The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index; 1 of the 29 sources its claims cite were checked for support.
Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in EGFR -Mutant NSCLC
Open accessPublished version of a preprint
Abstract
Purpose: Osimertinib was initially approved for T790M-positive non–small cell lung cancer (NSCLC) and, more recently, for first-line treatment of EGFR-mutant NSCLC. However, resistance mechanisms to osimertinib have been incompletely described. Experimental Design: Using cohorts from The University of Texas MD Anderson Lung Cancer Moonshot GEMINI and Moffitt Cancer Center lung cancer databases, we collected clinical data for patients treated with osimertinib. Molecular profiling analysis was performed at the time of progression in a subset of the patients. Results: In the 118 patients treated with osimertinib, 42 had molecular profiling at progression. T790M was preserved in 21 (50%) patients and lost in 21 (50%). EGFR C797 and L792 (26%) mutations were the most common resistance mechanism and were observed exclusively in T790M-preserved cases. MET amplification was the second most common alteration (14%). Recurrent alterations were observed in 22 genes/pathways, including PIK3CA, FGFR, and RET. Preclinical studies confirmed MET, PIK3CA, and epithelial-to-mesenchymal transition as potential resistance drivers. Alterations of cell-cycle genes were associated with shorter median progression-free survival (PFS, 4.4 vs. 8.8 months, P = 0.01). In 76 patients with progression, osimertinib was continued in 47 cases with a median second PFS (PFS2) of 12.6 months; 21 patients received local consolidation radiation with a median PFS of 15.5 months. Continuation of osimertinib beyond progression was associated with a longer overall survival compared with discontinuation (11.2 vs. 6.1 months, P = 0.02). Conclusions: Osimertinib resistance is associated with diverse, predominantly EGFR-independent genomic alterations. Continuation of osimertinib after progression, alone or in conjunction with radiotherapy, may provide prolonged clinical benefit in selected patients. See related commentary by Devarakonda and Govindan, p. 6112.
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36 Own result · 15 Not checked yet · 12 Own interpretation · 6 Own method · 2 No basis given · 1 Supported
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“These previously defined osimertinib-resistant EGFR mutations were exclusively observed in T790M-preserved cases; this association was statistically significant (11/19 vs. 0/21, p<0.001, Fisher exact test”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
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In the paper
“Median PFS2 was 12.6 months (95% CI, 8.3 to 15.5, Supple. Fig. 5)”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Subsequent treatment post-progression on osimertinib
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In the paper
“In the T790M-preserved group, previously defined osimertinib-resistant EGFR mutations (11/19; C797S: 8; C797G: 1; L792H: 2 [20] [21]) were the most common resistance mechanisms.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
What the sources say
- Not checked yetcites [20] Ercan, 2015, EGFR mutations and resistance to irreversible pyrimidine-based EGFR inhibitors, Clin Cancer Res source
- Not checked yetcites [21] Chen, 2017, Novel mutations on EGFR Leu792 potentially correlate to acquired resistance to osimertinib in advanced NSCLC, J Thorac Oncol source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Among the osimertinib-continued patients, 21 (45%) received palliative radiation for oligometastatic progressing lesions”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Subsequent treatment post-progression on osimertinib
plainn = 21- Asserted: passes — The authors put it forward as true.
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In the paper
“Median PFS1 was 8.4 months (95%CI, 6.7 to 10.7, Fig. 1A)”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Patient characteristics and efficacy of osimertinib
plainn = 118- Asserted: passes — The authors put it forward as true.
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In the paper
“We found that PIK3CA E545K overexpression confers moderate resistance to osimertinib (IC50 increased from 25nM to 67nM, p<0.01)”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
plaindirect- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Preclinical cell line findings translate to clinical osimertinib resistance in patients.
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“CNS metastasis prior to osimertinib was associated with inferior outcome (PFS1 10.4 vs 4.6 months; HR 1.9, 95% CI, 1.2 – 3.0, log-rank p=0.01”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Patient characteristics and efficacy of osimertinib
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“OS Dx for the entire cohort was 71.9 months (95% CI 51.4 – 92.1”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Subsequent treatment post-progression on osimertinib
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“median OS1 was 25.2 months (95% CI, 17.5 to 29.2, Supple. Fig. 2)”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Patient characteristics and efficacy of osimertinib
plainn = 118- Asserted: passes — The authors put it forward as true.
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“There was a trend for improved outcomes in the radiated population compared to non-radiated patients (PFS2 15.5 vs 8.2 months; HR 0.5; 95% CI 0.3 to 1.0, log-rank p=0.05”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Subsequent treatment post-progression on osimertinib
hedgedcorrelationaln = 21 ·- Asserted: passes — The authors put it forward as true.
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In the paper
“Osimertinib was continued beyond PD in 62% of patients (47/76).”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Subsequent treatment post-progression on osimertinib
plainn = 76- Asserted: passes — The authors put it forward as true.
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“whereas BRAF, FGFR2b, PDGFR overexpression did not significantly altered osimertinib sensitivity (Fig. 3D).”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
plain- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Preclinical cell line findings translate to clinical osimertinib resistance in patients.
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In the paper
“Recurrent alterations were observed in 22 genes/pathways, including PIK3CA, FGFR, and RET.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > Abstract > Results:
plainn = 118- Asserted: passes — The authors put it forward as true.
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In the paper
“When compared to osimertinib-continued patients, the discontinued group had shorter survival (OS 11.2 vs 6.1 months; HR 0.45, 95% CI 0.2–0.9, log-rank p=0.02”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Subsequent treatment post-progression on osimertinib
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Cell cycle gene alterations at the time of PD were associated with worse outcome when compared to wild-type (PFS1 8.8 vs. 4.4 months; HR 2.8, 95% CI 1.2 – 6.4, log-rank p=0.01”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Patient characteristics and efficacy of osimertinib
plaincorrelational- Asserted: passes — The authors put it forward as true.
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“two cases acquired KRAS alterations, one with CDK4/KRAS/MDM2 amplification and the other with KRAS Q61R mutation”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
plainn = 2- Asserted: passes — The authors put it forward as true.
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In the paper
“Median TTF on prior EGFR-TKI was 14 months (Table. 1).”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Patient characteristics and efficacy of osimertinib
plainn = 118- Asserted: passes — The authors put it forward as true.
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In the paper
“Two cases acquired PIK3CA E418K/E542K and E542K/E545K mutations (Pt. 35, 40, Supple Table 2)”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
plainn = 2- Asserted: passes — The authors put it forward as true.
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In the paper
“Seven patients with asymptomatic CNS diseases deferred brain radiation, among those, osimertinib CNS disease control rate was 86% (6/7)”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Patient characteristics and efficacy of osimertinib
plainn = 7- Asserted: passes — The authors put it forward as true.
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In the paper
“All variants had CADD≥20, which indicated high likelihood of biological function (among the 1% most deleterious mutations for the EGFR gene, Supple. Table 5).”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
hedged- Asserted: passes — The authors put it forward as true.
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“One tumor with pre-existing RB1/TP53/PIK3CA alterations underwent neuroendocrine trans-differentiation (Pt. 27, Supple Table 2).”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
plainSingle case- Asserted: passes — The authors put it forward as true.
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“In our cohort, tertiary EGFR mutations were the most common resistance mechanism (11/42, 26%).”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > Discussion
plain- Asserted: passes — The authors put it forward as true.
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“Nine cases lost the T790M resistant clones at the time of progression.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
plainn = 18- Asserted: passes — The authors put it forward as true.
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“In three of these cases, mutations potential resulting from clonal hematopoiesis were observed: TP53 C135W in Pt. 28, JAK2 V617F in Pt. 35, and MYC N353S in Pt. 42”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
hedgedn = 3- Asserted: passes — The authors put it forward as true.
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In the paper
“suggesting that c-met inhibition can overcome MET amplification mediated osimertinib resistance.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Preclinical cell line findings translate to clinical osimertinib resistance in patients.
None of the sources cited for this claim have been checked yet.
In the paper
“a strikingly long survival compared to median OS of 19–28 months with first- or second-generation EGFR TKIs[17–19].”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Subsequent treatment post-progression on osimertinib
What the sources say
- Not checked yetcites [17] Zhou, 2015, Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802), Ann Oncol source
- Not checked yetcites [18] Sequist, 2013, Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations, J Clin Oncol source
- Not checked yetcites [19] 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
plain- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The historical median OS of 19–28 months with first- or second-generation EGFR TKIs is a valid comparator for this cohort's OS from diagnosis.
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
“In cell lines, we observed E-cadherin loss and vimentin gain in HCC827 EGFR-TKI resistant cells (HCC827-ER1, Fig 3A) and in H1975 osimertinib-resistant cells (H1975-OR3 and OR13, Fig. 3E, Supple Fig. 7B), indicating that EMT could be a potential resistance mechanism to osimertinib.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Preclinical cell line findings translate to clinical osimertinib resistance in patients.
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
“Taken together, these preclinical data provide evidence that EGFR-independent mechanisms of resistance observed for first- and second-generation EGFR TKIs (MET amplification, PIK3CA mutation, EMT, beta adrenergic activation) may promote osimertinib resistance as well.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Preclinical cell line findings translate to clinical osimertinib resistance in patients.
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
“Despite the increasing role of osimertinib for treatment NSCLC, there is limited data regarding resistance mechanisms to this agent.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > INTRODUCTION:
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“However, in vitro work has also demonstrated that L718Q may still respond to first- and second-generation of EGFR inhibitors, especially when T790M is lost, as is the case for the patient No. 29[20].”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
What the sources say
- Not checked yetcites [20] Ercan, 2015, EGFR mutations and resistance to irreversible pyrimidine-based EGFR inhibitors, Clin Cancer Res source
hedgedconditionalSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“Nevertheless, the practice of continuation of TKI beyond progression is supported by previous reports of patients with indolent and small volume progression benefiting from continuation of TKIs[15, 29].”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > Discussion
What the sources say
- Not checked yetcites [15] Park, 2016, First-line erlotinib therapy until and beyond response evaluation criteria in solid tumors progression in Asian patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer: the ASPIRATION Study, JAMA Oncol source
- Not checked yetcites [29] Yap, 2017, Continuing EGFR inhibition beyond progression in advanced non-small cell lung cancer, Eur J Cancer source
plainconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Most recently, several groups reported that a subset of cases lost T790M at the time of progression[6, 12–14]”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > INTRODUCTION:
What the sources say
- Not checked yetcites [6] Yang, 2018, Investigating novel resistance mechanisms to third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer patients, Clin Cancer Res source
- Not checked yetcites [12] Oxnard, 2017, Osimertinib resistance mediated by loss of EGFR T790M is associated with early resistance and competing resistance mechanisms
- Not checked yetcites [13] Sonam Puri JKH, Knepper TC, Smith M, Boyle TA, Gray JE. Genomic profiling of EGFR T790M mutated non-small cell lung cancer to evaluate the mechanisms of resistance to osimertinib. J Thoracic Oncol 2017;12:S1848–S9. source
- Not checked yetcites [14] Lin, 2018, Outcomes in patients with non-small-cell lung cancer and acquired Thr790Met mutation treated with osimertinib: a genomic study, Lancet Respir Med source
plain- Asserted: passes — The authors put it forward as true.
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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
“Due to the nature of retrospective analysis, this result may be impacted by selection bias, where physicians had to choose discontinuation of osimertinib in cases with obvious progression and clinical deterioration.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“This practice is supported by randomized phase II trials showing that aggressive local consolidation therapy (LCT) increases time to progression compared to maintenance or observation in patients with oligometastatic NSCLC[30].”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > Discussion
What the sources say
- Not checked yetcites [30] Gomez, 2016, Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study, Lancet Oncol source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“MET amplification has been reported as a mechanism of resistance to gefitinib[8] and osimertinib[23].”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
What the sources say
- Not checked yetcites [8] Engelman, 2007, MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling, Science source
- Not checked yetcites [23] Ou, 2016, High MET amplification level as a resistance mechanism to osimertinib (AZD9291) in a patient that symptomatically responded to crizotinib treatment post-osimertinib progression, Lung Cancer source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“G724S also resides in the p-loop, and previous studies have shown that this mutation results in resistance to osimertinib in the presence of T790M[22].”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
What the sources say
- Not checked yetcites [22] Oztan, 2017, Emergence of EGFR G724S mutation in EGFR-mutant lung adenocarcinoma post progression on osimertinib, Lung Cancer source
boosteddirect- 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.
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
“Osimertinib resistance is associated with diverse, predominantly EGFR-independent genomic alterations.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > Abstract > Conclusions:
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The molecular alterations detected in the 42 profiled patients are representative of resistance mechanisms in the broader osimertinib-treated cohort.
In the paper
“This data is consistent with the recent report from Circulating Cell-Free Genome Atlas (CCGA) study showing that up to 54% of the somatic mutations detected in the blood samples from lung cancer patients were from hematopoietic cells’ somatic mutations, but not from tumors[28].”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
What the sources say
- Not checked yetcites [28] Charles Swanton OV, Aravanis A, Hubbell E, Maddala T, Beausang JF, Filippova D, et al Prevalence of clonal hematopoiesis of indeterminate potential (CHIP) measured by an ultra-sensitive sequencing assay: exploratory analysis of the Circulating Cancer Genome Atlas (CCGA) study. J Clin Oncol 36:15s, 2018 (suppl; abstr 12003). source
plaincorrelationaln = 3- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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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
“Continuation of osimertinib post-progression, alone or in conjunction with radiotherapy, may provide prolonged clinical benefit in selected patients.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > Abstract > Conclusions:
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
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
“Other than oncogene driver-mediated resistance, we showed that neuroendocrine and mesenchymal cellular rewiring and cytokine changes in the tumor microenvironment can also impact tumor cell’s sensitivity to therapy.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > Discussion
plainconditional- 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.
- Rests on an assumption: Preclinical cell line findings translate to clinical osimertinib resistance in patients.
- Probably not a substantial claim. 9
- It may state two separate claims as one. 26
Every source the paper cites for this claim was checked and supports it.
In the paper
“Epithelial‐mesenchymal transition (EMT) has also been indicated as one mechanism of resistance to EGFR-TKIs[10].”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
What the sources say
- Supportedcites [10] Sequist, 2011, Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors, Sci Transl Med source
The Results section reports EMT-consistent changes in resistant tumors, including two cases with acquired vimentin expression and lost E-cadherin expression. The Discussion says the authors observed EMT in two cases of acquired EGFR-TKI resistance and in a cell line rendered resistant in vitro. This supports the claim's cautious wording, although the paper says the molecular connection remains unknown; page numbers are not available in the supplied copy. (LLM, conf=0.92)
hedgedcorrelational- 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.
- Supported
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 HCC827 cells, norepinephrine (10uM) significantly increased proliferation in the presence of osimertinib (from 10–50nM), suggesting resistance (red line, Fig. 3F). Propranolol (1uM), a non-selective beta-adrenergic blocker, restored osimertinib sensitivity in HCC827 cells (gray line, Fig. 3F)”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Preclinical cell line findings translate to clinical osimertinib resistance in patients.
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
“Of the acquired T790M cases, 47% (19/40) preserved and 53% (21/40) lost T790M at progression”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
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
“Of the 18 cases, 9 (50%) preserved T790M with 6 acquired EGFR C797S/L792H mutations”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
plainn = 18- 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
“Preclinical studies confirmed MET, PIK3CA, and epithelial-to-mesenchymal transition (EMT) as potential resistance drivers.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > Abstract > Results:
hedgedconditional- 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.
- Rests on an assumption: Preclinical cell line findings translate to clinical osimertinib resistance in patients.
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 cultured HCC827 cells (EGFR Del745_760) in erlotinib to develop EGFR TKI resistance and identified one clone (ER2) having increased c-Met protein expression and MET copy-number gain (Fig. 3A-3B). This clone was resistant to osimertinib (Supple. Fig. 7A) without resistant mutations in the EGFR exon 20 (Supple. Fig 7C), but exquisitely sensitive to c-met inhibitors”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Preclinical cell line findings translate to clinical osimertinib resistance in patients.
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
“whereas TP53 mutation and T790M loss were not (Supple. Fig. 4)”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Patient characteristics and efficacy of osimertinib
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“MET amplification has been reported as a mechanism of resistance to gefitinib[8] and osimertinib[23]. In our cohort, it was identified in T790M-preserved (5/19) and T790M-loss (1/21) cases, and the second most common resistance mechanism after EGFR tertiary mutations (5/42, 14%).”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
What the sources say
- Not checked yetcites [8] Engelman, 2007, MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling, Science source
- Not checked yetcites [23] Ou, 2016, High MET amplification level as a resistance mechanism to osimertinib (AZD9291) in a patient that symptomatically responded to crizotinib treatment post-osimertinib progression, Lung Cancer source
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
“T790M was preserved in 21 (50%) patients and lost in 21 (50%).”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > Abstract > Results:
plainn = 42- 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
“Three patients developed treatment-related pneumonitis and two patients developed treatment-related cardiotoxicity with decreased ejection.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Patient characteristics and efficacy of osimertinib
plaindirectn = 3- 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.
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 our preclinical models, PIK3CA hotspot mutation, but not BRAF, FGFR, and PDGFR overexpression alone, was found to contribute to osimertinib resistance.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Preclinical cell line findings translate to clinical osimertinib resistance in patients.
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 found that epinephrine reduces the sensitivity of EGFR mutant cells to osimertinib in vitro. Beta-adrenergic blockade with propranolol reversed this resistance phenotype.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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- 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.
- Rests on an assumption: Preclinical cell line findings translate to clinical osimertinib resistance in patients.
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
“Median follow-up on osimertinib was 13 months, with 63% alive at the time of analysis.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Patient characteristics and efficacy of osimertinib
plainn = 118- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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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
“one had FGFR3/FGFR19 amplification (Pt. 32, Supple Table 2), one had MET amplification (Pt. 36; FISH ratio: 7.4, Supple Table 2) and one had ERBB2 amplification (Pt. 40, Supple Table 2).”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
plain- 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.
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
“Among MET-amplified patients, CDK6 (4/5) and BRAF amplification (3/5) were common events”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
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
“There were 14 cases without potential resistance genetic drivers, 12 in T790M-preserved group”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
plainn = 14- Asserted: passes — The authors put it forward as true.
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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
“This data suggests that acquired PIK3CA hotspot mutations may drive contribute to osimertinib resistance, and that BRAF, FGFR, or PDGFR amplifications may be “passenger” events instead of “drivers”, or may not be able to promote resistance alone without additional concurrent alterations.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
hedgedconditionaln = 2- Asserted: passes — The authors put it forward as true.
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- 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.
- Rests on an assumption: Preclinical cell line findings translate to clinical osimertinib resistance in patients.
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
“supporting that stress hormones induce proliferation in the presence of osimertinib. Furthermore, such resistance can be overcome through beta-adrenergic blockade in EGFR-mutant T790M-negative lung cancer cells.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
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.
- Rests on an assumption: Preclinical cell line findings translate to clinical osimertinib resistance in patients.
In the paper
“In a randomized phase III trial[3], osimertinib significantly improved both progression-free survival (PFS) and objective response rate (ORR) when compared to platinum-pemetrexed chemotherapy for T790M-positive non-small cell lung cancer (NSCLC) after progression on 1st or 2nd generation EGFR-TKIs.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > INTRODUCTION:
What the sources say
- Not checked yetcites [3] Mok, 2017, Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer, N Engl J Med source
plaindirect- 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.
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
“Written informed consents were obtained the patients, and the studies were conducted in accordance with ethical guidelines including Declaration of Helsinki and U.S. Common Rule. The study was approved by the IRBs at MDACC and University of South Florida.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > PATIENTS AND METHODS: > Study population
plain- Asserted: passes — The authors put it forward as true.
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- 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
“We observed an AXL mutation in one case with acquired T790M/C797S (Pt. 12 Supple Table 2)[24], suggesting association with EMT.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
What the sources say
- Not checked yetcites [24] Zhang, 2012, Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer, Nat Genet source
hedgedcorrelationalSingle case- 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.
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 showed that many patients with EGFR-mutant NSCLC might have prolonged benefit from osimertinib beyond their initial progression event, especially when radiation was used at progression, suggesting a potential role for local consolidative therapy in this setting.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- 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
“Furthermore, we showed that T790M loss is common in osimertinib-resistant cases, and that these cases demonstrated a different pattern of resistance compared with the T790M-preserved cases.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“when compared to erlotinib or gefitinib in the first-line setting for EGFR mutant NSCLC, osimertinib showed a significant PFS benefit in favor of osimertinib in a phase III study (FLAURA trial, NCT02296125) [4].”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > INTRODUCTION:
What the sources say
- Not checked yetcites [4] Soria, 2018, Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer, N Engl J Med source
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
“In the clinical outcome analysis, the disease progression was based on physician assessment and not specific formal criteria.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Reports on individual cases or clinical series have demonstrated that EGFR exon 20 tertiary mutations, including C797S[5–7], MET amplification[8], HER2 amplification[9], small cell transformation[10], and epithelial-mesenchymal transition (EMT) [10, 11] are possible drivers of resistance.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > INTRODUCTION:
What the sources say
- Not checked yetcites [5] Thress, 2015, Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M, Nat Med source
- Not checked yetcites [6] Yang, 2018, Investigating novel resistance mechanisms to third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer patients, Clin Cancer Res source
- Not checked yetcites [7] Oxnard, 2018, Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib, JAMA Oncol source
- Not checked yetcites [8] Engelman, 2007, MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling, Science source
- Not checked yetcites [9] 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
hedgedconditional- 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
“Because of the relative proximity of the three genes in chromosome 7q (CDK6 at Chr7q21.2, MET at Chr7q31.2 BRAF at Chr7q34), it is possible that these amplifications arose from a single genomic event.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- 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
“In the genetic profiling analysis, in some cases different platforms were used for the pre-treatment and post-progression profiling; however, analysis of the platform-matched cases shows similar results as the overall analysis.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > Discussion
plain- Asserted: passes — The authors put it forward as true.
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- 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.
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 majority of the patients in our cohort received osimertinib as second- or later-lines of therapy (Table 1), with only six patients with baseline EGFR T790M or germline T790M receiving osimertinib as the first-line treatment”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > Discussion
plainn = 6- Asserted: passes — The authors put it forward as true.
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- 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
“Specifically, in most of the T790M-preserved cases, resistance is associated with continued EGFR activation through known resistance tertiary mutations (e.g. C797S) or activation of bypass signaling pathways, whereas resistance in T790M-loss cases occurs through diverse, and predominantly EGFR-independent mechanisms.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Stress hormone induced beta adrenergic pathway activation has recently been identified as a driver of resistance to first-generation TKIs and can be overcome by beta-adrenergic blockade[25]”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
What the sources say
- Not checked yetcites [25] Nilsson, 2017, Stress hormones promote EGFR inhibitor resistance in NSCLC: implications for combinations with beta-blockers, Sci Transl Med source
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.
Probably not a substantial claim. 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
“Both T790M-preserved and -loss groups had similar frequency with next-generation sequencing based paneled tests (14/19 vs. 15/21, Chi-Square p=0.87).”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
plainn = 42- 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.
The paper relies on this without support.
The molecular alterations detected in the 42 profiled patients are representative of resistance mechanisms in the broader osimertinib-treated cohort.
“Genomic profiling at the time of progression was available for 42 patients”
“The 18 platform-matched cases represent the common resistance mechanisms seen in our 42 cases cohort”
The paper relies on this without support.
Preclinical cell line findings translate to clinical osimertinib resistance in patients.
“Taken together, these preclinical data provide evidence that EGFR-independent mechanisms of resistance observed for first- and second-generation EGFR TKIs (MET amplification, PIK3CA mutation, EMT, beta adrenergic activation) may promote osimertinib resistance as well.”
The paper relies on this without support.
The historical median OS of 19–28 months with first- or second-generation EGFR TKIs is a valid comparator for this cohort's OS from diagnosis.
“a strikingly long survival compared to median OS of 19–28 months with first- or second-generation EGFR TKIs[17–19].”
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
“T790M-like-3R mutants, complex mutations comprising T790M and a known drug-resistance mutation (that is, C797S30, L718X31 or L792H18,31), were resistant to classical EGFR TKIs but retained selectivity for select ALK and PKC inhibitors such as brigatinib or midostaurin (Extended Data Fig. 7c).”
From Structure-based classification predicts drug response in EGFR-mutant NSCLC (2021) · cites this paper as [18]
In the citing paper
“EGFR mutations were determined from formalin-fixed paraffin-embedded tumours or digital-droplet PCR for blood samples by CLIA-certified methods as previously described18,37.”
From Structure-based classification predicts drug response in EGFR-mutant NSCLC (2021) · cites this paper as [18]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
“There were 14 cases without potential resistance genetic drivers, 12 in T790M-preserved group, which highlights our limited understanding of T790M-negative resistance mechanisms.”
§ Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC > RESULTS > Potential mechanisms of resistance to osimertinib
“In the T790M-preserved group, previously defined osimertinib-resistant EGFR mutations (11/19; C797S: 8; C797G: 1; L792H: 2 [20] [21]) were the most common resistance mechanisms.”
Citations
Cites
Osimertinib in Untreated EGFR -Mutated Advanced Non–Small-Cell Lung Cancer
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Self-citationRosell, R., Carcereny, E., Gervais, R., Vergnenegre, A., Massuti, B., Felip, E., Palmero, R., Garcia-Gomez, R., Pallares, C., Sanchez, J. M., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(11)70393-x · Cited by 5,489
Age-related clonal hematopoiesis associated with adverse outcomes
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MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling
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Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors
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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-citationSequist, L. V., Yang, J. C.-H., Yamamoto, N., O'Byrne, K., Hirsh, V., Mok, T., Geater, S. L., Orlov, S., Tsai, C.-M., Boyer, M., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.44.2806 · Cited by 3,228
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AZD9291 in EGFR Inhibitor–Resistant Non–Small-Cell Lung Cancer
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Research works printed but not linked: 1
- Oxnard, 2017, Osimertinib resistance mediated by loss of EGFR T790M is associated with early resistance and competing resistance mechanisms, S1767
Cited by
Sorted by citations
Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer
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Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management
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Structure-based classification predicts drug response in EGFR-mutant NSCLC
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Metadata
- Authors
- Le, X., Puri, S., Negrao, M. V., Nilsson, M. B., Robichaux, J., Boyle, T., Hicks, J. K., Lovinger, K. L., Roarty, E., Rinsurongkawong, W., Tang, M., Sun, H., Elamin, Y., Lacerda, L. C., Lewis, J., Roth, J. A., Swisher, S. G., Lee, J. J., William, W. N., Glisson, B. S., Zhang, J., Papadimitrakopoulou, V. A., Gray, J. E., & Heymach, J. V.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Moffitt Cancer Center (US)
- Corresponding author
- Gray, Jhanelle E.
- Heymach, John V.
- ORCID
- Le, Xiuning
- Puri, Sonam
- Negrao, Marcelo V.
- Nilsson, Monique B.
- Robichaux, Jacqulyne
- Boyle, Theresa
- Hicks, J. Kevin
- Lovinger, Katherine L.
- Rinsurongkawong, Waree
- Tang, Ming
- Sun, Huiying
- Elamin, Yasir
- Lewis, Jeff
- Roth, Jack A.
- Swisher, Stephen G.
- William, William N.
- Glisson, Bonnie S.
- Zhang, Jianjun
- Papadimitrakopoulou, Vassiliki A.
- Gray, Jhanelle E.
- Heymach, John V.
- Venue
- Clinical Cancer Research
- Published
- 2018-12-13
- Volume
- 24
- Issue
- 24
- Pages
- 6195-6203
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC6295279
- OpenAlex
- W2891909134
- Cited by
- 387
- References
- 34
- Citations by year
- 2026: 20 · 2025: 41 · 2024: 33 · 2023: 51 · 2022: 63 · 2021: 68 · 2020: 56 · 2019: 50 · 2018: 5
- FWCI
- 33.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- MD Anderson Cancer Center (P30 CA01667)
- NIH (R01 CA190628)
- UT Lung SPORE (P50 CA70907)
- 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-mutant non-small cell lung cancer, drug resistance mechanisms, T790M mutation, MET amplification, PIK3CA, fibroblast growth factor receptor, RET, epithelial-mesenchymal transition, cell cycle genes, progression-free survival, consolidation radiotherapy, overall survival
- MeSH terms
- Acrylamides, Adult, Aged, Aniline Compounds, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Female, Humans, Indoles, Lung Neoplasms, Male, Middle Aged, Mutation, Prognosis, Pyrimidines, Retrospective Studies, Survival Analysis, Treatment Outcome, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, Kaplan-Meier Estimate, Molecular Targeted Therapy, 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).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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