The DOI matches its Crossref record; 17 of the 18 references it cites were found in a registry or an index, and 1 are not checked yet; 4 of the 34 sources its claims cite were checked for support.
Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions
Open accessPublished version of a preprint
Abstract
EGFR exon 20 insertions (Ex20Ins) account for 4% to 10% of EGFR activating mutations in non–small cell lung cancer (NSCLC). EGFR Ex20Ins tumors are generally unresponsive to first- and second-generation EGFR inhibitors, and current standard of care for NSCLC patients with EGFR Ex20Ins is conventional cytotoxic chemotherapy. Therefore, the development of an EGFR TKI that can more effectively target NSCLC with EGFR Ex20Ins mutations represents a major advance for this patient subset. Osimertinib is a third-generation EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M; however, the activity of osimertinib in EGFR Ex20Ins NSCLC has yet to be fully assessed. Using CRISPR-Cas 9 engineered cell lines carrying the most prevalent Ex20Ins mutations, namely Ex20Ins D770_N771InsSVD (22%) or Ex20Ins V769_D770InsASV (17%), and a series of patient-derived xenografts, we have characterized osimertinib and AZ5104 (a circulating metabolite of osimertinib) activities against NSCLC harboring Ex20Ins. We report that osimertinib and AZ5104 inhibit signaling pathways and cellular growth in Ex20Ins mutant cell lines in vitro and demonstrate sustained tumor growth inhibition of EGFR-mutant tumor xenograft harboring the most prevalent Ex20Ins in vivo. The antitumor activity of osimertinib and AZ5104 in NSCLC harboring EGFR Ex20Ins is further described herein using a series of patient-derived xenograft models. Together these data support clinical testing of osimertinib in patients with EGFR Ex20Ins NSCLC. Mol Cancer Ther; 17(5); 885–96. ©2018 AACR.
Verified 2026-10-06 · 1 reference not checked yet
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37 Own result · 19 Not checked yet · 18 Own interpretation · 9 Own method · 5 No basis given · 1 Partly supported · accuracy not yet measured
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In the paper
“EGFR Ex20Ins tumors are generally unresponsive to 1st and 2nd generation EGFR inhibitors”
- Also stated in: § Introduction · plain
“Unlike Ex19del and L858R, most of the Ex20Ins mutations have been associated in pre-clinical and clinical studies with de novo resistance to the currently approved first-line EGFR-tyrosine kinase inhibitors (TKI), erlotinib, gefitinib and afatinib (2,4–8).”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Abstract
What the sources say
- Supportedcites [2] Arcila, 2013, EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics, Mol Cancer Ther source
The Introduction says EGFR exon 20 insertions have been associated with de novo resistance to erlotinib and gefitinib, as well as to irreversible inhibitors including afatinib. The Discussion cautions that responses vary by insertion, but that does not conflict with the citing sentence’s qualified statement that tumors are generally unresponsive. (LLM, conf=0.91)
- Not checked yetcites [4] Yasuda, 2012, EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications, Lancet Oncol source
- Partly supportedcites [5] Chen, 2016, Clinical efficacy of first-generation EGFR-TKIs in patients with advanced non-small-cell lung cancer harboring EGFR exon 20 mutations, Onco Targets Ther sourceExperimental — accuracy not yet measured
The Results (Efficacy of exon 20 mutations; page not provided) report a median progression-free survival of 1.9 months for patients with exon 20 insertions treated with first-generation EGFR inhibitors, supporting generally poor responsiveness. The paper does not identify A763_Y764insFQEA as an exception or establish resistance to afatinib; its Discussion instead reports possible benefit from afatinib in another study. (LLM, conf=0.86)
- Partly supportedcites [6] Naidoo, 2015, Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: Clinical outcomes and response to erlotinib, Cancer sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) says most EGFR exon 20 insertion variants resist erlotinib and that traditional EGFR TKIs are generally ineffective, supporting the citing sentence’s broad point. It identifies A763_Y764insFQEA as a responsive exception, but also reports a possible second responsive variant, V769_D770insASV. The paper does not establish the claim’s drug-specific resistance to gefitinib and afatinib. (LLM, conf=0.85)
- Supportedcites [7] Yasuda, 2013, Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer, Sci Transl Med source
The Discussion reports that most exon 20 insertions resist clinically achievable doses of gefitinib, erlotinib, and afatinib. It identifies A763_Y764insFQEA as an exception sensitive to gefitinib and erlotinib. The Results also report no responses to gefitinib or erlotinib among 16 patients with other insertions; the afatinib finding is based on in vitro models. (LLM, conf=0.93)
- Not checked yetcites [8] Yang, 2015, Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6, Lancet Oncol source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Introduction · plain
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
“in a PDX model (LG1423) harboring the same prevalent EGFR Ex20ins V769_D770InsASV variant as used in H2073 studies, daily dosing of 25 mg/kg osimertinib induced a superior tumor growth inhibition than the higher 20mg/kg dose of afatinib (60%, p<0.001 & 18%, p: non-significant respectively at day 22) when compared to the control group (Fig. 5A).”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > Osimertinib and AZ5104 are efficacious in EGFR Ex20Ins PDX models in vivo
plaindirectSingle case ·- Asserted: passes — The authors put it forward as true.
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In the paper
“the Ex20Ins SVD and ASV confer primary resistance to 7.5 mg/kg, a dose that represents the 40mg clinical starting dose of afatinib (Fig. 3A–B).”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > Osimertinib and AZ5104 induce tumor growth inhibition to a greater degree than afatinib in EGFR Ex20Ins in vivo xenograft models
plaindirect- Asserted: passes — The authors put it forward as true.
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- The authors state this as an assumption: A 7.5 mg/kg dose of afatinib in mice represents the 40 mg clinical starting dose.
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
“The efficacy of osimertinib was associated with robust and sustained inhibition of phospho-EGFR and downstream signalling markers (Fig. 5C and Fig. S8) following a single 25mg/kg dose.”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > Osimertinib and AZ5104 are efficacious in EGFR Ex20Ins PDX models in vivo
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“both gefitinib and afatinib also showed high potency only against the clinically sensitive H2073-FQEA, which was also similar to their wtEGFR activity (Fig. 2D–E).”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > The most prevalent EGFR exon 20 insertions are sensitive to osimertinib in vitro
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the 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.”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Discussion
What the sources say
- Not checked yetcites [13] Cross, 2014, AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer, Cancer Discov source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the first- and second-generation approved TKIs (gefitinib, erlotinib and afatinib) showed high levels of potency against phosphorylation of the Ex20InsFQEA variant using the Cos-7 engineered cell line model (Fig. 2A)”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > The most prevalent EGFR exon 20 insertions are sensitive to osimertinib in vitro
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“As expected, wt-EGFR was mostly located at the plasma membrane in the H2073-WT cells in the absence of ligand stimulation.”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > Characterisation of the activity of the Exon 20 insertion mutations
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“osimertinib induced superior tumor growth inhibition than erlotinib (93%, p<0.001 & 15%, p: non-significant respectively at day 20) when compared to the control group (Fig. 5B).”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > Osimertinib and AZ5104 are efficacious in EGFR Ex20Ins PDX models in vivo
plaindirectSingle case ·- Asserted: passes — The authors put it forward as true.
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In the paper
“Similarly, siRNA knockdown of EGFR inhibited the survival of both H2073-SVD and -ASV cell lines (Fig. S2A).”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > Characterisation of the activity of the Exon 20 insertion mutations
What the sources say
- Not checked yetcites Fig. S2A
plaindirect- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 32
- The quote only partly states this claim. 1
- Probably not a substantial claim. 14
None of the sources cited for this claim have been checked yet.
In the paper
“Accordingly, EGFR knockdown in these cells strongly inhibited signalling through the RAS/MAPK pathway (Fig. S2B) and induced caspase activation relative to control siRNA (Fig. S2C).”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > Characterisation of the activity of the Exon 20 insertion mutations
What the sources say
- Not checked yetcites Fig. S2B
- Not checked yetcites Fig. S2C
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The LXF2478 model, resistant to a once-daily administration of afatinib (20mg/kg) was sensitive to a once-daily administration of osimertinib (25 mg/kg) and AZ5104 (25 mg/kg) with 87% (p<0.001) and 81% (p<0.001) tumor growth inhibition respectively (measured at day 14), when compared to the control group (Fig. 5D).”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > Osimertinib and AZ5104 are efficacious in EGFR Ex20Ins PDX models in vivo
plaindirectSingle case ·- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“the two most prevalent forms of Ex20Ins, which account for approximately 40% of such patients (Fig. S1A–B).”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > Characterisation of the activity of the Exon 20 insertion mutations
What the sources say
- Not checked yetcites Fig. S1A–B
plain- Asserted: passes — The authors put it forward as true.
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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
“In the LU0387 model, once-daily administration of osimertinib (25mg/kg) and AZ5104 (50mg/kg for 7 days and 25mg/kg for 7days) induced 71% (p<0.001) tumor growth inhibition and 86% regression (p<0.001) respectively at day 15 when compared to the control group (Fig. 5E).”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > Osimertinib and AZ5104 are efficacious in EGFR Ex20Ins PDX models in vivo
plaindirectSingle case ·- Asserted: passes — The authors put it forward as true.
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It 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
“phospho-EGFR staining remained significantly diminished even after the 16 hour time point (Fig. 4A), consistent with their expected irreversible mode of action.”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > Osimertinib and AZ5104 inhibit EGFR phosphorylation and downstream signalling pathways in vivo
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“When cultured in 1% serum condition, the H2073-SVD and H2073-ASV cell lines grew independently of the addition of exogenous EGF, whereas the H2073-WT parental cell line was unable to proliferate in the absence of EGF (Fig.1A).”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > Characterisation of the activity of the Exon 20 insertion mutations
What the sources say
- Not checked yetcites Fig.1A
plain- Asserted: passes — The authors put it forward as true.
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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 compounds were well tolerated and minimal body weight loss (less than 10% of starting body weight) was observed (Fig. 3C–D).”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > Osimertinib and AZ5104 induce tumor growth inhibition to a greater degree than afatinib in EGFR Ex20Ins in vivo xenograft models
plain- Asserted: passes — The authors put it forward as true.
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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
“although downstream signalling markers similarly showed maximal inhibition after 6 hours, in contrast with phospho-EGFR, they displayed more transient inhibition (Fig. 4C–D).”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > Osimertinib and AZ5104 inhibit EGFR phosphorylation and downstream signalling pathways in vivo
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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 compounds were well tolerated and minimal body weight loss was observed compared to pre-dose starting body weight (Fig. S7D–E).”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > Osimertinib and AZ5104 are efficacious in EGFR Ex20Ins PDX models in vivo
plain- Asserted: passes — The authors put it forward as true.
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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
“Pharmacodynamic effects were confirmed by assessing phospho-EGFR inhibition by ELISA (Fig. 4A & Fig. S5A) and Western blot (Fig. 4B), and downstream signalling pathways inhibition by assessing phospho-AKT and phospho-ERK inhibition by immunoblotting (Fig. 4C–D & Fig. S5B–C).”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > Osimertinib and AZ5104 inhibit EGFR phosphorylation and downstream signalling pathways in vivo
plaindirect- Asserted: passes — The authors put it forward as true.
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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
“demonstrate sustained tumor growth inhibition of EGFR-mutant tumor xenograft harboring the most prevalent Ex20Ins in vivo”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
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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
“The proliferation of parental cells was stimulated by both EGF and serum treatment; however, these factors were unable to increase proliferation of the Exon20 insert mutants over 1% serum conditions”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > Characterisation of the activity of the Exon 20 insertion mutations
plaindirect- Asserted: passes — The authors put it forward as true.
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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
“in both the H2073-SVD and H2073-ASV cell lines, EGF receptor appears to be constitutively internalised and co-localised with EEA1, a marker of the early endosome (Fig.1C).”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > Characterisation of the activity of the Exon 20 insertion mutations
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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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
“We report that osimertinib and AZ5104 inhibit signalling pathways and cellular growth in Ex20Ins mutant cell lines in vitro”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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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
“Collectively these data demonstrate that the H2073-SVD and -ASV cell lines can grow independently of EGF while maintaining dependency on EGFR signalling pathway for survival”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > Characterisation of the activity of the Exon 20 insertion mutations
boosteddirect- Asserted: passes — The authors put it forward as true.
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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
“we were able to demonstrate for the first time in a disease-relevant cellular context that these prevalent mutations are sufficient to confer dependence of NSCLC cells on ligand-independent EGFR signalling, accompanied by hallmarks of the more common EGFR mutations such as constitutive receptor phosphorylation and receptor endosomal internalisation.”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
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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
“we demonstrated superior tumor inhibition activity of osimertinib compared to erlotinib and afatinib in a PDX harboring one of the most common EGFR Exon 20 insertions (V769_D770InsASV), consistent with the H2073 model harboring the same insert variant.”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Discussion
boosteddirectSingle case- Asserted: passes — The authors put it forward as true.
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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
“Additionally, we demonstrate activity against various less prevalent Ex20Ins mutations using engineered pre-clinical models and patient-derived xenografts (PDXs), indicating wider potential to target multiple variant forms.”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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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
“whilst afatinib similarly showed high levels of phospho-EGFR potency across the Ex20Ins variants in vitro, it also similarly displayed much higher level of potency against wt-EGFR when compared to osimertinib.”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Osimertinib is a third-generation EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M”
- Also stated in: § Introduction · plain
“Osimertinib is a next-generation EGFR TKI with activity against both canonical activating and T790M mutant forms of EGFR, and has gained approval (including in the U.S., Europe and Japan) for the treatment of T790M-positive advanced NSCLC (12,13).”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Abstract
What the sources say
- Not checked yetcites [12] Finlay, 2014, Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor, J Med Chem source
- Not checked yetcites [13] Cross, 2014, AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer, Cancer Discov source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Also stated in: § Introduction · plain
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 cell lines were used within 15 passages, and less than 6 months.”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Methods > Cell lines
plain- Asserted: passes — The authors put it forward as true.
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Probably 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
“A power analysis was performed whereby group sizes were calculated to enable statistically robust detection of tumor growth inhibition (≥ 5 per group) or pharmacodynamic endpoint (≥ 4 per group).”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Methods > Xenograft studies
plainn = 5- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It 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
“The work presented herein demonstrates that osimertinib has the potential to improve upon the current treatment options for NSCLC patients whose tumors harbor an Ex20Ins mutation, and warrants its further clinical investigation.”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Introduction
boostedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.
- Rests on an assumption: Tumors with exon 20 insertions probably rely on this EGFR alteration for growth and survival to the same degree as tumors with other transforming EGFR mutations.
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
“Studies in the United States were conducted in accordance with the guidelines established by the internal Institutional Animal Care and Use Committee (IACUC) and reported following the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines.”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Methods > Xenograft studies
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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 a previous report has postulated the potential of osimertinib in the Ex20Ins setting (14), this study was limited to using in vitro Ba/F3 engineered cell models”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Discussion
What the sources say
- Not checked yetcites [14] Hirano, 2015, In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer, Oncotarget source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Experiments were repeated for a minimum n=3.”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Methods > Cell transfection
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
“The PDX LG1423 was derived from a pleural effusion of a patient harboring EGFR Ex20ins (V769_D770InsASV) following written informed consent on a UC Davis IRB approved protocol for creating patient PDX and using an established IACUC approved protocol at Jackson Laboratory West (Sacramento, CA).”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Methods > Treatment of LG1423 patient-derived Xenograft
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It 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
“Collectively, these results demonstrate that osimertinib and its metabolite AZ5104 are highly active across a number of different Ex20Ins PDX models in vivo compared to afatinib, and further support the potential efficacy of osimertinib in patients harboring various EGFR Ex20Ins mutant tumors.”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > Osimertinib and AZ5104 are efficacious in EGFR Ex20Ins PDX models in vivo
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Randomization of animals onto study was based on initial tumor volumes to ensure equal distribution across groups.”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Methods > Xenograft studies
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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 cell lines were authenticated at AstraZeneca cell banking using DNA fingerprinting short tandem repeat (STR) assays and confirmed to be free of bacterial and viral contaminations by IDEXX.”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Methods > Cell lines
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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 animal studies were conducted in accordance with U.K. Home Office legislation, the Animal Scientific Procedures Act 1986, as well as the AstraZeneca Global Bioethics policy.”
- Also stated in: § Xenograft studies · plain
“All experimental work is outlined in project licence 70/8894, which has gone through the AstraZeneca Ethical Review Process.”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Methods > Xenograft studies
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Also stated in: § Xenograft studies · plain
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
“Collectively these data suggest that osimertinib and its metabolite AZ5104 can effectively inhibit EGFR-phosphorylation and proliferation of cell lines carrying Ex20Ins mutations in EGFR, and have a more favourable mutant-selective profile compared to currently approved first- and second-generation TKIs.”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Results > The most prevalent EGFR exon 20 insertions are sensitive to osimertinib in vitro
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Ex20Ins mutants account for the third most prevalent group of EGFR mutations, representing 4–10% of the segment.”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Discussion
What the sources say
- Not checked yetcites [2] Arcila, 2013, EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics, Mol Cancer Ther source
- Not checked yetcites [4] Yasuda, 2012, EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications, Lancet Oncol source
- Not checked yetcites [18] Planchard, 2016, Osimertinib Western and Asian clinical pharmacokinetics in patients and healthy volunteers: implications for formulation, dose, and dosing frequency in pivotal clinical studies, Cancer Chemother Pharmacol source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
“At the time of PDX creation the patient was EGFR-TKI naïve.”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Methods > Treatment of LG1423 patient-derived Xenograft
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“the activity of osimertinib in EGFR Ex20Ins NSCLC has yet to be fully assessed”
- Also stated in: § Introduction · plain
“osimertinib’s potential in the EGFR Ex20Ins patient population remains to be fully assessed”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Abstract
What the sources say
- Not checked yetcites [14] Hirano, 2015, In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer, Oncotarget source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Also stated in: § Introduction · plain
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
“our data supports osimertinib as having a differentiated profile compared to earlier generation TKIs: 1) high in vitro potency across a range of Ex20Ins variants, 2) evidence for a more consistent and favourable wtEGFR margin of selectivity, and 3) superior efficacy across a range of xenograft and PDX models at clinically relevant doses.”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
“The tumor inhibition activity of both osimertinib and AZ5104 was associated with potent mechanistic activity against EGFR target and downstream signalling pathways, although the transient nature of pathway suppression may imply that more durable inhibition would be required to achieve robust tumor shrinkage in these models.”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Discussion
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
“we suggest the work presented here provides sufficient evidence to warrant the clinical testing of osimertinib within this EGFR activating-mutant Ex20Ins population”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Discussion
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
In the paper
“The circulating metabolite AZ5104 also demonstrated potent activity, suggesting it could potentially contribute to the overall efficacy of osimertinib, although the clinical relevance remains unclear since the metabolite only exists at ~10% of parental levels (19).”
§ Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions > Discussion
What the sources say
- Not checked yetcites [19] Janne, 2015, AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer, N Engl J Med source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
Conventional cytotoxic chemotherapy remains the usual treatment for NSCLC patients with EGFR exon 20 insertions.
“current standard of care for NSCLC patients with EGFR Ex20Ins is conventional cytotoxic chemotherapy”
“for EGFR Ex20Ins the standard of care remains conventional cytotoxic therapies similar to the treatment of EGFR wild-type tumors.”
The paper relies on this without support.
Tumors with exon 20 insertions probably rely on this EGFR alteration for growth and survival to the same degree as tumors with other transforming EGFR mutations.
“Nevertheless, lung adenocarcinomas are likely as dependent on EGFR Ex20Ins as they are on other transforming EGFR mutations for their growth and survival.”
The paper relies on this without support.
Little is known about how exon 20 insertions drive tumorigenesis, and suitable disease models have been scarce.
“The molecular mechanisms underpinning Ex20Ins tumorigenicity remain poorly understood, compounded by the lack of disease-relevant model systems.”
The paper relies on this without support.
The Ex20Ins subgroup is largely refractory to current TKIs and remains a key area of unmet need.
“this Ex20Ins sub-group is largely refractory to current TKIs and remains a key area of unmet need requiring identification of new effective treatment options.”
The paper relies on this without support.
More than 100 potential Ex20Ins mutations have been identified, making it infeasible to profile all possible variants.
“A key challenge with the Ex20Ins is the much more diverse nature of the mutational landscape, with more than 100 potential mutations identified, so it is not feasible to profile all possible Ex20Ins variants.”
The authors state this as an assumption.
A 25 mg/kg dose of osimertinib in mice approximates the clinically approved 80 mg dose.
“a dose that approximates the clinically approved 80mg dose”
The authors state this as an assumption.
A 7.5 mg/kg dose of afatinib in mice represents the 40 mg clinical starting dose.
“a dose that represents the 40mg clinical starting dose of afatinib”
The paper relies on this without support.
Wild-type EGFR activity of TKIs is a key factor limiting achievable clinical exposures against the mutant EGFR target.
“The wild-type EGFR activity of TKIs is believed to be a key factor limiting the achievable clinical exposures against the mutant EGFR target, and therefore may impact clinical benefit.”
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
“Several next-generation EGFR TKIs (some with pan-HER activity) have demonstrated pre-clinical activity against EGFRex20ins and are in clinical development”
From Diverse EGFR Exon 20 Insertions and Co-Occurring Molecular Alterations Identified by Comprehensive Genomic Profiling of NSCLC (2018) · cites this paper as [10]
Citations
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Metadata
- Authors
- Floc'h, N., Martin, M. J., Riess, J. W., Orme, J. P., Staniszewska, A. D., Ménard, L., Cuomo, M. E., O'Neill, D. J., Ward, R. A., Finlay, M. R. V., McKerrecher, D., Cheng, M., Vang, D. P., Burich, R. A., Keck, J. G., Gandara, D. R., Mack, P. C., & Cross, D. A. E.
- Affiliations
- 1IMED Oncology, AstraZeneca, Cambridge, Cambridgeshire, United Kingdom.
- AstraZeneca (United Kingdom) (GB)
- UC Davis Comprehensive Cancer Center (US)
- 3IMED Discovery science, AstraZeneca, Cambridge, Cambridgeshire, United Kingdom.
- 4Jackson Laboratory West, Sacramento, California.
- Corresponding author
- Cross, Darren A.E.
- ORCID
- Venue
- Molecular Cancer Therapeutics
- Published
- 2018-04-30
- Volume
- 17
- Issue
- 5
- Pages
- 885-896
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- PMC
- PMC5932243
- OpenAlex
- W2793767564
- Cited by
- 115
- References
- 18
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 10 · 2023: 13 · 2022: 16 · 2021: 19 · 2020: 19 · 2019: 13 · 2018: 10
- FWCI
- 11.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- National Institutes of Health (5 K12 CA 138464)
- NCI (P30CA093373)
- 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 exon 20 insertion, non-small cell lung cancer, EGFR tyrosine kinase inhibitors, mutant-selective inhibitors, patient-derived xenografts, anticancer activity, drug metabolites
- MeSH terms
- Acrylamides, Aniline Compounds, Animals, Carcinoma, Non-Small-Cell Lung, Chlorocebus aethiops, Exons, Female, Humans, Indoles, Lung Neoplasms, Mutation, Piperazines, Pyrimidines, Mice, SCID, COS Cells, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, ErbB Receptors
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