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Cited by 684Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchLung Cancer Diagnosis and Treatment

Rociletinib in EGFR-Mutated Non–Small-Cell Lung Cancer

Open access
Sequist, Lecia V., Soria, Jean-Charles, Goldman, Jonathan W., Wakelee, Heather A., Gadgeel, Shirish M., Varga, Andrea, Papadimitrakopoulou, Vassiliki, Solomon, Benjamin J. +22 more·2015·New England Journal of Medicine
DOI 10.1056/nejmoa1413654
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Abstract

BACKGROUND: Non-small-cell lung cancer (NSCLC) with a mutation in the gene encoding epidermal growth factor receptor (EGFR) is sensitive to approved EGFR inhibitors, but resistance develops, mediated by the T790M EGFR mutation in most cases. Rociletinib (CO-1686) is an EGFR inhibitor active in preclinical models of EGFR-mutated NSCLC with or without T790M. METHODS: In this phase 1-2 study, we administered rociletinib to patients with EGFR-mutated NSCLC who had disease progression during previous treatment with an existing EGFR inhibitor. In the expansion (phase 2) part of the study, patients with T790M-positive disease received rociletinib at a dose of 500 mg twice daily, 625 mg twice daily, or 750 mg twice daily. Key objectives were assessment of safety, side-effect profile, pharmacokinetics, and preliminary antitumor activity of rociletinib. Tumor biopsies to identify T790M were performed during screening. Treatment was administered in continuous 21-day cycles. RESULTS: A total of 130 patients were enrolled. The first 57 patients to be enrolled received the free-base form of rociletinib (150 mg once daily to 900 mg twice daily). The remaining patients received the hydrogen bromide salt (HBr) form (500 mg twice daily to 1000 mg twice daily). A maximum tolerated dose (the highest dose associated with a rate of dose-limiting toxic effects of less than 33%) was not identified. The only common dose-limiting adverse event was hyperglycemia. In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the HBr form at any dose, the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59% (95% confidence interval [CI], 45 to 73), and the rate among the 17 patients with T790M-negative disease who could be evaluated was 29% (95% CI, 8 to 51). CONCLUSIONS: Rociletinib was active in patients with EGFR-mutated NSCLC associated with the T790M resistance mutation. (Funded by Clovis Oncology; ClinicalTrials.gov number, NCT01526928.).

Integrity signals

Registry

Crossref · 10.1056/nejmoa1413654

Cites

25 of 25 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 22 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In 20 patients with tumors not assessable for T790M centrally, the response rate was 15% (3 of 20).

    “Among 20 patients whose tumors were not assessable for T790M at the central laboratory, the response rate was 15% (3 of 20 patients).”
    Quote in the paperNot a substantial claim
  • Findingown data

    In 46 evaluable patients with centrally confirmed T790M-positive tumors given therapeutic doses, the objective response rate was 59% (95% CI, 45 to 73).

    “the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59% (95% confidence interval [CI], 45 to 73)”
    • Also stated in: § Efficacy · plain
      “The response rate among 46 patients with centrally confirmed T790M-positive tumors was 59% (95% confidence interval [CI], 45 to 73)”
    Quote in the paperSubstantial claim
  • Findingown data

    Among T790M-negative patients, the disease-control rate was 59% (10 of 17 patients).

    “the disease-control rate was 59% (10 of 17 patients)”
    Quote in the paperNot a substantial claim
  • Findingown data

    In 17 evaluable T790M-negative patients, the objective response rate was 29% (95% CI, 8 to 51).

    “the rate among the 17 patients with T790Mnegative disease who could be evaluated was 29% (95% CI, 8 to 51)”
    • Also stated in: § Efficacy · plain
      “Among 17 patients whose tumors were T790Mnegative by central testing, the response rate was 29% (95% CI, 8 to 51)”
    Quote in the paperSubstantial claim
  • Findingown data

    Among T790M-positive patients, the disease-control rate was 93% (43 of 46 patients).

    “the disease-control rate (the proportion of patients with a complete or partial response or stable disease) was 93% (43 of 46 patients)”
    Quote in the paperSubstantial claim
  • The quote only partly states this claim. 1
  • May combine two claims. 19
  • Classified as probably not a substantial claim. 11

  • The quote only partly states this claim.

    Findingown data

    QTc prolongation occurred in 11 patients (12%) receiving therapeutic doses.

    “QTc prolongation 11 (12) 3 (3) 3 (3) 5 (5)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Rociletinib's antitumor activity was seen irrespective of the initial activating mutation and in a heavily pretreated population with a median of four prior therapies.

    “The antitumor activity of rociletinib was observed regardless of initial activating mutation and in a trial population of heavily pretreated patients (median number of previous therapies, 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In this study, 72% of all patients and 70% of T790M-positive responders were taking an EGFR inhibitor immediately before study therapy.

    “in this study 72% of patients overall and 70% of T790M-positive patients who had a response were also taking an EGFR inhibitor immediately before study therapy”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In this trial, rociletinib was linked to tumor responses and durable disease control in heavily pretreated EGFR-mutated NSCLC patients from the US, Europe, and Australia who had developed the T790M resistance mutation.

    “In summary, rociletinib was associated with tumor responses and sustained disease control among patients with heavily pretreated EGFR-mutated NSCLC from the United States, Europe, and Australia in whom the T790M resistance mutation has developed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Consistent objective responses occurred at 900 mg twice daily of the free-base form and at every HBr dose, which were called therapeutic doses.

    “Objective responses were consistently observed at a dose of 900 mg twice daily of the free-base form and all doses of the HBr form (hereafter referred to as therapeutic doses).”
    Quote in the paperSubstantial claim

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

    Findingown data

    One patient developed a grade 1 maculopapular rash.

    “though a single patient had a grade 1 maculopapular rash.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    No maximum tolerated dose was established during the phase 1 portion.

    “A maximum tolerated dose was not defined in the phase 1 portion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    One patient had a treatment-related grade 4 event (hypokalemia), and no treatment-related grade 5 events occurred.

    “One patient had a treatment-related grade 4 event (hypokalemia), and there were no treatment-related grade 5 events.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Rociletinib was absorbed quickly and had an elimination half-life of 2 to 4 hours.

    “Rociletinib was absorbed rapidly, with an elimination half-life of 2 to 4 hours”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Twelve of 17 T790M-negative patients, and 80% of T790M-negative responders, had been taking an EGFR inhibitor immediately before rociletinib.

    “12 of the 17 T790M-negative patients, and 80% of the T790Mnegative patients who had a response, had been taking an EGFR inhibitor immediately before rociletinib.”
    Quote in the paperSubstantial claim

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

    Findingown data

    Some patients with preexisting diabetes were included and treated without incident.

    “The study included some patients with preexisting diabetes, who were treated uneventfully”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among T790M-positive patients, the response rate was 59%, and some experienced prolonged disease control.

    “The response rate of 59% and prolonged disease control among some T790M-positive patients are encouraging”
    • Also stated in: § Discussion · plain
      “A response rate of 59% with prolonged disease control was noted.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No maximum tolerated dose was found, since every dose tested had a cycle 1 dose-limiting toxicity rate below 33%.

    “A maximum tolerated dose (the highest dose associated with a rate of dose-limiting toxic effects of less than 33%) was not identified.”
    • Also stated in: § Patient Characteristics · plain
      “The maximum tolerated dose was not reached according to the protocol definition, because all doses studied had a cycle 1 rate of doselimiting toxic effects of less than 33%.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In this study, patients negative for T790M on the central assay had a 29% response rate (5 of 17) and median progression-free survival of 5.6 months.

    “Nevertheless, in our study, those who were T790M-negative on the central assay had a response rate of 29% (5 of the 17 patients) and a median progression-free survival of 5.6 months.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The central genotyping assay accurately identifies T790M mutation status in tumor biopsies.

  • May combine two claims.

    Premisecitation

    Xenograft models carrying EGFR-activating mutations, with or without T790M, showed durable tumor shrinkage with rociletinib, greatest when plasma levels stayed above 200 ng/mL.

    “In xenograft models with EGFR-activating mutations alone or combined with T790M resistance mutations, rociletinib resulted in durable tumor shrinkage, 7 which was most marked when plasma concentrations were maintained at more than 200 ng per milliliter across the dosing interval.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rociletinib is an orally available small molecule that covalently and selectively inhibits common EGFR mutations such as exon 19 deletions, L858R, and T790M, but not exon 20 insertions.

    “Rociletinib (CO-1686; Clovis Oncology) is a small-molecule, orally available, mutant-selective covalent inhibitor of commonly mutated forms of EGFR, including exon 19 deletions, L858R, and T790M, but not exon 20 insertions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rociletinib is an EGFR inhibitor that is active in preclinical models of EGFR-mutated non-small-cell lung cancer, both with and without the T790M mutation.

    “Rociletinib (CO-1686) is an EGFR inhibitor active in preclinical models of EGFR-mutated NSCLC with or without T790M.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] 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 conductown data

    The study followed the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice guidelines.

    “This study was conducted in accordance with the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Conference on Harmonisation.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Study investigators and the sponsor designed the study together.

    “The study was designed by study investigators together with the sponsor (Clovis Oncology).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    All patients gave written informed consent.

    “Written informed consent was obtained from all patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Afatinib monotherapy trials in patients with acquired resistance to erlotinib or gefitinib showed a response rate below 10% and progression-free survival of about 4 months.

    “For example, studies of afatinib monotherapy showed a response rate of less than 10% among patients with acquired resistance to erlotinib or gefitinib, with a progression-free survival of approximately 4 months.13,15”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] source

      Not checked in the free run.

    • cites [15] 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

    All authors decided to submit the manuscript and vouched for the data, analyses, and protocol fidelity.

    “All the authors made the decision to submit the manuscript for publication and vouch for the accuracy and completeness of the data and analyses reported and for the fidelity of the study to the protocol.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Several other molecules targeting T790M are in development.

    “although several other molecules are in development.11”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The best therapy so far for acquired resistance has been daily afatinib plus cetuximab every other week, yielding a 30% response rate and median progression-free survival of 4.7 months.

    “The most successful therapy to date for acquired resistance has been a combination of daily afatinib and the EGFR monoclonal antibody cetuximab every other week, with a response rate of 30% and a median progression-free survival of 4.7 months.16”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] 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 conductown data

    The sponsor gathered the data and analyzed it with the authors.

    “The sponsor collected the data and analyzed them in conjunction with the authors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The afatinib-cetuximab combination carries substantial skin and gastrointestinal toxicity that may restrict its use.

    “However, this combination is associated with substantial skin and gastrointestinal toxic effects, which may limit its use.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] source

      Not checked in the free run.

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

    Study design and conductown data

    Each site's local human investigations committee approved the protocol.

    “The protocol was approved by the local human investigations committee at each site.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Activation of the IGF-IR pathway is proposed as a resistance mechanism for EGFR inhibition.

    “Activation of the IGF-IR pathway is a proposed resistance mechanism for EGFR inhibition, 21,22”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] source

      Not checked in the free run.

    • cites [22] source

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28 of 28

  • The paper relies on this without support.

    No approved therapy specifically targets T790M.

    “There are no approved therapies that specifically target T790M”

  • The paper relies on this without support.

    Cytotoxic chemotherapy is the usual treatment for T790M-positive patients.

    “so cytotoxic chemotherapy is typically used.”

  • The paper relies on this without support.

    Approved EGFR inhibitors strongly inhibit wild-type EGFR, leading to rash and diarrhea as common dose-limiting toxicities.

    “currently approved EGFR tyrosine kinase inhibitors result in substantial inhibition of nonmutant EGFR, leading to rash and diarrhea as their two most common and dose-limiting side effects.”

  • The paper relies on this without support.

    The central genotyping assay accurately identifies T790M mutation status in tumor biopsies.

    “those who were T790M-negative on the central assay”

  • The paper relies on this without support.

    The rash, stomatitis, and paronychia syndrome is caused by inhibition of nonmutant EGFR.

    “the syndrome of rash, stomatitis, and paronychia that is associated with inhibition of nonmutant EGFR”

  • The paper relies on this without support.

    There are no approved therapies that specifically target T790M.

    “there are no approved therapies that specifically target T790M”

  • The paper relies on this without support.

    Rociletinib has a short half-life.

    “Because of the short half-life of rociletinib”
7 of 7

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?

  • Third-generation EGFR inhibitors that inhibit mutant EGFR with T790M produce responses in nearly two-thirds of patients.

    “Third generation EGFR inhibitors capable of inhibiting mutant EGFR with T790M produce responses in nearly two thirds of patients.”

    From The Allelic Context of the C797S Mutation Acquired upon Treatment with Third-Generation EGFR Inhibitors Impacts Sensitivity to Subsequent Treatment Strategies (2015) · cites this paper as [25]

  • CO-1686 and AZD9291 cause substantially less skin toxicity than typical EGFR TKIs.

    “In addition, both agents are associated with substantially less skin toxicity than typically observed for EGFR TKIs (17, 18).”

    From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [18]

  • Phase I studies of CO-1686 or AZD9291 have produced response rates above 50% in EGFR-mutant T790M NSCLC patients who progressed on gefitinib or erlotinib.

    “In phase I studies to date, treatment with either CO-1686 or AZD9291, has resulted in a RR > 50% in EGFR mutant EGFR T790M NSCLC patients that have developed resistance to gefitinib or erlotinib (17, 18).”

    From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [18]

  • Mutant-selective EGFR kinase inhibitors including WZ4002, CO-1686, and AZD9291 have demonstrated encouraging efficacy in preclinical models and in EGFR mutant NSCLC patients with EGFR T790M-mediated drug resistance.

    “These include the development of mutant selective EGFR kinase inhibitors, including WZ4002, CO-1686 and AZD9291, which to date have demonstrated encouraging efficacy in both preclinical models and in EGFR mutant NSCLC patients with EGFR T790M mediated drug resistance (14–18).”

    From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [18]

  • Sequist et al. reported preliminary results of the TIGER X study in patients with EGFR-mutated and T790M-positive NSCLC previously treated with an EGFR TKI, with a 59% ORR and median PFS exceeding 12 months, and most common toxicity hyperglycemia.

    “Recently, Sequist and coll. reported the preliminary results of the ongoing phase I/II study TIGER X in patients with NSCLC harboring EGFR mutations and T790M-positive that previously received an EGFR TKI. The results, albeit preliminary, are quite impressive with a 59% ORR and a median PFS not yet reached, but exceeding 12 months. The safety profile of this agent is also interesting with the most”

    From A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives (2015) · cites this paper as [86]

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Authors
Sequist, L. V., Soria, J.-C., Goldman, J. W., Wakelee, H. A., Gadgeel, S. M., Varga, A., Papadimitrakopoulou, V., Solomon, B. J., Oxnard, G. R., Dziadziuszko, R., Aisner, D. L., Doebele, R. C., Galasso, C., Garon, E. B., Heist, R. S., Logan, J., Neal, J. W., Mendenhall, M. A., Nichols, S., Piotrowska, Z., Wozniak, A. J., Raponi, M., Karlovich, C. A., Jaw-Tsai, S., Isaacson, J., Despain, D., Matheny, S. L., Rolfe, L., Allen, A. R., & Camidge, D. R.
Affiliations
  • Université Paris-Sud (FR)
  • University of California, Los Angeles (US)
  • Stanford Cancer Institute (US)
  • Wayne State University (US)
  • Institut Gustave Roussy (FR)
  • The University of Texas MD Anderson Cancer Center (US)
  • Peter MacCallum Cancer Centre (AU)
  • Harvard University (US)
  • University of Colorado Cancer Center (US)
  • Massachusetts General Hospital (US)
  • Clovis Oncology (United States) (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2015-04-30
Volume
372
Issue
18
Pages
1700-1709
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1413654
OpenAlex
W2126177831
Cited by
665
References
25
Citations by year
2026: 9 · 2025: 11 · 2024: 13 · 2023: 30 · 2022: 20 · 2021: 29 · 2020: 39 · 2019: 39 · 2018: 60 · 2017: 133 · 2016: 190 · 2015: 90 · 2014: 1 · 2013: 1
FWCI
125.77
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
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
rociletinib, EGFR-mutant non-small cell lung cancer, T790M mutation, EGFR inhibitors, acquired drug resistance, tyrosine kinase inhibitors, maximum tolerated dose, hyperglycemia, objective response rate, pharmacokinetics, anticancer activity, safety and tolerability, dose-limiting toxicity
MeSH terms
Acrylamides, Aged, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Dose-Response Relationship, Drug, Female, Humans, Hyperglycemia, Lung Neoplasms, Male, Middle Aged, Mutation, Pyrimidines, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, ErbB Receptors

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