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The use of next generation sequencing (NGS) to guide patient selection for phase 1 clinical trials

Miller, RE; Brown, NE; Speirs, A; Shaw, HM; Adeleke, S; Gougis, P; Bennett, P; ... Kristeleit, RS; + view all (2016) The use of next generation sequencing (NGS) to guide patient selection for phase 1 clinical trials. Annals of Oncology , 27 (Suppl 6) pp. 114-135. 10.1093/annonc/mdw368.44. Green open access

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Abstract

Background: Therapeutically targeting actionable mutations in cancer may increase response rates in Phase I clinical trials. We undertook a pilot study to assess the feasibility and therapeutic benefit of incorporating NGS screening into the patient pathway for phase 1 cancer trials. Methods: NGS tumour profiling was performed using a 22 gene amplicon-based panel (Life Technologies Colon & Lung V2) on 117 consecutive patients (pts) referred over a 13 month period for Phase I trials. BRCA1/2 analysis was performed in pts with epithelial ovarian cancer. Results: 117 pts (67% female) with a median age of 59 (range 22-78) years were included. Common tumour types were ovarian (n = 20), colorectal (n = 16), breast (n = 13), endometrial (n = 12) and lung (n = 8) cancer. NGS was successfully performed in 108 (92%) pts with a median time to results of 12 days (range 6-39). 82% of pts (89/108) had a detected variant in ≥ 1 gene with an average of 3 variants (range 0-26) in 2 genes (0-10) per case. Common mutations included TP53 (69%), KRAS (14%), PIK3CA (11%) and SMAD4 (9%). BRCA1/2 mutations were present in 11 (55%) ovarian cancer pts. Overall, 49 (45%) pts had ≥ 1 actionable mutation. Detected variants were reviewed in a local genomics review board to assess actionability prior to considering therapy. 53 pts were commenced on a Phase I trial; 18 (34%) were genotype directed. Median duration on trial was 73 days for pts on genotype (7-260 days) or non-genotype (20-582) directed trials with 50% and 24% of allocated patients continuing on study respectively. Of pts evaluable for response (n = 47), partial response (PR), stable disease (SD) and progressive disease (PD) were observed in 50%, 29% and 21% of pts on genotype directed trials and 20%, 37% and 43% of pts on non-genotype directed respectively. Excluding pts on BRCA1/2 directed trials, PR, SD and PD were observed in 33%, 33% and 33% of pts respectively in genotype-directed studies. Conclusions: NGS is feasible in real time and may affect clinical outcome in the phase 1 setting. Almost half of pts had a potentially actionable mutation. Initial response rates for pts treated on genotype-driven trials are encouraging. Benefit is likely to be augmented using a broader NGS panel which is planned for future assessment.

Type: Article
Title: The use of next generation sequencing (NGS) to guide patient selection for phase 1 clinical trials
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/annonc/mdw368.44
Publisher version: http://doi.org/10.1093/annonc/mdw368.44
Language: English
Additional information: Copyright © European Society for Medical Oncology 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Annals of Oncology following peer review. The definitive publisher-authenticated version Miller, RE; Brown, NE; Speirs, A; Shaw, HM; Adeleke, S; Gougis, P; Bennett, P; (2016) The use of next generation sequencing (NGS) to guide patient selection for phase 1 clinical trials. Annals of Oncology , 27 (Suppl 6) pp. 114-135 is available online at: http://doi.org/10.1093/annonc/mdw368.44.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/1528952
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