-reactive protein (CRP; HR 1.06, 95%CI: 1.00–1.11, p = 0.037) and negative programmed death-ligand 1 (PD-L1) status (HR 2.04, 95%CI: 1.32–3.15, p = 0.001), and on OS by CRP (HR 1.09, 95%CI: 1.03–1.14, p = 0.002). In men on ICI-CHT combinations, multivariate analyses (MVA) revealed squamous histology (HR 4.00, 95%CI: 1.41–11.2, p = 0.009) significant for PFS; and ECOG ≥ 2 (HR 5.58, 95%CI: 1.88–16.5, p = 0.002) and CRP (HR 1.19, 95%CI: 1.06–1.32, p = 0.002) for OS. Among women undergoing ICI monotherapy, no variable proved significant for PFS, while ECOG ≥ 2 had a significant interaction with OS (HR 1.90, 95%CI 1.04–3.46, p = 0.037). Women treated with ICI-CHT had significant MVA findings for CRP with both PFS (HR 1.09, 95%CI: 1.02–1.16, p = 0.007) and OS (HR 1.11, 95%CI: 1.03–1.19, p = 0.004). Although men and women responded similarly to both ICI mono- and ICI-CHT treatment, predictors of response differed by sex.

92P PD-L1 inhibitors as monotherapy for the first-line treatment of non-small cell lung cancer in PD-L1 positive patients: A safety data network meta-analysis

Immunotherapy (IT) targeting programmed cell death-1 receptor (PD-1) and programmed death-ligand 1 (PD-L1) has considerably improved the overall survival of non-small cell lung cancer (NSCLC) patients. This network meta-analysis (MA) evaluates the safety of first-line (1L) PD-L1 inhibitors monotherapy in advanced NSCLC patients compared to platinum-based chemotherapy (CT). We also compared the risk of Adverse Events (AEs) according to programmed cell death-1 receptor (PD-1) or PD-L1 inhibitors therapy.

Rationale and design of the CRAFT (Continuous ReAssessment with Flexible ExTension in Rare Malignancies) multicenter phase II trial

BackgroundApprovals of cancer therapeutics are primarily disease entity specific. Current molecular diagnostic approaches frequently identify actionable alterations in rare cancers or rare subtypes of common cancers for which the corresponding treatments are not approved and unavailable within clinical trials due to entity-related eligibility criteria. Access may be negotiated with health insurances. However, approval rates vary, and critical information required for a scientific evaluation of treatment-associated risks and benefits is not systematically collected. Thus clinical trials with optimized patient selection and comprehensive molecular characterization are essential for translating experimental treatments into standard care.Patients and methodsContinuous ReAssessment with Flexible ExTension in Rare Malignancies (CRAFT) is an open-label phase II trial for adults with pretreated, locally advanced, or metastatic solid tumors. Based on the evaluation by a molecular tumor board, patients are assigned to combinations of six molecularly targeted agents and a programmed death-ligand 1 (PD-L1) antagonist within seven study arms focusing on (i) BRAF V600 mutations; (ii) ERBB2 amplification and/or overexpression, activating ERBB2 mutations; (iii) ALK rearrangements, activating ALK mutations; (iv and v) activating PIK3CA and AKT mutations, other aberrations predicting increased PI3K–AKT pathway activity; (vi) aberrations predicting increased RAF–MEK–ERK pathway activity; (vii) high tumor mutational burden and other alterations predicting sensitivity to PD-L1 inhibition. The primary endpoint is the disease control rate (DCR) at week 16; secondary and exploratory endpoints include the progression-free survival ratio, overall survival, and patient-reported outcomes. Using Simon’s optimal two-stage design, 14 patients are accrued for each study arm. If three or fewer patients achieve disease control, the study arm is stopped. Otherwise, 11 additional patients are accrued. If the DCR exceeds 7 of 25 patients, the null hypothesis is rejected for the respective study arm.ConclusionsCRAFT was activated in October 2021 and will recruit at 10 centers in Germany.Trial registration numbersEudraCT: 2019-003192-18; ClinicalTrials.gov: NCT04551521.

Avenue - Avelumab in the Frontline Treatment of Advanced Classic Hodgkin Lymphoma - a Window Study

Avenue - Avelumab in the Frontline Treatment of Advanced Classic Hodgkin Lymphoma - a Window Study

Combining PD-1/PD-L1 inhibitor and PARP inhibitor: a new perspective on the treatment of triple negative breast cancer

Compared with other types of breast cancer, triple negative breast cancer has a poor survival prognosis due to its high aggressiveness and lack of effective therapeutic targets. Immune checkpoint (PD-1/PD-L1 and CTL-4) inhibitors have emerged as a breakthrough therapy in the treatment in various metastatic cancers. PARP inhibitors promote DNA damage in tumor cells, not only promoting immune initiation through a series of molecular mechanisms, but also leading to adaptive upregulation of programmed death ligand 1 (PD-L1) expression. Therefore, the combination of the two inhibitors can improve the efficacy of tumor treatment. We reviewed the research progress of their combined use in triple negative breast cancer, and put forward relevant ideas for further development, hoping to find the best treatment mode of the combined use of the two.

Programmed Death-Ligand 1 Expression in Breast Cancer Patients: Clinicopathological Associations from a Single-Institution Study.

PurposeTumor expression of programmed death-ligand 1 (PD-L1) is associated with evasion of immune response in several types of malignancies and such expression may render patients eligible for PD-L1 inhibitors. The use of immune checkpoint blockade therapy has been recently approved for the treatment of breast cancer. However, PD-L1 expression data are lacking among Jordanian breast cancer patients. In this study, the tumor PD-L1 expression was characterized in breast cancer patients to assess their eligibility for immune checkpoint blockade therapy. The study also aimed to explore the association between tumoral PD-L1 expression and the clinicopathologic characteristics and the prognostic factors in patients with breast cancer.Patients and MethodsTissue samples were available from 153 female patients with primary invasive breast cancer. Immunohistochemistry was performed on paraffin-embedded tumor sections that were stained with a PD-L1 antibody. Expression of tumor PD-L1 was correlated with demographics, clinicopathologic characteristics, and prognosis.ResultsThe mean age at diagnosis was 54.2±12.8 years (median 52, interquartile range 45–65). The percentage of PD-L1-positive tumors was 26.1%. PD-L1 expression on tumor cells significantly and positively correlated with tumor size (rho=0.174, p=0.032). PD-L1 positivity was significantly associated with the grade of carcinoma (p=0.001), HER2-positivity (p=0.015), and lymphovascular invasion (p=0.036). PD-L1 intensity was significantly associated with tumor stage (p=0.046). No significant associations were observed for the PD-L1 expression status or intensity with patient menopausal status, hormone receptor expression, and molecular subtypes. PD-L1 expression significantly correlated with a worse prognosis of breast cancer patients at the time of diagnosis (rho=0.230, p=0.005).ConclusionTumor PD-L1 expression was associated with advanced clinicopathologic features and worse prognosis in this cohort of Jordanian breast cancer patients. Future studies are needed to better understand the impact of PD-L1 blockade therapy on treatment outcomes in eligible breast cancer patients in Jordan.

Association of prior local therapy and outcomes with programmed-death ligand-1 inhibitors in advanced urothelial cancer.

To compare clinical outcomes with programmed-death ligand-1 immune checkpoint inhibitors (ICIs) in patients with advanced urothelial carcinoma (aUC) who have vs have not undergone radical surgery (RS) or radiation therapy (RT) prior to developing metastatic disease. We performed a retrospective cohort study collecting clinicopathological, treatment and outcomes data for patients with aUC receiving ICIs across 25 institutions. We compared outcomes (observed response rate [ORR], progression-free survival [PFS], overall survival [OS]) between patients with vs without prior RS, and by type of prior locoregional treatment (RS vs RT vs no locoregional treatment). Patients with de novo advanced disease were excluded. Analysis was stratified by treatment line (first-line and second-line or greater [second-plus line]). Logistic regression was used to compare ORR, while Kaplan-Meier analysis and Cox regression were used for PFS and OS. Multivariable models were adjusted for known prognostic factors. We included 562 patients (first-line: 342 and second-plus line: 220). There was no difference in outcomes based on prior locoregional treatment among those treated with first-line ICIs. In the second-plus-line setting, prior RS was associated with higher ORR (adjusted odds ratio 2.61, 95% confidence interval [CI]1.19-5.74]), longer OS (adjusted hazard ratio [aHR] 0.61, 95% CI 0.42-0.88) and PFS (aHR 0.63, 95% CI 0.45-0.89) vs no prior RS. This association remained significant when type of prior locoregional treatment (RS and RT) was modelled separately. Prior RS before developing advanced disease was associated with better outcomes in patients with aUC treated with ICIs in the second-plus-line but not in the first-line setting. While further validation is needed, our findings could have implications for prognostic estimates in clinical discussions and benchmarking for clinical trials. Limitations include the study's retrospective nature, lack of randomization, and possible selection and confounding biases.

Avelumab in Combination Regimens for Relapsed/Refractory DLBCL: Results from the Phase Ib JAVELIN DLBCL Study

BackgroundRelapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is associated with a poor prognosis despite the availability of multiple treatment options. Preliminary evidence suggests that DLBCL may be responsive to programmed death ligand 1 (PD-L1)/programmed death 1 inhibitors.ObjectiveThe JAVELIN DLBCL study was conducted to assess whether a combination of agents could augment and sustain the antitumor immunity of avelumab, an anti-PD-L1 antibody, in R/R DLBCL.MethodsThis was a multicenter, randomized, open-label, parallel-arm study with a phase Ib and a phase III component. Reported here are the results from the phase Ib study, wherein 29 adult patients with DLBCL were randomized 1:1:1 to receive avelumab in combination with utomilumab (an immunoglobulin G2 4-1BB agonist) and rituximab (arm A), avelumab in combination with utomilumab and azacitidine (arm B), or avelumab in combination with bendamustine and rituximab (arm C). The primary endpoints were dose-limiting toxicities and objective response as assessed by the investigator per Lugano Response Classification criteria.ResultsOf the seven patients in arm A, one (14.3%) experienced two grade 3 dose-limiting toxicities (herpes zoster and ophthalmic herpes zoster); no dose-limiting toxicities were reported in arms B or C. No new safety concerns emerged for avelumab. One partial response was reported in arm A, three complete responses in arm C, and no responses in arm B. Given the insufficient antitumor activity in arms A and B and the infeasibility of expanding arm C, the study was discontinued before initiation of the phase III component.ConclusionsThe low level of clinical activity suggests that PD-L1 inhibitor activity may be limited in R/R DLBCL.ClinicalTrials.gov IdentifierNCT02951156.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11523-021-00849-8.

Expression, prognostic significance and therapeutic implications of PD-L1 in gliomas.

The advent of checkpoint immunotherapy, particularly with programmed death‐1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) inhibitors, has provided ground‐breaking results in several advanced cancers. Substantial efforts are being made to extend these promising therapies to other refractory cancers such as gliomas, especially glioblastoma, which represents the most frequent and malignant glioma and carries an exceptionally grim prognosis. Thus, there is a need for new therapeutic strategies with related biomarkers. Gliomas have a profoundly immunosuppressive tumour micro‐environment and evade immunological destruction by several mechanisms, one being the expression of inhibitory immune checkpoint molecules such as PD‐L1. PD‐L1 is recognised as an important therapeutic target and its expression has been shown to hold prognostic value in different cancers. Several clinical trials have been launched and some already completed, but PD‐1/PD‐L1 inhibitors have yet to show convincing clinical efficacy in gliomas. Part of the explanation may reside in the vast molecular heterogeneity of gliomas and a complex interplay within the tumour micro‐environment. In parallel, critical knowledge about PD‐L1 expression is beginning to accumulate including knowledge on expression levels, testing methodology, co‐expression with other checkpoint molecules and prognostic and predictive value. This article reviews these aspects and points out areas where biomarker research is needed to develop more successful checkpoint‐related therapeutic strategies in gliomas.

Urothelial Carcinoma: Optimal Treatment Options in First-Line and Beyond

For many years, the standard treatment approach in first-line for advanced urothelial carcinoma (UC) was platinum-based chemotherapy, with the choice of agent dependent on cisplatin-eligibility and relatively limited second-line therapy options included taxanes or vinflunine, thus although with missing approval in Switzerland.^1^ In the last years, the treatment landscape has changed due to the emergence of new targeted approaches, including immune checkpoint inhibitors (ICIs).^2^ In Switzerland, programmed death-protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors including pembrolizumab, atezolizumab and nivolumab are currently approved for the treatment of locally advanced or metastatic UC in adults having progressed on platinum-based chemotherapy,^3–5^ as well as pembrolizumab and atezolizumab in PD-L1 positive treatment naïve patients if platinum unfit. Evidence from a recent phase III trial has led to a new standard of care with a switch maintenance approach with the PD-L1 inhibitor avelumab for UC patients who are progression-free following platinum-based chemotherapy. Several novel emerging targeted therapies such as antibody-drug conjugates (ADC) or fibroblast growth factor receptor (FGFR) inhibitors are also being investigated in treatment-naïve as well as pretreated, platinum-and checkpoint inhibitor refractory patients with locally advanced or metastatic UC. This article provides an overview of current treatment options in first- and subsequent-line settings.

PD-L1 Inhibitors as Monotherapy for the First-Line Treatment of Non-Small-Cell Lung Cancer in PD-L1 Positive Patients: A Safety Data Network Meta-Analysis.

This network meta-analysis (NMA) evaluates the safety of first-line programmed death-ligand 1 (PD-L1) inhibitor monotherapy in advanced NSCLC patients compared to platinum-based chemotherapy. We also compared the risk of adverse events (AEs) according to programmed cell death-1 receptor (PD-1) or PD-L1 inhibitors therapy. To that end, we conducted a series of metanalyses (MAs) using data from six phase III clinical trials, including 4053 patients. Our results show a reduced risk of any grade treatment-related AEs (risk ratio (RR) = 0.722 95% CI: 0.667–0.783, p = 0.002), and grade 3–5 AEs (RR = 0.406 95% CI: 0.340–0.485, p = 0.023) in immunotherapy as compared to chemotherapy. In contrast, a higher risk of immune-related AEs (irAEs) was estimated for immunotherapy versus chemotherapy. The subgroup MAs comparing PD-L1 to PD-1 inhibitors, determined a lower risk of AEs leading to treatment discontinuation in the anti-PD-L1 subgroup (RR = 0.47 95% CI: 0.29–0.75, p = 0.001); however, this statistically significant difference between anti-PD-L1 and anti-PD-1 subgroups was not reached for other safety outcomes analyzed. In conclusion, our findings show that PD-L1 inhibitor monotherapy improves safety outcomes in the 1L treatment of advanced NSCLC patients as compared to chemotherapy except for irAEs.

Immunotherapy and Targeting the Tumor Microenvironment: Current Place and New Insights in Primary Pulmonary NUT Carcinoma.

Primary pulmonary nuclear protein of testis carcinoma is a rare and highly aggressive malignant tumor. It accounts for approximately 0.22% of primary thoracic tumors and is little known, so it is often misdiagnosed as pulmonary squamous cell carcinoma. No effective treatment has been formed yet, and the prognosis is extremely poor. This review aims to summarize the etiology, pathogenesis, diagnosis, treatment, and prognosis of primary pulmonary nuclear protein of testis carcinoma in order to better recognize it and discuss the current and innovative strategies to overcome it. With the increasing importance of cancer immunotherapy and tumor microenvironment, the review also discusses whether immunotherapy and targeting the tumor microenvironment can improve the prognosis of primary pulmonary nuclear protein of testis carcinoma and possible treatment strategies. We reviewed and summarized the clinicopathological features of all patients with primary pulmonary nuclear protein of testis carcinoma who received immunotherapy, including initial misdiagnosis, disease stage, immunohistochemical markers related to tumor neovascularization, and biomarkers related to immunotherapy, such as PD-L1 (programmed death-ligand 1) and TMB (tumor mutational burden). In the meanwhile, we summarized and analyzed the progression-free survival (PFS) and the overall survival (OS) of patients with primary pulmonary nuclear protein of testis carcinoma treated with PD-1 (programmed cell death protein 1)/PD-L1 inhibitors and explored potential population that may benefit from immunotherapy. To the best of our knowledge, this is the first review on the exploration of the tumor microenvironment and immunotherapy effectiveness in primary pulmonary nuclear protein of testis carcinoma.

Assessment of PD-L1 Expression on Circulating Tumor Cells for Predicting Clinical Outcomes in Patients with Cancer Receiving PD-1/PD-L1 Blockade Therapies.

Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) blockade immunotherapies have changed the landscape of cancer therapy. However, the main limitation of these therapies is the lack of definitively predictive biomarkers to predict treatment response. Whether PD-L1 expression on circulating tumor cells (CTCs) is associated with the clinical outcomes of immunotherapy remains to be extensively investigated. One hundred fifty-five patients with different advanced cancers were enrolled in this study and treated with anti-PD-1/PD-L1 monoclonal antibodies. Using the Pep@MNPs method, CTCs were isolated and enumerated. The PD-L1 expression levels were analyzed by an immunofluorescence assay for semiquantitative assessment with four categories (negative, low, medium, and high). Prior to immunotherapy, 81.93% (127/155) of patients had PD-L1-positive CTCs, and 71.61% (111/155) had at least one PD-L1-high CTC. The group with PD-L1-positive CTCs had a higher disease control rate (DCR) (71.56%, 91/127), with a DCR of only 39.29% (11/28) for the remaining individuals (p=.001). The objective response rate and DCR in PD-L1-high patients were higher than those in the other patients (32.44% vs. 13.64%, p=.018 and 75.68% vs. 40.91%, p<.0001, respectively). The reduction in the counts and ratios of PD-L1-positive CTCs and PD-L1-high CTCs reflected a beneficial response to PD-1/PD-L1 inhibitors. Furthermore, patients with PD-L1-high CTCs had significantly longer progression-free survival (4.9 vs. 2.2 months, p<.0001) and overall survival (16.1 vs. 9.0 months, p=.0235) than those without PD-L1-high CTCs. The PD-L1 level on CTCs may serve as a clinically actionable biomarker for immunotherapy, and its dynamic changes could predict the therapeutic response. This study was designed to investigate the role of programmed death-ligand 1 (PD-L1) expression on circulating tumor cells in predicting and monitoring response to programmed death-1 (PD-1)/PD-L1 blockade immunotherapies in patients with advanced cancer. The results of the study showed that PD-L1-high-expression circulating tumor cells (CTCs) were both a predictive biomarker and a prognostic factor in patients with advanced cancer treated with anti-PD-1/PD-L1 monoclonal antibodies. These observations suggest that PD-L1 level on CTCs is a potential clinical biomarker for immunotherapy.

Impact of weight loss on treatment with PD-1/PD-L1 inhibitors plus chemotherapy in advanced non-small-cell lung cancer.

Programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors plus chemotherapy have become the standard first line of treatment in patients with advanced non-small-cell lung cancer (NSCLC). However, few studies have explicitly focused on the impact of weight loss on the efficacy of PD-1/PD-L1 inhibitors plus chemotherapy. Thus, we evaluated the clinical implications of weight loss on the survival outcomes in patients who received this treatment. We conducted a retrospective review of medical records of patients with advanced NSCLC who were treated with PD-1/PD-L1 inhibitors plus chemotherapy from December 2018 to December 2020. Significant weight loss was defined as an unintentional weight loss of 5% or more over 6months. We evaluated the progression-free survival (PFS) and overall survival (OS) of patients with or without weight loss. Among the 80 included patients, 37 (46%) had weight loss, and were associated with a lower objective response rate (30 vs 51%, P < 0.05), poorer PFS (2.3 vs 12.0months, P < 0.05), and poorer OS (10.8 vs 23.9months, P < 0.05) than those without weight loss. The Cox proportional-hazard ratios (95% confidence interval) of weight loss were 1.77 (1.01-3.10) for PFS and 2.90 (1.40-6.00) for OS, with adjustments for Eastern Cooperative Oncology Group performance status, PD-L1 tumour proportion score, histology, and central nervous system metastases. Pre-treatment weight loss may reduce treatment efficacy and shorten survival time in patients receiving PD-1/PD-L1 inhibitors plus chemotherapy. Early evaluation and intervention for weight loss might improve oncological outcomes in patients with advanced NSCLC.

Erratum.

Sorafenib, a multityrosine kinase inhibitor, is a standard treatment for advanced hepatocellular carcinoma (HCC), but the clinical response to sorafenib is seriously limited by drug resistance. Programmed death ligand-1 (PD-L1) is one of the most important inhibitory molecules involved in tumor immune evasion. Recently, it has been reported that PD-L1 could play crucial roles in drug resistance of many kinds of cancers. However, the expression, function, and regulation of PD-L1 in sorafenib-resistant hepatoma cells remain unclear. In this study, we reported that PD-L1 was overexpressed in sorafenib-resistant hepatoma cells, and shRNA-mediated PD-L1 depletion attenuated drug resistance and suppressed the migration, invasion, colony formation, and tumorigenesis in sorafenib-resistant hepatoma cells in vitro and in vivo. Mechanistic investigations indicated that loss of microRNA-1 (miR-1), a tumor-suppressive microRNA, contributed to the PD-L1 upregulation in sorafenib-resistant hepatoma cells, and PD-L1 was a direct regulatory target of miR-1. Further study revealed that an oncogenic transcriptional factor, nuclear factor E2-related factor 2 (NRF-2), was induced in sorafenib-resistant hepatoma cells and inhibited expression of miR-1 in vitro. From molecular mechanism insight back to the functional verification, we eventually demonstrated that miR-1 executed its tumor-suppressive effects on drug resistance and other malignant properties in sorafenib-resistant hepatoma cells partially by PD-L1 inhibition in vitro and in vivo. In conclusion, our data suggested that a NRF-2/miR-1/PD-L1 regulatory axis contributed to the development and maintenance of drug resistance and other tumorigenic properties in sorafenib-resistant hepatoma cells and provided a potential therapeutic target for overcoming sorafenib resistance in HCC.

Association of the advanced lung cancer inflammation index (ALI) with immune checkpoint inhibitor efficacy in patients with advanced non-small-cell lung cancer

BackgroundThe advanced lung cancer inflammation index [ALI: body mass index × serum albumin/neutrophil-to-lymphocyte ratio (NLR)] reflects systemic host inflammation, and is easily reproducible. We hypothesized that ALI could assist guidance of non-small-cell lung cancer (NSCLC) treatment with immune checkpoint inhibitors (ICIs).Patients and methodsThis retrospective study included 672 stage IV NSCLC patients treated with programmed death-ligand 1 (PD-L1) inhibitors alone or in combination with chemotherapy in 25 centers in Greece and Germany, and a control cohort of 444 stage IV NSCLC patients treated with platinum-based chemotherapy without subsequent targeted or immunotherapy drugs. The association of clinical outcomes with biomarkers was analyzed with Cox regression models, including cross-validation by calculation of the Harrell's C-index.ResultsHigh ALI values (>18) were significantly associated with longer overall survival (OS) for patients receiving ICI monotherapy [hazard ratio (HR) = 0.402, P < 0.0001, n = 460], but not chemo-immunotherapy (HR = 0.624, P = 0.111, n = 212). Similar positive correlations for ALI were observed for objective response rate (36% versus 24%, P = 0.008) and time-on-treatment (HR = 0.52, P < 0.001), in case of ICI monotherapy only. In the control cohort of chemotherapy, the association between ALI and OS was weaker (HR = 0.694, P = 0.0002), and showed a significant interaction with the type of treatment (ICI monotherapy versus chemotherapy, P < 0.0001) upon combined analysis of the two cohorts. In multivariate analysis, ALI had a stronger predictive effect than NLR, PD-L1 tumor proportion score, lung immune prognostic index, and EPSILoN scores. Among patients with PD-L1 tumor proportion score ≥50% receiving first-line ICI monotherapy, a high ALI score >18 identified a subset with longer OS and time-on-treatment (median 35 and 16 months, respectively), similar to these under chemo-immunotherapy.ConclusionsThe ALI score is a powerful prognostic and predictive biomarker for patients with advanced NSCLC treated with PD-L1 inhibitors alone, but not in combination with chemotherapy. Its association with outcomes appears to be stronger than that of other widely used parameters. For PD-L1-high patients, an ALI score >18 could assist the selection of cases that do not need addition of chemotherapy.

Clinical observation of the efficacy of PD-1/PD-L1 inhibitors in the treatment of patients with advanced solid tumors.

IntroductionProgrammed death 1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) inhibitors are proved to be promising and are applied for the treatment of a variety of solid tumors. This retrospective study evaluated the efficacy of PD‐1/PD‐L1 inhibitors in patients with advanced solid tumors and explore the effect of clinical characteristics on it.Materials and MethodsFrom October 2017 to April 2020, a total of 90 patients from Capital Medical University Affiliated Beijing Friendship Hospital were enrolled.ResultsAt a median follow‐up of 10.55 months, objective response was observed in 23 patients and the objective response rate was 25.6%. The median progression‐free survival (PFS) was 5.5 months (95% confidence interval [CI], 3.69–7.37). The 6m‐PFS was 45.8% and 12m‐PFS was 25.1%. The median overall survival (OS) was 16.9 months (95% CI, not reached [NR]‐NR). The 12m‐OS was 58.1% and 18m‐OS was 48.1%.ConclusionThe efficacy of PD‐1/PD‐L1 inhibitors in the treatment of advanced solid tumors was comparable to previous studies. ECOG performance status, smoking status, liver metastasis, neutrophil‐to‐lymphocyte ratio were independently correlated with PFS while liver metastasis and lactate dehydrogenase level were independently correlated with OS.