Comparison of efficacy and safety between PD-1 inhibitors and PD-L1 inhibitors plus platinum-etoposide as first-line treatment for extensive-stage small-cell lung cancer: a multicenter, real-world analysis.

BACKGROUND: Immunotherapy in combination with platinum-etoposide (EP) chemotherapy has been approved as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC). However, real-world (RW) data regarding the use of immune checkpoint inhibitors (ICIs) in ES-SCLC are lacking. We aimed to assess the differences between programmed death protein 1 (PD-1) inhibitors and programmed death ligand 1 (PD-L1) inhibitors, both in conjunction with EP chemotherapy, as first-line treatment for ES SCLC. METHODS: We conducted a real-world, multicenter, retrospective cohort, controlled study to compare the prognosis, efficacy, and safety of PD-1 and PD-L1 inhibitors in ES-SCLC patients when used along with chemotherapy. Each patient received up to six cycles of etoposide, carboplatin, or cisplatin combined with ICI drugs, including PD-1 and PD-L1 inhibitors. The primary endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS). The secondary endpoints were the investigator-assessed objective response rate (ORR) and disease control rate (DCR) according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). RESULTS: Between January 2017 and December 2021, 194 patients with ES-SCLC from three clinical centers in a PLA general hospital were included in our study, including 93 patients in the PD-1 group and 101 patients in the PD-L1 group. At the time of data cutoff, progression-free survival in the PD-1 group (median PFS, 6.8 months; 95% CI, 5.3-8.1) was similar to that in the PD-L1 group (median PFS, 6.4 months; 95% CI, 5.5-7.5); the stratified hazard ratio for PFS was 1.12 (95% CI, 0.83-1.53; P = 0.452). The median OS was similar in the PD-1 and PD-L1 groups (15.8 m vs. 17.7 m, P = 0.566); the hazard ratio was 0.90 (95% CI, 0.62-1.30, P = 0.566). The two groups had comparable investigator-assessed confirmed objective response rates (ORR) (76.3% vs. 76.2%). Adverse effect (AE)-related discontinuation occurred in 4 (4.3%) patients in the PD-1 group and 2 (2.0%) patients in the PD-L1 group. Deaths due to AEs of any cause occurred in 2 (2.2%) patients in the PD-1 inhibitor group and 1 (1.0%) patient in the PD-L1 inhibitor group. CONCLUSIONS: Our research revealed that there were no significant differences in efficacy or prognosis between PD-1 inhibitor + EP chemotherapy and PD-L1 inhibitor + EP chemotherapy. The two groups seemed to have comparable safety profiles, but the number of discontinuation or death events was too small to draw a firm conclusion.

Pralsetinib-associated pneumonia in RET fusion-positive non-small cell lung cancer.

OBJECTIVE: Oncogenic alternation in RET is one of the important targets of non-small cell lung cancer (NSCLC). Pralsetinib has shown great efficacy in RET fusion-positive NSCLC, but a series of adverse reactions will inevitably occur in the meantime. We aimed to explore the clinical characteristics of patients with pneumonia and recognition it in early stage, so patients could longer benefit from pralsetinib. METHODS: This is a multicenter, retrospective study. RET fusion-positive advanced NSCLC patients who developed pneumonia during pralsetinib treatment from January 2020 to December 2022 were included. Clinical data, time to onset of pneumonia, methods of pneumonia diagnosis, treatment with pneumonia, prognosis of pneumonia, and the effect of pneumonia on the efficacy of pralsetinib. RESULTS: A total of 8 patients with pneumonia were included in the study, most of which were non-smoking female patients and the main fusion gene was KIF5B (87.5%), which was consistent with the general characteristics of RET fusion population. The median occurrence time of pralsetinib-associated pneumonia was 2.15 (range 1.1-6.63) months. All patients were infected by opportunistic pathogens, and the most common pathogen was human herpesviruses and pneumospora yerbii. Fever was always the first symptom, and timely anti-infective treatment including antibiotics, antiviral drugs, and antifungal drugs was effective. Until February 28, 2023, the median follow-up time was 18.7 months, the mean PFS of patients was 17.4 months, and the median PFS was not reached. Fortunately, patients who restarted pralsetinib after infection control continued to benefit. CONCLUSIONS: Opportunistic infection may be a unique adverse effect of pralsetinib. During the treatment of pralsetinib, we should be vigilant about the occurrence of pneumonia and achieve early recognition and timely treatment.

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.

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.

Programmed Cell Death Protein 1 Inhibitor-Mediated Peripheral Neuropathy.

The discovery of immune checkpoint inhibitors (ICIs) has revolutionized the model of antitumor therapy. With the continuous deepening of the research on the mechanism of immunotherapy, ICIs, such as programmed cell death protein 1 (PD-1), programmed death-ligand 1 inhibitors and cytotoxic T lymphocyte-associated protein 4 inhibitors, have been widely used in a variety of tumors. Nevertheless, the use of ICI can also lead to a series of immune-related adverse events. Common immune-related adverse events include gastrointestinal toxicity, pulmonary toxicity, endocrine system toxicity, and skin toxicity. Neurologic adverse events are relatively rare, but they seriously affect the quality of life and shorten the survival time of patients. This article reports cases of peripheral neuropathy mediated by PD-1 inhibitors and retrieves the relevant literatures at home and abroad to summarize the neurotoxicity caused by PD-1 inhibitors, so as to strengthen the awareness of clinicians and patients on neurologic adverse reactions and mitigate potential adverse effects of implemented therapies.

The efficacy of immune checkpoint inhibitors in advanced EGFR-Mutated non-small cell lung cancer after resistance to EGFR-TKIs: Real-World evidence from a multicenter retrospective study.

Background: The efficacy of immune checkpoint inhibitors (ICIs) in pretreated EGFR-mutated non-small cell lung cancer (NSCLC) patients is controversial. We conducted this multicenter retrospective study to examine the efficacy of ICIs in a real world setting. Patients and methods: We collected 116 consecutive NSCLC patients with sensitive EGFR mutations who received ICIs alone or in combination after failure to respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs), and 99 patients were included for final analysis. The impacts of ICIs on the patients' objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were assessed. The relationships between outcomes and clinical characteristics were analyzed. Results: The ORR in patients with target lesions was 31.25% (95% CI: 22.18-41.52), and the DCR in all patients was 65.66% (95% CI: 55.44-74.91). The overall median PFS was 5.0 months (95% CI: 3.0-6.6), and the median OS was 15.9 months (95% CI: 10.8-23.8). The outcomes were better in patients receiving combination therapy with ECOG scores of 0-1 and no more than 2 lines of prior therapy, with a median PFS of 7.4 months (95% CI: 3.0-13.3) and a median OS of 29.0 months (95% CI: 11.7-NE). Primary EGFR mutation type and treatment mode were found to have a notable impact on clinical outcomes. Both median PFS and OS in patients with EGFR L858R mutation were significantly shorter than those in patients with EGFR exon 19 deletion (19del) (PFS: 2.5 versus 6.7 months, HR: 1.80, log-rank P=0.011; OS: 9.8 versus 26.9 months, HR: 2.48, log-rank P=0.002). Patients receiving combination therapy had notably longer median PFS and OS than those receiving monotherapy (PFS: 5.2 versus 3.0 months, HR: 0.54, log-rank P=0.020; OS: 19.0 versus 7.4 months, HR: 0.46, log-rank P=0.009). Conclusions: Our study suggests that ICI-based combination therapy is a potential strategy for EGFR-mutated NSCLC patients after EGFR-TKI failure. The efficacy may differ according to EGFR subtypes.

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.

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.

Efficacy and Safety of the Biosimilar IBI301 Plus Standard CHOP (I-CHOP) in Comparison With Rituximab Plus CHOP (R-CHOP) in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): A Randomized, Double-Blind, Parallel-Group, Phase 3 Trial.

INTRODUCTION: Patients with diffuse large B-cell lymphoma (DLBCL) have limited access to rituximab. IBI301 is a recombinant chimeric murine/human anti-CD20 monoclonal antibody and is a candidate biosimilar to rituximab. This study aimed to assess the therapeutic equivalence of IBI301 and rituximab in previously untreated patients with diffuse large B-cell lymphoma (DLBCL). METHODS: This multicenter, randomized, double-blind, parallel-group, phase 3 trial compared IBI301 and rituximab, both plus the chemotherapy of doxorubicin, cyclophosphamide, vindesine, and prednisone (CHOP), was conducted in 68 centers across China. Eligible patients with untreated CD20 positive (CD20+) DLBCL randomly received IBI301 (375 mg/m2) plus the standard CHOP or rituximab (375 mg/m2) plus the standard CHOP for six cycles of a 21-day cycle. The primary end point was the overall remission rate (ORR). Efficacy equivalence was defined if 95% CIs for the ORR difference between the two groups were within a ± 12.0% margin. RESULTS: Between August 22, 2016, and September 5, 2018, 419 patients were randomly allocated into the IBI301 group (N = 209) and rituximab group (N = 210). In the full analysis set, the ORR was 89.9% and 93.8% in the IBI301 and rituximab groups, respectively, and the ORR difference was -3.9% (95% CI - 9.1%-1.3%), falling within a ± 12.0% margin. The occurrences of treatment-emergent adverse events (TEAEs) (100% vs. 99.0%) and AEs of grade ≥ 3 (87.1% vs. 83.3%) were similar in the two groups (P > 0.05). CONCLUSIONS: IBI301 had a non-inferiority efficacy and a comparable safety compared with rituximab. IBI301 plus CHOP could be suggested as a candidate treatment regimen for untreated patients with CD20+ DLBCL. TRIAL REGISTRATION: This trial is registered on ClinicalTrials.gov (NCT02867566).

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.

Pretreatment hemoglobin level as a predictor to evaluate the efficacy of immune checkpoint inhibitors in patients with advanced non-small cell lung cancer.

BACKGROUND: Targeting immune checkpoints represents an immense breakthrough in cancer therapeutics. The prognostic value of hemoglobin (Hb) has been investigated in many malignancies including non-small cell lung cancer (NSCLC). However, the prognostic impact of pretreatment Hb count for immune checkpoint inhibitors (ICIs) in advanced NSCLC patients remains unclear. METHODS: A total of 310 late-stage NSCLC patients who received ICI therapies between January 2015 and March 2019 were prospectively enrolled. We used a propensity score-matched cohort analysis for this study. Patients' clinicopathological characteristics and pretreatment Hb concentration were assessed against the progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method and Cox proportional hazards regression. RESULTS: A propensity score (PS)-matched cohort analysis was applied to adjust for potential bias and to create two comparable groups according to patients' clinicopathological characteristics. The patients with normal baseline Hb levels (⩾110 g/L) had significantly longer PFS [median: 10.0 versus 4.0 months, hazard ratio (HR): 0.63, 95% confidence interval (CI): 0.46-0.86; p = 0.001] and OS [median: 17.6 versus 10.5 months, HR (95% CI): 0.56 (0.40-0.79); p < 0.001] than those with decreased Hb count (<110 g/L) in a PS-matched cohort (n = 255). For patients with normal pretreatment Hb levels, ICI combination therapy was significantly associated with better PFS [median: 11.1 versus 8.0 months, HR (95% CI): 0.74 (0.50-1.06); p = 0.09] and OS [median: 26.0 versus 12.9 months, HR (95% CI): 0.56 (0.37-0.86); p = 0.008] than monotherapy, but there was no such trend for patients with decreased baseline Hb levels. CONCLUSION: Our findings showed that normal pretreatment Hb count served as a favorable prognostic marker in advanced NSCLC patients treated with ICIs, representing an economical biomarker with readily measuring performance among all reported ones.

Association of the Pretreatment Lung Immune Prognostic Index with Survival Outcomes in Advanced Hepatocellular Carcinoma Patients Treated with PD-1 Inhibitors.

PURPOSE: At present, there are no validated biomarkers that can predict whether patients with advanced hepatocellular carcinoma (aHCC) are likely to benefit from anti-PD-1 therapy. We aimed to determine whether lung immune prognostic index (LIPI) is associated with outcomes in patients with aHCC treated with PD-1 inhibitors. PATIENTS AND METHODS: Patients undergoing initial treatment with PD-1 inhibitors for aHCC at a single center from January 1, 2015 to August 31, 2019 were included. The patients were stratified according to pretreatment LIPI based on a derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) ≥ 3 and a lactate dehydrogenase (LDH) level ≥ the upper limit of normal (ULN). Kaplan-Meier analysis and the Log rank test were used to calculate and compare survival between good LIPI and intermediate/poor LIPI scores. The prognostic values of LIPI for survival and disease control rate were evaluated using Cox proportional hazard and logistic regression models, respectively. RESULTS: Of the 108 study patients, 53 (49%) had a good LIPI (dNLR < 3 and LDH normal) and 55 (51%) had intermediate/poor LIPI (dNLR ≥ 3 or/and LDH ≥ ULN). With a median follow-up of 12.4 months, intermediate/poor LIPI was independently associated with shorter overall survival (OS) (hazard ratio [HR] 4.00; 95% CI, 2.00-8.03) and progression-free survival (PFS) (HR 2.65; 95% CI, 1.61-4.37). The median OS for good and intermediate/poor LIPI was not reached and was 13.7 (95% CI, 8.2-19.1) months, respectively, and the median PFS was 10.9 (95% CI, 8.9-12.9) and 4.0 (95% CI, 2.2-5.8) months (both P < 0.001), respectively. CONCLUSION: Pretreatment LIPI combined with a dNLR ≥ 3 and/or LDH ≥ ULN is associated with poor outcomes in patients with aHCC treated with PD-1 inhibitors. Further validation in large, prospective studies are warranted.

Dynamics of Serum Tumor Markers Can Serve as a Prognostic Biomarker for Chinese Advanced Non-small Cell Lung Cancer Patients Treated With Immune Checkpoint Inhibitors.

Background: Serum tumor markers carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), cytokeratin 19 fragment (CYFRA21-1) and squamous-cell carcinoma-related antigen (SCC-Ag) are routinely used for monitoring the response to chemotherapy or targeted therapy in advanced-stage non-small cell lung cancer (NSCLC), however their role in immunotherapy remains unclear. The aim of this study was to investigate whether dynamics of these serum markers were associated with the efficacy and prognosis of Chinese late-stage NSCLC patients treated with programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors. Methods: We initiated a longitudinal prospective study on advanced NSCLC patients treated with PD-1/PD-L1 inhibitors in Chinese PLA general hospital (Beijing, China). Blood samples of baseline and after 6 weeks' treatment were collected. CT scan were used by all patients to evaluate treatment efficacy according to RECIST 1.1. Serum tumor markers levels were measured with an electrochemical luminescence for SCC-Ag and with a chemiluminescent microparticle immunoassay for serum CEA, CA125, and CYFRA21-1. At least 20% decreases of the biomarkers from baseline were considered as meaningful improvements after 6 weeks of treatment with immune checkpoint inhibitors (ICIs). Optimization-based method was used to balance baseline covariates between different groups. Associations between serum tumor biomarker improvements and objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were analyzed. Results: A total of 308 Chinese patients with advanced NSCLC were enrolled in the study. After balancing baseline covariates, patients with meaningful improvements in <2 out of 4 biomarkers (CEA, CA125, CYFRA21-1, and SCC-Ag) was ended up with lower ORR (0.08 vs. 0.35, p < 0.001), shorten PFS (median: 5.4 vs. 12.5 months, p < 0.001), and OS (median: 11.7 vs. 25.6 months, p < 0.001) in the total population. Subgroup analysis of patients with adenocarcinoma revealed that patients with meaningful improvements in <2 out of 4 biomarkers had significant lower ORR (0.06 vs. 0.36, p < 0.001), shorten PFS (median: 4.1 vs. 11.9 months, p < 0.001), and OS (median: 11.9 vs. 24.2 months, p < 0.001). So as in patients with squamous cell carcinoma, meaningful improvements in at least 2 out of 4 biomarkers were linked to better ORR (0.42 vs. 0.08, p = 0.014), longer PFS (median: 13.1 vs. 5.6 months, p = 0.001), and OS (median: 25.6 vs. 10.9 months, p = 0.06). Conclusions: The dynamic change of CEA, CA125, CYFRA21-1, and SCC-Ag from baseline have prognostic value for late-stage NSCLC patients treated with PD-1/PD-L1 inhibitors. Decrease of associated biomarkers serum levels were associated with favorable clinical outcomes.

Association of immune-related pneumonitis with the efficacy of PD-1/PD-L1 inhibitors in non-small cell lung cancer.

BACKGROUND: Cutaneous adverse events (AEs) have been positively associated with immune checkpoint inhibitor (ICI) efficacy in patients with melanoma, but little is known regarding the association between checkpoint inhibitor pneumonitis (CIP) and programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) inhibitor efficacy in non-small cell lung cancer (NSCLC). METHODS: A single-institution, retrospective medical record review of patients with advanced or recurrent NSCLC who were treated with PD-1/PD-L1 inhibitors between 1 September 2015 and 1 June 2019 was conducted. A total of 276 NSCLC patients with or without immune-related pneumonitis who received at least one dose of ICIs and had at least one follow-up visit were identified. Kaplan-Meier curves of the progression-free survival (PFS) of patients stratified according to immune-related pneumonitis development were evaluated with the log-rank test as a preplanned primary objective. Multivariate analysis of PFS was performed with Cox proportional hazard regression models. RESULTS: In the cohort of 276 patients, 42 patients developed CIP attributed to PD-1/PD-L1 inhibitors. Survival analysis showed that the overall response rate was significantly higher in patients with CIP than in those without CIP (61.90% versus 29.91%, respectively, p < 0.01), and that CIP development was significantly associated with increased PFS (45.80 weeks versus 21.15 weeks, respectively, p < 0.01). Additionally, 16-week landmark analysis produced the same results. Similarly, subgroup analysis of PD-1 inhibitor-treated, nivolumab-treated, and pembrolizumab-treated groups also revealed that CIP increased survival in NSCLC patients. Additionally, grade 1-2 pneumonitis showed an association with increased ICI efficacy in NSCLC; however, grade 3-4 pneumonitis did not. In addition, only two of the four pneumonitis radiological subtypes showed associations with increased ICI efficacy in NSCLC. CONCLUSION: CIP is associated with enhanced PD-1/PD-L1 inhibitor efficacy in NSCLC patients. Grade 1-2 pneumonitis and the radiological features of hypersensitivity and cryptogenic organizing pneumonia (COP) may be signs of enhanced ICI efficacy. However, further studies with larger numbers of patients and longer follow-up times are needed to validate our findings.

Tumor Mutation Burden as a Potential Biomarker for PD-1/PD-L1 Inhibition in Advanced Non-small Cell Lung Cancer.

BACKGROUND: Immunotherapy based on programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors has revolutionized the treatment of non-small cell lung cancer (NSCLC). Patients with high PD-L1 expression or DNA mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) cancer are reported to benefit from PD-1/PD-L1 inhibitors. However, additional biomarkers are needed, and whether tumor mutation burden (TMB) can be a robust biomarker or not is still controversial. OBJECTIVE: We conducted this study to assess TMB as a biomarker for PD-1/PD-L1 inhibitor treatment in advanced NSCLC patients in a real-world setting. PATIENTS AND METHODS: Chinese NSCLC patients who received a PD-1/PD-L1 inhibitor at the People's Liberation Army General Hospital and who had pathological tissues available for TMB were retrospectively analyzed. Demographic and clinical information were evaluated. Targeted next-generation sequencing (NGS) of the tumor tissue was performed. The relationship between TMB and clinical benefit was assessed. RESULTS: Thirty-four patients treated with PD-1/PD-L1 inhibitors between March 2015 and January 2019 were analyzed. The TMB was greater in patients with complete response (CR)/partial response (PR) versus stable disease (SD) versus progressive disease (PD) (median 11 vs. 9.7 vs. 4.2 mutations/megabase [Mb]; p = 0.049). The median progression-free survival was 10.6 months in the TMB-high group versus 3.9 months in the TMB-low group (cut-off value = 10 mutations/Mb) (hazard ratio [HR] 0.26 [95% confidence interval 0.12-0.57], p = 0.0007). The median overall survival was 21.0 months and 11.6 months (HR 0.37 [0.17-0.81], p = 0.0126) in the TMB-high group and the TMB-low group, respectively. The disease control rate was higher in the TMB-high group than in the TMB-low group (100% vs. 70%, p = 0.024). CONCLUSIONS: High TMB was associated with a better outcome in advanced NSCLC patients who received PD-1/PD-L1 inhibitors in China. Further studies are needed to confirm our findings.

Anti-PD-1 Therapy plus Chemotherapy and/or Bevacizumab as Second Line or later Treatment for Patients with Advanced Non-Small Cell Lung Cancer.

Immune checkpoint inhibitor combination therapy exhibited outstanding efficacy in first line setting for advanced non-small cell lung cancer (aNSCLC) patients. However, whether PD-1 inhibitor combined treatment is effective in second line or later setting remains unknown. Therefore, we retrospectively evaluated the efficacy of combined therapy of PD-1 inhibitor with chemotherapy and/or bevacizumab compared to PD-1 inhibitor alone for aNSCLC patients in second line or later setting. Patients with aNSCLC who have received anti-PD-1 based therapy between 2015 and 2017 were screened, and 55 patients were ultimately included and divided into the monotherapy group (N=33) and the combination group (N=22). Patients treated with combination therapy exhibited superior PFS versus those treated with monotherapy (median PFS, 7.5 months vs 3.3 months; hazard ratio 0.28; 95% CI, 0.14-0.56; P<0.001). Objective response rate and disease control rate were 31.8% (7/22) and 95.5% (21/22) in the combination group and 10.0% (3/30) and 46.7% (14/30) in the monotherapy group, respectively (ORR, P=0.075; DCR, P<0.001). Five patients (22.7%) experienced grade 3-4 adverse events in the combination group and two patients (6.1%) in the monotherapy group. Taken together, our results indicated that for NSCLC patients who had failed on the first-line or later treatment, PD-1 inhibitor in combination with chemotherapy and/or bevacizumab might be a favorable treatment option. These findings warrant further validation in prospective studies.

Immune checkpoint inhibitors combined with chemotherapy for the treatment of advanced pancreatic cancer patients.

Immune checkpoint inhibitors (ICIs) represent a major breakthrough for cancer treatment. However, evidence regarding the use of ICIs in pancreatic cancer (PC) remained scarce. To assess the efficacy and safety of ICIs plus chemotherapy, patients with advanced PC were retrospectively recruited and were treated with either chemotherapy alone or chemotherapy plus ICIs. Patients previously treated with any agents targeting T-cell co-stimulation or checkpoint pathways were excluded. The primary outcome was overall survival (OS). The secondary outcomes were progression-free survival (PFS), overall response rate (ORR) and safety. In total, 58 patients were included (combination, n = 22; chemotherapy, n = 36). The combination group showed a significantly longer OS than the chemotherapy group [median, 18.1 vs 6.1 months, hazard ratio (HR) 0.46 (0.23-0.90), P = 0.021]. The median PFSs were 3.2 months in the combination group and 2.0 months in the chemotherapy group [HR 0.57 (0.32-0.99), P = 0.041]. The combination group and the chemotherapy group had similar ORRs (18.2% vs 19.4%, P = 0.906). All patients who achieved a partial response received a doublet chemotherapy regimen regardless of co-treatment with ICIs. Grade 3 or higher adverse events occurred in 31.8% of the patients in the combination group and in 16.9% of those receiving chemotherapy. Although the incidence of serious treatment-related adverse events was higher in the combination group than in the chemotherapy group, the difference was not significant (P = 0.183). Our findings suggest that the combination of ICIs with chemotherapy is both effective and tolerable for advanced PC. ICIs combined with a doublet chemotherapy regimen might be a preferable choice.