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Poster Discussion – NSCLC, metastatic

2685 - Longitudinal circulating tumour DNA (ctDNA) monitoring for early detection of disease progression and resistance in advanced NSCLC in FLAURA

Date

29 Sep 2019

Session

Poster Discussion – NSCLC, metastatic

Presenters

Jhanelle E. Gray

Citation

Annals of Oncology (2019) 30 (suppl_5): v851-v934. 10.1093/annonc/mdz394

Authors

J.E. Gray1, N. Peled2, A. Markovets3, N. Nogami4, J. Lee5, B.C. Cho6, B. Chewaskulyong7, M. Majem8, T. Reungwetwattana9, K. Vishwanathan10, A. Todd11, Y. Rukazenkov12, M. Johnson13, C. Barrett3, J. Chmielecki3, R. Hartmaier3, S.S. Ramalingam14

Author affiliations

  • 1 Department Of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, 33612 - Tampa/US
  • 2 Medical Oncology, Soroka Medical Center & Ben-Gurion University, Beer-Sheva/IL
  • 3 Translational Medicines, Research And Early Development, Oncology R&d, AstraZeneca, Boston/US
  • 4 Department Of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, 791-0280 - Matsuyama/JP
  • 5 Medical Oncology, Seoul National University Bundang Hospital, Seoul/KR
  • 6 Division Of Medical Oncology, Department Of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, 03722 - Seoul/KR
  • 7 Oncology Unit, Department Of Medicine, Chiang Mai University, Chiang Mai/TH
  • 8 Department Of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona/ES
  • 9 Division Of Medical Oncology, Department Of Medicine, Faculty Of Medicine, Ramathibodi Hospital, Mahidol University, 10400 - Bangkok/TH
  • 10 Clinical Pharmacology And Safety Science, R&d, AstraZeneca, Boston/US
  • 11 Oncology Biometrics, Oncology R&d, AstraZeneca, Cambridge/GB
  • 12 Oncology R&d, AstraZeneca, Cambridge/GB
  • 13 Quantitative Clinical Pharmacology, Research And Early Development, Oncology R&d, AstraZeneca, Cambridge/GB
  • 14 Department Of Hematology And Medical Oncology, Emory University, Winship Cancer Institute, Atlanta/US

Resources

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Abstract 2685

Background

In the phase III FLAURA study (NCT02296125), the 3rd-generation EGFR-TKI osimertinib showed superior efficacy to comparator EGFR-TKIs in previously untreated EGFR-mutated (EGFRm) advanced non-small cell lung cancer (NSCLC). Here we report results from an exploratory analysis of ctDNA for the early detection of disease progression (PD) in FLAURA.

Methods

Treatment-naïve patients (pts) with EGFRm (ex19del/L858R) locally advanced/metastatic NSCLC (n = 556) were randomised 1:1 (osimertinib 80 mg qd: comparator [gefitinib 250 mg qd/erlotinib 150 mg qd]). Plasma samples were collected on Days 1, 8 and 15, then every 21 days for weeks (W) 3–18, then every 6W thereafter. In pts who had a plasma sample on PD and/or discontinuation, ctDNA droplet digital PCR (ddPCR; Biodesix) for EGFRm (ex19del/L858R/T790M) was performed at all available time points and C797S for post-W6 time points. C797S and T790M were the only resistance mutations assayed. ctDNA progression was defined with respect to the nadir ctDNA result and its proximity to the ddPCR detection and quantification limits.

Results

The ctDNA progression analysis included 122/556 (22%) pts with valid longitudinal monitoring ddPCR data and RECIST PD by DCO1 (12 June 2017). Across both arms, ctDNA progression preceded or co-occurred with PD in 80/122 (66%) pts with 2.7 months (mo) median lead time; 9.5 mo median progression-free survival (mPFS; n = 80). Acquired C797S or T790M was detected in 57/122 (47%) pts with ctDNA progression (osimertinib 4/50 [8%] C797S, comparator 53/72 [74%] T790M); median time to detection was 16.7 and 8.4 mo for the osimertinib and comparator arms, respectively, mirroring overall mPFS. In pts with ctDNA progression and PD (n = 106), acquired T790M and C797S were detected either at the same time as, or earlier than PD in 41/106 (38%) pts (osimertinib 2/39 [5%], comparator 39/67 [58%]); median lead time was 1.4 mo.

Conclusions

ctDNA monitoring may allow for earlier identification of pts who progress on first-line EGFR-TKI therapy and the detection of EGFR-mediated resistance mechanisms in advance of PD in EGFRm NSCLC. Future work aims to explore early detection of non-EGFR-mediated resistance.

Clinical trial identification

NCT02296125.

Editorial acknowledgement

Writing support was provided by Donna Tillotson, PhD of iMed Comms, Macclesfield, UK, an Ashfield Company, part of UDG Healthcare plc, and funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

J.E. Gray: Research grant / Funding (institution): Array; Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Takeda. N. Peled: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Takeda; Advisory / Consultancy: Eli Lilly; Honoraria (self): Foundation Medicine; Shareholder / Stockholder / Stock options: NovellusDx; Honoraria (self): Gaurdant360. A. Markovets: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. N. Nogami: Honoraria (self): Pfizer Inc.; Honoraria (self): Chugai Pharmaceutical Co. Ltd; Honoraria (self): Eli Lilly; Honoraria (self): Taiho Pharmaceutical Co. Ltd; Honoraria (self): AstraZeneca; Honoraria (self): Kyowa Hakko Kirin; Honoraria (self): Ono Pharmaceutical Co. Ltd; Honoraria (self): BMS; Honoraria (self): MSD. B.C. Cho: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): MOGAM Institute; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Dong-A ST; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Licensing / Royalties: Champions Oncology; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Yuhan; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Ono; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Dizal Pharma; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (institution), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (institution), Advisory / Consultancy: BMS; Honoraria (institution), Advisory / Consultancy: Pfizer; Honoraria (institution), Advisory / Consultancy: Eli Lilly; Honoraria (institution), Advisory / Consultancy: Takeda; Shareholder / Stockholder / Stock options: TheraCanVac Inc. B. Chewaskulyong: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca. M. Majem: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer; Advisory / Consultancy: Tesaro; Speaker Bureau / Expert testimony: Hellsin; Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre; Speaker Bureau / Expert testimony: Amgen. K. Vishwanathan: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. A. Todd: Full / Part-time employment: AstraZeneca. Y. Rukazenkov: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. M. Johnson: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. C. Barrett: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. Chmielecki: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. R. Hartmaier: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options, Licensing / Royalties, Nfe2l2 exon 2 ano/or exon 3 loss from work conducted at Foundation Medicine; provisional patent filed: Foundation Medicine. S.S. Ramalingam: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy: Roche/Genentech; Honoraria (self), Advisory / Consultancy: Loxo; Honoraria (self), Advisory / Consultancy: Nektar; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Advaxis; Research grant / Funding (institution): Takeda. All other authors have declared no conflicts of interest.

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