The DOI matches its Crossref record; 62 of the 63 references it cites were found in a registry or an index; none of the 37 sources its claims cite is checked for support yet.
AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer
Open accessPublished version of a preprint
Abstract
First-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provide significant clinical benefit in patients with advanced EGFR-mutant (EGFRm+) non–small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent, and selective third-generation irreversible inhibitor of both EGFRm+ sensitizing and T790M resistance mutants that spares wild-type EGFR. This mono-anilino–pyrimidine compound is structurally distinct from other third-generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier generation EGFR TKIs. Preclinically, the drug potently inhibits signaling pathways and cellular growth in both EGFRm+ and EGFRm+/T790M+ mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR-mutant tumor xenograft and transgenic models. The treatment of 2 patients with advanced EGFRm+ T790M+ NSCLC is described as proof of principle. Significance: We report the development of a novel structurally distinct third-generation EGFR TKI, AZD9291, that irreversibly and selectively targets both sensitizing and resistant T790M+ mutant EGFR while harboring less activity toward wild-type EGFR. AZD9291 is showing promising responses in a phase I trial even at the first-dose level, with first published clinical proof-of-principle validation being presented. Cancer Discov; 4(9); 1046–61. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 973
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“Parental EGFRm+ lines (PC-9, H3255, HCC827, HCC4006, 11-18) were sensitive to AZD9291 as well as erlotinib, afatinib, and AZD8931 (a reversible equipotent inhibitor of EGFR, HER2 and HER3 signalling (40)) (Fig. 3B).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 potently and selectively targets mutant EGFR cell lines in vitro
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In the paper
“The drug exhibited nearly 200 times greater potency against L858R/T790M than wild-type EGFR (Supplementary Table S1A), consistent with the design goal of a mutant EGFR selective agent in comparison to early generation TKIs.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 is a mutant-selective, irreversible inhibitor of EGFR kinase activity
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In the paper
“Chronic long term daily oral dosing of AZD9291 resulted in complete and durable macroscopic responses of both PC-9 (Fig. 4C) and H1975 xenografts (Fig. 4D).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 causes profound and sustained regression in mutant EGFR in vivo xenograft models
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In the paper
“Moreover, a single oral dose of 200 mg/kg of AZD9291 in rats did not cause a significant change in blood glucose or insulin levels over a 24 hour period, consistent with lack of IGF-1R activity (data not shown).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 is a mutant-selective, irreversible inhibitor of EGFR kinase activity
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In the paper
“AZD9291 did induce some moderate tumor growth inhibition at 5 mg/kg/day (Supplementary Fig. S6E), suggesting AZD9291 or associated metabolites are not entirely inactive against wild-type EGFR in this model.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 causes profound and sustained regression in mutant EGFR in vivo xenograft models
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In the paper
“AZD9291 daily dosing was well tolerated in the animals with minimal body weight loss, (less than 5% of starting body weight) even after dosing for 200 days (Supplementary Fig. S6C (PC-9) and S6D (H1975)).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 causes profound and sustained regression in mutant EGFR in vivo xenograft models
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In the paper
“Therefore, AZ5104 exhibited a reduced selectivity margin against wild-type EGFR when compared to AZD9291.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 potently and selectively targets mutant EGFR cell lines in vitro
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In the paper
“In a separate large cell panel proliferation profiling study, AZD9291 was also poorly active in vitro (IC50 ~1 μM) against both NSCLC NCI-H820 and EBC-1 cell lines that harbor MET amplification and mutant EGFR (data not shown).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 potently and selectively targets mutant EGFR cell lines in vitro
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In the paper
“The second generation irreversible TKIs, afatinib and dacomitinib, showed activity against T790M EGFR in vitro, although this activity is may not be achievable at exposures that can be reached in the clinic.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 potently and selectively targets mutant EGFR cell lines in vitro
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Similar tumor shrinkage was seen after administration of 5 mg/kg/day AZD9291 in H3255 (L858R) (Supplementary Fig. S6A) and PC-9VanR (ex19 del/ T790M) (Supplementary Fig. S6B) xenografts after 14 days.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 causes profound and sustained regression in mutant EGFR in vivo xenograft models
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- It may state two separate claims as one. 49
- Probably not a substantial claim. 25
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In the paper
“whilst AZ5104 harbored somewhat greater potency against ex19del (2 nM in PC-9), T790M (2 nM in H1975) and wild-type EGFR (33 nM in LOVO) cell lines.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 potently and selectively targets mutant EGFR cell lines in vitro
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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In the paper
“Again, this contrasted to second generation TKIs, afatinib and dacomitinib, which showed much less activity against T790M lines and were associated with much greater potency towards wild-type EGFR (Fig. 3A).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 potently and selectively targets mutant EGFR cell lines in vitro
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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In the paper
“Subsequent murine in vivo studies revealed that AZD9291 was metabolized to produce at least two circulating metabolite species, AZ5104 and AZ7550.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 is a mutant-selective, irreversible inhibitor of EGFR kinase activity
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Similar long term dosing studies were performed in the H3255 model, with 5 mg/kg/day AZD9291 causing non-measurable tumors in all 8 dosed mice by day 53. By contrast, only one mouse treated with 6.25 mg/kg gefitinib achieved non-measurable tumor status (Supplementary Fig. S6A).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 causes profound and sustained regression in mutant EGFR in vivo xenograft models
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In the paper
“AZD9291 demonstrated good bioavailability, was widely distributed in tissues, and had moderate clearance resulting in a half-life of around 3 hours after oral dosing in the mouse (Supplementary Fig. S5).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 causes profound and sustained regression in mutant EGFR in vivo xenograft models
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In the paper
“Compared to afatinib and AZ5104, AZD9291 exhibited moderate potency against H1781 cells, which harbor a VC insertion at G776 in exon 20 of HER2 (42), with an IC50 of 80 nM (Supplementary Fig. S4A). However, AZD9291 was more effective at inhibiting growth of these cells than erlotinib.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > Activity of AZD9291 against rare EGFR and HER2 mutants in vitro
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In the paper
“The circulating active metabolites in plasma each had a similar half-life, and the total exposure levels (AUC) were approximately 68 and 33% compared to the parent compound for AZ7550 and AZ5104, respectively (Supplementary Fig S5).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 causes profound and sustained regression in mutant EGFR in vivo xenograft models
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“although H1650 cells retained higher phospho-AKT levels due to loss of PTEN (38).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 potently and selectively targets mutant EGFR cell lines in vitro
What the sources say
- Not checked yetcites [38] Sos, 2009, PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR., Cancer Res source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“AZD9291 is a novel oral, potent and selective third generation irreversible inhibitor of both EGFRm+ sensitizing and T790M resistance mutants that spares wild-type EGFR.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Abstract
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“However, consistent with its greater wild-type EGFR potency, the AZ5104 metabolite showed more potency than AZD9291 against phospho-HER2 (Supplementary Fig. S2A-C).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 is a mutant-selective, irreversible inhibitor of EGFR kinase activity
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In the paper
“As a comparison, gefitinib at 6.25 mg/kg/day, a clinically representative dose, induced less tumor regression, and tumors began to re-grow after approximately 90 days.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 causes profound and sustained regression in mutant EGFR in vivo xenograft models
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In the paper
“Furthermore, preliminary data in a single mouse with tumor driven by an ex19del mutant alone (45) also responded rapidly to AZD9291 (Supplementary Fig. S7A).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 causes profound and sustained regression in mutant EGFR in vivo transgenic tumor models
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“AZD9291 showed minimal off-target kinase activity, with only a limited number of additional kinases showing greater than 60% inhibition at 1 μM and moderate IC50 potencies such as ErbB2/4, ACK1, ALK, BLK, BRK, MLK1 and MNK2 (Supplementary Table S1B).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 is a mutant-selective, irreversible inhibitor of EGFR kinase activity
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In the paper
“Consistent with phospho-EGFR data, the metabolite AZ5104 again demonstrated much greater potency across cell lines in a phenotypic assay, whereas AZ7550 was broadly similar, with the same overall profile maintained (Supplementary Table S1E).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 potently and selectively targets mutant EGFR cell lines in vitro
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In the paper
“For the EGFRvIII mutant, AZD9291 demonstrated lower potency compared to afatinib and AZD8931. AZ5104, however displayed a higher level of activity (Supplementary Figure S3C).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > Activity of AZD9291 against rare EGFR and HER2 mutants in vitro
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In the paper
“Within days of treatment, 5 of 5 C/L858R mice displayed nearly 80% reduction in tumor volume by magnetic resonance imaging MRI (see Methods and (47)) after therapy with both afatinib or AZD9291, while 5 of 5 mice treated with vehicle showed tumor growth (Figs. 5A (top) and 5B).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 causes profound and sustained regression in mutant EGFR in vivo transgenic tumor models
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In the paper
“In contrast, although AZ5104 exhibited the same overall profile, it was more potent against mutant and wild-type EGFR forms, thus demonstrating a smaller selectivity margin compared to parent (Supplementary Table S1A).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 is a mutant-selective, irreversible inhibitor of EGFR kinase activity
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In the paper
“In EGFR recombinant enzyme assays (Millipore), AZD9291 showed an apparent IC50 of 12 nM against L858R and 1 nM against L858R/T790M; these are called apparent since the amount of active enzyme changes over time and thus IC50 is time-dependent for irreversible agents.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 is a mutant-selective, irreversible inhibitor of EGFR kinase activity
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In the paper
“Once daily dosing of AZD9291 induced significant dose-dependent regression in both PC-9 (ex19del) and H1975 (L858R/T790M) tumor xenograft models, with tumor shrinkage observed at doses as low as 2.5mg/kg/day in both models after 14 days (Fig. 4A, B).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 causes profound and sustained regression in mutant EGFR in vivo xenograft models
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In the paper
“In H1975 xenografts, 5 mg/kg/day AZD9291 resulted in complete responses in 10 of 12 tumors. Re-growth was observed after approximately 50 days treatment with 1 mg/kg/day, but an increased dose of 25 mg/kg/day AZD9291 re-induced tumor regression possibly suggesting re-growth was still driven by T790M EGFR.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 causes profound and sustained regression in mutant EGFR in vivo xenograft models
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In the paper
“In line with the phosphorylation data, AZD9291 showed high levels of phenotype potency in both sensitizing-mutant (mean IC50 of 8 nM in PC-9) and T790M (mean IC50 of 11 and 40 nM in H1975 and PC-9VanR respectively) EGFR cell lines, whilst having much less activity towards wild-type EGFR (mean IC50 of 650 and 461 nM in Calu3 and H2073 respectively) (Fig. 3A).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 potently and selectively targets mutant EGFR cell lines in vitro
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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In the paper
“All EGFR TKIs were effective against EGFR L861Q (consistent with kinase profiling data (Table 1)), G719S, and the exon 19 insertion, although AZD9291 was somewhat less potent compared with the AZ5104 metabolite against these mutant EGFR forms (Supplementary Figure S3A).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > Activity of AZD9291 against rare EGFR and HER2 mutants in vitro
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In the paper
“By contrast, in C/L+T animals, only AZD9291 treatment induced significant tumor shrinkage (Figs. 5A (middle&bottom) and 5C), while both vehicle- and afatinib-treated mice showed viable tumor (Fig. 5C).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 causes profound and sustained regression in mutant EGFR in vivo transgenic tumor models
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In the paper
“Indeed, whilst chronic treatment with gefitinib or afatinib commonly caused acquired resistance in PC-9 cells in vitro through gain of T790M, acquired resistance to AZD9291 through T790M was not observed (Fig. 3C).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 potently and selectively targets mutant EGFR cell lines in vitro
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In the paper
“In biochemical assays, AZ7550 had a comparable potency and selectivity profile to the parent (Supplementary Table S1A).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 is a mutant-selective, irreversible inhibitor of EGFR kinase activity
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In the paper
“AZD9291 showed similar potency to early generation TKIs in inhibiting EGFR phosphorylation in EGFR cells harboring sensitising EGFR mutants including PC-9 (ex19del), H3255 (L858R) and H1650 (ex19del) (Fig. 2A), with mean IC50 values ranging from 13 to 54 nM for AZD9291.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 potently and selectively targets mutant EGFR cell lines in vitro
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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In the paper
“Interestingly, although downstream signaling molecules similarly showed maximal inhibition after 6 hours, in contrast to phospho-EGFR, they displayed more transient inhibition (Fig. 6A).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > Pharmacodynamic confirmation of target inhibition by AZD9291
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“No visible tumors were evident after 20 days dosing of 25 mg/kg/day AZD9291 in the H1975 xenograft model. Moreover, the complete responses were maintained for the duration of the study period with no evidence of tumor progression during 200 days of treatment. No growth was observed for an additional 30 days after treatment was stopped.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 causes profound and sustained regression in mutant EGFR in vivo xenograft models
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“and potentially lung cancer-associated HER2 mutants”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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In the paper
“It is also interesting to note that we not yet seen resistance to AZD9291 due to direct mutation of cysteine 797 (data not shown), which would render the receptor refractory to irreversible agents, in an analogous manner T790M prevents inhibition by early generation drugs.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Discussion
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In the paper
“We describe here the identification, characterization and early clinical development of AZD9291, a novel oral, irreversible, third generation TKI with a distinct profile from gefitinib, erlotinib, afatinib, and dacomitinib.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Discussion
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“but in vitro data suggests the potential to target both HER2 and HER4 kinase activity.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Both patients had a duration of response of approximately 9 months and were progression-free on 20 mg/day AZD9291 for approximately 11 months, until disease progression by RECIST 1.1.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > Proof of principle clinical activity of AZD9291 in patients with acquired resistance to EGFR TKIs
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Both patients continue to receive AZD9291 treatment on study as per protocol, as they continue to derive clinical benefit according to their treating physicians.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > Proof of principle clinical activity of AZD9291 in patients with acquired resistance to EGFR TKIs
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“AZD9291 and AZ5104 also appear to be effective against other rare drug-sensitive EGFR mutants”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Discussion
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Rash and diarrhea were mostly mild and reported in only a minority of patients, consistent with low activity against wild-type EGFR.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Discussion
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Consistent with AZD9291 being less active against wild-type EGFR, in these two cases there were no rash events and only one reported CTCAE Grade 1 diarrhea.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > Proof of principle clinical activity of AZD9291 in patients with acquired resistance to EGFR TKIs
Strength:plain· not yet calibratedn = 2Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No significant aberration of blood glucose levels were noted in either patient during the study.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > Proof of principle clinical activity of AZD9291 in patients with acquired resistance to EGFR TKIs
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Both patients’ tumors harbored drug sensitive EGFR mutations in addition to documented T790M mutations (according to local testing results).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > Proof of principle clinical activity of AZD9291 in patients with acquired resistance to EGFR TKIs
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The two responding patients' tumors truly harbored T790M according to the local testing results.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Preliminary clinical pharmacokinetic analysis indicates that AZD9291, AZ5104 and AZ7550 have a half-life of at least 50 hours, longer than would be predicted from the preclinical data, which results in a desirable flat PK profile after multiple once daily dosing (Fig 7A).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > Proof of principle clinical activity of AZD9291 in patients with acquired resistance to EGFR TKIs
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Tumor shrinkage on AZD9291 was 39.7% at scan 1, 48.3% by scan 2 (Fig. 7B), remained at 48.3% at both scan 3 and scan 4, and was 51.7% at scan 5 (data not shown).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > Proof of principle clinical activity of AZD9291 in patients with acquired resistance to EGFR TKIs
Strength:plain· not yet calibratedSingle caseTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“but like other EGFR TKIs are not potent against an EGFR exon 20 insertion.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Discussion
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“However, it is now well established that acquisition of a second mutation in EGFR, resulting in substitution of threonine at the “gatekeeper” amino acid 790 to methionine (T790M) is the most common resistance mechanism and is detected in tumor cells from more than 50% of patients after disease progression (20, 21).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Introduction
What the sources say
- Not checked yetcites [20] Kobayashi, 2005, EGFR mutation and resistance of non-small-cell lung cancer to gefitinib., N Engl J Med source
- Not checked yetcites [21] Pao, 2005, Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain., PLoS Med source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Unfortunately, whilst patients with EGFRm+ tumors typically show good initial responses to first generation TKIs, most patients who respond to therapy ultimately develop disease progression after about 9-14 months of treatment (7-11).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Introduction
What the sources say
- Not checked yetcites [7] Maemondo, 2010, Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR., N Engl J Med source
- Not checked yetcites [8] Mitsudomi, 2009, Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial., Lancet Oncol source
- Not checked yetcites [9] Mok, 2009, Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma., N Engl J Med source
- Not checked yetcites [10] Rosell, 2012, Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial., Lancet Oncol source
- Not checked yetcites [11] Zhou, 2011, Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study., Lancet Oncol source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although in mice, the pharmacokinetic half-life of AZD9291 is only ~3 hours, phospho-EGFR staining remained significantly diminished even after the 30 hour time point, consistent with its expected irreversible mode of action.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > Pharmacodynamic confirmation of target inhibition by AZD9291
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“By contrast, this same 5 mg/kg/day dose level was sufficient to induce profound and sustained tumor shrinkage in both H1975 and PC-9 mutant EGFR tumor xenograft models (Figs. 4A-B), consistent with AZD9291 having a significant selectivity margin over wild-type EGFR.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 causes profound and sustained regression in mutant EGFR in vivo xenograft models
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Second-generation irreversible EGFR TKIs such as afatinib (24) and dacomitinib (25) are effective in untreated EGFR mutant lung cancer (26, 27).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Introduction
What the sources say
- Not checked yetcites [24] Li, 2008, BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models., Oncogene source
- Not checked yetcites [25] Engelman, 2007, PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib., Cancer Res source
- Not checked yetcites [26] Ramalingam, 2012, Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer., J Clin Oncol source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, taken together, this mechanistic data confirmed the third generation TKI properties of AZD9291 compared to earlier generation agents: equivalent activity against sensitizing mutant EGFR, superior activity towards T790M and increased selectivity margin against wild-type EGFR.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 potently and selectively targets mutant EGFR cell lines in vitro
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Furthermore, these first generation TKIs are associated with side effects that include skin rash and diarrhea that are due to the inhibition of wild-type EGFR in skin and gastrointestinal organs (12).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Introduction
What the sources say
- Not checked yetcites [12] Burtness, 2009, NCCN Task Force Report: Management of dermatologic and other toxicities associated with EGFR inhibition in patients with cancer., J Natl Compr Cancer Netw source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“However, as monotherapy, they have failed to overcome T790M-mediated resistance in patients (28, 29), because concentrations at which these irreversible TKIs overcome T790M activity pre-clinically are not achievable in humans due to dose-limiting toxicity related to non-selective inhibition of wild-type EGFR (30).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Introduction
What the sources say
- Not checked yetcites [28] Miller, 2012, Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial., Lancet Oncol source
- Not checked yetcites [29] Katakami, 2013, LUX-lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both., J Clin Oncol source
- Not checked yetcites [30] Eskens, 2008, A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours., Br J Cancer source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“As expected, tumors harboring EGFRL858R were sensitive to erlotinib, while tumors expressing EGFRL858R + T790M were resistant (46).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Results > AZD9291 causes profound and sustained regression in mutant EGFR in vivo transgenic tumor models
What the sources say
- Not checked yetcites [46] Regales, 2007, Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors., PLoS ONE source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“A surprising finding in the afatinib plus cetuximab study was that tumors with undetectable levels of T790M also displayed tumor shrinkage, suggesting that a T790M-independent but EGFR-dependent pathway of resistance exists.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Discussion
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All cDNAs were re-sequenced to verify that no additional codon-changing mutations were present.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Materials and Methods > Modelling the binding mode of AZD9291
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All patients were treated on trial NCT01802632 with written informed consent from patients and approval appropriate Institutional Review Boards (For the two patients disclosed in this manuscript the Ethics committees are as follows; Korean patient: Seoul National University Hospital (EC), UK patient: North West – GM Central, North West Centre of REC, Manchester).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Materials and Methods > Immunohistochemistry
Strength:plain· not yet calibratedn = 2Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All AZ cell lines were tested and authenticated by short-tandem repeat analysis (STR).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Materials and Methods > Modelling the binding mode of AZD9291
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In the paper
“Prior to treatment, mice were scanned at least twice to confirm the presence of growing lung nodules and to avoid treating false-positive animals.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Materials and Methods > Modelling the binding mode of AZD9291
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Mutations in EGFR occur in 10-35% of NSCLCs and confer sensitivity to the EGFR TKIs erlotinib, gefitinib, and afatinib (6).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Discussion
What the sources say
- Not checked yetcites [6] Pao, 2010, Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer., Nat Rev Cancer source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
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In the paper
“Pao lab cell lines were re-genotyped multiple times to confirm the presence of known EGFR mutations by standard Sanger sequencing to ensure the accuracy of experiments.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Materials and Methods > Modelling the binding mode of AZD9291
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, taken together, this supports the hypothesis that AZD9291 could also offer an attractive treatment option in EGFRm+ TKI-naïve patients, through targeting both sensitizing and T790M tumour cell populations that co-exist in a proportion of tumors, which may then lead to delayed disease progression and ultimately increased survival benefit.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For pharmacodynamic studies, mice were randomized at a mean tumor volume of approximately 0.5-0.8cm3 using the same randomization criteria as the tumor growth inhibition studies.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Materials and Methods > Modelling the binding mode of AZD9291
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Randomisation for animal studies is based on initial tumor volumes to ensure equal distribution across groups.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Materials and Methods > Modelling the binding mode of AZD9291
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“A power analysis is performed whereby group sizes are calculated to enable statistically robust detection of tumor growth inhibition.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Materials and Methods > Modelling the binding mode of AZD9291
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Prior to identification of “third generation” EGFR TKIs, the most promising targeted regimen in patients with acquired resistance had been the combination of afatinib plus cetuximab, which induced a 32% response rate and median progression-free survival of 4.7 months in a heavily pre-treated cohort (52) with a significant degree of skin and gastrointestinal (diarrhea) toxicity.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Discussion
What the sources say
- Not checked yetcites [52] Sequist, 2013, First-in-human evaluation of CO-1686, an irreversible, selective, and potent tyrosine kinase inhibitor of EGFR T790M., J Clin Oncol source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“This property may be important as HER2 amplification may mediate acquired resistance to EGFR TKI in some cases (13).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Discussion
What the sources say
- Not checked yetcites [13] Takezawa, 2012, HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation., Cancer Discov source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Third generation EGFR TKI agents such as AZD9291 have the potential to overcome these limitations and improve markedly the treatment options to patients who have progressed on TKI treatment due to T790M.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Earlier generation EGFR TKIs have toxicities related to wild-type EGFR and resistance mechanisms that limit their effectiveness.
In the paper
“In more than half of patients, tumor cells at the time of progression harbor a second-site T790M mutation, which confers resistance to these EGFR TKIs (23).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Discussion
What the sources say
- Not checked yetcites [23] Yun, 2008, The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP., Proc Natl Acad Sci U S A source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In the phase I trial of AZD9291 in EGFRm+ NSCLC patients that had progressed on earlier generation TKIs, evidence of efficacy has been seen at all doses studied so far, with AZD9291 induced partial radiographic responses in patients whose tumors were known to harbor T790M, from the first dose cohort onwards (49, 53).”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Discussion
What the sources say
- Not checked yetcites [49] Ranson, 2013, Preliminary results from a Phase I study with AZD9291: an irreversible inhibitor of epidermal growth factor receptor (EGFR) activating and resistance mutations in non-small cell lung cancer (NSCLC)., Eur J Cancer
- Not checked yetcites [53] Soria, 2013, First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M)., J Thoracic Oncol
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In the first into man study a cohort size of 6 for the starting dose is standard practice, to provide sufficient safety and tolerability data about a dose level without exposing too many patients to a dose which may not be clinically beneficial.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Materials and Methods > Immunohistochemistry
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Biochemical profiling together with in vitro cellular phosphorylation and phenotype studies have collectively shown that AZD9291 is highly potent against EGFRm+ and T790M resistant EGFR mutants with a wide margin of selectivity against wild type EGFR activity and exhibits a high degree of selectivity against other kinases outside the EGFR family.”
§ AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper relies on this without support.
The two responding patients' tumors truly harbored T790M according to the local testing results.
“Both patients’ tumors harbored drug sensitive EGFR mutations in addition to documented T790M mutations (according to local testing results).”
“Analysis of tumor tissue, from a biopsy taken immediately before AZD9291 study entry, using direct dideoxynucleotide-based sequencing, revealed presence of a T790M mutation (data not shown).”
The paper relies on this without support.
Current EGFR TKIs generally penetrate the blood-brain barrier poorly, and their activity in brain metastases is variable and influenced by dose, blood-brain barrier disruption, and efflux transporter expression.
“Although there are reports of TKIs providing benefit in treatment of EGFRm+ BM, current TKIs are believed to have generally poor properties for penetrating across the blood brain barrier (BBB), and thus their activity will be variable and influenced by such factors as dose, level of BBB disruption and efflux transporter expression across individuals.”
The paper relies on this without support.
Earlier generation EGFR TKIs have toxicities related to wild-type EGFR and resistance mechanisms that limit their effectiveness.
“However, toxicities related to wild-type EGFR and the emergence of resistance mechanisms have limited the effectiveness of these drugs.”
The paper relies on this without support.
AZD9291 is structurally distinct from other third-generation EGFR TKIs.
“Since AZD9291 is structurally distinct, it will be critical to understand which resistance mechanisms are induced through treatment with AZD9291 and whether different “third generation” TKIs engage common escape mechanisms.”
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?
In the citing paper
“such as WZ 4002, osimertinib, and rociletinib, which were specifically designed for T790M mutants rather than WT-EGFR. including.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [118]
In the citing paper
“These resistances are often associated with T790M mutations, resulting in the development of the third-generation EGFR TKIs,118”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [118]
In the citing paper
“AZD9291, reported by Cross et al., is a novel oral, potent, and selective third-generation irreversible inhibitor that inhibits EGFR (T790M) resistant mutation without affecting wild-type EGFR [71].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [71]
In the citing paper
“The overall objective tumor response rate was 51%, indicating that AZD9291 was highly effective in patients with EGFR (T790M) mutant lung cancer whose disease had progressed during previous treatment with EGFR tyrosine kinase inhibitors [71, 72].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [71]
In the citing paper
“These agents are designed to specifically inhibit mutant EGFR (ie, 19del-EGFR, L858R-EGFR and/or T790M+EGFR), sparing the WT receptor.14–18”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [15]
In the citing paper
“The presence of the T790M mutation was observed in approximately 50% of the cases in which biopsy was obtained at the time of relapse following gefitinib or erlotinib treatment in patients with the exon 19 deletion or the L858R EGFR mutation.”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [15]
In the citing paper
“second- and third-generation TKIs are now available for tumors harboring certain EGFR and ALK resistance mutations (12, 13).”
In the citing paper
“As demonstrated previously using EGFR TKI (13) or using siRNA against EGFR (Fig. S2A), the survival of H2073-WT cell line is dependent on EGFR.”
From Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions (2018) · cites this paper as [13]
In the citing paper
“in mice the pharmacokinetic half-life of osimertinib and AZ5104 is only approximately 3 hours (13)”
From Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions (2018) · cites this paper as [13]
In the citing paper
“Osimertinib is a third-generation EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M”
From Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions (2018) · cites this paper as [13]
In the citing paper
“here we report pre-clinical activity of osimertinib and AZ5104 (a circulating metabolite of osimertinib) (13), against these two most clinically prevalent variants of Ex20Ins mutations.”
From Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions (2018) · cites this paper as [13]
In the citing paper
“Using in vitro phospho-EGFR studies, osimertinib and its active metabolite AZ5104 effectively inhibited Ex20Ins mutant forms of EGFR, at potencies comparable to the common activating and T790M mutants previously published (13).”
From Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions (2018) · cites this paper as [13]
In the citing paper
“Osimertinib is an oral, third-generation, irreversible EGFR-TKI that selectively inhibits both sensitizing EGFR mutations and Thr790Met (T790M) resistance mutations.”
From Osimertinib for Patients With Non–Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Multicenter, Open-Label, Phase II Trial (KCSG-LU15-09) (2020) · cites this paper as [11]
In the citing paper
“Cysteine 797 is the site of covalent binding for all three of these agents (14–16).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [16]
In the citing paper
“They are not only more potent on EGFR T790M, but also selectively inhibit mutant over WT EGFR and hence should lead to increased clinical efficacy and less toxicity compared with afatinib (14–16).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [16]
In the citing paper
“CO-1686 is structurally more closely related to WZ4002 than to AZD9291 and in all of the models tested CO-1686 is very similar in vitro to WZ4002 (14–16).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [16]
In the citing paper
“These include the development of mutant selective EGFR kinase inhibitors, including WZ4002, CO-1686 and AZD9291, which to date have demonstrated encouraging efficacy in both preclinical models and in EGFR mutant NSCLC patients with EGFR T790M mediated drug resistance (14–18).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [16]
In the citing paper
“Both 2G and 3G EGFR‐TKI are irreversible small‐molecule inhibitors that covalently bind to EGFR kinase by targeting the cysteine‐797 residue, located in the ATP binding pocket, and 3G EGFR‐TKI are considered to be more specific for EGFR sensitizing mutations than 2G EGFR‐TKI.12, 13, 14”
In the citing paper
“Osimertinib and rociletinib are 3rd generation EGFR-TKIs, both of which are reported to be effective in lung cancer cells harboring EGFR T790M in preclinical models [30, 32].”
In the citing paper
“Preliminary pharmacokinetic profile, showing total plasma concentrations of osimertinib, was reported [30].”
In the citing paper
“The mean plasma concentration of 6 patients treated with once-daily 20 mg oral osimertinib dosing in the AURA phase I study (NCT01802632) was around 100 nM”
In the citing paper
“Osimertinib is an oral, irreversible EGFR-TKI that is selective for both EGFR and T790M resistance mutations with activity in the central nervous system (CNS).19–21”
From Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer (2017) · cites this paper as [19]
In the citing paper
“The presence of the T790M variant reduces binding of first-generation or second-generation EGFR-TKIs to the ATP-binding pocket of EGFR, thereby reducing EGFR-TKI–mediated inhibition of downstream signaling and potentially leading to disease progression.17–19”
From Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer (2017) · cites this paper as [18]
In the citing paper
“The presence of the T790M variant reduces binding of first-generation or second-generation EGFR-TKIs to the ATP-binding pocket of EGFR, thereby reducing EGFR-TKI–mediated inhibition of downstream signaling and potentially leading to disease progression.17–19”
From Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer (2017) · cites this paper as [19]
In the citing paper
“A third generation of EGFR inhibitors followed afatinib; these covalent inhibitors selectively target the T790M mutant over wild-type EGFR, and include WZ4002 (Dana–Farber Cancer Institute)43, osimertinib44,45 and rociletinib (Clovis Oncology; CO-1686)46 (Fig. 2c).”
From Advances in covalent drug discovery (2022) · cites this paper as [44]
In the citing paper
“Standard of care is rapidly changing with the development of third-generation, mutant-selective EGFR-TKIs that have activity against cells that harbor TKI-sensitive EGFR mutations. Unlike conventional EGFR-TKIs, this activity is maintained in the presence of T790M resistance mutation.8,9”
From Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non–Small-Cell Lung Cancer (2016) · cites this paper as [8]
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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.
L858R substitution is described in the reverse direction
Minor"Substitution of leucine for arginine" means replacing arginine with leucine. The notation L858R specifies the opposite: leucine is replaced by arginine at position 858.
“substitution of leucine for arginine at position 858”
“(L858R)”
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Self-citationHigh T790M detection rate in TKI-naive NSCLC with EGFR sensitive mutation: truth or artifact?
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Research works printed but not linked: 2
- Ranson, 2013, Preliminary results from a Phase I study with AZD9291: an irreversible inhibitor of epidermal growth factor receptor (EGFR) activating and resistance mutations in non-small cell lung cancer (NSCLC)., Eur J Cancer, 49, S15
- Ranson, 2013, AZD9291: an irreversible, potent and selective tyrosine kinase inhibitor (TKI) of activating (EGFRm+) and resistance (T790M) mutations in advanced NSCLC., J Thorac Oncol, 8, S389
Cited by
Sorted by citations
Osimertinib in Untreated EGFR -Mutated Advanced Non–Small-Cell Lung Cancer
Soria, J.-C., Ohe, Y., Vansteenkiste, J., Reungwetwattana, T., Chewaskulyong, B., Lee, K. H., Dechaphunkul, A., Imamura, F., Nogami, N., Kurata, T., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1713137 · Cited by 5,508
Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer
Mok, T. S., Wu, Y.-L., Ahn, M.-J., Garassino, M. C., Kim, H. R., Ramalingam, S. S., Shepherd, F. A., He, Y., Akamatsu, H., Theelen, W. S. M. E., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1612674 · Cited by 3,379
Self-citationOverall Survival with Osimertinib in Untreated, EGFR -Mutated Advanced NSCLC
Ramalingam, S. S., Vansteenkiste, J., Planchard, D., Cho, B. C., Gray, J. E., Ohe, Y., Zhou, C., Reungwetwattana, T., Cheng, Y., Chewaskulyong, B., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1913662 · Cited by 2,914
Thai, A. A., Solomon, B., Sequist, L. V. D., Gainor, J. F., & Heist, R. S. (2021) · The Lancet · doi:10.1016/s0140-6736(21)00312-3 · Cited by 2,753
Planchard, D., Popat, S., Kerr, K., Novello, S., Smit, E. F., Faivre-Finn, C., Mok, T. S., Reck, M., Van Schil, P. E., Hellmann, M. D., et al. (2018) · Annals of Oncology · doi:10.1093/annonc/mdy275 · Cited by 2,274
Metadata
- Authors
- Cross, D. A. E., Ashton, S. E., Ghiorghiu, S., Eberlein, C., Nebhan, C. A., Spitzler, P. J., Orme, J. P., Finlay, M. R. V., Ward, R. A., Mellor, M. J., Hughes, G., Rahi, A., Jacobs, V. N., Brewer, M. R., Ichihara, E., Sun, J., Jin, H., Ballard, P., Al-Kadhimi, K., Rowlinson, R., Klinowska, T., Richmond, G. H. P., Cantarini, M., Kim, D.-W., Ranson, M. R., & Pao, W.
- Affiliations
- 1Oncology Innovative Medicines and
- Vanderbilt University (US)
- AstraZeneca (United Kingdom) (GB)
- Seoul National University Hospital (KR)
- University of Manchester (GB)
- ORCID
- Venue
- Cancer Discovery
- Published
- 2014-09-01
- Volume
- 4
- Issue
- 9
- Pages
- 1046-1061
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC4315625
- OpenAlex
- W2088540000
- Cited by
- 2,246
- References
- 63
- Citations by year
- 2026: 164 · 2025: 186 · 2024: 191 · 2023: 181 · 2022: 206 · 2021: 199 · 2020: 220 · 2019: 210 · 2018: 209 · 2017: 191 · 2016: 157 · 2015: 113 · 2014: 18
- FWCI
- 131.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- AstraZeneca
- National Cancer Institute (R01CA121210, P01CA129243, U54CA143798, P50CA090949, P30CA068485)
- National Institute of General Medical Sciences (T32GM007347)
- 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
- osimertinib, EGFR tyrosine kinase inhibitors, T790M mutation, EGFR-mutant non-small cell lung cancer, drug resistance, irreversible kinase inhibitors, third-generation EGFR-TKI, targeted therapy
- MeSH terms
- Acrylamides, Aniline Compounds, Animals, Antineoplastic Agents, Disease Models, Animal, Female, Humans, Indoles, Lung Neoplasms, Male, Middle Aged, Models, Molecular, Molecular Conformation, Mutation, Phosphorylation, Protein Binding, Pyrimidines, Signal Transduction, Treatment Outcome, Genes, erbB-2, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Cell Line, Tumor, Tumor Burden, Protein Kinase Inhibitors, Cell Proliferation, 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.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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.
What counts as a claim ›How we measure confidence ›How we check this ›
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