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Cited by 98Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchLung Cancer Diagnosis and Treatment

Examining Treatment Outcomes with Erlotinib in Patients with Advanced Non–Small Cell Lung Cancer Whose Tumors Harbor Uncommon EGFR Mutations

Open access
Klughammer, Barbara, Brugger, Wolfram, Cappuzzo, Federico, Ciuleanu, Tudor, Mok, Tony, Reck, Martin, Tan, Eng Huat, Delmar, Paul +5 more·2016·Journal of Thoracic Oncology
DOI 10.1016/j.jtho.2015.12.107
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Abstract

INTRODUCTION: Exon 19 deletions and the exon 21 L858R mutation of the epidermal growth factor receptor gene (EGFR) predict activity of EGFR tyrosine kinase inhibitors, including erlotinib; however, the ability of less common EGFR mutations to predict efficacy of erlotinib is unclear. METHODS: The efficacy of erlotinib in individual patients with rare EGFR mutations from the MERIT, SATURN, TITAN, TRUST, ATLAS, BeTa, and FASTACT-2 trials was analyzed and compared with data from the literature. RESULTS: In the patients tested for biomarkers, the frequency of rare mutations identified here ranged from 1.7% (eight of 467) in the SATURN study to 7.4% (27 of 364) in ATLAS. Some rare mutations were associated with greater clinical benefit from EGFR tyrosine kinase inhibitor therapy or improved prognosis independent of treatment, whereas others appeared to have a poorer prognosis. In particular, exon 18 G719 mutations, exon 19 K757R and E746G mutations, the exon 20 S768I mutation, and the exon 21 G836S mutation appeared to confer a good outcome with erlotinib treatment, whereas exon 18 S720I showed a particularly poor outcome. Owing to the small number of patients with each mutation, however, it is difficult to confirm whether these rare mutations do indeed confer sensitivity or resistance to erlotinib. CONCLUSIONS: Erlotinib can have different efficacy depending on the specific EGFR mutation. More research is needed to create a central database such as the My Cancer Genome database of rare mutations to definitively confirm whether these mutations are activating, resistant, or neutral.

AI snapshot

Written from the paper’s full text.

TL;DR

In an individual-patient analysis across seven erlotinib trials, efficacy varied by specific uncommon EGFR mutation, with some rare mutations appearing favorable and others poor. Small patient numbers per mutation prevented definitive confirmation of sensitivity or resistance.

Key findings

  • Among biomarker-tested patients, rare EGFR mutation frequency ranged from 1.7% (8/467) in SATURN to 7.4% (27/364) in ATLAS.
  • Exon 18 G719 mutations, exon 19 K757R and E746G, exon 20 S768I, and exon 21 G836S appeared to confer a good outcome with erlotinib; examples include a SATURN G719C patient with partial response, PFS 500 days, and OS 795 days, and a FASTACT-2 S768I patient with OS 1909 days.
  • Exon 18 S720I was stated to show a particularly poor outcome; results tables report S720P patients with OS 285 and 302 days and an S720F patient with OS 89 days.
  • T790M was generally consistent with short PFS, but when combined with exon 18 mutations, two TRUST patients had stable disease and PFS greater than 1 year.

Methods

  • Retrospective, case-report-style analysis of individual patients with rare EGFR mutations from baseline tumor samples in MERIT, SATURN, TITAN, TRUST, ATLAS, BeTa, and FASTACT-2, compared with published literature.
  • Mutation testing differed by study: PCR/Sanger sequencing for MERIT and TRUST; PCR requiring at least 5000 tumor cells and 60% tumor content for SATURN and TITAN; cobas 4800 for FASTACT-2; Surveyor/WAVE for ATLAS; and denaturing HPLC for BeTa. Tumor sampling was mandatory for MERIT, SATURN, and TITAN and optional for TRUST, ATLAS, BeTa, and FASTACT-2.
  • Outcomes reported by exon included best response, PFS, and OS for individual patients.

Limitations

  • Stated: the small number of patients with each mutation makes it difficult to confirm whether rare mutations confer sensitivity or resistance to erlotinib, and such analyses are unlikely to reach statistical significance.
  • Stated: differences in study design, endpoints, and agents investigated make it hard to pool data reliably; testing only common exon 19 and 21 mutations may miss patients who could benefit, and tumor mutation profiles may change over the disease course.
  • Evident from the text: no formal statistical comparison or power calculation is presented, and the analysis combines heterogeneous assays, treatment lines, and regimens with literature comparisons rather than a systematic pooled analysis.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.jtho.2015.12.107

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 12 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Exon 18 G719 mutations appeared to confer a good outcome with erlotinib treatment.

    “In particular, exon 18 G719 mutations, exon 19 K757R and E746G mutations, the exon 20 S768I mutation, and the exon 21 G836S mutation appeared to confer a good outcome with erlotinib treatment, whereas exon 18 S720I showed a particularly poor outcome.”
    Quote in the paperSubstantial claim
  • Findingown data

    An unknown G719 mutation in FASTACT-2 gave an OS of 1008 days.

    “A patient in FASTACT-2 with an unknown G719 mutation achieved an OS of 1008 days (>2.5 years).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Exon 18 S720I mutation showed a particularly poor outcome with erlotinib treatment.

    “In particular, exon 18 G719 mutations, exon 19 K757R and E746G mutations, the exon 20 S768I mutation, and the exon 21 G836S mutation appeared to confer a good outcome with erlotinib treatment, whereas exon 18 S720I showed a particularly poor outcome.”
    Quote in the paperSubstantial claim
  • Findingnone given

    P.A767_S768INSSVSS and P.M766_A767INSASV from TITAN were associated with short PFS and OS.

    “P.A767_S768INSSVSS and P.M766_A767INSASV from the TITAN study were associated with short PFS and OS.”
    Quote in the paperSubstantial claim
  • Findingown data

    In patients tested for biomarkers, the frequency of rare EGFR mutations identified in this analysis ranged from 1.7% (8/467) in SATURN to 7.4% (27/364) in ATLAS.

    “In the samples tested for biomarkers, the frequency of rare mutations identified in this analysis ranged from 1.7% (eight of 467) in the SATURN study to 7.4% (27 of 364) in ATLAS.”
    • Also stated in: § Abstract · plain
      “In the patients tested for biomarkers, the frequency of rare mutations identified here ranged from 1.7% (eight of 467) in the SATURN study to 7.4% (27 of 364) in ATLAS.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The mutation testing methods used across the different clinical studies are sufficiently accurate and comparable to identify rare EGFR mutations.
  • May combine two claims. 21
  • Classified as probably not a substantial claim. 12

  • May combine two claims.

    Findingown data

    Some rare EGFR mutations were associated with greater clinical benefit from EGFR TKI therapy or improved prognosis independent of treatment, whereas others appeared to have a poorer prognosis.

    “Some mutations were associated with greater clinical benefit from EGFR TKI therapy or with improved prognosis regardless of treatment, showing both predictive and prognostic effects of certain rare mutations, whereas others appeared to have a detrimental effect on survival.”
    • Also stated in: § Abstract · hedged
      “Some rare mutations were associated with greater clinical benefit from EGFR tyrosine kinase inhibitor therapy or improved prognosis independent of treatment, whereas others appeared to have a poorer prognosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    G719A plus T725M in SATURN gave a PFS of 169 days and OS of 343 days.

    “In SATURN, a G719A mutation plus T725M resulted in a PFS of 169 days and OS of 343 days”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    P848L, H870Y, G836S, and L858R+T790M all resulted in OS of longer than 1.5 years, with G836S also providing PFS of longer than 1 year and partial response.

    “However, P848L, H870Y, G836S, and L858R þ T790M mutations all resulted in an OS of longer than 1.5 years (547 days), with the G836S mutation also providing a PFS of longer than 1 year (>365 days) and partial response observed as the best overall response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Other exon 19 mutations generally had shorter PFS and OS than K757R and E746G, with best response of progression or stable disease.

    “Other exon 19 mutations generally had shorter PFS and OS than the previously mentioned mutations, with a best response of progression or stable disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    S768I appeared to confer sensitivity to erlotinib, with OS of 1909 days in FASTACT-2 and 1106 days in TRUST with an additional V774M mutation.

    “S768I appeared to confer sensitivity to erlotinib, with a patient from FASTACT-2 reaching an OS of 1909 days (>5 years) and a female Asian patient from the TRUST study with an additional V774M mutation having an OS of 1106 days (>3 years).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    G719A in TRUST gave a PFS of 463 days and OS of 488 days.

    “whereas in TRUST, a patient with G719A had a PFS of 463 days and OS of 488 days.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    K757R and E746G appeared sensitizing, with PFS of 250 and 415 days in MERIT and BeTa, respectively, and OS of more than 1 year (435 and 462 days).

    “Mutations that appeared sensitizing to EGFR TKIs were K757R (n ¼ 1) and E746G (n ¼ 1), which resulted in a PFS of 250 and 415 days in MERIT and BeTa, respectively, and an OS of more than 1 year (435 days in MERIT and 462 days in BeTa).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    G719C appears to confer a PFS and OS benefit, with one SATURN patient having a partial response, PFS of 500 days, and OS of 795 days.

    “The mutation to cysteine (G719C) appears to confer a PFS and OS benefit, with one patient from the SATURN study reporting a partial response, PFS of 500 days, and OS of 795 days (>2 years).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Generally rare exon 21 mutations resulted in PFS of less than 6 months and OS of less than 1 year, with best response of progression or stable disease.

    “Generally rare mutations in exon 21 resulted in a PFS of less than 6 months (182 days) and an OS of less than 1 year, with disease progression or stable disease reported as the best response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    T790M combined with exon 18 mutations gave stable disease and PFS of more than 1 year in two TRUST patients.

    “When combined with exon 18 mutations, however, a response of stable disease and a PFS of more than 1 year was seen in two patients from the TRUST study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    S720P had poor response and short OS, with OS less than 1 year in two ATLAS patients (285 and 302 days).

    “Poor response and short OS were observed with the S720P mutation, with an OS less than 1 year seen in two patients from the ATLAS study (285 and 302 days).”
    Quote in the paperSubstantial claim

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

    Findingnone given

    Eight exon 20 mutations appeared to be insertions.

    “Across the exon 20 mutations reported, eight appeared to be insertions.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Erlotinib is approved for first-line treatment of patients whose tumors harbor activating mutations of EGFR.

    “erlotinib was also approved for the first-line treatment of patients whose tumors harbor activating mutations of the epidermal growth factor receptor gene (EGFR).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3][4][5]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 639 patients, response rate was lower for rare versus common mutations (41.6% vs 66.5%, p=0.001) and median PFS was lower (7.7 vs 11.4 months, p=0.001).

    “When patients were treated with EFGR TKIs, the response rate was significantly lower for those with rare mutations than for those with common mutations (41.6% versus 66.5%, p ¼ 0.001) and the median progression-free survival (PFS) was also lower (7.7 versus 11.4 months, p ¼ 0.001).8”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Chiu, 2015, Epidermal growth factor receptor tyrosine kinase inhibitor treatment response in advanced lung adenocarcinomas with G719X/L861Q/S768I mutations, J Thorac Oncol source

      Not checked in the free run.

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

    Study design and conductnone given

    In SATURN and TITAN, samples had to have at least 5000 tumor cells and a minimum 60% tumor cell content.

    “these samples had to have at least 5000 tumor cells and a minimum 60% tumor cell content.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    For other exon 19 mutations, results were comparable to the overall study population, so EGFR TKI treatment is unlikely to be of reduced benefit in these patients.

    “However, these results were comparable with the results for the overall study population, so EGFR TKI treatment is unlikely to be of reduced benefit in these patients.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The overall study population outcomes provide a valid reference for assessing whether a rare mutation confers clinical benefit.

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

    Premisecitation

    In an afatinib post hoc analysis, 75 of 600 patients (12%) had rare EGFR mutations, and median PFS varied by mutation type.

    “In a post hoc analysis from three clinical studies of afatinib (LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6), 75 of 600 patients (12%) had rare EGFR mutations, and after afatinib treatment, the median PFS varied depending on the type of mutation.10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] 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.

  • May combine two claims.

    Interpretationown data

    H870Y and G836S patients continued erlotinib after progression, which could be linked to their longer OS.

    “The patient with the H870Y mutation (OS 691 days) and another patient with a G836S mutation (OS 763 days) both continued to receive erlotinib treatment after progression, which could be linked to their longer OS.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Some patients with rare mutations had a particularly positive outcome with erlotinib treatment, which may help identify uncommon mutations potentially predictive of efficacy benefit.

    “Also, some patients with rare mutations had a particularly positive outcome with erlotinib treatment, which may help to identify those uncommon mutations that are potentially predictive of an efficacy benefit with this therapy.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The overall study population outcomes provide a valid reference for assessing whether a rare mutation confers clinical benefit.

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

    Study design and conductnone given

    Exons 18 through 21 were amplified by PCR, with multiple independent products sequenced.

    “Exons 18 through 21 were amplified by PCR, with multiple independent products sequenced.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Mutations other than the most commonly known resistance and activating mutations had to be identified in at least two PCR products to be confirmed.

    “Mutations other than the most commonly known resistance and activating mutations had to be identified in at least two PCR products to be confirmed.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    The ability of less common EGFR mutations to predict efficacy of erlotinib is unclear.

    “the ability of less common EGFR mutations to predict efficacy of erlotinib is unclear.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Online registries of oncogenic mutations, such as MyCancerGenome, contain incomplete information about observed outcomes with different treatments in different tumors.

    “Online registries of oncogenic mutations, such as MyCancerGenome, 37 may act as a central repository of observed outcomes with different treatments in different tumors, but this information is still incomplete and will require further research and knowledge sharing by all cancer researchers and clinicians to become a feasible clinical resource.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] My Cancer Genome. DNA-Mutation Inventory to Refine and Enhance Cancer Treatment (DIRECT). http://www.mycancergenome.org/about/direct. Accessed March 13, 2015.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Large-scale investigation in clinical trials is unlikely to be an option in evaluating treatments in very small patient subgroups.

    “Large-scale investigation in clinical trials is unlikely to be an option in evaluating treatments in these very small patient subgroups, so clinicians will need to be proactive in finding other methods to determine optimal therapy choice.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Targeted mutations occur at extremely rare frequencies.

  • May combine two claims.

    Premisecitation

    In Yang et al., G719 point mutations (n=18) treated with afatinib achieved ORR 77.8%, PFS 13.8 months, and OS 26.9 months.

    “When patients with point mutations at G719 (n ¼ 18) were treated with afatinib, they achieved an objective response rate (ORR) of 77.8%, PFS of 13.8 months, and OS of 26.9 months in a study by Yang et al. 10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] 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.

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

    Interpretationreasoning

    The reverse approach of identifying exceptional responders then doing full gene analysis can be time-consuming and relies on patients being given off-label experimental treatments to assess response, which is not an option for many clinicians owing to strict formularies and reimbursement issues.

    “The limitation of this approach is that it can be a time-consuming process and would rely on patients being given off-label experimental treatments to assess whether their tumors respond, which is not an option for many clinicians owing to strict formularies and reimbursement issues.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    In NEJ002, OS was lower for rare mutations (G719X or L861Q) than common (p=0.002); gefitinib-treated rare had shorter OS (11.9 vs 29.3 months, p<0.001); carboplatin-paclitaxel had similar OS (p=0.358).

    “In the NEJ002 study, OS was significantly lower for patients with rare mutations (G719X or L861Q) than for those with common EGFR mutations (p ¼ 0.002).Patients with rare EGFR mutations (G719X or L861Q) treated with gefitinib had a significantly shorter OS (11.9 versus 29.3 months; p < 0.001).Interestingly, OS was similar between patients with uncommon and common mutations when treated with carbop”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Wantanbe, 2014, Effectiveness of gefitinib against non–small-cell lung cancer with the uncommon EGFR mutations G719X and L861Q, J Thorac Oncol source

      Not checked in the free run.

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

    Premisecitation

    Some researchers have identified patients with exceptional responses to specific therapies and then carried out full gene analysis on tumor tissue to identify which mutation may be driving that response.

    “Some researchers have taken the reverse approach to that taken in this analysis and have identified patients with exceptional responses to specific therapies, and then carried out full gene analysis on patients' tumor tissue to identify which mutation may be driving that response.36”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Imielinski, 2014, Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma, J Clin Invest source

      Not checked in the free run.

28 of 28

  • The paper relies on this without support.

    Exon 19 deletions and the exon 21 L858R mutation are the most common activating EGFR mutations used to guide treatment decisions in NSCLC.

    “The most common activating mutations used to guide treatment decisions in NSCLC are deletions in exon 19 of EGFR and the specific point mutation L858R in exon 21”

  • The paper relies on this without support.

    The overall study population outcomes provide a valid reference for assessing whether a rare mutation confers clinical benefit.

    “When compared with the PFS and OS results from the overall populations of each study, the G719A mutation appeared to be sensitizing, but to a lesser extent than the G719C mutation.”

  • The paper relies on this without support.

    The mutation testing methods used across the different clinical studies are sufficiently accurate and comparable to identify rare EGFR mutations.

    “EGFR mutation testing was carried out using different methods across the different clinical studies.”

  • The paper relies on this without support.

    The literature data on rare EGFR mutations are comparable to the data from this analysis.

    “evaluating the results from this analysis in comparison with data from the literature.”

  • The paper relies on this without support.

    The mutation profile of a patient's tumor may change throughout the course of disease.

    “Another consideration limiting the current approach is that the mutation profile of a patient's tumor may change throughout the course of disease.”

  • The paper relies on this without support.

    The difference between activating, neutral, and resistance mutations can make a sizable difference in how a patient's disease responds to EGFR TKI therapy.

    “As the difference between activating, neutral, and resistance mutations can make a sizable difference in how a patient's disease responds to EGFR TKI therapy, it is important to identify as many of these mutations as possible to guide treatment, however infrequent particular mutations are.”

  • The paper relies on this without support.

    These mutations are increasingly being detected by standard testing methods.

    “As these mutations are increasingly being detected by standard testing methods, it is important to have a central repository of information about the implications of specific mutations for patient prognosis and treatment choice.”

  • The paper relies on this without support.

    Targeted mutations occur at extremely rare frequencies.

    “The difficulty in testing the efficacy of targeted agents against specific mutations is that because they occur at extremely rare frequencies, it is practically impossible to enroll enough patients to power a clinical trial except by using large-scale screening and complicated treatment allocation algorithms.”

  • The paper relies on this without support.

    The U.S. labels for first-line erlotinib and afatinib specify indications as exon 19 deletions and exon 21 L858R, whereas the EU labels mention only EGFR activating mutations, so rare mutations could be included.

    “This can be seen by comparing the U.S. labels for first-line erlotinib and afatinib, on which the indications are specified as exon 19 deletions and exon 21 L858R, with the EU labels, which mention only EGFR activating mutations (therefore, rare mutations could be included).”
9 of 9

Claims other papers make about this one

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

Self-check

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

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

  • Poor-outcome conclusion names S720I, but the reported cases are S720P and S720F

    Minor

    The paper concludes that S720I showed a particularly poor outcome, but its exon 18 results describe poor outcomes for S720P and S720F. Table 1 likewise lists S720P and S720F cases, with no S720I case.

  • Codon 860 is assigned to two different exons

    Minor

    Table 3 places K860E among exon 20 mutations, whereas Table 4 places a mutation at the same codon, K860N, among exon 21 mutations.

  • Codon 746 is assigned to two different exons

    Minor

    Table 3 lists D746A as an exon 20 mutation, while Table 2 lists E746G at codon 746 as an exon 19 mutation. The two entries also disagree on the original amino acid at that codon.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 31

  1. Shepherd, 2005, Erlotinib in previously treated non-small-cell lung cancer, N Engl J Med, 353, 123, 10.1056/NEJMoa050753 · DOI · Paper page
  2. Cappuzzo, 2010, Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study, Lancet Oncol, 11, 521, 10.1016/S1470-2045(10)70112-1 · DOI · Paper page
  3. Rosell, 2009, Screening for epidermal growth factor mutations in lung cancer, N Engl J Med, 361, 958, 10.1056/NEJMoa0904554 · DOI · Paper page
  4. Zhou, 2011, Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study, Lancet Oncol, 12, 735, 10.1016/S1470-2045(11)70184-X · DOI · Paper page
  5. 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, 13, 239, 10.1016/S1470-2045(11)70393-X · DOI · Paper page
  6. Arrieta, 2015, The impact of common and rare EGFR mutations in response to EGFR tyrosine kinase inhibitors and platinum-based chemotherapy in patients with non-small-cell lung cancer, Lung Cancer, 87, 169, 10.1016/j.lungcan.2014.12.009 · DOI
  7. Chiu, 2015, Epidermal growth factor receptor tyrosine kinase inhibitor treatment response in advanced lung adenocarcinomas with G719X/L861Q/S768I mutations, J Thorac Oncol, 10, 793, 10.1097/JTO.0000000000000504 · DOI · Paper page
  8. Baek, 2015, Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small-cell lung cancer except both exon 19 deletion and exon 21 L858R: a retrospective analysis in Korea, Lung Cancer, 87, 148, 10.1016/j.lungcan.2014.11.013 · DOI
  9. Tan, 2010, A multicentre phase II gene expression profiling study of putative relationships between tumor biomarkers and clinical response with erlotinib in non-small-cell lung cancer, Ann Oncol, 21, 217, 10.1093/annonc/mdp520 · DOI
  10. Reck, 2010, Erlotinib in advanced non-small-cell lung cancer: efficacy and safety findings of the global phase IV Tarceva Lung Cancer Survival Treatment study, J Thorac Oncol, 5, 1616, 10.1097/JTO.0b013e3181f1c7b0 · DOI
  11. Schneider, 2008, Epidermal growth factor receptor-related tumor markers and clinical outcomes with erlotinib in non-small cell lung cancer: an analysis of patients from German centers in the TRUST study, J Thorac Oncol, 3, 1446, 10.1097/JTO.0b013e31818ddcaa · DOI
  12. Pirker, 2008, Clinical outcomes with erlotinib in relation to biomarker status: analyses from the open-label TRUST study in advanced non-small-cell lung cancer (NSCLC), Ann Oncol, 19, viii100
  13. Ciuleanu, 2012, Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study, Lancet Oncol, 13, 300, 10.1016/S1470-2045(11)70385-0 · DOI · Paper page
  14. Brugger, 2011, Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non–small-cell lung cancer, J Clin Oncol, 29, 4113, 10.1200/JCO.2010.31.8162 · DOI
  15. Wu, 2013, Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial, Lancet Oncol, 14, 777, 10.1016/S1470-2045(13)70254-7 · DOI
  16. Herbst, 2011, Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial, Lancet, 377, 1846, 10.1016/S0140-6736(11)60545-X · DOI
  17. Johnson, 2013, ATLAS: randomized, double-blind, placebo-controlled, phase IIIB trial comparing bevacizumab therapy with or without erlotinib, after completion of chemotherapy, with bevacizumab for first-line treatment of advanced non–small-cell lung cancer, J Clin Oncol, 31, 3926, 10.1200/JCO.2012.47.3983 · DOI
  18. Han, 2005, Predictive and prognostic impact of epidermal growth factor receptor mutation in non–small-cell lung cancer patients treated with gefitinib, J Clin Oncol, 23, 2493, 10.1200/JCO.2005.01.388 · DOI
  19. 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, 17, 3812, 10.1158/1078-0432.CCR-10-3408 · DOI · Paper page
  20. Chou, 2005, Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer, Clin Cancer Res, 11, 3750, 10.1158/1078-0432.CCR-04-1981 · DOI
  21. Peng, 2015, Comparison of uncommon EGFR exon 21 L858R compound mutations with single mutation, Onco Targets Ther, 8, 905
  22. Ning, 2015, Mapping inhibitor response to the in-frame deletions, insertions and duplications of epidermal growth factor receptor (EGFR) in non-small cell lung cancer, J Recept Signal Transduct Res, 22, 1
  23. Agbarya, 2014, Getting out of a wheelchair: an uncommon insertion mutation in exon 19 of EGFR responsive to erlotinib, SpringerPlus, 3, 507, 10.1186/2193-1801-3-507 · DOI
  24. Chan, 2013, An uncommon insertion mutation in exon 19 of EGFR showed stable disease after TKI treatment, J Thorac Oncol, 8, e107, 10.1097/JTO.0b013e3182a471e0 · DOI · Paper page
  25. Gazdar, 2009, Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors, Oncogene, 28, 24, 10.1038/onc.2009.198 · DOI · Paper page
  26. Masago, 2010, Good clinical response to gefitinib in a non-small-cell lung cancer patient harboring a rare somatic epidermal growth factor gene point mutation; codon 768 AGC > ATC in exon 20 (S768I), Jpn J Clin Oncol, 40, 1105, 10.1093/jjco/hyq087 · DOI · Paper page
  27. Pallan, 2014, Rare EGFR exon 20 S768I mutation predicts resistance to targeted therapy: a report of two cases, J Thorac Oncol, 9, 75, 10.1097/JTO.0000000000000308 · DOI
  28. Kancha, 2009, Functional analysis of epidermal growth factor receptor (EGFR) mutations and potential implications for EGFR targeted therapy, Clin Cancer Res, 15, 460, 10.1158/1078-0432.CCR-08-1757 · DOI · Paper page
  29. Lund-Iversen, 2012, Clinicopathological characteristics of 11 NSCLC patients with EGFR-exon 20 mutations, J Thorac Oncol, 7, 1471, 10.1097/JTO.0b013e3182614a9d · DOI
  30. Wantanbe, 2014, Effectiveness of gefitinib against non–small-cell lung cancer with the uncommon EGFR mutations G719X and L861Q, J Thorac Oncol, 9, 189, 10.1097/JTO.0000000000000048 · DOI · Paper page
  31. Imielinski, 2014, Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma, J Clin Invest, 124, 1582, 10.1172/JCI72763 · DOI

Cited by

Sorted by citations

Authors
Klughammer, B., Brugger, W., Cappuzzo, F., Ciuleanu, T., Mok, T., Reck, M., Tan, E. H., Delmar, P., Klingelschmitt, G., Yin, A.-Y., Spleiss, O., Wu, L., & Shames, D. S.
Affiliations
  • F. Hoffmann-La Roche AG (CH)
  • University of Freiburg (DE)
  • Ospedale di Livorno (IT)
  • Iuliu Hațieganu University of Medicine and Pharmacy (RO)
  • Prince of Wales Hospital (CN)
  • German Center for Lung Research (DE)
  • National Cancer Centre Singapore (SG)
  • Genentech (US)
Corresponding author
Klughammer, Barbara
ORCID
Venue
Journal of Thoracic Oncology
Publisher
Elsevier BV
Published
2016-04
Volume
11
Issue
4
Pages
545-555
ISSN
1556-0864 (ISSN-L)
DOI
10.1016/j.jtho.2015.12.107
OpenAlex
W2283037401
Cited by
98
References
5
Citations by year
2026: 2 · 2025: 3 · 2024: 7 · 2023: 8 · 2022: 9 · 2021: 8 · 2020: 13 · 2019: 15 · 2018: 8 · 2017: 18 · 2016: 7
FWCI
14.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Thoracic Oncology (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
F. Hoffmann-La Roche
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
Keywords
erlotinib, EGFR mutation, uncommon EGFR mutations, advanced non-small cell lung cancer, EGFR tyrosine kinase inhibitors, exon 18 mutations, exon 20 mutations, exon 21 mutation, treatment response, prognostic factors, drug resistance
MeSH terms
Erlotinib Hydrochloride, Adult, Aged, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Clinical Trials as Topic, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Treatment Outcome, Protein Kinase Inhibitors, ErbB Receptors

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