Publications by authors named "Valery Breder"

5 Publications

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Lenvatinib versus sorafenib for first-line treatment of unresectable hepatocellular carcinoma: patient-reported outcomes from a randomised, open-label, non-inferiority, phase 3 trial.

Lancet Gastroenterol Hepatol 2021 Aug 2;6(8):649-658. Epub 2021 Jun 2.

FSBSI N N Blokhin Russian Cancer Research Center, Moscow, Russia.

Background: Hepatocellular carcinoma is the third-leading cause of cancer-related death worldwide. Preservation of health-related quality of life (HRQOL) during treatment is an important therapeutic goal. The aim of this study was to evaluate the effect of treatment with lenvatinib versus sorafenib on HRQOL.

Methods: REFLECT was a previously published multicentre, randomised, open-label, non-inferiority phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic treatment for unresectable hepatocellular carcinoma. Eligible patients were aged 18 years or older with unresectable hepatocellular carcinoma and one or more measurable target lesion per modified Response Evaluation Criteria in Solid Tumors criteria, Barcelona Clinic Liver Cancer stage B or C categorisation, Child-Pugh class A, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or lower, and adequate organ function. Patients were randomly assigned (1:1) via an interactive voice-web response system; stratification factors for treatment allocation included region; macroscopic portal vein invasion, extrahepatic spread, or both; ECOG performance status; and bodyweight. Patient-reported outcomes (PROs), collected at baseline, on day 1 of each subsequent cycle, and at the end of treatment, were evaluated in post-hoc analyses of secondary and exploratory endpoints in the analysis population, which was the subpopulation of patients with a PRO assessment at baseline. A linear mixed-effects model evaluated change from baseline in PROs, including European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and hepatocellular carcinoma-specific QLQ-HCC18 scales (both secondary endpoints of the REFLECT trial). Time-to-definitive-deterioration analyses were done based on established thresholds for minimum differences for worsening in PROs. Responder analyses explored associations between HRQOL and clinical response. This study is registered with ClinicalTrials.gov, NCT01761266.

Findings: Of 954 eligible patients randomly assigned to lenvatinib (n=478) or sorafenib (n=476) between March 14, 2013, and July 30, 2015, 931 patients (n=468 for lenvatinib; n=463 for sorafenib) were included in this analysis. Baseline PRO scores reflected impaired HRQOL and functioning and considerable symptom burden relative to full HRQOL. Differences in overall mean change from baseline estimates in most PRO scales generally favoured the lenvatinib over the sorafenib group, although the differences were not nominally statistically or clinically significant. Patients treated with lenvatinib experienced nominally statistically significant delays in definitive, meaningful deterioration on the QLQ-C30 fatigue (hazard ratio [HR] 0·83, 95% CI 0·69-0·99), pain (0·80, 0·66-0·96), and diarrhoea (0·52, 0·42-0·65) domains versus patients treated with sorafenib. Significant differences in time to definitive deterioration were not observed for other QLQ-C30 domains, and there was no difference in time to definitive deterioration on the global health status/QOL score (0·89, 0·73-1·09). For most PRO scales, differences in overall mean change from baseline estimates favoured responders versus non-responders. Across all scales, HRs for time to definitive deterioration were in favour of responders; median time to definitive deterioration for responders exceeded those for non-responders by a range of 4·8 to 14·6 months.

Interpretation: HRQOL for patients undergoing treatment for unresectable hepatocellular carcinoma is an important therapeutic consideration. The evidence of HRQOL benefits in clinically relevant domains support the use of lenvatinib compared with sorafenib to delay functional deterioration in advanced hepatocellular carcinoma.

Funding: Eisai and Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S2468-1253(21)00110-2DOI Listing
August 2021

Utility of cfDNA Fragmentation Patterns in Designing the Liquid Biopsy Profiling Panels to Improve Their Sensitivity.

Front Genet 2019 12;10:194. Epub 2019 Mar 12.

Atlas Oncology Diagnostics, Ltd., Moscow, Russia.

Genotyping of cell-free DNA (cfDNA) in plasma samples has the potential to allow for a noninvasive assessment of tumor biology, avoiding the inherent shortcomings of tissue biopsy. Next generation sequencing (NGS), a leading technology for liquid biopsy analysis, continues to be hurdled with several major issues with cfDNA samples, including low cfDNA concentration and high fragmentation. In this study, by employing Ion Torrent PGM semiconductor technology, we performed a comparison between two multi-biomarker amplicon-based NGS panels characterized by a substantial difference in average amplicon length. In course of the analysis of the peripheral blood from 13 diagnostic non-small cell lung cancer patients, equivalence of two panels, in terms of overall diagnostic sensitivity and specificity was shown. A pairwise comparison of the allele frequencies for the same somatic variants obtained from the pairs of panel-specific amplicons, demonstrated an identical analytical sensitivity in range of 140 to 170 bp amplicons in size. Further regression analysis between amplicon length and its coverage, illustrated that NGS sequencing of plasma cfDNA equally tolerates amplicons with lengths in the range of 120 to 170 bp. To increase the sensitivity of mutation detection in cfDNA, we performed a computational analysis of the features associated with genome-wide nucleosome maps, evident from the data on the prevalence of cfDNA fragments of certain sizes and their fragmentation patterns. By leveraging the support vector machine-based machine learning approach, we showed that a combination of nucleosome map associated features with GC content, results in the increased accuracy of prediction of high inter-sample sequencing coverage variation (areas under the receiver operating curve: 0.75, 95% CI: 0.750-0.752 vs. 0.65, 95% CI: 0.63-0.67). Thus, nucleosome-guided fragmentation should be utilized as a guide to design amplicon-based NGS panels for the genotyping of cfDNA samples.
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http://dx.doi.org/10.3389/fgene.2019.00194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422983PMC
March 2019

Efficacy and Safety of the Biosimilar ABP 215 Compared with Bevacizumab in Patients with Advanced Nonsquamous Non-small Cell Lung Cancer (MAPLE): A Randomized, Double-blind, Phase III Study.

Clin Cancer Res 2019 04 7;25(7):2088-2095. Epub 2019 Jan 7.

Amgen Inc., Thousand Oaks, California.

Purpose: This phase III study compared clinical efficacy and safety of the biosimilar ABP 215 with bevacizumab reference product (RP) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC).

Patients And Methods: Patients were randomized 1:1 to ABP 215 or bevacizumab 15 mg/kg every three weeks for 6 cycles. All patients received carboplatin and paclitaxel every three weeks for ≥4 and ≤6 cycles. The primary efficacy endpoint was risk ratio of objective response rate (ORR); clinical equivalence was confirmed if the 2-sided 90% confidence interval (CI) of the risk ratio was within the margin of 0.67 to 1.5. Secondary endpoints included risk difference of ORR, duration of response (DOR), progression-free survival (PFS), and overall survival (OS); pharmacokinetics, adverse events (AEs), and incidence of antidrug antibodies (ADAs) were monitored.

Results: A total of 820 patients were screened; 642 were randomized to ABP 215 ( = 328) and bevacizumab ( = 314). Overall, 128 (39.0%) and 131 (41.7%) patients in the ABP 215 and bevacizumab groups, respectively, had objective responses [ORR risk ratio: 0.93 (90% CI, 0.80-1.09)]. In the ABP 215 and bevacizumab group, 308 (95.1%) and 289 (93.5%) patients, respectively, had at least 1 AE; 13 (4.0%) and 11 (3.6%) experienced a fatal AE. Anti-VEGF toxicity was low and comparable between treatment groups. At week 19, median trough serum drug concentration was 132 μg/mL (ABP 215 group) and 129 μg/mL (bevacizumab group). No patient tested positive for neutralizing antibodies.

Conclusions: ABP 215 is similar to bevacizumab RP with respect to clinical efficacy, safety, immunogenicity, and pharmacokinetics. The totality of evidence supports clinical equivalence of ABP 215 and bevacizumab.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2702DOI Listing
April 2019

Towards standardization of next-generation sequencing of FFPE samples for clinical oncology: intrinsic obstacles and possible solutions.

J Transl Med 2017 01 31;15(1):22. Epub 2017 Jan 31.

Atlas Biomed Group, Moscow, 121069, Russia.

Background: Next generation sequencing has a potential to revolutionize the management of cancer patients within the framework of precision oncology. Nevertheless, lack of standardization decelerated entering of the technology into the clinical testing space. Here we dissected a number of common problems of NGS diagnostics in oncology and introduced ways they can be resolved.

Methods: DNA was extracted from 26 formalin fixed paraffin embedded (FFPE) specimens and processed with the TrueSeq Amplicon Cancer Panel (Illumina Inc, San Diego, California) targeting 48 cancer-related genes and sequenced in single run. Sequencing data were comparatively analyzed by several bioinformatics pipelines.

Results: Libraries yielded sufficient coverage to detect even low prevalent mutations. We found that the number of FFPE sequence artifacts significantly correlates with pre-normalization concentration of libraries (rank correlation -0.81; p < 1e-10), thus, contributing to sample-specific variant detection cut-offs. Surprisingly, extensive validation of EGFR mutation calls by a combination of aligners and variant callers resulted in identification of two false negatives and one false positive that were due to complexity of underlying genomic change, confirmed by Sanger sequencing. Additionally, the study of the non-EGFR amplicons revealed 33 confirmed unique mutations in 17 genes, with TP53 being the most frequently mutated. Clinical relevance of these finding is discussed.

Conclusions: Reporting of entire mutational spectrum revealed by targeted sequencing is questionable, at least until the clinically-driven guidelines on reporting of somatic mutations are established. The standardization of sequencing protocols, especially their data analysis components, requires assay-, disease-, and, in many cases, even sample-specific customization that could be performed only in cooperation with clinicians.
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http://dx.doi.org/10.1186/s12967-017-1125-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282851PMC
January 2017