4325 - Multiple synchronous mechanisms may contribute to osimertinib resistance in non-small cell lung cancer (NSCLC) patients: insights of the MATCH-R study

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.