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. 2019 Mar 27:3:PO.18.00210.
doi: 10.1200/PO.18.00210. eCollection 2019.

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

Sebastian Michels  1 , Carina Heydt  1 , Bianca van Veggel  2 , Barbara Deschler-Baier  3 , Nuria Pardo  4 , Kim Monkhorst  2 , Vanessa Rüsseler  1 , Jan Stratmann  5 , Frank Griesinger  6 , Susanne Steinhauser  7 , Anna Kostenko  1 , Joachim Diebold  8 , Jana Fassunke  1 , Rieke Fischer  1 , Walburga Engel-Riedel  9 , Oliver Gautschi  8 , Eva Geissinger  10 , Stefan Haneder  1 , Michaela A Ihle  1 , Hans-Georg Kopp  11 , Adrianus J de Langen  2 , Alex Martinez-Marti  4 , Lucia Nogova  1 , Thorsten Persigehl  1 , Dennis Plenker  1 , Michael Puesken  1 , Ernst Rodermann  12 , Andreas Rosenwald  10 , Andreas H Scheel  1 , Matthias Scheffler  1 , Werner Spengler  13 , Ruth Seggewiss-Bernhardt  14 , Johannes Brägelmann  1   7 , Martin Sebastian  5 , Bart Vrugt  15 , Martin Hellmich  7 , Martin L Sos  1   7 , Lukas C Heukamp  16 , Enriqueta Felip  4 , Sabine Merkelbach-Bruse  1 , Egbert F Smit  2 , Reinhard Büttner  1 , Jürgen Wolf  1
Affiliations

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

Sebastian Michels et al. JCO Precis Oncol. .

Abstract

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.

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Conflict of interest statement

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.

Figures

FIG 1.
FIG 1.
Flowchart of the study population and cohorts. CNV, copy number variation; EGFR, epidermal growth factor receptor; ERBB2, human epidermal growth factor receptor 2 gene; MET, mesenchymal-epithelial transition factor; MPS, massively parallel sequencing; NSCLC, non–small-cell lung cancer; RECIST, Response Evaluation Criteria in Solid Tumors; seq, sequencing; TKI, tyrosine kinase inhibitor.
FIG 2.
FIG 2.
Map of genetic aberrations detected by sequencing (single nucleotide variant [SNV] and insertion/deletion [INDEL]) and copy number variation (CNV) analyses in biopsy specimens of epidermal growth factor receptor (EGFR) p.T790M-positive patients before treatment with a third-generation EGFR tyrosine kinase inhibitor (TKI; ie, osimertinib, rociletinib, nazartinib; upper block; cohort B; n = 56) and at progression to the specific treatment (lower block; cohort C; n = 29). The change in the frequency of specific aberrations during the course of treatment in matched samples is indicated in the lower block on the far right (Matched Δ). Half boxes indicate incomplete molecular work-up. Freq, frequencies; PD, progressive disease; PR, partial response; SCLC, small-cell lung cancer; SD, stable disease; WT, wild type.
FIG 3.
FIG 3.
(A) Waterfall plot showing the best change in percent of the target lesions according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 per patient during treatment with a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI; n = 56; cohort B). (*) Patient with progressive disease (PD) as best response but no target lesion measurement possible. Kaplan-Meier graphs displaying (B) progression-free survival and (C) overall survival for patients with EGFR p.T790M-positive non–small-cell lung cancer (NSCLC) with and without mesenchymal-epithelial transition factor (MET) amplification (ampl), who received treatment with third-generation EGFR TKIs. Both median overall survival and progression-free survival are dramatically reduced in the presence of MET amplifications. ERBB2, human epidermal growth factor receptor 2 gene; WT, wild type.
FIG 4.
FIG 4.
(A) Timeline showing the course of treatment of a female patient diagnosed with stage IV at 51 years of age. After treatment with gefitinib (gefi), platinum-doublet chemotherapy (chemo), and afatinib, the patient received osimertinib (osi; progression-free survival, 7.3 months). A progressive paraesophageal lesion was biopsied and revealed a KRAS p.G12S mutation and loss of p.T790M. The patient received local radiotherapy and died approximately 1.5 months later. (B) Timeline showing the course of treatment of a 76-year-old female patient initially diagnosed at stage II. Treatment with erlotinib was initiated once an epidermal growth factor receptor (EGFR) del19 was detected at recurrence of the disease. At progression, a p.T790M mutation was detected, and treatment with nazartinib was started, resulting in a good partial response. At progression, another biopsy at the spot indicated by the yellow arrow was collected, revealing a KRAS p.G12C mutation. (C) Analysis of the KRAS p.G12C mutation by Sanger sequencing. Electropherogram of the reverse sequencing reaction showing the nucleotide change c.33_34delinsCT. (D) Detection of the KRAS p.G12C mutation by massively parallel sequencing. The nucleotide change c.33_34delinsCT is visualized by the integrative genomics viewer. FU, follow-up; PD, progressive disease.
FIG 5.
FIG 5.
(A) Map of genetic aberrations detected by sequencing (single nucleotide variant [SNV] and insertion/deletions [INDELs]) and copy number variation (CNV) analyses in biopsy specimens collected after treatment with a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI; cohort C; n = 29). Patients were clustered in four groups: (I) changes outside of EGFR only, (II) changes in EGFR and outside of EGFR, (III) changes in EGFR only, and (IV) no changes found. The change in the frequency of specific aberrations during the course of treatment in matched samples is indicated in the lower block on the far right (Matched Δ). Half boxes indicate incomplete molecular work-up. (B) Progression-free survival of patients by cluster. Median progression-free survival (95% CI): I, 9.6 months (6.7 to 12.6 months); II, 7.3 (3.7 to 11.0 months); III, 8.2 (6.5 to 9.9 months); and IV, 4.8 (0.0 to 9.6 months). Levels of statistical significance for comparison of clusters were P > .1. (C) Overall survival by cluster from progressive disease (PD) on third-generation EGFR inhibitor treatment until death. Median overall survival (95% CI): I, 5 months (2.1 to 8.0 months); II, 8 (2.3 to 13.7 months); III, 3.3 (2.3 to 4.4 months); and IV, 1.7 (0.0 to 15.6 months). Levels of statistical significance for comparison of clusters were P > .1. ERBB2, human epidermal growth factor receptor 2 gene; freq, frequencies; MET, mesenchymal-epithelial transition factor; PR, partial response; SCLC, small-cell lung cancer; SD, stable disease; WT, wild type. (*) n = 5; 17%.
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