Challenges of Using Predictive Biomarkers in Clinical Trials

2015 ◽  
pp. 147-162
Keyword(s):  
Clinical Trials ◽  
Predictive Biomarkers

scholarly journals BIOM-60. BIOMARKER EVALUATION FOR IMIPRIDONE ONC206 REVEALS ClpP, ATF4, MYC, EGFR and HIF1 AS KEY PREDICTORS OF ANTI-CANCER EFFICACY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii14-ii15
Author(s):  
Sara Morrow ◽  
Mathew Garnett ◽  
Ultan McDermott ◽  
Cyril Benes ◽  
Joshua Allen ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Strong Predictor ◽  
Predictive Biomarkers ◽  
Receptor Expression ◽  
Tumor Type ◽  
Anticancer Efficacy ◽  
Type Selection ◽  
Egfr Expression ◽  
Transport Chain ◽  
Biomarker Evaluation

Abstract ONC206 is a DRD2 antagonist and ClpP agonist that is a chemical derivative of ONC201, which is in Phase II clinical trials for H3 K27M-mutant glioma. We have previously reported that dopamine receptor expression correlates with ONC201 and ONC206 efficacy. Here, we evaluated additional predictive biomarkers for both agents in the GDSC panel using RNA-seq expression data. ClpP emerged as a strong predictor of efficacy for ONC206 (IC50: p = 1.83E-4, AUC: 9.92E-13). ClpP activation enhances degradation of its substrates, including electron transport chain members responsible for oxidative phosphorylation (OXPHOS). Imipridones activate the integrated stress response involving ATF4 and cause proteasomal degradation of c-myc, which also reduces OXPHOS. Accordingly, high ATF4 (IC50: p = 4.92E-5, AUC: p=2.84E-9) and elevated c-myc correlated with ONC206 efficacy (IC50: p = 6.42E-6, AUC: 3.31E-12). EGFR expression is inversely correlate with DRD2 expression in glioma and its activation is associated with glycolysis. Low EGFR expression correlated with increased ONC206 efficacy (IC50: p = 4.32E-7, AUC: p = 6.44E-20). Loss of HIF1 shunts cellular metabolism toward OXPHOS. Low HIF1 expression correlated with increased anticancer efficacy for ONC206 (IC50: p = 1.96E-3, AUC: p = 1.56E-11). Expression of each of the five markers was significantly different in cell lines that achieved an IC90 with ONC206 (~10%) versus those that did not. A similar analysis for ONC201 revealed that ClpP, MYC and EGFR are more predictive of efficacy relative to ATF4 and HIF1. Combinatorial biomarker analyses revealed MYC/EGFR as the most significant predictor of IC50 for both agents. ClpP/MYC and ClpP/HIF1 were the most significant predictors of AUC for ONC201 and ONC206, respectively. Ongoing studies are further investigating tumor type enrichment of biomarkers. Prediction of innate imipridone sensitivity using biomarkers identified in this study may guide patient and tumor type selection in clinical trials.

Angiogenic and T-effector subgroups identified by gene expression profiling (GEP) and propensity for PBRM1 and BAP1 alterations in clear cell renal cell carcinoma (ccRCC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 343-343
Author(s):  
Pedro C. Barata ◽  
Shuchi Gulati ◽  
Andrew Elliott ◽  
Arpit Rao ◽  
Hans J. Hammers ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Trials ◽  
Hierarchical Clustering ◽  
Immune Cell ◽  
Expression Profiles ◽  
Gene Expression Signature ◽  
Predictive Biomarkers ◽  
Primary Tumors ◽  
Metastatic Sites ◽  
Patient Subgroups

343 Background: With the emergence of multiple active treatment options in RCC, predictive biomarkers for optimal treatment selection are lacking. Gene expression data from IMmotion151 and Javelin Renal 101 clinical trials generated anti-angiogenic and immune signatures that warrant further validation. We aimed to describe the genomic and gene expression profiles in a multi-institutional database of patients with ccRCC, and its association with other biomarkers of interest. Methods: Whole transcriptome sequencing was performed for ccRCC patient samples submitted to a commercial CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ) from February 2019 to September 2020. Tumor GEP and hierarchical clustering based on the validated 66-gene signature (D’Costa et al, 2020) were used to identify patient subgroups. Samples from both primary tumors and metastatic sites were included. Results: A total of 316 patients with ccRCC, median age 62 (range 32-90), 71.8% men, were included. Tissue samples were obtained from primary tumor (46.5%), lung (12.3%), bone (9.5%), liver (4.7%) and other metastatic sites (27%). Gene expression analysis identified angiogenic, mixed and T-effector subgroups in 24.1%, 51.3% and 24.7%, respectively. Patients with angiogenic subgroup tumors compared to those with T-effector subgroup tumors were more likely to be older (63 versus 60 years, p=0.035), female (40.8% versus 16.7%, p=0.0009) and more frequently found in pancreatic/small bowel metastases (75% versus 12.5%, p=0.0103). Biomarkers of potential response to immunotherapy such as PD-L1 (p=0.0021), TMB (not significant), and dMMR/MSI-H status (not significant) were more frequent in the T-effector subgroup. PBRM1 mutations were more common in the angiogenic subgroup (62.0% vs 37.5%, p=0.0034) while BAP1 mutations were more common in the T-effector subgroup (18.6% versus 3.0%, p= 0.0035). Immune cell population abundance (e.g. NK cells, monocytes) and immune checkpoint gene expression (TIM-3, PD-L1, PD-L2, CTLA4) were also increased in the T-effector subgroup. Conclusions: Our hierarchical clustering results based on the 66-gene expression signature were concordant with results from prior studies. Patient subgroups identified by evaluation of angiogenic and T-effector signature scores exhibit significantly different mutations and immune profiles. These findings require prospective validation in future biomarker-selected clinical trials.

scholarly journals New drug developments in metastatic gastric cancer

2018 ◽  
Vol 11 ◽  
pp. 175628481880807 ◽  
Author(s):  
Aaron C. Tan ◽  
David L. Chan ◽  
Wasek Faisal ◽  
Nick Pavlakis
Keyword(s):  
Gastric Cancer ◽  
Clinical Trials ◽  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Predictive Biomarkers ◽  
Metastatic Gastric Cancer ◽  
New Era

Metastatic gastric cancer is associated with a poor prognosis and novel treatment options are desperately needed. The development of targeted therapies heralded a new era for the management of metastatic gastric cancer, however results from clinical trials of numerous targeted agents have been mixed. The advent of immune checkpoint inhibitors has yielded similar promise and results from early trials are encouraging. This review provides an overview of the systemic treatment options evaluated in metastatic gastric cancer, with a focus on recent evidence from clinical trials for targeted therapies and immune checkpoint inhibitors. The failure to identify appropriate predictive biomarkers has hampered the success of many targeted therapies in gastric cancer, and a deeper understanding of specific molecular subtypes and genomic alterations may allow for more precision in the application of novel therapies. Identifying appropriate biomarkers for patient selection is essential for future clinical trials, for the most effective use of novel agents and in combination approaches to account for growing complexity of treatment options.

scholarly journals Definition of a new blood cell count (BCT) score for early survival prediction for non-small cell lung cancer patients treated with atezolizumab: Integrated analysis of 4 multicenter clinical trials

2021 ◽  
Author(s):  
jianguo Zhou ◽  
Ada Hang-Heng Wong ◽  
haitao wang ◽  
Su-han Jin ◽  
Fangya Tan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Treatment Cycle ◽  
Single Agent ◽  
Predictive Biomarkers ◽  
Small Cell ◽  
Blood Cell Count ◽  
Small Cell Lung ◽  
Nsclc Patients ◽  
Agent Treatment

Introduction Immune checkpoint inhibitor (ICI) therapy is a major breakthrough in non-small cell lung cancer (NSCLC) treatment. However, valid predictive biomarkers are lacking. Blood cell count test (BCT) provides a direct quantification of various types of immune cells (ICs) to reveal the immune landscape to predict ICI treatment. Methods This study analyzed four international, multi-center clinical trials (OAK, BIRCH, POPLAR and FIR trials) to conduct post-hoc analyses of NSCLC patients undergoing atezolizumab (anti-PD-L1) single-agent treatment (n = 1,479) or docetaxel single-agent treatment (n = 707). BCT was conducted at three timepoints: pre-treatment (T1), the first day of treatment cycle 3 (T2), and first day of treatment cycle 5 (T3). Univariate and multivariate Cox regression analyses were conducted to identify early BCT biomarkers to predict atezolizumab treatment outcomes in NSCLC patients. Results The BCT biomarkers of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) at timepoint T3 and neutrophil-to-monocyte ratio (NMR) at timepoint T2 were identified as strong predictive biomarkers for atezolizumab (Ate)-treated NSCLC patients in comparison to docetaxel (Dtx)-treated patients regarding overall survival (OS) (BCTscore low-risk: HR Ate vs Dtx = 1.54 (95% CI: 1.04-2.27), P = 0.036; high-risk: HR Ate vs Dtx = 0.84 (95% CI: 0.62-1.12), P = 0.236). This identified BCTscore model showed better OS AUC in the OAK (AUC12month=0.696), BIRCH (AUC12month=0.672) and POPLAR+FIR studies (AUC12month=0.727) than that of each of the three single BCT biomarkers. Conclusion The BCTscore model is a valid predictive and prognostic biomarker for atezolizumab-treated NSCLC patients.

Is There a Precise Adjuvant Therapy for Esophagogastric Carcinoma?

2018 ◽  
pp. 280-291 ◽  
Author(s):  
Elizabeth Cartwright ◽  
Florence K. Keane ◽  
Peter C. Enzinger ◽  
Theodore Hong ◽  
Ian Chau
Keyword(s):  
Clinical Trials ◽  
Treatment Options ◽  
Locally Advanced ◽  
Predictive Biomarkers ◽  
Standard Of Care ◽  
Global Consensus ◽  
Esophagogastric Cancer ◽  
Genetic Features ◽  
Related Mortality ◽  
Optimal Treatment Strategy

Esophagogastric cancer remains a leading cause of cancer-related mortality worldwide. The prognosis for patients with locally advanced disease is poor and the majority of patients with operable tumors treated with surgery alone will have recurrent disease. A multimodal approach to treatment with adjunctive chemotherapy or chemoradiotherapy is therefore the standard of care for these patients. However, there is no global consensus on the optimal treatment strategy and international guidelines vary. National clinical trials inform local practice: neoadjuvant, perioperative, and adjuvant chemotherapy and radiotherapy combinations are all possible treatment options in the management of resectable esophagogastric cancer. A number of clinical trials are ongoing, which seek to directly compare multimodal treatment options and hope to provide clarity in this area. Furthermore, increased understanding of the molecular and genetic features of esophagogastric cancer may help to guide management of operable disease by determining optimal patient selection through identification of predictive biomarkers of response and the application of novel targeted agents.

Drug Development: Neoadjuvant Opportunities in Breast Cancer

2013 ◽  
pp. 73-79
Author(s):  
Priya Rastogi ◽  
Charles E. Geyer ◽  
Eleftherios P. Mamounas ◽  
Angela DeMichele
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Cancer Biology ◽  
Residual Disease ◽  
Pathologic Complete Response ◽  
Predictive Biomarkers ◽  
Preoperative Therapy ◽  
New Agents ◽  
Her2 Breast Cancer ◽  
Improved Outcomes

Preoperative therapy allows for a higher rate of breast conserving surgery and has been shown equivalent to adjuvant therapy. Preoperative therapy provides an opportunity to obtain insights into breast cancer biology and to accelerate the evaluation of new therapies. Clinical trials have shown that women who achieve a pathologic complete response (pCR) have substantially improved outcomes compared with those who do not achieve a pCR. The U.S. Food and Drug Administration (FDA) meta-analysis demonstrated that the association of pCR and long-term outcomes is greater in women with aggressive breast cancer subtypes. In patients with HER2+ breast cancer, the addition of trastuzumab to chemotherapy in the neoadjuvant setting has doubled pCR and correlated with improved outcomes. Clinical trials will evaluate tailoring the use of radiation therapy in patients who have received neoadjuvant therapy. Trials have established neoadjuvant endocrine therapy as a valid treatment and research option for ER-rich breast cancer. The neoadjuvant setting allows for evaluation of endocrine therapies in combination with newer targeted therapies in the appropriate patient populations. The neoadjuvant setting provides opportunity to accelerate the evaluation of new agents, improve pCR rates, and identify predictive biomarkers for response. This setting provides the opportunity for screening new agents in combination with chemotherapy while obtaining serial biopsies to understand biology of response and resistance. Although current standard therapies provide substantial benefits for patients with a pCR, patients with residual disease are at substantial risk for disease recurrence. New agents are being evaluated in patients with high-risk residual disease following standard treatment regimens.

scholarly journals Ethics of Mandatory Research Biopsy for Correlative End Points Within Clinical Trials in Oncology

2010 ◽  
Vol 28 (15) ◽  
pp. 2635-2640 ◽  
Author(s):  
Jeffrey Peppercorn ◽  
Iuliana Shapira ◽  
Deborah Collyar ◽  
Teresa Deshields ◽  
Nancy Lin ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Clinical Decision Making ◽  
Predictive Biomarkers ◽  
Clinical Decision ◽  
Cancer Tissue ◽  
End Points ◽  
Research Participants ◽  
Group B ◽  
Treatment Alternatives

Clinical investigators in oncology are increasingly interested in using molecular analysis of cancer tissue to understand the biologic bases of response or resistance to novel interventions and to develop prognostic and predictive biomarkers that will guide clinical decision making. Some scientific questions of this nature can only be addressed, or may best be addressed, through the conduct of a clinical trial in which research biopsies are obtained from all participants. However, trial designs with mandatory research biopsies have raised ethical concerns related to the risk of harm to participants, the adequacy of voluntary informed consent, and the potential for misunderstanding among research participants when access to an experimental intervention is linked to the requirement to undergo a research biopsy. In consideration of the ethical and scientific issues at stake in this debate, the Cancer and Leukemia Group B Ethics Committee proposes guidelines for clinical trials involving mandatory research biopsies. Any cancer clinical trial that requires research biopsies of participants must be well designed to address the scientific question, obtain the biopsy in a way that minimizes risk, and ensure that research participants are fully informed of the risks, rationale, and requirements of the study, as well as of treatment alternatives. Further guidelines and discussions of this issue are specified in this position paper. We feel that if these principles are respected, an informed adult with cancer can both understand and voluntarily consent to participation in a clinical trial involving mandatory research biopsy for scientific end points.

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