Association of Pertuzumab, Trastuzumab, and Docetaxel Combination Therapy With Overall Survival in Patients With Metastatic Breast Cancer | Breast Cancer | JAMA Network Open | JAMA Network
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Figure.  Kaplan-Meier Estimates of Overall Survival
Kaplan-Meier Estimates of Overall Survival

Survival function estimates from Flatiron Health (FH) data are shown for all patients and trial-eligible patients, respectively. Survival function estimates for the CLEOPATRA trial population are displayed with a dashed gray line, and shaded areas represent 95% CIs. NR indicates not reached.

aDigitized overall survival.

bSensitivity analysis, which included patients for whom Eastern Cooperative Oncology Group performance status was missing.

Table.  Patient Demographic and Clinical Characteristicsa
Patient Demographic and Clinical Characteristicsa
1.
Swain  SM, Miles  D, Kim  SB,  et al; CLEOPATRA study group.  Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study.   Lancet Oncol. 2020;21(4):519-530. doi:10.1016/S1470-2045(19)30863-0 PubMedGoogle ScholarCrossref
2.
Khozin  S, Miksad  RA, Adami  J,  et al.  Real-world progression, treatment, and survival outcomes during rapid adoption of immunotherapy for advanced non–small cell lung cancer.   Cancer. 2019;125(22):4019-4032. doi:10.1002/cncr.32383 PubMedGoogle ScholarCrossref
3.
Guyot  P, Ades  AE, Ouwens  MJ, Welton  NJ.  Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves.   BMC Med Res Methodol. 2012;12:9. doi:10.1186/1471-2288-12-9 PubMedGoogle ScholarCrossref
4.
Quan  H, Sundararajan  V, Halfon  P,  et al.  Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data.   Med Care. 2005;43(11):1130-1139. doi:10.1097/01.mlr.0000182534.19832.83 PubMedGoogle ScholarCrossref
5.
Rahardja  S, Tan  RYC, Sultana  R, Leong  FL, Lim  EH.  Efficacy, patterns of use and cost of pertuzumab in the treatment of HER2+ metastatic breast cancer in Singapore: the National Cancer Centre Singapore experience.   World J Clin Oncol. 2020;11(3):143-151. doi:10.5306/wjco.v11.i3.143 PubMedGoogle ScholarCrossref
6.
Gamucci  T, Pizzuti  L, Natoli  C,  et al.  A multicenter retrospective observational study of first-line treatment with pertuzumab, trastuzumab and taxanes for advanced HER2 positive breast cancer patients: RePer Study.   Cancer Biol Ther. 2019;20(2):192-200. doi:10.1080/15384047.2018.1523095 PubMedGoogle ScholarCrossref
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    Research Letter
    Oncology
    January 13, 2021

    Association of Pertuzumab, Trastuzumab, and Docetaxel Combination Therapy With Overall Survival in Patients With Metastatic Breast Cancer

    Author Affiliations
    • 1Global Access, F. Hoffmann-La Roche Ltd, Basel, Switzerland
    • 2Pharma International Informatics, F. Hoffmann-La Roche Ltd, Basel, Switzerland
    • 3Strategic Insights & Advance Analytics, F. Hoffmann-La Roche Ltd, Basel, Switzerland
    • 4PHMR Ltd, London, United Kingdom
    JAMA Netw Open. 2021;4(1):e2027764. doi:10.1001/jamanetworkopen.2020.27764
    Introduction

    In 2012, the combination of pertuzumab, trastuzumab, and docetaxel was approved by the US Food and Drug Administration for the treatment of patients with ERBB2 (formerly HER2)–positive metastatic breast cancer (MBC) who have not received prior anti-ERBB2 therapy or chemotherapy. The approval was based on data from the phase 3 pertuzumab, trastuzumab, and docetaxel for ERBB2-positive metastatic breast cancer (CLEOPATRA) trial.1 End-of-study results have confirmed the long-term benefit of this combination in the trial population1; however, there has been limited analysis of its real-world effectiveness. To fill this evidence gap, we undertook a retrospective cohort study within the Flatiron Health electronic health record–derived database to assess the effectiveness of pertuzumab, trastuzumab, and docetaxel treatment of ERBB2-positive MBC in real-world US patients.

    Methods

    The Flatiron Health database includes information from more than 265 cancer clinics across the United States.2 Research with the database was approved by the Copernicus Group Institutional Review Board, which waived informed consent because all data were deidentified. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies was followed. For this study, data from January 1, 2011, through October 31, 2020, were included for patients with an International Classification of Diseases, Ninth Revision (ICD-9) or International Classification of Diseases, Tenth Revision (ICD-10) diagnosis of breast cancer, documentation confirming MBC and a positive ERBB2 test result, who received pertuzumab, trastuzumab, and docetaxel combination therapy after their MBC diagnosis as first-line therapy for MBC. Patients were excluded if they were younger than 18 years at the time of treatment initiation, had fewer than 2 clinic encounters after treatment initiation, or had a gap of more than 90 days between the diagnosis of MBC and initiation of the collection of structured data.

    Baseline patient demographic and clinical characteristics were summarized using descriptive statistics, and the Kaplan-Meier method was used to evaluate overall survival (OS). The Kaplan-Meier curve for OS from the CLEOPATRA trial was digitized, and individual patient-level survival times were estimated using the Guyot algorithm to allow for comparison with the Flatiron Health cohort using log-rank tests.1,3

    Sensitivity analyses were performed excluding patients who did not meet key inclusion criteria of the CLEOPATRA clinical trial: patients with Eastern Cooperative Oncology Group performance status greater than 1 (with or without missing values), brain metastases, and a history of comorbidities included in the Charlson comorbidity index.4

    Analyses were performed using Python 3.8 series programming language (Python Software Foundation), with Bonferroni-corrected, 2-sided P < .05 considered statistically significant.

    Results

    In total, 546 patients with ERBB2-positive MBC received combined pertuzumab, trastuzumab, and docetaxel therapy. Of these, 541 (99.1%) were women, 329 (60.3%) were White, and their median age at treatment initiation was 59 (interquartile range, 50-66) years. The Flatiron Health cohort differed in some patient characteristics from that of the CLEOPATRA trial (Table). The median follow-up for the cohort was 45.3 months (95% CI, 40.6-48.0 months) and median OS was 48.6 months (95% CI, 41.4-53.9 months). Overall survival did not differ from that in the CLEOPATRA trial (Figure; digitized OS, 56.4 months; 95% CI, 51.0-71.9 months; log-rank test, P = .05). In the sensitivity analysis excluding trial-ineligible patients (leaving 211 patients), survival did not differ from that in the CLEOPATRA trial (median OS, 55.6 months; 95% CI, 46.7-82.4 months); log-rank test P > .99).

    Discussion

    Overall survival in this real-world cohort of ERBB2-positive patients with MBC who were treated with pertuzumab, trastuzumab, and docetaxel combination therapy was similar to that demonstrated in the CLEOPATRA trial. The findings are comparable with recent real-world studies from Singapore (median, 51.5 [95% CI, 35.8-60.0] after median follow-up of 20.6 months5) and Italy (3-year overall survival, 72.2% after median follow-up of 21 months6).

    Limitations of electronic health records are well documented and include incomplete information on some variables, such as comorbidities, adverse events, metastases, performance status, date of death, and adjuvant/neoadjuvant treatments.2 Our analysis is also limited by the relatively short median follow-up of the cohort. Despite these limitations, the results suggest that the benefit of pertuzumab, trastuzumab, and docetaxel combination therapy demonstrated in clinical trials is being realized in real-world populations.

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    Article Information

    Accepted for Publication: October 5, 2020.

    Published: January 13, 2021. doi:10.1001/jamanetworkopen.2020.27764

    Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2021 Ramagopalan SV et al. JAMA Network Open.

    Corresponding Author: Sreeram V. Ramagopalan, PhD, Global Access, F. Hoffman-La Roche Ltd, Grenzacherstrasse 124 CH-4070, Basel, Switzerland (sreeram.ramagopalan@roche.com).

    Author Contributions: Dr Ramagopalan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr Ramagopalan acts as the guarantor.

    Concept and design: Ramagopalan, Ray, Sammon.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Ramagopalan, Rathore, Ray, Sammon.

    Critical revision of the manuscript for important intellectual content: Pisoni, Sammon.

    Statistical analysis: Pisoni, Rathore.

    Supervision: Ramagopalan, Ray.

    Conflict of Interest Disclosures: Dr Sammon reported receiving grants from F Hoffmann-La Roche Ltd (nonpersonal, institutional funding) during the conduct of the study and from Bristol-Myers Squibb, Merck Sharpe & Dohme, Immunocore, Stemline Therapeutics, and Ferring Pharmaceuticals (all were nonpersonal, institutional funding) outside the submitted work. Mr Rathore reported receiving personal fees from F. Hoffman-La Roche Ltd as an external business partner during the conduct of the study. No other disclosures were reported.

    Funding/Support: This study was funded by F. Hoffman-La Roche.

    Role of the Funder/Sponsor: The funder was involved in all aspects of the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication.

    References
    1.
    Swain  SM, Miles  D, Kim  SB,  et al; CLEOPATRA study group.  Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study.   Lancet Oncol. 2020;21(4):519-530. doi:10.1016/S1470-2045(19)30863-0 PubMedGoogle ScholarCrossref
    2.
    Khozin  S, Miksad  RA, Adami  J,  et al.  Real-world progression, treatment, and survival outcomes during rapid adoption of immunotherapy for advanced non–small cell lung cancer.   Cancer. 2019;125(22):4019-4032. doi:10.1002/cncr.32383 PubMedGoogle ScholarCrossref
    3.
    Guyot  P, Ades  AE, Ouwens  MJ, Welton  NJ.  Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves.   BMC Med Res Methodol. 2012;12:9. doi:10.1186/1471-2288-12-9 PubMedGoogle ScholarCrossref
    4.
    Quan  H, Sundararajan  V, Halfon  P,  et al.  Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data.   Med Care. 2005;43(11):1130-1139. doi:10.1097/01.mlr.0000182534.19832.83 PubMedGoogle ScholarCrossref
    5.
    Rahardja  S, Tan  RYC, Sultana  R, Leong  FL, Lim  EH.  Efficacy, patterns of use and cost of pertuzumab in the treatment of HER2+ metastatic breast cancer in Singapore: the National Cancer Centre Singapore experience.   World J Clin Oncol. 2020;11(3):143-151. doi:10.5306/wjco.v11.i3.143 PubMedGoogle ScholarCrossref
    6.
    Gamucci  T, Pizzuti  L, Natoli  C,  et al.  A multicenter retrospective observational study of first-line treatment with pertuzumab, trastuzumab and taxanes for advanced HER2 positive breast cancer patients: RePer Study.   Cancer Biol Ther. 2019;20(2):192-200. doi:10.1080/15384047.2018.1523095 PubMedGoogle ScholarCrossref
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