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Real-world Treatment Patterns and Clinical Outcomes Associated With Palbociclib Combination Therapy: A Multinational, Pooled Analysis From the Ibrance Real World Insights Study

Open AccessPublished:November 28, 2022DOI:https://doi.org/10.1016/j.clinthera.2022.11.004

      Abstract

      Purpose

      Palbociclib was the first cyclin-dependent kinase 4/6 inhibitor approved by the US Food and Drug Administration for use in combination with aromatase inhibitors (AIs) as initial endocrine-based therapy or with fulvestrant in postmenopausal women who previously received endocrine therapy based on data from randomized clinical trials. Real-world studies examining the effectiveness of palbociclib in large, diverse patient populations in routine clinical practice were needed.

      Patients and Methods

      Ibrance Real World Insights (IRIS) was a retrospective medical record review study of women with confirmed hormone receptor–positive, HER2-negative advanced/metastatic breast cancer treated with palbociclib plus an AI or with palbociclib plus fulvestrant according to approved indications. Participating physicians reviewed medical records of up to 16 sequentially presenting patients, collecting demographic and clinical data. Outcomes included objective response rates, progression-free rates, and survival rates overall and in patients stratified according to age, race and ethnicity, Eastern Cooperative Oncology Group (ECOG) performance status (PS), disease-free interval, visceral disease, liver metastases, bone-only metastases, and previous lines of therapy.

      Findings

      Data were abstracted by 417 physicians for 2954 patients in 13 countries; 1415 patients (47.9%) were ≥65 years of age, 369 patients (12.5%) had an ECOG PS ≥2 at initiation, and 835 patients (28.3%) were races other than White. The 12-month progression-free rate was 88% for palbociclib plus an AI and 79% for palbociclib plus fulvestrant; the 12-month survival rate was 96% in both groups. The objective response rates were 80% for palbociclib plus an AI and 75% for palbociclib plus fulvestrant. Palbociclib was similarly effective in most subgroups examined.

      Implications

      Data from IRIS provide in-depth, real-world evidence for the use of palbociclib in a range of breast cancer populations in multiple countries. These data support the findings of the randomized PALOMA-2 and PALOMA-3 studies.

      Key words

      Introduction

      Approximately 2.3 million women were newly diagnosed with breast cancer (BC) worldwide in 2020; the estimated 685,000 deaths made female BC the fifth leading cause of cancer mortality.
      • Sung H
      • Ferlay J
      • Siegel RL
      • et al.
      Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.
      At diagnosis, 29% of patients have disease that has spread to regional lymph nodes and a further 6% have metastatic disease.
      National Cancer Institute
      Cancer Stat Facts: Female Breast Cancer. Surveillance, Epidemiology, and End Results Program.
      Hormone receptor–positive/HER2-negative (HR+/HER2) BC—the most common subtype—is diagnosed in an estimated 68% of patients.
      National Cancer Institute
      Cancer Stat Facts: Female Breast Cancer Subtype. Surveillance, Epidemiology, and End Results Program.
      Traditionally, HR+/HER2advanced or metastatic BC (ABC/MBC) was treated using endocrine therapies (eg, tamoxifen, fulvestrant, or aromatase inhibitors [AIs], including letrozole, anastrozole, and exemestane).
      National Comprehensive Cancer Network
      Clinical Practice Guidelines in Oncology. Breast Cancer (version 5.2021).
      ,
      • Cardoso F
      • Paluch-Shimon S
      • Senkus E
      • et al.
      5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5).
      In recent years, BC subtyping, the emergence of endocrine resistance, and the development of targeted agents have shifted treatment strategies toward personalized treatment and improved health outcomes for patients with ABC/MBC.
      • Ballinger TJ
      • Meier JB
      • Jansen VM.
      Current landscape of targeted therapies for hormone-receptor positive, HER2 negative metastatic breast cancer.
      Palbociclib,* the first cyclin-dependent kinase 4/6 inhibitor to be developed, has altered the treatment landscape since its approval by the US Food and Drug Administration for use in combination with AIs as initial endocrine-based therapy or with fulvestrant in postmenopausal women who previously received endocrine therapy.
      *Trademark: IbranceⓇ (Pfizer, New York, NY).
      Although randomized controlled studies provide crucial efficacy data for new treatments, real-world studies are needed to examine the effectiveness of medications in large, diverse patient populations treated in routine clinical practice. The multicountry Ibrance Real World Insights (IRIS) study aimed to fill the gap between clinical trials and real-world clinical practice in 13 countries. Several country-specific analyses have been conducted to date.
      • Waller J
      • Mitra D
      • Mycock K
      • et al.
      Real-world treatment patterns and clinical outcomes in patients receiving palbociclib for hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer in Argentina: The IRIS study.
      • Mycock K
      • Zhan L
      • Taylor-Stokes G
      • Milligan G
      • Mitra D.
      Real-world palbociclib use in HR+/HER2- advanced breast cancer in Canada: The IRIS study.
      • Taylor-Stokes G
      • Mitra D
      • Waller J
      • Gibson K
      • Milligan G
      • Iyer S
      Treatment patterns and clinical outcomes among patients receiving palbociclib in combination with an aromatase inhibitor or fulvestrant for HR+/HER2-negative advanced/metastatic breast cancer in real-world settings in the US: Results from the IRIS study.
      We now present a pooled analysis of data from all 13 countries participating in IRIS to improve understanding of treatment patterns, clinical characteristics, and outcomes in patients treated with palbociclib in the real-world setting. Real-world data may help inform physicians and health care stakeholders’ treatment decisions, especially those involving specific patient subgroups traditionally underrepresented in clinical studies.

      Patients and Methods

      Study Design

      IRIS was a retrospective medical record review study that used standardized methods to study cohorts of women treated with palbociclib-based regimens (ie, palbociclib plus an AI [P+AI] or palbociclib plus fulvestrant [P+F]) according to approved indications in 13 countries (Supplemental Table I) to provide insight into treatment patterns and outcomes in a large sample of patients.
      • Waller J
      • Mitra D
      • Mycock K
      • et al.
      Real-world treatment patterns and clinical outcomes in patients receiving palbociclib for hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer in Argentina: The IRIS study.
      • Mycock K
      • Zhan L
      • Taylor-Stokes G
      • Milligan G
      • Mitra D.
      Real-world palbociclib use in HR+/HER2- advanced breast cancer in Canada: The IRIS study.
      • Taylor-Stokes G
      • Mitra D
      • Waller J
      • Gibson K
      • Milligan G
      • Iyer S
      Treatment patterns and clinical outcomes among patients receiving palbociclib in combination with an aromatase inhibitor or fulvestrant for HR+/HER2-negative advanced/metastatic breast cancer in real-world settings in the US: Results from the IRIS study.
      Eligible physicians recruited from community and academic practices had a prespecified and sufficiently large caseload of patients with HR+/HER2ABC/MBC (Supplemental Table II). Patient eligibility criteria are given in Supplemental Table III. Briefly, patients were female and ≥18 years of age, had confirmed HR+/HER2ABC/MBC, were treated with palbociclib according to the drug license in the relevant country. Patients with current or prior enrollment in interventional clinical trials were excluded. To increase potential follow-up for clinical outcomes data, all patients initiated use of P+AI ≥6 months or P+F ≥3 months before the abstraction date. Patients therefore had the potential to have ≥6 months of follow-up but could have discontinued treatment within this period because of disease progression or for other reasons.
      The study was conducted in accordance with International Society for Pharmacoepidemiology recommendations and Guidelines for Good Pharmacoepidemiology Practices. The study protocol and statistical analysis plan were approved by the Western Institutional Review Board (A5481090).

      Data Source and Abstraction

      Each physician completed an electronic case report form by retrospectively abstracting medical record data for up to 16 sequentially selected patients who met the study inclusion criteria. Physicians were asked to consecutively sample patients’ records from an index date (defined as 60 days after the physician first prescribed P+AI or P+F) through the date of each patient's last available medical record, death, or date of record abstraction, whichever occurred first.
      Demographic and clinical characteristics were abstracted, such as age, race and ethnicity, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and metastatic site(s) at MBC diagnosis. Data were also collected on treatment characteristics (eg, starting doses and dose modifications) and reasons for palbociclib regimen changes or discontinuation. Clinical outcomes included objective response rate (ORR), clinical benefit rate (CBR), progression-free rate (PFR), and survival rate (SR) at various time points (Table I). Subgroup analyses were conducted on patients stratified according to age, race and ethnicity, ECOG PS, disease-free interval (defined as the time from the end of adjuvant endocrine therapy to the diagnosis of ABC/MBC), visceral disease, liver metastases, bone-only metastases, and previous lines of therapy.
      Table IClinical outcome definitions.
      Clinical OutcomeDefinition
      Clinical response
       Complete responseWhere complete response (ie, complete resolution of all visible disease) has been recorded at any time (no 24-week minimum)
       Partial responseWhere partial response (ie, partial reduction in size of visible disease in some or all areas without any areas of increase in visible disease) has been recorded at any time (no 24-week minimum)
       Stable disease ≥24 weeksPatient continued to receive palbociclib for a minimum of 24 weeks, without complete or partial response, death, treatment switch, or progression
       Stable disease <24 weeksStable disease recorded for initial response, with a subsequent progression recorded within <24 weeks or treatment switch for reason other than progression within <24 weeks or death without recorded progression within <24 weeks
       Progressive diseaseProgressive disease (ie, an increase in visible disease and/or presence of any new lesions) recorded for initial response without a subsequent partial or complete response recorded
      Derived clinical end points
       Objective response rateProportion of patients achieving a complete or partial response as assessed by the physician and reported in the patient records; radiologic confirmation was not required, and no criteria to reevaluate were provided
       Clinical benefit rateProportion of patients who achieved a complete or partial response or had stable disease for ≥24 weeks as assessed by the physician
       Progression-free rateProportion of patients with no evidence of progression or death at 6, 12, 18, and 24 months
       Survival rateProportion of patients alive at 6, 12, 18, and 24 months

      Statistical Analysis

      All analyses were descriptive, and no formal hypothesis was tested. Time-to-event outcomes were calculated using Kaplan-Meier estimates at 6, 12, 18, and 24 months. The CBR data were censored for patients with <24 weeks of data still receiving palbociclib with no evidence of complete response (CR), partial response (PR), or stable disease. The 95% CIs were calculated using the Clopper-Pearson method for categorical variables and the t distribution for continuous variables. Analyses were conducted using Stata statistical software, version 17.0 (StataCorp LLC, College Station, Texas), and missing data were not imputed.

      Results

      Physician and Patient Demographic Characteristics

      Between July 2017 and May 2020 (Supplemental Table IV), 417 physicians abstracted data for 2954 patients (Supplemental Table V). Physician types included medical or clinical oncologists (n = 316 [75.8%]), oncologist hematologists (n = 42 [10.1%]), and gynecologists (n = 27 [6.5%]). Most physicians had treated >20 patients with palbociclib as indicated (n = 211 [50.8%]); 121 physicians (29.2%) had treated 11 to 20 patients, and 83 physicians (20.0%) had treated 5 to 10 patients.
      Patient characteristics are summarized in Tables II and III. Notably, 1415 patients (47.9%) were ≥65 years of age, 369 patients (12.5%) had an ECOG PS at initiation of ≥2, and 835 patients (28.3%) were of races other than White. Visceral disease was present in 1242 patients (48.3%) with metastases; 1120 patients (43.6%) had bone-only metastases, and 339 patients (13.2%) had liver involvement only.
      Table IIDemographic characteristics of patients in the Ibrance Real World Insights study overall, by regimen, and by line of therapy.
      Data are presented as number (percentage) of patients unless otherwise indicated.
      CharacteristicOverall (N = 2954)Palbociclib and AIPalbociclib and Fulvestrant
      All (n = 1748)First Line (n = 1621)Second Line or Later (n = 127)All (n = 1206)First Line (n = 552)Second Line or Later (n = 654)
      Age at palbociclib therapy initiation, y
      Mean (SD)63.3 (10.5)63 (10.5)63.1 (10.6)62 (10.0)63.7 (10.4)62.6 (10.5)64.5 (10.2)
      Median (range)64 (29–90)64 (29–90)64 (29–90)63 (34–90)64 (30–90)63 (30–90)65 (32–90)
      Age group, y
       <651539 (52.1)917 (52.5)844 (52.1)73 (57.5)622 (51.6)311 (56.3)311 (47.6)
       ≥651415 (47.9)831 (47.5)777 (47.9)54 (42.5)584 (48.4)241 (43.7)343 (52.4)
      Race and ethnicity
       White non-Hispanic2119 (71.7)1257 (71.9)1186 (73.2)71 (55.9)862 (71.5)412 (74.6)450 (68.8)
       Black non-Hispanic156 (5.2)99 (5.6)92 (5.7)7 (5.5)57 (4.8)16 (2.9)41 (6.3)
       Hispanic/Latino214 (7.2)132 (7.6)120 (7.4)12 (9.4)82 (6.8)21 (3.8)61 (9.3)
       Middle Eastern77 (2.6)42 (2.4)38 (2.3)4 (3.1)35 (2.9)12 (2.2)23 (3.5)
       Asian284 (9.6)161 (9.2)132 (8.1)29 (22.9)123 (10.2)67 (12.1)56 (8.5)
       Other
      Includes 15 Native Americans, 81 of mixed race, and 8 of other races and/or ethnicities (not specified).
      104 (3.5)57 (3.3)53 (3.3)4 (3.1)47 (3.9)24 (4.4)23 (3.5)
      AI = aromatase inhibitor.
      low asterisk Data are presented as number (percentage) of patients unless otherwise indicated.
      Includes 15 Native Americans, 81 of mixed race, and 8 of other races and/or ethnicities (not specified).
      Table IIIClinical characteristics of patients in the Ibrance Real World Insights study overall, by regimen, and by line of therapy.
      Data are presented as number (percentage) of patients unless otherwise indicated.
      CharacteristicOverallPalbociclib + AIPalbociclib + Fulvestrant
      AllFirst LineSecond Line or LaterAllFirst LineSecond Line or Later
      Menopausal status at study entry
       Perimenopausal39 (1.3)16 (0.9)14 (0.9)2 (1.6)23 (1.9)17 (3.1)6 (0.9)
       Premenopausal28 (0.9)00028 (2.3)6 (1.1)22 (3.4)
       Natural menopause2623 (88.8)1561 (89.3)1450 (89.5)111 (87.4)1062 (88.1)489 (88.6)573 (87.6)
       Menopause induced by surgery106 (3.6)66 (3.8)58 (3.6)8 (6.3)40 (3.3)17 (3.1)23 (3.5)
       Menopause induced by LHRH suppression158 (5.3)105 (6.0)99 (6.1)6 (4.7)53 (4.4)23 (4.2)30 (4.6)
      ECOG PS at initiation
       01092 (37.0)684 (39.1)640 (39.5)44 (34.6)408 (33.8)198 (35.9)210 (32.1)
       11448 (49.0)821 (47.0)760 (46.9)61 (48.0)627 (52.0)282 (51.1)345 (52.8)
       ≥2369 (12.5)220 (12.6)201 (12.4)19 (15.0)149 (12.3)52 (9.4)97 (13.6)
       Unknown/not assessed45 (1.5)23 (1.3)20 (1.2)3 (2.4)22 (1.8)20 (3.6)2 (0.3)
      Disease stage at study entry
       Locoregionally advanced (stage IIIb, IIIc)383 (13.0)210 (12.0)186 (11.5)24 (18.9)173 (14.3)92 (16.7)81 (12.4)
       Metastatic (stage IV)2571 (87.0)1538 (88.0)1435 (88.5)103 (81.1)1033 (85.7)460 (83.3)573 (87.6)
      Occurrence of breast cancer
       Recurrent1604 (54.3)574 (32.8)517 (31.9)57 (44.9)1030 (85.4)538 (97.5)492 (75.2)
       De novo1350 (45.7)1174 (67.2)1104 (68.1)70 (55.1)176 (14.6)14 (2.5)162 (24.8)
      Disease-free interval
       No previous AET1679 (59.6)1343 (77.7)1242 (77.5)101 (80.2)336 (30.9)20 (4.3)316 (50.6)
       ≤12 mo757 (26.9)176 (10.2)161 (10)15 (11.9)581 (53.5)374 (81.1)207 (33.1)
       >12 mo379 (13.5)210 (12.1)200 (12.5)10 (7.9)169 (15.6)67 (14.5)102 (16.3)
      Metastatic sites
       No. of patients2571153814351031033460573
       Visceral1242 (48.3)765 (49.7)711 (49.5)54 (52.4)477 (46.2)225 (48.9)252 (44.0)
       Lung involvement842 (32.7)532 (34.6)492 (34.3)40 (38.8)310 (30.0)136 (29.6)174 (30.4)
       Liver involvement491 (19.1)294 (19.1)272 (19.0)22 (21.4)197 (19.1)100 (21.7)97 (16.9)
       Brain63 (2.5)42 (2.7)38 (2.6)4 (3.9)21 (2.0)11 (2.4)10 (1.7)
       Lung842 (32.7)532 (34.6)492 (34.3)40 (38.8)310 (30.0)136 (29.6)174 (30.4)
       Ovary31 (1.2)24 (1.6)22 (1.5)2 (1.9)7 (0.7)2 (0.4)5 (0.9)
       Liver only339 (13.2)192 (12.5)183 (12.8)9 (8.7)147 (14.2)78 (17.0)69 (12.0)
       Nonvisceral1329 (51.7)773 (50.3)724 (50.5)49 (47.6)556 (53.8)235 (51.1)321 (56.0)
       Bone1777 (69.1)1087 (70.7)1018 (70.9)69 (67.0)690 (66.8)266 (57.8)424 (74.0)
       Lymph nodes877 (34.1)533 (34.7)494 (34.4)39 (37.9)344 (33.3)157 (34.1)186 (32.4)
       Skin or soft tissue225 (8.8)151 (9.8)142 (9.9)9 (8.7)74 (7.2)29 (6.3)45 (7.9)
       Bone only1120 (43.6)671 (43.6)631 (44.0)40 (38.8)449 (43.5)172 (37.4)277 (48.3)
      Prior therapy for EBC
       No. of patients1604574517571030538492
       Surgery1286 (80.2)502 (87.5)462 (89.4)40 (70.2)784 (76.1)413 (76.8)371 (75.4)
       Radiotherapy1111 (69.3)431 (75.1)393 (76.0)38 (66.7)680 (66.0)337 (62.6)343 (69.7)
       Neoadjuvant treatment151 (9.4)59 (10.3)52 (10.1)7 (12.3)92 (8.9)44 (8.2)48 (9.8)
       Adjuvant chemotherapy603 (37.6)284 (49.5)255 (49.3)29 (50.9)319 (31.0)140 (26.0)179 (36.4)
       Adjuvant endocrine therapy1275 (79.5)405 (70.6)379 (73.3)26 (45.6)870 (84.5)532 (98.9)338 (68.7)
      Prior therapy for ABC or MBC
       No. of patients781127127654654
       Targeted therapy49 (6.3)1 (0.8)1 (0.8)48 (7.3)48 (7.3)
       Endocrine therapy635 (81.3)54 (42.5)54 (42.5)581 (88.8)581 (88.8)
       Chemotherapy157 (20.1)73 (57.5)73 (57.5)84 (12.8)84 (12.8)
       Other17 (2.2)8 (6.3)8 (6.3)9 (1.4)9 (1.4)
      Lines of treatment for ABC or MBC
       No. of patients2954174816211271206552654
       11919 (65.0)1443 (82.6)1443 (89)0476 (39.5)476 (86.2)0
       2807 (27.3)233 (13.3)139 (8.6)94 (74.0)574 (47.6)65 (11.8)509 (77.8)
       ≥3228 (7.7)72 (4.1)39 (2.4)33 (25.9)156 (12.9)11 (2.0)145 (12.2)
      Palbociclib follow-up time from initiation, mo
       No. of patients2954174816211271206552654
       Mean (SD)11.3 (6.8)12.3 (6.5)12.3 (6.5)13.0 (7.0)9.8 (6.9)9.1 (6.5)10.5 (7.1)
       Median (range)9.1 (3.0–37.9)10.0 (5.9–37.9)10.0 (5.9–37.9)10.2 (6.0–35.6)7.4 (3.0–37.4)7.0 (3.0–36.7)7.7 (3.0–37.4)
      ABC = advanced breast cancer; AET = adjuvant endocrine therapy; AI = aromatase inhibitor; EBC = early breast cancer; ECOG PS = Eastern Cooperative Oncology Group performance status; LHRH, luteinizing hormone-releasing hormone; MBC = metastatic breast cancer.
      low asterisk Data are presented as number (percentage) of patients unless otherwise indicated.

      Treatment Patterns in the Pooled Population

      In total, 1748 patients (59.2%) received P+AI (1621 first line and 127 second or later line), and 1206 patients (40.8%) received P+F (552 first line and 654 second or later line). The median follow-up time for patients in the P+AI group was 10.0 months (mean [SD], 12.6 [6.5] months); the median follow-up time for P+F was 7.4 months (mean [SD], 9.8 [6.9] months).
      Most patients (n = 2563 [86.8%]) began treatment with palbociclib at the recommended dose of 125 mg/d (Table IV). Physicians reported toxic effects and age as the most common reasons (64.1% and 41.6%, respectively) for prescribing patients a lower dose. A total of 466 patients (15.8%) had ≥1 dose reductions, most reported as a result of adverse or toxic effects (444 of 466 patients [95.3%]). At the time of data abstraction, treatment was ongoing in 2348 patients (79.5%) and had been discontinued in 606 patients (20.5%). The most common reason for discontinuation was disease progression (448 of 566 patients [79.2%]); 31 patients (5.5%) discontinued treatment because of adverse or toxic effects.
      Table IVClinical treatment patterns and dose adjustments.
      Data are presented as number (percentage) unless otherwise indicated.
      DoseOverallPalbociclib + AIPalbociclib + fulvestrant
      AllFirst LineSecond Line or LaterAllFirst LineSecond Line or Later
      Combination partner, AI
       No. of patients142914291316113
       Anastrozole254 (17.8)254 (17.8)231 (17.6)23 (20.4)
       Exemestane103 (7.2)103 (7.2)87 (6.6)16 (14.2)
       Letrozole1072 (75.0)1072 (75.0)998 (75.8)74 (65.5)
      Line of therapy palbociclib received
       No. of patients2954174816211271206552654
       12173 (73.6)1621 (92.7)1621 (100.0)0552 (45.8)552 (100.0)0
       2678 (23.0)111 (6.4))0111 (87.4)567 (47.0)0567 (86.7)
       ≥3103 (3.5)16 (0.9)016 (12.6)87 (7.2)087 (13.3)
      Starting dose of palbociclib, mg/d
       No. of patients2954174816211271206552654
       1252563 (86.8)1538 (88)1432 (88.3)106 (83.5)1025 (85.0)479 (86.8)546 (83.5)
       100310 (10.5)166 (9.5)149 (9.2)17 (13.4)144 (11.9)57 (10.3)87 (13.3)
       7581 (2.7)44 (2.5)40 (2.5)4 (3.1)37 (3.1)16 (2.9)21 (3.2)
      Reason for starting palbociclib dose <125 mg/d
       No. of patients2091139914964947
       To avoid toxic effects134 (64.1)80 (70.8)71 (71.7)9 (64.3)54 (56.3)27 (55.1)27 (57.4)
       ECOG PS45 (21.5)24 (21.2)21 (21.2)3 (21.4)21 (21.9)12 (24.5)9 (19.1)
       Age87 (41.6)47 (41.6)41 (41.4)6 (42.9)40 (41.7)19 (38.8)21 (44.7)
       Presence of comorbidities23 (11.0)14 (12.4)14 (14.1)09 (9.4)3 (6.1)6 (12.8)
       Patient request22 (10.5)10 (8.8)10 (10.1)012 (12.5)8 (16.3)4 (8.5)
       Other34 (16.3)19 (16.8)11 (11.1)8 (57.1)15 (15.6)4 (8.2)11 (23.4)
      Dose reduction (any starting dose)
       No. of patients2954174816211271206552654
       Dose reduction466 (15.8)307 (17.6)288 (17.8)19 (15.0)159 (13.2)75 (13.6)84 (12.8)
      Reason for dose reduction
       No. of patients466307288191597584
       Adverse or toxic effects444 (95.3)292 (95.1)274 (95.1)18 (94.7)152 (95.6)71 (94.7)81 (96.4)
       Patient request29 (6.2)19 (6.2)19 (6.6)010 (6.3)6 (8.0)4 (4.8)
       Other8 (1.7)6 (2.0)5 (1.7)1 (5.3)2 (1.3)1 (1.3)1 (1.2)
      Palbociclib treatment status
       No. of patients2954174816211271206552654
       Treatment ongoing2348 (79.5)1403 (80.3)1315 (81.1)88 (69.3)945 (78.4)439 (79.5)506 (77.4)
       Treatment discontinued606 (20.5)345 (19.7)306 (18.9)39 (30.7)261 (21.6)113 (20.5)148 (22.6)
      Reason for discontinuation
      Reason unknown for 40 patients because partner therapy in regimen is ongoing.
       No. of patients5663342953923293139
       PD following initial control/response359 (63.4))209 (62.6)186 (63.1)23 (59)150 (64.7)53 (57)97 (69.8)
       PD without initial control/response89 (15.7)52 (15.6)44 (14.9)8 (20.5)37 (15.9)16 (17.2)21 (15.1)
       Treatment cost10 (1.8)4 (1.2)2 (0.7)2 (5.1)6 (2.6)4 (4.3)2 (1.4)
       Pill burden/compliance10 (1.8)7 (2.1)7 (2.4)03 (1.3)3 (3.2)0
       Adverse or effects31 (5.5)18 (5.4)16 (5.4)2 (5.1)13 (5.6)7 (7.5)6 (4.3)
       Patient request43 (7.6)31 (9.3)31 (10.5)012 (5.2)7 (7.5)5 (3.6)
       Other22 (3.9)15 (4.5)12 (4.1)3 (7.7)7 (3.0)3 (3.2)4 (2.9)
      AI = aromatase inhibitor; ECOG PS = Eastern Cooperative Oncology Group performance status; PD = progressive disease.
      low asterisk Data are presented as number (percentage) unless otherwise indicated.
      Reason unknown for 40 patients because partner therapy in regimen is ongoing.

      Clinical Outcomes in the Pooled Sample Population by Treatment Received

      Palbociclib Plus Aromatase Inhibitors

      Overall, 257 of 1734 evaluable patients (14.8%) treated with P+AI had a CR as their best response, and 1138 (65.6%) achieved a PR for an ORR of 80.4% (Table V). Kaplan-Meier estimates of 12- and 24-month PFRs were 87.5% and 65.7%, respectively; 12- and 24-month SRs were 96.4% and 90.3%, respectively. The ORR was 80.9% in patients treated with P+AI in the first line and 75.2% in those treated in the second or later lines. The CBR was 95.8% in patients treated with P+AI in the first line and 95.2% in those treated in the second or later lines. Twelve-month PFRs were 88.5% and 73.9% in the first-line and second-line or later subgroups; 12-month SRs were 96.8% and 91.5%, respectively. Twenty-four-month PFRs were 65.7% and 62.5% in the first-line and second-line or later subgroups; 24-month SRs were 90.8% and 84.6%, respectively. Kaplan-Meier curves for the PFRs and SRs are shown in Supplemental Figure 1.
      Table VClinical response to palbociclib treatment by line of therapy.
      Data are presented number (percentage) of patients unless otherwise indicated.
      Palbociclib + AIPalbociclib + fulvestrant
      OverallAllFirst LineSecond Line or LaterAllFirst LineSecond Line or Later
      Best response
       No. of patients2898173416091251164533631
       Complete response372 (12.8)257 (14.8)244 (15.2)13 (10.4)115 (9.9)64 (12.0)51 (8.1)
       Partial response1894 (65.4)1138 (65.6)1057 (65.7)81 (64.8)756 (64.9)326 (61.2)430 (68.1)
       Stable disease ≥24 weeks406 (14)265 (15.3)240 (14.9)25 (20.0)141 (12.1)68 (12.8)73 (11.6)
       Stable disease <24 weeks60 (2.1)27 (1.6)24 (1.5)3 (2.4)33 (2.8)14 (2.6)19 (3)
       Stable disease (censored)94 (3.2)00094 (8.1)50 (9.4)44 (7.0)
       Progressive disease72 (2.5)47 (2.7)44 (2.7)3 (2.4)25 (2.1)11 (2.1)14 (2.2)
       Objective response rate2266 (78.2)1395 (80.4)1301 (80.9)94 (75.2)871 (74.8)390 (73.2)481 (76.2)
      Clinical benefit rate
       Upper bound (including SD [censored])2766 (95.4)1660 (95.7)1541 (95.8)119 (95.2)1106 (95.0)508 (95.3)598 (94.8)
       Lower bound (including SD [censored])2672 (92.2)1660 (95.7)1541 (95.8)119 (95.2)1012 (86.9)458 (85.9)554 (87.8)
      Progression-free survival rate, %
       No. of patients2949174316171261206552654
       6 months95.796.596.892.994.395.193.6
       12 months84.787.588.573.979.283.376.2
       18 months70.975.576.462.562.168.458.0
       24 months60.965.765.762.551.253.550.6
      Overall survival rate, %
       No. of patients2904173216061261172532640
       6 months98.899.299.299.298.399.397.5
       12 months96.196.496.891.595.596.794.7
       18 months92.493.193.489.191.395.089.2
       24 months89.490.390.884.687.992.884.9
      AI = aromatase inhibitor.
      low asterisk Data are presented number (percentage) of patients unless otherwise indicated.

      Palbociclib Plus Fulvestrant

      Overall, 115 patients (9.9%) treated with P+F had a CR as their best response and 756 (64.9%) achieved a PR, for an ORR of 74.8%. Kaplan-Meier estimates of 12- and 24-month PFRs were 79.2% and 51.2%, respectively; 12- and 24-month SRs were 95.5% and 87.9%. The ORR was 73.2% in patients treated in the first line and 76.2% in those treated in the second or later lines. The CBR was 95.3% in patients treated with P+F in the first line and 94.8% in those treated in the second or later lines. Twelve-month PFRs were 83.3% and 76.2% in the first-line and second-line or later subgroups, respectively; 12-month SRs were 96.7% and 94.7%, respectively. Twenty-four-month PFRs were 53.5% and 50.6% in the first-line and second-line or later subgroups, respectively; 24-month SRs were 92.8% and 84.9%, respectively.

      Clinical Outcomes in Patient Subgroups

      The 12-month PFRs for most subgroups were clustered around each regimen's respective overall rate (87.5% for P+AI and 79.2% for P+F). The PFR trends were generally similar in patients treated with P+AI and P+F (Figure 1); however, some exceptions were observed. Among the ethnic subgroups, the 12-month PFR was lowest in Asian patients (76.4% and 74.6% for P+AI and P+F, respectively); Black patients who received P+F had the highest 12-month PFR (92.1%). In the ECOG PS subgroups, the 12-month PFR was lowest in those with ECOG PS ≥2 (73.6% and 72.8% for P+AI and P+F, respectively). In the prior treatment lines subgroups, the 12-month PFR was lowest in patients with 2 prior lines of treatment in the P+AI cohort (72.0%) and in patients with ≥3 prior lines of treatment in the P+F cohort (58.3%). As with PFR, there was some variation in 12-month SRs. Among the ethnic subgroups, the 12-month SR was lower in Hispanic versus White patients receiving P+AI (89.2% v 97.6%, respectively). In the ECOG PS subgroups, the 12-month SR was lowest in patients with ECOG PS ≥2 (81.6% and 75.0% for P+AI and P+F, respectively). In the visceral disease status subgroups, the 12-month PFR was lower in P+AI patients with visceral versus nonvisceral disease (93.7% vs 98.7%, respectively).
      Figure 1
      Figure 1Twelve-month progression-free rate by subgroup in (A) patients treated with palbociclib plus an aromatase inhibitor and (B) palbociclib plus fulvestrant. Other race and ethnicity includes Native American, mixed race, and other (not specified). Dotted lines represent rates in the overall cohorts. ABC = advanced breast cancer; ECOG PS = Eastern Cooperative Oncology Group performance status; MBC = metastatic breast cancer; NH, non-Hispanic.
      Overall trends were similar when 24-month PFRs and SRs were examined by patient subgroups, with some variation according to patient ethnicity and ECOG PS (Supplemental Figures 2 and 3) (Figure 2).
      Figure 2
      Figure 2Twelve-month survival rate by subgroup in (A) patients treated with palbociclib plus an aromatase inhibitor and (B) palbociclib plus fulvestrant. Other race and ethnicity includes Native American, mixed race, and other (not specified). Dotted lines represent rates in the overall cohorts. ABC = advanced breast cancer; ECOG PS = Eastern Cooperative Oncology Group performance status; MBC = metastatic breast cancer; NH = non-Hispanic.

      Discussion

      When considered alongside the results of randomized clinical trials, real-world data can inform physicians, payers, and other health care stakeholders and assist in prescriber treatment decisions. The IRIS study investigated treatment patterns and outcomes in 2954 patients with HR+/HER2 ABC/MBC in 13 countries to address the relative lack of real-world evidence for palbociclib in the MBC setting. The current pooled analysis of data indicates that use of palbociclib in combination with AIs or fulvestrant in the first or later lines was associated with favorable outcomes and low rates of dose adjustments in patients.
      In this pooled analysis, an overall ORR of 78% was observed, with a CR of >10% and a CBR of 92%. The ORR in the P+AI first-line cohort was 81% and the CBR was 96%, results that compare favorably with data from the PALOMA-2 study (ORR, 42%; CBR, 67%).
      • Finn RS
      • Martin M
      • Rugo HS
      • et al.
      Palbociclib and letrozole in advanced breast cancer.
      Similarly, the results from the P+F second-line or later cohort (ORR, 76%; CBR, 95%) compare favorably with efficacy data from PALOMA-3 (ORR, 19%; CBR 67%).
      • Cristofanilli M
      • Turner NC
      • Bondarenko I
      • et al.
      Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial.
      Although not directly comparable due to differences in study designs (eg, PALOMA used RECIST [Response Evaluation Criteria in Solid Tumours] criteria and IRIS did not) and populations, the IRIS real-world findings generalize to the global population, closing the efficacy-effectiveness gap by complementing the internally valid findings of clinical trials.
      More comparable with the IRIS data perhaps are results from other real-world studies examining palbociclib in patients with ABC/MBC, including the MARIA study in Italian and German patients
      • De Laurentiis M
      • Harbeck N
      • Law E
      • et al.
      Abstract P3-11-25: Real-world treatment patterns and clinical outcomes among women with HR+/HER2- advanced or metastatic breast cancer treated in real-world settings in Italy and Germany.
      and the US Flatiron Health database analysis.
      • DeMichele A
      • Cristofanilli M
      • Brufsky A
      • 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.
      In an interim analysis of the MARIA (MRD Assay Evaluates Recurrence and Response via a Tumor Informed Assessment) study, 12-month PFRs were 80% in patients treated with first-line P+AI and 68% in those receiving first-line P+F,
      • De Laurentiis M
      • Harbeck N
      • Law E
      • et al.
      Abstract P3-11-25: Real-world treatment patterns and clinical outcomes among women with HR+/HER2- advanced or metastatic breast cancer treated in real-world settings in Italy and Germany.
      similar to the PFRs of 88% and 79%, respectively, observed in the present study. Likewise, the Flatiron Health database study reported 24-month overall survival rates of 78% for patients treated with palbociclib and letrozole,
      • DeMichele A
      • Cristofanilli M
      • Brufsky A
      • 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.
      closer to the 90% 24-month SR observed in patients treated with P+AI in the present study than the results of the PALOMA-2 study.
      Treatment patterns observed in this pooled analysis of IRIS data reflect previous reports from individual country cohorts.
      • Waller J
      • Mitra D
      • Mycock K
      • et al.
      Real-world treatment patterns and clinical outcomes in patients receiving palbociclib for hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer in Argentina: The IRIS study.
      • Mycock K
      • Zhan L
      • Taylor-Stokes G
      • Milligan G
      • Mitra D.
      Real-world palbociclib use in HR+/HER2- advanced breast cancer in Canada: The IRIS study.
      • Taylor-Stokes G
      • Mitra D
      • Waller J
      • Gibson K
      • Milligan G
      • Iyer S
      Treatment patterns and clinical outcomes among patients receiving palbociclib in combination with an aromatase inhibitor or fulvestrant for HR+/HER2-negative advanced/metastatic breast cancer in real-world settings in the US: Results from the IRIS study.
      Some differences were observed between PALOMA and IRIS. The proportion of patients with liver metastases was low in IRIS (13%), somewhat lower than the 40% of patients with liver involvement in the PALOMA-3 study.
      • Cristofanilli M
      • Turner NC
      • Bondarenko I
      • et al.
      Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial.
      In IRIS, >85% of patients started treatment with 125 mg/d and dose-reduction rates were low, regardless of line of therapy. This low dose-reduction rate may be a result of the high ORR, low incidence of adverse effects, and favorable toxicity profile of palbociclib. Although many therapies used to treat cancer are limited by their toxicity profile, the IRIS study found that palbociclib is a relatively tolerable treatment option for patients around the globe and may serve as a viable treatment alternative for patients unable to tolerate chemotherapy.
      A key feature of this study was the subgroup analysis, whereby the effectiveness of palbociclib was measured in patients categorized according to age, race and ethnicity, disease-free interval, ECOG PS, disease status, and prior therapy. In line with the results of the subgroup analysis in the Flatiron Health database study,
      • DeMichele A
      • Cristofanilli M
      • Brufsky A
      • 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.
      the current analysis indicates that palbociclib was similarly effective in the majority of subgroups examined.
      In their review of Phase III studies, Kouzy et al
      • Kouzy R
      • Jaoude JA
      • Mainwaring W
      • et al.
      Performance status restriction in phase III cancer clinical trials.
      reported that 88% of Phase III cancer studies listed on ClinicalTrials.gov between 2003 and 2018 specified an upper PS restriction cutoff and 96% of 238,213 patients had an ECOG PS of 0 or 1. Similarly, Keim-Malpass et al
      • Keim-Malpass J
      • Alcalá HE
      Association of age at cancer diagnosis and clinical trial participation.
      reported that only 5% of 3829 patients aged ≥65 years surveyed in the Behavioral Risk Factor Surveillance System had ever participated in a clinical study related to their cancer care and that adults aged ≥65 years had significantly lower odds of trial participation than those aged <18 years (odds ratio, 0.14; 95% CI, 0.06–0.35). Given that the IRIS study was not restricted by age or PS, a considerable number patients aged ≥65 years or with an ECOG PS ≥2 were included in this analysis, providing data for commonly underrepresented populations. In fact, 48% of patients in the IRIS program were aged ≥65 years and 28% had an ECOG PS of ≥2. When considering ECOG PS, the PFR was worst at 12 months in patients with ECOG PS ≥2 who were treated with P+AI, but this was not true for 24-month PFRs. Furthermore, our data suggest that palbociclib-based regimens were similarly effective in older and younger patients, which was unexpected. The rationale for this phenomenon is likely multifactorial but may be in part due to tailoring of doses to accommodate older patients. Notably, many of the patients who started treatment at a lower dose than recommended did so because of their age.
      Some differences were observed in the 12-month PFR according to race and ethnicity as well as treatment received. Black patients receiving P+AI had worse 12-month PFRs than White patients. In contrast, Black patients receiving P+F had better 12- and 24-month PFRs than White patients. Asian patients in the P+AI group had the worst 12- and 24-month PFRs but better than mean 24-month PFRs if receiving P+F. At 12 and 24 months, the SRs were largely similar across all ethnicity groups.
      The 12-month PFR results from the P+AI Asian subgroup were comparable to data from a real-world analysis of 145 patients receiving palbociclib combinations across 8 institutions in Korea.
      • Lee J
      • Park HS
      • Won HS
      • et al.
      Real-world clinical data of palbociclib in Asian metastatic breast cancer patients: Experiences from eight institutions.
      In that study, patients treated with palbociclib and letrozole had a 12-month PFR of 75%, similar to the Asian P+AI cohort in IRIS. Conversely, patients treated with P+F had a 12-month PFR of 33%, considerably lower than the 12-month PFR of 76% observed in Asian P+F-treated patients in IRIS.
      Although this real-world study provides valuable insights into the demographic and clinical characteristics of patients in clinical practice, such as palbociclib treatment patterns, dose adjustments, and reasons for discontinuation, some limitations of the study should be considered. This was a descriptive study, limiting the robustness of the findings in the absence of statistical tests. As with studies of this nature, selection bias may have resulted from the fact that only physicians willing to participate were included. This was mitigated by recruiting physicians across a range of geographic regions and treatment settings and by asking physicians to sequentially select consecutive patients in line with the index date. Data were pooled across heterogenous groups of patients, with the inherent implications of such pooling. The follow-up time was relatively short compared with some clinical studies; however, this study provided an insight into the demographic and clinical characteristics of patients receiving palbociclib in the real-world treatment setting, relatively soon after its introduction into clinical practice.

      Conclusions

      The IRIS study program has provided in-depth real-world evidence on treatment patterns and clinical outcomes associated with palbociclib in multiple countries. Data such as these are increasingly used by a variety of stakeholders, including prescribers, to shed light on global treatment patterns and clinical outcomes among specific patient subgroups in whom data may be scarce. These findings accompany the results of the randomized PALOMA-2 and PALOMA-3 studies and support the use of palbociclib in the broad range of patients encountered in the real-world setting. Future research with longer follow-up periods is needed to capture median progression-free and survival outcomes.

      Acknowledgments

      Medical writing and editorial assistance were provided by Deirdre Carman, PhD, of Alispera Communications Ltd (Cheshire, UK), funded by Pfizer Inc. Author contributions are as follows: conception and design: Debanjali Mitra, Katie Mycock, Gavin Taylor-Stokes; Collection and assembly of data: Debanjali Mitra, Katie Mycock, Gavin Taylor-Stokes, Christian Atkinson; data analysis and interpretation: all authors; manuscript writing: all authors; final approval of manuscript: all authors; accountable for all aspects of the work: all authors.

      Declaration of Interest

      Katie Mycock is an employee of Adelphi Real World and paid consultant to Pfizer in connection with the development of this manuscript. Kent A. Hanson is funded by the UIC/Pfizer Health Economics and Outcomes Research Fellowship (2020-2022). Gavin Taylor-Stokes is an employee of Adelphi Real World and paid consultant to Pfizer in connection with the development of this manuscript. Gary Milligan is an employee of Adelphi Real World and paid consultant to Pfizer in connection with the development of this manuscript. Christian Atkinson is an employee of Adelphi Real World and paid consultant to Pfizer in connection with the development of this manuscript. Debanjali Mitra is an employee and stockholder in Pfizer Inc. Salena Preciado is an employee of Pfizer Inc at the time of the study. Ernest H. Law is an employee and stockholder in Pfizer Inc. The authors have indicated that they have no other conflicts of interest regarding the content of this article.

      Funding Sources

      Pfizer supported the study in conception and design, with collection and assembly of the data, analyzing and interpreting the data, and the writing and approval of the manuscript.

      Appendix. Supplementary materials

      References

        • Sung H
        • Ferlay J
        • Siegel RL
        • et al.
        Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.
        CA Cancer J. Clin. 2021; 71: 209-249
        • National Cancer Institute
        Cancer Stat Facts: Female Breast Cancer. Surveillance, Epidemiology, and End Results Program.
        2021
        • National Cancer Institute
        Cancer Stat Facts: Female Breast Cancer Subtype. Surveillance, Epidemiology, and End Results Program.
        2019 (–2020)
        • National Comprehensive Cancer Network
        Clinical Practice Guidelines in Oncology. Breast Cancer (version 5.2021).
        2021
        • Cardoso F
        • Paluch-Shimon S
        • Senkus E
        • et al.
        5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5).
        Ann Oncol. 2020; 31: 1623-1649
        • Ballinger TJ
        • Meier JB
        • Jansen VM.
        Current landscape of targeted therapies for hormone-receptor positive, HER2 negative metastatic breast cancer.
        Frontiers Oncol. 2018; 8: 308
        • Waller J
        • Mitra D
        • Mycock K
        • et al.
        Real-world treatment patterns and clinical outcomes in patients receiving palbociclib for hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer in Argentina: The IRIS study.
        J Glob Oncol. 2019; 5Jgo1800239
        • Mycock K
        • Zhan L
        • Taylor-Stokes G
        • Milligan G
        • Mitra D.
        Real-world palbociclib use in HR+/HER2- advanced breast cancer in Canada: The IRIS study.
        Curr. Oncol. 2021; 28: 678-688
        • Taylor-Stokes G
        • Mitra D
        • Waller J
        • Gibson K
        • Milligan G
        • Iyer S
        Treatment patterns and clinical outcomes among patients receiving palbociclib in combination with an aromatase inhibitor or fulvestrant for HR+/HER2-negative advanced/metastatic breast cancer in real-world settings in the US: Results from the IRIS study.
        Breast. 2019; 43: 22-27
        • Finn RS
        • Martin M
        • Rugo HS
        • et al.
        Palbociclib and letrozole in advanced breast cancer.
        N Engl J Med. 2016; 375: 1925-1936
        • Cristofanilli M
        • Turner NC
        • Bondarenko I
        • et al.
        Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial.
        Lancet Oncol. 2016; 17: 425-439
        • De Laurentiis M
        • Harbeck N
        • Law E
        • et al.
        Abstract P3-11-25: Real-world treatment patterns and clinical outcomes among women with HR+/HER2- advanced or metastatic breast cancer treated in real-world settings in Italy and Germany.
        Cancer Res. 2020; 80 (P3-11-25-P13-11-25)
        • DeMichele A
        • Cristofanilli M
        • Brufsky A
        • 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
        • Kouzy R
        • Jaoude JA
        • Mainwaring W
        • et al.
        Performance status restriction in phase III cancer clinical trials.
        J. Clin. Oncol. 2020; 38 (–2059): 2059
        • Keim-Malpass J
        • Alcalá HE
        Association of age at cancer diagnosis and clinical trial participation.
        JAMA Network Open. 2021; 4 (–e2037573)e2037573
        • Lee J
        • Park HS
        • Won HS
        • et al.
        Real-world clinical data of palbociclib in Asian metastatic breast cancer patients: Experiences from eight institutions.
        Cancer Res. Treat. 2021; 53: 409-423