Genomic CpG methylation and TKI-response of the patient with advanced stage lung adenocarcinoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE147377 | GEO | 2021/03/01
REPOSITORIES: GEO
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Project description:Purpose: To determine the 8-week disease control rate (DCR) of sorafenib monotherapy in patients with advanced non-small-cell lung cancer (NSCLC) in the BATTLE trial. Methods: Patients with pre-treated NSCLC consented to baseline biopsies for pre-specified biomarkers assessment and biomarker discovery. Sorafenib was given at 400 mg orally twice daily until tumor progression or unacceptable toxicity. Outcomes by pre-specified biomarkers were analyzed and a Sorafenib sensitivity signature developed using high-throughput gene expression profiles of NSCLC cell lines and baseline biopsies. Results: 105 patients were eligible and 98 patients were evaluable. Median age was 62 (range 34-81) years, 51% of patients were male, 75% were former/current smokers, and 89% had an ECOG performance status of 0-1. Median prior chemotherapies for stage IV NSCLC were two. Median follow-up was 9.4 (range: 1.3-32.2) months. Overall, 8-week DCR was 58.2%. Patients with EGFR mutations had significantly lower 8-week DCR compared to patients with wild-type tumors (23.1% vs. 64.2%, P=0.0119), and patients with K-RAS mutations had the highest 8-week DCR (67%). Most commonly reported treatment-related adverse events include hand-foot syndrome (59.6%), fatigue (42.3%), rash (40.4%), diarrhea (38.5%), and weight loss (38.5%). Sorafenib sensitivity signature developed in cell lines was associated with an improved outcome. Conclusion: Patients with wild-type EGFR, including those with K-RAS mutation, may benefit from sorafenib as opposed to patients with EGFR mutation. We identify a gene expression signature associated with an improved outcome in patients with wild-type EGFR treated with sorafenib. BATTLE-2 trial is ongoing to validate those results. ClinicalTrials.gov number, NCT00411671.
2014-06-01 | GSE31428 | GEO
Project description:Purpose: To determine the 8-week disease control rate (DCR) of sorafenib monotherapy in patients with advanced non-small-cell lung cancer (NSCLC) in the BATTLE trial. Methods: Patients with pre-treated NSCLC consented to baseline biopsies for pre-specified biomarkers assessment and biomarker discovery. Sorafenib was given at 400 mg orally twice daily until tumor progression or unacceptable toxicity. Outcomes by pre-specified biomarkers were analyzed and a Sorafenib sensitivity signature developed using high-throughput gene expression profiles of NSCLC cell lines and baseline biopsies. Results: 105 patients were eligible and 98 patients were evaluable. Median age was 62 (range 34-81) years, 51% of patients were male, 75% were former/current smokers, and 89% had an ECOG performance status of 0-1. Median prior chemotherapies for stage IV NSCLC were two. Median follow-up was 9.4 (range: 1.3-32.2) months. Overall, 8-week DCR was 58.2%. Patients with EGFR mutations had significantly lower 8-week DCR compared to patients with wild-type tumors (23.1% vs. 64.2%, P=0.0119), and patients with K-RAS mutations had the highest 8-week DCR (67%). Most commonly reported treatment-related adverse events include hand-foot syndrome (59.6%), fatigue (42.3%), rash (40.4%), diarrhea (38.5%), and weight loss (38.5%). Sorafenib sensitivity signature developed in cell lines was associated with an improved outcome. Conclusion: Patients with wild-type EGFR, including those with K-RAS mutation, may benefit from sorafenib as opposed to patients with EGFR mutation. We identify a gene expression signature associated with an improved outcome in patients with wild-type EGFR treated with sorafenib. BATTLE-2 trial is ongoing to validate those results. ClinicalTrials.gov number, NCT00411671. Gene expression profiles were measured in 37 core biopsies from patients with refractory non-small cell lung cancer treated with sorafenib in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. We report a Sorafenib sensitivity gene expression signature trained in vitro (separate GEO submission), and tested in baseline biopsies collected in the BATTLE trial.
2014-06-01 | E-GEOD-31428 | biostudies-arrayexpress
Project description:Purpose: To determine the 8-week disease control rate (DCR) of sorafenib monotherapy in patients with advanced non-small-cell lung cancer (NSCLC) in the BATTLE trial. Methods: Patients with pre-treated NSCLC, ECOG performance status (PS) 0-2, consented to biopsies to test for biomarker assessment. Sorafenib was given at 400 mg orally twice daily until tumor progression or an unacceptable toxicity. Tumor evaluations were performed at baseline and every 8 weeks. Correlations of outcomes by biomarker groups were analyzed. Results: 105 patients were eligible and 98 patients were evaluable. Median age was 62 (range 34-81) years, 51% of patients were male, 75% were former/current smokers, and 89% had an ECOG PS of 0-1. Median prior chemotherapies for stage IV NSCLC were two. Median follow-up was 9.4 (range: 1.3-32.2) months. Eight-week DCRs by histology were 59.1%, 57.1%, and 55.6% for adenocarcinomas, squamous cell carcinomas and other histologies respectively. Patients with tumors harboring EGFR mutations had significantly lower 8-week DCR compared to patients with wild-type tumors (23.1% vs. 64.2%, P=0.0119), and patients with tumors harboring K-RAS mutations had the highest 8-week DCR (67%). Most commonly reported treatment-related adverse events include hand-foot syndrome (59.6%), fatigue (42.3%), rash (40.4%), diarrhea (38.5%), and weight loss (38.5%). Conclusion: 8-week DCR was better in patients treated with sorafenib who had EGFR wild-type tumors (including those with K-RAS mutations) when compared to those who had EGFR mutations. Additional analyses are warranted to further explore the biology of these tumors and related patient outcomes with sorafenib treatment. ClinicalTrials.gov number, NCT00411671.
2012-06-18 | GSE32036 | GEO
Project description:Afamitresgene autoleucel, an HLA-restricted autologous specific peptide enhanced affinity receptor (SPEAR) T-cell therapy targeting MAGE-A4, was developed to treat HLA-A*02 positive patients with MAGE-A4 expressing solid tumors. A multicenter, dose-escalation, Phase 1 trial (NCT03132922) was conducted evaluating afamitresgene autoleucel in patients with relapsed or refractory (≥1 prior line of therapy) metastatic solid tumors. The primary endpoint was safety. The secondary endpoint was anti-tumor activity including overall response rate, best overall response, time to response, duration of response, duration of stable disease, progression-free survival and overall survival. Thirty-eight patients were treated with afamitresgene autoleucel across 9 tumor types, including 16 with synovial sarcoma (SS). Overall, afamitresgene autoleucel was well tolerated. The most common adverse events were cytopenias. Cytokine release syndrome occurred in 55% of all patients with severity grade ≤2 in 90% of reported cases. Overall response rate (ORR) was 24% and disease control rate (DCR) was 74% with objective responses in 7 patients with SS, 1 patient with non-small cell lung cancer, and 1 patient with head and neck squamous cell carcinoma. ORR in patients with SS, all prior treated with ifosfamide chemotherapy, was 44%, and DCR was 94%. Median progression-free survival and overall survival were 20.4 weeks (95% CI: 10.0, 52.1) and 58.1 weeks (95% CI: 36.3,-), respectively, for patients with SS and 12.3 weeks (95% CI: 10.857, 19.1) and 42.9 weeks (95% CI: 20.7, -), respectively, for the overall population. Translational findings demonstrated that afamitresgene autoleucel infiltrates into tumors, has an IFNγ-driven mechanism-of-action, and triggers adaptive immune responses. Overall, afamitresgene autoleucel has an acceptable safety profile with early and durable responses in HLA-A*02 positive patients with MAGE-A4 expressing solid tumors, especially in patients with metastatic SS. The recommended treatment regimen for Phase 2 evaluation involves lymphodepleting chemotherapy consisting of cyclophosphamide 600 mg/m2 x 3 days and fludarabine 30 mg/m2 x 4 days followed by afamitresgene autoleucel at a dose range of 1 to 10 billion transduced T-cells.
2022-05-05 | GSE202156 | GEO
Project description:Afatinib may augment pembrolizumab therapy and improve the ORR in HNSCC patients. The paired tissue analysis showed that afatinib, an epidermal growth factor (EGFR) tyrosine kinase inhibitor, may enhance antigen presentation, natural killer cell–mediated cytotoxicity, and immune reactions. We also identified unaltered methyl-thioadenosine phosphorylase (MTAP) levels, EGFR amplification, and high programmed death-ligand 1 expression as possible predictive biomarkers for therapeutic outcomes.
2021-12-10 | GSE190575 | GEO
Project description:Sitravatinib is an immunomodulatory tyrosine kinase inhibitor that can augment responses when combined with programmed death-1 (PD-1) inhibitors such as nivolumab. We report a phase 2 study of neoadjuvant sitravatinib in combination with nivolumab in patients with locally advanced clear cell renal cell carcinoma (ccRCC) prior to curative nephrectomy (NCT03680521). The primary endpoint was objective response rate (ORR) prior to surgery with a null hypothesis ORR = 5% and the alternative hypothesis set at ORR = 30%. Secondary endpoints included correlative immune effects and disease-free survival (DFS). Twenty patients were evaluable for safety and 17 for efficacy. The ORR was 11.8%, and 24-month DFS probability was 88·0% (95% CI 61.0 to 97.0). There were no grade 4/5 treatment-related adverse events. Correlative blood and tissue analyses showed changes in the tumour microenvironment resulting in an immunologically active tumour by the time of surgery. These data suggest that short-term neoadjuvant sitravatinib and nivolumab does not substantially increase ORR but can modulate the immune microenvironment and yield high DFS probabilities in patients with locally advanced ccRCC.
2022-09-06 | GSE212525 | GEO
Project description:Focal adhesion kinase (FAK) is frequently amplified and acts as an immune modulator across cancer types. However, evidence illustrates that targeting FAK is most effective in combination therapy rather than in monotherapy. Here, we demonstrated that the FAK inhibitor, IN10018, and pegylated liposome doxorubicin (PLD) exerted effective antitumor activity preclinically and clinically (clinical trial ID: CTR20200913). The clinical study is a phase Ib trial which includes dose confirmation and expansion sections. The primary endpoint is objective response rate (ORR). Secondary endpoints include disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. As of the data cutoff date (30 November 2022), a total of 61 platinum-resistant ovarian cancer (PROC) patients were enrolled and no IN10018-related grade 4 or 5 adverse effects (AEs) were reported. The ORR was 46.3% (95% confidence interval (CI): 32.6%, 60.4%) and the DCR was 83.3% (95% CI: 70.7%, 92.1%). The median PFS was 7.26 months (95% CI: 5.16 - 8.02 months), and the median duration of response (DoR) was 6.93 months (95% CI: 4.17 - 9.13 months). The primary and secondary endpoints were met. The median OS was not reached, and still maturing. Notably, the regimen exhibited response latency and long-lasting effects in the clinical trial, outcomes frequently observed in immunotherapy. Our preclinical study revealed that the 2-drug combination can maximize the immunogenic cell death (ICD) of cancer cells, boosting the maturation of dendritic cells (DCs) and stimulating CD8 T cells to strengthen the antitumor effects. At present, immune checkpoint blockade (ICB) is widely considered to exert long-term treatment benefits by activating antitumor immunity. However, many cancer patients show poor clinical responses to ICB due in part to the lack of immunogenic niche. Our work confirmed that IN10018 in combination with PLD can prime the tumor microenvironment, supplementing it with sufficient tumor-infiltrating lymphocytes (TILs) to activate antitumor immunity. Correspondingly, animal studies validated that the antitumor effects of ICB can be significantly enhanced by this doublet regimen. The preclinical results warrant further clinical exploration for the triplet regimen with IN10018, PLD, and ICB.
2023-12-31 | GSE233112 | GEO
Project description:Genomic alterations that activate Fibroblast Growth Factor Receptor 2 (FGFR2) are common in intrahepatic cholangiocarcinoma (ICC), a deadly bile duct malignancy. FGFR kinase inhibitors (FGFRi) have shown promising efficacy against FGFR2+ ICC in clinical trials, leading to the regulatory approval of the ATP-competitive FGFR inhibitors, pemigatinib and infigratinib (BGJ398), for this subset of patients who failed standard treatment . However, the objective response rate (ORR) for each FGFR inhibitor (FGFRi) studied to date in FGFR2+ ICC is <45% and disease progression invariably arises within ~6-12 months. By employing high-throughput drug screens and signaling studies, we identified signaling feedback via the EGFR pathway as a major mediator of adaptive resistance to FGFR kinase inhibition in a set of patient-derived ICC models. To further gain insights into the synergistic effects of the EGFR/FGFR combination and address the mechanisms underlying the survival pathway reactivation, we performed RNA sequencing in our FGFR-driven ICC models (ICC21 and ICC10-6). For these studies, we treated FGFR2 fusion+ ICC cell lines ICC21/ICC10-6 with four conditions (DMSO/Infigratinib/Afatinib/Combo) for 4 hours followed by RNA sequencing.
2024-03-21 | E-MTAB-11324 | biostudies-arrayexpress
Project description:<h4><strong>INTRODUCTION:</strong> The identification of frequent acquired mutations shows that patients with oligodendrogliomas have divergent biology with differing prognoses regardless of histological classification. A better understanding of molecular features as well as their metabolic pathways is essential.</h4><h4><strong>OBJECTIVES: </strong>The aim of this study was to examine the relationship between the tumor metabolome, six genomic aberrations (isocitrate dehydrogenase1 [IDH1] mutation, 1p/19q codeletion, tumor protein p53 [TP53] mutation, O<sup>6</sup>-methylguanin-DNA methyltransferase [MGMT] promoter methylation, epidermal growth factor receptor [EGFR] amplification, phosphate and tensin homolog [PTEN] methylation), and the patients' survival time.</h4><h4><strong>METHODS:</strong> We applied <sup>1</sup>H high-resolution magic-angle spinning (HRMAS) nuclear magnetic resonance (NMR) spectroscopy to 72 resected oligodendrogliomas.</h4><h4><strong>RESULTS:</strong> The presence of IDH1, TP53, 1p19q codeletion, MGMT promoter methylation reduced the relative risk of death, whereas PTEN methylation and EGFR amplification were associated with poor prognosis. Increased concentration of 2-hydroxyglutarate (2HG), N-acetyl-aspartate (NAA), myo-inositol and the glycerophosphocholine/phosphocholine (GPC/PC) ratio were good prognostic factors. Increasing the concentration of serine, glycine, glutamate and alanine led to an increased relative risk of death.</h4><h4><strong>CONCLUSION:</strong> HRMAS NMR spectroscopy provides accurate information on the metabolomics of oligodendrogliomas, making it possible to find new biomarkers indicative of survival. It enables rapid characterization of intact tissue and could be used as an intraoperative method.</h4>
2021-10-06 | MTBLS869 | MetaboLights
Project description:Immune checkpoint inhibitors (ICIs) targeting PD-1/L1 have modest efficacy in hepatocellular carcinoma (HCC) as single agents, but combination regimens have demonstrated increased clinical benefit at the expense of treatment toxicities. Exposed phosphatidylserine suppresses the innate immune response in the tumor microenvironment (TME). Targeting phosphatidylserine does not induce tumor responses in the clinical setting when used as monotherapy or in combination with cytotoxic and targeted therapies, but may induce pro-inflammatory and –immune stimulating effects that enhance ICI activity. This hypothesis was tested in a single-arm phase 2 trial evaluating bavituximab, a phosphatidylserine targeting antibody, plus pembrolizumab in patients with unresectable HCC who had not received prior systemic treatments (ClinicalTrials.gov ID: NCT03519997). The primary end point was investigator-assessed objective response rate (ORR) among evaluable patients, and secondary end points included progression-free survival (PFS) and the incidence of adverse events. Among 28 evaluable patients, the ORR was 32.1%, including 2 complete responses, and a disease control rate of 64.3%. Median PFS was 6.3 months (95% CI, 1.3-11.3 months). Treatment related adverse events of any grade occurred in 45.7% of patients with grade 3 or 4 adverse events occurring in 14.3% of patients. Exploratory analyses of baseline tumor specimens showed that a depletion of B cells, and the expression of smooth muscle actin and immune checkpoints in stroma was associated with tumor response. An RNA-based TME assay which distinguishes immune-rich of inflammatory tumors was also shown to be predictive of ORR. These results suggest that targeting phosphatidylserine may lead to synergistic effects with ICIs without increasing toxicity rates, and future studies on this therapeutic strategy may be guided by biomarkers characterizing the TME.
2024-02-08 | GSE242154 | GEO