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Cited by 201Lung Cancer Treatments and MutationsLung Cancer Diagnosis and TreatmentHER2/EGFR in Cancer Research

The International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation–Positive Non–Small Cell Lung Cancer: Status in 2016

Open access
Tan, Daniel S.W., Yom, Sue S., Tsao, Ming S., Pass, Harvey I., Kelly, Karen, Peled, Nir, Yung, Rex C., Wistuba, Ignacio I. +13 more·2016·Journal of Thoracic Oncology
DOI 10.1016/j.jtho.2016.05.008
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Abstract

Mutations in the epidermal growth factor receptor gene (EGFR) represent one of the most frequent "actionable" alterations in non-small cell lung cancer (NSCLC). Typified by high response rates to targeted therapies, EGFR tyrosine kinase inhibitors (TKIs) are now established first-line treatment options and have transformed the treatment paradigm for NSCLC. With the recent breakthrough designation and approval of the third-generation EGFR TKI osimertinib, available systemic and local treatment options have expanded, requiring new clinical algorithms that take into account individual patient molecular and clinical profiles. In this International Association for the Study of Lung Cancer commissioned consensus statement, key pathologic, diagnostic, and therapeutic considerations, such as optimal choice of EGFR TKI and management of brain metastasis, are discussed. In addition, recommendations are made for clinical guidelines and research priorities, such as the role of repeat biopsies and use of circulating free DNA for molecular studies. With the rapid pace of progress in treating EGFR-mutant NSCLC, this statement provides a state-of-the-art review of the contemporary issues in managing this unique subgroup of patients.

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  • Premisecitation

    EGFR mutation-positive NSCLC has a distinct clinical course characterized by high response rates to tyrosine kinase inhibitors.

    “As a classic oncogene-driven solid tumor, EGFR mutation-positive NSCLC has a unique disease course typified by high response rates to tyrosine kinase inhibitors (TKIs).6”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Mok, 2009, Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, N Engl J Med source

      Not checked in the free run.

  • Premisecitation

    The EGFR T790M somatic mutation is the most frequent alteration found in about half of tumors that progress on first- or second-generation EGFR TKIs.

    “with the EGFR T790M somatic mutation being the most frequent alteration detected in approximately half of progressing tumors.[14][15][16]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [14] Sequist, 2011, Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors, Sci Transl Med source

      Not checked in the free run.

    • cites [15] Hata, 2013, Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: cComparison between T790M mutation-positive and mutation-negative populations, Cancer source

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    • cites [16] Yu, 2013, Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers, Clin Cancer Res source

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  • Premisecitation

    Sanger sequencing can detect known and novel EGFR mutations, such as C797S, in the setting of resistance to third-generation EGFR TKIs.

    “whereas Sanger sequencing may uncover known and novel mutations (e.g., C797S) in the context of resistance to third-generation EGFR TKIs.39”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Thress, 2015, Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M, Nat Med source

      Not checked in the free run.

  • Premisecitation

    Next-generation EGFR TKIs designed to target T790M produce high and durable responses in advanced EGFR-mutant NSCLC that has progressed after first- or second-generation EGFR TKIs.

    “Next-generation EGFR TKIs have since been developed specifically to target the T790M mutation, 17,18 and they have demonstrated high and durable responses in patients with advanced EGFRmutant NSCLC who have been previously treated and in whom firstor second-generation EGFR TKIs have failed.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [17] Zhou, 2009, Novel mutant-selective EGFR kinase inhibitors against EGFR T790M, Nature source

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    • cites [18] Janne, 2015, AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer, N Engl J Med source

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  • Premisecitation

    Third-generation EGFR TKIs have shown a median progression-free survival of 9.6 months in patients without central nervous system metastases.

    “with the recent approval of third-generation EGFR TKIs that demonstrated a median PFS of 9.6 months (for patients without central nervous system [CNS] metastases).18”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Janne, 2015, AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer, N Engl J Med source

      Not checked in the free run.

  • May combine two claims. 30
  • Classified as probably not a substantial claim. 2

  • May combine two claims.

    Premisecitation

    In the AURA study, osimertinib produced an objective response rate up to 51% in patients with T790M mutations confirmed by repeat tumor biopsy and 21% in T790M-negative tumors.

    “In the setting of clinical resistance to EGFR TKI, the extended phase I study (AURA) of the thirdgeneration inhibitor osimertinib (AZD9291) confers an objective response rate (ORR) of up to 51% in patients with T790M mutations confirmed in repeat tumor biopsies and 21% in T790M-negative tumors.18”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Janne, 2015, AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer, N Engl J Med source

      Not checked in the free run.

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    Premisecitation

    Reported failure rates for EGFR testing are about 5-30%, mostly because of inadequate sample material or tumor cellularity below the minimum required.

    “the reported failure rates for testing are approximately 5% to 30%, mostly owing to inadequate sample materials or lower than the minimum required tumor cellularity.[40][41][42]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [40] Shiau, 2014, Sample features associated with success rates in population-based EGFR mutation testing, J Thorac Oncol source

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    • cites [41] Leary, 2012, Establishing an EGFR mutation screening service for non-small cell lung cancer—sample quality criteria and candidate histological predictors, Eur J Cancer source

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    • cites [42] Hlinkova, 2013, Evaluation of 2-year experience with EGFR mutation analysis of small diagnostic samples, Diagn Mol Pathol source

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    Interpretationcitation

    Targeting MET and IGF1R are rational combination strategies, but their clinical efficacy remains unproven.

    “Other approaches that are also being tested include targeting common escape pathways, such as MET proto-oncogene, receptor tyrosine kinase (MET) and insulin-like growth factor 1 receptor (IGF1R).68,69 Although these are rational combinations, their clinical efficacy is unproven”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [68] Wu, 2014, Safety and efficacy of INC280 in combination with gefitinib (gef) in patients with EGFR-mutated (mut), MET-positive NSCLC: A single-arm phase lb/ll study, J Clin Oncol source

      Not checked in the free run.

    • cites [69] Tan, 2015, Phase Ib trial of afatinib and BI 836845 in advanced non-small cell lung cancer (NSCLC), Ann Oncol source

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    Premisecitation

    In the EURTAC trial, baseline cfDNA was detected in 78% of patients (76 of 97), and the presence of L858R mutation in cfDNA was suggested to be a negative prognostic factor.

    “In the EURTAC trial, a peptide nucleic acid-mediated 5 0 -nuclease real-time polymerase chain reaction (PCR) assay was used to detect cfDNA at baseline in 78% of patients (76 of 97), which suggested that the presence of L858R mutation in cfDNA is a negative prognostic factor.53”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Karachaliou, 2015, Association of EGFR L858R mutation in circulating free DNA with survival in the EURTAC trial, JAMA Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In LUX Lung-7, median PFS was 11.0 months with afatinib versus 10.9 months with gefitinib, with a hazard ratio of 0.73 (95% CI 0.57-0.95, p=0.017).

    “Although the median PFS times for afatinib and gefitinib were 11.0 versus 10.9 months, respectively, the hazard ratio demonstrated a significant difference at 0.73 (95% confidence interval: 0.57-0.95,p ¼ 0.017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Park, 2016, Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial, Lancet Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most studies of uncommon EGFR mutations are retrospective case reports and show differential sensitivity by mutation type.

    “Most of the studies are retrospective, comprising individual case reports in patients treated with both firstand second-generation TKIs that highlight differential sensitivities based on mutation type.62,63”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [62] Wu, 2011, Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer, Clin Cancer Res source

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    • cites [63] Watanabe, 2014, Effectiveness of gefitinib against non-small-cell lung cancer with the uncommon EGFR mutations G719X and L861Q, J Thorac Oncol source

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    Premisecitation

    There are fewer data on EGFR TKI activity for uncommon EGFR mutations, which occur in about 10% of patients.

    “There are fewer data regarding activity of EGFR TKIs for uncommon EGFR mutations, which are found in approximately 10% of patients.[60][61][62]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [60] 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

      Not checked in the free run.

    • cites [61] Beau-Faller, 2014, Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network, Ann Oncol source

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    • cites [62] Wu, 2011, Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer, Clin Cancer Res source

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    Premisecitation

    In the ASPIRATION study, selected patients with slow growth, no symptoms, or few lesions at progression could continue erlotinib beyond RECIST progression; 54% (93/171) were eligible, and median postprogression erlotinib duration was 3.1 months.

    “The ASPIRATION study showed that in selected patients whose tumor was judged to have slow growth, lack of symptoms, or a small number of lesions at PD, erlotinib beyond the point of PD according to RECIST could be continued at the investigators' discretion.Approximately half of the cohort (54% [93 of 171]) were eligible to continue EGFR TKI beyond progression, and the median duration of postprog”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] 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 in the free run.

  • May combine two claims.

    Premisecitation

    Few studies directly compare gefitinib and erlotinib, but retrospective studies suggest no efficacy difference.

    “There are few studies comparing the relative efficacy of gefitinib versus erlotinib, although retrospective studies suggest that there is no difference in efficacy.55”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Lim, 2014, Comparison of clinical outcomes following gefitinib and erlotinib treatment in non-small-cell lung cancer patients harboring an epidermal growth factor receptor mutation in either exon 19 or 21, J Thorac Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the ASPIRATION postprogression group, patients had ECOG performance status 0-1 at progression, longer median PFS, improved depth of response, and longer time from best response to RECIST progression.

    “Patient characteristics in the postprogression treatment group included an Eastern Cooperative Oncology Group performance status of 0 to 1 at time of progression, longer median PFS, improved depth of response, and longer time from best objective response to RECIST-based progression.72”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] 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 in the free run.

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    Premisecitation

    Histological transformation to squamous cell cancer and small cell lung cancer has been described, with small cell transformation consistently associated with RB1 loss.

    “Histological transformation to both squamous cell cancer 76 and small cell lung cancers 16 has also been described, with the latter shown to be consistently associated with loss of retinoblastoma 1 gene (RB1).77”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [76] Jukna, 2016, Squamous Cell carcinoma “transformation” concurrent with secondary T790M mutation in resistant EGFR-mutated adenocarcinomas, J Thorac Oncol source

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    • cites [77] Niederst, 2015, RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer, Nat Commun source

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    Premisecitation

    In unselected NSCLC, combining EGFR TKIs with chemotherapy showed PFS benefit in the EGFR activating mutation subgroup but no clinically relevant OS advantage.

    “EGFR TKIs combined with chemotherapy have been evaluated in unselected NSCLC.In subgroup analysis, PFS benefit has been observed in patients with EGFR activating mutations; however, a clinically relevant OS advantage has not been demonstrated.65”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] OuYang, 2013, Combination of EGFR-TKIs and chemotherapy as first-line therapy for advanced NSCLC: a meta-analysis, PLoS One source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Not all exon 20 insertions or duplications are insensitive to EGFR TKIs; the FQEA insertion at A763_Y764 confers sensitivity to first- and second-generation EGFR TKIs.

    “not all exon 20 insertions or duplications are insensitive to EGFR TKIs, with the FQEA insertion at position A763_Y764 (in the middle of the c-helix) conferring sensitivity to firstand second-generation EGFR TKIs.60,64”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [60] 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

      Not checked in the free run.

    • cites [64] Yasuda, 2013, Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer, Sci Transl Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Other resistance mechanisms include MET amplification (5-30%), HER2 amplification (12%), PIK3CA mutation (5%), and BRAF mutation (1%).

    “Other resistance mechanisms involve bypass pathways such as MET proto-oncogene, receptor tyrosine kinase gene (MET) amplification (5%-30% depending on thresholds), erb-b2 receptor tyrosine kinase 2 (HER2) amplification (12%), phosphatidylinositol-4,5bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation (5%), and B-Raf proto-oncogene, serine/threonine kinase gene (BRAF) mutation (1%)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [14] Sequist, 2011, Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors, Sci Transl Med source

      Not checked in the free run.

    • cites [16] Yu, 2013, Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers, Clin Cancer Res source

      Not checked in the free run.

    • cites [75] Ohashi, 2012, Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1, Proc Natl Acad Sci U S A source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because all classes of alterations are therapeutically relevant in NSCLC, NGS-based assays that can detect rearrangements, copy number changes, and insertions/deletions make a compelling case for NGS-based molecular prescreening.

    “some NGS-based assays offer the possibility of detecting chromosomal rearrangements, copy number variations, and insertions or deletions, thus making a compelling case for NGS-based molecular prescreening because all classes of alterations-point mutations, rearrangements, copy number changes, and insertions or deletions-are therapeutically relevant in the management of NSCLC.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A meta-analysis comparing cfDNA with tissue genotyping found sensitivity 0.62 and specificity 0.96, with higher sensitivity in stage III and IV disease.

    “A meta-analysis reported a sensitivity of 0.62 and a specificity of 0.96 as compared with tissue genotyping as the standard, 52 with higher sensitivity observed in patients with stage III and IV disease.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Qiu, 2015, Circulating tumor DNA is effective for the detection of EGFR mutation in non-small cell lung cancer: a meta-analysis, Cancer Epidemiol Biomarkers Prev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a single-center series of 126 patients, repeat biopsy was feasible in 74.6%, and 20% of successful biopsies had inadequate tissue for mutation analysis.

    “In a single-center series of 126 patients, repeat biopsy was feasible in 74.6% of patients, with 20% of patients with successful biopsies having inadequate tissue for mutational analysis, 51”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Yoon, 2012, Repeat biopsy for mutational analysis of non-small cell lung cancers resistant to previous chemotherapy: adequacy and complications, Radiology source

      Not checked in the free run.

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    Premisecitation

    Combinations with immune checkpoint inhibitors have produced durable responses but have not yet clearly shown better efficacy than TKI alone.

    “Combinations with immune checkpoint inhibitors have shown durable responses, 70 but they have not yet clearly shown better efficacy than TKI alone”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Rizvi, 2014, Safety and response with nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus erlotinib in patients (pts) with epidermal growth factor receptor mutant (EGFR MT) advanced NSCLC, J Clin Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In LUX Lung-7, grade 3 or higher diarrhea (13% vs 1%), rash (9% vs 3%), and fatigue (6% vs 0%) led to more dose reductions with afatinib than gefitinib (42% vs 2%).

    “the increased rates of grade 3 or higher adverse events such as diarrhea (13% versus 1%), rash (9% versus 3%), and fatigue (6% versus 0%) resulted in more dose reductions in the afatinib arm compared with in the gefitinib arm (42% versus 2%).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Park, 2016, Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial, Lancet Oncol source

      Not checked in the free run.

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    Premisecitation

    The T790M mutation has been attributed to steric hindrance from the methionine residue and has also been shown in direct binding assays to increase ATP affinity.

    “Although attributed to steric hindrance imposed by the methionine residue, the T790M mutation has also been shown in direct binding assays to increase adenosine triphosphate affinity.74”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Yun, 2008, The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP, Proc Natl Acad Sci U S A source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In LUX Lung-7, objective response rates were higher with afatinib (70% vs 56%, p=0.0083), including in L858R (66% vs 42%) and exon 19 deletion (73% vs 66%) subgroups.

    “the proportion of patients who achieved an objective tumor response was higher with afatinib (70% versus 56%, p ¼ 0.0083) and this difference was observed in both the L858R mutation (66% versus 42%) and exon 19 deletion (73% versus 66%) subgroups.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Park, 2016, Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial, Lancet Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In that case series, from the time of local therapy, median time to progression was 10 months and median time to new systemic therapy was 22 months.

    “From the time of local therapy, the median time to progression was 10 months and the median time to new systemic therapy was 22 months.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Yu, 2012, Local therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors, J Clin Oncol source

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

    Premisecitation

    Brain metastases will develop in at least 25% to 30% of patients with NSCLC.

    “Brain metastases will develop in at least 25% to 30% of patients with NSCLC.103”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Sorensen, 1988, Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis, J Clin Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the IMPRESS study, adding gefitinib to pemetrexed-cisplatin after progression on a first-line EGFR TKI produced no difference in response rates (32% versus 34%) or median PFS (5.4 months in both groups).

    “No difference in response rates (32% versus 34%) or median PFS (5.4 months in both groups) was demonstrated.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] Soria, 2015, Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial, Lancet Oncol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The role of surgery or locally ablative therapy in oligometastatic or oligoprogressive disease is limited to highly selected cases and depends to some degree on the natural history of disease in each patient.

    “the role for surgery or locally ablative therapy (image-guided or stereotactic radiation) in oligometastatic or oligoprogressive disease is limited to highly selected cases and is to a certain degree dependent on the natural history of disease in each individual patient.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Most data on local therapy for oligometastatic disease come from retrospective case series, with only a few series examining EGFR-mutant patients.

  • May combine two claims.

    Premisecitation

    In a multi-institutional phase II study combining erlotinib with WBRT in 40 patients with NSCLC, the ORR was 86% and median survival was 11.8 months; in patients with a known EGFR mutation, median survival was 19.1 months.

    “The ORR was 86% and the median survival was 11.8 months, but in patients with a known EGFR mutation, it was 19.1 months.115”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [115] Welsh, 2013, Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer, J Clin Oncol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The cfDNA/tumor biopsy findings illustrate the impact of biological heterogeneity and the complementary role of noninvasive genotyping.

    “to some extent illustrating the impact of biological heterogeneity and the complementary role of noninvasive genotyping.101”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [101] Sundaresan, 2016, Detection of T790M, the acquired resistance EGFR mutation, by tumor biopsy versus noninvasive blood-based analyses, Clin Cancer Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    That RTOG trial closed early because of poor accrual and because the three arms were not statistically different.

    “The study closed early on account of poor accrual and because the three arms were not statistically different.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [116] Sperduto, 2013, A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320, Int J Radiat Oncol Biol Phys source

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

    Premisecitation

    The traditionally cited prognosis for brain metastases is a median OS of less than 3 months without treatment and less than 6 months for most patients.

    “The traditionally cited prognosis is grim, with a median OS of less than 3 months without treatment and less than 6 months for most patients.106,107”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [106] Sundstrom, 1998, Prognosis of patients treated for intracranial metastases with whole-brain irradiation, Ann Med source

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    • cites [107] Sperduto, 2008, A validation study of a new prognostic index for patients with brain metastases: the Graded Prognostic Assessment, J Neurosurg

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  • May combine two claims.

    Premisecitation

    EGFR TKIs have independent activity in the CNS, with response rates up to 86% in small series of patients treated exclusively with EGFR TKIs.

    “EGFR TKIs have independent activity in the CNS, with response rates ranging up to 86% in small series of patients treated exclusively with EGFR TKIs 112,113”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [112] Park, 2012, Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation, Lung Cancer source

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    • cites [113] Wu, 2013, Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG-0803), Ann Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the RADIANT trial of stage IB to IIIA resected NSCLC, the subset of patients with EGFR mutations had prolongation of disease-free survival, but it was not statistically significant.

    “In the large prospective RADIANT trial of stage IB to IIIA resected NSCLC, the subset of patients harboring EGFR mutations had a prolongation of disease-free survival, albeit not a statistically significant prolongation.128”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] Kelly, 2015, Adjuvant erlotinib versus placebo in patients with stage IB-IIIA non-small-cell lung cancer (RADIANT): a randomized, double-blind, phase III trial, J Clin Oncol source

      Not checked in the free run.

31 of 31

  • The paper relies on this without support.

    EGFR mutations are among the most frequent actionable alterations in NSCLC.

    “Mutations in the epidermal growth factor receptor gene (EGFR) represent one of the most frequent”

  • The paper relies on this without support.

    Resistance to EGFR TKIs almost invariably occurs.

    “However, resistance to TKIs almost invariably occurs and several molecular mechanisms have been described”

  • The paper relies on this without support.

    Median overall survival after first- or second-generation EGFR TKIs has reached 2 to 3 years.

    “The median overall survival (OS) after firstor secondgeneration EGFR TKIs has reached 2 to 3 years”

  • The paper relies on this without support.

    A sensitivity of 1% to 5% is considered acceptable for EGFR mutation testing.

    “In general, a sensitivity of 1% to 5% is considered acceptable and the procedure should be conducted in a clinically approved diagnostic laboratory.”

  • The paper relies on this without support.

    The Roche cobas 4800 system is the only FDA-approved companion diagnostic for erlotinib.

    “Although the Roche cobas 4800 system (Roche Molecular Systems, Inc.) is the only U.S. Food and Drug Administration (FDA)-approved companion diagnostic for erlotinib”

  • The paper relies on this without support.

    The Roche cobas 4800 assay covers only 28 mutations, which comprise approximately 95% of known EGFR alterations.

    “the Roche cobas 4800 assay covers only the 28 mutations that comprise approximately 95% of known EGFR alterations”

  • The paper relies on this without support.

    Approximately 60% of tested specimens come from the primary lung tumor, and the remainder come from metastatic sites.

    “Approximately 60% of the specimens are from the primary lung tumor, with the remainder from metastatic sites.”

  • The paper relies on this without support.

    There remains a significant chance of false negativity when ascertaining T790M in cfDNA at present.

    “Nevertheless, there remains a significant chance of false negativity in ascertaining T790M in cfDNA at present, underscoring the continued role for traditional tissue-based molecular diagnosis.”

  • The paper relies on this without support.

    Eight randomized phase III trials established the superior efficacy of first- and second-generation EGFR TKIs versus chemotherapy.

    “With eight randomized phase III trials establishing the superior efficacy of firstand second-generation EGFR TKIs versus chemotherapy”

  • The paper relies on this without support.

    The incidence of adverse events such as rash and diarrhea is more pronounced with second-generation EGFR TKIs.

    “Although the incidence of adverse events such as rash and diarrhea is more pronounced with second-generation EGFR TKIs”

  • The paper relies on this without support.

    Most randomized clinical trials do not reveal differences in overall survival when comparing upfront TKI versus chemotherapy.

    “Although most randomized clinical trials do not reveal differences in OS when comparing an upfront TKI versus chemotherapy”

  • The paper relies on this without support.

    In the largest pooled analysis to date, objective responses to afatinib occurred in G719X (77.8%, 14/18), L861Q (56.3%, 9/16), and S768I (100%, 8/8) mutations.

    “According to the largest pooled analysis to date, which pooled data from LUX Lung 2, LUX Lung 3, and LUX Lung 6, objective responses to afatinib were observed in patients with G719X (77.8% [14 of 18]), L861Q (56.3%, [nine of 16]), and S768I (100% [eight of eight]) mutations.”

  • The paper relies on this without support.

    EGFR TKIs generally do not cure patients.

    “As EGFR TKIs generally do not cure patients, a range of combinatorial approaches with other active agents is very appealing.”

  • The paper relies on this without support.

    The T790M mutation in exon 20 of EGFR is the most common mechanism of resistance to first- and second-generation EGFR TKIs.

    “The emergence of the T790M mutation in exon 20 of EGFR is the most common mechanism of resistance to firstand second-generation EGFR TKIs (erlotinib, gefitinb, and afatinib).”

  • The paper relies on this without support.

    Transcriptomic and proteomic perturbations such as AXL overexpression, PTEN loss, IGF1/IGF1R activation, NF-kB activation, and epithelial-to-mesenchymal transition have been implicated in resistance, though they are less frequently reported due to lack of robust assays.

    “Beyond genomic alterations, transcriptomic and proteomic perturbations such as AXL receptor tyrosine kinase overexpression, phosphatase and tension homolog loss, insulin-like growth factor 1/insulin-like growth factor 1 receptor (IGF1/IGF1R) activation, nuclear factor-kappa-B activation, and epithelial to mesenchymal transition have also been implicated, although these are less frequently reported”

  • The paper relies on this without support.

    The FDA granted accelerated approval to osimertinib in November 2015.

    “With further robust data arising from the phase II trial of osimertinib (AURA2), the FDA granted accelerated approval to osimertinib in November 2015.”

  • The paper relies on this without support.

    The FDA's Oncologic Drugs Advisory Committee recommended against accelerated approval of rociletinib, and Clovis Oncology decided to stop further clinical development of rociletinib.

    “Because the FDA's Oncologic Drugs Advisory Committee recommended against accelerated approval of rociletinib, Clovis Oncology decided to stop further clinical development of rociletinib as part of its company strategy.”

  • The paper relies on this without support.

    Tumor heterogeneity can exist between different disease sites and even within the same site, and sampling bias may inadvertently cause a missed T790M mutation.

    “Tumor heterogeneity can exist between different disease sites (e.g., primary lesion versus liver metastasis) and even within the same site, and sampling bias may inadvertently result in a missed T790M mutation.”

  • The paper relies on this without support.

    Systemic chemotherapy tends to be ineffective against brain metastases because of the blood-brain barrier, and palliative radiotherapy is frequently used.

    “Because of the blood-brain barrier, systemic chemotherapy tends to be ineffective against brain metastases and palliative radiotherapy is frequently used.”

  • The paper relies on this without support.

    A complete response to an EGFR TKI is unlikely, but TKIs frequently produce partial responses or stable disease.

    “Although it is unlikely that a complete response will be achieved with a TKI, TKIs frequently produce partial responses or stable disease”

  • The paper relies on this without support.

    The median OS of patients with EGFR-mutant NSCLC remains only approximately 2 to 3 years.

    “the median OS of patients with EGFRmutant NSCLC still remains only approximately 2 to 3 years”

  • The paper relies on this without support.

    Most data on local therapy for oligometastatic disease come from retrospective case series, with only a few series examining EGFR-mutant patients.

    “One major limitation is that most of the data are derived from retrospective case series, with only a few series examining the management of oligometastases in patients with EGFR mutations.”
22 of 22

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?

  • Among patients with EGFR-mutant advanced NSCLC, EGFR TKIs are standard first-line therapy.

    “Among patients with advanced non–small-cell lung cancer with a mutant epidermal growth factor receptor (EGFR), EGFR tyrosine kinase inhibitors (TKIs) are the standard first-line therapy.1–4”

    From Osimertinib or Platinum–Pemetrexed in <i>EGFR</i> T790M–Positive Lung Cancer (2017) · cites this paper as [3]

Self-check

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

  • Plasma T790M percentage does not match the count

    Minor

    Fourteen of 37 patients is 37.8%, not 35%.

    Reported 35 · recomputed 37.837838

1 of 1

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Authors
Tan, D. S. W., Yom, S. S., Tsao, M. S., Pass, H. I., Kelly, K., Peled, N., Yung, R. C., Wistuba, I. I., Yatabe, Y., Unger, M., Mack, P. C., Wynes, M. W., Mitsudomi, T., Weder, W., Yankelevitz, D., Herbst, R. S., Gandara, D. R., Carbone, D. P., Bunn, P. A., Mok, T. S. K., & Hirsch, F. R.
Affiliations
  • National Cancer Centre Singapore (SG)
  • University of California, San Francisco (US)
  • University Health Network (CA)
  • NYU Langone Health (US)
  • UC Davis Comprehensive Cancer Center (US)
  • Tel Aviv University (IL)
  • Greater Baltimore Medical Center (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • Aichi Cancer Center (JP)
  • Thomas Jefferson University (US)
  • International Association for the Study of Lung Cancer (US)
  • Kindai University (JP)
  • University Hospital Zurich (CH)
  • Icahn School of Medicine at Mount Sinai (US)
  • Yale Cancer Center (US)
  • The Ohio State University (US)
  • University of Colorado Cancer Center (US)
  • Chinese University of Hong Kong (HK)
Corresponding author
Mok, Tony S.K.
ORCID
Venue
Journal of Thoracic Oncology
Publisher
Elsevier BV
Published
2016-07
Volume
11
Issue
7
Pages
946-963
ISSN
1556-0864 (ISSN-L)
DOI
10.1016/j.jtho.2016.05.008
OpenAlex
W2403654892
Cited by
201
References
129
Citations by year
2026: 3 · 2025: 3 · 2024: 10 · 2023: 8 · 2022: 14 · 2021: 20 · 2020: 13 · 2019: 27 · 2018: 37 · 2017: 44 · 2016: 21 · 2014: 1
FWCI
38.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Thoracic Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
Funders
  • Bristol-Myers Squibb
  • Eli Lilly and Company
  • Pfizer
  • AstraZeneca
  • GlaxoSmithKline
  • Gilead Sciences
  • International Association for the Study of Lung Cancer
  • Ariad Pharmaceuticals
  • Celgene
  • AstraZeneca Canada
  • National Comprehensive Cancer Network
  • Eisai
  • Genentech
  • EMD Serono
  • Chugai Pharmaceutical
  • Pfizer Canada
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Keywords
EGFR mutation, non-small cell lung cancer, EGFR tyrosine kinase inhibitors, osimertinib, targeted therapy, first-line therapy, brain metastasis management, repeat biopsy, cell-free DNA, molecular profiling, treatment selection algorithm
MeSH terms
Brain Neoplasms, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mutation, Drug Resistance, Neoplasm, Consensus, Protein Kinase Inhibitors, ErbB Receptors

About these checks

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

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

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

Statistics and arithmetic are recomputed, not judged.

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

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