High Programmed Death-ligand 1 Research Articles

The prevalence of PD-L1 expression in patients with advanced oesophageal cancer: the EXCEED observational study

AimsThere are limited data on programmed death ligand 1 (PD-L1) expression in oesophageal cancer (OC) from multicentre studies conducted across China. We aimed to determine the prevalence of high PD-L1...

Comparison of PD-L1 Expression Between Preoperative Biopsy Specimens and Surgical Specimens in Non-Small Cell Lung Cancer

Background: Recent advances in perioperative immunotherapies have led to a new era in the perioperative treatment of resectable, non-small cell lung cancer (NSCLC). Although the choice of neoadjuvant, adjuvant or perioperative immunotherapy remains controversial, few reports have compared programmed death ligand-1 (PD-L1) expression as a biomarker between preoperative biopsy specimens and surgical specimens. Methods: We retrospectively reviewed consecutive patients with NSCLC whose preoperative biopsy specimens and surgical specimens were tested for PD-L1 (22C3) and PD-L1 (SP263), respectively, from June 2022 to February 2024. The three categorical classifications of PD-L1 expression (negative [<1%], low [1–49%], and high [≥50%]) were compared between the two tests. Results: Of the 33 patients, 13 patients had negative PD-L1 expression, 9 patients had low PD-L1 expression and 11 patients had high PD-L1 expression with preoperative biopsy specimens, while 18 patients had negative PD-L1 expression, 10 patients had low PD-L1 expression and 5 patients had high PD-L1 expression with surgical specimens. The concordance rate for the three categorical classifications of PD-L1 expression between the preoperative biopsy specimens and surgical specimens was 57.6%. Conclusions: PD-L1 expression may differ between preoperative biopsy specimens and surgical specimens. PD-L1 expression evaluated using small biopsy specimens may be largely influenced by chance due to intra-tumoral heterogeneity.

Expression and relationship of PD-L1, CD24, and CD47 in hepatitis B virus associated hepatocellular carcinoma

Immune checkpoint inhibitor (ICI) therapy is the new standard treatment for advanced or metastatic hepatocellular carcinoma (HCC); however, many patients still fail to respond. This study explored the expression and prognosis of programmed death ligand 1 (PD-L1), cluster of differentiation 24 (CD24), and cluster of differentiation 47 (CD47) in patients with hepatitis B virus-associated HCC (HBV-associated HCC). We analyzed sequencing data from the Cancer Genome Atlas (TCGA) and investigated the expression of PD-L1, CD24, and CD47 in HBV-associated HCC patients by immunohistochemistry and their relationship with prognosis and clinicopathological factors. HCC data from the TCGA database show that PD-L1 was substantially correlated with various immune cells. In 67 patients with HBV-associated HCC, high PD-L1 and CD24 expression levels were related to poor overall survival (OS) and progression-free survival (PFS). PD-L1 expression was significantly associated with the staging of HBV-associated HCC (p = 0.011) and Ki67 expression (p = 0.024). Correlation analysis between variables reveals that PD-L1 was significantly positively correlated with CD24 and CD47. High expression of PD-L1 and CD24 are risk factors for poor prognosis in HBV-associated HCC patients following curative resection. PD-L1 is significantly correlated with CD24 and CD47.

Clinical impact of cancer cachexia on the outcome of patients with non-small cell lung cancer with PD-L1 tumor proportion scores of ≥50% receiving pembrolizumab monotherapy versus immune checkpoint inhibitor with chemotherapy.

This retrospective, multicenter cohort study aimed to determine whether cancer cachexia serves as a biomarker for determining the most effective treatment for patients having non-small-cell lung cancer (NSCLC) with high programmed death ligand 1 (PD-L1) expression treated with immune checkpoint inhibitors (ICIs) alone or combined with chemotherapy (ICI/chemotherapy). We included 411 patients with advanced NSCLC with a PD-L1 tumor proportion score of ≥50%. The patients were treated with pembrolizumab monotherapy or ICI/chemotherapy. Cancer cachexia was defined as a weight loss of >5% of the total body weight or a body mass index of <20 kg/m2 coupled with an additional weight loss of >2% within 6 months before starting treatment. Eighty-five (21%) patients met the cancer cachexia criteria. Overall survival (OS) was significantly shorter in patients with cachexia than in those without cachexia in both the pembrolizumab monotherapy group (17.2 vs. 35.8 months, p < 0.001) and the ICI/chemotherapy group (27.0 months vs. not reached, p = 0.044). However, after stratifying by cancer cachexia status, no significant difference in OS was observed between the pembrolizumab monotherapy and chemoimmunotherapy groups, regardless of cachexia. In conclusion, ICI/chemotherapy offers limited benefits for NSCLC patients with high PD-L1 expression and concurrent cancer cachexia. Considering the frailty associated with cachexia, ICI monotherapy may be preferred to ICI/chemotherapy for these patients. New interventions that can better address the negative prognostic impact of cachexia in patients treated using ICIs with or without chemotherapy remain warranted.

Study on the mechanism of liver cancer immune escape mediated by MINDY1 through regulation of PD-L1 ubiquitination level.

The novel deubiquitinase enzyme, motif interacting with ubiquitin-containing novel DUB family-1 (MINDY1), is highly expressed in liver cancer tissues and plays a crucial role in maintaining the stemness of liver cancer cells. Programmed death ligand-1 (PD-L1) is an immunosuppressive molecule overexpressed by tumour cells. The potential role of MINDY1 in inhibiting the stemness of liver cancer cells by deubiquitinating PD-L1 has not yet been reported. To investigate the mechanism by which MINDY1 mediates immune escape in liver cancer through the regulation of PD-L1 ubiquitination, we examined the expression levels of MINDY1 and PD-L1 in liver cancer and adjacent tissues from 50 hepatocellular carcinoma (HCC) patients using protein imprinting and immunohistochemistry. We analyzed the relationship between the expression levels of MINDY1 and PD-L1 in liver cancer tissues and their correlation with the 5-year tumor-free survival rates of patients. Subsequently, MINDY1 expression was knocked down in Huh7 cells using small interfering RNA (siRNA) interference or upregulated through transfection with a MINDY1 overexpression plasmid. The effects of MINDY1 knockdown or overexpression on the proliferation, apoptosis, migration, and invasion of HCC cells, as well as the regulation of PD-L1 binding and ubiquitination, were assessed. The 5-year tumor-free survival rates were significantly lower in both the high MINDY1 expression group and the high PD-L1 expression group (χ2 = 4.919 and 13.158, respectively).A significant difference in survival was observed between the high and low MINDY1 expression groups (χ2= 27.415). MINDY1 was found to directly interact with PD-L1, with MINDY1 gene knockdown promoting PD-L1 ubiquitination and MINDY1 overexpression inhibiting PD-L1 ubiquitination. All comparisons yielded statistically significant results (P < 0.05). In conclusion, MINDY1 inhibits the malignant progression of liver cancer by inhibiting PD-L1 ubiquitination and mediating immune escape.

Real-world data of first-line treatment with pembrolizumab for NSCLC with high PD-L1 expression in elderly patients: a subgroup analysis of HOT/NJLCG2001.

In the first-line treatment of elderly patients with advanced-stage non-small cell lung cancer (NSCLC) with high programmed death-ligand 1 (PD-L1) expression (tumor proportion score≥50%), this study aimed to determine whether pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum-based chemotherapy (COMB) should be selected. We performed a retrospective multicenter study (sub-analysis of the HOT/NJLCG2001 trial) of 299 patients with NSCLC with high PD-L1 expression who received MONO or COMB as the first-line treatment between December 2018 and January 2020. We selected patients aged 75years and older and assessed the clinical efficacy and toxicity. In total, 81 (median age: 79years) and 19 (median age: 76years) patients received MONO and COMB, respectively. Twenty patients with a performance status (PS) score of 2-3 were enrolled in the MONO group. The median progression-free survival (PFS) was 7.8 and 8.9months in the MONO and COMB groups, respectively. The median overall survival (OS) was 14.6 and 20.3months, and the 2-year survival rates were 38.8 and 49.9%, respectively. Furthermore, 29.6% and 26.3% of patients discontinued treatment due to adverse events, respectively. In MONO, patients with PS 0-1 had a longer PFS (10.5months) and OS (21.7months) than those with PS 2-3 (0.7 and 1.6months, respectively). Some elderly patients with NSCLC and high PD-L1 expression might benefit from COMB; however, MONO is considered the preferred treatment. MONO may not be an effective or feasible treatment for patients with PS 2-3, even with high PD-L1 expression.

Clinicopathological Analysis of 14 Cases of Primary Pulmonary Lymphoepithelial Carcinoma

Primary pulmonary lymphoepithelial carcinoma (PPLEC) is a rare form of lung malignancy, accounting for only 0.7% of all lung cancers. It is currently classified as a distinct subtype within squamous cell carcinomas. This study aims to explore the clinicopathological characteristics of PPLEC and its subtypes, with the objective of enhancing understanding and improving diagnostic accuracy for this disease. A retrospective analysis was conducted on the clinical, pathological, imaging, and prognostic data of 14 patients diagnosed with PPLEC at the First Affiliated Hospital of Soochow University between February 2019 and June 2023. A total of 14 cases of PPLEC were identified, including 5 cases of the Regaud type, with ages ranging from 33 to 73 years, comprising 2 males and 3 females; and 9 cases of the Schmincke type, with ages ranging from 36 to 79 years, including 4 males and 5 females. Computed tomography (CT) scans consistently demonstrated soft tissue masses or nodular shadows. Reagud type mainly showed peripheral masses and Schmincke type mainly showed central masses. Pathological examination revealed tumor cells exhibiting syncytial-like growth, accompanied by lymphocytic infiltration and stromal fibrosis, with the Regaud type showing well-defined borders combined with granulomatous inflammation, while the Schmincke type exhibited indistinct tumor margins. Immunohistochemistry showed that CK, CK5/6, P40 and P63 were positive, and the Ki-67 index of Regaud type was lower than that of Schmincke type; notably, all 8 cases tested for programmed death-ligand 1 (PD-L1) were positive. Epstein-Barr virus-encoded RNA (EBER) in situ hybridization was positive in all instances. Among these cases, 6 underwent surgical treatment, and 8 received comprehensive therapy; by the end of the follow-up period, all 14 patients remained alive. PPLEC is a rare form of malignant lung tumor associated with Epstein-Barr virus (EBV) infection. The Regaud and Schmincke subtypes display distinct imaging and pathological characteristics. In the early stages of the disease, surgical intervention is the primary treatment method; however, for advanced stages, a multimodal treatment approach is utilized, resulting in a relatively favorable prognosis. Immunotherapy represents a promising and effective treatment modality for patients with middle to advanced stage disease exhibiting high PD-L1 expression levels.

Pembrolizumab with or without Concurrent Chemotherapy in Metastatic Non–Small-Cell Lung Cancer with High Programmed Death Ligand 1 Expression

Pembrolizumab with or without Concurrent Chemotherapy in Metastatic Non–Small-Cell Lung Cancer with High Programmed Death Ligand 1 Expression

Validation of the Scottish Inflammatory Prognostic Score (SIPS) in NSCLC Patients Treated with First-Line Pembrolizumab.

The Scottish Inflammatory Prognostic Score (SIPS), combining albumin (≥/<35 g/L) and neutrophil count (≤/>7.5 × 109/L), has been identified as a prognostic biomarker for patients with non-small cell lung cancer (NSCLC) undergoing treatment with pembrolizumab monotherapy. We sought to validate this biomarker of systemic inflammation in an external cohort. Patients treated with first-line pembrolizumab for advanced NSCLC with programmed death-ligand 1 (PD-L1) expression ≥ 50% at an English cancer centre were identified. Pre-treatment clinicopathological characteristics and the SIPS were recorded. The relationship between these and progression-free survival (PFS) and overall survival (OS) was examined. Among 257 patients evaluated, 56% (n = 144) were classified as SIPS 0, 36% (n = 93) as SIPS 1, and 8% (n = 20) as SIPS 2. Factors such as age, performance status (PS) and brain metastases presence were significantly correlated with SIPS categories. Multivariate analysis revealed that both SIPS and PD-L1 status were independently associated with PFS and OS. The combination of SIPS with either PS or PD-L1 expression enhanced the ability to detect patients with the most favourable or poorest survival. Our study confirms the prognostic significance of the SIPS in patients with advanced NSCLC treated with pembrolizumab in the context of high PD-L1 expression. SIPS offers a straightforward, clinically applicable approach to patient stratification, potentially guiding therapeutic decisions and enhancing outcomes in advanced NSCLC. Future research should focus on validating these findings in prospective studies and exploring the integration of SIPS into clinical practice, alongside other prognostic markers, to optimize treatment strategies.

The Prevalence of Programmed Death Ligand-1 (PD-L1) Expression in Non-Small Cell Lung Cancer: An Experience From Tertiary Care Hospital.

The prevalence of programmed cell death ligand-1(PD-L1) expression in non-small cell lung cancer (NSCLC) within unselected populations remains a research topic, though PD-L1 expression is important in guiding treatment decisions. The study objective was to ascertain the prevalence ofPD-L1 expression in patients of NSCLC and its association with clinicopathological characteristics and other gene mutations. Samples from patients with NSCLCs were analyzed in the study to determine the expression of PD-L1 through immunohistochemistry (IHC) using rabbit anti-human PDL-1/CD274 monoclonal antibody. Correlation analysis was done using Pearson's correlation coefficient (r). The study analyzed the association between PD-L1 expression and clinicopathological features. A total of 245 consecutive patients (154 men with 62.9%) with NSCLCs were subjected to PD-L1 testing, and 30.6% (n=75) were identified to be positive. It was twice as prevalent in men than women, with 154 men and 91 females, respectively. The PD-L1 expression failed to demonstrate any statistical significance with age, gender, smoking status, type of materials, location of biopsy, Eastern Cooperative Oncology Group Performance Status, and Epidermal Growth Factor Receptor mutation. High PD-L1 expression with tumor proportion score (TPS ≥ 50) was observed in 38.8% of patients, and it was more prevalent in female patients 29 (38.7%), smokers 59 (78.7%), stage IV tumors 44 (58.7%), and stage III tumors 28 (37.3%). Our study in Kerala showed PD-L1 expression in NSCLC patients, correlated with clinicopathologic factors. Males, COPD, ALK+, and advanced-stage tumors had higher expression. Females, smokers, poorly differentiated tumors, and stage IV tumors had high PD-L1.

PD-L1+ Lymphocytes Are Associated with CD4+, Foxp3+CD4+, IL17+CD4+ T Cells and Subtypes of Macrophages in Resected Early-Stage Non-Small Cell Lung Cancer.

The non-canonical PD-L1 pathway revealed that programmed-death ligand 1 (PD-L1) expression in immune cells also plays a crucial role in immune response. Moreover, immune cell distribution in a tumour microenvironment (TME) is pivotal for tumour genesis. However, the results remain controversial and further research is needed. Distribution of PD-L1-positive (PD-L1+) tumour-infiltrating lymphocytes in the context of TME was assessed in 72 archival I-III stage surgically resected NSCLC tumour specimens. Predominant PD-L1+ lymphocyte distribution in the tumour stroma, compared to islets, was found (p = 0.01). Higher PD-L1+ lymphocyte infiltration was detected in smokers due to their predominance in the stroma. High PD-L1+ lymphocyte infiltration in tumour stroma was more common in tumours with higher CD4+ T cell infiltration in islets and stroma, Foxp3+CD4+ T cell infiltration in islets and lover M1 macrophage infiltration in the stroma (p = 0.034, p = 0.034, p = 0.005 and p = 0.034 respectively). Meanwhile, high PD-L1+ lymphocyte infiltration in islets was predominantly found in tumours with high levels of IL-17A+CD4+ T cells in islets and Foxp3+CD4+ T cells in islets and stroma (p = 0.032, p = 0.009 and p = 0.034, respectively). Significant correlations between PD-L1+ lymphocytes and tumour-infiltrating CD4+, Foxp3+CD4+, IL-17A+CD4+ T cells and M2 macrophages were found. An analysis of the tumour-immune phenotype revealed a significant association between PD-L1 expression and IL17+CD4+ and Foxp3+CD4+ immune phenotypes. PD-L1+ lymphocytes are associated with the distribution of CD4+, Foxp3+CD4+, IL17A+CD4+ T cells, M1 and M2 macrophages in TME of resected NSCLC.

Brief Report: Not Created Equal: Survival Differences by KRAS Mutation Subtype in NSCLC Treated With Immunotherapy

IntroductionThe predictive and prognostic implications of different KRAS mutation (KRASm) subtypes in metastatic NSCLC have not been clearly defined. We used a nationwide observational database to investigate whether KRASm subtypes differ in their association with survival in metastatic NSCLC treated with immune checkpoint inhibitor (ICI)-based therapy, across programmed death-ligand 1 (PD-L1) levels. MethodsPatients with advanced nonsquamous NSCLC who initiated first-line ICI-based therapy from 2016 to 2021 and had known PD-L1 expression and comprehensive genomic profiling including KRAS, STK11, KEAP1, and TP53 were included. Within PD-L1 expression subgroups (<1%, 1%–49%, ≥50%), Cox multivariable regression was used to evaluate the association between KRASm subtypes (G12C, G12V, G12D, other KRASm) and overall survival, estimated using Kaplan-Meier methodology. ResultsAmong the 1539 patients, 819 patients were KRAS wild type (KRASwt) and 720 were KRASm (296 KRAS G12C, 143 KRAS G12V, 97 KRAS G12D, 184 other KRASm). In the 50% or higher PD-L1 subgroup, patients with KRAS G12V had worse survival (median overall survival [mOS] = 8.2 mo) compared with KRASwt (mOS = 13.3 mo) and other KRAS subgroups (mOS ranging from 13.4 to 19.9 mo). On adjusted Cox multivariable regression in the 50% or higher PD-L1 subgroup, the hazard ratio for death for KRAS G12V ranged from 1.53 to 1.78 compared with KRASwt and other KRASm subtypes (all p < 0.05). ConclusionsAlthough patients with 50% or higher PD-L1 with KRAS G12C, G12D, and other subtypes exhibited similar survival to KRASwt, KRAS G12V was associated with significantly worse survival than KRASwt and other KRASm subtypes. All KRASm should not be regarded as uniform predictors of ICI responsiveness, even with high PD-L1 expression; KRAS G12V tumors may have worse outcomes with ICI-based therapy and benefit from treatment intensification.

PD-L1 as a Biomarker for the Efficacy of Durvalumab in Stage III EGFR Mutant NSCLC.

Durvalumab consolidation is less effective in patients with epidermal growth factor receptor mutant (EGFR M+) NSCLC. Studies of durvalumab on EGFR M+ NSCLC as an expression of programmed death-ligand 1 (PD-L1) expression are limited. The purpose of this study was to determine the effect of durvalumab on PD-L1 expression in EGFR M+ patients. This study included 249 unresectable stage III NSCLC patients treated with durvalumab. The primary outcome was progression-free survival (PFS). Cox multivariate analysis was performed based on EGFR and PD-L1 statuses: EGFR M-, PD-L1 ≥50% (cohort A); EGFR M-, PD-L1 <50% (cohort B); EGFR M+, PD-L1 ≥50% (cohort C); and EGFR M+, PD-L1 <50% (cohort D). Overall, 31 of 249 (12.4%) and 218 of the 249 (87.6%) patients had EGFR M+ and EGFR M- NSCLC, respectively. Median PFSs and OSs did not differ (PFS: 16.6 vs. 18.7 months, p=0.591; OS: 37.4 vs. 35.7 months, p=0.271). Median PFS of cohort A did not significantly differ from the median PFSs of cohorts B and C, but it was significantly longer than the median PFS of cohort D (23.7 vs. 15.2 months, p=0.045). Cox multivariate analysis revealed that cohort D exhibited a worse PFS (adjusted hazard ratio=2.27, 95% confidence interval=1.11-4.66, p=0.025) compared with cohort A. Median OSs were not different between the four cohorts. Durvalumab consolidation provided similar benefit in EGFR M+ patients with PD-L1 ≥50% compared with EGFR M- patients. A therapeutic role of durvalumab in patients with EGFR M+, high PD-L1 unresectable stage III NSCLC should be considered.

The efficacy and safety of neoadjuvant immunochemotherapy in resectable stage I-III non-small cell lung cancer: a systematic review and network meta-analysis.

Neoadjuvant immunochemotherapy (NICT) is a new treatment method for resectable non-small-cell lung cancer (NSCLC). Network meta-analysis assessed efficacy, safety, and optimal treatment. We searched for randomized controlled trials (RCTs) comparing NICT with neoadjuvant chemotherapy (NCT) in PubMed, Embase, Web of Science, Cochrane Library, and international conferences. Outcomes were surgical resection rate, pathological complete response(pCR),event-free survival (EFS), and Grade 3-5 treatment-related adverse events (TRAEs). RCTs of 3,387 patients, six treatment combinations, and two modalities were included. Meta-analysis showed that NICT yielded higher pCR and EFS rates than NCT. The toripalimab-chemotherapy combination had the highest surgical resection rate (OR = 1.68, 95% CI: 1.05-2.73), pCR (OR = 38.84, 95% CI: 11.05-268.19) and EFS (HR = 0.40, 95% CI: 0.28-0.58).This regimen worked well for patients with low programmed death-ligand 1 (PD-L1) expression or squamous cell pathology. For high PD-L1 expression and patients with NSCLC, neoadjuvant nivolumab with chemotherapy had the most efficacy. The incidence of treatment-related adverse events increased with longer treatment cycles, with perioperative nivolumab combined with chemotherapy showing the worst safety profile (RR = 1.32, 95% CI: 1.00-1.76), while neoadjuvant nivolumab combined with chemotherapy alone had the best safety profile (RR = 0.91, 95% CI: 0.68-1.21). Indirect comparison showed no survival benefit for neoadjuvant-adjuvant immunotherapy (HR = 0.93, 95% CI: 0.65-1.35). In the indirect comparison between the two immune checkpoint inhibitors(ICIs), although there was no significant difference in EFS (HR = 0.81, 95% CI: 0.61-1.08), PD-1 inhibitors may still be the most effective treatment option. NICT effectively and safely treats resectable NSCLC. The optimal treatment combination is typically toripalimab and chemotherapy. Treatment based on PD-L1 expression and pathological type is recommended.

Depth of response and treatment outcomes of immune checkpoint inhibitor-based therapy in patients with advanced non-small cell lung cancer and high PD-L1 expression: An exploratory analysis of retrospective multicenter cohort.

The association between depth of response (DpR) and treatment outcomes has been documented across various types of cancer. Immune checkpoint inhibitor (ICI)-based treatment is globally used as first-line treatment for non-small cell lung cancer (NSCLC) with programmed death-ligand 1 (PD-L1) expression ≥ 50%. However, in this population, the significance of DpR is not elucidated. Patients with advanced NSCLC and PD-L1 expression ≥ 50% who received ICI-monotherapy or ICI plus chemotherapy were retrospectively enrolled into this study. Treatment responses were grouped into DpR 'quartiles' by percentage of maximal tumor reduction (Q1 = 1-25%, Q2 = 26-50%, Q3 = 51-75%, and Q4 = ≥ 76%), and no tumor reduction (NTR). The association between DpR and survival rates were determined using hazard ratios (HR) generated by the Cox proportional hazards model. The Kaplan-Meier method was used to determine survival outcomes. A total of 349 patients were included, of which 214 and 135 patients received pembrolizumab monotherapy and ICI plus chemotherapy, respectively, as first-line treatments. The majority of the patients were male. All DpR quartiles, especially Q4, showed an association with progression-free survival (PFS)/overall survival (OS). In the Q4 cohort, patients who received pembrolizumab had a longer PFS than those who received ICI plus chemotherapy. High DpR was associated with longer PFS and OS, with a more pronounced effect observed with pembrolizumab monotherapy than with ICI plus chemotherapy.

Association of TP53 Mutation Status and Sex with Clinical Outcome in Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors: A Retrospective Cohort Study.

Some studies suggest that TP53 mutations are associated with the response to immune checkpoint inhibitors (ICI) in patients with non-small cell lung cancer (NSCLC) and also contribute to sex disparities in several cancers. Thus, we hypothesized that TP53 mutations might serve as sex-dependent genomic biomarkers of ICI treatment response in patients with NSCLC. Clinical data of 100 patients with metastatic NSCLC treated with ICI monotherapy at Seoul National University Bundang Hospital (SNUBH) were retrospectively reviewed. Genomic and clinical datasets of The Cancer Genome Atlas and an ICI-treated lung cancer cohort (cBioPortal) were also analyzed. In SNUBH cohort, no statistically significant difference was observed in the median progression-free survival (PFS) according to TP53 mutation status (p=0.930); however, female patients with TP53 mutations (MT) had a significantly prolonged median PFS compared to wild-type (WT) (6.1 months in TP53 MT vs. 2.6 months in TP53 WT; p=0.021). Programmed death-ligand 1 (PD-L1) high (≥ 50%) expression was significantly enriched in female patients with TP53 MT (p=0.005). The analysis from publicly available dataset also revealed that females with NSCLC with TP53 MT showed significantly longer PFS than those with TP53 WT (p < 0.001). In The Cancer Genome Atlas analysis, expression of immune-related genes, and tumor mutation burden score in TP53 MT females were higher than in males without TP53 MT. Female patients with NSCLC with TP53 mutations had high PD-L1 expression and showed favorable clinical outcomes following ICI therapy, suggesting a need for further research to explore the role of TP53 mutations for sex disparities in response to ICI therapy.

Three-dimensional iodine mapping quantified by dual-energy CT for predicting programmed death-ligand 1 expression in invasive pulmonary adenocarcinoma

We examined the association between texture features using three-dimensional (3D) io-dine density histogram on delayed phase of dual-energy CT (DECT) and expression of programmed death-ligand 1 (PD-L1) using immunostaining methods in non-small cell lung cancer. Consecutive 37 patients were scanned by DECT. Unenhanced and enhanced (3 min delay) images were obtained. 3D texture analysis was performed for each nodule to obtain 7 features (max, min, median, mean, standard deviation, skewness, and kurtosis) from iodine density mapping and extracellular volume (ECV). A pathologist evaluated a tumor proportion score (TPS, %) using PD-L1 immunostaining: PD-L1 high (TPS ≥ 50%) and low or negative expression (TPS < 50%). Associations between PD-L1 expression and each 8 parameter were evaluated using logistic regression analysis. The multivariate logistic regression analysis revealed that skewness and ECV were independent indicators associated with high PD-L1 expression (skewness: odds ratio [OR] 7.1 [95% CI 1.1, 45.6], p = 0.039; ECV: OR 6.6 [95% CI 1.1, 38.4], p = 0.037). In the receiver-operating characteristic analysis, the area under the curve of the combination of skewness and ECV was 0.83 (95% CI 0.67, 0.93) with sensitivity of 64% and specificity of 96%. Skewness from 3D iodine density histogram and ECV on dual energy CT were significant factors for predicting PD-L1 expression.

PD-L1 expression and its correlation with tumor biomarkers in Chinese urothelial bladder cancer

Data on prevalence of programmed death ligand-1 (PD-L1) expression and its correlation with tumor biomarkers in Chinese patients with muscle-invasive urothelial bladder cancer (MIUBC) are scarce. We investigated the prevalence of PD-L1 expression, PD-L1 expression in tumor cells (TC) and immune cells (IC), and its correlation with tumor biomarkers (CD8+ T cells and tumor mutation burden [TMB]) in Chinese patients with newly diagnosed MIUBC (NCT03433924). Of 248 patients enrolled, 229 with PD-L1 data available were analysed. High PD-L1 expression (≥ 25% of TC or IC with PD-L1 expression) was observed in 120 (52.4%) patients. 59 cases showed positive staining in ≥ 25% of TC, and 82 cases had positive staining in ≥ 25% of IC. High expression of CD8+ T cell and TMB (> 10 mutations/megabase) was observed in 44.5% and 54.1% patients, respectively. A positive correlation was observed between percentage of TC with membrane PD-L1 positivity and CD8+ T cells (0.34; P < 0.001) and between IC with membrane PD-L1 positivity and CD8+ T cells (0.44; P < 0.001). There is high prevalence of PD-L1 expression in Chinese patients with MIUBC, suggesting that a sizable subset of patients could benefit from immunotherapy. The correlation of PD-L1 expression with tumor biomarkers provide clues for mechanisms underlying the effects of biomarkers for predicting efficacy.

Unraveling the influence of TTF-1 expression on immunotherapy outcomes in PD-L1-high non-squamous NSCLC: a retrospective multicenter study.

Several studies explored the association between thyroid transcription factor-1 (TTF-1) and the therapeutic efficacy of immunotherapy. However, the effect of TTF-1 on the therapeutic efficacy of programmed death-1 (PD-1) inhibitor/chemoimmunotherapy in patients with non-squamous non-small cell lung cancer (non-Sq NSCLC) with a programmed death-ligand 1 (PD-L1) tumor proportion score of 50% or more who are highly susceptible to immunotherapy remains unresolved. Therefore, we evaluated whether TTF-1 has a clinical impact on this population. Patients with non-Sq NSCLC and high PD-L1 expression who received PD-1 inhibitor monotherapy or chemoimmunotherapy between May 2017 and December 2020 were retrospectively enrolled. Treatment efficacy was compared after adjusting for baseline differences using propensity score matching. Among the 446 patients with NSCLC with high PD-L1 expression, 266 patients with non-Sq NSCLC were analyzed. No significant differences in therapeutic efficacy were observed between the TTF-1-positive and -negative groups in the overall and propensity score-matched populations. Of chemoimmunotherapy, pemetrexed containing regimen significantly prolonged progression-free survival compared to chemoimmunotherapy without pemetrexed, regardless of TTF-1 expression (TTF1 positive; HR: 0.46 (95% Confidence interval: 0.26-0.81), p<0.01, TTF-1 negative; HR: 0.29 (95% Confidence interval: 0.09-0.93), p=0.02). TTF-1 expression did not affect the efficacy of PD-1 inhibitor monotherapy or chemoimmunotherapy in patients with non-Sq NSCLC with high PD-L1 expression. In this population, pemetrexed-containing chemoimmunotherapy demonstrated superior anti-tumor efficacy, irrespective of TTF-1 expression.

Real-world first-line treatment with pembrolizumab for non-small cell lung carcinoma with high PD-L1 expression: Updated analysis.

Selecting pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum-based chemotherapy (COMB) for patients with nonsmall cell lung cancer (NSCLC) and high programmed death-ligand 1 (PD-L1) expression is an important issue in clinical practice. We previously conducted a retrospective multicenter observational study of patients with NSCLC and high PD-L1 expression who received MONO or COMB as a first-line treatment. Here, we report updated data and evaluate the long-term outcomes. We performed a retrospective multicenter study of 298 patients with NSCLC and high PD-L1 expression who received MONO or COMB as first-line treatment between December 2018 and January 2020. We reviewed the medical records and assessed the clinical efficacy and toxicity using a prolonged data cutoff. In total, 164 (median age: 74 years) and 134 (median age: 68 years) patients received MONO and COMB, respectively; patients who received COMB were younger and had better performance statuses (0-1). At the prolonged data cutoff, the median follow-up was 20.2 (range: 0.1-41.4) months. The median progression-free survivals were 7.5 and 13.1 months, and overall survivals (OSs) were 17.2 and 33.7 months for MONO and COMB, respectively. Treatment discontinuation rates were 21.9% and 20.1% for the MONO and COMB, respectively. With prolonged follow-up, although COMB demonstrated an OS benefit and higher objective response rate than MONO, in the propensity score matching analysis COMB didn't demonstrate a significant benefit compared to the MONO. COMB may be effective as a first-line treatment for NSCLC with high PD-L1 expression in a selected subset of patients.