Genomic Profiling Identifies Outcome-Relevant Mechanisms of Innate and Acquired Resistance to Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Lung Cancer.

Purpose: Third-generation epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors (TKIs) are effective in acquired resistance (AR) to early-generation EGFR TKIs in EGFR-mutant lung cancer. However, efficacy is marked by interindividual heterogeneity. We present the molecular profiles of pretreatment and post-treatment samples from patients treated with third-generation EGFR TKIs and their impact on treatment outcomes.
Methods: Using the databases of two lung cancer networks and two lung cancer centers, we molecularly characterized 124 patients with EGFR p.T790M-positive AR to early-generation EGFR TKIs. In 56 patients, correlative analyses of third-generation EGFR TKI treatment outcomes and molecular characteristics were feasible. In addition, matched post-treatment biopsy samples were collected for 29 patients with progression to third-generation EGFR TKIs.
Results: Co-occurring genetic aberrations were found in 74.4% of EGFR p.T790-positive samples (n = 124). Mutations in TP53 were the most frequent aberrations detected (44.5%; n = 53) and had no significant impact on third-generation EGFR TKI treatment. Mesenchymal-epithelial transition factor ( MET ) amplifications were found in 5% of samples (n = 6) and reduced efficacy of third-generation EGFR TKIs significantly (eg, median progression-free survival, 1.0 months; 95% CI, 0.37 to 1.72 v 8.2 months; 95% CI, 1.69 to 14.77 months; P ≤ .001). Genetic changes in the 29 samples with AR to third-generation EGFR TKIs were found in EGFR (eg, p.T790M loss, acquisition of p.C797S or p.G724S) or in other genes (eg, MET amplification, KRAS mutations).
Conclusion: Additional genetic aberrations are frequent in EGFR-mutant lung cancer and may mediate innate and AR to third-generation EGFR TKIs. MET amplification was strongly associated with primary treatment failure and was a common mechanism of AR to third-generation EGFR TKIs. Thus, combining EGFR inhibitors with TKIs targeting common mechanisms of resistance may delay AR.
Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Sebastian MichelsHonoraria: Novartis, Pfizer, AstraZeneca, Boehringer Ingelheim, Roche Pharma AG Consulting or Advisory Role: Boehringer Ingelheim, Pfizer, Roche Pharma AG Research Funding: Pfizer (Inst), Novartis (Inst), Bristol-Myers Squibb (Inst) Travel, Accommodations, Expenses: NovartisCarina HeydtHonoraria: AstraZeneca, IlluminaNuria PardoOther Relationship: PfizerKim MonkhorstConsulting or Advisory Role: Pfizer, Roche Molecular Diagnostics, MSD, AstraZeneca, AbbVie, Bristol-Myers Squibb Speakers' Bureau: Quadia Research Funding: AstraZeneca, Roche Molecular Diagnostics, Personal Genome Diagnostics Travel, Accommodations, Expenses: Takeda, Pfizer, RocheVanessa RüsselerTravel, Accommodations, Expenses: Ventana Medical SystemsJan StratmannHonoraria: Bristol-Myers Squibb Travel, Accommodations, Expenses: NovartisFrank GriesingerHonoraria: Genentech, Boehringer Ingelheim, Pfizer, AbbVie, MSD, Bristol-Myers Squibb, Ipsen, Novartis Consulting or Advisory Role: AstraZeneca, Genentech, Pfizer, Boehringer Ingelheim, MSD, Bristol-Myers Squibb, Celgene, Takeda, AbbVie, Novartis, Bayer Research Funding: AstraZeneca (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), MSD (Inst), Celgene (Inst), Eli Lilly (Inst), Novartis (Inst), Pfizer (Inst), Roche (Inst), Takeda (Inst)Jana FassunkeHonoraria: AstraZenecaRieke FischerHonoraria: Bristol-Myers Squibb, Roche, MSD Research Funding: Bristol-Myers Squibb (Inst), MSD (Inst) Travel, Accommodations, Expenses: MediolanumOliver GautschiOther Relationship: AstraZeneca, PfizerEva GeissingerHonoraria: MSD Sharp & Dohme Consulting or Advisory Role: NovartisHans-Georg KoppHonoraria: MSD Oncology, Boehringer Ingelheim, LEO Pharma, PharmaMar, Roche, Pfizer, Chugai Pharma, Takeda Consulting or Advisory Role: MSD Oncology, Bristol-Myers Squibb, Sanofi, Roche, AstraZeneca Travel, Accommodations, Expenses: Sanofi, Eli Lilly, Amgen, Novartis, PharmaMar, Boehringer Ingelheim, MSD Oncology, Bristol-Myers SquibbAdrianus J. de LangenConsulting or Advisory Role: AstraZeneca (Inst), Bristol-Myers Squibb (Inst), MSD Oncology (Inst), Roche (Inst), Boehringer Ingelheim (Inst), Pfizer (Inst) Research Funding: AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Merck Serono (Inst), MSD Oncology (Inst), Roche (Inst)Alex Martinez-MartiHonoraria: Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Boehringer Ingelheim Consulting or Advisory Role: Bristol-Myers Squibb, F. Hoffmann-La Roche, Merck Sharp & Dohme, Pfizer, Boehringer Ingelheim Speakers' Bureau: F. Hoffmann-La Roche, Bristol-Myers Squibb, Boehringer Ingelheim Research Funding: Merck Serono Travel, Accommodations, Expenses: Bristol-Myers Squibb, F. Hoffmann-La Roche, MSD Oncology, Boehringer IngelheimLucia NogovaHonoraria: Pfizer, Celgene, Novartis, Roche, Boehringer Ingelheim, Janssen, Bristol-Myers Squibb Consulting or Advisory Role: Novartis, Boehringer Ingelheim, Bristol-Myers Squibb, Roche, Janssen, Pfizer Research Funding: Pfizer, (Inst), Bristol-Myers Squibb (Inst), Novartis (Inst), MSD (Inst), Janssen (Inst) Travel, Accommodations, Expenses: Novartis, Pfizer, Celgene, Boehringer IngelheimDennis PlenkerStock and Other Ownership Interests: Roche, Foundation Medicine Patents, Royalties, Other Intellectual Property: A patent of NRG1 fusions has been filedMichael PueskenConsulting or Advisory Role: MSD Travel, Accommodations, Expenses: ShireErnst RodermannConsulting or Advisory Role: Amgen, CelgeneAndreas H. ScheelHonoraria: MSD, Bristol-Myers Squibb, Roche, Dako/Agilent Technologies Consulting or Advisory Role: MSD, Bristol-Myers Squibb, Roche, Dako/Agilent TechnologiesMatthias SchefflerHonoraria: Healthcare Consulting Cologne, Boehringer Ingelheim, Takeda Consulting or Advisory Role: Boehringer Ingelheim, Takeda Travel, Accommodations, Expenses: Boehringer IngelheimRuth Seggewiss-BernhardtHonoraria: Novartis, Celgene, Roche, Bristol-Myers Squibb, Ipsen, Pfizer, AstraZeneca Consulting or Advisory Role: MSD, Pfizer Travel, Accommodations, Expenses: Astellas Pharma, Celgene, IpsenMartin SebastianHonoraria: AstraZeneca, Novartis, Pfizer/EMD Serono, MSD, Takeda, Bristol-Myers Squibb, Eli Lilly, Genentech, Boehringer Ingelheim, AbbVie Consulting or Advisory Role: Genentech, MSD, AstraZeneca, AbbVie, Takeda, Eli Lilly, Boehringer Ingelheim, Novartis, Bristol-Myers Squibb, Pfizer, Celgene Travel, Accommodations, Expenses: Pfizer, TakedaMartin L. SosResearch Funding: Novartis, NovartisLukas C. HeukampEmployment: NEO New Oncology, Hämatopathologie Hamburg Honoraria: Roche Pharma, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim Consulting or Advisory Role: Roche Pharma, Bristol-Myers Squibb, NovartisEnriqueta FelipConsulting or Advisory Role: Pfizer, Roche, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Celgene, Guardant Health, Novartis, Takeda, AbbVie, Blueprint Medicines, Eli Lilly, Merck KGaA, Merck Sharp & Dohme Speakers' Bureau: AstraZeneca, Bristol-Myers Squibb, Novartis, Boehringer Ingelheim, Merck Sharp & Dohme, Roche, Pfizer, AbbVie, Eli Lilly, Merck KGaA, Takeda Research Funding: Fundación Merck Salud (Inst), EMD Serono (Inst)Sabine Merkelbach-BruseHonoraria: AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer, Roche Pharma Consulting or Advisory Role: Bristol-Myers Squibb, Novartis, PfizerEgbert F. SmitConsulting or Advisory Role: Eli Lilly, AstraZeneca (Inst), Boehringer Ingelheim (Inst), Genentech (Inst), Bristol-Myers Squibb (Inst), Merck KGaA (Inst), MSD Oncology (Inst), Takeda (Inst), Bayer (Inst) Research Funding: Boehringer Ingelheim (Inst), Bayer (Inst), Genentech (Inst), AstraZeneca (Inst), Bristol-Myers Squibb (Inst)Reinhard BüttnerStock and Other Ownership Interests: Co-founder and CSO for Targos Mol. Pathol. (Kassel/Germany) and TAMP (Atlanta, GA) Honoraria: AstraZeneca, AbbVie, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Serono, MSD, Novartis, Qiagen, Pfizer, Roche Research Funding: Roche (Inst)Juergen WolfHonoraria: AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Novartis, Roche Consulting or Advisory Role: AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai Pharma, Ignyta, Eli Lilly, MSD Oncology, Novartis, Pfizer, Roche Research Funding: Bristol-Myers Squibb, Novartis, Pfizer No other potential conflicts of interest were reported.
(© 2019 by American Society of Clinical Oncology.)