To determine correlation of inter reader variability in sum of diameters using RECIST 1.1 with end point assessment in lung cancer.

e13557 Background: Lung cancer is the leading cause of cancer death in the world including more than 160,000 deaths in the US. The purpose of the study was to determine whether inter reader variability in Sum of Diameters (SOD) of tumor burden has any correlation with variability in end point assessment in lung cancer progression. RECIST 1.1 is based on the SOD of target lesions seen on imaging studies. Response criteria for evaluation of target lesions include - Complete response (CR), Partial response (PR), Progressive disease (PD) and Stable disease (SD). The key determinant of patient response is based on Target Lesion response which in turn is determined by SOD. Inter reader variability study plays an important role in the development of reliable diagnostic tools and understanding of imaging outcomes given the confounding factors like effusion, atelectasis and consolidation in lung cancer that affect Target Lesion selection. Methods: Retrospective analysis of 470 patients was carried out using RECIST 1.1. Double read with adjudication is the preferred read model for submission studies where images are read by two independent reviewers blinded to treatment allocation. As per RECIST 1.1, lesions were measured in the longest diameter for non-nodal and short axis for nodal lesions. This was followed by the calculation of SOD for total tumor burden. If these two primary reviewers disagree, then a third radiologist, the “adjudicator”, reviews the assessments performed by the first two radiologists and selects between the more accurate one. For further analysis, patients were divided into 2 groups, the one with no adjudication i.e. agreement between both readers and the second group with adjudication i.e. disagreement between both readers and ANOVA was used to perform analysis of Variance. Results: Of 470 patients, 332 patients with disagreement were adjudicated, while there was agreement on 138 patients assessments between both readers. SOD of baseline visits for all patients was assessed using ANOVA - single factor with following results: F ratio of 4.76 for Disagreement group was more than F crit (3.86) with P-value 0.03, while for Agreement group F value was less than F crit. Conclusions: There is a direct relationship of variability in SOD at baseline between two readers to the possibility of disagreement in their end point assessment. Additional rules around selection and measurement of Target Lesions should be proposed in protocol to reduce variability and improve endpoint assessment outcomes.[Table: see text]

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Overexpression of 14-3-3γ Induces the Migration and Invasion of Human Lung Adenocarcinoma A549 Cells

Journal of Health Science and Medical Research ◽

10.31584/jhsmr.2021796 ◽

2021 ◽

Author(s):

Pritsana Raungrut ◽

Nidanut Champoochana ◽

Paramee Thongsuksai ◽

Kamontip Promnares

Keyword(s):

Lung Cancer ◽

Cancer Progression ◽

A549 Cells ◽

Migration And Invasion ◽

P Value ◽

Transwell Assay ◽

Scratch Assay ◽

Invasion And Migration ◽

Tumor Cell Migration

Objective: 14-3-3 gamma (γ) is known to modulate the development and progression of many cancers. However, the evidence in lung cancer is still unclear. In this study, effects of 14-3-3γ on tumor cell migration and invasion were investigated. Material and Methods: A 14-3-3γ expression vector was made and transfected into A549 cells. In-vitro scratch assay and transwell assay were applied to assess migration and invasion, respectively. Western blotting was used to detect expression of proteins related to epithelial–mesenchymal transition.Results: Closing rate of scratch wounds, both in classical and non-classical scratch assay, was significantly increased in 14-3-3γ-overexpressing cells in comparison to the controls. Similarly, by transwell assay, a significant increase in the invasion and migration was shown in the 14-3-3γ-overexpressing cells in comparison to the null vector cells, by approximately 79.2% (p-value=0.002) and 131.2% (p-value<0.001), respectively. In addition, increased 14-3-3γ expression resulted in a significant increase of β-catenin and Snail but not for E-cadherin and vimentin. Conclusion: The study demonstrates the role of 14-3-3γ protein on lung cancer progression via migration and invasion processes, possibly providing a new targeted therapy for non-small cell lung cancer.

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Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment of Stage IIIA-N2 EGFR-Mutant Non–Small-Cell Lung Cancer (EMERGING-CTONG 1103): A Randomized Phase II Study

Journal of Clinical Oncology ◽

10.1200/jco.19.00075 ◽

2019 ◽

Vol 37 (25) ◽

pp. 2235-2245 ◽

Cited By ~ 22

Author(s):

Wen-Zhao Zhong ◽

Ke-Neng Chen ◽

Chun Chen ◽

Chun-Dong Gu ◽

Jun Wang ◽

...

Keyword(s):

Lung Cancer ◽

Adjuvant Therapy ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Pathologic Complete Response ◽

Complete Response ◽

Small Cell ◽

Small Cell Lung ◽

Stage Iiia ◽

End Point

PURPOSE To assess the benefits of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as neoadjuvant/adjuvant therapies in locally advanced EGFR mutation-positive non–small-cell lung cancer. PATIENTS AND METHODS This was a multicenter (17 centers in China), open-label, phase II, randomized controlled trial of erlotinib versus gemcitabine plus cisplatin (GC chemotherapy) as neoadjuvant/adjuvant therapy in patients with stage IIIA-N2 non–small-cell lung cancer with EGFR mutations in exon 19 or 21 (EMERGING). Patients received erlotinib 150 mg/d (neoadjuvant therapy, 42 days; adjuvant therapy, up to 12 months) or gemcitabine 1,250 mg/m2 plus cisplatin 75 mg/m2 (neoadjuvant therapy, two cycles; adjuvant therapy, up to two cycles). Assessments were performed at 6 weeks and every 3 months postsurgery. The primary end point was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; secondary end points were pathologic complete response, progression-free survival (PFS), overall survival, safety, and tolerability. RESULTS Of 386 patients screened, 72 were randomly assigned to treatment (intention-to-treat population), and 71 were included in the safety analysis (one patient withdrew before treatment). The ORR for neoadjuvant erlotinib versus GC chemotherapy was 54.1% versus 34.3% (odds ratio, 2.26; 95% CI, 0.87 to 5.84; P = .092). No pathologic complete response was identified in either arm. Three (9.7%) of 31 patients and zero of 23 patients in the erlotinib and GC chemotherapy arms, respectively, had a major pathologic response. Median PFS was significantly longer with erlotinib (21.5 months) versus GC chemotherapy (11.4 months; hazard ratio, 0.39; 95% CI, 0.23 to 0.67; P < .001). Observed adverse events reflected those most commonly seen with the two treatments. CONCLUSION The primary end point of ORR with 42 days of neoadjuvant erlotinib was not met, but the secondary end point PFS was significantly improved.

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Objective response of the dual CYP17-Lyase (L) inhibitor / androgen receptor (AR) antagonist, VT-464, in patients with CRPC.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.273 ◽

2016 ◽

Vol 34 (2_suppl) ◽

pp. 273-273

Author(s):

Luke T. Nordquist ◽

Neal D. Shore ◽

Johann S. De Bono ◽

Shilpa Gupta ◽

William R. Berry ◽

...

Keyword(s):

Progressive Disease ◽

De Novo ◽

Objective Response ◽

Complete Response ◽

Target Lesion ◽

The Third ◽

Recist 1.1 ◽

Clinical Resistance ◽

Treatment Naïve ◽

Clinical Trial Information

273 Background: VT-464 is an oral, CYP17-L inhibitor and non-clinically an antagonist of the AR and its variants associated with clinical resistance to enzalutamide (ENZ) and abiraterone (AA). The safety, tolerability and initial pharmacodynamic effects (tumor responses, PSA and testosterone (T) decreases) of VT-464 given without steroid supplementation either bid with food or QD at night with dinner were evaluated in the Phase (Ph) 1/2 studies INO-VT-464-CL-001 (NCT02012920) and INO-VT-464-CL-004 (NCT02361086), respectively. Patients were either treatment-naïve (TN), or had failed AA or ENZ or AA/ENZ/chemotherapy (at least 2 out of the three). Preliminary objective response results from both studies are presented herein. Methods: Target lesions were assessed at baseline and during therapy using CT or MRI. Target lesion responses were categorized as a complete response (CR), partial response (PR), progressive disease (PD), or stable disease (SD) using RECIST 1.1. Patients with ≥ 1 target lesion and ≥ 1 post-baseline scan following VT-464 BID (INO-VT-464-CL-001) or QD (INO-VT-464-CL-004) were included in the analysis. Results are reported through a data cutoff of 01 Sep 2015. Results: Combined, 23 patients (8 TN, 4 AA, 7 ENZ, 4 AA/ENZ/chemotherapy) from both Ph 1/2 studies had ≥ 1 target lesion and ≥ 1 post-baseline scan. Of 15 patients included who were treated BID (Study 001), 1 had PD, 12 had SD and 2 had a PR. Of 8 patients who were treated QD (Study 004), 2 had PD, 5 had SD and 1 had a PR. No patient had a CR in either study. For the 3 patients with PRs one patient had a prior response to ENZ but failed taxane-based chemotherapy, another was de novo resistant to ENZ, while the third was TN. For the 3 PRs, one was confirmed with a repeat scan 8-weeks later and the others have repeat scans pending. Conclusions: Potent and selective CYP17-L inhibition, PSA reductions, and objective tumor responses in TN and ENZ-failure patients have been observed with oral VT-464 administered bid (de Bono et al, GU ASCO 2015) or QD (Shore et al, GU ASCO 2016). Preliminary results demonstrate that the QD regimes are as efficacious as BID regimens. All Ph 2 CRPC studies now utilize a 750 mg QD regimen. Clinical trial information: NCT02012920 and NCT02361086.

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Response criteria for intratumoral immunotherapy in solid tumors: ItRECIST.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.3141 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 3141-3141

Author(s):

Gregory V. Goldmacher ◽

Anuradha D. Khilnani ◽

Robert H. I. Andtbacka ◽

Jason J. Luke ◽

F. Stephen Hodi ◽

...

Keyword(s):

Solid Tumors ◽

Evaluation Criteria ◽

Response Assessment ◽

Target Lesion ◽

Tumor Burden ◽

Therapeutic Modality ◽

Overall Response ◽

Recist 1.1 ◽

Trial Protocols ◽

Systemic Responses

3141 Background: The approval of intratumoral (IT) immunotherapy for metastatic melanoma and the active development of numerous novel IT drugs have created a need for standardized evaluation of response to this unique treatment strategy. The Response Evaluation Criteria in Solid Tumors (RECIST) is not suitable for assessing responses separately for injected and noninjected tumors. Building on RECIST concepts, we propose an IT immunotherapy RECIST (itRECIST) to capture data and assess local and systemic responses in a standardized fashion for clinical trials involving IT immunotherapies. Methods: itRECIST will address the unique needs of IT immunotherapy trials but, where possible, aligns with RECIST 1.1 and iRECIST. It does not dictate which lesions to inject but provides guidelines for collecting data and assessing response as treatment evolves. Results: itRECIST enables overall response assessment, separate response assessments in injected and noninjected lesions, and continued assessment following modifications of therapy at initial progression. At baseline, lesions are classified into 4 categories: target injected, target noninjected, nontarget injected, and nontarget noninjected. After baseline, lesions can be reclassified from noninjected to injected if the investigator decides to change the lesions to inject, but target and nontarget designations never change. Overall response at each assessment is based on target lesion response (injected and noninjected), nontarget lesion response, and absence/appearance of new lesions. Noninjected lesion response is determined by comparing tumor burden with baseline and nadir values. Injected lesion assessment is based on visit-to-visit changes in the lesions injected during treatment and on a combined assessment once the patient is off treatment. A new response category is defined to capture progression that would be “confirmed” per iRECIST even though injected lesions are responding and therapy continues. Multiple examples have been created to aid in training and adoption. Conclusions: itRECIST is an important step toward a standardized method of response assessment for this promising and evolving therapeutic modality. The proposed guidelines can be adopted into trial protocols and routine clinical practice without the need for complex additional assessments by treating physicians. Until there is evidence to support wider use, itRECIST is intended only to support standardized collection of data and to facilitate exploratory analysis. Authors G.V.G. and A.D.K. contributed equally to this work.

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