Efficacy of afatinib or osimertinib plus cetuximab combination therapy for non-small-cell lung cancer with EGFR exon 20 insertion mutations

Hasegawa, Hirotsugu; Yasuda, Hiroyuki; Hamamoto, Junko; Masuzawa, Keita; Tani, Tetsuo; Nukaga, Shigenari; Hirano, Tôru; Kobayashi, Keigo; Manabe, Tadashi; Terai, Hideki; Ikemura, Shinnosuke; Kawada, Ichiro; Naoki, Katsuhiko; Soejima, Kenzo

doi:10.1016/j.lungcan.2018.11.039

Cited by 43 publications

(39 citation statements)

References 20 publications

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“…Although, single clinical cases and structural studies suggest that some exon 20ins may indeed respond to osimertinib [104,106], the efficacy of this drug on these mutations at approved or higher dosage remains to be substantiated by additional dose-adjusted clinical studies and awaits the results of specific ongoing trials [107]. Recent preclinical data have shown that the combination of afatinib or osimertinib with the anti-EGFR monoclonal antibody cetuximab may inhibit the growth of NSCLC cells carrying certain types of exon 20ins in vitro or in a xenograft mouse model [108]. Although skin toxicity is a substantial limiting factor for the clinical application of this combined treatment, recently PR was reported with the usage of afatinib + cetuximab in three of four NSCLC patients with EGFR exon 20ins receiving this therapeutic combination [109,110].…”

Section: Clinical and Preclinical Studies Shedding Light On Intrinmentioning

confidence: 99%

Intrinsic Resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

Santoni-Rugiu

Melchior

Urbanska

et al. 2019

Cancers

125

126

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Activating mutations in the epidermal growth factor receptor gene occur as early cancer-driving clonal events in a subset of patients with non-small cell lung cancer (NSCLC) and result in increased sensitivity to EGFR-tyrosine-kinase-inhibitors (EGFR-TKIs). Despite very frequent and often prolonged clinical response to EGFR-TKIs, virtually all advanced EGFR-mutated (EGFRM+) NSCLCs inevitably acquire resistance mechanisms and progress at some point during treatment. Additionally, 20–30% of patients do not respond or respond for a very short time (<3 months) because of intrinsic resistance. While several mechanisms of acquired EGFR-TKI-resistance have been determined by analyzing tumor specimens obtained at disease progression, the factors causing intrinsic TKI-resistance are less understood. However, recent comprehensive molecular-pathological profiling of advanced EGFRM+ NSCLC at baseline has illustrated the co-existence of multiple genetic, phenotypic, and functional mechanisms that may contribute to tumor progression and cause intrinsic TKI-resistance. Several of these mechanisms have been further corroborated by preclinical experiments. Intrinsic resistance can be caused by mechanisms inherent in EGFR or by EGFR-independent processes, including genetic, phenotypic or functional tumor changes. This comprehensive review describes the identified mechanisms connected with intrinsic EGFR-TKI-resistance and differences and similarities with acquired resistance and among clinically implemented EGFR-TKIs of different generations. Additionally, the review highlights the need for extensive pre-treatment molecular profiling of advanced NSCLC for identifying inherently TKI-resistant cases and designing potential combinatorial targeted strategies to treat them.

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Section: Clinical and Preclinical Studies Shedding Light On Intrinmentioning

confidence: 99%

Intrinsic Resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

Santoni-Rugiu

Melchior

Urbanska

et al. 2019

Cancers

125

126

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“…Preclinical evaluation of afatinib or osimertinib plus cetuximab demonstrated a mild but statistically significant additive antitumor effect of these combinations against several EGFR exon 20 insertion mutations in vitro . Afatinib plus cetuximab also significantly inhibited the growth of tumors harboring EGFR A767_V769dupASV and EGFR Y764_V765insHH, in vivo , while single-agent treatments did not ( 30 ). With regard to clinical data, among four patients with EGFR exon 20 insertions treated with afatinib plus cetuximab in the Netherlands, three patients had a partial response (PR), and the median PFS was 5.4 months ( 31 ).…”

Section: Discussion and Concluding Remarksmentioning

confidence: 99%

Case Report: Afatinib Treatment in a Patient With NSCLC Harboring a Rare EGFR Exon 20 Mutation

et al. 2021

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Unlike most other primary epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC), exon 20 insertions, comprising approximately 4% to 10% of all EGFR mutations, are generally considered to be resistant to EGFR tyrosine kinase inhibitors (TKIs). However, EGFR exon 20 insertions are structurally and pharmacologically heterogeneous, with variability in their position and size having implications for response to different EGFR TKIs. The second-generation ErbB family blocker, afatinib, is approved for the first-line treatment of EGFR mutation-positive NSCLC and has been shown to have a broad inhibitory profile against common and uncommon EGFR mutations. Here, we describe a patient with bilateral multifocal lung adenocarcinoma harboring a very rare EGFR exon 20 insertion (c.2317_2319dup3; p.H773dup), who has been receiving treatment with afatinib for 4.5 years. To our knowledge, this is the first report describing long-term benefit for a patient treated with afatinib with this rare exon 20 insertion. We are aware of two further cases with this rare EGFR mutation. One patient, also reported here, has early-stage lung adenocarcinoma and has not yet received systemic therapy for NSCLC. The other patient received afatinib in the context of a global compassionate use program and had progressive disease. Our findings may be of clinical relevance for patients carrying tumors with this rare mutation as epidemiological evidence suggests that p.H773dup may function as a driver mutation in NSCLC. Together with previous preclinical and clinical evidence for the activity of afatinib against certain EGFR exon 20 insertions, these findings warrant further investigation.

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“…8 In addition, despite a high ORR (55%), median PFS was only 5.5 months, suggesting that an alternative treatment option is necessary for NSCLC patients with EGFR exon 20 insertion mutations such as afatinib or osimertinib plus cetuximab combination strategy. 7,27 Considering the low mutant to wild-type ratio of IC 50 that might be a biased parameter, osimertinib might be an alternative treatment for patients with NSCLC and EGFR exon 20 insertions as in a promising NSCLC case of EGFR D770insSVD mutation that responded to osimertinib. 28 Structurally, we constructed homology models of EGFR exon 20 insertions.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Modeling of Osimertinib for NSCLC With EGFR Exon 20 Insertion Mutations

Lee

Kim

et al. 2019

Journal of Thoracic Oncology

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Introduction: NSCLC with EGFR exon 20 insertion mutations is the third most common type of EGFR-mutant NSCLC and is resistant to EGFR tyrosine kinase inhibitors (TKIs). This study was conducted to evaluate the efficacies of firstto third-generation EGFR TKIs against NSCLC cells harboring EGFR exon 20 insertion mutations. Methods: We developed seven EGFR exon 20 insertionmutant Ba/F3 models and one patient-derived NSCLC (SNU-3173) of subtypes A763insFQEA, V769insASV, D770insSVD, D770insNPG, P772insPR, H773insH, H773insNPH, and H773insAH. Cell viability assays, immunoblotting, and Nethyl-N-nitrosourea mutagenesis screenings were performed. EGFR exon 20 insertion-mutant structures and couplings with osimertinib, a third-generation EGFR TKI, were modeled and compared. Results: EGFR exon 20 insertion-mutant NSCLC cells, excluding EGFR A763insFQEA, were resistant to firstgeneration EGFR TKIs (concentration that inhibits 50% [IC 50 ], 1.1 ± 0.067 to 5.4 ± 0.115 mM). Mutants were sensitive to second-generation EGFR TKIs (IC 50 , 0.02 ± 0.0002 to 161.8 ± 18.7nM), except EGFR H773insH (IC 50 , 46.3 ± 8.0 to 352.5 ± 22.7nM). The IC 50 ratios for mutant to wild-type cells were higher than those for third-generation EGFR TKIs. Third-generation EGFR TKI osimertinib was highly potent against EGFR exon 20 insertion-mutant cells (IC 50 , 14.7-62.7 nM), including EGFR H773insH, and spared wild-type EGFR cells. N-ethyl-N-nitrosourea mutagenesis screening of EGFR exon 20 insertion-mutant Ba/F3 cells showed various second sites for EGFR mutations, mostly at exons 20 and 21, including E762K, P794S, and G796D. In addition, osimertinib-resistant cells were established by stepwise exposure to osimertinib and harbored EGFR E762K mutation. Conclusions: Osimertinib is active against EGFR exon 20 insertion-mutant NSCLC and flexibly binds within drugbinding pockets in preclinical models.

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Efficacy of afatinib or osimertinib plus cetuximab combination therapy for non-small-cell lung cancer with EGFR exon 20 insertion mutations

Cited by 43 publications

References 20 publications

Intrinsic Resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

Intrinsic Resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

Case Report: Afatinib Treatment in a Patient With NSCLC Harboring a Rare EGFR Exon 20 Mutation

Preclinical Modeling of Osimertinib for NSCLC With EGFR Exon 20 Insertion Mutations

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