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Cited by 468Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchCancer Genomics and Diagnostics

Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer

Open access
Robichaux, Jacqulyne P., Elamin, Yasir Y., Tan, Zhi, Carter, Brett W., Zhang, Shuxing, Liu, Shengwu, Li, Shuai, Chen, Ting +16 more·2018·Nature Medicine
DOI 10.1038/s41591-018-0007-9PMC PMC5964608
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Abstract

Although most activating mutations of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancers (NSCLCs) are sensitive to available EGFR tyrosine kinase inhibitors (TKIs), a subset with alterations in exon 20 of EGFR and HER2 are intrinsically resistant and lack an effective therapy. We used in silico, in vitro, and in vivo testing to model structural alterations induced by exon 20 mutations and to identify effective inhibitors. 3D modeling indicated alterations restricted the size of the drug-binding pocket, limiting the binding of large, rigid inhibitors. We found that poziotinib, owing to its small size and flexibility, can circumvent these steric changes and is a potent inhibitor of the most common EGFR and HER2 exon 20 mutants. Poziotinib demonstrated greater activity than approved EGFR TKIs in vitro and in patient-derived xenograft models of EGFR or HER2 exon 20 mutant NSCLC and in genetically engineered mouse models of NSCLC. In a phase 2 trial, the first 11 patients with NSCLC with EGFR exon 20 mutations receiving poziotinib had a confirmed objective response rate of 64%. These data identify poziotinib as a potent, clinically active inhibitor of EGFR and HER2 exon 20 mutations and illuminate the molecular features of TKIs that may circumvent steric changes induced by these mutations.

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Crossref · 10.1038/s41591-018-0007-9

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Claims the paper makes

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  • Findingown data

    Six HER2 exon 20 mutations and HER2 L755P were activating mutations in Ba/F3 cells.

    “and six HER2 exon 20 mutations and HER2 L755P, which is located in exon 19, were activating mutations (Supplementary Fig. 1c).”
    Quote in the paperSubstantial claim
  • Findingown data

    HER2 exon 20 mutants (n = 6) were resistant to first-generation (IC50 = 1.2-13 μM) and third-generation (IC50 = 114-505 nM) TKIs.

    “In addition, HER2 exon 20 mutants (n = 6) were resistant to first-generation (Fig. 1f, IC50 = 1.2–13 μM), and third-generation (Fig. 1h, IC50 = 114–505 nM) TKIs.”
    Quote in the paperSubstantial claim
  • Findingown data

    With the exception of EGFR A763insFQEA, EGFR exon 20 insertions (n = 6) were resistant to first-generation (IC50 = 3.3-10 μM), second-generation (IC50 = 40-135 nM), and third-generation (IC50 = 103-850 nM) EGFR TKIs.

    “With the exception of EGFR A763insFQEA, EGFR exon 20 insertions (n = 6) were resistant to first-generation (Fig. 1c, half-maximal inhibitory concentration (IC50) = 3.3–10 μM), second-generation (Fig. 1d, IC50 = 40–135 nM), and third-generation (Fig. 1e, IC50 = 103–850 nM) EGFR TKIs (Supplementary Fig. 2 and Supplementary Table 1).”
    Quote in the paperSubstantial claim
  • Findingown data

    Among 280 patients with EGFR-mutant NSCLC, 129 had classical EGFR mutations and 9 had EGFR exon 20 insertion mutations and received single-agent erlotinib, gefitinib, or afatinib.

    “Among 280 patients with EGFR-mutant NSCLC, we identified 129 patients with classical EGFR mutations (exon 19 deletions and the mutations encoding p.L858R and p.L861Q) and 9 patients with EGFR exon 20 insertion mutations that received single-agent treatment with erlotinib, gefitinib, or afatinib.”
    Quote in the paperSubstantial claim
  • Findingown data

    Of nine patients with EGFR exon 20 insertion, objective response was observed in only one patient with S768delinsIL who received afatinib.

    “Of the nine patients with an EGFR exon 20 insertion, OR was observed in only one patient harboring a deletion–insertion mutation (S768delinsIL) who received afatinib (Supplementary Fig. 1a).”
    Quote in the paperSubstantial claim
  • May combine two claims. 34
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Findingown data

    Patients with classical EGFR mutations had median PFS 14 months, whereas those with EGFR exon 20 insertion mutations had median PFS 2 months (P < 0.0001).

    “Patients with NSCLC harboring classical EGFR mutations had a median PFS of 14 months, whereas patients with EGFR exon 20 insertion mutations had a median PFS of only 2 months (P < 0.0001, log-rank test; Fig. 1a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In GEMM and xenograft models, poziotinib resulted in 80% tumor reduction in 4 weeks and 50% tumor reduction in 10 d, whereas afatinib did not reduce tumor burden in either model.

    “Lastly, in GEMM and xenograft models, poziotinib resulted in 80% tumor reduction in 4 weeks and 50% tumor reduction in 10 d, whereas afatinib did not reduce tumor burden in either model.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Tumor volume reduction in GEMMs and xenografts predicts clinical antitumor activity of poziotinib in humans.

  • May combine two claims.

    Findingown data

    3D modeling suggested EGFR exon 20 insertion mutants are similar to EGFR T790M in alignment of gatekeeper Thr790, resulting in increased ATP affinity and reduced binding of first-generation inhibitors, rendering resistance to noncovalent inhibitors.

    “Our modeling suggested that EGFR exon 20 insertion mutants (Supplementary Fig. 5a) are similar to EGFR T790M in the alignment of the gatekeeper residue Thr790, which results in increased affinity to ATP and a reduced binding of first-generation inhibitors, rendering these mutations resistant to noncovalent inhibitors.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: 3D modeling predictions of drug-binding pocket changes accurately represent the conformation of EGFR or HER2 exon 20 mutants in cells and patients.

  • May combine two claims.

    Findingown data

    As of January 2018, 5 of 11 patients had progressed, and median PFS had not yet been reached (median follow-up 6.6 months).

    “Although the clinical data is not yet mature, as of January 2018, 5 of 11 patients have progressed, and the median PFS has not yet been reached (median follow-up, 6.6 months).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Poziotinib had an average IC50 of 1.9 nM in Ba/F3 cell lines with HER2 exon 20 mutation, 200 times more potent than osimertinib and 6 times more potent than afatinib in vitro.

    “Moreover, poziotinib had an average IC50 value of 1.9 nM in Ba/F3 cell lines with a HER2 exon 20 mutation, making poziotinib 200 times more potent than osimertinib and 6 times more potent than afatinib in vitro.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Ba/F3 cell lines expressing EGFR or HER2 exon 20 mutations are a valid model for assessing drug sensitivity of these mutants.

  • May combine two claims.

    Findingown data

    Western blotting of CUT014 revealed considerable inhibition of p-EGFR after 10 nM poziotinib, but p-EGFR was not substantially inhibited by afatinib until 1,000 nM.

    “Western blotting of the CUT014 cell line revealed that there was considerable inhibition of p-EGFR following treatment with 10 nM poziotinib, but p-EGFR was not substantially inhibited by afatinib until a treatment concentration of 1,000 nM was reached (Supplementary Fig. 7c,d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Poziotinib had an average IC50 of 1.0 nM in Ba/F3 cell lines with EGFR exon 20 mutation, approximately 100 times more potent than osimertinib and 40 times more potent than afatinib in vitro.

    “Poziotinib had an average IC50 value of 1.0 nM in Ba/F3 cell lines with an EGFR exon 20 mutation, making poziotinib approximately 100 times more potent than osimertinib and 40 times more potent than afatinib in vitro.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Ba/F3 cell lines expressing EGFR or HER2 exon 20 mutations are a valid model for assessing drug sensitivity of these mutants.

  • May combine two claims.

    Findingown data

    HER2 exon 20 insertions induce a constitutively active conformation, preventing binding of noncovalent HER2 inhibitor lapatinib, which binds to HER2 in the inactive conformation.

    “In addition, HER2 exon 20 insertions (Supplementary Fig. 5b) induce a constitutively active conformation, preventing the binding of the noncovalent HER2 inhibitor lapatinib, which binds to HER2 in the inactive conformation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: 3D modeling predictions of drug-binding pocket changes accurately represent the conformation of EGFR or HER2 exon 20 mutants in cells and patients.

  • May combine two claims.

    Findingown data

    3D modeling showed osimertinib fits into drug-binding pocket of EGFR T790M and EGFR L858R/T790M mutant receptors, but in exon 20 mutants large changes sterically hinder binding of third-generation inhibitors.

    “Although osimertinib fits into the drug-binding pocket of EGFR T790M and EGFR L858R/T790M mutant receptors (Fig. 2h and Supplementary Fig. 6b), in exon 20 mutants, large changes within the drug-binding pocket sterically hinder the binding of third-generation inhibitors (Fig. 2i, denoted in red).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: 3D modeling predictions of drug-binding pocket changes accurately represent the conformation of EGFR or HER2 exon 20 mutants in cells and patients.

  • May combine two claims.

    Findingown data

    In YUL-0019 xenograft, afatinib showed no significant reduction in tumor burden, but tumor volume did not increase unlike vehicle.

    “In contrast, mice that received afatinib showed no significant reduction in tumor burden; however, tumor volume did not increase, unlike tumors in mice treated with vehicle control (Fig. 3g).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Tumor volume reduction in GEMMs and xenografts predicts clinical antitumor activity of poziotinib in humans.

  • May combine two claims.

    Findingown data

    Poziotinib reduced tumor volume by 60% in GEMMs bearing HER2 exon 20 insertion, higher than the 37% previously observed for afatinib in the identical GEMM.

    “Tumor volume was reduced by 60% in GEMMs bearing a HER2 exon 20 insertion (Fig. 3b,d); this is a higher level of tumor reduction than the 37% previously observed for afatinib in the identical GEMM26.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Perera, S. A. et al. HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy. Proc. Natl Acad. Sci. USA 106, 474–479 (2009). source

      Not checked in the free run.

    • Rests on an assumption: Tumor volume reduction in GEMMs and xenografts predicts clinical antitumor activity of poziotinib in humans.

  • May combine two claims.

    Findingown data

    Poziotinib was 2.7 times more potent than afatinib in H1781, 15 times more potent in CUT014, and more than 100 times more potent in YUL-0019.

    “Poziotinib was 2.7 times more potent than afatinib in the H1781 cell line, 15 times more potent than afatinib in the CUT014 cell line, and more than 100 times more potent than afatinib in the YUL-0019 cell line (Fig. 2e,f and Supplementary Fig. 7b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Poziotinib is smaller and has greater flexibility, allowing it to fit into the sterically hindered drug-binding pocket of exon 20 insertion mutants.

    “However, poziotinib is smaller and has greater flexibility, allowing it to fit into the sterically hindered drug- binding pocket of exon 20 insertion mutants (Fig. 2i).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: 3D modeling predictions of drug-binding pocket changes accurately represent the conformation of EGFR or HER2 exon 20 mutants in cells and patients.

  • May combine two claims.

    Findingown data

    In a phase 2 study in patients with NSCLC with EGFR exon 20 mutations, the majority (55%) of patients received a dose reduction, with the two most common adverse events being skin rash and diarrhea.

    “The majority (55%) of patients received a dose reduction, with the two most common adverse events being known EGFR-inhibitor-related toxicities: skin rash and diarrhea.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Western blotting of Ba/F3 cells bearing an EGFR exon 20 insertion showed erlotinib and osimertinib did not substantially inhibit p-EGFR, except A763insFQEA showed partial inhibition at low doses.

    “western blotting of Ba/F3 cells bearing an EGFR exon 20 insertion mutation demonstrated that erlotinib and osimertinib did not substantially inhibit phosphorylated EGFR (p-EGFR), with the exception of the EGFR A763insFQEA mutant cell line, in which there was partial inhibition at low doses of drug.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Poziotinib reduced tumor volume by 80% in GEMMs with EGFR exon 20 mutation, whereas afatinib at a clinically relevant dose had a 35% increase in tumor volume and was not significantly different from vehicle.

    “Tumor volume was determined through MRI, and poziotinib reduced tumor volume by 80% in GEMMs with an EGFR exon 20 mutation (Fig. 3a,c), whereas mice treated with a clinically relevant dose of afatinib31,32 had a 35% increase in tumor volume and were not significantly different from mice treated with vehicle control.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Tumor volume reduction in GEMMs and xenografts predicts clinical antitumor activity of poziotinib in humans.

  • May combine two claims.

    Findingown data

    In vitro, poziotinib is approximately 40 times more potent than afatinib and 65 times more potent than dacomitinib in cell lines bearing EGFR exon 20 mutants.

    “Here, we report that in vitro, poziotinib is approximately 40 times more potent than afatinib and 65 times more potent than dacomitinib in cell lines bearing EGFR exon 20 mutants.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Poziotinib effectively inhibited growth of H1781, CUTO14, and YUL-0019 cell lines with average IC50 values of 7.7 nM, 1.84 nM, and 0.30 nM, respectively.

    “In addition, poziotinib effectively inhibited growth of the human cell line H1781, which harbors a HER2 exon 20 insertion mutation, and of patient-derived cell lines CUTO14 (EGFR A767dupASV) and YUL-0019 (EGFR N771delinsFH), which had an average IC50 value of 7.7 nM, 1.84 nM, and 0.30 nM, respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    EGFR exon 20 insertion mutants were 1.4 times more resistant to afatinib, 5.6 times more resistant to osimertinib, and 24 times more resistant to rociletinib than EGFR T790M mutant.

    “Moreover, EGFR exon 20 insertion mutants were 1.4 times more resistant to afatinib, 5.6 times more resistant to osimertinib, and 24 times more resistant to rociletinib than the EGFR T790M mutant (Fig. 2g).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    About 10-12% of EGFR-mutant NSCLC tumors have an in-frame insertion in exon 20 of EGFR and are generally resistant to EGFR TKIs.

    “However, approximately 10–12% of EGFR-mutant NSCLC tumors have an in-frame insertion within exon 20 of EGFR6,15,16,17 and are generally resistant to EGFR TKIs.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] Mitsudomi, T. & Yatabe, Y. Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci. 98, 1817–1824 (2007). source

      Not checked in the free run.

    • cites [15] Oxnard, G. R. et al. Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J. Thorac. Oncol. 8, 179–184 (2013). source

      Not checked in the free run.

    • cites [16] Yasuda, H. et al. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci. Transl. Med. 5, 216ra177 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Clinical data and prior studies demonstrate limited activity of available EGFR TKIs in NSCLC driven by EGFR exon 20 insertion and validate the need for alternative treatment strategies.

    “These clinical data as well as results from prior studies16,18 demonstrate the limited activity of the available EGFR TKIs in NSCLC driven by an EGFR exon 20 insertion and validate the need for alternative treatment strategies for these specific tumors.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [16] Yasuda, H. et al. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci. Transl. Med. 5, 216ra177 (2013). source

      Not checked in the free run.

    • cites [18] Yasuda, H., Kobayashi, S. & Costa, D. B. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet Oncol. 13, e23–e31 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most activating EGFR-mutant NSCLCs respond to available EGFR TKIs, but a subset with EGFR or HER2 exon 20 alterations is intrinsically resistant and lacks effective therapy.

    “Although most activating mutations of epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancers (NSCLCs) are sensitive to available EGFR tyrosine kinase inhibitors (TKIs), a subset with alterations in exon 20 of EGFR and HER2 are intrinsically resistant and lack an effective therapy.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] Mitsudomi, T. & Yatabe, Y. Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci. 98, 1817–1824 (2007). source

      Not checked in the free run.

    • cites [15] Oxnard, G. R. et al. Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J. Thorac. Oncol. 8, 179–184 (2013). source

      Not checked in the free run.

    • cites [16] Yasuda, H. et al. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci. Transl. Med. 5, 216ra177 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a recent study of rare EGFR and HER2 exon 20 mutations, heterogeneous response to covalent quinazoline-based second-generation inhibitors was found; concentrations required to target more common exon 20 insertion mutations were above clinically achievable.

    “In a recent study of rare EGFR and HER2 exon 20 mutations, the authors found a heterogeneous response to covalent quinazoline-based second-generation inhibitors, such as dacomitinib and afatinib; however, the concentrations that were required to target more common exon 20 insertion mutations were above what are clinically achievable24.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Kosaka, T. et al. Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors. Cancer Res. 77, 2712–2721 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TKIs targeting HER2 have limited activity in HER2-mutant tumors, with ORRs below 40% reported by many studies, although some preclinical activity was seen in mouse models bearing mutated HER2 treated with afatinib.

    “The data thus far suggest that TKIs targeting HER2 (afatinib, lapatinib, neratinib, dacomitinib) have limited activity in patients with HER2-mutant tumors, with objective response rates (ORRs) of below 40% reported by many studies19,20,21,22,23,25, although some preclinical activity was observed in mouse models bearing mutated HER2 that were treated with afatinib26.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [19] Arcila, M. E. et al. Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin. Cancer Res. 18, 4910–4918 (2012). source

      Not checked in the free run.

    • cites [20] Mazières, J. et al. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J. Clin. Oncol. 31, 1997–2003 (2013). source

      Not checked in the free run.

    • cites [21] Costa, D. B. et al. Pulse afatinib for ERBB2 exon 20 insertion-mutated lung adenocarcinomas. J. Thorac. Oncol. 11, 918–923 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    90% of HER2 mutations in NSCLC are exon 20 mutations, and about 3% of NSCLC patients harbor HER2 mutations.

    “In addition, 90% of HER2 mutations in NSCLC are exon 20 mutations, and approximately 3% of patients with NSCLC harbor HER2 mutations19,20.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [19] Arcila, M. E. et al. Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin. Cancer Res. 18, 4910–4918 (2012). source

      Not checked in the free run.

    • cites [20] Mazières, J. et al. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J. Clin. Oncol. 31, 1997–2003 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Modeling of EGFR A763insFQEA demonstrated that insertions before residue 764 do not exhibit this effect and do not induce drug resistance.

    “However, modeling of EGFR A763insFQEA demonstrated that insertions before residue 764 do not exhibit this effect and do not induce drug resistance16.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Yasuda, H. et al. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci. Transl. Med. 5, 216ra177 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Phase 1 and 2 clinical testing of poziotinib demonstrate that 16 mg/day doses are tolerable and a plasma concentration of 150 nM can be achieved.

    “Although many patients required dose reduction, results from phase 1 and 2 clinical testing of poziotinib demonstrate that 16 mg/day doses are tolerable and that a plasma concentration of 150 nM can be achieved37,38,39,40.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [37] Kim D.-W. et al. Phase I studies of HM781-36B, an irreversible pan-HER tyrosine kinase inhibitor (TKI) in patients with advanced solid tumor and the therapeutic potential in patients with advanced non-small cell lung cancer (NSCLC). J. Thorac. Oncol. 8, S607 (2013).

      Not checked in the free run.

    • cites [38] Kim, T. M. et al. A phase I study of HM781–36B, a novel pan-HER inhibitor, in patients (pts) with advanced solid tumors. J. Clin. Oncol. 30, 3076 (2012). source

      Not checked in the free run.

    • cites [39] Noh, Y. H. et al. Population pharmacokinetics of HM781-36 (poziotinib), pan-human EGF receptor (HER) inhibitor, and its two metabolites in patients with advanced solid malignancies. Cancer Chemother. Pharmacol. 75, 97–109 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a study by Cha et al., poziotinib covalently binds and inhibits mutant EGFR and HER2 kinases and induces cell death in EGFR and HER2 mutated NSCLC cell lines in vitro.

    “In a study by Cha et al.29, the authors demonstrate that poziotinib (HM781-36B) covalently binds and inhibits mutant EGFR and HER2 kinases and induces cell death in EGFR and HER2 mutated NSCLC cell lines in vitro.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Cha, M. Y. Antitumor activity of HM781-36B, a highly effective pan-HER inhibitor in erlotinib-resistant NSCLC and other EGFR-dependent cancer models. Int. J. Cancer 10, 2445–2454 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Although plasma protein-binding to poziotinib may reduce poziotinib activity, this plasma concentration is well above the required concentration for inhibition of mutant EGFR exon 20.

    “Although plasma protein-binding to poziotinib may reduce poziotinib activity, this plasma concentration is well above the required concentration for inhibition of mutant EGFR exon 20.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Previously, patients with EGFR and/or HER2 exon 20 mutations have been excluded from clinical trials owing to lack of response to targeted therapy, demonstrating urgent need for new approaches.

    “Previously, patients with EGFR and/or HER2 exon 20 mutations have been excluded from clinical trials owing to lack of response to targeted therapy, demonstrating the urgent need for new approaches to treat these patients15.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Oxnard, G. R. et al. Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J. Thorac. Oncol. 8, 179–184 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Taken together, these data indicate that although poziotinib shares a similar quinazoline backbone with afatinib and dacomitinib, additional features of the kinase inhibitor result in increased activity and relative specificity for EGFR exon 20 mutants compared with the more common T790M mutant.

    “Taken together, these data indicate that although poziotinib shares a similar quinazoline backbone with afatinib and dacomitinib, additional features of the kinase inhibitor result in increased activity and relative specificity for EGFR exon 20 mutants compared with the more common T790M mutant.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Each year in the United States, approximately 4% of patients diagnosed with NSCLC, approximately 7,000 people, bear EGFR and/or HER2 exon 20 insertion mutations.

    “Each year in the United States alone, approximately 4% of patients diagnosed with NSCLC, which is approximately 7,000 people, bear EGFR and/or HER2 exon 20 insertion mutations36.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2017. CA Cancer J. Clin. 67,7–30 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Predicted activity of poziotinib was confirmed using in vitro and in vivo models demonstrating potent antitumor activity in cells with these mutations.

    “Moreover, the predicted activity of poziotinib was confirmed using in vitro and in vivo models demonstrating the potent antitumor activity of poziotinib in cells with these mutations.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    In the YUL-0019 PDX study, mice were randomized into four treatment groups: afatinib, two doses of poziotinib, or vehicle.

    “When tumors reached 300 mm3, mice were randomized into four treatment groups: 20 mg/kg afatinib, 5 mg/kg poziotinib, 10 mg/kg poziotinib, or vehicle control (20% PEG-400, 3% Tween-80 in dH2O).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All cell lines used were free of mycoplasma.

    “All cell lines were free of mycoplasma.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    In the GEMM studies, mice with equal initial tumor volume were nonblindly randomized to vehicle, afatinib, or poziotinib.

    “Mice with equal initial tumor volume were nonblindly randomized to vehicle, 20 mg/kg afatinib, or 10 mg/kg poziotinib daily upon obvious tumor formation as determined through MRI.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Restaging scans were retrospectively assessed according to RECIST version 1.1 to determine response rate in patients with EGFR exon 20 insertion.

    “Restaging scans were obtained at 6- to 8-week intervals during treatment and were retrospectively assessed according to RECIST, version 1.1 to determine the response rate in patients with NSCLC with an EGFR exon 20 insertion.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Cell line identity was confirmed by DNA fingerprinting using short tandem repeats and compared with ATCC reference fingerprints.

    “Cell line identity was confirmed through DNA fingerprinting via short tandem repeats using the PowerPlex 1.2 kit (Promega). Fingerprinting results were compared with reference fingerprints from ATCC.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Mice humanely euthanized for events unrelated to tumor burden were excluded from the final analysis in all in vivo studies.

    “Mice that were humanely euthanized for events unrelated to tumor burden were excluded from the final analysis.”
    • Also stated in: § Statistical analysis · plain
      “For all in vivo studies, mice humanely euthanized for events unrelated to tumor burden were excluded from the final analysis”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Representative images are shown of two separate protein isolations and blots run in duplicate.

    “Representative images are shown of two separate protein isolations and blots run in duplicate.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    In the LU0387 PDX study, mice were randomized into three treatment groups: 5 mg/kg poziotinib, 10 mg/kg poziotinib, or vehicle.

    “When tumors reached a volume of 100–200 mm3 mice were randomized into three treatment groups: 5 mg/kg poziotinib, 10 mg/kg poziotinib, or vehicle control (20% PEG-400, 3% Tween-80 in dH2O).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Each experiment was replicated three separate times to provide biological replicates unless otherwise indicated.

    “Each experiment was replicated three separate times to give biological replicates unless indicated otherwise.”
    Quote in the paperNot a substantial claim
42 of 42

  • The paper relies on this without support.

    Ba/F3 cell lines expressing EGFR or HER2 exon 20 mutations are a valid model for assessing drug sensitivity of these mutants.

    “As an initial step in screening for drugs targeting EGFR or HER2 exon 20 mutants, we stably expressed 7 EGFR and 11 HER2 mutations in Ba/F3 cells.”

  • The paper relies on this without support.

    3D modeling predictions of drug-binding pocket changes accurately represent the conformation of EGFR or HER2 exon 20 mutants in cells and patients.

    “3D modeling indicated alterations restricted the size of the drug-binding pocket, limiting the binding of large, rigid inhibitors.”

  • The paper relies on this without support.

    Tumor volume reduction in GEMMs and xenografts predicts clinical antitumor activity of poziotinib in humans.

    “We next tested the in vivo efficacy of poziotinib using genetically engineered mouse models (GEMMs) of NSCLC driven by an EGFR or HER2 exon 20 insertion.”

  • The paper relies on this without support.

    The first 11 patients in the phase 2 trial are representative of the broader population of patients with EGFR exon 20 mutant NSCLC.

    “Of the first 11 patients, 7 of 11 (64%) had a confirmed objective partial radiological response based on response evaluation criteria in solid tumors (RECIST) that was due to poziotinib (Fig. 4a).”

  • The paper relies on this without support.

    The 64% objective response rate observed in 11 patients is representative of the broader population of patients with EGFR exon 20 insertion mutations.

    “This hypothesis is supported by the 64% ORR observed in the 11 patients currently enrolled in clinical trial NCT03066206 and described in this study.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Xenograft dosing is described as both daily and five days per week

    Minor

    The results say the YUL-0019 xenograft mice received treatment daily for 10 days, whereas the methods specify dosing five days per week.

  • The number of erlotinib-resistant cell lines differs

    Minor

    The results calculate an average across seven erlotinib-resistant cell lines, but the methods say two such cell lines were generated. The text does not account for the other five.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Kim D.-W. et al. Phase I studies of HM781-36B, an irreversible pan-HER tyrosine kinase inhibitor (TKI) in patients with advanced solid tumor and the therapeutic potential in patients with advanced non-small cell lung cancer (NSCLC). J. Thorac. Oncol. 8, S607 (2013).

Cited by

Sorted by citations

Authors
Robichaux, J. P., Elamin, Y. Y., Tan, Z., Carter, B. W., Zhang, S., Liu, S., Li, S., Chen, T., Poteete, A., Estrada-Bernal, A., Le, A. T., Truini, A., Nilsson, M. B., Sun, H., Roarty, E., Goldberg, S. B., Brahmer, J. R., Altan, M., Lu, C., Papadimitrakopoulou, V., Politi, K., Doebele, R. C., Wong, K.-K., & Heymach, J. V.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • Dana-Farber Cancer Institute (US)
  • University of Colorado Cancer Center (US)
  • Yale Cancer Center (US)
  • Johns Hopkins University (US)
  • NYU Langone Health (US)
Corresponding author
Heymach, John V.
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2018-04-23
Volume
24
Issue
5
Pages
638-646
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-018-0007-9
PMC
PMC5964608
OpenAlex
W2801651204
Cited by
468
References
52
Citations by year
2026: 28 · 2025: 41 · 2024: 37 · 2023: 78 · 2022: 66 · 2021: 69 · 2020: 77 · 2019: 49 · 2018: 23
FWCI
41.22
Type
journal article
Language
en
Update notices
correction (2024-08-20)
Open access
Licence
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (R01CA166480, R01CA190628, R01CA140594, R01CA234183, P50CA070907, P50CA058187, P30CA016672, P50CA196530)
  • National Institute of General Medical Sciences (R01GM070737)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
poziotinib, EGFR exon 20 mutations, non-small cell lung cancer, tyrosine kinase inhibitors, drug resistance, steric hindrance, drug-binding pocket, patient-derived xenografts, genetically engineered mouse models, objective response rate
MeSH terms
Afatinib, Animals, Binding Sites, Carcinoma, Non-Small-Cell Lung, Cell Line, Disease Models, Animal, Exons, Humans, Lung Neoplasms, Mutation, Quinazolines, Mutagenesis, Insertional, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm, Tumor Burden, Protein Kinase Inhibitors, Mice, Epithelial-Mesenchymal Transition, ErbB Receptors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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