Real-World Effectiveness of Palbociclib Plus Letrozole vs Letrozole Alone for Metastatic Breast Cancer With Lung or Liver Metastases: Flatiron Database Analysis

Adam Brufsky, Xianchen Liu, Benjamin Li, Lynn McRoy, Rachel M Layman, Adam Brufsky, Xianchen Liu, Benjamin Li, Lynn McRoy, Rachel M Layman

Abstract

Background: Cyclin-dependent kinase 4/6 inhibitors are a standard treatment for patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). However, real-world data on effectiveness in patients with liver or lung metastatic disease is limited. This study compared outcomes of palbociclib plus letrozole versus letrozole alone in patients with HR+/HER2- MBC with lung or liver metastasis treated in routine clinical practice in the United States.

Methods: This retrospective analysis used Flatiron Health's database of electronic health records. Women with HR+/HER2- MBC and liver or lung metastasis received first-line palbociclib plus letrozole or letrozole alone between February 2015 and February 2019. Real-world progression-free survival (rwPFS) was defined as time from start of treatment to death or disease progression. Stabilized inverse probability treatment weighting (sIPTW) was used to balance baseline demographic and clinical characteristics between palbociclib plus letrozole versus letrozole cohorts. Cox proportional-hazards models were used to estimate the effectiveness of palbociclib plus letrozole versus letrozole alone in rwPFS and overall survival (OS).

Results: The study included 353 patients with lung metastasis, 123 with liver metastasis, and 75 with both. After sIPTW, palbociclib plus letrozole versus letrozole alone was significantlly associated with prolonged rwPFS (hazard ratio (HR), 0.56) and OS (HR, 0.58) (both p<0.001) in all patients. Palbociclib plus letrozole compared with letrozole alone demonstrated a median rwPFS of 16.5 versus 10.5 months, respectively (adjusted HR, 0.52; P<0.001), a median OS of not reached versus 40.3 months (adjusted HR, 0.60; P<0.01) in patients with lung metastasis, and median OS of 30.1 versus 16.8 months (adjusted HR, 0.56; P<0.03 in patients with liver metastasis. In patients with liver metastasis, palbociclib plus letrozole had a median rwPFS of 10.7 months versus 8.0 months in the letrozole alone cohort (adjusted HR, 0.70; P=0.12).

Conclusions: In this real-world population, palbociclib in combination with letrozole is associated with improved outcomes compared with letrozole alone for patients with HR+/HER2- MBC and liver or lung metastasis in the first-line setting. The findings support first-line palbociclib in combination with an aromatase inhibitor as standard of care for HR+/HER2- MBC regardless of visceral disease.

Clinical trial registration: NCT04176354.

Keywords: HR+/HER2−; metastatic breast cancer; palbociclib; real-world data; visceral metastasis.

Conflict of interest statement

AB, Consulting fees or honorarium from Pfizer Inc, AstraZeneca, Lilly, Novartis, and Sanofi. XL, BL, and LM, Pfizer employee and Pfizer stockholder. RL, Consulting fees from Pfizer Inc, Eli Lilly, Celcuity, and Novartis, research support from Pfizer Inc, Eli Lilly, Novartis, GlaxoSmithKline, Puma, Zentalis, and Celcuity. The authors declare that this study received funding from Pfizer Inc. The funder had the following involvement with the study: data acquisition, study design, data analysis, and coauthoring the paper. No authors received funding or payment for coauthoring the paper from the funder.

Copyright © 2022 Brufsky, Liu, Li, McRoy and Layman.

Figures

Figure 1
Figure 1
Kaplan-Meier curves of real-world progression-free survival in patients with visceral (lung and/or liver) metastasis. sIPTW analysis (A) and PSM analysis (B); number of patients at risk are shown. LET, letrozole; PAL, palbociclib; PSM, propensity score matching; rwPFS, real-world progression-free survival; sIPTW, stabilized inverse probability treatment weighting.
Figure 2
Figure 2
Kaplan-Meier curves of overall survival in patients with visceral (lung and/or liver) metastasis. sIPTW analysis (A) and PSM analysis (B); number of patients at risk are shown. LET, letrozole; NR, not reached; OS, overall survival; PAL, palbociclib; PSM, propensity score matching; sIPTW, stabilized inverse probability treatment weighting.
Figure 3
Figure 3
Kaplan-Meier curves of real-world progression-free survival and overall survival in patients with lung metastasis. Analysis of rwPFS (A) and OS (B) adjusted for demographic and clinical variables; number of patients at risk are shown. LET, letrozole; NR, not reached; OS, overall survival; PAL, palbociclib; rwPFS, real-world progression-free survival. *Hazard ratios were estimated by multivariate Cox regression models adjusted for baseline demographic and clinical variables.
Figure 4
Figure 4
Kaplan-Meier curves of real-world progression-free survival and overall survival in patients with liver metastasis. Analysis of rwPFS (A) and OS (B) adjusted for demographic and clinical variables; number of patients at risk are shown. LET, letrozole; OS, overall survival; PAL, palbociclib; rwPFS, real-world progression-free survival. *Hazard ratios were estimated by multivariate Cox regression models adjusted for baseline demographic and clinical variables.

References

    1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin (2021) 71:7–33. doi: 10.3322/caac.21654
    1. Redig AJ, McAllister SS. Breast Cancer as a Systemic Disease: A View of Metastasis. J Intern Med (2013) 274:113–26. doi: 10.1111/joim.12084
    1. Wang R, Zhu Y, Liu X, Liao X, He J, Niu L. The Clinicopathological Features and Survival Outcomes of Patients With Different Metastatic Sites in Stage IV Breast Cancer. BMC Cancer (2019) 19:1091. doi: 10.1186/s12885-019-6311-z
    1. Wu Q, Li J, Zhu S, Wu J, Chen C, Liu Q, et al. . Breast Cancer Subtypes Predict the Preferential Site of Distant Metastases: A SEER Based Study. Oncotarget (2017) 8:27990–6. doi: 10.18632/oncotarget.15856
    1. National Comprehensive Cancer Network . NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 8.2021. National Comprehensive Cancer Network; (2021). Available at: . Accessed October 29, 2021.
    1. Robertson JFR, Di Leo A, Johnston S, Chia S, Bliss JM, Paridaens RJ, et al. . Meta-Analyses of Visceral Versus Non-Visceral Metastatic Hormone Receptor-Positive Breast Cancer Treated by Endocrine Monotherapies. NPJ Breast Cancer (2021) 7:11. doi: 10.1038/s41523-021-00222-y
    1. He M, Li JJ, Zuo WJ, Ji L, Jiang YZ, Hu XC, et al. . Metastatic Breast Cancer Patients With Lung or Liver Metastases Should Be Distinguished Before Being Treated With Fulvestrant. Cancer Med (2019) 8:6212–20. doi: 10.1002/cam4.2453
    1. Ettl J. Management of Adverse Events Due to Cyclin-Dependent Kinase 4/6 Inhibitors. Breast Care (Basel) (2019) 14:86–92. doi: 10.1159/000499534
    1. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. . The Cyclin-Dependent Kinase 4/6 Inhibitor Palbociclib in Combination With Letrozole Versus Letrozole Alone as First-Line Treatment of Oestrogen Receptor-Positive, HER2-Negative, Advanced Breast Cancer (PALOMA-1/TRIO-18): A Randomised Phase 2 Study. Lancet Oncol (2015) 16:25–35. doi: 10.1016/S1470-2045(14)71159-3
    1. Rugo HS, Finn RS, Dieras V, Ettl J, Lipatov O, Joy AA, et al. . Palbociclib Plus Letrozole as First-Line Therapy in Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer With Extended Follow-Up. Breast Cancer Res Treat (2019) 174:719–29. doi: 10.1007/s10549-018-05125-4
    1. Dawood S, Brzozowski K. Efficacy of CDK4/6i in the Visceral Crisis Setting: Result From a Real-World Database. J Clin Oncol (2021) 39:abst 1047. doi: 10.1200/JCO.2021.39.15_suppl.1047
    1. Sherman RE, Anderson SA, Dal Pan GJ, Gray GW, Gross T, Hunter NL, et al. . Real-World Evidence - What is it and What Can It Tell Us? N Engl J Med (2016) 375:2293–7. doi: 10.1056/NEJMsb1609216
    1. Blumenthal GM, Gong Y, Kehl K, Mishra-Kalyani P, Goldberg KB, Khozin S, et al. . Analysis of Time-to-Treatment Discontinuation of Targeted Therapy, Immunotherapy, and Chemotherapy in Clinical Trials of Patients With non-Small-Cell Lung Cancer. Ann Oncol (2019) 30:830–8. doi: 10.1093/annonc/mdz060
    1. Liu R, Rizzo S, Whipple S, Pal N, Pineda AL, Lu M, et al. . Evaluating Eligibility Criteria of Oncology Trials Using Real-World Data and AI. Nature (2021) 592:629–33. doi: 10.1038/s41586-021-03430-5
    1. Curtis MD, Griffith SD, Tucker M, Taylor MD, Capra WB, Carrigan G, et al. . Development and Validation of a High-Quality Composite Real-World Mortality Endpoint. Health Serv Res (2018) 53:4460–76. doi: 10.1111/1475-6773.12872
    1. Singal G, Miller PG, Agarwala V, Li G, Kaushik G, Backenroth D, et al. . Association of Patient Characteristics and Tumor Genomics With Clinical Outcomes Among Patients With Non-Small Cell Lung Cancer Using a Clinicogenomic Database. JAMA (2019) 321:1391–9. doi: 10.1001/jama.2019.3241
    1. Collins JM, Nordstrom BL, McLaurin KK, Dalvi TB, McCutcheon SC, Bennett JC, et al. . A Real-World Evidence Study of CDK4/6 Inhibitor Treatment Patterns and Outcomes in Metastatic Breast Cancer by Germline BRCA Mutation Status. Oncol Ther (2021) 9:575–89. doi: 10.1007/s40487-021-00162-4
    1. DeMichele A, Cristofanilli M, Brufsky A, Liu X, Mardekian J, McRoy L, et al. . Comparative Effectiveness of First-Line Palbociclib Plus Letrozole Versus Letrozole Alone for HR+/HER2- Metastatic Breast Cancer in US Real-World Clinical Practice. Breast Cancer Res (2021) 23:37. doi: 10.1186/s13058-021-01409-8
    1. Austin PC. The Use of Propensity Score Methods With Survival or Time-to-Event Outcomes: Reporting Measures of Effect Similar to Those Used in Randomized Experiments. Stat Med (2014) 33:1242–58. doi: 10.1002/sim.5984
    1. Tripathy D, Im SA, Colleoni M, Franke F, Bardia A, Harbeck N, et al. . Ribociclib Plus Endocrine Therapy for Premenopausal Women With Hormone-Receptor-Positive, Advanced Breast Cancer (MONALEESA-7): A Randomised Phase 3 Trial. Lancet Oncol (2018) 19:904–15. doi: 10.1016/S1470-2045(18)30292-4
    1. Hortobagyi GN. Ribociclib for the First-Line Treatment of Advanced Hormone Receptor-Positive Breast Cancer: A Review of Subgroup Analyses From the MONALEESA-2 Trial. Breast Cancer Res (2018) 20:123. doi: 10.1186/s13058-018-1050-7
    1. Gao JJ, Cheng J, Bloomquist E, Sanchez J, Wedam SB, Singh H, et al. . CDK4/6 Inhibitor Treatment for Patients With Hormone Receptor-Positive, HER2-Negative, Advanced or Metastatic Breast Cancer: A US Food and Drug Administration Pooled Analysis. Lancet Oncol (2020) 21:250–60. doi: 10.1016/S1470-2045(19)30804-6
    1. Im SA, Lu YS, Bardia A, Harbeck N, Colleoni M, Franke F, et al. . Overall Survival With Ribociclib Plus Endocrine Therapy in Breast Cancer. N Engl J Med (2019) 381:307–16. doi: 10.1056/NEJMoa1903765
    1. Schettini F, Giudici F, Giuliano M, Cristofanilli M, Arpino G, Del Mastro L, et al. . Overall Survival of CDK4/6-Inhibitor-Based Treatments in Clinically Relevant Subgroups of Metastatic Breast Cancer: Systematic Review and Meta-Analysis. J Natl Cancer Inst (2020) 112:1089–97. doi: 10.1093/jnci/djaa071
    1. Johnston S, O'Shaughnessy J, Martin M, Huober J, Toi M, Sohn J, et al. . Abemaciclib as Initial Therapy for Advanced Breast Cancer: MONARCH 3 Updated Results in Prognostic Subgroups. NPJ Breast Cancer (2021) 7:80. doi: 10.1038/s41523-021-00289-7
    1. Palleschi M, Maltoni R, Ravaioli S, Vagheggini A, Mannozzi F, Fanini F, et al. . Ki67 and PR in Patients Treated With CDK4/6 Inhibitors: A Real-World Experience. Diagnostics (Basel) (2020) 10:573. doi: 10.3390/diagnostics10080573
    1. De Angelis C, Fu X, Cataldo ML, Nardone A, Pereira R, Veeraraghavan J, et al. . Activation of the IFN Signaling Pathway is Associated With Resistance to CDK4/6 Inhibitors and Immune Checkpoint Activation in ER-Positive Breast Cancer. Clin Cancer Res (2021) 27:4870–82. doi: 10.1158/1078-0432.CCR-19-4191

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir