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Clinical Trial
. 2019 Apr;174(3):719-729.
doi: 10.1007/s10549-018-05125-4. Epub 2019 Jan 10.

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

H S Rugo  1 , R S Finn  2 , V Diéras  3   4 , J Ettl  5 , O Lipatov  6 , A A Joy  7 , N Harbeck  8 , A Castrellon  9 , S Iyer  10 , D R Lu  11 , A Mori  12 , E R Gauthier  13 , C Huang Bartlett  14 , K A Gelmon  15 , D J Slamon  2
Affiliations
Clinical Trial

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

H S Rugo et al. Breast Cancer Res Treat. 2019 Apr.

Abstract

Purpose: In the initial PALOMA-2 (NCT01740427) analysis with median follow-up of 23 months, palbociclib plus letrozole significantly prolonged progression-free survival (PFS) in women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) [hazard ratio (HR) 0.58; P < 0.001]. Herein, we report results overall and by subgroups with extended follow-up.

Methods: In this double-blind, phase 3 study, post-menopausal women with ER+/HER2- ABC who had not received prior systemic therapy for their advanced disease were randomized 2:1 to palbociclib-letrozole or placebo-letrozole. Endpoints include investigator-assessed PFS (primary), safety, and patient-reported outcomes (PROs).

Results: After a median follow-up of approximately 38 months, median PFS was 27.6 months for palbociclib-letrozole (n = 444) and 14.5 months for placebo-letrozole (n = 222) (HR 0.563; 1-sided P < 0.0001). All subgroups benefited from palbociclib treatment. The improvement of PFS with palbociclib-letrozole was maintained in the next 2 subsequent lines of therapy and delayed the use of chemotherapy (40.4 vs. 29.9 months for palbociclib-letrozole vs. placebo-letrozole). Safety data were consistent with the known profile. Patients' quality of life was maintained.

Conclusions: With approximately 15 months of additional follow-up, palbociclib plus letrozole continued to demonstrate improved PFS compared with placebo plus letrozole in the overall population and across all patient subgroups, while the safety profile remained favorable and quality of life was maintained. These data confirm that palbociclib-letrozole should be considered the standard of care for first-line therapy in patients with ER+/HER2- ABC, including those with low disease burden or long disease-free interval. Sponsored by Pfizer; ClinicalTrials.gov: NCT01740427.

Keywords: Breast cancer; Cyclin-dependent kinase inhibitor; ER+; HER2−; Letrozole; Palbociclib.

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Conflict of interest statement

Conflict of interest

HSR’s institution received research funding from Plexxikon, Macrogenics, OBI Pharma, Eisai, Pfizer, Novartis, Eli Lilly, Roche, and Merck. RSF received consulting fees from Pfizer, Bayer, Novartis, Bristol-Myers Squibb, Merck, Eli Lilly, Eisai, and Roche/Genentech as well as other research funding from Pfizer. VD received consulting fees from Genentech, Eli Lilly, Pfizer, Astellas, AbbVie, Novartis Pharma KK, Daichy, Tesaro, NSD, Seattle Genetics, and Roche-Peru, as well as speakers bureau fees from Pfizer, Novartis Pharma KK, and Roche-Peru. JE received consulting fees from Eli Lilly, Novartis, Pfizer, Roche, and Eisai, performed contracted research for Celgene, and received honoraria from Eli Lilly, Novartis, Pfizer, Roche, TEVA, and Pierre Fabre. AAJ received consulting fees from Amgen, AbbVie, AstraZeneca, BMS, Eli Lilly, Pfizer, Novartis, and Roche. NH received consulting fees for Eli Lilly, Novartis, and Pfizer. AC received consulting/advisory fees from Agendia. KAG received consulting/advisory fees from Pfizer, Novartis, AstraZeneca, NanoString Technologies, Merck, Eli Lilly, Genomic Health, Roche, Seattle Genetics, and Mylan. DJS received consulting fees from Pfizer, Eli Lilly, and Novartis, performed contracted research for Pfizer and Novartis, is a Pfizer stockholder, received travel accommodation/expenses from Pfizer and BioMarin, and has a leadership role with BioMarin. CHB, ERG, SI, DRL, and AM are employees of and own stock in Pfizer. OL has nothing to disclose.

Ethical approval

This trial complies with the current laws of the countries in which it was performed.

Figures

Fig. 1
Fig. 1
a Investigator-assessed progression-free survival (ITT population). b Forest plot of investigator-assessed PFS overall and across subgroups (ITT population). BICR blinded independent central review, ECOG PS Eastern Cooperative Oncology Group performance status, ET endocrine therapy, HR hazard ratio, IA investigator assessed, ITT intent-to-treat, LET letrozole, PFS progression-free survival, NE not estimable, NR not reached, PAL palbociclib, PBO placebo, TFI treatment-free interval. a: 1-sided P value from the log-rank test. b: Per tumor site. c: Protocol-defined disease-free interval is equivalent to TFI in this analysis and refers to TFI since completion of prior (neo)adjuvant therapy and onset of metastatic disease or disease recurrence. d: A few patients initially enrolled as having measurable disease were later found to have non-measurable disease beyond bone-only disease
Fig. 2
Fig. 2
Investigator-assessed PFS in subgroups of patients (ITT population). Kaplan–Meier curves for a bone-only and b single disease site—both representing low disease burden—and c no prior endocrine therapy with non-visceral disease. HR hazard ratio, ITT intent-to-treat, NE not estimable, PFS progression-free survival
Fig. 3
Fig. 3
Kaplan–Meier estimates of time to initiation of subsequent systemic anticancer therapies (anticancer treatment included any anticancer related systemic therapy and surgery for the disease under study) (ITT population) a Time from randomization to first subsequent therapy. b Time from randomization to second subsequent therapy (if the difference in time to initiation of the second subsequent therapy between the 2 treatment arms was shortened compared with the difference between the median PFS values, it may suggest that the treatment benefit of the first subsequent therapy was compromised. If the difference was similar, it suggests no compromise regarding the efficacy of the first subsequent therapy). c Time from randomization to first subsequent chemotherapy. EFS event-free survival, ITT intent-to-treat
Fig. 4
Fig. 4
Between-treatment comparison of changes from baseline for FACT-B scores (PRO analysis set included patients in the PRO-evaluable population [i.e., patients with a baseline and ≥ 1 postbaseline assessment before the end of the study treatment]) a FACT-B scales of overall scores. b FACT-B total score by subgroups. BC breast cancer, ECOG PS Eastern Cooperative Oncology Group performance status, FACT-B Functional Assessment of Cancer Therapy-Breast, FACT-G Functional Assessment of Cancer Therapy-General, LET letrozole, PAL palbociclib, PBO placebo, PRO patient-reported outcome, TFI treatment-free interval, TOI Trial Outcome Index
See this image and copyright information in PMC

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