Immunotherapy for advanced non-small cell lung cancer with negative programmed death-ligand 1 expression: a literature review.

Background and Objective: Lung cancer, mainly non-small cell lung cancer (NSCLC), is a serious threat to human life. In particular, the prognosis for advanced patients is poor, with the 5-year survival rate being exceedingly low. In recent years, immune checkpoint inhibition has changed the pattern of the treatment of a variety of cancers, including lung cancer; however, not all patients can benefit from immunotherapy, and thus finding the right biomarkers is particularly important for guiding precise treatment. Programmed death-ligand 1 (PD-L1) expression is one of the most valuable biomarkers for predicting the efficacy of lung cancer immunotherapy. Several studies have confirmed that patients with high PD-L1 expression are more likely to benefit from immunotherapy, but there is a high proportion of people with negative PD-L1 expression constituting a patient population that cannot be ignored. This article reviews the distribution of PD-L1 expression, the methods for evaluating PD-L1, and the effectiveness of immunotherapy for advanced NSCLC with negative PD-L1 expression. Methods: We performed a literature review to identify relevant data published until September 2022. In order to organize related information, we searched for literature in PubMed; abstracts and reports published in the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), the World Conference on Lung Cancer (WCLC), and other congresses; and clinical trial information registered on ClinicalTrials.gov. Information on the distribution of PD-L1 expression, detection of PD-L1, and immunotherapy efficacy for NSCLC with negative PD-L1 expression was collated and reviewed. Key Content and Findings: The incidence of PD-L1 expression in patients with stage IIIB/IV NSCLC is similar in all regions of the world, but PD-L1 expression level is associated with certain clinicopathological features. The expression of PD-L1 can be evaluated by various detecting methods. Some immunotherapy regimens have better efficacy than traditional chemotherapy in patients with negative PD-L1 expression. Conclusions: Patients with NSCLC and negative PD-L1 expression can receive better survival benefits under some immunotherapy types, and these may represent a better treatment option for this relatively small patient population.

Efficacy and safety of anti-PD-1 monotherapy versus anti-PD-1 antibodies plus lenvatinib in patients with advanced hepatocellular carcinoma: a real-world experience.

Background: The efficacy of anti-programmed cell death (PD)-1 monotherapy in advanced hepatocellular carcinoma (aHCC) is limited, and combination therapy with lenvatinib and pembrolizumab has shown promising results. However, comparative studies between immune monotherapies and combination therapies are lacking. Objectives: To investigate the efficacy and safety of anti-PD-1 monotherapy (PD-1) and anti-PD-1 plus lenvatinib (PD-1 + L) in patients with aHCC to guide clinical treatment decisions. Design: A retrospective study was conducted on a cohort of patients with aHCC who received either PD-1 monotherapy or PD-1 + L combination therapy between January 2018 and January 2020. Methods: The study retrospectively reviewed the medical records of 94 eligible patients with aHCC, with 39 in the PD-1 group and 55 in the PD-1 + L group. The efficacy outcomes, including objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety, were assessed. Results: With a median follow-up of 30.1 months, the PD-1 + L group demonstrated a significantly higher ORR (32.7% versus 10.3%, p = 0.013), better DCR (80.0% versus 53.8%, p = 0.012), longer median PFS (10.6 versus 4.4 months, p < 0.001) and longer median OS (18.4 versus 8.5 months, p = 0.013) than PD-1 group. For the responders, the efficacy of the two groups was durable (DOR was 11.6 versus 3.5 months, p = 0.009). Subgroup analyses based on prior tyrosine kinase inhibitor (TKI) treatment and the presence or absence of macrovascular tumor thrombosis or extrahepatic metastases favored the PD-1 + L group. The combination therapy was a good predictor of PFS and OS in multivariate analysis. Grade 3/4 treatment-related adverse events were more common in PD-1 + L group, with higher incidences of hypertension and hand-foot skin reactions. Conclusions: PD-1 monotherapy and PD-1 plus lenvatinib combination therapy were well-tolerated in patients with aHCC. PD-1 + L showed significantly better survival benefits than PD-1 monotherapy.

Understanding the impact of PD-1 and lenvatinib combination therapy on advanced hepatocellular carcinoma Abstract: This plain language summary provides a description of our research on the combination therapy of PD-1 and lenvatinib for advanced Hepatocellular carcinoma (aHCC). We aimed to investigate the effectiveness and safety of this treatment approach and offer insights for clinical decisions. Why was this study done? HCC is a challenging condition to treat, especially in advanced stages. We explored whether the combination of two drugs, PD-1 and lenvatinib, can offer better outcomes for patients with aHCC than PD-1 monotherapy. What did the researchers do? We conducted a retrospective study on patients diagnosed with aHCC who received PD-1 alone or PD-1 combined with lenvatinib between January 2018 and January 2020. We analysed the medical records to assess the treatment's efficacy and safety. What did the researchers find? After a median follow-up of 30.1 months, we observed significant improvements in the combination therapy group, with higher response rates, better disease control, longer progression free survival, and more extended overall survival than those in the PD-1 monotherapy group. Responders in the combination group also experienced a longer duration of response. What do the findings mean? Our results address the lack of data for real-world clinical experiences regarding anti-PD-1 monotherapy for patients with aHCC compared to immunotherapy plus lenvatinib are lacking. The combination of PD-1 and lenvatinib was more effective and offered better survival benefits for patients with aHCC than PD-1 alone. These results could provide new hope for patients with this challenging condition. Limitations: The study was conducted at a single centre with relatively few patients. Additionally, most patients had hepatitis B-associated liver cancer, which may limit the generalisability of our findings to other populations. Conclusions: PD-1 plus lenvatinib is a promising treatment option for patients with aHCC. It is well-tolerated, and its effectiveness surpasses that of PD-1 therapy alone. Our findings could potentially guide clinicians in making treatment decisions for patients with aHCC.

Gut mycobiome as a potential non-invasive tool in early detection of lung adenocarcinoma: a cross-sectional study.

BACKGROUND: The gut mycobiome of patients with lung adenocarcinoma (LUAD) remains unexplored. This study aimed to characterize the gut mycobiome in patients with LUAD and evaluate the potential of gut fungi as non-invasive biomarkers for early diagnosis. METHODS: In total, 299 fecal samples from Beijing, Suzhou, and Hainan were collected prospectively. Using internal transcribed spacer 2 sequencing, we profiled the gut mycobiome. Five supervised machine learning algorithms were trained on fungal signatures to build an optimized prediction model for LUAD in a discovery cohort comprising 105 patients with LUAD and 61 healthy controls (HCs) from Beijing. Validation cohorts from Beijing, Suzhou, and Hainan comprising 44, 17, and 15 patients with LUAD and 26, 19, and 12 HCs, respectively, were used to evaluate efficacy. RESULTS: Fungal biodiversity and richness increased in patients with LUAD. At the phylum level, the abundance of Ascomycota decreased, while that of Basidiomycota increased in patients with LUAD. Candida and Saccharomyces were the dominant genera, with a reduction in Candida and an increase in Saccharomyces, Aspergillus, and Apiotrichum in patients with LUAD. Nineteen operational taxonomic unit markers were selected, and excellent performance in predicting LUAD was achieved (area under the curve (AUC) = 0.9350) using a random forest model with outcomes superior to those of four other algorithms. The AUCs of the Beijing, Suzhou, and Hainan validation cohorts were 0.9538, 0.9628, and 0.8833, respectively. CONCLUSIONS: For the first time, the gut fungal profiles of patients with LUAD were shown to represent potential non-invasive biomarkers for early-stage diagnosis.

Prediction model for hyperprogressive disease in patients with advanced solid tumors received immune-checkpoint inhibitors: a pan-cancer study.

BACKGROUND: Hyper progressive disease (HPD) describes the phenomenon that patients can't benefit from immunotherapy but cause rapid tumor progression. HPD is a particular phenomenon in immunotherapy but lacks prediction methods. Our study aims to screen the factors that may forecast HPD and provide a predictive model for risky stratifying. METHODS: We retrospectively reviewed advanced-stage tumor patients who received immune checkpoint inhibitors (ICI) in the General PLA Hospital. Subsequently, we calculated the tumor growth kinetics ratio (TGKr) and identified typical HPD patients. Differences analysis of clinical characteristics was performed, and a predictive binary classification model was constructed. RESULTS: 867 patients with complete image information were screened from more than 3000 patients who received ICI between January 2015 and January 2020. Among them, 36 patients were identified as HPD for TGKr > 2. After the propensity score matched, confounding factors were limited. Survival analysis revealed that the clinical outcome of HPD patients was significantly worse than non-HPD patients. Besides, we found that Body Mass Index (BMI), anemia, lymph node metastasis in non-draining areas, pancreatic metastasis, and whether combined with anti-angiogenesis or chemotherapy therapy were closely connected with the HPD incidence. Based on these risk factors, we constructed a visualised predicted nomogram model, and the Area Under Curve (AUC) is 0.850 in the train dataset, whereas 0.812 in the test dataset. CONCLUSION: We carried out a retrospective study for HPD based on real-world patients and constructed a clinically feasible and practical model for predicting HPD incidence, which could help oncologists to stratify risky patients and select treatment strategies.

Deciphering pathogenic cellular module at single-cell resolution in checkpoint inhibitor-related pneumonitis.

Checkpoint inhibitor pneumonitis (CIP) is the most common fatal immune-related adverse event; however, its pathophysiology remains largely unknown. Comprehensively dissecting the key cellular players and molecular pathways associated with CIP pathobiology is critical for precision diagnosis and develop novel therapy strategy of CIP. Herein, we performed a comprehensive single-cell transcriptome analysis to dissect the complexity of the immunological response in the bronchoalveolar lavage fluid (BALF) microenvironment. CIP was characterized by a dramatic accumulation of CXCL13+ T cells and hyperinflammatory CXCL9+ monocytes. T-cell receptor (TCR) analysis revealed that CXCL13+ T cells exhibited hyperexpanded- TCR clonotypes, and pseudotime analysis revealed a potential differentiation trajectory from naïve to cytotoxic effector status. Monocyte trajectories showed that LAMP3+ DCs derived from CXCL9+ monocytes possessed the potential to migrate from tumors to the BALF, whereas the differentiation trajectory to anti-inflammatory macrophages was blocked. Intercellular crosstalk analysis revealed the signaling pathways such as CXCL9/10/11-CXCR3, FASLG-FAS, and IFNGR1/2-IFNG were activated in CIP+ samples. We also proposed a novel immune signature with high diagnostic power to distinguish CIP+ from CIP- samples (AUC = 0.755). Our data highlighted key cellular players, signatures, and interactions involved in CIP pathogenesis.

Efficacy and safety of pembrolizumab versus sintilimab treatment in patients with advanced squamous lung cancer: A real-world study in China.

Importance: Both pembrolizumab and sintilimab have been approved by the Chinese State Drug Administration (NMPA) for the first-line treatment of patients with advanced squamous lung cancer. The differences of the two drugs in efficacy and safety are unclear. Objectives: To compare the real-world efficacy and safety of first-line treatments in patients with advanced squamous lung cancer. Materials and methods: This was a retrospective review of patients with advanced squamous carcinoma who received sintilimab or pembrolizumab in combination with chemotherapy as first-line therapy between June 2018 and April 2022 in the Chinese PLA Hospital. The primary objective was to compare the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) between the two groups. Secondary objectives were to compare the disease control rate (DCR) and to analyze adverse events (AEs) between the two groups. Results: A total of 164 patients were enrolled, including 63 patients (38.4%) in the sintilimab-combined chemotherapy group and 101 patients (61.6%) in the pembrolizumab-combined chemotherapy group. The ORR was 65.10% in the sintilimab group and 61.40% in the pembrolizumab group (P=0.634). The DCR was 92.10% and 92.10% in the sintilimab and pembrolizumab groups, respectively (P=0.991). The median PFS was 22.2 months for patients treated with sintilimab group compared with 16.5 months for patients treated with pembrolizumab group[hazard ratio (HR) = 0.743; 95% confidence interval (CI): 0.479-1.152; P = 0.599]. Patients treated with pembrolizumab did not achieve a median OS, and patients treated with sintilimab had a median OS of 30.7 months. In the sintilimab group, the incidence of all treatment-related adverse events (TRAEs) was 92.1% (58/63), and the incidence of grade 3-4 TRAEs of 42.9% (27/63). In the pembrolizumab group, the incidence of all TRAEs was 90.1% (91/101), and the incidence of grade 3-4 TRAEs was 37.6% (38/101). Conclusion: In the clinical treatment of Chinese patients with advanced squamous lung cancer, first-line treatment with sintilimab in combination with chemotherapy provided similar efficacy to pembrolizumab in combination with chemotherapy, and the treatment-related adverse effect profiles were comparable between the two groups, including similar rates of grade 3-4 and all adverse events.

Outcome of immune checkpoint inhibitors in patients with extensive-stage small-cell lung cancer and brain metastases.

Objectives: Brain metastases (BMs) are common in extensive-stage small-cell lung cancer (SCLC) and are underrepresented in pivotal clinical trials that demonstrate the efficacy of immune checkpoint inhibitors (ICIs). We conducted a retrospective analysis to assess the role of ICIs in BM lesions in less selected patients. Materials and methods: Patients with histologically confirmed extensive-stage SCLC who were treated with ICIs were included in this study. Objective response rates (ORRs) were compared between the with-BM and without-BM groups. Kaplan-Meier analysis and the log-rank test were used to evaluate and compare progression-free survival (PFS). The intracranial progression rate was estimated using the Fine-Gray competing risks model. Results: A total of 133 patients were included, 45 of whom started ICI treatment with BMs. In the whole cohort, the overall ORR was not significantly different for patients with and without BMs (p = 0.856). The median progression-free survival for patients with and without BMs was 6.43 months (95% CI: 4.70-8.17) and 4.37 months (95% CI: 3.71-5.04), respectively (p =0.054). In multivariate analysis, BM status was not associated with poorer PFS (p = 0.101). Our data showed that different failure patterns occurred between groups, with 7 patients (8.0%) without BM and 7 patients (15.6%) with BM having intracranial-only failure as the first site progression. The cumulative incidences of brain metastases at 6 and 12 months were 15.0% and 32.9% in the without-BM group and 46.2% and 59.0% in the BM group, respectively (Gray's p<0.0001). Conclusions: Although patients with BMs had a higher intracranial progression rate than patients without BMs, the presence of BMs was not significantly associated with a poorer ORR and PFS with ICI treatment in multivariate analysis.

Factors for incidence risk and prognosis of synchronous brain metastases in pulmonary large cell carcinoma patients: a population-based study.

BACKGROUND: Patients with pulmonary large cell carcinoma (LCC) have a high incidence of synchronous brain metastases (SBM) and a poor prognosis. Our study was to evaluate the predictive and prognostic value of the clinical characteristics of pulmonary LCC patients with SBM at initial diagnosis by utilizing the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: LCC patients, diagnosed from 2010 to 2019, were identified from the latest SEER database which was released in April 2022. Logistic regression and Cox regression were used to identify the predictive and prognostic factors for LCC patients with SBM. Propensity score matching (PSM) and Kaplan-Meier analyses were applied to assess different therapy modalities. RESULTS: A total of 1375 LCC patients were enrolled in this study and 216 (15.7%) of them had SBM at the initial diagnosis. The median overall survival (OS) of LCC patients with SBM was 4 months. Multivariate Cox regression identified age 60-79 (OR 0.57; 95% CI 0.41-0.78; p < 0.001), age ≥ 80 (OR 0.23; 95% CI 0.12-0.45; p < 0.001) and bone metastases (OR 1.75; 95% CI 1.22-2.51; p < 0.001) as significant independent predictors for developing SBM. Multivariable Cox regression revealed that age 60-79, T stage, bone metastases and chemotherapy were independent prognostic factor for OS. The surgery combined with chemotherapy and radiotherapy group, in which all patients were N0 stage and had no other site-specific metastases, exhibited the best median OS of 15 months. CONCLUSIONS: LCC patients with age < 60 or bone metastases were more likely to have SBM at initial diagnosis. Age, T stage, bone metastases and chemotherapy were independent prognostic factors for OS of LCC patients with SBM. Highly selected patients might achieve the best survival benefit from surgery combined with chemotherapy and radiotherapy.

Rechallenge of immunotherapy beyond progression in patients with extensive-stage small-cell lung cancer.

Background: Rechallenge of immunotherapy beyond progression (RIBP) has been demonstrably effective in a variety of cancers. Our study aims to investigate the efficacy of RIBP in small-cell lung cancer (SCLC) patients under real-world conditions. Methods: SCLC patients who experienced progressive disease after receiving programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors combined with chemotherapy from January 2017 to October 2021 were enrolled. The study population was divided into two groups: the RIBP group and the discontinuation of immunotherapy beyond progression (DIBP) group. Inverse propensity score weighting (IPSW) method was used to balance the clinical baseline characteristics. The short-term and long-term efficacy of the two groups was compared. Results: 100 SCLC patients were included in this study. There were 45 patients in the RIBP group and 55 patients in the DIBP group. The disease control rate (DCR) and the proportion of durable clinical benefit (DCB) were significantly higher in the RIBP group (DCR: 79.7% vs. 55.7%, p = 0.027; DCB: 40.7 vs. 20.7%, p = 0.025) after weighting. The median progressive-free survival (PFS) in the RIBP group was significantly longer than the DIBP group in the total population (mPFS: 4.8 vs. 2.4 months, p = 0.002), while there was no significant difference in overall survival (OS) of the two groups (mOS: 17.4 vs. 8.0 months, p = 0.098). In the weighted first-line initial immunotherapy subgroup, PFS and OS were significantly improved in the RIBP group (mPFS: 4.5 vs. 2.8 months, p = 0.017; mOS: 11.6 vs. 5.4 months, p = 0.028). After weighting, the RIBP group had a significantly longer PFS than the DIBP group in the SD/PD response to the initial immunotherapy subgroup (mPFS: 6.8 vs. 1.8 months, p = 0.026). Conclusion: Rechallenge of PD-1/PD-L1 inhibitors could bring benefits to SCLC patients, especially in the first-line initial immunotherapy subgroup or SD/PD response to the initial immunotherapy subgroup.

Rate and risk factors of recurrent immune checkpoint inhibitor-related pneumonitis in patients with lung cancer.

Background: Immune checkpoint inhibitors (ICIs) have become standard treatments for lung cancer patients. Immune checkpoint inhibitor-related pneumonitis (CIP) was the leading cause of death among ICIs-related adverse events (irAEs). Recurrent episodes of CIP without rechallenge of ICIs were reported in several cases and maybe a unique feature of CIP. Knowledge gaps remain regarding the rate and risk factors associated to CIP's recurrence. Methods: Data from 1,102 lung cancer patients receiving ICIs treatment between January 2016 and January 2021 were retrospectively collected and analyzed. CIP was diagnosed according to typical clinical features and/or new typical imaging changes. Recurrence of CIP (CIP-R) was defined as recurrent CIP after initial CIP improved after proper treatment. Logistic regression was used to assess risk factors associated with CIP recurrence. Results: Eighty out of 1,102 (7.26%) patients were diagnosed with CIP. Twenty of those 78 (25.64%) patients suffered CIP-R, 2 patients died and were therefore excluded from the denominator. The median onset of initial pneumonitis for patients without and with recurrence was 3.49 months [interquartile range (IQR), 0.26-31.93 months] and 2.78 months (IQR, 1.22-20.93 months), respectively (P=0.48). The median interval duration between initial CIP and CIP-R was 1.54 months (IQR, 0.98-16.70 months). Recurrence of CIP was more common in males (P=0.03), squamous histology (P=0.016), and in patients who received chest radiotherapy (P=0.049). The duration of prednisolone equivalent dose ≥15 mg/day in CIP-R was significantly shorter, at 3.71 weeks (2.86-6.57 weeks) compared with 6.36 weeks in those without recurrence (IQR, 3.12-9.86 weeks) (P=0.001). Non-squamous histology [odds ratio (OR), 0.182; 95% confidence interval (CI): 0.038-0.860; P=0.031] and prolonged administration of prednisolone equivalent dose ≥15 mg/day for more than 4 weeks (OR, 0.082; 95% CI: 0.02-0.342; P=0.001) were independently associated with a decreased odds of CIP-R development. Conclusions: CIP-R in a real-world lung cancer cohort is not uncommon, both in patients with and without rechallenge of ICIs. A duration of prednisolone equivalent dose ≥15 mg/day of at least 4 weeks during the tapering process of corticosteroids were recommend in patients with CIP.

Combined effect of tetracycline and copper ion on catalase activity of microorganisms during the biological phosphorus removal.

Microbial catalase is a key enzyme that affects the activities of microorganisms, and the catalase activity is affected by pollutants in wastewater. However, the effects of mixed pollutants on catalase activity are rather complex. To reveal the effect of the mixed pollutants on catalase activity of microorganisms, the present study investigated tetracycline and copper ion as pollutants during the biological phosphorus removal. Three concentration ratios of tetracycline and copper ion and 27 different concentration gradients were designed through the direct equipartition ray and the dilution factor method. The effects of mixed pollutants on the catalase activity of microorganisms were analyzed by the nonlinear regression equation and concentration-addition model. The results showed that, with the increase of actuation duration and the pollutant concentration, the inhibitory effects on the catalase activity of microorganisms obviously increased, which indicated that the inhibitory effects are concentration-dependent and time-dependent. The concentration-addition model suggested that when the ratio was 0.297, the combined effect of mixed pollutants on the activity of microbial catalase was mainly antagonism. When the ratio is 0.894, the combined effect was mainly additivity. When the ratio was 2.676, the combined effect transformed from synergism to additivity and antagonism. The study of the combined effects of tetracycline and copper ion on the catalase activity is helpful to further study their ecotoxicological mechanisms in wastewater treatment.

Association of the pretreatment lung immune prognostic index with survival outcomes in advanced gastric cancer patients treated with immune checkpoint inhibitors.

PURPOSE: Recently, the lung immune prognostic index (LIPI) is considered to be associated with outcomes in multiple solid tumors treated with immune checkpoint inhibitors (ICIs). We sought to determine whether LIPI has the same predictive effect in advanced gastric cancer (AGC). METHODS: The clinical data of a real-world, retrospective cohort of AGC patients treated with ICIs were retrospectively analyzed. Based on pre-treatment dNLR>3 and LDH>250 U/L, patients were assigned to one of three groups: good (0 factors), intermediate (1 factor), and poor (2 factors). The subjects were divided into two groups: LIPI-good and LIPI-intermediate/poor groups. Then, the disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were compared between these two groups. RESULTS: Finally, 120 patients were enrolled in the study, for both the good group and intermediate/poor group, DCR was 69.5% vs. 42.1% (P = 0.004). In a multivariate analysis, the LIPI-intermediate/poor group was associated with progressive disease, with an OR of 2.57 (95% CI, 1.05-6.30; P = 0.039). Patients with a good LIPI score had a longer survival compared with those with intermediate/poor scores, with an estimated median OS of 10.4 vs. 3.9 months (HR = 2.59, 95% CI: 1.69-3.98) and a median PFS of 7.7 vs. 2.1 months (HR=2.95, 95% CI:1.91-4.56). Multivariate analysis indicated that the intermediate/poor LIPI was independently associated with OS (HR: 2.32, 95% CI: 1.44-3.72) and PFS (HR: 2.48, 95% CI: 1.53-4.03). CONCLUSIONS: These data are the first to suggest that the pretreatment LIPI was well correlated with the outcomes of patients with AGC treated with ICIs.

Response Efficacy of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-Analysis.

BACKGROUND: Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have demonstrated promise in treating a variety of advanced cancers; however, little is known regarding their efficacy under various clinical situations, including different cancer types, treatment lines, drug combinations, and therapeutic regimens. METHODS: Published articles and conference abstracts (in English) in PubMed, Embase, the Cochrane Central Register, and Web of Science were searched up to February 10, 2020. The data were analyzed by the meta-analysis program in Stata. RESULTS: A total of 16,400 patients from 91 clinical trials were included in this meta-analysis. PD-1/PD-L1 inhibitors had a mean ORR of 19.56% (95% CI: 15.09-24.03), a median TTR of 2.05 months (m) (95%CI: 1.85-2.26), and a median DOR of 10.65 m (95%CI: 7.78-13.52). First-line treatment had a higher ORR (36.57% vs. 13.18%) but a shorter DOR (9.00 m vs. 13.42 m) compared to the second-line or subsequent treatment. Immunotherapy combined with chemotherapy (I+C) (46.81% [95%CI: 36.02-57.60]) had a statistically significant higher ORR compared to immunotherapy (I) (17.75% [95%CI: 14.47-21.03]) or immunotherapy combined with immunotherapy (I+O) (12.25% [95%CI: 1.56-22.94]), while I+C (8.09 m [95%CI: 6.86-9.32]) appeared to reduce the DOR compared to I (12.39 m [95%CI: 7.60-17.18]). PD-1 inhibitors were associated with better ORR (21.65% vs. 17.60%) and DOR (11.26 m vs. 10.03 m) compared to PD-L1 inhibitors. There were no significant differences in TTR under different situations. CONCLUSIONS: PD-1/PD-L1 inhibitors were promising immunotherapeutic agents to achieve satisfactory response efficacies with different cancer types, treatment lines, drug combinations, and therapeutic regimens. This comprehensive summary of the response efficacy of PD-1/PD-L1 inhibitors serves as a reference for clinicians to make evidence-based decisions.

Efficacy and safety of crizotinib plus bevacizumab in ALK/ROS-1/c-MET positive non-small cell lung cancer: an open-label, single-arm, prospective observational study.

BACKGROUND: Crizotinib is a tyrosine kinase inhibitor (TKI) effective in ALK/ROS-1/c-MET positive non-small cell lung cancer (NSCLC) patients. Bevacizumab is an antiangiogenic monoclonal antibody, and improves clinical benefit of NSCLC in combination with EGFR-TKIs or chemotherapy. However, the efficacy and safety of crizotinib plus bevacizumab in treating naive ALK/ROS-1/c-MET positive NSCLC patients have not been studied. METHODS: In this open-label, single-arm, prospective observational study, locally advanced or metastatic ALK rearrangement/ROS-1 fusion/c-MET amplification NSCLC patients were treated with crizotinib (250 mg orally twice daily) and bevacizumab (7.5 mg/kg intravenous every three weeks) until disease progression or intolerant toxicity or death. Primary end point was progressive free survival (PFS), secondary end points were duration of response (DOR), overall response rate (ORR), disease control rate (DCR) and safety. Patients receiving ≥1 cycle of treatment were evaluated. FINDINGS: Fourteen patients were eligible for analyzing between June 2016 and October 2017. There were 12 patients with ALK rearrangement, 1 patient with ROS-1 fusion, and 1 patient with c-MET amplification. The median follow-up time was 42.8 months. The median PFS and DOR of the patients with ALK rearrangement were 13.9 and 14.8 months respectively. Of the 12 patients, 7 gained partial response, 5 gained stable disease. The ORR and DCR were 58.3% and 100%. The PFS were 12.9 months and 1.9 months for patient with ROS-1 fusion or c-MET amplification. The most two common treatment-related adverse events were fatigue (28.6%) and rash (21.4%). 3 patients discontinued therapy because of liver damage or hemoptysis. INTERPRETATION: This study demonstrated that crizotinib plus bevacizumab showed benefit in treating naive ALK rearrangement NSCLC patients, and the toxicity was relatively tolerant. Our results suggested that crizotinib plus bevacizumab might be a promising treatment strategy in ALK/ROS-1/c-MET positive NSCLC patients.

Prognostic value of baseline and change in neutrophil-to-lymphocyte ratio for survival in advanced non-small cell lung cancer patients with poor performance status receiving PD-1 inhibitors.

BACKGROUND: Advanced non-small cell lung cancer (NSCLC) patients with poor performance status (PS) are likely to receive programmed cell death 1 (PD-1) inhibitors, despite limited evidence. The aim of the present study was to report the clinical outcomes and potential prognostic biomarkers in advanced NSCLC patients with poor PS receiving PD-1 inhibitors. METHODS: We conducted a retrospective study enrolling 101 advanced NSCLC patients from our hospital. Data of patients with poor PS 2-4 receiving PD-1 inhibitors were retrieved from medical records. Patients were stratified based on dichotomized baseline neutrophil-to-lymphocyte ratio (NLR), change in NLR (ΔNLR; 6 weeks post-treatment NLR minus baseline NLR), and their combination. The receiver-operating characteristic curve was used to assess the best cutoff for NLR. Multivariate Cox analysis was used to evaluate the prognostic value of NLR and ΔNLR for patients' survival. RESULTS: The optimal cutoff for NLR was 4.5. The median follow-up was 25.7 months, baseline NLR ≥4.5, and ΔNLR ≥0, which were independently and significantly associated with shorter overall survival (both P=0.002) and progression-free survival (P=0.004 for NLR and P<0.001 for ΔNLR). Furthermore, simultaneous elevation of the 2 factors was associated with worsened prognosis; patients with both NLR ≥4.5 and ΔNLR ≥0 had significantly increased risk of death [hazards ratio (HR): 10.79, 95% confidence interval (CI): 4.30-27.10] and disease progression (HR: 10.49, 95% CI: 4.39-25.09), compared with both low NLR and ΔNLR patients. Patients with either NLR ≥4.5 or ΔNLR ≥0 showed an intermediate risk for death (HR: 3.12, 95% CI: 1.35-7.21) and progression (HR: 3.45, 95% CI: 1.62-7.36). CONCLUSIONS: High baseline NLR and increased post-treatment NLR might aid in the stratification of high progression and death risk groups in advanced NSCLC patients with poor PS receiving PD-1 inhibitors.

Systemic Immune-Inflammation Index and Changes of Neutrophil-Lymphocyte Ratio as Prognostic Biomarkers for Patients With Pancreatic Cancer Treated With Immune Checkpoint Blockade.

The efficacy of current treatment regimens for pancreatic cancer (PC) remains unsatisfactory. In recent years, immune checkpoint blockade (ICB) therapy has shown promising anti-tumor outcomes in many malignancies, including PC. Inexpensive and readily available biomarkers which predict therapeutic responses and prognosis are in critical need. Systemic immune-inflammation index (SII) and neutrophil-lymphocyte ratio (NLR) are emerging predictors for prognosis of various tumors. We aim to investigate the prognostic significance of baseline SII, NLR, and their changes in PC patients treated with ICB. Our retrospective analysis included PC patients treated with ICB therapy in the Chinese PLA General Hospital. All demographic, biological, and clinical data were extracted from medical records. Relative changes of SII after two doses of ICB were defined as ΔSII% and calculated as (SIIafter 2 doses-SIIbaseline)/SIIbaseline, and so was the case for ΔNLR%. Overall survival (OS) and progression-free survival (PFS) were compared using Kaplan-Meier curves. The prognostic significance of baseline SII, NLR, and their changes was assessed in univariate and multivariate analyses using the Cox proportional hazard regression model. In total, 122 patients with PC treated with ICB were included in the present analysis. Elevated baseline SII (HR=3.28; 95% CI:1.98-5.27; P=0.03) and ΔNLR% (HR=2.21; 95% CI:1.03-4.74; P=0.04) were significantly correlated with an increased risk of death. For PC patients receiving ICB combined with chemotherapies or radiotherapies as the first-line treatment, increased baseline SII was a negative predictor for both OS (HR=8.06; 95% CI:1.71-37.86; P=0.01) and PFS (HR=2.84; 95%CI:1.37-10.38; P=0.04). Our study reveals the prognostic value of baseline SII and NLR changes in PC patients receiving ICB therapy. The clinical utility of these prognostic biomarkers needs to be further studied in prospective studies.

The Synergistic Effect of PARP Inhibitors and Immune Checkpoint Inhibitors.

Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated great promise for treating cancers with homologous recombination (HR) defects, such as germline BRCA1/2 mutation. Further studies suggest that PARP inhibitors (PARPi) can also exhibit efficacy in HR-competent cancers, by amplifying the DNA damage and inducing immunogenic cell death, and PARPi lead to increasing tumor neoantigen, upregulation of interferons and PD-L1, and modulation of the tumor microenvironment, which may facilitate a more profound antitumor immune response. Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 or CTLA-4 have achieved impressive success in the treatment of different malignancies. However, only a subset of populations derive clinical benefit, and the biomarkers and resistance mechanisms are not fully understood. Therefore, given that PARPi could potentiate the therapeutic effect of ICIs, PARPi combined with ICIs are becoming an alternative for patients who cannot benefit from ICI monotherapy. In this review, we focus on the mechanisms and immune role of PARPi and discuss the rationale and clinical studies of this combined regimen.

Efficacy and safety of anti-PD-1-based therapy in combination with PARP inhibitors for patients with advanced solid tumors in a real-world setting.

BACKGROUND: Rationale exists for combining immune checkpoint inhibitors and PARP inhibitors (PARPi), and results of clinical trials in ovarian cancer are promising, but data in other cancers are limited. METHOD: Efficacy and safety of PARPi/anti-PD-1 in advanced solid tumors were retrospectively analyzed. The efficacy measures included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). RESULTS: This retrospective study included data from 40 patients. The ORR was 27.5% (95% CI, 13.0-42.0%), with a DCR of 85.0% (95% CI, 73.4-96.6%). Except four patients in first-line treatment (three with PR and one with SD), the ORR of ≥second-line treatment, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) was 22.2%, 23.1% and 28.6%, and the DCR was 83.3%, 84.6% and 71.4%, separately. The median PFS of all patients, ≥second-line treatment, NSCLC and SCLC was 4.6 m, 4.2 m, 4.5 m and 3.7 m. The median OS was 9.4 m, 11.4 m, 12.7 m and 5.4 m, respectively. Multivariable analysis revealed that BRCA1/2 mutation was positively correlated with ORR (P = 0.008), and LDH≥250U/L was negatively correlated with lowered DCR (P = 0.018), while lymphocyte number, ECOG and LDH significantly influenced both PFS and OS. We found that the possible resistant mechanisms were sarcomatous degeneration and secondary mutation, including BRCA2 truncation mutation, A2M, JAK1,T790M, KEAP1 and mTOR mutation. 37.5% patients had ≥grade 3 adverse events. CONCLUSION: PARPi/anti-PD-1 is an effective and tolerable method for patients with advanced solid tumors, and BRCA1/2 is a potential biomarker.

Anti-PD-1/L1 plus anti-angiogenesis therapy as second-line or later treatment in advanced lung adenocarcinoma.

PURPOSE: Anti-programmed cell death protein 1 or its ligand (anti-PD-1/L1) monotherapy has become the standard second-line treatment in advanced lung adenocarcinoma. However, the strategy treatment of anti-PD-1/L1 plus anti-angiogenesis therapy has not been evaluated. We conducted this retrospective study to assess the efficacy and safety of anti-PD-1/L1 plus anti-angiogenesis therapy in patients with advanced lung adenocarcinoma in the second-line or later setting. METHODS: Patients with advanced lung adenocarcinoma who received anti-PD-1/L1 plus anti-angiogenesis therapy or anti-PD-1/L1 monotherapy in the second-line or later treatment from March 2015 to May 2019 in PLA General Hospital were retrospectively analyzed. The progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety were assessed. Multivariate analyses of PFS and OS were performed with Cox proportional hazard regression models. RESULTS: Seventy-four patients were included in our study. Twenty-five patients were treated with anti-PD-1/L1 plus anti-angiogenesis therapy, and forty-nine patients were treated with anti-PD-1/L1 monotherapy. The disease control rate (DCR) was higher in the anti-PD-1/L1 plus anti-angiogenesis group than in the anti-PD-1/L1 monotherapy group (92.0% vs. 46.9%, P = 0.0004). The median progression-free survival (PFS) was 5.1 months vs. 2.0 months (HR 0.551 [95% confidence interval 0.337-0.902], P = 0.002) and median overall survival (OS) was 14.3 months vs. 8.4 months (HR 0.549 [95% CI 0.305-0.990], P = 0.046), respectively. Multivariate Cox proportional hazard regression models showed that anti-PD-1/L1 plus anti-angiogenesis group had prolonged PFS (HR 0.541 [95% CI 0.298-0.981], P = 0.033). The incidences of grade 3/4 adverse events were 12% (3/25) in anti-PD-1/L1 plus anti-angiogenesis group and 6% (3/49) in anti-PD-1/L1 monotherapy group. CONCLUSION: Compared with anti-PD-1/L1 monotherapy, anti-PD-1/L1 plus anti-angiogenesis therapy could significantly improve the clinical response and bring longer PFS and OS in patients with advanced lung adenocarcinoma who had failed first-line or later treatment. Further prospective studies are needed to validate our findings.