Time to treatment failure of palbociclib and letrozole as second-line therapy or beyond in hormone receptor-positive advanced breast cancer

Abstract

Purpose

The management of endocrine therapy resistance is one of the most challenging facets of advanced breast cancer treatment. Palbociclib is an inhibitor of cyclin-dependent kinases 4 and 6 approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer in combination with fulvestrant in postmenopausal women with disease progression following endocrine therapy. However, treatment responsiveness of tumors to palbociclib after multiple lines of endocrine therapy is not clearly established. The purpose of this study was to determine the efficacy of palbociclib and letrozole in patients pretreated with one or more lines of endocrine therapy.

Methods

This was a single-center, retrospective cohort study of all postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer patients who received palbociclib and letrozole as a second-line endocrine therapy or beyond (and no prior cyclin-dependent kinases 4 and 6 inhibitor therapy) between February 1, 2015, and July 31, 2016. The primary objective was to evaluate time to treatment failure of palbociclib in combination with letrozole as a second-line of therapy or beyond.

Results

Fifty-three patients meeting eligibility criteria were included in the analysis. For the primary outcome, the median time to treatment failure of palbociclib and letrozole was 6.3 months (95% CI 3.1–7.4 months). Progression-free survival of palbociclib and letrozole therapy was 6.4 months (95% CI 4.9–8.3 months).

Conclusions

Palbociclib and letrozole therapy is a viable, effective treatment option for metastatic breast cancer patients who were not exposed to cyclin-dependent kinases 4 and 6 inhibitors as a first-line endocrine therapy. The benefits of palbociclib and letrozole therapy were seen without excessive toxicity, and although neutropenia was common, it may be managed with dose reduction.

Keywords

Palbociclib endocrine therapy metastatic disease endocrine resistance

Introduction

Palbociclib is a first-in-class, oral, reversible, small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), which play an important role in the regulation of cell cycle progression. Palbociclib is currently approved for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer (MBC) in combination with an aromatase inhibitor (AI) as initial endocrine therapy in postmenopausal women, and in combination with fulvestrant in postmenopausal women with disease progression following endocrine therapy.^1,2 However, after palbociclib was initially FDA-approved in February 2015, many metastatic HR-positive breast cancer patients who progressed on prior endocrine therapies and/or chemotherapy were started on palbociclib and letrozole as a second-line of therapy or beyond. The efficacy of palbociclib and letrozole is unknown in tumors that have been pretreated with other endocrine therapy regimens.

Palbociclib was FDA-approved based upon the positive results of the phase II PALOMA-1 trial.³ Although an overall survival advantage has not yet been demonstrated with palbociclib, the confirmatory phase III PALOMA-2 trial found that median progression-free survival was prolonged in postmenopausal women receiving first-line palbociclib in combination with letrozole versus letrozole alone (24.8 months vs. 14.5 months; p < 0.001).⁴ The PALOMA-3 trial evaluated palbociclib as a second-line or beyond therapy in combination with fulvestrant in patients who progressed on initial endocrine therapy. The median progression-free survival was significantly improved with the combination of palbociclib and fulvestrant compared to fulvestrant alone (9.2 months vs. 3.8 months; p < 0.0001).⁵

The management of endocrine therapy resistance is one of the most challenging facets of advanced breast cancer treatment. As compelling as the findings from the PALOMA trials are, the treatment responsiveness of tumors to palbociclib and letrozole after multiple lines of endocrine therapy is not clearly established. In PALOMA-3, the majority of the intent-to-treat population (87%) received two or fewer previous lines of endocrine therapy.⁵ In vitro data suggest that the expression of cyclin-dependent kinases (CDKs) is maintained in breast cancers with varying susceptibilities to endocrine therapy. Therefore, the mediation of endocrine therapy resistance via a targeted therapy such as palbociclib could represent a valuable therapeutic option for endocrine-refractory patients.⁶ Additionally, endocrine-refractory patients have historically been treated with single-agent cytotoxic chemotherapy which has higher rates of toxicities and reduced quality life versus endocrine therapy. Palbociclib may delay the initiation of chemotherapy and allow patients to remain on endocrine therapy longer.⁵

The recommended dosing regimen for palbociclib is 125 mg once daily for 21 days, followed by a 7-day rest period to complete a 28-day treatment cycle.¹ However, many patients are not able to tolerate the recommended dosing regimen due to grades 3 and 4 neutropenia and may require dose reductions. One of the most common reasons for dose reductions is grades 3 and 4 neutropenia, which occurred in 65% of patients in the PALOMA-3 trial. Despite the high rates of neutropenia observed with palbociclib use in the PALOMA trials, a minimal rate of febrile neutropenia (FN) was reported (in PALOMA-3, for instance, 1% of patients receiving fulvestrant and palbociclib experienced FN versus 1% of patients receiving fulvestrant alone).⁵ Due to the significant amount of patients that require dose reductions, it is important to evaluate if these dose modifications impact time to treatment failure (TTF) with palbociclib.

Since the majority of the female patients included in the PALOMA-2 trial had not been exposed to multiple lines of endocrine therapy previously, the efficacy of palbociclib plus letrozole in this setting is unknown. Additionally, it is unknown whether the high rates of neutropenia and subsequent dose reductions of palbociclib affect its efficacy and/or TTF. Therefore, the primary objective goal of this study was to determine the TTF of palbociclib in combination with letrozole in postmenopausal women pretreated with one or more lines of endocrine therapy.

Methods

Study design and setting

This was a single-center, retrospective cohort study conducted at a 306-bed academic cancer center with six outpatient locations of all postmenopausal HR-positive, HER2-negative MBC patients who received palbociclib in combination with letrozole as a second-line endocrine therapy or beyond between February 1, 2015, and July 31, 2016. The study was approved by the Clinical Scientific Review Committee and Institutional Review Board at The Ohio State University. For this type of study, formal consent is not required.

Inclusion and exclusion criteria

Patients were included if all of the following criteria were met: MBC who received treatment with palbociclib in combination with letrozole as second-line endocrine therapy or beyond, postmenopausal female defined as natural menopause (no menses > 12 months) or by surgery through oophorectomy or by ovarian suppression through the use of luteinizing hormone-releasing hormone (LHRH) agonists (during the entirety of AI and palbociclib therapy), 18 years or older and younger than 90 years, confirmed HR-positive (at least 1% estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive cells), HER2-negative (immunohistochemistry 0 or 1+; if 2+, confirmed negativity by fluorescence in-situ hybridization). Patients were excluded if they were male (as men were not included in the PALOMA trials), incarcerated, or had prior CDK4/6 inhibitor exposure.

Data collection

Demographic and clinical data were collected from the patient’s electronic medical record. Data collection included baseline demographics, previous AI exposure, previous fulvestrant exposure, previous adjuvant or neoadjuvant chemotherapy and number of therapies, line of endocrine therapy for metastatic disease, use of LHRH agonist during palbociclib and letrozole therapy, palbociclib dose (as recorded on outpatient prescriptions) throughout therapy to determine the median prescribed dose of palbociclib, cycle numbers when palbociclib doses were reduced, number of cycles of palbociclib received, absolute neutrophil counts and absolute lymphocyte counts, TTF of palbociclib and letrozole therapy, and PFS on palbociclib and letrozole therapy. Toxicities were classified using the Common Terminology Criteria Adverse Events version 4.0. Adherence was not evaluated given the retrospective nature of this study. Palbociclib prescriptions were filled through many different specialty pharmacies and patient diaries were not kept.

Primary and secondary outcomes

The primary outcome was TTF of palbociclib in combination with letrozole as a second-line of endocrine therapy or beyond in patients with HR-positive MBC. Secondary outcomes included: TTF of most recent previous line of endocrine therapy, TTF of treatment based on median palbociclib dose, TTF of patients who previously received chemotherapy for metastatic disease, TTF of patients who received an LHRH agonist during palbociclib and letrozole therapy, PFS on palbociclib and letrozole treatment for all patients, and the incidence of grade ≥3 neutropenia and lymphopenia. TTF was defined as the difference in days from the date therapy began (or the date the original prescription was written if the start date was not recorded) to the last date of therapy. PFS was defined as the difference in days from the date therapy began (or the date the original prescription was written if the start date was not recorded) to progression.

Statistical analysis

Descriptive statistics were performed according to the type of data contained within each particular data set, and the data are presented as number (%), median (interquartile range), or mean as appropriate. Categorical variables were compared using the Chi-square test. Kaplan–Meier methods were used to estimate the median PFS and TTF. Tests were found to be significant with a p value of less than 0.05.

Results

Patient population

Two hundred and one patients were identified as having been prescribed palbociclib during the study timeframe at the institution, and the majority of these were excluded as they received palbociclib as first-line endocrine therapy (82 patients) or in combination with fulvestrant (50 patients). Fifty-three patients meeting eligibility criteria were included in the analysis. The median age was 60 (40–79) years, 49 patients (92%) were Caucasian, and the median ECOG Performance Status was 1 (0–3); 13 patients (25%) originally presented with de-novo metastatic disease, 16 patients (30%) had bone-only disease, and 33 patients (60%) had visceral disease. Twenty-nine patients (55%) had received previous chemotherapy for MBC, and the median line of endocrine therapy for metastatic disease was 3 (2–6). Five patients (9%) received ovarian suppression with an LHRH agonist (the institutional standard is the goserelin 3.6 mg implant every 28 days) during palbociclib therapy. Baseline characteristics and treatment history are summarized in Table 1.

Table 1.

Patient characteristics.

Characteristic	n = 53
Median age, years (range)	60 (40–79)
Caucasian, n (%)	49 (92%)
Median ECOG performance status, n (range)	1 (0–3)
De-novo metastatic disease, n (%)	13 (25%)
Disease site, n (%)
Bone only	16 (30%)
Visceral (liver, lungs, brain, and/or abdominal cavity)	32 (60%)
Brain	10 (19%)
Previous systemic therapy
Prior aromatase inhibitor exposure, n (%)	47 (89%)
Prior fulvestrant exposure, n (%)	46 (87%)
Previous adjuvant chemotherapy, n (%)	31 (58%)
Previous chemotherapy for MBC, n (%)	29 (55%)
Median prior lines of chemotherapy for MBC, n (range)	1 (0–6)
Median line of endocrine therapy for MBC, n (range)	3 (2–6)
Use of LHRH agonist during palbociclib therapy, n (%)	5 (9%)

MBC: metastatic breast cancer; LHRH: luteinizing hormone-releasing hormone.

Outcomes

For the primary outcome, the median TTF of palbociclib and letrozole was 6.3 months (95% CI 3.1–7.4 months), see figure 1. Thirty-nine patients (74%) stopped the therapy due to progression of disease. The median TTF of the most recent previous line of endocrine therapy was 10.6 months (95% CI 7.6–15.6). The median TTF of palbociclib and letrozole based on the median palbociclib dose received (75 mg, 100 mg, 112.5 mg, and 125 mg) was 9.8 months (95% CI 5.3–NA), 8.3 months (95% CI 2.9–NA), 2.9 months (95% CI 1.4–6.0), and 4.0 months (95% CI 2.4–7.4), respectively. The median TTF of patients who had previously received chemotherapy for metastatic disease was 5.3 months (95% CI 2.4–6.8 months), see figure 2. The median TTF of patients who received an LHRH agonist during the palbociclib and letrozole therapy was 14.0 months (95% CI 6.8–14.0). PFS of palbociclib and letrozole therapy was 6.4 months (95% CI 4.9–8.3 months), see figure 3. The primary and secondary outcomes are summarized in Table 2.

Table 2.

Primary and secondary outcomes.

Outcome	n = 53
Median time to treatment failure (TTF), months	6.3 (95% CI 3.1–7.4)
Median time to treatment failure (TTF) based on receipt of chemotherapy for metastatic disease, months
Received chemotherapy for metastatic disease	5.3 (95% CI 2.4–6.8)	p = 0.0573
No prior chemotherapy for metastatic disease	7.4 (95% CI 0.3–14)
Median time to treatment failure (TTF) of most recent previous line of endocrine therapy, months	10.6 (95% CI 7.6–15.6)
Median time to treatment failure (TTF) based on median palbociclib dose received, months
75 mg	9.8 (95% CI 5.3–NA)	p = 0.0751
100 mg	8.3 (95% CI 2.9–NA)
112.5 mg	2.9 (95% CI 1.4–6.0)
125 mg	4.0 (95% CI 2.4–7.4)
Median time to treatment failure (TTF) based on receipt of LHRH agonist, months
Received LHRH agonist	14.0 (95% CI 6.8–14.0)	p = 0.2548
Did not receive LHRH agonist	5.6 (95% CI 2.8–7.4)
Median progression-free survival (PFS), months	6.4 (95% CI 4.9–8.3)

LHRH: luteinizing hormone-releasing hormone.

Twenty-eight patients (53%) received a median palbociclib dose of 125 mg. The median number of palbociclib cycles received was 6 (1–22). Dose reductions of palbociclib were observed in 29 patients (55%), and the median cycle number for patients requiring a first dose reduction was 2 (1–14); 25 patients (47%) experienced grade 3/4 neutropenia, and 16 patients (30%) experienced grade 3/4 leukopenia. Characterization of palbociclib dosing and adverse events is summarized in Table 3.

Table 3.

Palbociclib dosing and adverse events.

Characteristic	n = 53
Median palbociclib dose received, n (%)
75 mg	6 (11%)
100 mg	15 (28%)
112.5 mg	4 (8%)
125 mg	28 (53%)
Median number of palbociclib cycles received, n (range)	6 (1–22)
Dose reduction of palbociclib needed, n (%)	29 (55%)
Median cycle number, n (range)
First dose reduction	2 (1–14)
Second dose reduction	6 (2–14)
Incidence of adverse events during therapy, n (%)
Grade ≥ 3 neutropenia	25 (47%)
Grade ≥ 3 lymphopenia	16 (30%)

Discussion

To our knowledge, this cohort review represents the first real-world evaluation of palbociclib in combination with letrozole as a second-line of endocrine therapy or beyond in MBC patients. At the time of its FDA approval in February 2015, many patients at our institution had already received first-line endocrine therapy but had not yet been exposed to palbociclib. The median TTF of second-line or beyond palbociclib and letrozole therapy was determined to be 6.3 months in this study, providing important efficacy information supporting the use of palbociclib and letrozole treatment in MBC patients who did not receive a CDK4/6 inhibitor in the first-line setting.

The median PFS of second-line or beyond palbociclib and letrozole was 6.4 months compared to the median TTF of 6.3 months indicating that most patients failed the therapy due to disease progression, not due to decreased tolerability or toxicity of palbociclib and letrozole. This is an especially important finding considering that nearly 50% of patients in this study experienced grade 3 or higher neutropenia and 55% of patients required a dose reduction of palbociclib. Unfortunately, no conclusions were able to be drawn from this study about the TTF of palbociclib and letrozole based on median palbociclib dose due to limited sample sizes. However, in PALOMA-3, dose reductions for grades 3 or 4 neutropenia were not found to have an adverse effect on PFS.⁷ Therefore, although neutropenia is common, it is easily managed with palbociclib dose reductions and/or delays and does not appear to result in undue toxicity or decreased efficacy. Further studies are needed to evaluate the effect of dose reductions on the efficacy of first-line palbociclib therapy.

While direct comparisons cannot be made between this study and PALOMA-3, the median PFS of second-line or beyond palbociclib and letrozole therapy observed in this study is shorter than the PFS observed in PALOMA-3 (9.5 months),⁵ which studied palbociclib as a second-line or beyond therapy in combination with fulvestrant. However, patients were not excluded from our study based on performance status, and many had brain metastases (19% of patients) or had received multiple prior lines of chemotherapy for metastatic disease, potentially decreasing the PFS. More patients in this study were pretreated with cytotoxic chemotherapy in the metastatic setting than in PALOMA-3 (55% vs. 33%, respectively). Patients in this study were also more heavily pretreated with endocrine therapy: 21 patients (40%) received three or more prior lines of endocrine treatment, whereas only 47 patients (14%) did in PALOMA-3.⁵ In our study, 46 patients (87%) had received fulvestrant prior to treatment with palbociclib and letrozole.

The median TTF of second-line or beyond palbociclib and letrozole in patients previously receiving chemotherapy for metastatic disease was 5.3 months compared to the median TTF of 7.4 months in patients who had not received prior chemotherapy for metastatic disease (p = 0.0573). This finding is not completely unexpected since many patients who receive chemotherapy for advanced disease have visceral metastases which are associated with a poorer prognosis. Additionally, the patients in our study who received chemotherapy for metastatic disease tended to have been treated with a higher number of prior endocrine therapies. Although the TTF was shorter in patients who had received prior chemotherapy, palbociclib and letrozole may still provide benefit to this patient population.

There are several limitations to our study. This is a retrospective cohort review conducted at single center with a small sample size. Since data collection occurred retrospectively, there is the possibility of errors due to confounding and bias. Although no patient diaries were available to measure the treatment compliance, standard practice in our clinics is to see patients prior to each new treatment cycle to assess labs, compliance, and toxicity; prescription refills were not provided as a new prescription was generated at each visit.

In summary, for MBC patients who have previously received endocrine therapy, including multiple lines of endocrine therapy and/or prior fulvestrant, second-line or beyond palbociclib and letrozole may provide benefit. The benefits of palbociclib and letrozole therapy were seen without excessive toxicity, and although neutropenia was common, it may be managed with dose reduction. Although the PFS benefit of palbociclib has been shown to be greatest when palbociclib is used in the first-line setting, palbociclib and letrozole therapy appears to be a viable, effective treatment option for MBC patients who were not exposed to a CDK4/6 inhibitor as a first-line endocrine therapy.

Footnotes

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Author CAV received consulting fees from serving on an advisory board for Pfizer. Author MJB received consulting fees from serving on an advisory board for Novartis. The other authors declare that they have no conflict of interest.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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