Research ArticleClinical Studies

Subsequent-abemaciclib Treatment After Disease Progression on Palbociclib in Patients With ER-positive HER2-negative Metastatic Breast Cancer

HIROHITO SEKI, TAKASHI SAKURAI, AKIHISA SAKURADA, TETSUHIKO KINOSHITA and KEN SHIMIZU
Anticancer Research February 2022, 42 (2) 1099-1106; DOI: https://doi.org/10.21873/anticanres.15572

Abstract

Background/Aim: This study investigated the efficacy of continuing cyclin-dependent kinase (CDK) 4 and 6 inhibitors in patients with estrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2– ) metastatic breast cancer (MBC) after disease progression on prior-palbociclib combined with endocrine therapy (ET). Patients and Methods: This retrospective study based on 25 ER+/HER2– MBC patients reported the efficacy and predictive factors of subsequent-abemaciclib after disease progression on prior-palbociclib. Results: The overall response rate and clinical benefit rate were 16.0% and 44.0%, respectively. The median progression-free survival (PFS) was 5.3 months. In multivariate analysis, the best overall response (BOR) to prior-palbociclib was the only independent predictive factor for PFS (p=0.015). The median time to chemotherapy was 33.9 months. The median PFS in patients treated with next-line chemotherapy after progression on subsequent-abemaciclib was 6.2 months. Conclusion: BOR to prior-palbociclib was the only independent predictive factor for PFS in ER+/HER2– MBC patients undergoing subsequent-abemaciclib after disease progression on prior-palbociclib.

Key Words:

Breast cancer is the most common malignant disease and a major cause of cancer-related deaths among women worldwide (1). With the development of novel drugs over the past few decades, the prognosis has improved (2, 3). Consequently, treatment regimens for estrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC) have evolved. One of the popular strategies to interfere with cancer progression is targeting molecular components of the cell cycle, such as the cyclin-dependent kinase 4 and 6 (CDK4/6)-cyclin D complex that controls the G1 to S phase transition (4). Thus, a combination of endocrine therapy (ET) with a CDK4/6 inhibitor (CDK4/6i) was approved for ER+/HER2– MBC.

Palbociclib was the first approved CDK4/6i to be used in combination with ET for ER+/HER2– MBC treatment. PALOMA 2 and PALOMA 3, which were phase III trials including postmenopausal women with hormone receptor-positive (HR+)/HER2– MBC, showed significantly improved progression-free survival (PFS) in the patients treated with palbociclib plus ET (5, 6). In addition, the efficacy of palbociclib combined with ET has been reported in real-world data (7). Abemaciclib was another CDK4/6i approved for ER+/HER2– MBC. MONARCH 2 and MONARCH 3, which were also phase III trials, showed significantly improved PFS in the patients treated with abemaciclib plus ET (8, 9).

Currently, CDK4/6i combined with ET has become the standard of care as first- or second-line treatment for ER+/HER2– MBC. However, at present, there are no guidelines for the selection of appropriate treatments after disease progression on prior CDK4/6i treatment combined with ET (10). Therefore, this retrospective study aimed to verify the efficacy and evaluate predictive factors of clinical outcomes in the patients with ER+/HER2– MBC during subsequent-abemaciclib treatment after disease progression on prior-palbociclib combined with ET.

Patients and Methods

In total, 81 patients with ER+/HER2– MBC were treated with palbociclib and ET at our medical center between December 2017 and November 2020. Among them, 25 patients who received subsequent-abemaciclib after disease progression on prior-palbociclib were included. All patients provided informed consent for the indicated treatment. This retrospective study was approved by the relevant ethics approval board (no. 20-12), and all procedures involving human subjects were conducted in accordance with the Declaration of Helsinki and its latest amendments (11).

Palbociclib (125 mg/day, oral) was administered on days 1-21, followed by 7 days of treatment in every 28-day cycle. Abemaciclib (300 mg/day, oral) was administered on days 1-28 in every 28-day cycle. Letrozole or anastrozole was administered on days 1-28 in every 28-day cycle. Fulvestrant (500 mg, intramuscular) was administered on days 1 and 15 (cycle 1) and then every 28 days, starting from day 1 of cycle 1. The therapeutic effects were evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1) (12). The severity of treatment-related adverse events (TRAEs) was recorded and graded according to the National Cancer Institute Common Terminology Criteria for Treatment Adverse Events (CTCAE v4.0) (13).

Statistical analysis. Statistical analysis was performed using SPSS 23.0 (SPSS Inc., Chicago, IL, USA). Clinicopathological variables were compared using Fisher’s exact test. The Mann–Whitney U-test was used to compare categorical variables. PFS and time to chemotherapy (TTC) were estimated using Kaplan–Meier analysis with 95%CIs. HRs were estimated using the Cox proportional hazard regression models. Statistical significance was set at p<0.05.

Results

Patient characteristics. The median age was 69 years, and four women were premenopausal. Stage IV disease occurred in 28.0% (7/25) and visceral metastases were observed in 68.0% (17/25) of the patients. The treatment line of prior-palbociclib was the first-line in 3 (12.0%), second-line in 11 (44.0%), and third- and late-line in 11 patients (44.0%). The median PFS of prior-palbociclib plus ET was 6.3 months (95%CI=5.814-6.786). Subsequent-abemaciclib combined with fulvestrant after disease progression on prior-palbociclib was administered in 64.0% (16/25) of the patients. Median numbers of previous ET and chemotherapy of subsequent-abemaciclib were 2 and 0, respectively (Table I).

View this table:
Table I.

Patient characteristics.

Efficacy. Subsequent-abemaciclib after disease progression on prior-palbociclib resulted in an ORR and clinical benefit rate (CBR) of 16.0% (4/25) and 44.0% (11/25), respectively (Table II). Kaplan–Meier curve analysis showed that the median PFS was 5.3 months (95%CI=3.082-7.518) (Figure 1). Univariate analysis revealed that the best overall response (BOR) ≥PR and progression-free interval (PFI) ≥6 months in prior-palbociclib contributed to better clinical outcomes. Moreover, in multivariate analysis, BOR to prior-palbociclib was the only independent predictive factor for PFS (HR=0.190; 95%CI=0.050-0.722; p=0.015) (Table III).

View this table:
Table II.

Best overall response rate in patients with ER+/HER– MBC who were treated with subsequent-abemaciclib after disease progression on prior-palbociclib.

Figure 1.
Figure 1.

Kaplan–Meier curve analysis of the progression-free survival in patients with ER+/HER2– MBC who were treated with subsequent-abemaciclib after disease progression on prior-palbociclib. PFS: Progression-free survival; ER: estrogen receptor; HER2: human epidermal growth factor receptor 2; MBC: metastatic breast cancer; ET: endocrine therapy; CI: confidence interval.

View this table:
Table III.

Univariate and multivariate analyses of the progression-free survival in patients with ER+/HER2– MBC treated with subsequent-abemaciclib after progression on prior-palbociclib.

Treatment-related adverse events. With regard to grade ≥3 TRAEs in the subsequent-abemaciclib, neutropenia and diarrhea were observed in 16.0% (4/25); appetite loss and fatigue in 12.0% (3/25); leukopenia and anemia in 8.0% (2/25); and thrombocytopenia and liver dysfunction in 4.0% (1/25) of patients (Table IV).

View this table:
Table IV.

Treatment related toxicities in patients with ER+/HER2– MBC treated with subsequent-abemaciclib after disease progression on prior-palbociclib.

Exposures to the treatment. Twelve patients (48.0%) required dose reduction due to TRAEs grade ≥3 in subsequent-abemaciclib. Of them, 10 patients required one dose-level reduction and 2 needed two dose-level reductions. Three patients (12.0%) required dose discontinuation: two had uncontrollable appetite loss and nausea and one had pneumonia (Table V).

View this table:
Table V.

Dose reduction and discontinuation of subsequent-abemaciclib in patients with ER+/HER2– MBC after disease progression on prior-palbociclib.

Time to the first use of chemotherapy and treatments after subsequent CDK4/6i administration. Of the 25 patients, 12 were not administered any prior chemotherapy and the median TTC in those treated with subsequent-abemaciclib was 33.9 months (95%CI=11.334-56.136) (Figure 2). Next-line treatment after disease progression on subsequent-abemaciclib in the patients who were not administered prior chemotherapy was performed in 2 (8.0%) who were treated with ET and in 12 (48.0%) who were treated with chemotherapy (1 taxane-based, 7 eribulin, and 4 oral 5-fluorouracil). The median PFS in patients treated with chemotherapy after disease progression on subsequent-abemaciclib treatment was 6.2 months (95%CI=3.484-8.916) (Figure 3).

Figure 2.
Figure 2.

Kaplan–Meier curve analysis of the time to treatment chemotherapy in patients with ER+/HER2– MBC who were treated with subsequent-abemaciclib after disease progression on palbociclib (no administration of any prior chemotherapy, n=12). TTC: Time to treatment chemotherapy; ER: estrogen receptor; HER2, human epidermal growth factor receptor 2; MBC: metastatic breast cancer; CI: confidence interval.

Figure 3.
Figure 3.

Kaplan–Meier curve analysis of the progression-free survival in patients with ER+/HER2– MBC treated with next-line chemotherapy after subsequent-abemaciclib following disease progression on prior-palbociclib. ER: Estrogen receptor; HER2: human epidermal growth factor receptor 2; MBC: metastatic breast cancer; CI: confidence interval; PFS: progression-free survival.

Discussion

Although CDK4/6i combined with ET has become the standard of care as an early-line treatment for ER+/HER2– MBC, an appropriate treatment after disease progression on CDK4/6i combined with ET has not been clarified. The current guidelines do not recommend continuation of treatment with CDK4/6i after disease progression on this therapy (2, 14). However, it was reported that continuation of CDK4/6i was frequently administered as a subsequent treatment following palbociclib administration in 42.2% of the patients compared to 25.6% treated with chemotherapy and 16.4% with ET alone in the USA in real-word clinical practice (15). Furthermore, abemaciclib might have efficacy after disease progression on palbociclib plus ET since it is known that abemaciclib has different properties from palbociclib (16-18). Indeed, it was reported that a subset of patients with HR+/HER2– MBC may continue to benefit from continuation of treatment with CDK4/6i after disease progression (19). Thus, this retrospective study reported the efficacy and predictive factors of subsequent-abemaciclib after disease progression on prior-palbociclib in patients with ER+/HER2– MBC.

No clinical trials have been reported that compared the efficacy of next-line treatment after disease progression on prior-palbociclib. However, in PALOMA 3, which included patients treated with palbociclib combined with fulvestrant as a second- or third-line treatment for ER+/HER2– MBC, the overall duration of immediate subsequent palbociclib therapy post-progression was 4.9 months and that for fulvestrant, chemotherapy, ET, targeted therapy, and everolimus was 4.9, 5.6, 4.0, 4.2, and 4.3 months, respectively (20), which is in agreement with a PFS of 5.3 months in our study. Therefore, this previous study and our results suggest that subsequent-abemaciclib after disease progression on prior-palbociclib has acceptable efficacy for ER+/HER2– MBC.

Recently, Wander et al. reported clinical outcomes in response to abemaciclib after disease progression on prior-palbociclib in heavily pretreated patients with ER+/HER2– MBC (19). They demonstrated that the median PFS was 5.3 months and a subset of these patients continued to benefit from abemaciclib treatment after progression on prior-palbociclib. Furthermore, this retrospective analysis showed that there was no relationship between the duration of clinical benefit while on palbociclib and the subsequent duration of abemaciclib administration, which supports our results. Although the univariate analysis showed significant differences in the PFS in subsequent-abemaciclib administration for both BOR and PFI in prior-palbociclib, in multivariate analysis, BOR to prior-palbociclib treatment was the only independent predictive factor in this study. Therefore, this suggests that a subset of patients with ER+/HER2– MBC with high response to prior-palbociclib may benefit from subsequent-abemaciclib, regardless of the treatment duration of prior-palbociclib.

It is considered that the reasons for the clinical benefit of subsequent-abemaciclib after disease progression on prior-palbociclib may be the possible lack of cross-resistance to CDK4/6i and the different properties between palbociclib and abemaciclib as CDK4/6is. Recently, some studies have reported cross-resistance between different CDK4/6is (21, 22). However, one preclinical study demonstrated a contrasting result (16). In addition, another preclinical study also reported that only abemaciclib among CDK4/6is showed a tumor growth suppression effect in the ribociclib plus letrozole-resistant cell line (17). Therefore, it is speculated that some patients who have been treated with CDK4/6i may not acquire cross-resistance to various CDK4/6is and may have clinical benefit from subsequent CDK4/6i treatment after disease progression on a different CDK4/6i. Although inhibition of both CDK4 and 6 was effective in regulating the cell cycle in ER+/HER2– MBC, selective inhibition of CDK4 was more effective due to the higher expression levels of CDK4 and cyclin D1 than those of CDK6 (23). While both palbociclib and abemaciclib inhibit CDK4 and CDK6, differences in efficacy and selectivity for CDK 4 and 6 inhibition have been observed in preclinical studies (16, 17). Indeed, selective inhibition of CDK4 vs. CDK6 by abemaciclib was approximately 10 times stronger than that achieved with palbociclib (18). Furthermore, it was also reported that other kinases, including CDK2, may be involved in cell cycle regulation. A previous study demonstrated that ER+ breast cancer cells were resistant to CDK4/6i and evaded cytostasis through noncanonical cyclin D1-CDK2-mediated S-phase entry (24). In a preclinical study, abemaciclib also inhibited kinases other than CDK4/6, including CDK2/cyclin A/E, which has been associated with resistance to CDK4/6 inhibition, and CDK1/cyclin B, which may explain its unique toxicity profile (17). In addition, it has been demonstrated that abemaciclib had additive effects, such as strong cell senescence and apoptosis-inducing action, compared with other CDK4/6is (18). Therefore, these unique effects of abemaciclib may contribute to the efficacy of treatment after disease progression on prior-palbociclib in patients with ER+/HER2– MBC.

In this study, fulvestrant combined with prior-palbociclib and subsequent-abemaciclib were administered to 84.0% and 64.0% of the patients, respectively, indicating that this efficacy was not due to the change in the ET regimen but possibly the direct effect of abemaciclib. MONARCH 1 demonstrated that single-agent abemaciclib was effective in patients with refractory HR+/HER2– MBC who had progressed on or after prior ET and had one or two lines of chemotherapy in the metastatic setting, with an ORR of 19.7%, CBR 42.4%, and median PFS 6.0 months, which supports our results (14). Therefore, there is a possibility that among the patients who benefited from the subsequent-abemaciclib plus ET after disease progression on palbociclib were those who benefited from abemaciclib alone in this study.

There is a concern that the severity of TRAEs may increase with subsequent-abemaciclib treatment after the administration of palbociclib. In this study, grade 3 or higher neutropenia, anemia, and diarrhea rates were 16.0%, 8.0%, and 16.0%, respectively, which were similar to those in the phase III trial of abemaciclib combined with ET, which were 13.4%, 7.2%, and 26.5%, respectively (9). In addition, dose reduction rate was 50%, and dose discontinuation 12.0% in this study, which were similar to those in a previous retrospective study that reported a dose reduction rate of 48.0% and dose discontinuation of 9.2% for subsequent-abemaciclib after the administration of palbociclib (19). Therefore, the safety profile of subsequent-abemaciclib is unlikely to be affected by prior-palbociclib, and TRAEs are generally manageable with current guidance.

When treating patients with MBC, it is important not only to improve prognosis but also to minimize the TRAEs. In general, chemotherapy may cause various uncontrollable TRAEs, such as hair loss and peripheral neuropathy. Therefore, it is more preferable to control disease using non-cytotoxic therapy for as long as possible in patients with ER+/HER2– MBC. In this study, the median TTC was 33.6 months in 12 patients who had not been treated with any previous chemotherapy. PALOMA 1 and PALOMA 2 showed that the median TTC was longer in the palbociclib plus letrozole group than in the letrozole alone group as first-line treatment in ER+/HER2– MBC (25, 26). Thus, these findings suggest that continuing CDK4/6i plus ET might contribute to prolonging TTC in ER+/HER2– MBC.

Furthermore, it is unknown whether subsequent-abemaciclib may compromise the efficacy of the next-line chemotherapy. Twelve patients (48.0%) were treated with next-line chemotherapy after disease progression on subsequent-abemaciclib, and 7 (28.0%) with eribulin in this study. The ORR to eribulin was reported to be 12%, CBR 23%, and median PFS 3.7 months in patients with MBC who received prior treatment involving two to five regimens in the EMBRACE study (27). The median PFS in patients treated with chemotherapy after subsequent-abemaciclib in this study was 6.2 months, which suggests that subsequent-abemaciclib after disease progression on prior-palbociclib may not compromise the benefit of next-line chemotherapy.

This study had limitations, including its retrospective design, small sample size, and different treatment lines of prior-palbociclib and subsequent-abemaciclib. However, it is meaningful to further investigate the effectiveness of subsequent-abemaciclib at the time when the appropriate treatment option for the disease progression on CDK4/6i combined with ET has not yet been established. In the future, prospective clinical trials should confirm the efficacy of continuing CDK4/6i in patients who have progressed on previous treatment.

Our findings suggest that BOR to prior-palbociclib treatment is the only independent predictive factor for PFS in subsequent-abemaciclib for ER+/HER2– MBC after disease progression on palbociclib. Furthermore, subsequent-abemaciclib after disease progression on prior-palbociclib is safe and tolerable and might contribute to longer TTC in patients without affecting the benefit of next-line chemotherapy. Therefore, if suitable patients are selected, subsequent-abemaciclib might be a candidate treatment option for those with ER+/HER2– MBC after disease progression on palbociclib. Prospective clinical trial results and further evaluation of subsequent-abemaciclib treatment after disease progression on palbociclib are warranted.

Acknowledgements

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Footnotes

  • Conflicts of Interest

    The Authors report no conflicts of interest related to this study.

  • Authors’ Contributions

    Drafting of the manuscript: H. SEKI, T. SAKURAI; Literature search and analysis: H. SEKI, Data extraction: H. SEKI, A Sakurada, T. Kinoshita, K. Shimizu, Manuscript editing: H. SEKI.

  • Received November 23, 2021.
  • Revision received December 15, 2021.
  • Accepted December 19, 2021.

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Subsequent-abemaciclib Treatment After Disease Progression on Palbociclib in Patients With ER-positive HER2-negative Metastatic Breast Cancer
HIROHITO SEKI, TAKASHI SAKURAI, AKIHISA SAKURADA, TETSUHIKO KINOSHITA, KEN SHIMIZU
Anticancer Research Feb 2022, 42 (2) 1099-1106; DOI: 10.21873/anticanres.15572
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