Effects of sintilimab plus chemotherapy as first-line treatment on health-related quality of life in patients with advanced esophageal squamous cell carcinoma: results from the randomized phase 3 ORIENT-15 study.

Background: In ORIENT-15 study, sintilimab plus chemotherapy demonstrated significant improvement on overall survival (OS) versus placebo plus chemotherapy in first-line treatment of advanced esophageal squamous cell carcinoma (ESCC). Here, we report effect of sintilimab plus chemotherapy on health-related quality of life (HRQoL) in patients with advanced ESCC. Methods: From December 14, 2018 to August 28, 2022, HRQoL was evaluated in all randomized patients using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), EORTC Quality of Life Questionnaire Oesophageal Cancer Module 18 items (QLQ-OES18), and visual analogue scale (VAS) of the EuroQol five-dimensional five-level questionnaire (EQ-5D-5L). Mean scores of each scale were described by treatment group through week 60. Least-squares mean (LSM) score change from baseline through week 24 were analyzed using the mixed-model repeated-measures method. Time to the first onset of deterioration (TTD) and OS for each scale were estimated. Clinical Trials Registration: NCT03748134. Findings: As of August 28, 2022, 689 of 690 enrolled patients were assessed for HRQoL analysis (sintilimab group: 340, placebo group: 349). Median follow-up was 32.2 months. Differences in LSM favored sintilimab over placebo for QLQ-C30 social functioning (LSM difference: 3.06, 95% CI: 0.55 to 5.57; P = 0.0170), pain (-2.24, 95% CI: -4.30 to -0.17; P = 0.0337), fatigue (-2.24, 95% CI: -4.46 to -0.02; P = 0.0479), constipation (-3.27, 95% CI -5.49 to -1.05; P = 0.0039), QLQ-OES18 pain (-1.77, 95% CI -3.11 to -0.43; P = 0.0097), trouble swallowing saliva (-2.09, 95% CI: -3.77 to -0.42; P = 0.0146), and choked when swallowing (-3.23, 95% CI: -5.60 to -0.86; P = 0.0076). TTD favored sintilimab over placebo for QLQ-OES18 dysphagia (Hazard ratio [HR]: 0.76, 95% CI: 0.61-0.94, P = 0.0104), and trouble swallowing saliva (HR: 0.48, 95% CI: 0.35-0.67, P < 0.0001). Improved OS were observed in patients with better performance in several functioning and symptom scales of QLQ-C30 and QLQ-QES18. Interpretation: The statistically significant differences of several HRQoL scales and improvements in delayed deterioration observed in our study further support the use of sintilimab plus chemotherapy as first-line treatment for advanced ESCC. Funding: This study was funded by Innovent Biologics and was co-funded by Eli Lilly.

Utilizing a novel model of PANoptosis-related genes for enhanced prognosis and immune status prediction in kidney renal clear cell carcinoma.

Kidney renal clear cell carcinoma (KIRC) is the most common histopathologic type of renal cell carcinoma. PANoptosis, a cell death pathway that involves an interplay between pyroptosis, apoptosis and necroptosis, is associated with cancer immunity and development. However, the prognostic significance of PANoptosis in KIRC remains unclear. RNA-sequencing expression and mutational profiles from 532 KIRC samples and 72 normal samples with sufficient clinical data were retrieved from the Cancer Genome Atlas (TCGA) database. A prognostic model was constructed using differentially expressed genes (DEGs) related to PANoptosis in the TCGA cohort and was validated in a Gene Expression Omnibus (GEO) cohorts. Incorporating various clinical features, the risk model remained an independent prognostic factor in multivariate analysis, and it demonstrated superior performance compared to unsupervised clustering of the 21 PANoptosis-related genes alone. Further mutational analysis showed fewer VHL and more BAP1 alterations in the high-risk group, with alterations in both genes also associated with patient prognosis. The high-risk group was characterized by an unfavorable immune microenvironment, marked by reduced levels of CD4 + T cells and natural killer cells, but increased M2 macrophages and regulatory T cells. Finally, the risk model was predictive of response to immune checkpoint blockade, as well as sensitivity to sunitinib and paclitaxel. The PANoptosis-related risk model developed in this study enables accurate prognostic prediction in KIRC patients. Its associations with the tumor immune microenvironment and drug efficacy may offer potential therapeutic targets and inform clinical decisions.

Nomogram based on multiparametric analysis of early-stage breast cancer: Prediction of high burden metastatic axillary lymph nodes.

BACKGROUND: The Z0011 and AMAROS trials found that axillary lymph node dissection (ALND) was no longer mandatory for early-stage breast cancer patients who had one or two metastatic axillary lymph nodes (mALNs). The aim of our study was to establish a nomogram which could be used to quantitatively predict the individual likelihood of high burden mALN (≥3 mALN). METHODS: We retrospectively analyzed 564 women with early breast cancer who had all undergone both ultrasound (US) and magnetic resonance imaging (MRI) to examine axillary lymph nodes before radical surgery. All the patients were divided into training (n = 452) and validation (n = 112) cohorts by computer-generated random numbers. Their clinicopathological features and preoperative imaging associated with high burden mALNs were evaluated by logistic regression analysis to develop a nomogram for predicting the probability of high burden mALNs. RESULTS: Multivariate analysis showed that high burden mALNs were significantly associated with replaced hilum and the shortest diameter >10 mm on MRI, with cortex thickness >3 mm on US (p < 0.05 each). These imaging criteria plus higher grade (grades II and III) and quadrant of breast tumor were used to develop a nomogram calculating the probability of high burden mALNs. The AUC of the nomogram was 0.853 (95% CI: 0.790-0.908) for the training set and 0.783 (95% CI: 0.638-0.929) for the validation set. Both internal and external validation evaluated the accuracy of nomogram to be good. CONCLUSION: A well-discriminated nomogram was developed to predict the high burden mALN in early-stage breast patients, which may assist the breast surgeon in choosing the appropriate surgical approach.

Quercetin: A promising drug candidate against the potential SARS-CoV-2-Spike mutants with high viral infectivity.

The emergence of SARS-CoV-2-Spike mutants not only enhances viral infectivity but also lead to treatment failure. Gaining a comprehensive understanding of the molecular binding mode between the mutant SARS-CoV-2-Spike and human ACE2 receptor is crucial for therapeutic development against this virus. Building upon our previous predictions and verifications regarding heightened viral infectivity of six potential SARS-CoV-2-Spike mutants, this study aims to further investigate the potential disruption of the interaction between these mutants and ACE2 by quercetin, a Chinese herbal compound. Molecular docking and dynamics simulations results reveal that the binding sites of quercetin particularly enriched around a specific "cavity" at the interface of Spike/ACE2 complex, indicating a favorable region for quercetin to interfere with Spike/ACE2 interaction. Virus infection assay confirms that quercetin not only attenuates wild-type virus infectivity but also suppresses the infectivity of all six tested SARS-CoV-2-Spike mutants. Therefore, quercetin represents a promising therapeutic candidate against both wild-type and potential future variants of SARS-CoV-2 exhibiting high viral infectivity.

Optimal therapy for concomitant EGFR and TP53 mutated non-small cell lung cancer: a real-world study.

BACKGROUND: Non-small cell cancer (NSCLC) patients with concomitant epidermal growth factor receptor (EGFR) and TP53 mutations have a poor prognosis with the treatment of tyrosine kinase inhibitors (TKIs), and may benefit from a combination regimen preferentially. The present study aims to compare the benefits of EGFR-TKIs and its combination with antiangiogenic drugs or chemotherapy in patients with NSCLC harboring EGFR and TP53 co-mutation in a real-life setting. METHODS: This retrospective analysis included 124 patients with advanced NSCLC having concomitant EGFR and TP53 mutations, who underwent next-generation sequencing prior to treatment. Patients were classified into the EGFR-TKI group and combination therapy group. The primary end point of this study was progression-free survival (PFS). The Kaplan-Meier (KM) curve was drawn to analyze PFS, and the differences between the groups were compared using the logarithmic rank test. Univariate and multivariate cox regression analysis was performed on the risk factors associated with survival. RESULTS: The combination group included 72 patients who received the regimen of EGFR-TKIs combined with antiangiogenic drugs or chemotherapy, while the EGFR-TKI monotherapy group included 52 patients treated with TKI only. The median PFS was significantly longer in the combination group than in the EGFR-TKI group (18.0 months; 95% confidence interval [CI]: 12.1-23.9 vs. 7.0 months; 95% CI: 6.1-7.9; p < 0.001) with greater PFS benefit in TP53 exon 4 or 7 mutations subgroup. Subgroup analysis showed a similar trend. The median duration of response was significantly longer in the combination group than in the EGFR-TKI group. Patients with 19 deletions or L858R mutations both achieved a significant PFS benefit with combination therapy versus EGFR-TKI alone. CONCLUSION: Combination therapy had a higher efficacy than EGFR-TKI alone for patients with NSCLC having concomitant EGFR and TP53 mutations. Future prospective clinical trials are needed to determine the role of combination therapy for this patient population.

A Randomized Phase III Study of Anlotinib Versus Bevacizumab in Combination With CAPEOX as First-Line Therapy for RAS/BRAF Wild-Type Metastatic Colorectal Cancer: A Clinical Trial Protocol.

Background: Chemotherapy combined with antivascular endothelial growth factor (VEGF) or anti-epidermal growth factor receptor monoclonal antibodies is the most promising approach to prolong survival and improve the quality of life of patients with unresectable metastatic colorectal cancer (mCRC). Anlotinib is an oral antiangiogenic tyrosine kinase inhibitor that targets VEGF receptors 1/2/3, fibroblast growth factor receptors 1-4, and platelet-derived growth factor receptors a/ß. Since anlotinib combined with oxaliplatin and capecitabine (CAPEOX) as a first-line treatment was previously shown to be effective and safe for patients with RAS/BRAF wild-type (WT) mCRC, we designed this randomized, open-label, parallel-group, non-inferiority, phase III study to evaluate the efficacy and safety of anlotinib plus CAPEOX versus bevacizumab plus CAPEOX in patients with RAS/BRAF WT mCRC. Methods/design: The primary inclusion criteria are Eastern Cooperative Oncology Group performance status 0/1, confirmed RAS/BRAF WT colorectal adenocarcinoma, and unresectable metastases assessed by a multidisciplinary team. The main exclusion criteria are as follows: high microsatellite instability or deficient mismatch repair status, resectable or potentially resectable metastases, and previous systemic therapy for mCRC. A total of 698 patients will be randomized into the anlotinib and bevacizumab groups in a 1:1 ratio. Patients will receive 4 to 8 cycles of induction therapy (CAPEOX plus anlotinib or bevacizumab), followed by maintenance treatment (capecitabine plus anlotinib or bevacizumab) until disease progression or unacceptable toxicity. Progression-free survival (PFS) assessed by an independent review committee is the primary endpoint, whereas investigator-assessed PFS, overall survival, objective response rate, disease control rate, duration of response, resection rate of liver metastases, quality of life, and safety are the secondary endpoints. Enrollment commenced in May 2021. Discussion: A prospective, randomized, phase III trial will provide a meaningful comparison of the efficacy and safety of anlotinib plus CAPEOX with standard treatment for patients with unresectable RAS/BRAF WT mCRC.

Is lung involvement a favorable prognostic factor for pancreatic ductal adenocarcinoma with synchronous liver metastases?-A propensity score analysis.

BACKGROUND: For advanced pancreatic cancer, pulmonary metastases (PM) have been considered favorable factors compared to metastases of other sites, but it remains unknown whether the prognosis of patients with synchronous liver and lung metastases is better than that of non-PM. METHODS: Data was derived from a two-decade cohort and included 932 cases of pancreatic adenocarcinoma with synchronous liver metastases (PACLM). Propensity score matching (PSM) was applied to balance 360 selected cases, grouped into PM (n = 90) and non-PM (n = 270). Overall survival (OS) and survival-related factors were analyzed. RESULTS: In PSM-adjusted data, the median OS was 7.3 and 5.8 months, for PM and non-PM, respectively (p = 0.16). Multivariate analysis revealed that male gender, poor performance status, higher hepatic tumor burden, ascites, elevated carbohydrate antigen 19-9, and lactate dehydrogenase were factors of poor survival (p < 0.05). Chemotherapy was the only independent significant factor of favorable prognosis (p < 0.05). CONCLUSION: Although lung involvement was indicated to be a favorable prognostic factor for patients with PACLM in the whole cohort, PM were not associated with better survivals in the subset of cases subjected to PSM adjustment.

MCT4/Lactate Promotes PD-L1 Glycosylation in Triple-Negative Breast Cancer Cells.

Triple-negative breast cancer (TNBC) has the highest percentage of lymphocytic infiltration among breast cancer subtypes, and TNBC patients may benefit from anti-PD-1/PD-L1 immunotherapy. However, some cases whether the immune checkpoint blockade (ICB) shows low targeting efficiency have occurred and effective synergistic targets need to be found, which inspired our exploration of the co-expression analysis of MCT4 (SLC16A3) and PD-L1 (CD274) and their potential regulatory mechanisms. After bioinformatic analysis of the relationship between MCT4 and PD-L1, we validated their positive co-expression relationship in triple-negative breast cancer through multiple immunohistochemical staining (mIHC), CRISPR/Cas9, and lentiviral transduction for MCT4 knockout (sgMCT4/231 KO) or overexpression (pEGFP-N1-MCT4/231). We examined the effect of lactate treatment on PD-L1 expression in triple-negative breast cancer cells by qRT-PCR and Western blot. Combined with our results, we found that MCT4 positively regulated PD-L1 expression through discharging lactate and stabilized PD-L1 through promoting its glycosylation by the classic WNT pathway in MDA-MB-231 cells. More importantly, the high co-expression of MCT4 and PD-L1 appears to predict more effective targets for treating TNBC, which would improve immune checkpoint therapy for TNBC.

Systematic Analysis of Molecular Subtypes and Immune Prediction Based on CD8 T Cell Pattern Genes Based on Head and Neck Cancer.

CD8+ T lymphocytes, also known as cytotoxic T lymphocytes, are the most powerful antitumour cells in the human body. Patients with head and neck squamous cell carcinoma (HNSCC) in whom CD8+ T lymphocyte infiltration is high have a better prognosis. However, the clinical significance and prognostic significance of CD8+ T cell-related regulatory genes in HNSCC remain unclear, and further research is required. In total, 446 CD8+ T cell-related genes were obtained using WGCNA. It was discovered that 111 genes included within the TCGA and GSE65858 datasets were intimately linked to the patient's prognosis. These genes were included in the subsequent analysis. According to consensus clustering analysis, HNSCC samples were classified into 3 subtypes (IC1, IC2, and IC3). There were substantial differences between the three subtypes in terms of immunological molecules, immune function, and the response to drug treatment. In addition, the 8-gene signature, which was generated premised on CD8+ T cell-related genes, exhibited stable prognostic prediction in the TCGA and GEO datasets and different HNSCC patient subgroups and independently served as a prognostic indicator for HNSCC. More importantly, the 8-gene signature effectively predicted immunotherapy response. We first constructed a molecular subtype of HNSCC based on CD8+ T cell-related genes. Between the three subtypes, there were significant differences in the prognosis, clinical features, immunological molecules, and drug treatment response. The 8-gene signature that was further constructed effectively predicted prognosis and immunotherapy response.

Clinicopathological Features, Staging Classification, and Clinical Outcomes of Esophageal Melanoma: Evaluation of a Pooled Case Series.

Studies that have attempted to validate the staging systems and the predictors of survival for patients with primary malignant melanoma of the esophagus (PMME) have been underpowered given their scarcity and small scale. We aimed to review a large number of PMME cases to know more about its clinicopathological features, TNM staging systems, and survival predictors of PMME. Case reports on PMME were extracted from PubMed/Medline through bibliography search and our center. A total of 287 PMME cases were identified. The majority of the patient population was male (72.08%). The most common location of PMME was the lower esophagus (50.62%) and middle esophagus (35.39%). Among the patients, 82.28% received surgical intervention. The median overall survival (OS) duration was 15 months (0.5-244). The American Joint Commission on Cancer staging classification (AJCC) for the mucosal melanoma of the upper aerodigestive tract with stage IVB and IVC integrated in stage IVA showed better distribution of OS than that for esophageal carcinoma. T stage, N stage, and surgery had significant impacts on OS duration in univariate analysis. However, only T stage and N stage were identified as independent factors for OS duration in the multivariate Cox models. PMME is an aggressive tumor with poor prognosis. The AJCC staging system for mucosal melanoma with stage IVB and IVC integrated in stage IVA may be a better option for staging PMME patients. T stage and N stage are independent factors for OS.

Isoliquiritigenin inhibits non-small cell lung cancer progression via m6A/IGF2BP3-dependent TWIST1 mRNA stabilization.

BACKGROUND: N6-methyladenosine (m6A) has been identified to regulate the tumorigenesis and development of various tumors, including non-small cell lung cancer (NSCLC). Isoliquiritigenin (ISL), derived from the Chinese herb licorice, shows a significant anti-tumor activity on multiple human cancers. However, the role of ISL on NSCLC through m6A is still unclear. PURPOSE: Here, we investigated the anti-tumor effect of ISL on NSCLC, and explored whether ISL affected the NSCLC phenotype by modulating its m6A modification. METHODS: Cell proliferation, migration and invasion assays were performed to evaluate the inhibitory effects of ISL on NSCLC cells. M6A enrichment was determined by m6A quantitative analysis. The mechanism regarding IGF2BP3 was explored using RIP-PCR, MeRIP-qPCR and RNA decay analysis. RESULTS: ISL significantly repressed the proliferation, migration and invasion of NSCLC cells in vitro. In addition, m6A reader IGF2BP3 expression significantly increased in NSCLC tissues compared to adjacent tissues, and was positively correlated with NSCLC patients' poor survival. Mechanistically, ISL reduced m6A modification and down-regulated IGF2BP3 expression in NSCLC. Furthermore, IGF2BP3 enhanced the mRNA stability of twist family bHLH transcription factor 1 (TWIST1) in m6A-dependent manner. Moreover, ISL treatment combined with TWSIT1 knockdown effectively reversed IGF2BP3 overexpression-induced NSCLC cells' proliferation, migration and invasion. CONCLUSION: Our findings uncover that ISL might function as an anticarcinogen through targeting IGF2BP3/m6A/TWIST1 axis for NSCLC.

Epifriedelinol Ameliorates DMBA-Induced Breast Cancer in Albino Rats by Regulating the PI3K/AKT Pathway.

We evaluated the protective effect of epifriedelinol against breast cancer and postulated an underlying mechanism. Breast cancer was induced by a single dose of 50 mg/kg 7,12-Dimethylbenanthracene (DMBA), and rats were treated with 100 or 200 mg/kg (i.p.) epifriedelinol for 4 weeks. We then evaluated the effect of epifriedelinol on tumor growth, oxidative stress and serum inflammatory cytokine levels in DMBA-induced breast cancer. Protein and mRNA levels were determined using western blotting and quantitative reverse transcription polymerase chain reaction, respectively. The tumor volume and weight were significantly (p < 0.01) decreased in the epifriedelinol-treated group compared to the negative control group. Epifriedelinol decreased the altered levels of oxidative stress and serum inflammatory cytokines in rats with DMBA-induced breast cancer. Protein levels of PI3K, AKT and mTOR and mRNA levels of PI3K, AKT, Map3k1, Erbb2 and Pdk1 were decreased in the mammary tissue of epifriedelinol-treated rats with DMBA-induced breast cancer. Apoptosis was significantly induced in the epifriedelinol-treated group compared to the negative control group. In conclusion, epifriedelinol ameliorates DMBA-induced breast cancer by regulating the PI3K/AKT pathway.

Apatinib and Ginsenoside-Rb1 Synergetically Control the Growth of Hypopharyngeal Carcinoma Cells.

BACKGROUND: Apatinib is an anticancer drug known to inhibit the vascular endothelial growth factor receptor-2 (VEGFR-2) through regulating tyrosine kinases. Drug resistance and reduced activity in various cancers is the matter of great concern; thus, researchers opt to use combination of the two or more drugs. So far, its gynergetic anticancer role with a traditional Chinese drug Ginsenoside-Rb1 (G-Rb1) has not been studied in cancers including hypopharyngeal carcinoma. OBJECTIVE: The current study is aimed at investigating the anticancer synergetic effects of G-Rb1 and apatinib in hypopharyngeal carcinoma. METHODS: The synergetic effects of both drugs on cell proliferation, wound healing and cell migration, and cell apoptosis were studied in hypopharyngeal carcinoma cells. Furthermore, the xenograft rat model was generated, and tumor inhibition was monitored after treating rats with both drugs as mono- and combination therapy. In addition, protein expression and localization were performed by western blotting and immunofluorescent staining, respectively. RESULTS: The analyses of the data showed that combination therapy of apatinib and G-Rb1 significantly inhibited the proliferation, migration, and wound healing capability of hypopharyngeal carcinoma cells. Moreover, the glycolysis rate of the cells in the combination therapy (apatinib and G-Rb1) group was significantly decreased as compared to that in the monotherapy group or no treatment group, suggesting that the glycolysis inhibition led to the inhibition of tumor growth. Moreover, the combination therapy on xenograft rats dramatically reduced the tumor size. Furthermore, combination therapy also exhibited an increased count of CD3+ and CD4+ T cells, as well as the ratio between CD4+ and CD8+ T cells. CONCLUSION: Interestingly, a combination of apatinib and G-Rb1 induced more tumor cell apoptosis and reduced cell proliferation than the individual drug treatment and promote antitumor immunity by enhancing immunomodulatory molecules. Thus, we believe that this study could serve as a valuable platform to assess the synergetic anticancer effects of the herbal as well as synthetic medicines.

Icotinib alone or with bevacizumab as first-line therapy in Chinese patients with advanced nonsquamous non-small cell lung cancer and activating EGFR mutations: A retrospective study.

BACKGROUND: This study focused on comparing the safety and therapeutic effects between icotinib monotherapy and icotinib plus bevacizumab combined therapy in non-small cell lung cancer (NSCLC) cases harboring EGFR mutations. METHODS: Data were collected retrospectively from the Cancer Institute and Hospital of Tianjin Medical University between October 2018 and December 2019, where the NSCLC cases that harbored EGFR mutations underwent first-line therapy with icotinib in the presence or absence of bevacizumab. This study included 90 cases, of which 60 patients were in the icotinib group (I) and 30 in the icotinib plus bevacizumab group (IB). RESULTS: The follow-up period to evaluate median PFS in our study was 18 months. Median PFS was 18.0 months (95% confidence interval [CI]: 14.7-21.3) with icotinib plus bevacizumab and 11 months (95% CI: 8.9-13.1) with icotinib alone (hazard ratio 0·54, 95% CI: 0.31-0.92; p = 0.029). According to the subgroup analyses based on the type of EGFR genomic aberration, a prolonged median PFS was observed in the cases harboring exon 21 point mutation (Ex21.L858R) in the IB group compared to the I group (not reached vs. 11 months [8.8-13.2], p = 0.021). However, the difference between the cases harboring exon 19 deletions in the EGFR gene was not significant. The DCR and ORR were comparable between both groups. Substantially higher incidences of hypertension and proteinuria were observed in the combined group compared to the icotinib monotherapy group. CONCLUSIONS: This is the first study to provide further evidence of the benefits of applying icotinib in combination with bevacizumab as first-line treatment for advanced NSCLC cases harboring EGFR mutations. However, these findings need to be verified through prospective phase 3 clinical studies.

Apatinib prevents natural killer cell dysfunction to enhance the efficacy of anti-PD-1 immunotherapy in hepatocellular carcinoma.

Apatinib, a selective vascular endothelial growth factor receptor 2-tyrosine kinase inhibitor, has demonstrated activity against a wide range of solid tumors, including advanced hepatocellular carcinoma (HCC). Preclinical and preliminary clinical results have confirmed the synergistic antitumor effects of apatinib in combination with anti-programmed death-1 (PD-1) blockade. However, the immunologic mechanism of this combination therapy remains unclear. Here, using a syngeneic HCC mouse model, we demonstrated that treatment with apatinib resulted in attenuation of tumor growth and increased tumor vessel normalization. Moreover, our results indicated that natural killer cells, but not CD4+ or CD8+ T cells mediated the therapeutic efficacy of apatinib in HCC mouse models. As expected, the combined administration of apatinib and anti-PD-1 antibody into tumor-bearing mice generated potent immune responses resulting in a remarkable reduction of tumor growth. Furthermore, increased interferon-γ and decreased tumor necrosis factor-α and interleukin-6 levels were observed, suggesting the potential benefits of combination therapy with PD-1 blockade and apatinib in HCC.

Camrelizumab in Combination with Apatinib in Patients with Advanced Hepatocellular Carcinoma (RESCUE): A Nonrandomized, Open-label, Phase II Trial.

PURPOSE: We assessed the efficacy and safety of camrelizumab [an anti-programmed death (PD-1) mAb] plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS: This nonrandomized, open-label, multicenter, phase II study enrolled patients with advanced HCC who were treatment-naïve or refractory/intolerant to first-line targeted therapy. Patients received intravenous camrelizumab 200 mg (for bodyweight ≥50 kg) or 3 mg/kg (for bodyweight <50 kg) every 2 weeks plus oral apatinib 250 mg daily. The primary endpoint was objective response rate (ORR) assessed by an independent review committee (IRC) per RECIST v1.1. RESULTS: Seventy patients in the first-line setting and 120 patients in the second-line setting were enrolled. As of January 10, 2020, the ORR was 34.3% [24/70; 95% confidence interval (CI), 23.3-46.6] in the first-line and 22.5% (27/120; 95% CI, 15.4-31.0) in the second-line cohort per IRC. Median progression-free survival in both cohorts was 5.7 months (95% CI, 5.4-7.4) and 5.5 months (95% CI, 3.7-5.6), respectively. The 12-month survival rate was 74.7% (95% CI, 62.5-83.5) and 68.2% (95% CI, 59.0-75.7), respectively. Grade ≥3 treatment-related adverse events (TRAE) were reported in 147 (77.4%) of 190 patients, with the most common being hypertension (34.2%). Serious TRAEs occurred in 55 (28.9%) patients. Two (1.1%) treatment-related deaths occurred. CONCLUSIONS: Camrelizumab combined with apatinib showed promising efficacy and manageable safety in patients with advanced HCC in both the first-line and second-line setting. It might represent a novel treatment option for these patients.See related commentary by Pinato et al., p. 908.

Effect of pretreatment with dexamethasone on the efficacy and immune-related adverse events of immunotherapy in first-line treatment for advanced non-small cell lung cancer: a network meta-analysis of randomized control trials.

BACKGROUND: The pretreatment of dexamethasone on the efficacy and immune-related adverse events of immunotherapy involving programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PDL1) inhibitors is an effective option for the first-line treatment of advanced non-small-cell lung cancer (NSCLC). With the immunosuppressive effect, corticosteroids may be used to reduce the efficacy of PDL1 blockade, as well as prevent overactive immune responses, thereby reducing the occurrence of immune-related adverse events (irAEs). This study quantitatively summarized the current evidence, and compared the efficacy and toxicity of therapies involving chemotherapy plus PDL1 inhibitors plus dexamethasone pretreatment (I+C+D) with chemotherapy plus PDL1 inhibitors (I+C) and therapies involving PDL1 inhibitors or chemotherapy alone (I or C). METHODS: The protocol of this study was registered with PROSPERO (CRD42021227281). By using a network meta-analysis approach, the different treatments were compared and ranked based on their effectiveness and rates of irAEs at the different grades. Risk rates were determined through direct meta-analysis and indirect treatment comparison. RESULTS: 12 randomized clinical trials were included with a total of 7155 NSCLC patients. Network meta-analysis generated 15 comparisons. The combination treatment of I+C+D showed a longer progression-free survival and overall survival, while I+C was less toxic, and the toxicity of I+C+D or that of I+C had been significantly decreased, compared to that of monotherapy with either drug. According to the ranking analysis, I+C+D is consistently proved to be the most effective therapeutic strategy, while I+C is linked to the lowest rate of irAEs, with the rate of grade value of ≥3 irAEs. CONCLUSION: The combination treatment of I+C+D is the most effective approach for the first-line treatment of NSCLC patients treated with I+C, I, or C.

Anlotinib optimizes anti-tumor innate immunity to potentiate the therapeutic effect of PD-1 blockade in lung cancer.

BACKGROUND: Many anti-angiogenic agents have the potential to modulate the tumor microenvironment and improve immunotherapy. Anlotinib has demonstrated anti-tumor efficacy in non-small cell lung cancer (NSCLC) in third-line clinical trials. However, its roles in immune regulation and potentially synergistic anti-tumor effect in combination with immune checkpoint inhibition remain unclear. METHODS: Here, based on a syngeneic lung cancer mouse model, the intratumoral immunological changes post-anlotinib treatment in the model were assessed. Furthermore, it was tested whether anlotinib could enhance the anti-tumor effect of αPD-1 in vivo. RESULTS: This study shows that anlotinib increased infiltration of the innate immune cells, including natural killer (NK) cells, and antigen-presenting cells (APC), which include M1-like tumor-associated macrophages (TAM) and dendritic cells (DC), whereas the percentage of M2-like TAM was dramatically reduced. Subsequently, when combined with PD-1/PD-L1 (programmed cell death 1/PD-1 ligand 1) blockade, anlotinib conferred significantly synergistic therapeutic benefits. CONCLUSIONS: Overall, these findings describe a role for anlotinib in the innate immune cells in the tumor microenvironment and a potentially synergistic anti-tumor combination with immune checkpoint inhibition.

Safety and Efficacy of Apatinib Monotherapy for Unresectable, Metastatic Esophageal Cancer: A Single-Arm, Open-Label, Phase II Study.

LESSONS LEARNED: Patient compliance with the oral dosage treatment was good, with no need for hospitalization. Patients with tracheal and esophageal fistulas can take crushed apatinib by nutrient tube, with the same bioavailability and efficacy. Apatinib may be an effective and safe second- or further-line treatment for advanced esophageal cancer. BACKGROUND: Apatinib is an inhibitor of vascular endothelial growth factor receptor-2 (VEGFR2), which is thought to play a role in esophageal cancer progression. Our goal was to evaluate the efficacy and safety of apatinib in patients with unresectable esophageal cancer and to examine whether VEGFR2 expression influenced the clinical response. METHODS: This single-arm, open-label, investigator-initiated phase II study enrolled patients with advanced squamous cell carcinoma (SCC) or adenocarcinoma of the esophagus or esophagogastric junction who were admitted to Tianjin Medical University Cancer Institute and Hospital between August 2017 and January 2019. Apatinib monotherapy (500 mg/day) was given orally or via an enteral tube until disease progression, unacceptable toxicity, withdrawal, or death. Patients were followed until treatment was discontinued or death. The main endpoints were tumor response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs). RESULTS: Among 32 patients screened for inclusion, 30 were included in the safety and survival analyses (i.e., received apatinib), and 26 were included in the efficacy analysis (at least one imaging follow-up). Median follow-up time and exposure to apatinib were 5.34 months and 72 days, respectively. Among 26 patients included in the efficacy analysis, 2 had a partial response (PR; 7.7%) and 14 had stable disease (SD; 53.8%). The overall response rate (ORR) was 7.7%, and the disease control rate (DCR) was 61.5%. Median PFS and OS were 4.63 months (95% confidence interval, 2.11-7.16 months) and 6.57 months (4.90 months to not estimable), respectively. Fifteen patients (50.0%) experienced treatment-related AEs, most commonly hypertension (26.7%), diarrhea (20.0%), and hand-foot-skin reaction (10.0%). No patients had grade ≥4 treatment-related AEs. CONCLUSION: Apatinib was effective as second- or further-line treatment for advanced esophageal cancer.