Abstract 4325
Background
Osimertinib (osi) is a third-generation EGFR-TKI selective for sensitizing (EGFRm) and p.T790M resistance mutations approved for metastatic NSCLC. Despite a primary benefit, almost all patients (pts) develop acquired resistance, whose mechanisms are not completely characterized.
Methods
Metastatic NSCLC pts who performed a tissue and plasma biopsy at osi progression, and optionally before, were identified from the prospective MATCH-R trial (NCT02517892). Targeted next-generation sequencing (NGS, 74 to 82 genes), comparative genomic hybridization (CGH), whole exome sequencing (WES), and RNA sequencing (RNA-Seq) were performed on the tissue. All molecular alterations were reviewed, those related to definitive or potential resistance mechanism were included in the analysis.
Results
The 31 pts included (23 [74%] women) had the tissue biopsy analysis at osi progression by NGS (97%), CGH (87%) and WES+RNA-Seq (61%). Additional cfDNA genomic profile was available for 17 pts (55%). Two pts received osi as first-line and 29 (94%) at previous EGFR TKI resistance. Most frequent acquired resistance to osi was EGFR on-target alterations (n = 12, 39%): 9 p.C797S, 2 p.L817Q and 1 EGFR amplification (amp). 4 pts (3 p.C797S and 1 p.L817Q) also had EGFR amp as potential concurrent resistance. Off-target resistance alterations were found in 11 (35%) tumors: 5 fusions involving oncogenes (16%, RET, MET, BRAF, ALK, FGFR3, and NTRK1), 2 with BRAF p.V600E mutation (6%) which co-occurred with p.C797S, then MET amp, HER2 amp, KRAS mut, and PIK3CA mut in 1 (3%). More than one resistance mechanism was found in 14 tumors (45%), more than two in 5 (16%). DNA repair gene alterations were observed in 10 pts (32%). Median TMB, assessed in 18 tumors, was 2.52 mutations/Mb, 1 was classified as high. p.T790M loss (54%) was associated with a more aggressive progression pattern compared with p.T790M maintain. For 20 pts a paired pre-osi biopsy was analyzed; 4 alterations (20%, 1 on-target, 3 off-target) were already detected.
Conclusions
Resistance mechanisms to osi are more complex than expected since more than one alteration was recognized in 45% of pts. Combination strategy might be needed.
Clinical trial identification
NCT02517892.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Diego Enrico was recipient of the grant DUERTECC (Diplôme Universitaire Européen de Recherche Translationnelle et Clinique en Cancérologie) for 2018-2019.
Disclosure
Y. Loriot: Honoraria (self): Roche, MSD, Astellas, Janssen, AstraZeneca, BMS, Seattle Genetics, Sanofi, Clovis, Pfizer; Honoraria (institution): Roche, MSD, Astellas, Janssen, AstraZeneca, BMS, Seattle Genetics, Sanofi, Clovis, Incyte, Pfizer; Research grant / Funding (institution): Roche, MSD, Sanofi; Travel / Accommodation / Expenses: Roche, MSD, Janssen, AstraZeneca, Seattle Genetics,; Licensing / Royalties: Pending patent (USA 62/455211, Europe 17209098.7). D. Planchard: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, MedImmune, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Research grant / Funding (institution): AstraZeneca, Bristol-Myers Squibb, AbbVie, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo; Travel / Accommodation / Expenses: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim , Roche, Merck,Novartis, prIME Oncology, Pfizer. S. Michiels: Advisory / Consultancy, Statistical advice : Janssen Cilag France; Advisory / Consultancy, Data and safety monitoring member : Hexal, J&J, Ipsen, Neovacs, Genticel, Mabxience, Steba, IQVIA, Roche, Sensorion, Biophytis . C. Massard: Leadership role: Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint Medicines, Boehringer Ingelheim, Bristol; Research grant / Funding (institution): Astrazeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Non-remunerated activity/ies: Astrazeneca, Bayer, BMS, Boringher Ingelheim, Johnson & Johnson, Lilly, MedImmune, Merck, NH TherAGuiX, Pfizer, Roche; Advisory / Consultancy: Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, Novartis, Pfizer, Roche, Sanofi, Orion . J. Soria: Advisory / Consultancy: AstraZeneca, BMS, Merck, Pfi zer/Merck Serono, and Roche; Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options: AstraZeneca. F. André: Research grant / Funding (institution): NVS, AZ, Roche, Daiichi, Lilly, Pfizer. B. Besse: Research grant / Funding (institution): AbbVie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma. All other authors have declared no conflicts of interest.
Resources from the same session
4294 - The Patient Voice: An Irish Survey of Nutrition Attitudes & Access to Dietetic Care Throughout the Cancer Journey
Presenter: Erin Stella Sullivan
Session: Poster Display session 1
Resources:
Abstract
1925 - Homcology: home chemotherapy delivery in a simultaneous care project for frail advanced cancer patients
Presenter: Claudio Chini
Session: Poster Display session 1
Resources:
Abstract
4701 - Treatment-related adverse events and tolerability in patients with advanced non-squamous non-small cell lung cancer treated with first-line checkpoint inhibitors in combination with chemotherapy
Presenter: Ruth D'cunha
Session: Poster Display session 1
Resources:
Abstract
2985 - Clinical utility of a systematic toxicity assessment form (STAF) in patients with breast cancer receiving adjuvant or neoadjuvant therapy.
Presenter: Jwa Hoon Kim
Session: Poster Display session 1
Resources:
Abstract
2358 - Physicians’ satisfaction with Health-related quality of life (HRQoL) assessment in daily clinical practice using electronic patient-reported outcome (ePRO) for cancer patients.
Presenter: Guillaume Mouillet
Session: Poster Display session 1
Resources:
Abstract
5172 - Predictors of Survival in Patients with Incurable Cancer
Presenter: Erin Stella Sullivan
Session: Poster Display session 1
Resources:
Abstract
2281 - Patients and Physicians' Satisfaction with Telemedicine (TM) in Cancer Care and Factors that Correlate with a Positive Patient’s Experience
Presenter: Hurria Gondal
Session: Poster Display session 1
Resources:
Abstract
2193 - Adherence to ESMO 2014 guidelines on bone-targeting agent (BTA) initiation for breast and prostate cancer patients: real-world insights from practicing European physicians
Presenter: Alex Rider
Session: Poster Display session 1
Resources:
Abstract
2200 - Use of skeletal-related events preventive agents in patients with solid tumours and bone metastases in central Denmark
Presenter: Anders Boysen
Session: Poster Display session 1
Resources:
Abstract
2504 - Inadequacy of current definition and staging system of Medication-Related Osteonecrosis of Jaw (MRONJ) released by AAOMS : a Computed Tomography study in 151 cancer and myeloma patients
Presenter: Vittorio Fusco
Session: Poster Display session 1
Resources:
Abstract