Abstract
Purpose
The optimal treatment following endocrine therapy (ET) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) has not been established. We aimed to investigate treatment patterns and time to treatment failure (TTF) of subsequent therapy after palbociclib in a Japanese real-world setting.
Methds
This retrospective observational study used de-identified data of patients with advanced breast cancer treated with palbociclib, using a nationwide claims database (April 2008 to June 2021). Measures included the type of subsequent therapies after palbociclib (endocrine-based therapy: ET alone, ET + CDK4/6i, and ET + mammalian target of rapamycin inhibitor [mTORi]; chemotherapy; chemotherapy + ET; and others) and their TTFs. The median TTF and 95% confidence interval (CI) were estimated using the Kaplan-Meier method.
Results
Of 1170 patients treated with palbociclib, 224 and 235 received subsequent therapies after first- and second-line palbociclib treatment, respectively. Among them, 60.7% and 52.8% were treated with endocrine-based therapies as first subsequent therapy, including ET + CDK4/6i (31.2% and 29.8%, respectively). The median TTF (95% CI) of ET alone, ET + CDK4/6i, and ET + mTORi as first subsequent therapy after first-line palbociclib were 4.4 (2.8–13.7), 10.9 (6.5–15.6), and 6.1 (5.1–7.2) months, respectively. No apparent relationship between the treatment duration of prior ET + palbociclib and subsequent abemaciclib was observed.
Conclusion
This real-world study revealed that one-third of the patients received sequential CDK4/6i after ET + palbociclib, and treatment duration of ET + CDK4/6i following ET + palbociclib was the longest among the treatment options. Further data are awaited to determine whether ET + targeted therapy with CDK4/6i and mTORi provides acceptable treatment options following ET + palbociclib.
Keywords: Breast cancer, Endocrine therapy, Cyclin-dependent kinase 4/6 inhibitor, Palbociclib, Real-world, And subsequent therapy
Highlights
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No optimal treatments after endocrine therapy (ET) + cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) has been established.
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This study investigated treatment patterns and treatment duration after palbociclib in a Japanese real-world setting (n = 1170).
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More than 60% were treated with endocrine-based therapies after palbociclib, and one-thirds continued ET + CDK4/6i.
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ET + CDK4/6i provided the longest treatment duration among treatment options.
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ET + targeted therapy may provide acceptable treatment options after palbociclib.
1. Introduction
Breast cancer (BC) is one of the most common types of cancer. The hormone receptor positive (HR+) subtype accounts for approximately 71% of BC cases [1], with endocrine therapy (ET) being the standard of care. Current guidelines recommend aromatase inhibitor (AI) plus (+) a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) as the first-line treatment for HR+/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC) [[2], [3], [4]]. When AI monotherapy is used as the first-line treatment, fulvestrant + CDK4/6i is recommended as second-line treatment [2]. However, data on subsequent therapy after ET + CDK4/6i are currently limited, and the optimal treatment after ET + CDK4/6i has not been established [[2], [3], [4]].
Clinical trials of CDK4/6i for HR+/HER2− ABC reported the treatment type and duration of subsequent therapy after ET + CDK4/6i [[5], [6], [7], [8], [9], [10], [11], [12]]. When ET + CDK4/6i was used as the first-line treatment, approximately over half of the patients were treated with endocrine-based therapy as the first subsequent therapy [5,6,[10], [11], [12]], and among the Japanese subgroups, the median duration of the first subsequent therapy after ET + palbociclib was 6.4–8.3 months [11,12]. Clinical trials assessing sequential CDK4/6i are currently underway [[13], [14], [15], [16]], and results supporting sequential CDK4/6i use have been recently reported in the phase II double-blind MAINTAIN trial among patients who progressed during prior therapy with ET + CDK4/6i [17]. Although previous clinical trials have shown common use of endocrine-based therapies following ET + CDK4/6i [5,6,[10], [11], [12]], with limited information available to date, data are needed to establish optimal treatment options following CDK4/6i and assess whether sequential CDK4/6i provides a sufficient treatment duration.
Two types of CDK4/6i are currently available in Japan for HR+/HER2− ABC: palbociclib [18,19] and abemaciclib [20,21]. Both agents selectively inhibit CDK4/6 and induce exclusive G1 arrest [22,23]. Palbociclib is a first-in-class CDK4/6i launched in Japan in December 2017 [19], and abemaciclib was subsequently launched in November 2018 [21]. We previously investigated real-world palbociclib treatment patterns for HR+/HER2− ABC in a Japanese clinical setting using a nationwide claims database [24]. In this present study, we aimed to investigate the treatment patterns and time to treatment failure (TTF) of a subsequent therapy after palbociclib treatment in a real-world setting. Palbociclib and abemaciclib are strongly recommended as the first- and second-line treatments in Japan [2], and palbociclib was launched as a first-in-class CDK4/6i. Therefore, we focused on patients treated with palbociclib in these front-line settings.
2. Methods
2.1. Study design and data source
This retrospective observational database study used data from April 2008 to June 2021 (study period), extracted from one of the largest hospital-based medical claims databases in Japan [25] and managed by Medical Data Vision Co., Ltd. (MDV, Tokyo, Japan). The MDV database stores individual-level, de-identified data including demographics and claims. As of June 2021, the database population comprises approximately 36.4 million inpatients and outpatients from 445 nationwide medical institutions including 219 cancer therapeutic facilities, that use a diagnosis procedure combination per-diem payment system (DPC/PDPS) [26]. The included institutions account for approximately 25% of all hospitals nationwide adopting this system.
This study used anonymized information as classified under the amended Act on the Protection of Personal information [27] and it is secondary use of data originally collected for healthcare claims purposes. According to the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan [28], this study did not require approval from an institutional review board and informed patient consent.
2.2. Patient selection
Patients with HR+/HER2− ABC treated with palbociclib were identified in the database following Sawaki et al. [24]. The included patients had 1) diagnosis records of BC (International Statistical Classification of Diseases and Related Health Problems, 10th revision [ICD-10]: C50.xx), 2) ≥1 prescription records of ET (anastrozole, letrozole, exemestane, tamoxifen citrate, toremifene citrate, fulvestrant, or medroxyprogesterone acetate; Supplementary Table S1), and 3) ≥1 records of palbociclib following a surgery or metastasis record (Supplementary Table S2). Surgery or metastasis records were used to identify advanced BC. The excluded patients had ≥1 prescriptions for HER2-targeted therapy (trastuzumab, trastuzumab emtansine, trastuzumab deruxtecan, pertuzumab, or lapatinib tosilate hydrate).
2.3. ABC treatment lines
The first-line treatment (regardless of palbociclib use) was defined as follows: 1) for patients with a surgery record, the first treatment following the adjuvant ET, which was defined as the earliest ET started within 365 days of the latest surgery record; and 2) for patients without a surgery record, the first treatment following the earliest metastasis record. We verified that the latter patients 2) had not received BC treatment during 180 days before the earliest metastasis record. A subsequent treatment (regardless of palbociclib use) following the first line was defined as a second line. The detailed methodology to identify the first- and subsequent-treatment lines, including measures to prevent misclassification of treatment lines, has been described in our previous study [24].
The regimen was defined as any BC treatment(s) received within 30 days of earlier treatment initiation. Each regimen was considered to end if the following was identified: 1) a BC treatment that was not used in the previous treatment line (including switching to another product of the same class [ET, CDK4/6i, etc.]); or 2) a gap period of ≥120 days from the last to subsequent BC treatment. The treatment duration was defined as the difference between the corresponding treatment end date and the start date + one day. Follow-up was censored at the end of patient data or study period.
2.4. Measures
The measures included the type of first subsequent therapy after ET + palbociclib as follows: endocrine-based therapy (ET alone, ET + CDK4/6i [palbociclib or abemaciclib], ET + mammalian target of rapamycin inhibitor [mTORi, everolimus]); chemotherapy (chemotherapy alone or chemotherapy + bevacizumab); chemotherapy + ET; and others (Supplementary Table S1). The TTF of the first subsequent therapy after palbociclib was also examined. The definition of TTF was the same as that of treatment duration. Because the database did not contain reasons for treatment failure, treatment failure due to disease progression and adverse events were evaluated together as TTF events.
2.5. Statistical analysis
Baseline patient characteristics were summarized using descriptive statistics. The first subsequent therapy after palbociclib was evaluated separately for patients treated with palbociclib in the first- and second-line settings. Additionally, for patients treated with palbociclib as the first-line treatment, the type of the first subsequent therapy was stratified by the prior palbociclib treatment duration (≤6, 7–<12, and ≥12 months).
The TTF of the first subsequent therapy after palbociclib was stratified by: prior palbociclib treatment line (first and second lines); type of subsequent therapy among patients treated with palbociclib as the first-line therapy; and three patterns of the CDK4/6i sequence among patients treated with ET + palbociclib as the first-line therapy and ET + CDK4/6i (palbociclib or abemaciclib) in a subsequent line of therapy. To assess the effect of endocrine sensitivity on the TTF of each subsequent therapy, the following two subgroups were also examined: patients who initiated first-line therapy in ≤12 months of the end of adjuvant therapy (endocrine-resistant subgroup) and 2) those who initiated first-line therapy >12 months after the end of adjuvant therapy or those without adjuvant therapy (endocrine-sensitive subgroup). The three patterns of CDK4/6i sequence were as follows: 1) both ET and CDK4/6i switched (i.e., ET was switched to another type, and palbociclib was switched to abemaciclib), 2) only ET switched (i.e., ET was switched to another ET, but palbociclib was continued), and 3) only CDK4/6i switched (i.e., the same ET was continued, but palbociclib was switched to abemaciclib). The Kaplan-Meier method was used to estimate the median TTF of the first subsequent therapy and the follow-up period for patients with subsequent therapies. The 95% confidence interval (CI) for the estimator of TTF was also estimated. Additionally, TTF of ET + palbociclib and that of a subsequent abemaciclib treatment were visually examined for each patient treated with palbociclib as the first-line therapy.
No imputation was performed for missing data. All statistical analyses were performed using SAS v9.4 (SAS Institute, NC, USA) and R v3.4.0 or later (R Foundation for Statistical Computing, Vienna, Austria).
3. Results
3.1. Baseline characteristics of patients treated with palbociclib
Among the 185,865 patients with HR+/HER2− ABC identified in the MDV database, 1170 treated with palbociclib in any treatment lines were identified (Table 1). The median (Q1, Q3) age at palbociclib initiation was 64 (53, 72) years, including 13.0% premenopausal and 87.0% postmenopausal patients. Among 152 premenopausal patients, 115 received adjuvant ET, and 73 of them were treated with goserelin and/or leuprorelin before first-line therapy. The adjuvant ET record was identified in 608 patients (52.0%), and most (526 patients) had a ≤12-month gap period between the end of adjuvant ET and initiation of the first-line therapy.
Table 1.
Baseline characteristics of patients treated with palbociclib.
| Characteristics | Treated with palbociclib in |
||
|---|---|---|---|
| Any line (n = 1170) | 1st line (n = 398) | 2nd line (n = 358) | |
| Age at palbociclib initiation, median (Q1, Q3) | 64 (53, 72) | 64 (51, 71) | 65 (55, 72) |
| Sex, n (%) | |||
| Male | 7 (0.6) | 2 (0.5) | 2 (0.6) |
| Female | 1163 (99.4) | 396 (99.5) | 356 (99.4) |
| Menopausal statusa, n (%) | |||
| Premenopausal | 152 (13.0) | 65 (16.3) | 45 (12.6) |
| Postmenopausal | 1018 (87.0) | 333 (83.7) | 313 (87.4) |
| Charlson comorbidity indexb, median (Q1, Q3) | 8 (8, 9) | 8 (8, 9) | 8 (8, 9) |
| Comorbidityc, n (%) | |||
| Peptic ulcer disease | 196 (16.8) | – | – |
| Mild liver disease | 112 (9.6) | – | – |
| Chronic pulmonary disease | 87 (7.4) | – | – |
| Congestive heart failure | 53 (4.5) | – | – |
| Diabetes without chronic complication | 34 (2.9) | – | – |
| Chemotherapy history for advanced breast cancer, n (%) | 211 (18.0) | 0 (0.0) | 45 (12.6) |
| Adjuvant ET record, n (%) | |||
| No | 562 (48.0) | 182 (45.7) | 190 (53.1) |
| Yes | 608 (52.0) | 216 (54.3) | 168 (46.9) |
| Gap period between adjuvant ET and first-line therapy | |||
| >12 months | 82 (7.0) | 34 (8.5) | 27 (7.5) |
| ≤12 months | 526 (45.0) | 182 (45.7) | 141 (39.4) |
| ET prescribed in combination with palbociclib | |||
| Fulvestrant | 698 (59.7)d | 227 (57.0) | 223 (62.3) |
| Letrozole | 335 (28.6)d | 136 (34.2) | 87 (24.3) |
| Exemestane | 46 (3.9)d | 8 (2.0) | 17 (4.7) |
| Anastrozole | 41 (3.5)d | 8 (2.0) | 15 (4.2) |
| Tamoxifen | 8 (0.7)d | 3 (0.8) | 1 (0.3) |
| Toremifen | 3 (0.3)d | 1 (0.3) | 1 (0.3) |
| Other | 39 (3.3)d | 15 (3.8) | 14 (3.9) |
Abbreviations: Q1, first quartile; Q3, third quartile; ET, endocrine therapy.
Notes.
Menopausal status was inferred based on goserelin and/or leuprorelin records.
The Charlson comorbidity index score [29] was estimated based on Quan et al. [30] (maximum score of 29).
The comorbidities with >2.5% are shown. The comorbidities depicted in the table were identified in the month when the first palbociclib line was initiated.
For patients who received palbociclib in multiple lines, the earliest line of ET combined with palbociclib was counted.
3.2. First subsequent therapy after palbociclib
Of the 1170 patients, 406 were still on palbociclib at the end of the study period, while 764 had discontinued treatment with palbociclib (Supplementary Table S3). Most of the 764 patients (738, 96.6%) received subsequent therapy after palbociclib treatment, with an estimated median follow-up of 11.8 months. Of the 1170 patients, 398 and 358 were treated with palbociclib in the first- and second-line settings, respectively. Among these, 235 (59.0%) and 239 (66.8%) patients, discontinued the first- and second-line treatments, respectively, and 224 (of 235, 95.3%) and 235 (of 239, 98.3%) treated with any subsequent therapy, respectively were further examined.
Among the 224 patients treated with ET + palbociclib in the first-line setting, 60.7% were subsequently treated with endocrine-based therapies, including ET + CDK4/6i (palbociclib or abemaciclib) in 31.2% of cases (Fig. 1). Chemotherapy was administered to 34.4% of the patients. Among the 235 patients treated with ET + palbociclib in the second-line setting, 52.8% were subsequently treated with endocrine-based therapies, including ET + CDK4/6i (29.8%). Chemotherapy was administered to 41.3% of the patients. The abemaciclib + fulvestrant regimen was the most commonly administered subsequent therapy after the first- and second-line therapies (16.1% and 12.8%, respectively), followed by bevacizumab + paclitaxel (12.1% and 12.8%, respectively) and everolimus + exemestane (11.2% and 11.5%, respectively) (Table 2).
Fig. 1.
Type of first subsequent therapy after a) 1st-line and b) 2nd-line palbociclib treatment
Abbreviations: ET, endocrine therapy; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; mTORi, mammalian target of rapamycin inhibitor.
Notes:Patients treated with palbociclib in the first- or second-line settings (n = 459 of 1170 patients) are shown. CDK4/6i refers to palbociclib and abemaciclib.
Table 2.
Regimen of first subsequent therapy after 1st-line and 2nd-line palbociclib treatment.
| Regimen | After 1st-line palbociclib (n = 224) |
After 2nd-line palbociclib (n = 235) |
|---|---|---|
| n (%) | n (%) | |
| ET alone | 39 (17.4) | 24 (10.2) |
| Fulvestrant | 17 (7.6) | 5 (2.1) |
| Tamoxifen | 6 (2.7) | 5 (2.1) |
| Exemestane | 4 (1.8) | 4 (1.7) |
| Letrozole | 4 (1.8) | 3 (1.3) |
| Toremifene | 3 (1.3) | 1 (0.4) |
| ET + CDK4/6i | 70 (31.2) | 70 (29.8) |
| Abemaciclib + fulvestrant | 36 (16.1) | 30 (12.8) |
| Abemaciclib + letrozole | 10 (4.5) | 9 (3.8) |
| Fulvestrant + palbociclib | 9 (4.0) | 8 (3.4) |
| Letrozole + palbociclib | 8 (3.6) | 8 (3.4) |
| ET + mTORi | 27 (12.1) | 30 (12.8) |
| Everolimus + exemestane | 25 (11.2) | 27 (11.5) |
| Chemotherapy alone | 50 (22.3) | 67 (28.5) |
| Eribulin | 13 (5.8) | 16 (6.8) |
| Tegafur + gimeracil + oteracil | 12 (5.4) | 18 (7.7) |
| Capecitabine | 11 (4.9) | 18 (7.7) |
| Paclitaxel | 3 (1.3) | 6 (2.6) |
| Cyclophosphamide + epirubicin | 3 (1.3) | 4 (1.7) |
| Chemotherapy + bevacizumab | 27 (12.1) | 30 (12.8) |
| Bevacizumab + paclitaxel | 27 (12.1) | 30 (12.8) |
| Chemotherapy + ET | 4 (1.8) | 9 (3.8) |
Abbreviations: ET, endocrine therapy; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; mTORi, mammalian target of rapamycin inhibitor.
Notes:Regimens used by ≥ 3 patients and patients treated with palbociclib in the first- or second-line settings (n = 459 of 1170 patients) are shown. CDK4/6i refers to palbociclib and abemaciclib.
Supplementary Fig. S1 shows the type of the first subsequent therapy stratified by the duration of the first-line palbociclib treatment (≤6, 7–<12, and ≥12 months). Subsequent therapies were generally similar between patients treated with palbociclib for ≤6 and 7–<12 months as the first-line treatment. Among patients treated with palbociclib for ≥12 months, more patients used ET alone (24.1%) and ET + CDK4/6i (37.9%) than those with a shorter duration of palbociclib treatments (14.4% and 32.2% for ≤6 months, respectively; and 15.8% and 25.0% for 7–<12 months, respectively; Supplementary Fig. S1).
3.3. TTF of the first subsequent therapy after palbociclib
The median TTF (95% CI) of the first subsequent therapy after palbociclib was 7.5 (6.5–8.4) months and 7.4 (6.5–8.4) months among patients treated with palbociclib in the first- and second-line settings, respectively (Fig. 2).
Fig. 2.
TTF of the first subsequent therapy after palbociclib treatment
Abbreviation: TTF, time to treatment failure; CI, confidence interval.
Notes:Patients treated with palbociclib in the first- or second-line settings (n = 459 of 1170 patients) are shown.
With respect to TTF stratified by the type of the first subsequent therapy, the median TTF (95% CI) of the first subsequent endocrine monotherapy was 4.4 (2.8–13.7) months, while that of ET + CDK4/6i and ET + mTORi was 10.9 (6.5–15.6) and 6.1 (5.1–7.2) months, respectively (Fig. 3 and Supplementary Fig. S2). The TTF of chemotherapy alone and chemotherapy + bevacizumab was 7.2 (4.9–8.5) and 9.4 (6.1–12.1) months, respectively. The subgroup analysis stratified by endocrine sensitivity showed that, the TTF of ET + CDK4/6i was relatively long in both endocrine-resistant and endocrine-sensitive subgroups (Supplementary Fig. S3).
Fig. 3.
TTF of the first subsequent therapy after palbociclib (stratified by type of subsequent therapy)
Abbreviations: TTF, time to treatment failure; ET, endocrine therapy; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; mTORi, mammalian target of rapamycin inhibitor; NE, not estimable.
Notes: The numbers represent the median TTF (95% confidence interval). Patients treated with palbociclib in the first-line setting are shown, and 7 patients treated with therapies not listed above are not shown (n = 217 of 1170 patients). CDK4/6i refers to palbociclib and abemaciclib.
With respect to TTF stratified by the pattern of the CDK4/6i sequence, the median TTF (95% CI) of the first subsequent therapy was 7.7 (2.6–not estimable [NE]) months among patients who switched both ET and CDK4/6i (i.e., ET was switched to another type, and palbociclib was switched to abemaciclib) following the first-line ET + palbociclib (Fig. 4). The median TTF of patients who switched the type of ET while sequentially using palbociclib was 8.7 (2.9–11.2) months, and that of patients who switched CDK4/6i (i.e., palbociclib to abemaciclib) while on the same type of ET in the following second line was 20.1 (6.5–NE) months.
Fig. 4.
TTF of ET plus palbociclib and that of the first subsequent ET plus CDK4/6i (stratified by three patterns of CDK4/6i sequence)
Abbreviations: TTF, time to treatment failure; ET, endocrine therapy; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; NE, not estimable.
Notes: The numbers represent the median TTF (95% confidence interval). Patients treated with ET + palbociclib in the first-line setting and subsequent ET + CDK4/6i (palbociclib or abemaciclib) are shown, and those treated with CDK4/6i + other combinations or other therapies in the first subsequent line are not shown (n = 64 of 1170 patients).
Visual examination revealed no apparent relationship between the duration of prior ET + palbociclib and that of subsequent abemaciclib (Fig. 5). Of the 54 patients who received ET + abemaciclib as the second-line treatment after first-line ET + palbociclib, 11 switched to abemaciclib at 125 mg/day of palbociclib, and 4 of whom switched within 2 months of starting palbociclib treatments.
Fig. 5.
TTF of prior palbociclib and the subsequent abemaciclib for individual patients
Abbreviations: TTF, time to treatment failure; ET, endocrine therapy.
Notes: Patients treated with palbociclib plus ET in the first-line setting and abemaciclib plus other therapies or monotherapy in the subsequent line of therapy (n = 54 of 1170 patients) are shown. The patient number shown on the y-axis is arbitrary.
4. Discussion
This study is the first to report the treatment patterns and TTF of the subsequent therapy after palbociclib treatment using hospital-based medical claims data in a Japanese real-world setting. We found that more than 60% of patients with HR+/HER2− ABC were subsequently treated with endocrine-based therapies following palbociclib, and approximately one-third of the patients continued on CDK4/6i. The median TTF of the first subsequent therapy was 7.5 months among patients treated with ET + palbociclib as the first-line therapy. Among various subsequent therapies, TTF of the first subsequent ET + CDK4/6i was the longest, with a median TTF of 10.9 months.
Our real-world study showed that 60.7% of patients treated with palbociclib as the first-line therapy were subsequently treated with endocrine-based therapies, consistent with the PALOMA-2 study involving patients treated with letrozole + palbociclib as the first-line therapy [5] and its subgroup analysis involving Japanese patients [12]. A noteworthy result of our real-world study was that approximately 30% of patients treated with palbociclib in the first and second lines continued on CDK4/6i, consistent with a real-world study from the U.S [31]. Although various guidelines currently do not support CDK4/6i sequential use [[2], [3], [4]], these observed results indicate that CDK4/6i sequential use may be fairly common in clinical practice. A previous preclinical study suggested that different types of CDK4/6i target different CDK proteins (e.g., palbociclib and ribociclib inhibit CDK4/6, and abemaciclib inhibits CDK4/6/9) [32]. Such a sequential use may correspond to this evidence. However, contrary evidence is also available from cellular studies, in which HR + BC cells with acquired resistance to CDK4/6i were cross-resistant to another CDK4/6i [33,34]; thus, further clinical and translational research is warranted.
Among the first subsequent therapies following palbociclib, the median TTF of ET + CDK4/6i was the longest (10.9 months). Additionally, generally similar results were also found in the endocrine-resistant and endocrine-sensitive subgroups, with relatively long TTF for ET + CDK4/6i. Although evidence is limited, a previous real-world study has shown a longer progression free survival (PFS) for patients who sequentially used CDK4/6i following the first-line CDK4/6i treatment than among those who used the non-CDK4/6i treatment (median PFS, 17.3 vs. 8.4 months [35]). Evidence from another real-world study also supports sequential CDK4/6i use, with a PFS of 11.27 months for patients who continued on CDK4/6i (presumably, palbociclib, ribociclib, and abemaciclib) and 4.73 months for those who switched to chemotherapy [36]. Furthermore, a study based on a retrospective chart review reported median PFS of 17.0 months in patients who received hormone-based therapy following first-line palbociclib [37]. Additionally, favorable preliminary evidence supporting sequential CDK4/6i use was reported in the phase II MAINTAIN trial [17]. The phase II PACE trial is underway [14], with a preliminary report recently presented at a conference [38]. Gombos et al. [39] state that there are no solid data confirming the efficacy of sequential CDK4/6i use and optimal sequencing. Continuing inhibition of the CDK4/6 pathway after CDK4/6i exposure remains an important clinical question. Further data are eagerly awaited to determine ET + CDK4/6i provides the acceptable treatment option following ET + palbociclib.
One of the remaining clinical questions is the optimal pattern of the CDK4/6i sequence following ET + palbociclib (i.e., switching both ET and CDK4/6i, only ET, or only CDK4/6i). In the present study, the median TTF was 20.1 months for patients who switched from ET + palbociclib to the same ET + abemaciclib, and this duration was longer than that of any other subgroup (7.7–8.7 months). Caution should be exercised in interpreting this result because the median TTF of the prior palbociclib was short (5.6 months) compared to the other subgroups (10.6–12.5 months), and this subgroup (same ET + abemaciclib) may include patients who switched to abemaciclib owing to adverse events rather than disease progression. To date, no prospective clinical data on fulvestrant + abemaciclib following ET + palbociclib exists; however, the phase III postMONARCH trial is underway [16], and a subset of this trial and the phase II PACE trial [14] may answer this question.
The median TTF of ET + mTORi following ET + palbociclib was 6.1 months in the present study, and the result is generally similar to the median PFS (7.8 months) of everolimus plus-exemestane in a phase III randomized clinical trial involving patients with HR + ABC with recurrence/progression during or after a non-steroidal AI [40]. Previous reports have shown that sensitivity to mTORi was maintained in CDK4/6i-resistant cell lines [33]. Further data may shed light on the efficacy of ET + mTORi following ET + palbociclib. In contrast, the TTF of endocrine monotherapy was the shortest (median TTF, 4.4 months) among the first subsequent therapies following palbociclib, and was shorter than the previously reported median PFS (6.5 months) [41] or median TTF (6.18 months) [42] for patients with estrogen receptor-positive ABC treated with fulvestrant in the second-line settings. In addition, recent reports revealed a much shorter PFS with endocrine monotherapy following ET + CDK4/6i (median PFS, 1.9 [43] and 1.94 [44] months). Cancer biology alterations were observed in CDK4/6i-resistant cell lines in a nonclinical study, and this alteration suppressed the responsiveness to ETs [33]. Although these comparisons, especially between observational studies and clinical trials, should be carefully made, these results suggest that currently available endocrine monotherapy may be ineffective after CDK4/6i treatment. Nonetheless, we consider that our results should be interpreted with caution, as each of our treatment group may have heterogeneous patient backgrounds in terms of including endocrine sensitivity. Numerous treatment strategies and novel agents are currently being investigated [3,4,[13], [14], [15], [16],45,46], and further reports and the development of resistance-based treatment strategies are eagerly awaited.
4.1. Limitations
This study has limitations. Some patients' medical histories may be incomplete because this study used a hospital-based medical claims database; patients’ medical histories before registering in the database and after switching to other hospitals or clinics may be uncaptured in the database. Small proportions of patients (5% and 2% in first and second lines, respectively), although not examined in the present study in detail, who had discontinued palbociclib treatment did not receive further treatment, possibly due to change of hospital or death during palbociclib treatment. The database did not contain information on the reason for treatment failure including treatment switch, and clearly distinguishing treatment failure/switch was not possible owing to disease progression or adverse events. Similarly, the cancer stage or HR+/HER2− diagnosis was not recorded in the database; therefore, we identified patients with HR+/HER2− ABC based on the records of diagnosis/surgery, ETs, and HER2-targeted therapies. Some patient characteristics such as site of metastasis [47], ECOG Performance Status, and histopathological characteristics (e.g., tumor grade and histology) that are likely to affect TTF and patient prognosis are uncaptured in the database. As our treatment groups may have heterogeneous patient backgrounds, we have additionally provided two separate Kaplan-Meier estimates for patients with variable endocrine sensitivity. Further investigations incorporating these patient backgrounds and investigating additional endpoints such as overall survival are required. The follow-up duration from initiation of the subsequent therapy was relatively short (median: 11.8 months). The patients examined in the present study may have largely comprised those who had prematurely discontinued palbociclib treatment. Of the 1170 patients, approximately 35% were still receiving palbociclib at the end of the study period and were not examined further. Therefore, evaluation with an extended follow-up will be of clinical value. Finally, the findings of this study may not be generalizable to all patients in Japan because the database contains data from facilities equipped with emergency departments and participating in the MDV database.
5. Conclusion
This real-world study revealed that more than 60% of patients were subsequently treated with endocrine-based therapies following the first-line palbociclib treatment, and approximately one-third of the patients continued on CDK4/6i in Japan. ET + CDK4/6i provided the longest treatment duration. Further data are awaited to determine whether ET + targeted therapy with CDK4/6i and mTORi provides acceptable treatment options following ET + palbociclib.
Statements and declarations
Competing interests
Yasuaki Muramatsu and Kanae Togo are employees of Pfizer Japan Inc. (Tokyo, Japan) and shareholders of Pfizer Inc. Hiroji Iwata has received honoraria and research funding from AstraZeneca K.K. and Pfizer and fees for promotional materials from AstraZeneca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Author contributions
The authors certify that each co-author listed on this page participated sufficiently in the work to take responsibility for the content, and that all those who qualify are listed. Individual contributions are as follows: Conceptualization, Masataka Sawaki, Yasuaki Muramatsu, and Hiroji Iwata; Methodology, Masataka Sawaki, Yasuaki Muramatsu, and Kanae Togo; Resources, Kanae Togo; Writing – original draft preparation, Masataka Sawaki, Yasuaki Muramatsu, and Kanae Togo; Writing – review and editing, Masataka Sawaki, Yasuaki Muramatsu, Kanae Togo, and Hiroji Iwata. In addition to the above, all authors gave final approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Data availability
The data that support the findings of this study are available for purchase from Medical Data Vision Co., Ltd. (MDV) and restrictions apply to the availability of these data due to contractual agreements between MDV and hospitals. For inquiries about access to the dataset used in this study, please contact MDV (website: (JP) https://www.mdv.co.jp; (ENG) https://en.mdv.co.jp/; e-mail: ebm_sales@mdv.co.jp).
Ethics approval
This retrospective observational study used the anonymized, secondary data originally collected for healthcare claims purposes. According to the Ethical Guidelines for Medical and Biological Research Involving Human Subjects in Japan, this study did not require approval from an institutional review board and informed patient consent.
Consent to participate
Not applicable.
Consent to publish
Not applicable.
Acknowledgements
The authors would like to thank Tetsumi Toyoda of Clinical Study Support, Inc. for statistical analysis and Rie Hagihara of Clinical Study Support for medical writing and editorial support, and both were funded by Pfizer Japan Inc. This work was supported by Pfizer Japan Inc. (Tokyo, Japan). The sponsor was involved in the study design, analysis, interpretation of data, the writing of the report, decision to publish, and preparation of the manuscript.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.breast.2023.05.006.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available for purchase from Medical Data Vision Co., Ltd. (MDV) and restrictions apply to the availability of these data due to contractual agreements between MDV and hospitals. For inquiries about access to the dataset used in this study, please contact MDV (website: (JP) https://www.mdv.co.jp; (ENG) https://en.mdv.co.jp/; e-mail: ebm_sales@mdv.co.jp).