The Experts below are selected from a list of 222 Experts worldwide ranked by ideXlab platform
Heather A Wakelee - One of the best experts on this subject based on the ideXlab platform.
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a highly sensitive and quantitative test platform for detection of nsclc egfr mutations in urine and plasma
Journal of Thoracic Oncology, 2016Co-Authors: Karen L Reckamp, Chris Karlovich, Lecia V Sequist, Heather A Wakelee, Ross D Camidge, Geoffrey R Oxnard, Vladislava O Melnikova, Karena Kosco, Maurice Perol, Peter J P CroucherAbstract:Abstract Introduction In approximately 60% of patients with NSCLC who are receiving EGFR tyrosine kinase inhibitors, resistance develops through the acquisition of EGFR T790M mutation. We aimed to demonstrate that a highly sensitive and quantitative next-generation sequencing analysis of EGFR mutations from urine and plasma specimens is feasible. Methods Short footprint mutation enrichment next-generation sequencing assays were used to interrogate EGFR activating mutations and the T790M resistance mutation in urine or plasma specimens from patients enrolled in TIGER-X (NCT01526928), a phase 1/2 clinical study of Rociletinib in previously treated patients with EGFR mutant–positive advanced NSCLC. Results Of 63 patients, 60 had evaluable tissue specimens. When the tissue result was used as a reference, the sensitivity of EGFR mutation detection in urine was 72% (34 of 47 specimens) for T790M, 75% (12 of 16) for L858R, and 67% (28 of 42) for exon 19 deletions. With specimens that met a recommended volume of 90 to 100 mL, the sensitivity was 93% (13 of 14 specimens) for T790M, 80% (four of five) for L858R, and 83% (10 of 12) for exon 19 deletions. A comparable sensitivity of EGFR mutation detection was observed in plasma: 93% (38 of 41 specimens) for T790M, 100% (17 of 17) for L858R, and 87% (34 of 39) for exon 19 deletions. Together, urine and plasma testing identified 12 additional T790M-positive cases that were either undetectable or inadequate by tissue test. In nine patients monitored while receiving treatment with Rociletinib, a rapid decrease in urine T790M levels was observed by day 21. Conclusions DNA derived from NSCLC tumors can be detected with high sensitivity in urine and plasma, enabling diagnostic detection and monitoring of therapeutic response from these noninvasive "liquid biopsy" samples.
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updated results from tiger x a phase i ii open label study of Rociletinib in patients pts with advanced recurrent t790m positive non small cell lung cancer nsclc
Journal of Clinical Oncology, 2016Co-Authors: Jonathan W Goldman, Heather A Wakelee, Karen L Reckamp, Jeancharles Soria, Ross D Camidge, Shirish M Gadgeel, Vassiliki A Papadimitrakopoulou, M Perol, Shannon Matheny, Darrin DespainAbstract:9045Background: Rociletinib is an oral, irreversible tyrosine kinase inhibitor of mutant epidermal growth factor receptor. Previously, we reported that Rociletinib is active at doses ≥ 500 mg BID i...
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epidermal growth factor receptor egfr genotyping of matched urine plasma and tumor tissue from non small cell lung cancer nsclc patients pts treated with Rociletinib
Journal of Clinical Oncology, 2016Co-Authors: Heather A Wakelee, Chris Karlovich, Karen L Reckamp, Jonathan W Goldman, Jeancharles Soria, Shirish M Gadgeel, M Perol, Benjamin Solomon, Vladislava O Melnikova, Joel W NealAbstract:9001Background: Rociletinib is an oral inhibitor of mutant EGFR, including T790M. We compared EGFR mutation detection in circulating tumor DNA from blood and urine to that in matched tissue in TIGE...
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Rociletinib a third generation egfr tyrosine kinase inhibitor current data and future directions
Expert Opinion on Pharmacotherapy, 2016Co-Authors: Jody C Chuang, Ameen A Salahudeen, Heather A WakeleeAbstract:ABSTRACTIntroduction: Major advances have been made since the discovery of driver mutations and their targeted therapies, especially in the treatment of patients with epidermal growth factor receptor (EGFR) mutations. Despite their initial efficacy in the majority of the patients with such driver mutations, all targeted therapies are limited by the eventual development of resistance mechanisms.Areas Covered: EGFR T790M mutation is a common resistance mechanism after treatment with first or second generation EGFR tyrosine kinase inhibitors (TKI). Rociletinib is one of the third generation EGFR TKIs with activity against T790M and activating EGFR mutations while sparing the wild-type EGFR. In this review, we discuss the current understanding and available data on Rociletinib, including the side effects associated with the medication. We will also review the BEAMing plasma test to detect T790M mutation without the need for repeat biopsy. Lastly, we review the potential resistance mechanisms after progression...
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abstract a31 assessment of egfr mutations in matched urine plasma and tumor tissue in nsclc patients treated with Rociletinib co 1686
Molecular Cancer Therapeutics, 2015Co-Authors: Shirish M Gadgeel, Chris Karlovich, Lecia V Sequist, Heather A Wakelee, Ross D Camidge, M Perol, Geoffrey R Oxnard, Vlada Melnikova, Karena Kosco, Cecile Rose T VibatAbstract:Background: The acquisition of suitable tumor tissue is a challenge for a significant fraction of late-stage NSCLC patients who require EGFR testing to inform choice of therapy. An alternative for these patients could be the assessment of EGFR mutations in circulating tumor DNA (ctDNA). In this study, we examined the detection of EGFR T790M mutation in ctDNA from urine, assessed urine sample requirements, and compared the results with contemporaneously matched tumor tissue and plasma in TIGER-X (NCT01526928), a Phase 1/2 clinical study of Rociletinib in previously treated mutant EGFR patients with advanced NSCLC. Rociletinib is an oral, potent, small-molecule irreversible tyrosine kinase inhibitor that selectively targets mutant forms of EGFR, including T790M, L858R and Del(19), while sparing wild-type EGFR. Methods: 63 Stage IIIB/IV NSCLC patients enrolled in either Phase 1 or 2 components of TIGER-X and representing all therapeutic dose groups consented to optional urine collection. Maximum sample volumes were 100 mL for urine and 2 mL for plasma. To maximize assay sensitivity in urine, samples containing the recommended sample volume of ≥90 mL (≥ 90% of maximum in this study) were evaluated; all samples received were processed to assess this recommendation. Urinary and plasma ctDNA were tested for mutations by the same EGFR assays using a sensitive and quantitative short footprint assay method that employs a mutation enrichment step followed by next generation sequencing. Results: Urine volumes ranged from 8-100 mL with a median DNA yield of 313 ng (N = 63). The median DNA yield was 299 ng for urine specimens with volume Conclusions: The analysis of ctDNA from urine identified a similar proportion of T790M+ patients as tissue-based testing with highest PPA amongst patients with urine volumes ≥90 mL. Discordant samples between urine and tissue that were not identified by the tumor test may be explained by tumor heterogeneity and/or inadequate biopsy. EGFR mutation detection from urine increases with urine volume and DNA yields and should be considered as a viable approach, particularly when tumor tissue is not available. Lastly, monitoring urine ctDNA T790M mutations longitudinally with baseline and post-therapy sampling could be clinically useful to determine benefit from therapy. Citation Format: Shirish Gadgeel, Chris Karlovich, Vlada Melnikova, Lecia V. Sequist, D. Ross Camidge, Heather Wakelee, Maurice Perol, Geoffrey R. Oxnard, Karena Kosco, Cecile Rose T. Vibat, Elaina Mann, Shannon Matheny, Lindsey Rolfe, Mitch Raponi, Mark G. Erlander, Karen Reckamp. Assessment of EGFR mutations in matched urine, plasma and tumor tissue in NSCLC patients treated with Rociletinib (CO-1686). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A31.
Chris Karlovich - One of the best experts on this subject based on the ideXlab platform.
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egfr genotyping of matched urine plasma and tumor tissue in patients with non small cell lung cancer treated with Rociletinib an egfr tyrosine kinase inhibitor
JCO Precision Oncology, 2018Co-Authors: Jonathan W Goldman, Chris Karlovich, Lecia V Sequist, Karen L Reckamp, Ross D Camidge, Shirish M Gadgeel, M Perol, Vlada Melnikova, Aleksandra Franovic, Stephen V LiuAbstract:PurposeLiquid biopsies represent an attractive alternative to tissue biopsies, particularly rebiopsies, in determining patient eligibility for targeted therapies. Clinical utility of urine genotyping, however, has not been explored extensively. We evaluated epidermal growth factor receptor (EGFR) T790M detection in matched urine, plasma, and tissue and the clinical outcomes of patients with advanced non–small-cell lung cancer treated with Rociletinib.MethodsTissue (n = 540), plasma (n = 482), and urine (n = 213) were collected from evaluable patients enrolled in TIGER-X, a phase I/II study. Genotyping was performed by therascreen EGFR testing in tissue, BEAMing in plasma, and a quantitative short footprint assay (Trovera) in urine, which was used to further examine discordant samples.ResultsPositive percent agreement with tissue T790M results was similar for urine (82%; 142 of 173) and plasma (81%; 313 of 387) genotyping. Urine and plasma together identified more patients who were T790M positive (92%) tha...
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improved egfr mutation detection using combined exosomal rna and circulating tumor dna in nsclc patient plasma
Annals of Oncology, 2017Co-Authors: Anne Krug, Chris Karlovich, D Enderle, T Priewasser, S Bentink, A Spiel, K Brinkmann, J Emenegger, Dominik G Grimm, Elena CastellanosrizaldosAbstract:Abstract Background A major limitation of circulating tumor DNA (ctDNA) for somatic mutation detection has been the low level of ctDNA found in a subset of cancer patients. We investigated whether using a combined isolation of exosomal RNA (exoRNA) and cell-free DNA (cfDNA) could improve blood-based liquid biopsy for EGFR mutation detection in non-small-cell lung cancer (NSCLC) patients. Patients and methods Matched pretreatment tumor and plasma were collected from 84 patients enrolled in TIGER-X (NCT01526928), a phase 1/2 study of Rociletinib in mutant EGFR NSCLC patients. The combined isolated exoRNA and cfDNA (exoNA) was analyzed blinded for mutations using a targeted next-generation sequencing panel (EXO1000) and compared with existing data from the same samples using analysis of ctDNA by BEAMing. Results For exoNA, the sensitivity was 98% for detection of activating EGFR mutations and 90% for EGFR T790M. The corresponding sensitivities for ctDNA by BEAMing were 82% for activating mutations and 84% for T790M. In a subgroup of patients with intrathoracic metastatic disease (M0/M1a; n = 21), the sensitivity increased from 26% to 74% for activating mutations (P = 0.003) and from 19% to 31% for T790M (P = 0.5) when using exoNA for detection. Conclusions Combining exoRNA and ctDNA increased the sensitivity for EGFR mutation detection in plasma, with the largest improvement seen in the subgroup of M0/M1a disease patients known to have low levels of ctDNA and poses challenges for mutation detection on ctDNA alone. Clinical Trials NCT01526928
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abstract 1009 comprehensive ctdna sequencing reveals mechanisms of resistance to Rociletinib in egfr t790m mutated nsclc
Cancer Research, 2017Co-Authors: Elena Helman, Chris Karlovich, Thomas Harding, Andrew Simmons, Mitch Raponi, Darya Chudova, Daniel A Simon, Richard B Lanman, Amirali TalasazAbstract:Background: First and second-generation EGFR tyrosine kinase inhibitors (TKIs) have benefited patients with EGFR-mutated non-small cell lung cancer (NSCLC), but resistance invariably develops after a median of 9-16 months. In ~60% of patients, resistance is mediated by a second mutation in EGFR, namely T790M. Hence, third-generation EGFR TKIs such as osimertinib and Rociletinib were developed to target both activating EGFR mutations as well as T790M. Unfortunately, patients also develop resistance to these therapies through mechanisms that have not yet been thoroughly explored. Since repeat tissue biopsies pose potential complications from invasive procedures, circulating tumor DNA (ctDNA) testing is increasingly used in the clinical setting to identify potentially targetable mechanisms of resistance. Methods: Matched pre-treatment and progression plasma from 57 patients with EGFR-mutated NSCLC treated with Rociletinib were profiled using a 70-gene ctDNA targeted next-generation sequencing panel (Guardant360) that detects somatic single nucleotide variants, short insertions and deletions, fusions, and copy number variants. Pre-treatment EGFR ctDNA allele fractions were also determined by BEAMing, a technique based on droplet digital PCR followed by flow cytometry. Pre-treatment tumor EGFR status was assessed by the therascreen EGFR test. Results: In all 57 pre-treatment samples profiled, plasma-based ctDNA analysis detected the initial EGFR driver and T790M resistance mutations that were identified in the matched tumor. Interestingly, we found that 12% (7/57) of patients had evidence of compound EGFR driver mutations at baseline, including E709A-L858R, K860I-L858R, and L718V-L858R. EGFR T790M mutations in plasma were observed subclonally (present on average at 40% of the allele fraction of the driver mutation), suggesting tumor heterogeneity at baseline. The correlation coefficients (r) between Guardant360 and BEAMing for EGFR L858R, Exon19Del, and T790M were 0.90, 0.92, 0.95, respectively. Upon progression on Rociletinib, 5% of patients (3/57) developed the EGFR C797S resistance mutation, 5% (3/57) developed focal MET amplification, and 2% (1/57) developed a NTRK1 fusion that were not present in the matched baseline plasma. Additionally, 4 deleterious BRCA1/2 alterations (2 germline and 2 somatic) were identified, with the somatic alterations emerging at progression. In 14% (8/57) of the patients, mutations in genes involved in the RAS/RAF signaling pathway, including KRAS Q61H, KRAS K117N and NF1 Q1822*, emerged or increased at progression. Conclusions: Plasma ctDNA revealed heterogeneity and multiple mechanisms of resistance in Rociletinib treated patients. Thus comprehensive ctDNA sequencing allows for the identification of potentially actionable alterations and may help inform the choice of next therapy for patients progressing on a third-generation EGFR TKI. Citation Format: Elena Helman, Andrew D. Simmons, Chris A. Karlovich, Thomas C. Harding, Mitch Raponi, Darya I. Chudova, Daniel A. Simon, Richard B. Lanman, AmirAli Talasaz. Comprehensive ctDNA sequencing reveals mechanisms of resistance to Rociletinib in EGFR T790M-mutated NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1009. doi:10.1158/1538-7445.AM2017-1009
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a highly sensitive and quantitative test platform for detection of nsclc egfr mutations in urine and plasma
Journal of Thoracic Oncology, 2016Co-Authors: Karen L Reckamp, Chris Karlovich, Lecia V Sequist, Heather A Wakelee, Ross D Camidge, Geoffrey R Oxnard, Vladislava O Melnikova, Karena Kosco, Maurice Perol, Peter J P CroucherAbstract:Abstract Introduction In approximately 60% of patients with NSCLC who are receiving EGFR tyrosine kinase inhibitors, resistance develops through the acquisition of EGFR T790M mutation. We aimed to demonstrate that a highly sensitive and quantitative next-generation sequencing analysis of EGFR mutations from urine and plasma specimens is feasible. Methods Short footprint mutation enrichment next-generation sequencing assays were used to interrogate EGFR activating mutations and the T790M resistance mutation in urine or plasma specimens from patients enrolled in TIGER-X (NCT01526928), a phase 1/2 clinical study of Rociletinib in previously treated patients with EGFR mutant–positive advanced NSCLC. Results Of 63 patients, 60 had evaluable tissue specimens. When the tissue result was used as a reference, the sensitivity of EGFR mutation detection in urine was 72% (34 of 47 specimens) for T790M, 75% (12 of 16) for L858R, and 67% (28 of 42) for exon 19 deletions. With specimens that met a recommended volume of 90 to 100 mL, the sensitivity was 93% (13 of 14 specimens) for T790M, 80% (four of five) for L858R, and 83% (10 of 12) for exon 19 deletions. A comparable sensitivity of EGFR mutation detection was observed in plasma: 93% (38 of 41 specimens) for T790M, 100% (17 of 17) for L858R, and 87% (34 of 39) for exon 19 deletions. Together, urine and plasma testing identified 12 additional T790M-positive cases that were either undetectable or inadequate by tissue test. In nine patients monitored while receiving treatment with Rociletinib, a rapid decrease in urine T790M levels was observed by day 21. Conclusions DNA derived from NSCLC tumors can be detected with high sensitivity in urine and plasma, enabling diagnostic detection and monitoring of therapeutic response from these noninvasive "liquid biopsy" samples.
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circulating tumour dna profiling reveals heterogeneity of egfr inhibitor resistance mechanisms in lung cancer patients
Nature Communications, 2016Co-Authors: Jacob J Chabon, Henry J Haringsma, Andrew Simmons, Alexander F Lovejoy, Mohammad Shahrokh Esfahani, Aaron M Newman, David M Kurtz, Henning Stehr, Florian Scherer, Chris KarlovichAbstract:Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor Rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after Rociletinib. Increased MET copy number is the most frequent Rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, Rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment.
Jonathan W Goldman - One of the best experts on this subject based on the ideXlab platform.
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egfr genotyping of matched urine plasma and tumor tissue in patients with non small cell lung cancer treated with Rociletinib an egfr tyrosine kinase inhibitor
JCO Precision Oncology, 2018Co-Authors: Jonathan W Goldman, Chris Karlovich, Lecia V Sequist, Karen L Reckamp, Ross D Camidge, Shirish M Gadgeel, M Perol, Vlada Melnikova, Aleksandra Franovic, Stephen V LiuAbstract:PurposeLiquid biopsies represent an attractive alternative to tissue biopsies, particularly rebiopsies, in determining patient eligibility for targeted therapies. Clinical utility of urine genotyping, however, has not been explored extensively. We evaluated epidermal growth factor receptor (EGFR) T790M detection in matched urine, plasma, and tissue and the clinical outcomes of patients with advanced non–small-cell lung cancer treated with Rociletinib.MethodsTissue (n = 540), plasma (n = 482), and urine (n = 213) were collected from evaluable patients enrolled in TIGER-X, a phase I/II study. Genotyping was performed by therascreen EGFR testing in tissue, BEAMing in plasma, and a quantitative short footprint assay (Trovera) in urine, which was used to further examine discordant samples.ResultsPositive percent agreement with tissue T790M results was similar for urine (82%; 142 of 173) and plasma (81%; 313 of 387) genotyping. Urine and plasma together identified more patients who were T790M positive (92%) tha...
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updated results from tiger x a phase i ii open label study of Rociletinib in patients pts with advanced recurrent t790m positive non small cell lung cancer nsclc
Journal of Clinical Oncology, 2016Co-Authors: Jonathan W Goldman, Heather A Wakelee, Karen L Reckamp, Jeancharles Soria, Ross D Camidge, Shirish M Gadgeel, Vassiliki A Papadimitrakopoulou, M Perol, Shannon Matheny, Darrin DespainAbstract:9045Background: Rociletinib is an oral, irreversible tyrosine kinase inhibitor of mutant epidermal growth factor receptor. Previously, we reported that Rociletinib is active at doses ≥ 500 mg BID i...
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epidermal growth factor receptor egfr genotyping of matched urine plasma and tumor tissue from non small cell lung cancer nsclc patients pts treated with Rociletinib
Journal of Clinical Oncology, 2016Co-Authors: Heather A Wakelee, Chris Karlovich, Karen L Reckamp, Jonathan W Goldman, Jeancharles Soria, Shirish M Gadgeel, M Perol, Benjamin Solomon, Vladislava O Melnikova, Joel W NealAbstract:9001Background: Rociletinib is an oral inhibitor of mutant EGFR, including T790M. We compared EGFR mutation detection in circulating tumor DNA from blood and urine to that in matched tissue in TIGE...
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torsades de pointes with pseudo t wave alternans during Rociletinib therapy novel manifestation of a rare side effect
Journal of the American College of Cardiology, 2016Co-Authors: Alexandra Teng, Jonathan W Goldman, Michael Share, Jeffrey J Hsu, Edward B Garon, Eric H Yang, Roderick TungAbstract:Rociletinib is a new third generation epidermal growth factor receptor tyrosine kinase inhibitor (TKI) treatment for non-small cell lung cancer. Known side effects include hyperglycemia and QT prolongation. We describe the first case of Rociletinib associated macroscopic pseudo-T wave alternans with
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3105 dose optimization of Rociletinib for egfr mutated nsclc benefit risk analysis from the tiger x trial
European Journal of Cancer, 2015Co-Authors: J C Soria, Jonathan W Goldman, Shirish M Gadgeel, M Perol, H Wakelee, D R Camidge, B Solomon, G R Oxnard, V Papadimitrakopoulou, Karen L ReckampAbstract:Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from the authors of this poster. Dose optimization of Rociletinib for EGFR mutated NSCLC: benefit-risk analysis from the TIGER-X trial Jean-Charles Soria,1 Jonathan W. Goldman,2 Heather Wakelee,3 Shirish Gadgeel,4 D. Ross Camidge,5 Ben Solomon,6 Helena Yu,7 Geoffrey R. Oxnard,8 Sai-Hong Ignatius Ou,9 Vassiliki Papadimitrakopoulou,10 Maurice Perol,11 Karen Reckamp,12 Andrea Varga,1 Rafal Dziadziuszko,13 Cristos Chouaid,14 Alexis Cortot,15 Pascal Do,16 Denis Moro-Sibilot,17 Michel Poudenx,18 Darrin Despain,19 Shannon Matheny,19 Lecia V. Sequist20 1Gustave Roussy Cancer Center, Villejuif, France; 2UCLA Medical Center, Santa Monica, CA, USA; 3Stanford University Medical Center, Stanford, CA, USA; 4Barbara Karmanos Cancer Institute, Detroit, MI, USA; 5University of Colorado, Denver, CO, USA; 6Peter MacCallum Cancer Centre, Melbourne, Australia; 7Memorial Sloan Kettering Cancer Center, New York, NY, USA; 8Dana Farber Cancer Institute, Boston, MA, USA; 9University of California, Irvine, Orange, CA, USA; 10MD Anderson Cancer Center, Houston, TX, USA; 11Hospices Civils de Lyon, Lyon, France; 12City of Hope Comprehensive Cancer Center, Duarte, CA, USA; 13Medical University of Gdansk, Gdansk, Poland; 14CHI Creteil, Creteil, France; 15Lille University, Lille, France; 16Centre Francois Baclesse, Caen, France; 17CHU Grenoble, Grenoble, France; 18CLCC Antoine Lacassagne, Nice, France; 19Clovis Oncology, Inc., San Francisco, CA, USA; 20Massachusetts General Hospital, Boston, MA, USA
Karen L Reckamp - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of Rociletinib versus chemotherapy in patients with egfr mutated non small cell lung cancer results of tiger 3 a phase iii randomized study
JTO Clinical and Research Reports, 2021Co-Authors: James Chihhsin Yang, Karen L Reckamp, Youngchul Kim, Silvia Novello, Egbert F Smit, Jong Seok Lee, Wallace Akerley, Collin M Blakely, Harry J M Groen, Lyudmila BazhenovaAbstract:Abstract Introduction The TIGER-3 (NCT02322281) study was initiated to compare the efficacy and safety of Rociletinib, a third-generation EGFR tyrosine kinase inhibitor (TKI) that targets EGFR T790M and common EGFR-activating mutations, versus chemotherapy in patients with NSCLC who progressed on first- or second-generation EGFR TKIs. Methods Patients with advanced or metastatic EGFR-mutated NSCLC with disease progression on standard therapy (previous EGFR TKI and platinum-based chemotherapy) were randomized to oral Rociletinib (500 or 625 mg twice daily) or single-agent chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel). Results Enrollment was halted when Rociletinib development was discontinued in 2016. Of 149 enrolled patients, 75 were randomized to Rociletinib (n = 53: 500 mg twice daily; n = 22: 625 mg twice daily) and 74 to chemotherapy. The median investigator-assessed progression-free survival (PFS) was 4.1 months (95% confidence interval [CI]: 2.6–5.4) in the Rociletinib 500-mg group and 5.5 months (95% CI: 1.8–8.1) in the 625-mg group versus 2.5 months (95% CI: 1.4–2.9) in the chemotherapy group. An improved PFS was observed in patients with T790M-positive NSCLC treated with Rociletinib (n = 25; 500 mg and 625 mg twice daily) versus chemotherapy (n = 20; 6.8 versus 2.7 mo; hazard ratio = 0.55, 95% CI: 0.28–1.07, p = 0.074). Grade 3 or higher hyperglycemia (24.0%), corrected QT prolongation (6.7%), diarrhea (2.7%), and vomiting (1.3%) were more frequent with Rociletinib than chemotherapy (0%, 0%, 1.4%, and 0%, respectively). Conclusions Rociletinib had a more favorable median PFS versus chemotherapy but had higher rates of hyperglycemia and corrected QT prolongation in patients with advanced EGFR-mutated NSCLC who progressed on previous EGFR TKI. Incomplete enrollment prevented evaluation of the primary efficacy end point.
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efficacy and safety of Rociletinib versus chemotherapy in patients with egfr mutated nsclc the results of tiger 3 a phase 3 randomized study
JTO Clinical and Research Reports, 2021Co-Authors: James Chihhsin Yang, Karen L Reckamp, Youngchul Kim, Silvia Novello, Egbert F Smit, Jong Seok Lee, Wallace Akerley, Collin M Blakely, Harry J M Groen, Lyudmila BazhenovaAbstract:Abstract Introduction The TIGER-3 (NCT02322281) study was initiated to compare the efficacy and safety of Rociletinib, a third-generation EGFR tyrosine kinase inhibitor (TKI) that targets EGFR T790M and common EGFR-activating mutations, versus chemotherapy in patients with NSCLC who progressed on first- or second-generation EGFR TKIs. Methods Patients with advanced or metastatic EGFR-mutated NSCLC with disease progression on standard therapy (previous EGFR TKI and platinum-based chemotherapy) were randomized to oral Rociletinib (500 or 625 mg twice daily) or single-agent chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel). Results Enrollment was halted when Rociletinib development was discontinued in 2016. Of 149 enrolled patients, 75 were randomized to Rociletinib (n = 53: 500 mg twice daily; n = 22: 625 mg twice daily) and 74 to chemotherapy. The median investigator-assessed progression-free survival (PFS) was 4.1 months (95% confidence interval [CI]: 2.6–5.4) in the Rociletinib 500-mg group and 5.5 months (95% CI: 1.8–8.1) in the 625-mg group versus 2.5 months (95% CI: 1.4–2.9) in the chemotherapy group. An improved PFS was observed in patients with T790M-positive NSCLC treated with Rociletinib (n = 25; 500 mg and 625 mg twice daily) versus chemotherapy (n = 20; 6.8 versus 2.7 mo; hazard ratio = 0.55, 95% CI: 0.28–1.07, p = 0.074). Grade 3 or higher hyperglycemia (24.0%), corrected QT prolongation (6.7%), diarrhea (2.7%), and vomiting (1.3%) were more frequent with Rociletinib than chemotherapy (0%, 0%, 1.4%, and 0%, respectively). Conclusions Rociletinib had a more favorable median PFS versus chemotherapy but had higher rates of hyperglycemia and corrected QT prolongation in patients with advanced EGFR-mutated NSCLC who progressed on previous EGFR TKI. Incomplete enrollment prevented evaluation of the primary efficacy end point.
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egfr genotyping of matched urine plasma and tumor tissue in patients with non small cell lung cancer treated with Rociletinib an egfr tyrosine kinase inhibitor
JCO Precision Oncology, 2018Co-Authors: Jonathan W Goldman, Chris Karlovich, Lecia V Sequist, Karen L Reckamp, Ross D Camidge, Shirish M Gadgeel, M Perol, Vlada Melnikova, Aleksandra Franovic, Stephen V LiuAbstract:PurposeLiquid biopsies represent an attractive alternative to tissue biopsies, particularly rebiopsies, in determining patient eligibility for targeted therapies. Clinical utility of urine genotyping, however, has not been explored extensively. We evaluated epidermal growth factor receptor (EGFR) T790M detection in matched urine, plasma, and tissue and the clinical outcomes of patients with advanced non–small-cell lung cancer treated with Rociletinib.MethodsTissue (n = 540), plasma (n = 482), and urine (n = 213) were collected from evaluable patients enrolled in TIGER-X, a phase I/II study. Genotyping was performed by therascreen EGFR testing in tissue, BEAMing in plasma, and a quantitative short footprint assay (Trovera) in urine, which was used to further examine discordant samples.ResultsPositive percent agreement with tissue T790M results was similar for urine (82%; 142 of 173) and plasma (81%; 313 of 387) genotyping. Urine and plasma together identified more patients who were T790M positive (92%) tha...
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a highly sensitive and quantitative test platform for detection of nsclc egfr mutations in urine and plasma
Journal of Thoracic Oncology, 2016Co-Authors: Karen L Reckamp, Chris Karlovich, Lecia V Sequist, Heather A Wakelee, Ross D Camidge, Geoffrey R Oxnard, Vladislava O Melnikova, Karena Kosco, Maurice Perol, Peter J P CroucherAbstract:Abstract Introduction In approximately 60% of patients with NSCLC who are receiving EGFR tyrosine kinase inhibitors, resistance develops through the acquisition of EGFR T790M mutation. We aimed to demonstrate that a highly sensitive and quantitative next-generation sequencing analysis of EGFR mutations from urine and plasma specimens is feasible. Methods Short footprint mutation enrichment next-generation sequencing assays were used to interrogate EGFR activating mutations and the T790M resistance mutation in urine or plasma specimens from patients enrolled in TIGER-X (NCT01526928), a phase 1/2 clinical study of Rociletinib in previously treated patients with EGFR mutant–positive advanced NSCLC. Results Of 63 patients, 60 had evaluable tissue specimens. When the tissue result was used as a reference, the sensitivity of EGFR mutation detection in urine was 72% (34 of 47 specimens) for T790M, 75% (12 of 16) for L858R, and 67% (28 of 42) for exon 19 deletions. With specimens that met a recommended volume of 90 to 100 mL, the sensitivity was 93% (13 of 14 specimens) for T790M, 80% (four of five) for L858R, and 83% (10 of 12) for exon 19 deletions. A comparable sensitivity of EGFR mutation detection was observed in plasma: 93% (38 of 41 specimens) for T790M, 100% (17 of 17) for L858R, and 87% (34 of 39) for exon 19 deletions. Together, urine and plasma testing identified 12 additional T790M-positive cases that were either undetectable or inadequate by tissue test. In nine patients monitored while receiving treatment with Rociletinib, a rapid decrease in urine T790M levels was observed by day 21. Conclusions DNA derived from NSCLC tumors can be detected with high sensitivity in urine and plasma, enabling diagnostic detection and monitoring of therapeutic response from these noninvasive "liquid biopsy" samples.
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updated results from tiger x a phase i ii open label study of Rociletinib in patients pts with advanced recurrent t790m positive non small cell lung cancer nsclc
Journal of Clinical Oncology, 2016Co-Authors: Jonathan W Goldman, Heather A Wakelee, Karen L Reckamp, Jeancharles Soria, Ross D Camidge, Shirish M Gadgeel, Vassiliki A Papadimitrakopoulou, M Perol, Shannon Matheny, Darrin DespainAbstract:9045Background: Rociletinib is an oral, irreversible tyrosine kinase inhibitor of mutant epidermal growth factor receptor. Previously, we reported that Rociletinib is active at doses ≥ 500 mg BID i...
Lecia V Sequist - One of the best experts on this subject based on the ideXlab platform.
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egfr genotyping of matched urine plasma and tumor tissue in patients with non small cell lung cancer treated with Rociletinib an egfr tyrosine kinase inhibitor
JCO Precision Oncology, 2018Co-Authors: Jonathan W Goldman, Chris Karlovich, Lecia V Sequist, Karen L Reckamp, Ross D Camidge, Shirish M Gadgeel, M Perol, Vlada Melnikova, Aleksandra Franovic, Stephen V LiuAbstract:PurposeLiquid biopsies represent an attractive alternative to tissue biopsies, particularly rebiopsies, in determining patient eligibility for targeted therapies. Clinical utility of urine genotyping, however, has not been explored extensively. We evaluated epidermal growth factor receptor (EGFR) T790M detection in matched urine, plasma, and tissue and the clinical outcomes of patients with advanced non–small-cell lung cancer treated with Rociletinib.MethodsTissue (n = 540), plasma (n = 482), and urine (n = 213) were collected from evaluable patients enrolled in TIGER-X, a phase I/II study. Genotyping was performed by therascreen EGFR testing in tissue, BEAMing in plasma, and a quantitative short footprint assay (Trovera) in urine, which was used to further examine discordant samples.ResultsPositive percent agreement with tissue T790M results was similar for urine (82%; 142 of 173) and plasma (81%; 313 of 387) genotyping. Urine and plasma together identified more patients who were T790M positive (92%) tha...
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a highly sensitive and quantitative test platform for detection of nsclc egfr mutations in urine and plasma
Journal of Thoracic Oncology, 2016Co-Authors: Karen L Reckamp, Chris Karlovich, Lecia V Sequist, Heather A Wakelee, Ross D Camidge, Geoffrey R Oxnard, Vladislava O Melnikova, Karena Kosco, Maurice Perol, Peter J P CroucherAbstract:Abstract Introduction In approximately 60% of patients with NSCLC who are receiving EGFR tyrosine kinase inhibitors, resistance develops through the acquisition of EGFR T790M mutation. We aimed to demonstrate that a highly sensitive and quantitative next-generation sequencing analysis of EGFR mutations from urine and plasma specimens is feasible. Methods Short footprint mutation enrichment next-generation sequencing assays were used to interrogate EGFR activating mutations and the T790M resistance mutation in urine or plasma specimens from patients enrolled in TIGER-X (NCT01526928), a phase 1/2 clinical study of Rociletinib in previously treated patients with EGFR mutant–positive advanced NSCLC. Results Of 63 patients, 60 had evaluable tissue specimens. When the tissue result was used as a reference, the sensitivity of EGFR mutation detection in urine was 72% (34 of 47 specimens) for T790M, 75% (12 of 16) for L858R, and 67% (28 of 42) for exon 19 deletions. With specimens that met a recommended volume of 90 to 100 mL, the sensitivity was 93% (13 of 14 specimens) for T790M, 80% (four of five) for L858R, and 83% (10 of 12) for exon 19 deletions. A comparable sensitivity of EGFR mutation detection was observed in plasma: 93% (38 of 41 specimens) for T790M, 100% (17 of 17) for L858R, and 87% (34 of 39) for exon 19 deletions. Together, urine and plasma testing identified 12 additional T790M-positive cases that were either undetectable or inadequate by tissue test. In nine patients monitored while receiving treatment with Rociletinib, a rapid decrease in urine T790M levels was observed by day 21. Conclusions DNA derived from NSCLC tumors can be detected with high sensitivity in urine and plasma, enabling diagnostic detection and monitoring of therapeutic response from these noninvasive "liquid biopsy" samples.
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assessment of egfr mutation status in matched plasma and tumor tissue of nsclc patients from a phase i study of Rociletinib co 1686
Clinical Cancer Research, 2016Co-Authors: Chris Karlovich, Jonathan H Goldman, Jongmu Sun, Elaina Mann, Lecia V Sequist, Krzysztof Konopa, Wei Wen, Philipp Angenendt, Leora Horn, David R SpigelAbstract:Purpose: The evaluation of plasma testing for the EGFR resistance mutation T790M in NSCLC patients has not been broadly explored. We investigated the detection of EGFR activating and T790M mutations in matched tumor tissue and plasma, mostly from patients with acquired resistance to first-generation EGFR inhibitors. Experimental Design: Samples were obtained from two studies, an observational study and a phase I trial of Rociletinib, a mutant-selective inhibitor of EGFR that targets both activating mutations and T790M. Plasma testing was performed with the cobas EGFR plasma test and BEAMing. Results: The positive percent agreement (PPA) between cobas plasma and tumor results was 73% (55/75) for activating mutations and 64% (21/33) for T790M. The PPA between BEAMing plasma and tumor results was 82% (49/60) for activating mutations and 73% (33/45) for T790M. Presence of extrathoracic (M1b) versus intrathoracic (M1a/M0) disease was found to be strongly associated with ability to identify EGFR mutations in plasma ( P EGFR levels to ≤10 molecules/mL was seen by day 21 of treatment in 7 of 8 patients with documented partial response. Conclusions: These findings suggest the cobas and BEAMing plasma tests can be useful tools for noninvasive assessment and monitoring of the T790M resistance mutation in NSCLC, and could complement tumor testing by identifying T790M mutations missed because of tumor heterogeneity or biopsy inadequacy. Clin Cancer Res; 22(10); 2386–95. ©2016 AACR .
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update to Rociletinib data with the recist confirmed response rate
The New England Journal of Medicine, 2016Co-Authors: Lecia V Sequist, Jeancharles Soria, Ross D CamidgeAbstract:To the Editor: In our Journal article that was published on April 30, 2015,1 we described the activity of Rociletinib, an epidermal growth factor receptor (EGFR) inhibitor with specificity for the T790M mutation, in patients with EGFR mutation–positive lung cancer in the phase 1 TIGER-X trial. The key finding was a response rate of 59% (95% confidence interval [CI], 45 to 73) among 46 patients with biopsy-proven T790M-mediated resistance to previously administered EGFR inhibitors. In November 2015, Clovis Oncology issued a press release that contained updated data from a pooled cohort of patients from TIGER-X and TIGER-2 (another phase 2 . . .
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abstract a31 assessment of egfr mutations in matched urine plasma and tumor tissue in nsclc patients treated with Rociletinib co 1686
Molecular Cancer Therapeutics, 2015Co-Authors: Shirish M Gadgeel, Chris Karlovich, Lecia V Sequist, Heather A Wakelee, Ross D Camidge, M Perol, Geoffrey R Oxnard, Vlada Melnikova, Karena Kosco, Cecile Rose T VibatAbstract:Background: The acquisition of suitable tumor tissue is a challenge for a significant fraction of late-stage NSCLC patients who require EGFR testing to inform choice of therapy. An alternative for these patients could be the assessment of EGFR mutations in circulating tumor DNA (ctDNA). In this study, we examined the detection of EGFR T790M mutation in ctDNA from urine, assessed urine sample requirements, and compared the results with contemporaneously matched tumor tissue and plasma in TIGER-X (NCT01526928), a Phase 1/2 clinical study of Rociletinib in previously treated mutant EGFR patients with advanced NSCLC. Rociletinib is an oral, potent, small-molecule irreversible tyrosine kinase inhibitor that selectively targets mutant forms of EGFR, including T790M, L858R and Del(19), while sparing wild-type EGFR. Methods: 63 Stage IIIB/IV NSCLC patients enrolled in either Phase 1 or 2 components of TIGER-X and representing all therapeutic dose groups consented to optional urine collection. Maximum sample volumes were 100 mL for urine and 2 mL for plasma. To maximize assay sensitivity in urine, samples containing the recommended sample volume of ≥90 mL (≥ 90% of maximum in this study) were evaluated; all samples received were processed to assess this recommendation. Urinary and plasma ctDNA were tested for mutations by the same EGFR assays using a sensitive and quantitative short footprint assay method that employs a mutation enrichment step followed by next generation sequencing. Results: Urine volumes ranged from 8-100 mL with a median DNA yield of 313 ng (N = 63). The median DNA yield was 299 ng for urine specimens with volume Conclusions: The analysis of ctDNA from urine identified a similar proportion of T790M+ patients as tissue-based testing with highest PPA amongst patients with urine volumes ≥90 mL. Discordant samples between urine and tissue that were not identified by the tumor test may be explained by tumor heterogeneity and/or inadequate biopsy. EGFR mutation detection from urine increases with urine volume and DNA yields and should be considered as a viable approach, particularly when tumor tissue is not available. Lastly, monitoring urine ctDNA T790M mutations longitudinally with baseline and post-therapy sampling could be clinically useful to determine benefit from therapy. Citation Format: Shirish Gadgeel, Chris Karlovich, Vlada Melnikova, Lecia V. Sequist, D. Ross Camidge, Heather Wakelee, Maurice Perol, Geoffrey R. Oxnard, Karena Kosco, Cecile Rose T. Vibat, Elaina Mann, Shannon Matheny, Lindsey Rolfe, Mitch Raponi, Mark G. Erlander, Karen Reckamp. Assessment of EGFR mutations in matched urine, plasma and tumor tissue in NSCLC patients treated with Rociletinib (CO-1686). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A31.
