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Progression-free Survival Outcome Is Independent of Objective Response in Patients With Estrogen Receptor-positive, Human Epidermal Growth Factor Receptor 2-negative Advanced Breast Cancer Treated With Palbociclib Plus Letrozole Compared With Letrozole: Analysis From PALOMA-2

Open AccessPublished:September 04, 2019DOI:https://doi.org/10.1016/j.clbc.2019.08.009

      Abstract

      Background

      In PALOMA-2, palbociclib + letrozole significantly prolonged progression-free survival (PFS) versus placebo + letrozole in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2) advanced breast cancer (ABC). We investigated clinical outcomes of patients who achieved or did not achieve a confirmed objective response (OR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (data cutoff: May 31, 2017).

      Patients and Methods

      Postmenopausal patients untreated for ER+/HER2 ABC were randomized 2:1 to palbociclib + letrozole or placebo + letrozole. Median PFS, median duration of OR, baseline characteristics, and palbociclib exposure were compared in patients with or without OR by treatment arm.

      Results

      In the intent-to-treat population, OR was achieved by 194 (44%) of 444 and 77 (35%) of 222 patients in the palbociclib and placebo arms, respectively (odds ratio, 1.5; 95% confidence interval [CI], 1.0-2.1; P = .0156). Regardless of treatment, more OR than non-OR patients had de novo metastatic disease (47%-50% and 28%-31%, respectively) and no prior endocrine therapy (55% and 35%-37%, respectively). Rates of palbociclib dose reduction owing to adverse events were similar regardless of OR (41% and 38%, respectively). Among the patients with OR during the study, approximately 50% achieved OR within the first 3 months regardless of treatment. The median PFS was significantly prolonged with palbociclib + letrozole versus placebo + letrozole in patients with measurable disease in both OR (37.2 months; 95% CI, 28.1 months to not estimable vs. 27.4 months; 95% CI, 22.2-31.1 months; hazard ratio, 0.66; 95% CI, 0.47-0.94; P = .009) and non-OR groups (10.9 months; 95% CI, 8.2-11.2 months vs. 5.6 months; 95% CI, 5.3-8.3 months; hazard ratio, 0.72; 95% CI, 0.54-0.97; P = .016).

      Conclusions

      Palbociclib + letrozole provided significant clinical benefit versus placebo + letrozole to patients with ER+/HER2 ABC regardless of achieving RECIST-defined OR.

      Keywords

      Introduction

      Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors in combination with endocrine therapy are the current standard of care for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2) advanced breast cancer (ABC) in premenopausal and postmenopausal women.
      National Comprehensive Cancer Network
      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Breast cancer. Version 4.2017.
      • Cardoso F.
      • Costa A.
      • Senkus E.
      • et al.
      3rd ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 3).
      Palbociclib is a selective, orally active CDK4/6 inhibitor.
      Pfizer Canada Inc
      Ibrance Product Monograph. Kirkland, Quebec: Pfizer Canada Inc.
      • Finn R.S.
      • Dering J.
      • Conklin D.
      • et al.
      PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro.
      In the open-label, phase II PALOMA-1 (Palbociclib: Ongoing Trials in the Management of Breast Cancer) study, palbociclib plus letrozole significantly improved progression-free survival (PFS) versus letrozole alone in postmenopausal women with estrogen receptor-positive (ER+)/HER2 ABC, leading to the accelerated approval of the combination in the United States.
      • Finn R.S.
      • Crown J.P.
      • Lang I.
      • 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.
      • Beaver J.A.
      • Amiri-Kordestani L.
      • Charlab R.
      • et al.
      FDA approval: palbociclib for the treatment of postmenopausal patients with estrogen receptor-positive, HER2-negative metastatic breast cancer.
      The phase III PALOMA-2 study, designed to confirm the results of PALOMA-1, demonstrated that median PFS was significantly prolonged with the combination of palbociclib plus letrozole versus placebo plus letrozole (27.6 vs. 14.5 months; hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.46-0.69; 1-sided P < .001; data cutoff date of May 31, 2017) as first-line treatment for postmenopausal women with ER+/HER2 ABC.
      • Rugo H.S.
      • Finn R.S.
      • Diéras V.
      • 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.
      In parallel with the PFS prolongation observed with palbociclib in PALOMA-2, the rate of confirmed objective response (OR) was also higher in the palbociclib arm compared with the placebo arm in both the overall patient population (42.1% vs. 34.7%, respectively), as well as in patients with measurable disease (55.3% vs. 44.4%).
      • Finn R.S.
      • Martin M.
      • Rugo H.S.
      • et al.
      Palbociclib and letrozole in advanced breast cancer.
      The aim of this analysis was to examine the clinical outcomes of patients in the PALOMA-2 study who achieved a confirmed OR compared with those who did not.

      Patients and Methods

      Study Design and Patients

      PALOMA-2 was a phase III, multicenter, double-blind, placebo-controlled, randomized trial in postmenopausal women with ER+/HER2 ABC (NCT01740427). Study eligibility criteria have been reported previously.
      • Finn R.S.
      • Martin M.
      • Rugo H.S.
      • et al.
      Palbociclib and letrozole in advanced breast cancer.
      Eligible patients were postmenopausal with a confirmed diagnosis of ER+/HER2 locoregionally recurrent or metastatic disease who had not been previously treated with any anticancer systemic therapy; were not candidates for curative therapy; had an Eastern Cooperative Oncology Group performance status of 0 to 2; and were required to have evidence of measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, or bone disease as their only site of disease. Patients were excluded from study entry in the event of disease recurrence during or within 12 months of completing prior (neo)adjuvant treatment with a nonsteroidal aromatase inhibitor, if they had advanced symptomatic visceral spread of disease, or if they received prior treatment with any CDK4/6 inhibitor. This unplanned post hoc analysis was based on the data cutoff of May 31, 2017. The study is ongoing to collect overall survival data.

      Treatment

      Patients were randomized 2:1 to receive palbociclib 125 mg orally once daily for 3 weeks, followed by 1 week off treatment (3/1 schedule), plus letrozole (2.5 mg orally once daily, continuous) or placebo plus letrozole. Palbociclib dose modification (ie, dose reduction/interruption or cycle delay) was permitted in the event of treatment-related toxicity.

      Data Analyses

      Analyses were conducted in the intent-to-treat (ITT) population among all patients (including patients at study entry with visceral disease [lung and/or liver involvement] and nonvisceral disease [absence of lung and/or liver involvement; inclusive of patients with bone-only disease]). Analyses were also conducted in subgroups of patients with measurable disease at baseline (excluding patients with bone-only disease and other patients with nonmeasurable disease beyond bone-only). Patients were stratified by achievement (or not) of an OR (defined as a confirmed complete response or partial response according to RECIST version 1.1) during the study treatments. Baseline characteristics, median duration of OR (mDOR), safety, and palbociclib exposure were summarized in patients with or without an OR by treatment arm. Investigator-assessed PFS (defined as the time from randomization to radiologically confirmed disease progression according to RECIST version 1.1, or death during the study) was summarized in patients with or without a confirmed OR by treatment arm.
      The Kaplan-Meier method was used to obtain estimates of median PFS, with corresponding 2-sided 95% CIs. A Cox proportional hazards model was used to calculate hazard ratios, and 1-sided P values were from the log-rank test. No adjustments were made for multiple comparison testing.
      Safety assessments were conducted in the safety population, which included all patients who received ≥ 1 dose of study drug, with treatment assignments designated according to actual study treatment received, as previously described.
      • Finn R.S.
      • Martin M.
      • Rugo H.S.
      • et al.
      Palbociclib and letrozole in advanced breast cancer.
      Adverse events (AEs) were analyzed descriptively for patients in the safety population. Incidences of AEs were recorded in case report forms, and the severity of AEs was graded in accordance with the Medical Dictionary for Regulatory Activities (MedDRA) version 20.0, and include data up to 28 days after the last dose of study drug.

      Results

      Patients and Treatment

      Between February 28, 2013, and July 29, 2014, a total of 666 patients were enrolled in PALOMA-2 and received palbociclib plus letrozole (n = 444) or placebo plus letrozole (n = 222). In the palbociclib and placebo arms, 338 (76.1%) and 171 (77.0%) patients, respectively, had measurable disease at baseline, whereas 103 (23.2%) and 48 (21.6%) patients had bone-only disease. Among all patients, 194 (43.7%) patients in the palbociclib arm and 77 (34.7%) in the placebo arm achieved an OR (odds ratio, 1.5; 95% CI, 1.0-2.1; P = .0156). Among patients with measurable disease, 194 (57.4%) and 76 (44.4%) achieved an OR, respectively (odds ratio, 1.7; 95% CI, 1.1-2.5; P = .0038). Regardless of treatment, a higher percentage of patients with an OR had de novo metastatic disease, no prior radiation therapy, or no prior systemic therapy (including hormonal therapy and chemotherapy) compared with those without an OR (Table 1). In addition, more patients in the non-OR group had a shorter disease-free interval than patients in the OR group. In the non-OR group, a higher percentage of patients in the palbociclib arm had stable disease for ≥ 24 weeks compared with the placebo arm (72.8% vs. 53.8%, respectively), whereas more patients receiving placebo plus letrozole (25.5%) compared with palbociclib plus letrozole (13.6%) had objective progression (defined as absence of a complete response, partial response, or stable disease at any tumor assessment during the entire study). Among patients in the ITT population who achieved an OR, median time from randomization to first assessment of tumor response was 3 months in the palbociclib arm and 5 months in the placebo arm.
      Table 1Demographic and Baseline Characteristics
      Among all patients, which includes patients with visceral disease (lung and/or liver involvement) and nonvisceral disease (absence of lung and/or liver involvement; inclusive of patients with bone-only disease).
      CharacteristicOR, n (%)Non-OR, n (%)
      Palbociclib + Letrozole (n = 194)Placebo + Letrozole (n = 77)Palbociclib + Letrozole (n = 250)Placebo + Letrozole (n = 145)
      Median age (range), y63.0 (32-89)62.0 (28-84)61.0 (30-88)61.0 (32-88)
       <65108 (55.7)49 (63.6)155 (62.0)92 (63.4)
       ≥6586 (44.3)28 (36.4)95 (38.0)53 (36.6)
      Race
       White150 (77.3)57 (74.0)194 (77.6)115 (79.3)
       Black5 (2.6)2 (2.6)3 (1.2)1 (0.7)
       Asian27 (13.9)13 (16.9)38 (15.2)17 (11.7)
       Other12 (6.2)5 (6.5)15 (6.0)12 (8.3)
      Median weight (range), kg65.9 (38.0-119.8)68.5 (43.8-121.0)70.6 (33.0-156.8)66.7 (35.0-124.8)
      Disease site
       Visceral120 (61.9)45 (58.4)94 (37.6)65 (44.8)
       Nonvisceral74 (38.1)32 (41.6)156 (62.4)80 (55.2)
       Bone-only diseaseNANA103 (41.2)47 (32.4)
      Measurable disease194 (100.0)76 (98.7)144 (57.6)95 (65.5)
       Visceral
      Percentages based on total number of patients with measurable disease.
      120 (61.9)45 (59.2)94 (65.3)65 (68.4)
       Nonvisceral
      Percentages based on total number of patients with measurable disease.
      74 (38.1)31 (40.8)50 (34.7)30 (31.6)
      Disease-free interval
       De novo metastatic97 (50.0)36 (46.8)70 (28.0)45 (31.0)
       ≤12 mo27 (13.9)12 (15.6)71 (28.4)36 (24.8)
       >12 mo70 (36.1)29 (37.7)109 (43.6)64 (44.1)
       ≤24 mo32 (16.5)14 (18.2)91 (36.4)50 (34.5)
       >24 mo65 (33.5)27 (35.1)89 (35.6)50 (34.5)
      Prior (neo)adjuvant therapy received
       Prior endocrine therapy87 (44.8)35 (45.5)163 (65.2)91 (62.8)
       No prior endocrine therapy107 (55.2)42 (54.5)87 (34.8)54 (37.2)
      Involved disease sites
      Involved sites included both target and nontarget sites; sites with multiple lesions were counted once and each “other” disease site was counted as a separate disease site.
       Breast85 (43.8)36 (46.8)52 (20.8)38 (26.2)
       Bone129 (66.5)52 (67.5)196 (78.4)110 (75.9)
       Liver31 (16.0)17 (22.1)44 (17.6)29 (20.0)
       Lung90 (46.4)29 (37.7)60 (24.0)42 (29.0)
       Lymph node130 (67.0)47 (61.0)82 (32.8)64 (44.1)
       Other68 (35.1)26 (33.8)47 (18.8)38 (26.2)
      Number of involved sites
      Involved sites included both target and nontarget sites; sites with multiple lesions were counted once and each “other” disease site was counted as a separate disease site.
       116 (8.2)10 (13.0)122 (48.8)56 (38.6)
       263 (32.5)21 (27.3)54 (21.6)31 (21.4)
       366 (34.0)29 (37.7)46 (18.4)32 (22.1)
       431 (16.0)12 (15.6)20 (8.0)16 (11.0)
       >418 (9.3)5 (6.5)8 (3.2)10 (6.9)
      Prior surgeries117 (60.3)47 (61.0)209 (83.6)117 (80.7)
      Prior radiation therapies91 (46.9)40 (51.9)145 (58.0)85 (58.6)
      Prior systemic therapies97 (50.0)41 (53.2)180 (72.0)100 (69.0)
      Prior chemotherapy regimen for primary diagnosis78 (40.2)34 (44.2)135 (54.0)75 (51.7)
      Abbreviations: NA = not applicable; OR = objective response; RECIST = Response Evaluation Criteria in Solid Tumors.
      a Among all patients, which includes patients with visceral disease (lung and/or liver involvement) and nonvisceral disease (absence of lung and/or liver involvement; inclusive of patients with bone-only disease).
      b Percentages based on total number of patients with measurable disease.
      c Involved sites included both target and nontarget sites; sites with multiple lesions were counted once and each “other” disease site was counted as a separate disease site.
      The median daily dose in each treatment arm regardless of OR was 125 mg. The median duration of treatment for patients receiving palbociclib plus letrozole was approximately 30 months in the OR group (910 days; range, 49.0-1491.0 days) and about 12 months in the non-OR group (366.5 days; range, 1.0-1479.0 days). The median actual dose intensity (actual total dose taken per cycle divided by actual number of days in the cycle including delays) was similar regardless of response for patients treated with palbociclib (86.8 mg/day in the OR group [range, 38.6-107.1 mg/day] and 89.4 mg/day in the non-OR group [range, 45.0-125.0 mg/day]).

      Efficacy

      In patients with measurable disease in either treatment arm, nearly one-half achieved an OR within the first 3 months (ie, first postbaseline tumor assessment) and ≥ 90% within 1 year (Table 2). Median PFS was significantly prolonged with palbociclib plus letrozole versus placebo plus letrozole in the subset of patients with measurable disease regardless of OR (Figure 1), although nonresponders had a worse outcome overall. In the OR group with measurable disease, median PFS was 37.2 months (95% CI, 28.1 months to not estimable) in the palbociclib arm (n = 194) versus 27.4 months (95% CI, 22.2-31.1 months) in the placebo group (n = 76; hazard ratio, 0.66; 95% CI, 0.47-0.94; P = .009) (Figure 1A). In patients with measurable disease who did not achieve OR, the median PFS was 10.9 months (95% CI, 8.2-11.2 months) with palbociclib (n = 144) versus 5.6 months (95% CI, 5.3-8.3 months) with placebo (n = 95; hazard ratio, 0.72; 95% CI, 0.54-0.97; P = .016) (Figure 1B). In addition, approximately 90% of patients in the palbociclib arm and 81% of patients in the placebo arm had some decrease in tumor size at any assessment (Figure 2).
      Table 2Patients With Confirmed OR in the First 3, 6, 9, 12, or > 12 Months Post-treatment Initiation Among Patients With Measurable Disease
      Defined according to RECIST version 1.1 and excludes patients with bone-only disease and other patients with nonmeasurable disease beyond bone-only.
      at Baseline
      Time, n (%)Palbociclib + Letrozole (n = 194)Placebo + Letrozole (n = 76)
      ≤3 mo95 (49.0)35 (46.1)
      ≤6 mo145 (74.7)62 (81.6)
      ≤9 mo157 (80.9)66 (86.8)
      ≤12 mo174 (89.7)71 (93.4)
      >12 mo20 (10.3)5 (6.6)
      Abbreviations: OR = objective response; RECIST = Response Evaluation Criteria in Solid Tumors.
      a Defined according to RECIST version 1.1 and excludes patients with bone-only disease and other patients with nonmeasurable disease beyond bone-only.
      Figure thumbnail gr1
      Figure 1Kaplan-Meier Curves for Investigator-assessed PFS Among Patients With Measurable Diseasea at Baseline Who Achieved an OR (A) or Did Not Achieve an OR (B), and Among All Patientsb in the ITT Population Who Did Not Achieve an OR (C)
      Abbreviations: CI = confidence interval; ITT = intent-to-treat; NE = not estimable; OR = objective response; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumors. aDefined according to RECIST version 1.1 and excludes patients with bone-only disease and other patients with nonmeasurable disease beyond bone-only. bIncludes patients with visceral disease (lung and/or liver involvement) and nonvisceral disease (absence of lung and/or liver involvement; inclusive of patients with bone-only disease).
      Figure thumbnail gr2
      Figure 2Waterfall Plots for the Best Percentage Change in Tumor Size at any Time in Patients With Measurable Diseasea at Baseline Who Received Palbociclib Plus Letrozole (A) or Placebo Plus Letrozole (B)
      Abbreviations: ITT = intent-to-treat; RECIST = Response Evaluation Criteria in Solid Tumors. aDefined according to RECIST version 1.1 and excludes patients with bone-only disease and other patients with nonmeasurable disease beyond bone-only. For Each Treatment Arm, the Total n is Based on the ITT Population, Excluding Patients With Missing Values for Change From Baseline at All Visits Post-baseline and Those With Nonmeasurable Disease. Red Lines Indicate Response Criteria Based on RECIST Version 1.1. Upper Red Line: Progressive Disease Defined as a ≥ 20% Increase in the Sum of Diameters of Target Lesions. Lower Red Line: Partial Response Defined as a ≥ 30% Decrease in the Sum of Diameters of Target Lesions.
      Among all patients in the ITT population (inclusive of patients with bone-only disease), the median PFS was also significantly prolonged with palbociclib versus placebo in patients who did and who did not achieve an OR. In the OR group, median PFS was 37.2 months (95% CI, 28.1 months to not estimable) in the palbociclib arm (n = 194) versus 27.4 months (95% CI, 22.0-31.1 months) in the placebo arm (n = 77; hazard ratio, 0.65; 95% CI, 0.46-0.92; P = .007). In the non-OR group, median PFS in the palbociclib arm (n = 250) was 16.5 months (95% CI, 12.8-22.2 months) versus 8.2 months (95% CI, 5.6-11.0 months) in the placebo arm (n = 145; hazard ratio, 0.55; 95% CI, 0.43-0.70; P < .001) (Figure 1C). In patients who achieved an OR, mDOR was longer with palbociclib plus letrozole (27.7 months; 95% CI, 24.7-36.1 months) compared with placebo plus letrozole (20.9 months; 95% CI, 16.5-27.6 months).

      Safety

      The safety profile was similar in both OR and non-OR groups (data not shown). The percentage of patients in the palbociclib arm with no dose reduction was similar in both the OR and non-OR groups (58.2% and 62.4%, respectively), and the rates of palbociclib dose reduction or interruption/delay owing to AEs and permanent discontinuation owing to AEs were generally comparable in patients with and without an OR (Table 3).
      Table 3Permanent Study Treatment Discontinuation, Temporary Study Treatment Discontinuation, and Dose Reduction Owing to Treatment-emergent AEs (Safety Population)
      Patients who discontinued owing to AEs were selected from the Conclusion of Treatment case report form page, and treatment-related status was based on the AE case report form page.
      ,
      Among all patients (safety population).
      Event, n (%)ORNon-OR
      Palbociclib + Letrozole (n = 194)Placebo + Letrozole (n = 77)Palbociclib + Letrozole (n = 250)Placebo + Letrozole (n = 145)
      Patients with dose reduction owing to AE80 (41.2)2 (2.6)94 (37.6)2 (1.4)
      Discontinued owing to treatment-related AE8 (4.1)013 (5.2)0
      Patients with dose interruption or delay owing to AE165 (85.1)14 (18.2)184 (73.6)26 (17.9)
      Discontinued owing to treatment-related AE11 (5.7)1 (1.3)21 (8.4)3 (2.1)
      Abbreviations: AE = adverse event; OR = objective response; RECIST = Response Evaluation Criteria in Solid Tumors.
      a Patients who discontinued owing to AEs were selected from the Conclusion of Treatment case report form page, and treatment-related status was based on the AE case report form page.
      b Among all patients (safety population).

      Discussion

      The approval of cancer drugs by the United States Food and Drug Administration (FDA) was historically based on OR, which was considered a surrogate endpoint for overall survival.
      United States Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER)
      Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics.
      Although the OR endpoint captures drug antitumor activity, it may not capture the full clinical benefit of the treatment and may not necessarily translate into a PFS advantage.
      United States Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER)
      Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics.
      • Kaklamani V.G.
      Clinical implications of the progression-free survival endpoint for treatment of hormone receptor-positive advanced breast cancer.
      In the 1980s, the FDA determined that cancer drugs should be approved based on direct evidence of clinical benefit, such as overall survival, quality of life, and tumor-related symptoms—endpoints that may not be predicted by OR.
      United States Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER)
      Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics.
      Although overall survival is generally the preferred endpoint, PFS has gained acceptance as a primary endpoint in ABC clinical trials.
      • Kaklamani V.G.
      Clinical implications of the progression-free survival endpoint for treatment of hormone receptor-positive advanced breast cancer.
      Despite the evolution of endpoints used in clinical trials to support cancer drug approvals, it is often assumed that achievement of an OR is a surrogate for prolonged PFS.
      In this analysis, we explored the clinical benefit of palbociclib plus letrozole compared with placebo plus letrozole in patients who achieved or did not achieve a confirmed OR in PALOMA-2. Our findings demonstrated that palbociclib significantly prolonged median PFS compared with placebo regardless of whether patients achieved a confirmed OR, suggesting that OR is not a prerequisite for PFS prolongation in this population treated with endocrine therapy plus palbociclib. The improvement in PFS regardless of OR was seen in both the entire ITT population (inclusive of patients with bone-only disease), and also when excluding the ∼24% of patients without measurable disease. In general, the safety profile in patients with or without an OR was similar to previous findings in the overall population with no new safety signals observed (data not shown).
      • Finn R.S.
      • Martin M.
      • Rugo H.S.
      • et al.
      Palbociclib and letrozole in advanced breast cancer.
      Although patients in both arms of the study achieved OR, response was more likely in patients with de novo metastatic disease or fewer prior treatments. More patients receiving palbociclib plus letrozole achieved an OR compared with those in the placebo group (43.7% and 34.7%, respectively). Moreover, an OR rate of ∼44% in the palbociclib arm is encouraging in a population where more than 50% of patients had visceral disease. The median time to tumor response in the OR group with palbociclib was 3 months, an observation confounded by the fact that the first post-baseline scheduled disease assessment in PALOMA-2 occurred 3 months after randomization (per protocol). Therefore, patients could have achieved an earlier OR, but these data were not captured. In patients with measurable disease at baseline (excluding patients with bone-only disease), palbociclib plus letrozole also resulted in a significant improvement in median PFS versus placebo plus letrozole, regardless of OR status. These data are very relevant, as the prolonged PFS with the combination, including in patients with visceral disease and even in those without OR, should begin to challenge the dogma that chemotherapy is the preferred treatment for patients with visceral crisis.
      National Comprehensive Cancer Network
      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Breast cancer. Version 4.2017.
      Because ABC is incurable, the aim of cancer therapy during advanced disease is to delay disease progression and improve overall survival without negatively impacting quality of life.
      • Kaklamani V.G.
      Clinical implications of the progression-free survival endpoint for treatment of hormone receptor-positive advanced breast cancer.
      In this study, more patients in the palbociclib arm versus placebo arm achieved an OR, yet patients in the palbociclib arm had prolonged PFS regardless of OR status. This is of interest considering that there is significantly greater delay in deterioration of health-related quality of life in patients who achieve an OR versus those who do not in PALOMA-2.
      • Rugo H.S.
      • Diéras V.
      • Gelmon K.A.
      • et al.
      Impact of palbociclib plus letrozole on patient-reported health-related quality of life: results from the PALOMA-2 trial.
      Together, these results suggest that although both OR and non-OR patients treated with palbociclib achieve prolonged PFS, patients who achieved an OR may also experience a delay in the deterioration of quality of life compared with those who did not achieve an OR.
      Potential limitations of this analysis should be considered when interpreting the results, including its post hoc nature and that it was not controlled for multiple comparisons. Despite these limitations, these data suggest that palbociclib plus letrozole results in a significant clinical benefit regardless of OR.

      Conclusions

      In this analysis of PALOMA-2, achieving an OR with palbociclib plus letrozole was not required for PFS prolongation compared with placebo plus letrozole, demonstrating that achievement of an OR is not a prerequisite for improvement in PFS in this patient population. Among patients who achieved an OR, mDOR was longer in the palbociclib arm versus the placebo arm. In conclusion, palbociclib plus letrozole is an effective therapy option for patients with HR+/HER2 ABC regardless of whether patients achieve an OR on treatment.

      Clinical Practice Points

      • CDK4/6 inhibitors in combination with endocrine therapy are the current standard of care for ABC in both premenopausal and postmenopausal women.
      • In the PALOMA clinical trials, the first-in-class CDK4/6 inhibitor palbociclib in combination with endocrine therapy has demonstrated significant improvement in PFS in patients with primary and secondary resistant HR+/HER2 ABC.
      • The results from this analysis of PALOMA-2 demonstrated that patients benefited from palbociclib plus letrozole over placebo plus letrozole regardless of whether they attained an OR.

      Disclosure

      H.S. Rugo’s institution has received research funding from Plexxikon , MacroGenics , OBI Pharma , Eisai , Pfizer , Novartis , Eli Lilly , Roche, and Merck , and travel support from Pfizer. R.S. Finn has received consulting fees from Pfizer, AstraZeneca, Bayer, Novartis, Bristol-Myers Squibb, Eisai, Eli Lilly, Merck, and Roche, as well as other research funding from Pfizer , and honoraria from Bayer, Pfizer, Bristol-Myers Squibb, Novartis, Eisai, and Eli Lilly. K. Gelmon has received consultant/advisor fees from Pfizer, Novartis, AstraZeneca, Mylan, Roche, Bristol-Myers Squibb, NanoString Technologies, and Merck. A.A. Joy has received consulting fees from Amgen, AbbVie, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Pfizer, Novartis, and Roche. N. Harbeck has received consulting and speakers’ bureau fees from Eli Lilly, Novartis, and Pfizer. A. Castrellon has received consulting/advisory fees from Agendia. J.M. Walshe has received consultant fees from Roche, Genomic Health, and Pfizer and fees for non-CME services from Roche, Genomic Health, and Pfizer. M. Martin has received research grants from Roche and Novartis , consulting/advisory fees from AstraZeneca, Amgen, Taiho Oncology, Roche/Genentech, Novartis, PharmaMar, Eli Lilly, PUMA, and Pfizer, and speakers’ honoraria from AstraZeneca, Amgen, Roche/Genentech, Novartis, and Pfizer. V. Diéras has received consulting fees from Genentech, Eli Lilly, Pfizer, Astellas, AbbVie, AstraZeneca, Novartis Pharma KK, Daiichi Sankyo, Tesaro, MSD, Seattle Genetics, and Roche-Peru, as well as speakers’ bureau fees from Pfizer, Novartis Pharma KK, Eli Lilly, and Roche-Peru. H. Mukai has received research grants from Eisai , Daiichi Sankyo , Nippon Kayaku , and Pfizer and speakers’ honoraria from AstraZeneca, Taiho, and Pfizer. A. Mori, E. Gauthier, D.R. Lu, and E. Bananis are employees of and own stock in Pfizer.

      Acknowledgments

      This study was sponsored by Pfizer Inc. Authors from Pfizer Inc participated in designing the study; in collecting, analyzing, and interpreting the data; in writing the manuscript; and in the decision to submit the manuscript for publication. The authors would like to thank Dr Oleg Lipatov for contributions to the design of this work and to the acquisition of data and Dr Lynn McRoy of Pfizer Inc for assistance with data analysis and interpretation. Editorial and medical writing support was provided by Jill Shults, PhD, of Complete Healthcare Communications, LLC (North Wales, PA), a CHC Group company, and was funded by Pfizer Inc .
      Data Sharing Statement: Upon request, and subject to certain criteria, conditions, and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines, and medical devices (1) for indications that have been approved in the United States and/or Europe or (2) in programs that have been terminated (ie, development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.

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