Comparative effectiveness of first-line palbociclib plus letrozole versus letrozole alone for HR+/HER2− metastatic breast cancer in US real-world clinical practice

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Abstract

Background

Findings from randomized clinical trials may have limited generalizability to patients treated in routine clinical practice. This study examined the effectiveness of first-line palbociclib plus letrozole versus letrozole alone on survival outcomes in patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor–negative (HER2−) metastatic breast cancer (MBC) treated in routine clinical practice in the USA.

Patients and methods

This was a retrospective observational analysis of electronic health records within the Flatiron Health Analytic Database. A total of 1430 patients with ≥ 3 months of follow-up received palbociclib plus letrozole or letrozole alone in the first-line setting between February 3, 2015, and February 28, 2019. Stabilized inverse probability treatment weighting (sIPTW) was used to balance baseline demographic and clinical characteristics. Real-world progression-free survival (rwPFS) and overall survival (OS) were analyzed.

Results

After sIPTW adjustment, median follow-up was 24.2 months (interquartile range [IQR], 14.2–34.9) in the palbociclib group and 23.3 months (IQR, 12.7–34.3) in those taking letrozole alone. Palbociclib combination treatment was associated with significantly longer median rwPFS compared to letrozole alone (20.0 vs 11.9 months; hazard ratio [HR], 0.58; 95% CI, 0.49–0.69; P < 0.0001). Median OS was not reached in the palbociclib group and was 43.1 months with letrozole alone (HR, 0.66; 95% CI, 0.53–0.82; P = 0.0002). The 2-year OS rate was 78.3% in the palbociclib group and 68.0% with letrozole alone. A propensity score matching analysis showed similar results.

Conclusions

In this “real-world” population of patients with HR+/HER2− MBC, palbociclib in combination with endocrine therapy was associated with improved survival outcomes compared with patients treated with letrozole alone in the first-line setting.

Trial registration

Clinicaltrials.gov; NCT04176354

Supplementary Information

The online version contains supplementary material available at 10.1186/s13058-021-01409-8.

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Most cited references 23

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The central role of the propensity score in observational studies for causal effects

Paul R. Rosenbaum, Donald B Rubin (1983)

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Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies

Peter C Austin, Elizabeth A. Stuart (2015)

The propensity score is defined as a subject's probability of treatment selection, conditional on observed baseline covariates. Weighting subjects by the inverse probability of treatment received creates a synthetic sample in which treatment assignment is independent of measured baseline covariates. Inverse probability of treatment weighting (IPTW) using the propensity score allows one to obtain unbiased estimates of average treatment effects. However, these estimates are only valid if there are no residual systematic differences in observed baseline characteristics between treated and control subjects in the sample weighted by the estimated inverse probability of treatment. We report on a systematic literature review, in which we found that the use of IPTW has increased rapidly in recent years, but that in the most recent year, a majority of studies did not formally examine whether weighting balanced measured covariates between treatment groups. We then proceed to describe a suite of quantitative and qualitative methods that allow one to assess whether measured baseline covariates are balanced between treatment groups in the weighted sample. The quantitative methods use the weighted standardized difference to compare means, prevalences, higher‐order moments, and interactions. The qualitative methods employ graphical methods to compare the distribution of continuous baseline covariates between treated and control subjects in the weighted sample. Finally, we illustrate the application of these methods in an empirical case study. We propose a formal set of balance diagnostics that contribute towards an evolving concept of ‘best practice’ when using IPTW to estimate causal treatment effects using observational data. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

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Palbociclib and Letrozole in Advanced Breast Cancer.

Richard Finn, Miguel Martín, Hope Rugo … (2016)

Background A phase 2 study showed that progression-free survival was longer with palbociclib plus letrozole than with letrozole alone in the initial treatment of postmenopausal women with estrogen-receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. We performed a phase 3 study that was designed to confirm and expand the efficacy and safety data for palbociclib plus letrozole for this indication. Methods In this double-blind study, we randomly assigned, in a 2:1 ratio, 666 postmenopausal women with ER-positive, HER2-negative breast cancer, who had not had prior treatment for advanced disease, to receive palbociclib plus letrozole or placebo plus letrozole. The primary end point was progression-free survival, as assessed by the investigators; secondary end points were overall survival, objective response, clinical benefit response, patient-reported outcomes, pharmacokinetic effects, and safety. Results The median progression-free survival was 24.8 months (95% confidence interval [CI], 22.1 to not estimable) in the palbociclib-letrozole group, as compared with 14.5 months (95% CI, 12.9 to 17.1) in the placebo-letrozole group (hazard ratio for disease progression or death, 0.58; 95% CI, 0.46 to 0.72; P<0.001). The most common grade 3 or 4 adverse events were neutropenia (occurring in 66.4% of the patients in the palbociclib-letrozole group vs. 1.4% in the placebo-letrozole group), leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%), and fatigue (1.8% vs. 0.5%). Febrile neutropenia was reported in 1.8% of patients in the palbociclib-letrozole group and in none of the patients in the placebo-letrozole group. Permanent discontinuation of any study treatment as a result of adverse events occurred in 43 patients (9.7%) in the palbociclib-letrozole group and in 13 patients (5.9%) in the placebo-letrozole group. Conclusions Among patients with previously untreated ER-positive, HER2-negative advanced breast cancer, palbociclib combined with letrozole resulted in significantly longer progression-free survival than that with letrozole alone, although the rates of myelotoxic effects were higher with palbociclib-letrozole. (Funded by Pfizer; PALOMA-2 ClinicalTrials.gov number, NCT01740427 .).

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Author and article information

Contributors

Angela DeMichele:

ORCID: https://orcid.org/0000-0003-1297-4251

Angela.DeMichele@uphs.upenn.edu

Massimo Cristofanilli:

ORCID: https://orcid.org/0000-0002-4194-7175

Massimo.Cristofanilli@nm.org

Adam Brufsky:

ORCID: https://orcid.org/0000-0001-8080-7960

brufskyam@upmc.edu

Xianchen Liu: Jasonxc.Liu@pfizer.com

Jack Mardekian:

ORCID: https://orcid.org/0000-0003-4851-5161

jmardekian@gmail.com

Lynn McRoy: Lynn.McRoy@pfizer.com

Rachel M. Layman:

ORCID: https://orcid.org/0000-0002-8663-0331

RLayman@mdanderson.org

Birol Emir: Birol.Emir@pfizer.com

Mylin A. Torres: matorre@emory.edu

Hope S. Rugo: hope.rugo@ucsf.edu

Richard S. Finn:

ORCID: https://orcid.org/0000-0003-2494-2126

RFinn@mednet.ucla.edu

Journal

Journal ID (nlm-ta): Breast Cancer Res

Journal ID (iso-abbrev): Breast Cancer Res

Title: Breast Cancer Research : BCR

Publisher: BioMed Central (London )

ISSN (Print): 1465-5411

ISSN (Electronic): 1465-542X

Publication date (Electronic): 24 March 2021

Publication date PMC-release: 24 March 2021

Publication date (Print): 2021

Volume: 23

Electronic Location Identifier: 37

Affiliations

[1 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Abramson Cancer Center, , University of Pennsylvania, ; 3400 Civic Center Blvd, Philadelphia, PA 19104 USA

[2 ]GRID grid.16753.36, ISNI 0000 0001 2299 3507, Robert H. Lurie Cancer Center of Northwestern University, Feinberg School of Medicine, Chicago, ; 710 N Fairbanks Ct, Suite 8-250A, Chicago, IL 60611 USA

[3 ]GRID grid.412689.0, ISNI 0000 0001 0650 7433, UPMC Hillman Cancer Center, , University of Pittsburgh Medical Center, ; 300 Halket Street, Pittsburgh, PA 15213 USA

[4 ]GRID grid.410513.2, ISNI 0000 0000 8800 7493, Pfizer Inc, ; 235 42nd St, New York, NY 10017 USA

[5 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, The University of Texas MD Anderson Cancer Center, ; 1515 Holcombe Boulevard, Unit 1354, Houston, TX 77030 USA

[6 ]GRID grid.189967.8, ISNI 0000 0001 0941 6502, Winship Cancer Institute, Emory University School of Medicine, ; 1365 Clifton Rd. NE, Building A, 1st Floor, Rm. 1307A, Atlanta, GA 30322 USA

[7 ]GRID grid.266102.1, ISNI 0000 0001 2297 6811, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, ; 1825 4th Street, 3rd Floor, Box 1710, San Francisco, CA 94158 USA

[8 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, David Geffen School of Medicine at University of California Los Angeles, ; 2825 Santa Monica Blvd, Suite 200, Santa Monica, CA 90404 USA

Author information

Angela DeMichele https://orcid.org/0000-0003-1297-4251

Massimo Cristofanilli https://orcid.org/0000-0002-4194-7175

Adam Brufsky https://orcid.org/0000-0001-8080-7960

Jack Mardekian https://orcid.org/0000-0003-4851-5161

Rachel M. Layman https://orcid.org/0000-0002-8663-0331

Richard S. Finn https://orcid.org/0000-0003-2494-2126

Article

Publisher ID: 1409

DOI: 10.1186/s13058-021-01409-8

PMC ID: 7989035

PubMed ID: 33761995

SO-VID: 38ab2062-7784-4e1c-a90d-ce21376c6a8d

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 21 November 2020

Date accepted : 21 February 2021

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: hr+/her2−,metastatic breast cancer,palbociclib,letrozole,real-world data,comparative effectiveness

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: hr+/her2−, metastatic breast cancer, palbociclib, letrozole, real-world data, comparative effectiveness

Comparative effectiveness of first-line palbociclib plus letrozole versus letrozole alone for HR+/HER2− metastatic breast cancer in US real-world clinical practice

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Abstract

Background

Patients and methods

Results

Conclusions

Trial registration

Supplementary Information

Related collections

Karger: Oncology

Most cited references 23

The central role of the propensity score in observational studies for causal effects

Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies

Palbociclib and Letrozole in Advanced Breast Cancer.

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