Background
It is estimated that >150,000 patients were living with metastatic breast cancer (MBC) in the United States in 2017.1 Although progress in treatment strategies has led to significant improvement in overall survival in recent years,1–4 MBC remains largely incurable, resulting in the death of >40,000 patients each year.5 Cyclin-dependent kinase (CDK) 4/6 inhibitors are a class of agents recently introduced in the clinic for the treatment of advanced hormone receptor–positive (HR+) and HER2-negative (HER2–) breast cancer. Since the initial FDA approval in February 2015 of palbociclib in combination with letrozole in the first-line setting based on data from the PALOMA-1 trial,6,7 several phase III randomized trials have confirmed the efficacy of CDK4/6 inhibition in both first-line8–10 and endocrine-resistant settings,11–13 leading to the approval of palbociclib in combination with fulvestrant, and 2 other CDK4/6 inhibitors, ribociclib and abemaciclib. As the treatment landscape for HR+/HER2– MBC rapidly evolves, questions remain as to the optimal ordering of various treatment options and the efficacy of subsequent therapies post–disease progression while on a CDK4/6 inhibitor. An applied understanding of the practice patterns and outcomes of CDK4/6 inhibitors and subsequent treatments may generate a hypothesis for future prospective studies.
Therefore, this retrospective study was conducted to examine a single institution’s experience regarding physician practice patterns and the outcomes of palbociclib and subsequent therapies after disease progression on palbociclib in patients with MBC.
Methods
Patients
After approval was obtained from the Washington University in St. Louis Institutional Review Board, a retrospective chart review was performed of all patients with MBC treated at Washington University in St. Louis Siteman Cancer Center who received palbociclib from February 9, 2015, to August 10, 2017. Charts were reviewed through the institution’s electronic medical record database. All clinical encounters, basic demographic information, surgery and pathology reports, and treatment history were reviewed. Patients were deemed eligible for inclusion in this analysis if they met each of the following criteria: age ≥18 years, male or postmenopausal or premenopausal female receiving gonadotropin-releasing hormone agonist, diagnosis of stage IV de novo or recurrent breast cancer, and previous palbociclib treatment. A total of 200 patients met the inclusion criteria and their clinical data were collected. Duration of therapy was used to calculate progression-free survival (PFS) for each treatment regimen. Palbociclib treatment was considered first-line if it was administered in the setting of no prior systemic therapy in the metastatic setting or at least 1 year from the completion of adjuvant hormone therapy. Palbociclib was considered second-line if received postprogression on a first-line therapy for MBC or on relapse at or within 1 year from the completion of adjuvant hormone therapy. HR and HER2 status were defined using the ASCO/College of American Pathologists guidelines.14,15
Statistical Analysis
All statistical analyses were performed using SAS 9.4 (SAS Institute Inc.). The Kaplan-Meier product limit method was used to estimate median PFS (mPFS) and generate time-to-event curves. The log-rank test was used for all comparisons. All reported P values were 2-sided, and P≤.05 was considered statistically significant.
Results
Between February 2015 and August 2017, 230 patients were treated with palbociclib at our institution. A total of 200 patients, with a median follow-up of 19.5 months (range, 1.7–34.9 months), met the inclusion criteria and were included in the analysis (Figure 1). Patient demographics and clinical characteristics are detailed in Table 1. Of the patients, 98% were women, 78% were white, and 19.5% were black. Median age was 59.4 years (range, 50.7–67.7 years) at initiation of palbociclib treatment. Most patients (n=192) were diagnosed with HR+/HER2– disease. Of the combination therapies with palbociclib, 73.5% of the patients received palbociclib + letrozole and 25% received palbociclib + fulvestrant. Among the 42 patients who received palbociclib in the first-line setting, 39 (92.9%) received palbociclib + letrozole and the remaining 3 patients (7.1%) received palbociclib + fulvestrant. Among the 50 patients who received palbociclib in the second-line setting, 34 (68%) received palbociclib + letrozole and 14 (28%) received palbociclib + fulvestrant. In the third-line and beyond setting, 68.5% were treated with palbociclib + letrozole (n=74) and 30.6% with palbociclib + fulvestrant (n=33).
Common subsequent therapies after disease progression (DP) on palbociclib in metastatic breast cancer (MBC).
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 2; 10.6004/jnccn.2018.7094
Patient Demographics and Clinical Characteristics
Among the 192 patients with HR+/HER2– disease, mPFS on palbociclib was 20.7 months in the first-line setting (n=40) compared with 12.8 and 4.0 months in the second- (n=50) and subsequent-line settings (n=102), respectively (P<.001) (Figure 2). mPFS did not differ significantly among patients who received first-line palbociclib in the setting of either de novo metastatic disease (20.7 months; n=21) or at recurrence, which occurred at least 1 year from the completion of adjuvant therapy (not reached; n=21; P=.84). Similarly, no difference in mPFS was observed among the 50 patients who received palbociclib as second-line treatment, in the setting of relapse on adjuvant therapy (14.7 months; n=24), or at progression on first-line therapy in the metastatic setting (11.4 months; n=26; P=.31). The percentage of patients on palbociclib as a first-line treatment was approximately 15% during the first year after palbociclib approval, and increased to 25% to 30% at approximately 1.5 years after approval. Significantly more patients were given palbociclib as third- or later-line therapy during an earlier period (February 2015 through June 2016) compared with a later period (July 2016 through August 2017) (61% vs 46.5%; P=.0428).
Kaplan-Meier curves of progression-free survival in patients with HR-positive, HER2-negative metastatic breast cancer treated with palbo in the first-, second-, and third-line/beyond settings.
Abbreviations: HR, hormone receptor; mPFS; median progression-free survival; palbo, palbociclib.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 2; 10.6004/jnccn.2018.7094
Among the 133 patients who experienced disease progression on palbociclib, 104 moved on to the next line of treatment (Figure 1). Of these, 70 patients received chemotherapy and 32 received either hormone therapy with letrozole (n=10), fulvestrant (n=3), tamoxifen (n=2), or anastrozole (n=1), or hormone therapy in combination with targeted agents, including exemestane + everolimus (n=12), exemestane + entinostat (n=2), or fulvestrant + palbociclib (n=2). The most common regimens after progression on palbociclib were single-agent capecitabine (n=21), eribulin (n=16), nab-paclitaxel (n=15), and exemestane + everolimus (n=12; Figure 1). mPFS was 4.2 months for patients who received chemotherapy versus 5.6 months for those who received hormone therapy (P=.34), and was similar among patients on capecitabine, eribulin, and nab-paclitaxel. Exemestane + everolimus was the most commonly used hormone therapy combination after progression on palbociclib, with mPFS of 4.9 months. Among patients who received chemotherapy, mPFS was not reached, 4.7, and 4.1 months after progression on first-line (n=7), second-line (n=14), and subsequent-line palbociclib (n=49), respectively (P=.56; Figure 3). For patients who received hormone therapy or hormone therapy plus targeted agents, mPFS was 17.0, 9.3, and 4.2 months after progression on first-line (n=7), second-line (n=9), and subsequent-line palbociclib (n=16), respectively (P=.04; Figure 4). Among the 7 patients who received hormone therapy after progression on first-line palbociclib, 3 received letrozole, 1 received fulvestrant, 1 received fulvestrant + palbociclib, and 2 received exemestane + everolimus.
Kaplan-Meier curves of progression-free survival in patients treated with chemotherapy after disease progression on palbo administered in the first-, second-, or ≥third-line setting.
Abbreviations: mPFS, median progression-free survival; palbo, palbociclib.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 2; 10.6004/jnccn.2018.7094
Kaplan-Meier curves of progression-free survival in patients treated with hormone therapy after disease progression on palbo administered in the first-, second-, or ≥third-line setting.
Abbreviations: mPFS, median progression-free survival; palbo, palbociclib.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 2; 10.6004/jnccn.2018.7094
A total of 7 patients received combination palbociclib + fulvestrant after disease progression on palbociclib plus letrozole; among these patients, 3 (patients 6, 48, and 186) were switched to palbociclib + fulvestrant immediately after disease progression on palbociclib + letrozole for at least 6 months as first-line therapy. All 3 patients experienced prolonged disease control, with PFS of ≥7.9 (treatment is ongoing at time of analysis), 29.9, and 6.8 months. The remaining 4 patients received intervening therapy (3 received chemotherapy, 1 received exemestane + everolimus) before switching to palbociclib + fulvestrant, none of whom experienced disease stabilization for >6 months.
Data on neutropenia were collected and graded according to NCI Common Terminology Criteria for Adverse Events, version 4.1. Grade 1 neutropenia occurred in 15.5% of the patients (n=31), grade 2 in 31.5% (n=63), grade 3 in 38.5% (n=77), and grade 4 in 3% (n=6). Dose reductions occurred in 58 patients (29%). Information on nonhematologic adverse events (AE) was collected based on physician progress notes and not graded; AEs included mucositis (n=8; 4%), fatigue (n=7; 3.5%), abscess (n=4; 2%), nausea/vomiting (n=4; 2%), diarrhea (n=3; 1.5%), rash (n=3; 1.5%), elevated aspartate aminotransferase/alanine aminotransferase levels (n=3; 1.5%), and neuropathy, which occurred in at least 1.5% of patients.
Discussion
Palbociclib in combination with hormone therapy was shown to significantly improve PFS compared with hormone therapy alone in patients with advanced HR+/HER2– breast cancer,6,7 leading to FDA approval of palbociclib in combination with an aromatase inhibitor (AI; as first-line therapy) in February 2015, and with fulvestrant (for endocrine-resistant disease) in March 2017. Subsequently, 2 other CDK4/6 inhibitors, ribociclib and abemaciclib, gained FDA approval based on results of randomized phase III trials.8,10,12,13,16 Because CDK4/6 inhibitors are becoming a standard of care for the treatment of advanced HR+/HER2– breast cancer, an unmet need exists to assess their impact on clinical practice in the real-world setting.
In this retrospective single-institution study, palbociclib in combination with hormone therapy led to mPFS of 20.7, 12.8, and 4.0 months when administered in the first-line, second-line, and third-line or beyond settings, respectively. These results are comparable to the mPFS of 24.8 and 9.5 months in the PALOMA-2 (first-line setting)9 and PALOMA-3 (endocrine-resistant setting)11 trials, respectively, and 4.8 months in heavily pretreated patients with HR+/HER2– MBC17 treated with combination palbociclib and hormone therapy. These data confirmed the efficacy of palbociclib in an applied setting. Interestingly, a significant proportion of the patients received palbociclib in the third-line setting or beyond, which is consistent with 2 other retrospective studies that examined the real-world palbociclib practice pattern.18,19 This likely reflects the prescription of palbociclib for existing patients already receiving therapy for advanced disease. More patients were started on palbociclib in the first-line setting, with fewer patients in the third-line setting or beyond in more recent months. No unexpected AEs were observed in the present study, and clinically significant nonhematologic AEs were uncommon. Grade 3/4 neutropenia was observed in approximately 40% of patients and dose reductions occurred in 29%, comparable to results from previous phase III studies.9,11
CDK4/6 inhibitors have become an integral component in the treatment of advanced HR+ breast cancer. However, the optimal therapy after disease progression on a CDK4/6 inhibitor is unknown and no data are available in the literature regarding the efficacy of various treatment strategies. In this study, among the 104 patients who received subsequent therapy, 70 (67%) received chemotherapy and 32 (31%) received single-agent or combination hormone therapy. The higher proportion of patients who received chemotherapy is likely a reflection of treatment with palbociclib in the later settings. Nonetheless, hormone therapy was effective, leading to mPFS of 17.0, 9.3, and 4.2 months after disease progression on palbociclib administered in the first-line (n=7), second-line (n=9), and third-line or beyond settings (n=16), respectively. The efficacy of hormone therapy observed in this study provides reassurance for the practice and supports its use after disease progression on a CDK4/6 inhibitor. Comparison of efficacy between hormone therapy and chemotherapy cannot be made because of patient heterogeneity and selection bias.
Of the hormone therapy regimens administered after disease progression on palbociclib, exemestane + everolimus was most commonly prescribed; the mPFS was 4.9 months, which is relatively short compared with the 7.8 months reported in the BOLERO-2 trial.20 However, most patients received this combination beyond the third-line setting in our retrospective study, which differs from BOLERO-2 trial, and therefore the efficacy of this combination may be underestimated. Additionally, preclinical studies showed upregulation of PI3K pathway signaling to be a resistance mechanism to hormone therapy21,22 and CDK4/6 inhibition,23–25 and that PI3K/PDK1 pathway inhibition has antitumor activity on CDK4/6 inhibitor resistance.23–25 A larger sample size and prospective studies are necessary for more precise estimation of the PFS and predictors of response for mTOR inhibitors in the setting of CDK4/6 inhibitor resistance.
Synergistic antitumor activity between hormone therapy and CDK4/6 inhibition was initially observed in preclinical studies of HR+ breast cancer cell lines.26 Although CDK4/6 inhibitors, including palbociclib, have shown single-agent activity in patients who are endocrine-resistant,27–29 mPFS increased for palbociclib in combination with the hormone therapy on which disease previously progressed compared with palbociclib alone (10.8 vs 6.5 months; hazard ratio, 0.69; 95% CI, 0.4–1.1) in a randomized phase II trial of postmenopausal women with HR+/HER2– advanced breast cancer that progressed on the same hormone therapy.28 One practical consideration is whether continued CDK4/6 inhibition remains important at disease progression on combination AI + CDK4/6 inhibitor. In a small study of 16 patients with MBC treated with palbociclib and letrozole, mutations in ESR1 in the circulating tumor DNA detected early in therapy were associated with a significantly shorter PFS (3.3 vs 9.0 months; P=.038).30 Because ESR1 mutations are an established acquired resistance mechanism to AIs,31–34 perhaps a more effective endocrine therapy partner for the CDK4/6 inhibitor would be most effective in this setting. Notably, prolonged disease control was observed among the 3 patients who remained on palbociclib but switched from letrozole to fulvestrant at disease progression. All 3 patients had an initial clinical benefit (6 months of PFS) from letrozole + palbociclib combination therapy; however, whether these 3 patients harbored an ESR1 mutation and whether fulvestrant alone would have led to the same clinical benefit is unknown, and continued CDK4/6 inhibition postprogression is not standard practice.
The utility of continued CDK4/6 inhibition after progression is being addressed in prospective clinical trials. The ongoing PACE trial (ClinicalTrials.gov identifier: NCT03147287) is a randomized phase II study comparing the PFS for fulvestrant alone (Arm A) versus fulvestrant + palbociclib (Arm B) versus fulvestrant + palbociclib + avelumab (Arm C) in the setting of acquired resistance to previous CDK4/6 inhibition among patients with advanced HR+/HER2– breast cancer. The TRINITI-1 trial (NCT01857193) is a single-arm phase II trial assessing the antitumor activity of adding the CDK4/6 inhibitor ribociclib to combination exemestane + everolimus in patients who developed acquired resistance to CDK4/6 inhibitors. However, HR+/HER2– breast cancer is a clinically and molecularly heterogeneous group of diseases, and resistance mechanisms to CDK4/6 inhibitors may differ among individual patients. Loss of retinoblastoma protein as an acquired mechanism to CDK4/6 inhibitor has been observed in both preclinical23 and clinical settings,35 for which subsequent CDK4/6 inhibition may not be effective. In addition, amplification of CDK6,36 G1/S-phase cyclins,23 or fibroblast growth factor pathway components37 has been implicated in resistance to CDK4/6 inhibitors. An individualized treatment approach based on the specific resistance mechanisms may be necessary.
Our study has several limitations, including the relatively small sample size, the retrospective nature of the analysis, possible selection bias of treating physicians in choosing different treatment regimens, and the relatively short follow-up of 19 months. Nonetheless, this study confirmed the activity of palbociclib in combination with hormone therapy in an applied setting, and the activity of single-agent or combination hormone therapy in at least a subset of patients. The significant variation in practice patterns after disease progression on palbociclib necessitates future studies to address optimal treatment approaches in this setting.
Conclusions
To our knowledge, this is the first retrospective study that examined the applied practice pattern of prescribing the CDK4/6 inhibitor palbociclib and subsequent treatment regimens, and survival outcomes after disease progression on palbociclib. mPFS and safety profiles were comparable to those observed in previous studies. We also observed that more patients were started on palbociclib in the first-line setting in a more recent period. Among the wide range of treatment regimens prescribed after disease progression on palbociclib, capecitabine and combination exemestane + everolimus were among the most common. Although the practice pattern in our institution may not be generalizable to other institutions, and a few patients received nonstandard approaches such as continuation of CDK4/6 inhibition postprogression, our study confirmed the efficacy of CDK4/6 inhibitors and the activity of subsequent hormone therapy alone or in combination with mTOR inhibition. Future clinical trials that inform the ideal sequencing of various therapy regimens in the context of the clinical and molecular heterogeneity of advanced HR+ breast cancer are warranted.
See page 190 for related commentary.
Author Contributions: Study design: Krishnamurthy, Ma. Patient care and provision of clinical information: Ademuyiwa, Weilbaecher, Suresh, Bose, Cherian, Hernandez-Aya, Frith, Peterson. Acquisition of data: Xi, Oza, Thomas. Statistical data analysis: Xi. Supervision of data analysis: Luo. Study supervision: Ma. Drafting of manuscript: Xi, Oza, Ademuyiwa, Weilbaecher, Suresh, Bose, Cherian, Hernandez-Aya, Frith, Peterson, Luo, Krishnamurthy, Ma. Manuscript proofreading: Thomas. Critical revisions and final approval: Xi, Oza, Ademuyiwa, Weilbaecher, Suresh, Bose, Cherian, Hernandez-Aya, Frith, Peterson, Luo, Krishnamurthy, Ma.
Disclosures: Dr. Ademuyiwa has disclosed that he receives institutional research funding from Pfizer Inc. Dr. Bose has disclosed that he received an institutional research grant from Puma Biotechnology, is a consultant for Genentech, and receives honorarium from Novartis and Foundation Medicine, Inc. Dr. Ma has disclosed that she receives institutional research funding from Pfizer Inc. and is a consultant for Pfizer Inc., Eli Lilly and Company, and Novartis. The remaining authors have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.
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