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Cited by 3,379Lung Cancer Treatments and MutationsLung Cancer Diagnosis and TreatmentLung Cancer Research Studies

Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer

Open access
Mok, Tony S., Wu, Yi-Long, Ahn, Myung-Ju, Garassino, Marina C., Kim, Hye R., Ramalingam, Suresh S., Shepherd, Frances A., He, Yong +9 more·2017·New England Journal of Medicine
DOI 10.1056/nejmoa1612674PMC PMC6762027
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Abstract

BACKGROUND: Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed in such patients is unknown. METHODS: In this randomized, international, open-label, phase 3 trial, we assigned 419 patients with T790M-positive advanced non-small-cell lung cancer, who had disease progression after first-line EGFR-TKI therapy, in a 2:1 ratio to receive either oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles; maintenance pemetrexed was allowed. In all the patients, disease had progressed during receipt of first-line EGFR-TKI therapy. The primary end point was investigator-assessed progression-free survival. RESULTS: The median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; hazard ratio; 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001). The objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). Among 144 patients with metastases to the central nervous system (CNS), the median duration of progression-free survival was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; hazard ratio, 0.32; 95% CI, 0.21 to 0.49). The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib (23%) than with platinum therapy plus pemetrexed (47%). CONCLUSIONS: Osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced non-small-cell lung cancer (including those with CNS metastases) in whom disease had progressed during first-line EGFR-TKI therapy. (Funded by AstraZeneca; AURA3 ClinicalTrials.gov number, NCT02151981 .).

Integrity signals

Registry

Crossref · 10.1056/nejmoa1612674

Cites

25 of 25 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 34 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Median response duration was 9.7 months with osimertinib vs 4.1 months with platinum-pemetrexed.

    “On the basis of investigator assessment, the median response duration was 9.7 months (95% CI, 8.3 to 11.6) in the osimertinib group and 4.1 months (95% CI, 3.0 to 5.6) in the platinum–pemetrexed group.”
    Quote in the paperSubstantial claim
  • Findingown data

    Osimertinib yielded a significantly higher objective response rate than platinum-pemetrexed (71% vs 31%; OR 5.39; 95% CI 3.47-8.48; P<0.001).

    “The objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001).”
    • Also stated in: § EFFICACY · plain
      “The response rate was significantly better in the osimertinib group (71%; 95% CI, 65 to 76) than in the platinum–pemetrexed group (31%; 95% CI, 24 to 40) (odds ratio, 5.39; 95% CI, 3.47 to 8.48; P<0.001) (Table 2).”
    Quote in the paperSubstantial claim
  • Findingown data

    Improvement in outcomes with osimertinib over platinum-pemetrexed in tumor and plasma ctDNA T790M-positive subgroup was similar to that in the intention-to-treat population.

    “Improvement in outcomes with osimertinib over platinum–pemetrexed in the tumor and plasma ctDNA T790M-positive subgroup was similar to that in the intention-to-treat population.”
    Quote in the paperSubstantial claim
  • Findingown data

    The most common adverse events in the platinum-pemetrexed group were nausea (49%), decreased appetite (36%), constipation (35%), and anemia (30%).

    “The most commonly reported adverse events in the platinum–pemetrexed group were nausea (in 67 patients [49%]), decreased appetite (in 49 [36%]), constipation (in 47 [35%]), and anemia (in 41 [30%]).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Grade 3 or higher adverse events occurred in a lower proportion of osimertinib patients than platinum-pemetrexed patients (23% vs 47%).

    “The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib (23%) than with platinum therapy plus pemetrexed (47%).”
    • Also stated in: § SAFETY AND ADVERSE EVENTS · plain
      “Fewer patients reported adverse events of grade 3 or more in the osimertinib group than in the platinum–pemetrexed group (63 [23%] vs. 64 [47%]).”
    Quote in the paperSubstantial claim
  • May combine two claims. 12
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Findingown data

    QT interval prolongation occurred in 4% of osimertinib patients and 1% of platinum-pemetrexed patients.

    “A prolongation in the QT interval was recorded in 10 patients (4%) in the osimertinib group and 1 patient (1%) in the platinum–pemetrexed group, with all events of grade 1 or 2 in severity except for one grade 3 event in the osimertinib group.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The PFS hazard ratio favored osimertinib in all predefined subgroups analyzed, with HR <0.50 for each.

    “The hazard ratio for progression-free survival favored osimertinib across all predefined subgroups that were analyzed (hazard ratio, <0.50 for each subgroup) (Fig. 2), including patients with CNS metastases (median duration of progression-free survival, 8.5 months vs. 4.2 months; hazard ratio, 0.32; 95% CI, 0.21 to 0.49) (Fig. 1B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PFS by blinded independent central review was consistent with investigator-assessed PFS, with median 11.0 vs 4.2 months (adjusted HR 0.28; 95% CI 0.20-0.38; P<0.001).

    “The duration of progression-free survival according to blinded independent central review was consistent with the investigator-assessed durations, with a median of 11.0 months versus 4.2 months (adjusted hazard ratio, 0.28; 95% CI, 0.20 to 0.38; P<0.001).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Interstitial lung disease-like adverse events occurred in 4% of osimertinib patients and 1% of platinum-pemetrexed patients.

    “Interstitial lung disease–like adverse events were reported in 10 patients (4%) in the osimertinib group (nine events of grade 1 or 2 in severity and one death) and in 1 patient (1%) in the platinum–pemetrexed group (one grade 3 event).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All randomized patients were included in the intention-to-treat population used for all efficacy analyses.

    “All the patients who underwent randomization were included in the intention-to-treat population, which was used for all efficacy analyses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Overall, adverse events tended to be more severe in the platinum-pemetrexed group despite longer treatment duration with osimertinib.

    “Overall, adverse events tended to be more severe in the platinum–pemetrexed group, despite the longer treatment duration with osimertinib.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The safety analysis included all ITT patients who received at least one dose and had post-dose data.

    “The safety analysis included all the patients in the intention-to-treat population who had received at least one dose of a trial drug and for whom data were available after the administration of the drug.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The T790M variant lowers binding of first- or second-generation EGFR-TKIs to the ATP-binding pocket, which reduces downstream signaling inhibition and may contribute to progression.

    “The presence of the T790M variant reduces binding of first-generation or second-generation EGFR-TKIs to the ATP-binding pocket of EGFR, thereby reducing EGFR-TKI–mediated inhibition of downstream signaling and potentially leading to disease progression.17–19”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [17] Yun CH, Mengwasser KE, Toms AV, The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A 2008; 105: 2070– 5. 18227510 PMC2538882 source

      Not checked in the free run.

    • cites [18] Sos ML, Rode HB, Heynck S, Chemogenomic profiling provides insights into the limited activity of irreversible EGFR inhibitors in tumor cells expressing the T790M EGFR resistance mutation. Cancer Res 2010; 70: 868– 74. 20103621 source

      Not checked in the free run.

    • cites [19] Cross DA, Ashton SE, Ghiorghiu S, AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014; 4: 1046– 61. 24893891 PMC4315625 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a pooled analysis of two phase 2 studies of osimertinib 80 mg daily in 411 T790M-positive NSCLC patients, response rate was 66% by blinded independent central review and median PFS was 11.0 months.

    “These findings were confirmed in a pooled analysis of two subsequent phase 2 studies of osimertinib (at a dose of 80 mg once daily) in 411 patients with T790M-positive non–small-cell lung cancer, in which the response rate was 66% on blinded independent central review and the median duration of progression-free survival was 11.0 months.23”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Yang J, Ramalingam SS, Jänne PA, Cantarini M, Mitsudomi T. LBA2_PR: Osimertinib (AZD9291) in pre-treated pts with T790M-positive advanced NSCLC: updated Phase 1 (P1) and pooled Phase 2 (P2) results. J Thorac Oncol 2016; 11: Suppl: S152– S153. source

      Not checked in the free run.

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

    Study design and conductnone given

    The trial was conducted in accordance with Declaration of Helsinki, Good Clinical Practice, regulatory requirements, and sponsor bioethics policy.

    “The trial was conducted in accordance with the provisions of the Declaration of Helsinki, Good Clinical Practice guidelines (as defined by the International Conference on Harmonisation), applicable regulatory requirements, and the policy on bioethics and human biologic samples of the trial sponsor, AstraZeneca.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The trial was powered to detect a hazard ratio of 0.67 with 221 events, 80% power, and two-sided alpha 0.05.

    “We determined that 221 events of progression or death would provide a power of 80% to reject the null hypothesis of no significant difference in the duration of progression-free survival between the two treatment groups, assuming a treatment effect hazard ratio of 0.67 with a P value of 0.05 indicating two-sided statistical significance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Osimertinib is an oral irreversible EGFR-TKI selective for EGFR and T790M resistance mutations with CNS activity.

    “Osimertinib is an oral, irreversible EGFR-TKI that is selective for both EGFR and T790M resistance mutations with activity in the central nervous system (CNS).19–21”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [19] Cross DA, Ashton SE, Ghiorghiu S, AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014; 4: 1046– 61. 24893891 PMC4315625 source

      Not checked in the free run.

    • cites [20] Ballard P, Yates JW, Yang Z, Pre-clinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res 2016; 22: 5130– 40. 27435396 source

      Not checked in the free run.

    • cites [21] Yang JC-H, Kim D-W, Kim S-W, Osimertinib activity in patients (pts) with leptomeningeal (LM) disease from non-small cell lung cancer (NSCLC): updated results from BLOOM, a phase I study. J Clin Oncol 2016; 34: Suppl: 9002 abstract. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    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”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [1] Masters GA, Temin S, Azzoli CG, Systemic therapy for Stage IV non-small-cell lung cancer: American Society of Clinical Oncology Clinical Practice Guideline update. J Clin Oncol 2015; 33: 3488– 515. 26324367 PMC5019421 source

      Not checked in the free run.

    • cites [2] Novello S, Barlesi F, Califano R, Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016; 27: Suppl 5: v1– v27. 27664245 source

      Not checked in the free run.

    • cites [3] Tan DS, Yom SS, Tsao MS, 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. J Thorac Oncol 2016; 11: 946– 63. 27229180 source

      Not checked in the free run.

    • cites [4] National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: NSCLC (version 3.2017). 2016 (http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf). 28188192 source

      Not checked in the free run.

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

    Study design and conductnone given

    A sensitivity analysis of PFS by blinded independent central review was conducted.

    “A sensitivity analysis of progression-free survival by blinded independent central review was conducted.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Randomization was stratified according to Asian or non-Asian race.

    “Patients were stratified according to Asian or non-Asian race and were randomly assigned in a 2:1 ratio to receive oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The safety profile for osimertinib was consistent with that reported previously and differed from that in the platinum-pemetrexed group.

    “In AURA3, the safety profile for osimertinib was consistent with that reported previously and differed from that in the platinum–pemetrexed group.23”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Yang J, Ramalingam SS, Jänne PA, Cantarini M, Mitsudomi T. LBA2_PR: Osimertinib (AZD9291) in pre-treated pts with T790M-positive advanced NSCLC: updated Phase 1 (P1) and pooled Phase 2 (P2) results. J Thorac Oncol 2016; 11: Suppl: S152– S153. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In phase 1 AURA, osimertinib produced an objective response rate of 61% and median PFS of 9.6 months in T790M-positive NSCLC.

    “In the phase 1 component of AURA, a phase 1/2 trial (ClinicalTrials.gov number, ), the objective response rate for osimertinib in patients with T790M-positive non–small-cell lung cancer was 61%; the median duration of progression-free survival was 9.6 months.22”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Jänne PA, Yang JC-H, Kim D-W, AZD9291 in EGFR inhibitor–resistant non–small-cell lung cancer. N Engl J Med 2015; 372: 1689– 99. 25923549

      Not checked in the free run.

17 of 17

  • The paper relies on this without support.

    Platinum-pemetrexed was the standard of care for patients with T790M-positive advanced NSCLC after first-line EGFR-TKI at the time of trial initiation.

    “Chemotherapy was the standard control at the time of trial initiation.”
1 of 1

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 T790M-positive tumors following progression after first- or second-generation EGFR TKIs, second-line osimertinib has demonstrated significant efficacy compared with chemotherapy (median PFS 10.1 vs 4.4 months; HR 0.30, 95% CI 0.23-0.40, P<0.001).

    “In T790M-positive tumors, following progression after first- or second-generation EGFR TKIs, second-line osimertinib has demonstrated significant efficacy compared with chemotherapy (median PFS: 10.1 vs 4.4 months; HR, 0.30 (95% CI, 0.23‒0.40), P < 0.001).”

    From Afatinib for the treatment of <i>EGFR</i> mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [48]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Osimertinib is being studied in combination with other targeted therapies for NSCLC, such as inhibitors of the Met, Bcl-2, and MAPK pathways.

    “In addition to being used alone, osimertinib is also being studied in combination with other targeted therapies for NSCLC, such as inhibitors of the Met, Bcl-2, and MAPK pathways.138–140”

    From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [140]

  • Duration of response, progression-free survival, and overall survival are even more variable across these trials.

    “Even more variable are duration of response to targeted therapy, progression-free survival and overall survival16–26, 28–32, 35.”

    From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [21]

  • In first-line targeted therapy trials for oncogene-addicted NSCLC, objective response rates typically range from 50% to 83%, complete responses are rare, and some patients show de novo resistance.

    “Across clinical trials of first-line targeted therapy for oncogene-addicted subgroups of NSCLC, rates of objective response [G] typically range between 50% and 83% and complete responses [G] are rare; in addition, some patients exhibit de novo resistance16–26, 28–32, 35.”

    From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [21]

  • Osimertinib significantly improved PFS and ORR compared with platinum-pemetrexed chemotherapy for T790M-positive NSCLC after progression on first- or second-generation EGFR-TKIs.

    “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.”

    From Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in <i>EGFR</i> -Mutant NSCLC (2018) · cites this paper as [3]

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Soria J, 2015, J Thorac Oncol, 10, S207

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Authors
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., Lee, C. K., Sebastian, M., Templeton, A., Mann, H., Marotti, M., Ghiorghiu, S., & Papadimitrakopoulou, V. A.
Affiliations
  • Army Medical University (CN)
  • Emory University (US)
  • Goethe University Frankfurt (DE)
  • AstraZeneca (United Kingdom) (GB)
  • The University of Texas MD Anderson Cancer Center (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2017-02-16
Volume
376
Issue
7
Pages
629-640
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1612674
PMC
PMC6762027
OpenAlex
W2560717039
Semantic Scholar
bd8840946a65bec6d407a96092eda55497e49a58
Cited by
3,379
References
25
Citations by year
2026: 198 · 2025: 280 · 2024: 301 · 2023: 318 · 2022: 410 · 2021: 438 · 2020: 404 · 2019: 365 · 2018: 389 · 2017: 268 · 2016: 2 · 2015: 2
FWCI
305.08
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
  • Research Explorer (The University of Manchester) (submittedVersion, other-oa)
Funders
  • Cancer Research UK (20465)
  • National Cancer Institute (P30CA016672)
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 › Lung Cancer Research Studies
Keywords
osimertinib, T790M mutation, non-small cell lung cancer, EGFR tyrosine kinase inhibitor resistance, pemetrexed, carboplatin, cisplatin, second-line therapy, progression-free survival, central nervous system metastasis, brain metastases, objective response rate, adverse events
MeSH terms
Pemetrexed, Acrylamides, Adult, Aged, Aged, 80 and over, Aniline Compounds, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Female, Humans, Indoles, Lung Neoplasms, Male, Middle Aged, Mutation, Piperazines, Platinum, Pyrimidines, Disease-Free Survival, Young Adult, ErbB Receptors

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