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
1357 - Upfront atezolizumab chemoimmunotherapy-associated Immune-related adverse events in patients with advanced non-small cell lung cancer
Presenter: Francis Mogollon-Duffo
Session: Poster Display session 1
Resources:
Abstract
1851 - Nivolumab-induced and radiation recall pneumonitis in patients with non-small cell lung cancer: a multicenter real world analysis of 669 patients
Presenter: Nobuaki Mamesaya
Session: Poster Display session 1
Resources:
Abstract
851 - Retrospective analysis of immunotherapy prognostic scores in advanced NSCLC at Nottingham University Hospitals (UK)
Presenter: Cristina Lopez Escola
Session: Poster Display session 1
Resources:
Abstract
3639 - Applicability of lung immune prognostic index (LIPI) to predict efficacy of first-line pembrolizumab in advanced non-small-cell lung cancer (NSCLC)
Presenter: Xabier Mielgo Rubio
Session: Poster Display session 1
Resources:
Abstract
2950 - Delayed Onset Immune Related Adverse Effects (IRAEs) of Pembrolizumab in Non-Small Cell Lung Cancer
Presenter: Haixi Yan
Session: Poster Display session 1
Resources:
Abstract
3659 - Clinical implication of multiplex IHC and serologic biomarkers on Hyperprogression in NSCLC patients receiving Immune checkpoint blockers in real world.
Presenter: Joori Kim
Session: Poster Display session 1
Resources:
Abstract
4882 - Local ablative treatment and treatment beyond progression for oligo-progression in stage IV non-small cell lung cancer after tumor response to anti-PD1 treatment
Presenter: Florian Guisier
Session: Poster Display session 1
Resources:
Abstract
1358 - Atezolizumab in combination with chemotherapy for first-line treatment of advanced non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs)
Presenter: Francis Mogollon-Duffo
Session: Poster Display session 1
Resources:
Abstract
2170 - Prognostic Impact of Metastatic Sites for Pembrolizumab Efficacy as First-line therapy in Patients with PD-L1 tumor proportion score (TPS) ≥ 50% Advanced Non–Small Cell Lung Cancer: A Retrospective Multicenter Study
Presenter: Hayato Kawachi
Session: Poster Display session 1
Resources:
Abstract
3051 - Impact of visceral fat area as independent predictive factor in patients with advanced non-small cell lung cancer treated with nivolumab
Presenter: Yuki Sato
Session: Poster Display session 1
Resources:
Abstract