Abstract
Purpose
In the postMONARCH trial, abemaciclib plus fulvestrant (FUL) yielded a progression-free survival (PFS) of 6.0 months in hormone receptor (HR)-positive HER2-negative metastatic breast cancer patients who progressed after receiving CDK4/6 inhibitor plus endocrine therapy (ET). However, only 8% of these patients had previously received abemaciclib.
Methods
This multicenter, single-arm, phase II study enrolled patients who developed disease progression after abemaciclib plus ET. Patients were switched from aromatase inhibitor (AI)/tamoxifen (TAM) to FUL or from FUL to AI while continuing abemaciclib. The primary endpoint was PFS. The secondary endpoints were the overall response rate (ORR), clinical benefit rate (CBR), chemotherapy-free interval (CFI), overall survival (OS), and safety. Biomarker analysis was performed based on gene alterations.
Results
This study enrolled 65 patients from June 2021 to November 2023; 64 patients could be evaluated following 1 withdrawal. The median PFS for the 64 patients was 4.2 months (90% CI, 2.8–4.4). The median PFS was 7.1 months (95% CI, 3.9–11.3) in patients who switched from abemaciclib plus AI/TAM to abemaciclib plus FUL (n = 28, 43.8%), whereas it was 2.8 months (95% CI, 1.9–4.2) in patients switching from abemaciclib plus FUL to abemaciclib plus AI (n = 36, 56.3%). The ORR was 8.7% (95% CI, 2.4–20.8), the CBR was 23.9% (95% CI, 12.6–38.8), the CFI was 6.7 months (95% CI, 4.9–11.0), and the OS was 28.7 months (95% CI, 25.4–not estimable [NE]).
Conclusions
The primary endpoint was not met; switching from abemaciclib plus AI/TAM to abemaciclib plus FUL may be a clinically effective option.
jRCTs031210129
Date of registration JUNE 2, 2021.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10549-026-08031-2.
Keywords: CDK 4/6 inhibitor, Abemaciclib, Hormone receptor-positive HER2 negative breast cancer
Introduction
The standard treatment for hormone (HR)-positive HER2-negative breast cancer is cyclin-dependent kinase 4/6 (CDK4/6) inhibitors plus endocrine therapy (ET) [1], although the optimal treatment approach remains uncertain in patients who are refractory to this regimen. Oral selective estrogen receptor degraders are a treatment option for patients with ESR1 mutations, while AKT inhibitors or PIK3CA inhibitors are treatment options for those with mutations in the PI3K pathway. For those patients without specific genomic target genes, more treatment options are available: endocrine monotherapy, exemestane plus everolimus, or chemotherapy [2–5]. However, even in patients with target gene mutations, these treatments may be problematic due to adverse events or patient comorbidities.
Consequently, an unmet need remains for subsequent treatment options following disease progression with CDK4/6 inhibitors and endocrine therapy. Indeed, some patients who have been pretreated with CDK4/6 inhibitor and ET may still benefit from CDK4/6 inhibitor rechallenge, especially in cases of acquired resistance to ET. Several randomized phase II trials testing the efficacy of CDK4/6 inhibitor rechallenge have yielded mixed results depending on the specific CDK4/6 inhibitor (MAINTAIN, PACE, and PALMIRA trials) [6–8].
In the phase III postMONARCH trial, abemaciclib plus fulvestrant (FUL) yielded a progression-free survival (PFS) of 6.0 months in patients with HR-positive HER2-negative metastatic breast cancer who exhibited disease progression on a CDK4/6 inhibitor plus ET [9]. Abemaciclib rechallenge is an important next-line option after CDK4/6 inhibitors plus ET, but only 8% of patients received prior abemaciclib in the postMONARCH trial. Therefore, the evidence for abemaciclib rechallenge after prior abemaciclib plus ET remains limited, and there are still no biomarkers for identifying patients who are most likely to benefit from rechallenge with a CDK4/6 inhibitor.
Accordingly, this single-arm, phase II trial aimed to evaluate the clinical benefits of abemaciclib rechallenge. Translational research evaluating gene alterations was also conducted as accompanying exploratory research to assess the predictive biomarkers of abemaciclib resistance or sensitivity.
Methods
Study design and participants
This multicenter, single-arm, phase II study in Japan enrolled patients with breast cancer disease progression who were receiving abemaciclib plus ET. The main eligibility criteria were patients: 1) with histologically confirmed HR-positive HER2-negative invasive breast cancer; 2) with locally advanced, metastatic, or recurrent disease; 3) who had received no more than three lines of ET and one line of chemotherapy; 4) who had received abemaciclib plus ET achieved clinical benefits, had a complete response or partial response, or had stable disease for at least 6 months during abemaciclib-based treatment; 5) who had progressive disease confirmed after receiving the most recent combination therapy of abemaciclib and ET; and 6) whose most recent treatment before enrollment was combination therapy with abemaciclib and ET. This study excluded patients who had previously been treated with immune checkpoint inhibitors, everolimus, olaparib, or palbociclib for advanced or metastatic disease. Since ribociclib is not approved in Japan, none of the patients in this study had a history of ribociclib treatment.
Treatment and procedures
Patients were switched from aromatase inhibitor (AI)/tamoxifen (TAM) to FUL, or from FUL to AI, while continuing abemaciclib. In the group switching from FUL to AI, patients with a history of non-steroidal AI use as a previous treatment were administered steroidal AI during the trial, while those with a history of steroidal AI use were administered non-steroidal AI during the trial. Abemaciclib was administered orally at a dose of 150 mg twice daily on days 1–28 of a 28-day cycle. If dose reduction was required due to adverse events during previous treatment, the starting dose of abemaciclib was adjusted to the previous level (100 mg or 50 mg). This was combined with another endocrine agent that had not been used in prior therapy.
As ET, patients received either FUL or an AI. FUL (500 mg) was administered via intramuscular injection on days 1, 15, and 29, followed by maintenance dosing every 4 weeks. Alternatively, for those receiving an AI, anastrozole (1 mg), letrozole (2.5 mg), or exemestane (25 mg) was administered orally once daily throughout each 28-day cycle.
Endpoints
The primary endpoint was PFS. The secondary endpoints were the overall response rate (ORR), clinical benefit rate (CBR), chemotherapy-free interval (CFI), overall survival (OS), and safety. To examine the interaction of treatment effects on PFS and OS, subgroup analyses were performed based on gene alterations (e.g., ESR1 or PIK3CA mutations), disease site (visceral/bone only/other), previous lines of therapy for advanced or metastatic disease (first/second/third and more), ET (FUL/non-FUL) or chemotherapy, performance status (0/1), organs involved (1/2/≥3), and disease-free interval (<36/≥36 months) and menopausal status.
Tumor response was assessed via computed tomography at baseline, every 6 weeks for 12 months, and then every 12 weeks until disease progression, death, or study discontinuation, as per RECIST (version 1.1). Adverse events (AEs) were recorded using the Common Terminology Criteria for Adverse Events (version 5.0).
Biomarker analysis
To analyze circulating biomarkers, blood samples for liquid biopsy were collected at three time points: 1) prior to the initiation of abemaciclib rechallenge, 2) at 2 months post-rechallenge, and 3) during disease progression. Plasma was separated from the peripheral blood cells by centrifugation at 2000 g for 10 minutes at 4 °C, and then circulating tumor DNA (ctDNA) was extracted by centrifugation at 1600 g for 10 minutes at H.U. Frontier® (Tokyo, Japan). At Cancer Institute Hospital, Japanese Foundation for Cancer Research, plasma was separated by centrifugation at 300 g for 20 minutes, then ctDNA was extracted via centrifugation at 5000 g for 20 minutes at 20 °C and subsequently analyzed using the Oncomine Pan-Cancer Cell-Free Assay (Thermo Fisher Scientific®, Waltham, MA).
Statistical analysis
The threshold and expectation of the median PFS after the abemacilcib rechallenge were 3.0 and 5.0 months, respectively. A total of 59 cases were needed over the 2-year recruitment period and 1-year follow-up period to achieve a two-sided significance level of 5 and 80% power. Estimating a dropout/ineligibility rate of 10%, the target number for recruitment was 65 cases. Median PFS was estimated using the Kaplan–Meier method, with confidence interval (CI) calculated using the Brookmeyer and Crowley method. The protocol treatment was considered effective if the lower limit of the 90% CI for the median PFS exceeded 3 months. Subgroup analyses of PFS and OS were performed, and survival curves were generated using the Kaplan–Meier method. The hazard ratio (HR) and 95% CI were calculated using Cox proportional hazards models. Data analysis was performed using SAS (version 9.4), while biomarker analysis was performed using R (version 4.2.1) statistical software [10].
Ethics approval and consent to participate
All patients provided written informed consent before enrollment. The protocol was approved by the West Japan Oncology Group (WJOG) and the institutional review board/independent ethics committee (CRB3180008) in accordance with the ethical principles of the Declaration of Helsinki. The trial was registered with the Japan Registry of Clinical Trials (jRCTs031210129).
Results
Patients and treatment
From June 2021 to November 2023, 64 out of 65 enrolled patients could be evaluated following 1 withdrawal (Supplementary Figure S1). By the end of the study period, 54 out of 64 patients discontinued treatment due to disease progression.
Table 1 shows the patient characteristics. The median age was 56 years (range, 33–80 years), and the median number of prior treatment lines was 1 (range, 1–4). A total of 45 patients (70.3%) had visceral metastasis, while 13 patients (20.3%) had bone-only metastasis. Regarding treatment, 28 patients (43.7%) were switched from abemaciclib plus AI or TAM to abemaciclib plus FUL, whereas 36 (56.2%) were switched from abemaciclib plus FUL to abemaciclib plus AI. In the group that switched from FUL plus abemaciclib to AI plus abemaciclib; 15 of 36 patients (41.7%) had a history of treatment with non-steroidal AI or steroidal AI. The post-treatment regimens were chemotherapy (n = 28, 43.8%); endocrine monotherapy (n = 17, 26.6%); abemaciclib plus ET (n = 7, 10.9%); other (n = 2, 3.1%); and none (n = 4, 6.3%).
Table 1.
Patient characteristics
| Variables | ABE+AI/TAM →ABE＋FUL (n = 28) |
ABE+FUL →ABE＋AI (n = 36) |
All (n = 64) | |
|---|---|---|---|---|
| Age (range) | Median (range) | 54.5 (36–80) | 56.5 (33–80) | 56 (33–80) |
| <65 years | 23 (82.1) | 29 (80.6) | 52 (81.3) | |
| ≥65 years | 5 (17.9) | 7 (19.4) | 12 (18.8) | |
| Gender | Female | 28 (100) | 36 (100) | 64 (100) |
| ECOG-PS | 0 | 17 (60.7) | 26 (72.2) | 43 (67.2) |
| 1 | 11 (39.3) | 10 (27.8) | 21 (32.8) | |
| Clinical status | Metastatic | 12 (42.9) | 12 (33.3) | 24 (37.5) |
| Recurrence | 16 (57.1) | 24 (66.7) | 40 (62.5) | |
| Disease-free interval | <36 months | 4 (25.0) | 7 (29.2) | 11 (27.5) |
| ≥36 months | 12 (75.0) | 17 (70.8) | 29 (72.5) | |
| HR status | ER+ | 28 (100) | 36 (100) | 64 (100) |
| PgR+ | 21 (75.0) | 28 (77.8) | 49 (76.6) | |
| Site of metastasis | Bone-only | 6 (21.4) | 7 (19.4) | 13 (20.3) |
| Visceral metastasis | 20 (71.4) | 25 (69.4) | 45 (70.3) | |
| Other | 2 (7.1) | 4 (11.1) | 6 (9.4) | |
| Menopausal status | Premenopausal | 8 (28.6) | 16 (44.4) | 24 (37.5) |
| Postmenopausal | 20 (71.4) | 20 (55.6) | 40 (62.5) | |
| Prior treatment line | 1 | 18 (64.3) | 16 (44.4) | 34 (53.1) |
| 2 | 7 (25.0) | 13 (36.1) | 20 (31.3) | |
| ≥3 | 3 (10.7) | 7 (19.4) | 10 (15.7) | |
| Prior ET | TAM | 1 (3.6) | 0 | 1 (1.6) |
| ANA | 7 (25.0) * | 0 | 7 (10.9) | |
| LET | 20 (74.1) | 0 | 20 (31.3) | |
| FUL | 0 | 36 (100) | 36 (56.3) | |
| Current ET | ANA | 0 | 4 (10.8) | 4 (6.3) |
| LET | 0 | 16 (43.2) | 16 (25.0) | |
| EXE | 1 (3.6) * | 17 (45.9) | 18 (28.1) | |
| FUL | 27 (96.4) | 0 | 27 (42.2) |
Abbreviations: ABE, abemaciclib; AI, aromatase inhibitor; TAM, tamoxifen; ANA, anastrozole; LET, letrozole; EXE, exemestane; FUL, fulvestrant; HR, hormone receptor; ECOG-PS, Eastern Cooperative Oncology Group performance status
Note: Data presented as n (%), unless otherwise specified
*One patient switched from ANA to EXE because they had a history of receiving FUL
Efficacy
The median PFS was 4.2 months (90% CI, 2.8–4.4) (Fig. 1A). Since the lower limit of the 95% CI for PFS did not reach 3 months, the primary endpoint was not met. The secondary outcomes were as follows: ORR of 8.7% (95% CI, 2.4–20.8), CBR of 23.9% (95% CI, 12.6–38.8), CFI of 6.7 months (95% CI, 4.9–11.0), and OS of 28.7 months (95% CI, 25.4–not estimable [NE]) (Supplementary Table S1, Figure S2, 3). The median PFS was 7.1 months (95% CI, 3.9–11.3) in the abemaciclib plus FUL arm and 2.8 months (95% CI, 1.9–4.2) in the abemaciclib plus AI arm (Fig. 1B, C). In subgroup analyses of PFS, the only significant difference seen was that in prior ET (see Supplementary Table S2).
Fig. 1.
(A). PFS (all). (B). PFS (ABE+AI/TAM→ABE＋FUL). (C). PFS (ABE+FUL→ABE＋AI). Abbreviations: PFS, progression-free survival; ABE, abemaciclib; AI, aromatase inhibitor; TAM, tamoxifen; FUL, fulvestrant
Safety
Most adverse events were low grade. The most common grade 3 or higher adverse event was neutropenia, which occurred in 17 patients (26.6%) (Table 2). Diarrhea of any grade occurred in 14 patients (21.9%). Grade 3 febrile neutropenia and lung infections were observed in 2 patients (3.1%). No cases of interstitial lung disease were reported. The overall incidence of treatment-related AEs remained low throughout the study period.
Table 2.
Safety outcomes
| Variables | Any grade n (%) |
Grade ≥ 3 n (%) |
|---|---|---|
| Neutropenia | 26 (40.6) | 17 (26.6) |
| Anemia | 14 (21.9) | 4 (6.3) |
| Diarrhea | 14 (21.9) | 0 (0) |
| AST increased | 13 (20.3) | 1 (1.6) |
| White blood cell decreased | 10 (15.6) | 1 (1.6) |
| ALT increased | 9 (14.1) | 1 (1.6) |
| Creatinine increased | 8 (12.5) | 0 (0) |
| Platelet count decreased | 7 (10.9) | 1 (1.6) |
| Fatigue | 6 (9.4) | 0 (0) |
| Abdominal pain | 5 (7.8) | 0 (0) |
| COVID-19 | 4 (6.3) | 1 (1.6) |
| Febrile neutropenia | 2 (3.1) | 2 (3.1) |
| Lung infection | 2 (3.1) | 0 (0) |
Abbreviations: AST; aspartate aminotransferase, ALT; alanine aminotransferase
Note: An adverse event (AE) refers to any unfavorable and unintended sign, symptom, or disease occurring in a subject receiving protocol treatment, regardless of its causal relationship to the treatment or procedure
Biomarkers
Figure 2 shows the frequency of ctDNA alterations seen before abemaciclib rechallenge and during disease progression. Before abemaciclib rechallenge, fibroblast growth factor receptor 1 (FGFR1) amplification was associated with a shorter median PFS (HR, 5.05; 95% CI, 1.73–14.76; p = 0.003) and OS (HR, 4.44; 95% CI, 1.41–13.98; p = 0.01), while TP53 mutation was associated with a shorter median OS (HR, 2.78; 95% CI, 1.07–7.25; p = 0.04) (Supplementary Table S3A). Two months after the rechallenge, CCND1 amplification was associated with a shorter median PFS (HR, 2.40; 95% CI, 1.11–5.19; p = 0.03) (Supplementary Table S3A).
Fig. 2.
Frequency of ctDNA alterations before abemaciclib rechallenge and disease progression
During disease progression, the most frequently acquired gene alterations were TP53 mutations (n = 7, 13.0%) and CCND1 amplification (n = 5, 9.3%). The presence of TP53 mutations at progression was associated with a shorter median OS (mutant: 18.8 months [95% CI, 10.8–NA] vs. wild-type: 28.6 months [95% CI, 25.3–NA], HR, 4.17; 95% CI, 1.24–14.02; p = 0.02) (Fig. 3A, Supplementary Table S3B, C).
Fig. 3.
(A) OS by TP53 mutation at disease progression. (B) PFS by CCND1 amplification at disease progression in patients who switched from abemaciclib + AI/TAM to abemaciclib + FUL. (C) OS by CCND1 amplification at disease progression in patients who switched from abemaciclib + AI/TAM to abemaciclib + FUL. Abbreviations: OS, overall survival; PFS, progression-free survival; AI, aromatase inhibitor; TAM, tamoxifen; FUL, fulvestrant
Since TP53 mutation was associated with shorter OS at all time points (pre-rechallenge, 2 months post-rechallenge, and during progression), it was suggested as a prognostic biomarker. Out of 27 patients who switched from abemaciclib plus AI/TAM to abemaciclib plus FUL, the most frequently acquired alteration was CCND1 amplification (n = 4, 14.8%). This alteration was associated with a shorter median PFS (HR, 5.13; 95% CI, 1.43–18.4; p = 0.01) and OS (HR, 6.28; 95% CI, 1.26–31.25; p = 0.01) (Fig. 3B, C). No significant differences in PFS or OS were seen based on ESR1 or PIK3CA mutations.
Discussion
The AGAIN study was the first abemaciclib rechallenge study to switch from only abemaciclib. Although the primary endpoint was not met, patients who received abemaciclib plus FUL after progression on abemaciclib plus AI/TAM had a clinically meaningful median PFS of 7.1 months. In the group that switched from FUL plus abemaciclib to AI plus abemaciclib, approximately 40% of patients had a history of AI treatment; consequently, many patients exhibited AI resistance, which likely influenced the median PFS in both the overall population and the subgroup that switched from FUL to AI.
Several CDK4/6 inhibitor rechallenge trials have been conducted to date. For instance, the MAINTAIN trial, a randomized phase II trial of ribociclib plus ET after progression of CDK4/6 inhibitors (palbociclib: 86.5%; ribociclib: 11.7%), demonstrated a significant PFS benefit (5.79 vs. 2.76 months; hazard ratio [HR]: 0.57; p = 0.006) [6]. On the other hand, several randomized phase II studies (PACE and PALMIRA trials) did not demonstrate an improvement in PFS after switching patients from palbociclib plus ET to palbociclib plus ET [7,8]. The postMONARCH trial, the first randomized phase III study of abemaciclib rechallenge, demonstrated an improved median PFS of 6.0 months [9], but the previous CDK4/6 inhibitors were mostly palbociclib (59%) and ribociclib (33%), with abemaciclib representing a minority (8%). Accordingly, no study has fully explored abemaciclib rechallenge after previous abemaciclib therapy.
In recent years, there have been advancements in the development of treatments after resistance to CDK4/6 inhibitor plus ET. The CAPItello-291 study demonstrated that treatment with capivasertib (AKT inhibitor) plus FUL conferred a median PFS of 7.3 months in patients with AKT pathway-altered tumors who had previously received a CDK4/6 inhibitor plus AI [4]. In the phase II BYLieve study, alpelisib (PI3K inhibitor) plus FUL similarly conferred a median PFS of 7.4 in patients with PIK3CA-mutated breast cancer who had previously received a CDK4/6 inhibitor [11]. Our study revealed a median PFS of 7.1 months in patients who received abemaciclib plus FUL after progression on abemaciclib plus AI/TAM, which is comparable to those who received targeted therapy after a CDK4/6 inhibitor.
These findings suggest that abemaciclib rechallenge may be considered as a treatment option in cases where gene alterations of the AKT pathway are absent, AKT inhibitors or PIK3CA inhibitors are not applicable, or treatment continuation is difficult to AEs (e.g., grade 3 or higher rash). In HR-positive HER2-negative advanced breast cancer, one of the mechanisms of resistance to AI is acquired alterations in the ESR1 gene [12]. In the EMBER-3 trial, treatment with imlunestrant (i.e., oral selective estrogen receptor degrader) plus abemaciclib significantly improved the median PFS of patients with ESR1 mutations who progressed after previous treatment with AI with or without CDK4/6 inhibitor [2]. In the PALOMA-3 study, no difference in PFS was observed between the palbociclib plus FUL, regardless of ESR1 or PIK3CA status [13,14]. Moreover, in the MONARCH-2 study, no difference in PFS was observed between the abemaciclib plus FUL, regardless of ESR1 or PIK3CA status [15]. Similarly, our study found no difference in PFS among patients who switched from abemaciclib plus AI/TAM to abemaciclib plus FUL, regardless of ESR1 or PIK3CA status.
Based on the results of the EMBER3 trial and the subgroup analysis from our trial, which showed prolonged PFS in the group that switched from abemaciclib plus AI/TAM to abemaciclib plus FUL, even in patients with ESR1 mutations, it is suggested (in theory) that in cases where disease progresses on abemaciclib plus AI and an ESR1 mutation is detected, combination therapy with imlunestrant plus abemaciclib may be potentially effective. Verification in a prospective trial is considered useful.
Based on the results of the monarchE trial, abemaciclib plus AI/TAM is administered as adjuvant therapy to high-risk patients following curative surgery [16]. The efficacy of abemaciclib plus fulvestrant in the event of recurrence is unclear. However, since this abemaciclib rechallenge trial involves rechallenging with abemaciclib without an intervening period, abemaciclib plus FUL may be a treatment option if recurrence occurs during treatment with abemaciclib plus AI/TAM and there are no other treatment options, such as other molecularly targeted drugs. However, the efficacy of abemaciclib rechallenge after a time interval following the completion of adjuvant therapy has not been verified and remains unclear.
Because adverse events in the enrolled patients had been managed over the long term through supportive care (such as antidiarrheal agents) and dose reduction during prior treatment, the incidence of most adverse events (including diarrhea) that occurred for the first time after the start of this trial was lower than that reported in data from many other clinical trials.
In a phase III study of palbociclib plus FUL (PALOMA-3 trial), high cyclin E1 (CCNE1) mRNA expression was associated with palbociclib resistance [17]. In contrast, our biomarker analysis in the present abemaciclib rechallenge study revealed that CCND1 amplification was the most frequently acquired alteration, and this was associated with shorter PFS and OS among patients who switched from abemaciclib plus AI/TAM to abemaciclib plus FUL. In the MONNALESSA-7 trial, patients with CCND1 alterations at baseline had shorter median PFS in both the ribociclib plus ET arm and the ET-alone arm, suggesting the potential use of CCND1 as a prognostic biomarker [18]. However, CCND1 amplification was not associated with palbociclib sensitivity in the PALOMA-1/TRIO-18 trial [19]. Preclinical models and cell line studies have reported that tumors with CCND1 amplification and D-type cyclin-activating features may be highly sensitive to abemaciclib [20]. Nevertheless, no preclinical or clinical data support CCND1 amplification representing acquired resistance to abemaciclib. Our study suggests that CCND1 amplification may be a potential predictor of resistance to abemaciclib in patients who switched from abemaciclib plus AI/TAM to abemaciclib plus FUL.
In PALOMA-3, patients with TP53 mutations had a significantly worse PFS in both the palbociclib plus FUL arm and the FUL-only arm [21]. Moreover, in the MONALEESA-7 trial, patients with TP53 mutations similarly had a worse PFS in both the ribociclib plus ET arm and the ET-only arm [18]. In our study, patients with TP53 mutation similarly had a shorter OS at each time point (pre-rechallenge, 2 months post-rechallenge, and during progression), and thus TP53 mutation was considered a prognostic biomarker rather than a predictive marker. In PALOMA-3, patients with FGFR1 amplifications had a worse PFS in both the palbociclib plus FUL arm and the FUL-only arm [21]. In the MONALEESA-2 trial, patients with FGFR1 amplifications similarly had a worse PFS in both the ribociclib plus ET arm and the ET-only arm [22]. In our study, patients with FGFR1 amplifications exhibited shorter PFS and OS both before and 2 months after the rechallenge. Therefore, FGFR1 amplifications are regarded as a prognostic biomarker for patients receiving CDK4/6 inhibitors in combination with ET.
This study has several limitations. First, it is a single-arm, nonrandomized trial with a small sample size, resulting in a broader 95% CI, and thus further studies are required to validate these results. Second, the results of the biomarker analysis are considered exploratory due to the very small number of patients with mutations. Lastly, tumor activity prior to enrollment in the AGAIN study was not assessed using the RECIST criteria.
In conclusion, although the primary endpoint was not met, switching to abemaciclib plus FUL after progression on abemaciclib plus AI/TAM may be a clinically effective option.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Supplementary Material 1: Supplementary Table S1, S3A, Figure S1, S2, S3
Supplementary Material 2: Supplementary Table S2
Supplementary Material 3: Supplementary Table S3B
Supplementary Material 4: Supplementary Table S3C
Acknowledgements
We would like to thank all the participants in this study, including patients, caregivers, physicians, and medical workers.
Author contributions
Meiko Nishimura wrote the main manuscript text. All authors reviewed the manuscript.
Funding
This study was sponsored by Eli Lilly Japan K.K. and funded by the Japan Society of Clinical Oncology.
Data availability
All data supporting the findings of this study are available within the paper and its Supplementary Information.
Declarations
Competing interests
SK has received honoraria from Kyowa Kirin Co., Ltd., Daiichi-Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., MSD K.K., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Pfizer Japan Inc. CF has received honoraria from Daiichi-Sankyo Co., Ltd., Eisai Co., Ltd., Pfizer Japan Inc., Chugai Pharmaceutical Co., Ltd., MSD K.K., and Eli Lilly Japan K.K., and material from Daiichi-Sankyo Co., Ltd. YF has received honoraria from Eisai Co., Ltd., Daiichi-Sankyo Co., Ltd., Ono Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Taiho Pharmaceutical Co., Ltd., MSD K.K., Chugai Pharmaceutical Co., Ltd., and Astellas Pharma Inc. AY has received honoraria from Pfizer Japan Inc., AstraZeneca K.K., and Chugai Pharmaceutical Co., Ltd. SW has received honoraria from Daiichi-Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., MSD K.K., Eli Lilly Japan K.K., Kyowa Kirin Co., Ltd., Eisai Co., Ltd., and Pfizer Japan Inc. TT has received honoraria from Daiichi-Sankyo Co., Ltd., Eli Lilly Japan K.K., Gilead Sciences, and MSD K.K. HS has received honoraria from Daiichi-Sankyo Co., Ltd., Eli Lilly Japan K.K., Gilead Sciences, AstraZeneca K.K., and Pfizer Japan Inc. HS has received research funding (outside of submitting work to her institution): Eli Lilly Japan K.K. YO has received honoraria from Eli Lilly Japan K.K., Pfizer Japan Inc., Daiichi-Sankyo Co., Ltd., and AstraZeneca K.K. TK has received grants from Eli Lilly Japan K.K., AstraZeneca K.K., Guardant Health, Daiichi-Sankyo Co., Ltd., Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Be One, and Eisai Co., Ltd. TK has received consulting fees from Daiichi-Sankyo Co., Ltd., Astellas Pharma Inc., and received honoraria from Daiichi-Sankyo Co., Ltd., Ono Pharmaceutical Co., Ltd., Gilead Sciences, Astellas Pharma Inc., Eisai Co., Ltd., AstraZeneca K.K., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., and MSD K.K. TK has received payment for expert testimony from Astellas Pharma Inc. TK has received support for attending meetings and/or travel from Pfizer Japan Inc., and Eisai Co., Ltd. TK has participated on a Data Safety Monitoring Board or Advisory Board from Daiichi-Sankyo Co., Ltd., Ono Pharmaceutical Co., Ltd., Gilead Sciences, OncoTherapy Science, Eisai Co., Ltd., Astra Zeneca K.K., Taiho Pharmaceutical Co., Ltd., and Be One. TK received equipment, materials, drugs, medical writing, gifts, and other services from Daiichi-Sankyo Co., Ltd. The other authors have no conflicts of interest.
Footnotes
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Contributor Information
Meiko Nishimura, Email: meiko.nishimura@jfcr.or.jp.
Takahiro Kogawa, Email: takahiro.kogawa@jfcr.or.jp.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Material 1: Supplementary Table S1, S3A, Figure S1, S2, S3
Supplementary Material 2: Supplementary Table S2
Supplementary Material 3: Supplementary Table S3B
Supplementary Material 4: Supplementary Table S3C
Data Availability Statement
All data supporting the findings of this study are available within the paper and its Supplementary Information.