ABSTRACT
Chemoimmunotherapy has evolved as a standard treatment for advanced non-small cell lung cancer (aNSCLC). However, inevitable drug resistance has limited its efficacy, highlighting the urgent need for biomarkers of chemoimmunotherapy. A three-phase strategy to discover, verify, and validate longitudinal predictive autoantibodies (AAbs) for aNSCLC before and after chemoimmunotherapy was employed. A total of 528 plasma samples from 267 aNSCLC patients before and after anti-PD1 immunotherapy were collected, plus 30 independent formalin-fixed paraffin-embedded samples. Candidate AAbs were firstly selected using a HuProt high-density microarray containing 21,000 proteins in the discovery phase, followed by validation using an aNSCLC-focused microarray. Longitudinal predictive AAbs were chosen for ELISA based on responders versus non-responders comparison and progression-free survival (PFS) survival analysis. Prognostic markers were also validated using immunohistochemistry and publicly available immunotherapy datasets. We identified and validated a panel of two AAbs (MAX and DHX29) as pre-treatment biomarkers and another panel of two AAbs (MAX and TAPBP) as on-treatment predictive markers in aNSCLC patients undergoing chemoimmunotherapy. All three AAbs exhibited a positive correlation with early responses and PFS (p < 0.05). The kinetics of MAX AAb showed an increasing trend in responders (p < 0.05) and a tendency to initially increase and then decrease in non-responders (p < 0.05). Importantly, MAX protein and mRNA levels effectively discriminated PFS (p < 0.05) in aNSCLC patients treated with immunotherapy. Our results present a longitudinal analysis of changes in prognostic AAbs in aNSCLC patients undergoing chemoimmunotherapy.
Subject(s)
Autoantibodies , Carcinoma, Non-Small-Cell Lung , Immunotherapy , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Female , Male , Autoantibodies/blood , Middle Aged , Aged , Prognosis , Biomarkers, Tumor , AdultABSTRACT
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, although disease stratification using in-depth plasma proteomics has not been performed to date. By measuring more than 1000 proteins in the plasma of 147 DLBCL patients using data-independent acquisition mass spectrometry and antibody array, DLBCL patients were classified into four proteomic subtypes (PS-I-IV). Patients with the PS-IV subtype and worst prognosis had increased levels of proteins involved in inflammation, including a high expression of metalloproteinase inhibitor-1 (TIMP-1) that was associated with poor survival across two validation cohorts (n = 180). Notably, the combination of TIMP-1 with the international prognostic index (IPI) identified 64.00% to 88.24% of relapsed and 65.00% to 80.49% of deceased patients in the discovery and two validation cohorts, which represents a 24.00% to 41.67% and 20.00% to 31.70% improvement compared to the IPI score alone, respectively. Taken together, we demonstrate that DLBCL heterogeneity is reflected in the plasma proteome and that TIMP-1, together with the IPI, could improve the prognostic stratification of patients.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Tissue Inhibitor of Metalloproteinase-1 , Humans , Prognosis , Proteomics , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/pathology , Biomarkers , Retrospective StudiesABSTRACT
BACKGROUND: R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is a standard first-line treatment for diffuse large B-cell lymphoma (DLBCL). However, 20%-40% of patients survive less than 5 years. Novel prognostic biomarkers remain in demand. METHODS: Baseline plasma autoantibodies (AAbs) were assessed in 336 DLBCLs. In the discovery phase (n = 20), a high-density antigen microarray (â¼21,000 proteins) was used to expound AAb profiles. In the verification phase (n = 181), with a DLBCL-focused microarray, comparative results based on event-free survival at 24 months (EFS24) and lasso Cox regression models of progression-free survival (PFS) and overall survival (OS) were integrated to identify potential biomarkers. They were further validated by enzyme-linked immunosorbent assay in validation phase 1 (n = 135) and a dynamic cohort (n = 12). In validation phase 2, a two-AAb-based risk score was established. They were further validated in an immunohistochemistry cohort (n = 55) and four independent Gene Expression Omnibus datasets (n = 1598). RESULTS: Four AAbs (CREB1, N4BP1, UBAP2, and DEAF1) were identified that showed associations with EFS24 status (p < .05) and superior PFS and OS (p < .05). A novel risk score model based on CREB1 and N4BP1 AAbs was developed to predict PFS with areas under the curve of 0.72, 0.71, 0.76, and 0.82 at 1, 3, 5, and 7 years, respectively, in DLBCL treated with R-CHOP independent of the International Prognostic Index (IPI) and provided significant additional recurrence risk discrimination (p < .05) for the IPI. CREB1 and N4BP1 proteins and messenger RNAs were also associated with better PFS and OS (p < .05). CONCLUSIONS: This study identified a novel prognostic panel of CREB1, N4BP1, DEAF1, and UBAP2 AAbs that is independent of the IPI in DLBCL.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Humans , Prognosis , Rituximab/therapeutic use , Vincristine/therapeutic use , Prednisone/therapeutic use , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/genetics , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Biomarkers , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , DNA-Binding Proteins , Transcription FactorsABSTRACT
The response rate of anti-PD1 therapy is limited, and the influence of anti-PD1 therapy on cancer patients is unclear. To address these challenges, we conducted a longitudinal analysis of plasma proteomic changes with anti-PD1 therapy in non-small cell lung cancer (NSCLC), alveolar soft part sarcoma (ASPS), and lymphoma patients. We included 339 plasma samples before and after anti-PD1 therapy from 193 patients with NSCLC, ASPS, or lymphoma. The plasma proteins were detected using data-independent acquisition-mass spectrometry and customable antibody microarrays. Differential proteomic characteristics in responders (R) and non-responders (NR) before and after anti-PD1 therapy were elucidated. A total of 1019 proteins were detected using our in-depth proteomics platform and distributed across 10-12 orders of abundance. By comparing the differential plasma proteome expression between R and NR groups, 50, 206, and 268 proteins were identified in NSCLC, ASPS, and lymphoma patients, respectively. Th17, IL-17, and JAK-STAT signal pathways were identified upregulated in NR group, while cellular senescence and transcriptional misregulation pathways were activated in R group. Longitudinal proteomics analysis revealed the IL-17 signaling pathway was downregulated after treatment. Consistently, many proteins were identified as potential combinatorial therapeutic targets (e.g., IL-17A and CD22). Five noninvasive biomarkers (FLT4, SFTPB, GNPTG, F5, and IL-17A) were further validated in an independent lymphoma cohort (n = 39), and another three noninvasive biomarkers (KIT, CCL3, and TNFSF1) were validated in NSCLC cohort (n = 76). Our results provide molecular insights into the anti-PD1 therapy in cancer patients and identify new therapeutic strategies for anti-PD1-resistant patients.
Subject(s)
Anti-Infective Agents , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Lymphoma , Humans , Interleukin-17 , Carcinoma, Non-Small-Cell Lung/drug therapy , Proteomics , Lung Neoplasms/drug therapy , Penicillins , Biomarkers , Transferases (Other Substituted Phosphate Groups)ABSTRACT
INTRODUCTION: Identifying new biomarkers for predicting immune checkpoint inhibitors (ICIs) response in non-small cell lung cancer (NSCLC) is crucial. We aimed to assess the variant allele frequency (VAF)-related profile as a novel biomarker for NSCLC personalized therapy. METHODS: We utilized genomic data of 915 NSCLC patients via cBioPortal and a local cohort of 23 patients for model construction and mutational analysis. Genomic, transcriptomic data from 952 TCGA NSCLC patients, and immunofluorescence (IF) assessment with the local cohort supported mechanism analysis. RESULTS: Utilizing the random forest algorithm, a 15-gene VAF-related model was established, differentiating patients with durable clinical benefit (DCB) from no durable benefit (NDB). The model demonstrated robust performance, with ROC-AUC values of 0.905, 0.737, and 0.711 across training (n = 313), internal validation (n = 133), and external validation (n = 157) cohorts. Stratification by the model into high- and low-score groups correlated significantly with both progression-free survival (PFS) (training: P < 0.0001, internal validation: P < 0.0001, external validation: P = 0.0066) and overall survival (OS) (n = 341) (P < 0.0001). Notably, the stratification system was independent of PD-L1 (P < 0.0001) and TMB (P < 0.0001). High-score patients exhibited an increased DCB ratio and longer PFS across both PD-L1 and TMB subgroups. Additionally, the high-score group appeared influenced by tobacco exposure, with activated DNA damage response pathways. Whereas, immune/inflammation-related pathways were enriched in the low-score group. Tumor immune microenvironment analyses revealed higher proportions of exhausted/effector memory CD8 + T cells in the high-score group. CONCLUSIONS: The mutational VAF profile is a promising biomarker for ICI therapy in NSCLC, with enhanced therapeutic stratification and management as a supplement to PD-L1 or TMB.
Subject(s)
Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung , Gene Frequency , Immune Checkpoint Inhibitors , Lung Neoplasms , Mutation , Humans , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/immunology , Lung Neoplasms/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/immunology , Immune Checkpoint Inhibitors/therapeutic use , Biomarkers, Tumor/genetics , Male , Female , Gene Frequency/genetics , Mutation/genetics , Middle Aged , Aged , Cohort Studies , Treatment OutcomeABSTRACT
HLX01 (HanliKang®) is a rituximab biosimilar that showed bioequivalence to reference rituximab in untreated CD20-positive diffuse large B-cell lymphoma (DLBCL) in the phase 3 HLX01-NHL03 study. Here, we report the 5-year follow-up results from the open-label extension part. Patients were randomised to either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or HLX01 plus CHOP (H-CHOP) every 21 days for up to six cycles. The primary efficacy endpoint was overall survival (OS), and secondary efficacy endpoint was progression-free survival (PFS). Of the 407 patients enrolled in HLX01-NHL03, 316 patients (H-CHOP = 157; R-CHOP = 159) were included in the 5-year follow-up for a median duration of 65.1 (range, 2.2-76.5) months. 96.5% of the patients had an International Prognostic Index (IPI) of 1 or 2, and 17.7% had bone marrow involvement. The 5-year OS rates were 81.0% (95% CI: 74.9-87.5%) and 75.4% (95% CI: 68.9-82.6%)( HR: 0.75, 95% CI 0.47-1.20; p = 0.23) while 5-year PFS rates were 77.7% (95% CI: 71.4-84.6%) and 73.0% (95% CI: 66.3-80.3%) (HR: 0.84, 95% CI 0.54-1.30; p = 0.43) in the H-CHOP and R-CHOP groups, respectively. Treatment outcomes did not differ between groups regardless of IPI score and were consistent with the primary analysis. H-CHOP and R-CHOP provided no significant difference in 5-year OS or PFS in previously untreated patients with low or low-intermediate risk DLBCL.
Subject(s)
Biosimilar Pharmaceuticals , Lymphoma, Large B-Cell, Diffuse , Humans , Biosimilar Pharmaceuticals/adverse effects , Rituximab/adverse effects , Follow-Up Studies , Lymphoma, Large B-Cell, Diffuse/drug therapy , Cyclophosphamide/adverse effects , Doxorubicin , Prednisone/adverse effectsABSTRACT
BACKGROUND: This study aimed to develop and validate a novel risk stratification model and a web-based survival rate calculator to improve discriminative and predictive accuracy for diffuse large B-cell lymphoma (DLBCL) in the rituximab era. METHODS: We retrospectively collected pre-treatment data from 873 primary DLBCL patients who received R-CHOP-based immunochemotherapy regimens at the Cancer Hospital, Chinese Academy of Medical Sciences, from January 1, 2005, to December 31, 2018. An independent cohort of 175 DLBCL patients from Fujian Cancer Hospital was used for external validation. FINDINGS: Age, ECOG PS, number of extranodal sites, Ann Arbor stage, bulky disease, and LDH levels were screened to develop the nomogram and web-based survival rate calculator. The C-index of the nomogram in the training, internal validation, and external validation cohorts was 0.761, 0.758, and 0.768, respectively. The risk stratification model generated based on the nomogram effectively stratified patients into three distinct risk groups. K-M survival curves demonstrated that the novel risk stratification model exhibited a superior level of predictive accuracy compared to IPI, R-IPI, and NCCN-IPI both in training and two validation cohorts. Additionally, the area under the curve (AUC) value of the novel model (0.763) for predicting 5-year overall survival rates was higher than those of IPI (0.749), R-IPI (0.725), and NCCN-IPI (0.727) in the training cohort. Similar results were observed in both internal and external validation cohort. CONCLUSIONS: In conclusion, we have successfully developed and validated a novel risk stratification model and a web-based survival rate calculator that demonstrated superior discriminative and predictive accuracy compared to IPI, R-IPI, and NCCN-IPI in the rituximab era.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Lymphoma, Large B-Cell, Diffuse , Humans , Rituximab/therapeutic use , Survival Rate , Retrospective Studies , Prognosis , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cohort Studies , Lymphoma, Large B-Cell, Diffuse/pathology , Cyclophosphamide/therapeutic use , Prednisone/therapeutic use , Vincristine/therapeutic use , Doxorubicin/therapeutic use , Risk AssessmentABSTRACT
BACKGROUND: Antigen-presenting cells (APC)/T/NK cells are key immune cells that play crucial roles in fighting against malignancies including lung adenocarcinoma (LUAD). In this study, we aimed to identify an APC/T/NK cells-related gene signature (ATNKGS) and potential immune cell-related genes (IRGs) to realize risk stratification, prognosis, and immunotherapeutic response prediction for LUAD patients. METHODS: Based on the univariate Cox regression and the LASSO Cox regression results of 196 APC/T/NK cells-related genes collected from three pathways in the KEGG database, we determined the final genes and established the ATNKGS-related risk model. The single-cell RNA sequencing data were applied for key IRGs identification and investigate their value in immunotherapeutic response prediction. Several GEO datasets and an external immunotherapy cohort from Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, were applied for validation. RESULTS: In this study, nine independent public datasets including 1108 patients were enrolled. An ATNKGS containing 16 genes for predicting overall survival of LUAD patients was constructed with robust prognostic capability. The ATNKGS high risk group was related to significantly worse OS outcomes than those in the low-risk group, which were verified in TCGA and four GEO datatsets. A nomogram combining the ATNKGS risk score with clinical TNM stage achieved the optimal prediction performance. The single-cell RNA sequencing analysis revealed CTSL as an IRG of macrophage and monocyte. Moreover, though CTSL was an indicator for poor prognosis of LUAD patients, CTSL high expression group was associated with higher ESTIMATEScore, immune checkpoints expression, and lower TIDE score. Several immunotherapeutic cohorts have confirmed the response-predicting significance of CTSL in patients receiving immune checkpoint inhibitor (ICI) treatment. CONCLUSIONS: Our study provided an insight into the significant role of APC/T/NK cells-related genes in survival risk stratification and CTSL in response prediction of immunotherapy in patients with LUAD.
Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Humans , Prognosis , Antigen-Presenting Cells , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/therapy , Killer Cells, Natural , Immunotherapy , Lung Neoplasms/genetics , Lung Neoplasms/therapy , Sequence Analysis, RNAABSTRACT
BACKGROUND: To report the efficacy and safety data of immunotherapy plus angiogenic inhibitors treatment in lung adenocarcinoma patients. METHODS: Eligible patients with pathological or cytological confirmed locally advanced or metastatic lung adenocarcinoma and treated with immune checkpoint inhibitors (ICI) plus angiogenic inhibitors were enrolled. The primary endpoints were progressive free survival (PFS). The secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. RESULTS: A total of 46 consecutive enrolled patients received ICI plus angiogenic inhibitor, and the median follow-up was 9.6 months (range 1.5-32.5). The ORR and DCR were 8.7% (n = 4) and 50% (n = 23), respectively. Median PFS and OS were 2.9 months (95% CI 2.1-3.7) and 12.3 months (95% CI 7.6-17.0), respectively. Patients at stage IVB had an inferior PFS than stage IIIC or IVA (2.8 months vs 4.4 months, P = 0.003). The median PFS of patients who were treated with ICI plus bevacizumab was shorter than ICI plus anlotinib or apatinib (1.2 months vs 3.3 months, P = 0.005). The occurrence of hypertension during the combination treatment has been related to a tendency for prolonged PFS (5.5 months vs 2.6 months; P = 0.05). The overall incidence of treatment-related adverse events (TRAE) was 89.1% (n = 41), and grade 3-4 TRAE was occupied 21.4% (n = 10). CONCLUSION: This study objectively demonstrated that the treatment of ICI and antiangiogenic agents in lung adenocarcinoma could be a promising alternative therapeutic regimen, and the toxic effects were manageable. Subgroup analysis revealed that small molecular angiogenic inhibitors plus ICI and low tumor burden during treatment were better prognostic factors.
Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Humans , Angiogenesis Inhibitors , Immune Checkpoint Inhibitors , ImmunotherapyABSTRACT
Autoantibody (AAb) has a prominent role in prostate cancer (PCa), with few studies profiling the AAb landscape in Chinese patients. Therefore, the AAb landscape in Chinese patients was characterized using protein arrays. First, in the discovery phase, Huprot arrays outlined autoimmune profiles against ~ 21,888 proteins from 57 samples. In the verification phase, the PCa-focused arrays detected 25 AAbs selected from the discovery phase within 178 samples. Then, PCa was detected using a backpropagation artificial neural network (BPANN) model. In the validation phase, an enzyme-linked immunosorbent assay (ELISA) was used to validate four AAb biomarkers from 196 samples. Huprot arrays profiled distinct PCa, benign prostate diseases (BPD), and health AAb landscapes. PCa-focused array depicted that IFIT5 and CPOX AAbs could distinguish PCa from health with an area under curve (AUC) of 0.71 and 0.70, respectively. PAH and FCER2 AAbs had AUCs of 0.86 and 0.88 in discriminating PCa from BPD. Particularly, PAH AAb detected patients in the prostate-specific antigen (PSA) gray zone with an AUC of 0.86. Meanwhile, the BPANN model of 4-AAb (IFIT5, PAH, FCER2, CPOX) panel attained AUC of 0.83 among the two cohorts for detecting patients with gray-zone PSA. In the validation cohort, the IFIT5 AAb was upregulated in PCa compared to health (p < 0.001). Compared with BPD, PAH and FCER2 AAbs were significantly elevated in PCa (p = 0.012 and 0.039). We have demonstrated the first extensive profiling of autoantibodies in Chinese PCa patients, identifying novel diagnostic AAb biomarkers, especially for identification of gray-zone-PSA patients.
Subject(s)
Prostate-Specific Antigen , Prostatic Neoplasms , Male , Humans , Autoantibodies , Protein Array Analysis , East Asian People , Biomarkers, Tumor , Prostatic Neoplasms/diagnosisABSTRACT
An emerging view regarding cancer-associated fibroblast (CAF) is that it plays a critical role in tumorigenesis and immunosuppression in the tumor microenvironment (TME), but the clinical significance and biological functions of CAFs in non-small cell lung cancer (NSCLC) are still poorly explored. Here, we aimed to identify the CAF-related signature for NSCLC through integrative analyses of bulk and single-cell genomics, transcriptomics, and proteomics profiling. Using CAF marker genes identified in weighted gene co-expression network analysis (WGCNA), we constructed and validated a CAF-based risk model that stratifies patients into two prognostic groups from four independent NSCLC cohorts. The high-score group exhibits a higher abundance of CAFs, decreased immune cell infiltration, increased epithelial-mesenchymal transition (EMT), activated transforming growth factor beta (TGFß) signaling, and a limited survival rate compared with the low-score group. Considering the immunosuppressive feature in the high-score group, we speculated an inferior clinical response for immunotherapy in these patients, and this association was successfully verified in two NSCLC cohorts treated with immune checkpoint blockades (ICBs). Furthermore, single-cell RNA sequence datasets were used to clarify the molecular mechanisms underlying the aggressive and immunosuppressive phenotype in the high-score group. We found that one of the genes in the risk model, filamin binding LIM protein 1 (FBLIM1), is mainly expressed in fibroblasts and upregulated in CAFs compared to fibroblasts from normal tissue. FBLIM1-positive CAF subtype was correlated with increased TGFß expression, higher mesenchymal marker level, and immunosuppressive tumor microenvironment. Finally, we demonstrated that FBLIM1 might serve as a poor prognostic marker for immunotherapy in clinical samples. In conclusion, we identified a novel CAF-based classifier with prognostic value in NSCLC patients and those treated with ICBs. Single-cell transcriptome profiling uncovered FBLIM1-positive CAFs as an aggressive subtype with a high abundance of TGFß, EMT, and an immunosuppressive phenotype in NSCLC.
Subject(s)
Cancer-Associated Fibroblasts , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Cancer-Associated Fibroblasts/pathology , Lung Neoplasms/pathology , Prognosis , Single-Cell Gene Expression Analysis , Transforming Growth Factor beta/metabolism , Immunotherapy , Tumor Microenvironment/genetics , Cytoskeletal Proteins/genetics , Cytoskeletal Proteins/metabolism , Cell Adhesion Molecules/geneticsABSTRACT
BACKGROUND: This study aimed to assess the efficacy and safety of geptanolimab (GB226), a fully humanized, recombinant anti-programmed cell death-1 monoclonal antibody, in Chinese patients with refractory or relapsed (r/r) primary mediastinal large B-cell lymphoma (PMBCL). METHODS: This was a multicenter, open-label, single-arm phase II study (Gxplore-003), conducted at 43 hospitals in China (NCT03639181). Patients received geptanolimab intravenously at a dose of 3 mg/kg every 2 weeks until documented confirmed disease progression, intolerable toxicity, or any other cessation criteria was met. The primary endpoint was objective response rate (ORR) in the full analysis set assessed by the independent review committee (IRC) according to the Lugano Classification 2014. RESULTS: This study was prematurely terminated due to the slow rate of patient accrual. Between Oct 15th, 2018 and Oct 7th, 2020, 25 patients were enrolled and treated. By the data cutoff date on Dec 23rd, 2020, the IRC-assessed ORR was 68.0% (17/25; 95% confidence interval [CI] 46.5-85.1%), with the complete response rate of 24%. The disease control rate was 88% (22/25; 95%CI 68.8-97.5%). Median duration of response was not reached (NR) (95%CI, 5.62 months to NR), with 79.5% of patients having response durations of more than 12 months. Median progression-free survival was NR (95%CI, 6.83 months to NR). Treatment-related adverse events (TRAEs) were reported in 20 of 25 (80.0%) patients, and grade 3 or higher TRAEs occurred in 11 of 25 (44%) patients. No treatment-related deaths occurred. The immune-related adverse events (irAEs) of any grade were observed in 6 (24.0%) patients, and no grade 4 or grade 5 irAEs were reported. CONCLUSION: Geptanolimab (GB226) demonstrated promising efficacy and a manageable safety profile in Chinese patients with r/r PMBCL.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Thymus Neoplasms , Adult , Humans , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/pathology , Antibodies, Monoclonal/therapeutic use , Immune Checkpoint Inhibitors/therapeutic useABSTRACT
BACKGROUND: Rezivertinib (BPI-7711) is a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). This phase IIa study was part of a phase I/IIa study (NCT03386955), aimed to evaluate the efficacy and safety of rezivertinib as the first-line treatment for patients with locally advanced or metastatic/recurrent EGFR mutated non-small cell lung cancer (NSCLC). METHODS: Patients received the first-line treatment of 180 mg rezivertinib orally once daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was the objective response rate (ORR) assessed by blinded independent central review (BICR). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: From Jun 12, 2019, to Oct 17, 2019, 43 patients were enrolled. At the data cutoff date on Dec 23, 2021, the ORR by BICR was 83.7% (95% CI: 69.3-93.2%). The median DoR was 19.3 (95% CI: 15.8-25.0) months. The median PFS by BICR was 20.7 (95% CI: 13.8-24.8) months and 22.0 (95% CI: 16.8-26.3) months by investigators. Data on OS was immature. Totally, 40 (93.0%) patients had at least one treatment-related adverse event while 4 (9.3%) of them were grade ≥ 3. CONCLUSIONS: Rezivertinib (BPI-7711) showed promising efficacy and a favorable safety profile for the treatment among the locally advanced or metastatic/recurrent NSCLC patients with EGFR mutation in the first-line setting. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03386955.
Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Antineoplastic Agents/adverse effects , Protein Kinase Inhibitors/adverse effects , ErbB Receptors/genetics , ErbB Receptors/therapeutic use , MutationABSTRACT
BACKGROUND: Iruplinalkib (WX-0593) is an anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor. Here we reported the single-arm, phase II study (INTELLECT) results of the efficacy and safety of iruplinalkib for ALK-positive crizotinib-resistant advanced non-small cell lung cancer (NSCLC) patients. METHODS: ALK-positive crizotinib-resistant advanced NSCLC patients aged ≥18 years, with Eastern Cooperative Oncology Group performance status of 0-2 were eligible. Patients received iruplinalkib 180 mg orally once daily for a 21-day cycle with a 7-day lead-in phase at 60 mg orally once daily. The primary endpoint was the independent review committee (IRC)-assessed objective response rate (ORR). RESULTS: From August 7, 2019, to October 30, 2020, 146 patients were included. As of the data cut-off date on November 30, 2021, the median follow-up time was 18.2 months (95% confidence interval [CI] 16.8-18.8). IRC-assessed ORR and disease control rate (DCR) were 69.9% (95% CI 61.7-77.2%) and 96.6% (95% CI 92.2-98.9%), respectively. Investigator-assessed ORR and DCR were 63.0% (95% CI 54.6-70.8%) and 94.5% (95% CI 89.5-97.6%), respectively. Investigator-assessed median duration of response and progression-free survival (the same as median time to progression) were 13.2 months (95% CI 10.4-17.7) and 14.5 months (95% CI 11.7-20.0), respectively. Corresponding IRC-assessed results were 14.4 months (95% CI 13.1-not evaluable [NE]), 19.8 months (95% CI 14.5-NE), and NE (95% CI 14.5-NE), respectively. Investigator-assessed intracranial ORRs were 46% (41/90, 95% CI 35-56%) in patients with central nervous system metastases and 64% (27/42, 95% CI 48-78%) in patients with measurable intracranial lesions. Overall survival data were immature. Treatment-related adverse events (TRAEs) occurred in 136/146 (93.2%) patients. The most common TRAEs were aspartate aminotransferase increased (63 [43.2%]), alanine aminotransferase increased (54 [37.0%]), and blood creatine phosphokinase increased (51 [34.9%]). Dose interruption, reduction, and discontinuation due to TRAEs occurred in 21 (14.4%), 16 (11.0%), and four (2.7%) patients, respectively. CONCLUSIONS: In this study, iruplinalkib (WX-0593) demonstrated favorable efficacy and manageable safety profiles in patients with ALK-positive crizotinib-resistant advanced NSCLC. Iruplinalkib could be a new treatment option for this patient population. TRIAL REGISTRATION: Center for Drug Evaluation of National Medical Products Administration of China: CTR20190789, registered on April 28, 2019; ClinicalTrials.gov: NCT04641754, registered on November 24, 2020.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Adolescent , Adult , Carcinoma, Non-Small-Cell Lung/drug therapy , Crizotinib/therapeutic use , Lung Neoplasms/drug therapy , Protein-Tyrosine Kinases/therapeutic use , Anaplastic Lymphoma Kinase/therapeutic use , Proto-Oncogene Proteins/therapeutic use , Protein Kinase Inhibitors/therapeutic useABSTRACT
BACKGROUND: Furmonertinib (AST2818) is a brain penetrant pan-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both EGFR sensitizing mutations and T790M mutation. We report the pooled central nervous system (CNS) efficacy data of furmonertinib in patients with EGFR T790M mutated non-small cell lung cancer (NSCLC) from two phase 2 studies. METHODS: This was a pooled, post-hoc analysis of two phase 2 studies (NCT03127449 [phase 2a study of furmonertinib], NCT03452592 [phase 2b study of furmonertinib]). In the phase 2a study, patients received furmonertinib 40 mg, 80 mg, 160 mg, or 240 mg orally once daily. In the phase 2b study, all patients received furmonertinib 80 mg orally once daily. CNS efficacy of furmonertinib was analyzed in patients with baseline CNS lesions by an independent review center per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: A total of 132 patients with baseline CNS metastases were included in this analysis. In 52 patients with measurable CNS lesions, CNS objective response rates were zero (0/1), 65% (22/34), 85% (11/13), and 25% (1/4), and CNS disease control rates were zero (0/1), 97% (33/34), 100% (13/13), and 100% (4/4) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively. In patients with measurable or non-measurable CNS lesions, median CNS progression-free survival was 2.8 months (95% confidence interval [CI] 1.4-8.3), 11.6 months (95% CI 8.3-13.8), 19.3 months (95% CI 5.5-not available [NA]), and not reached (95% CI 2.8 months-NA) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively. CONCLUSIONS: Furmonertinib showed promising CNS efficacy in doses of 80 mg orally once daily or higher in patients with EGFR T790M mutated NSCLC. TRIAL REGISTRATION: Both studies were registered on ClinicalTrial.gov. The phase 2a study was registered with NCT03127449 on April 25, 2017; The phase 2b study was registered with NCT03452592 on March 2, 2018.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , ErbB Receptors/genetics , Protein Kinase Inhibitors/adverse effects , Mutation , Central Nervous System/pathology , Clinical Trials, Phase II as TopicABSTRACT
BACKGROUND: Pulmonary large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC) are two types of high-grade neuroendocrine carcinomas of the lung with poor prognosis. LCNEC has not been thoroughly studied due to its rarity, data are also lacking regarding the survival comparison and prognosis analysis of patients with locally advanced or metastatic LCNEC and SCLC. METHODS: Data of patients with LCNEC, SCLC, and other NSCLC who were diagnosed from 1975 to 2019 were extracted from the Surveillance, Epidemiology and End Results (SEER) database to estimate incidence. Those in stage III-IV and being diagnosed from 2010 to 2015 were utilized further to investigate their clinical characteristics and prognosis. Propensity score matching (PSM) analyses at a ratio of 1:2 was used to compare their survival outcomes. Nomograms of LCNEC and SCLC were established with internal validation, and the nomogram of SCLC was externally validated by 349 patients diagnosed in Cancer hospital, Chinese Academy of Medical Sciences & Peking Union Medical College from January 1, 2012 to December 31, 2018. RESULTS: The incidence of LCNEC has been increasing in recent decades, meanwhile that of SCLC and other types of NSCLC were decreasing. A total of 91,635 lung cancer patients, including 785 with LCNEC, 15,776 with SCLC, and 75,074 with other NSCLC were enrolled for further analysis. The survival of stage III-IV LCNEC resembles that of SCLC, and significantly worse than other types of NSCLC before and after PSM analysis. In pretreatment prognostic analysis, age, T stage, N stage, M stage, bone metastasis, liver metastasis, and brain metastasis were found to be associated with the survival of both LCNEC and SCLC, besides sex, bilaterality, and lung metastasis were additional prognostic factors for SCLC. Two nomograms and convenient online tools respectively for LCNEC and SCLC were established accordingly with favorable predicting accuracy of < 1-year, < 2-year, < 3-year survival probabilities. In external validation of the SCLC nomogram with a Chinese cohort, the AUCs of 1-year, 2-year and 3-year ROC were 0.652, 0.669, and 0.750, respectively. All the results of 1-, 2-, 3- year variable-dependent ROC curves verified the superior prognostic value of our nomograms for LCNEC and SCLC over the traditional T/N/M staging system. CONCLUSIONS: Based on large sample-based cohort, we compared the epidemiological trends and survival outcomes between locally advanced or metastatic LCNEC, SCLC, and other NSCLC. Furthermore, two prognostic evaluation approaches respectively for LCNEC and SCLC might present as practical tools for clinicians to predict the survival outcome of these patients and facilitate risk stratification.
Subject(s)
Carcinoma, Large Cell , Carcinoma, Neuroendocrine , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Small Cell Lung Carcinoma/pathology , Prognosis , Incidence , Lung Neoplasms/pathology , Carcinoma, Neuroendocrine/pathology , Carcinoma, Large Cell/drug therapyABSTRACT
BACKGROUND: As a potential target receptor tyrosine kinase, mesenchymal-epithelial transition factor (MET) exhibits high aberrant expression across various tumors. This study aimed to evaluated the safety, tolerability, efficacy and pharmacokinetics (PK) of BPI-9016M, a novel tyrosine kinase inhibitor (TKI) targeting c-MET, in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS/DESIGN: In this two-part multicenter phase Ib study, eligible patients with locally advanced or metastatic NSCLC harboring c-MET overexpression or MET exon 14 skipping mutation were enrolled into Part A (tested positive for c-MET overexpression [immunohistochemical staining score ≥ 2+]; 300 mg quaque die [QD], 450 mg QD and 600 mg QD cohorts) or Part B (tested positive for MET exon 14 skipping mutation; 400 mg bis in die [BID] cohort), respectively. The primary endpoints were safety, objective response rate (ORR) and disease control rate (DCR), the second endpoints were PK parameters, progression-free survival (PFS) and overall survival (OS). RESULTS: Between March 15, 2017 and September 18, 2021, 38 patients were enrolled (Part A, n = 34; Part B, n = 4). Of 38 patients, 32 (84.2%) patients completed the treatment protocol. As of the data cut-off date on January 27, 2022, all patients reported at least one treatment-emergent adverse event (TEAE). Ninety-two point one percent (35/38) of patients experienced treatment-related adverse events (TRAEs), and grade ≥ 3 TRAEs were observed in 11 (28.9%) patients. The most common TRAEs were elevated alanine aminotransferase (ALT, 14/38, 36.8%) and elevated aspartate aminotransferase (AST, 11/38, 28.9%). Only one (2.6%) patient had treatment-related serious adverse event (SAE) in 600 mg QD cohort due to thrombocytopenia. PK analysis showed BPI-9016M and its main metabolites (M1 and M2-2) reached steady state after seven days of continuous administration. At the dose of 300 mg QD and 450 mg QD, the exposure of BPI-9016M increased with increasing dose. Exposure of BPI-9016M was similar at 450 mg QD and 600 mg QD, which may exhibit a saturation trend. In all patients, ORR and DCR were 2.6% (1/38, 95% confidence interval [CI] 0.1-13.8%) and 42.1% (16/38, 95% CI 26.3-59.2%), respectively. Only one partial response (PR) patient was observed at a dose of 600 mg QD in Part A. In Part B, DCR was 75.0% (3/4, 95% CI 19.4-99.4%). The median PFS and OS in all 38 patients were 1.9 months (95% CI 1.9-3.7) and 10.3 months (95% CI 7.3-not evaluable [NE]), respectively. CONCLUSION: BPI-9016M showed manageable safety profile in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic NSCLC, but showed limited efficacy. TRIAL REGISTRATION: Clinicaltrials.gov NCT02929290 (11/10/2016).
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , Proto-Oncogene Proteins c-met/genetics , Mutation , Protein Kinase Inhibitors/therapeutic use , ExonsABSTRACT
BACKGROUND: Patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) have poor outcomes and few treatment options. We report the preliminary results of the efficacy and safety of PD-1 monoclonal antibody (mab) plus Rituximab for r/r DLBCL. METHODS: In this single-center, single-arm phase 2 and retrospective study, r/r DLBCL patients received PD-1 mab and Rituximab every 3 weeks. Immunohistochemistry, fluorescence in situ hybridization, and probe capture-based high-resolution sequencing were performed. Efficacy, safety and prognostic factors were analyzed. RESULTS: Between October 16th, 2018, and July 10th, 2022, 36 patients (10 patients in retrospective study and 26 patients in phase 2 study) were enrolled and received at least one dose of PD-1 mab combined with Rituximab. The objective response rate was 52.8%. The median progression free survival (PFS) and overall survival was 2.8 and 19.6 months, respectively. The median duration of response was 18.7 months. Rare grade 3 or 4 treatment related adverse events were observed. B2M mutations correlated with a significantly poor PFS (p = .013) and OS (p = .009) in DLBCL patients treated with this regimen. CONCLUSION: PD-1 mab combined with Rituximab could be a potential treatment option for r/r DLBCL with manageable safety profile.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Lymphoma, Non-Hodgkin , Humans , Rituximab/adverse effects , Antibodies, Monoclonal/adverse effects , Programmed Cell Death 1 Receptor , Retrospective Studies , In Situ Hybridization, Fluorescence , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/drug therapyABSTRACT
Autoantibodies (AAbs) targeted tumor-associated antigens (TAAs) have the potential for early detection of breast cancer. Here, 574 early-stage breast cancer (ES-BC) patients containing 4 subtypes (Luminal A, Luminal B, HER2+, TN), 126 benign breast disease (BBD) patients, and 199 normal healthy controls (NHC) were separated into three-phases to discover, verify, and validate AAbs. In discovery phase using high-throughput protein microarray, 37 AAbs with sensitivity of 31.25%-86.25% and specificity over 73% in ES-BC, and 40 AAbs with different positive rates between subtypes were identified as candidates. In verification phase, 18 AAbs were significantly increased compared with the Control (BBD and NHC) in focused array. Ten out of 18 AAbs exhibited a significant difference between subtypes (P < .05). In ELISA validation phase, 5 novel AAbs (anti-KJ901215, -FAM49B, -HYI, -GARS, -CRLF3) exhibited significantly higher levels in ES-BC compared with BBD/NHC (P < .05). The sensitivities of individual AAb and a 5-AAbs panel were 20.41%-28.57% and 38.78%, whereas the specificities were over 90% and 85.94%. Simultaneously, 4 AAbs except anti-GARS differed significantly between TN and non-TN subtype (P < .05). We constructed 3 random forest classifier models based on AAbs to discriminant ES-BC from Control or BBD, and to discern TN subtype, which yielded an area under the curve of 0.870, 0.860, and 0.875, respectively. Biological interaction analysis revealed 4 TAAs, except for KJ901215, that were associated with well known proteins of BC. This study discovered and stepwise validated 5 novel AAbs with the potential to diagnose ES-BC and discern TN subtype, indicating easy-to-detect and minimally invasive diagnostic value of serum AAbs ahead of biopsy for future application.
Subject(s)
Autoantibodies/blood , Breast Neoplasms/classification , Breast Neoplasms/diagnosis , Early Detection of Cancer/methods , Adolescent , Adult , Aged , Aged, 80 and over , Antigens, Neoplasm/immunology , Autoantibodies/immunology , Biomarkers, Tumor/blood , Breast Neoplasms/blood , Breast Neoplasms/immunology , Diagnosis, Differential , Enzyme-Linked Immunosorbent Assay , Female , Humans , Middle Aged , Protein Array Analysis , Reproducibility of Results , Sensitivity and Specificity , Young AdultABSTRACT
BACKGROUND: The use of immune checkpoint inhibitors (ICIs) for brain metastases (BMs) from non-small cell lung cancer (NSCLC) remains debatable. This study aimed to explore the efficacy of ICIs for NSCLC with BMs. We also evaluated the effect of BMs on outcomes of ICIs. METHODS: A systematic search of PubMed, Embase, Web of Science, and Cochrane databases was conducted to identify studies where the efficacy of ICIs against BMs from NSCLC, or the association between BMs and outcomes of ICIs were evaluated. Outcomes included intracranial objective response rate (icORR), intracranial disease control rate (icDCR), systemic ORR and DCR. RESULTS: Overall, 33 studies were included in this meta-analysis. The pooled icORR was 13% (95%CI 6-23%) and icDCR was 50% (95%CI 40-63%) for programmed cell death-ligand 1 (PD-L1) unselected patients with any BMs. For active BMs, pooled icORR was 15% (95%CI 6-28%) and icDCR was 47% (95% CI 36-57%). For PD-L1 ≥ 50% patients with any BMs, pooled icORR and icDCR were 68% (95%CI 57-80%) and 82% (95%CI 73-92%), respectively. Additionally, pooled systemic ORR and DCR for any BMs were 22% (95%CI 15-30%) and 41% (95%CI 18-67%), respectively. Patients with BMs had inferior progression-free survival (HR 1.19, 95%CI 1.07-1.33, P = 0.0016) and overall survival (HR 1.14, 95%CI 1.03-1.25, P = 0.011) when applying ICIs compared to those without BMs. However, no significant difference in systemic ORR between patients with and without BMs was observed (OR 0.94, 95%CI 0.72-1.20, P = 0.629). CONCLUSION: ICIs may be clinically active in NSCLC patients with BMs. More effective treatments for BMs from NSCLC are needed.