HR+, HER2− High-Risk, Node-Positive Early Breast Cancer

Most patients with HR+, HER2− breast cancer present with early-stage disease, so we first examined the role of abemaciclib in this disease setting. Critically, effective interventions at this stage can prevent relapse over long-term follow-up and are considered potentially curative [35, 36]. Patients with higher risk HR+ breast cancer may have greater chances of recurrence in the first few years after diagnosis and treatment, justifying additional measures in that space to prevent metastatic disease [37]. However, not all patients will experience recurrence, and it is important to identify those at higher recurrence risk to justify treatment intensification. Among prognostic factors, axillary lymph node (ALN) status remains the single most significant marker in EBC. Together, the clinicopathological features of nodal positivity, tumor size, tumor grade, and Ki-67 provide reliable ways of identifying a risk of recurrence [38]. Patients with N1 high-risk disease—which can be defined by additional risk features such as tumor size ≥ 5 cm and/or grade 3—have significantly elevated risk of recurrence and mortality compared with those with N1 non-high-risk disease [39]. Real-world data has demonstrated a 14.3% absolute difference in 5-year invasive disease-free survival (IDFS) rates (75.7% versus 90.0%) and a 6.3% difference in 5-year OS rates (86.5% versus 92.8%) between these groups [40]. Moreover, in this study, patients with 4+ ALN or 1–3 ALN and a tumor size ≥ 5cm and/or a grade 3 tumor had a 5-year IDFS of 70.9% and a 5-year OS of 81.6%, similar to patients with triple-negative breast cancer (TNBC), who had 5-year IDFS and OS of 74.3% and 79.2%, respectively [40]. These findings underscore the importance of early intervention and more intensive treatment strategies for early-stage patients at high risk of recurrence, as such approaches may help eradicate micrometastatic disease and improve long-term outcomes.

Adjuvant Abemaciclib in High-Risk Node-Positive Early Breast Cancer: monarchE

The monarchE trial (NCT0315599) was a phase 3, open-label, randomized study that evaluated adjuvant abemaciclib added to standard-of-care ET (AI or tamoxifen) versus ET alone in patients with high-risk, node-positive HR+, HER2− EBC [41]. The intent-to-treat (ITT) population (n = 5637) comprised two patient cohorts: cohort 1 (91%) included patients with high-risk clinicopathological factors (≥ 4 ALNs or 1–3 ALN with an additional high risk feature including histologic grade 3 or tumor size ≥ 5 cm), and cohort 2 (9%), which also included patients with 1–3 ALN without grade 3 or tumor ≥ 5 cm but with centrally assessed Ki-67 ≥ 20% [15]. Recruitment for cohort 2 began after cohort 1, and was added at the request of the FDA to explore the potential benefit of abemaciclib in patients with intermediate-risk clinicopathological features and highly proliferative tumors. Patients were randomized 1:1 to receive abemaciclib 150 mg twice daily (BID) plus ET or ET alone. ET was physician’s choice, including AI or tamoxifen, with or without or a gonadotropin-releasing hormone (GnRH) agonist in premenopausal patients [15, 41]. Abemaciclib was administered for 2 years concurrent with ET, the period of peak recurrence in high-risk EBC, and ET was subsequently continued in both arms for an additional 3–8 years as clinically indicated.

The monarchE primary endpoint of IDFS was met at 15.5 months of follow-up, with a statistically significant 25% reduction in risk of developing an IDFS event [41], leading to global approvals for abemaciclib in the EBC setting [42, 43]. Continued follow-up of the study population has demonstrated a carryover effect through 5 years [13], followed by stabilization of the curves through 7 years, with an absolute benefit in IDFS of 6.5% at 7 years (Fig. 2a) [11] in the ITT population. OS is the gold standard for establishing clinical benefit of cancer therapies [44]; however, few trials with standard of care ET have provided an OS benefit in HR+, HER2− EBC owing to the long follow-up needed to observe differences in survival, along with treatment imbalances and evolving therapies that improve outcomes across both study arms. Despite this high bar for OS, monarchE was designed to test for statistically significant OS At the primary OS analysis, abemaciclib plus ET demonstrated a statistically significant and clinically meaningful 16% reduction in the risk of death in the ITT population compared with ET alone (stratified hazard ratio [HR] 0.84; 95% confidence interval [CI] 0.72–0.98; two-sided P = 0.027), with a corresponding HR for cohort 1 of 0.84 (95% CI 0.71–0.98; nominal P = 0.024) and a 2% improvement in survival rates in both the ITT population and in cohort 1 [11]. This benefit was observed despite a numerically greater use of CDK4/6 inhibitors post progression in patients with distant recurrence on the ET alone arm (294/565 patients; 52%) than those on the abemaciclib plus ET arm (137/407 patients; 34%). Of note, there were fewer patients living with metastatic breast cancer in the abemaciclib plus ET arm (6.4%) than in the ET alone arm (9.4%). Treatment benefit for IDFS, DRFS, and OS was consistent across key subgroups, including patients with N1 disease, those who received neoadjuvant chemotherapy, and younger patients.

Fig. 2

Kaplan–Meier curves showing a IDFS in cohort 1 of monarchE [11], b PFS in the ITT populations of MONARCH 3 [7], c PFS in the ITT population of MONARCH 2 [12], d PFS in cohort A of MONARCH plus [8], and e PFS in cohort B of MONARCH plus [8]

Long-term safety findings in monarchE were consistent with earlier analyses [15, 41]. In the abemaciclib plus ET arm, the most common all-grade treatment-emergent adverse events (TEAEs) were diarrhea (84%), neutropenia (46%), and fatigue (41%), and in the ET-alone arm were arthralgia (38%), hot flush (23%), and fatigue (18%); TEAEs were mostly grade ≤ 2. The most frequent grade ≥ 3 TEAEs in the abemaciclib plus ET arm were neutropenia (20%), leukopenia (11%), and diarrhea (8%); in the ET-alone arm, these grade ≥ 3 TEAEs all occurred in ≤ 1% [15]. Other grade ≥ 3 adverse events (AEs) identified as of interest included venous thromboembolic events (VTE), pulmonary embolism (PE), and interstitial lung disease (ILD), which occurred in 1.4%, 1.0%, and < 1.0% of patients in the abemaciclib plus ET arm, respectively, compared with < 1.0% for all events in the ET-alone arm [15]. Of note, there is emerging evidence that suggests these AEs of interest may be a class effect of CDK4/6 inhibitors [45, 46]. The incidence of serious adverse events (SAEs) regardless of causality was approximately 7% in both arms [13]. While increases in aspartate aminotransferase and alanine aminotransferase were observed in 12% and 13% of patients receiving abemaciclib plus ET, respectively, compared with 5% and 6%, respectively, for patients receiving ET alone, there were no cases meeting Hy’s Law criteria [15].

As stated, any-grade diarrhea occurred in 84% of abemaciclib-treated patients, with grade 1/2 events occurring in 76%, and grade ≥ 3 in 8%; notably, diarrhea tended to occur early during treatment (median time to onset of 8 days) [47]. The incidence of diarrhea decreased over time and in most cases lasted for < 1 week without recurrence [47]. Per protocol, patients were instructed to take anti-diarrheal agents at the first sign of diarrhea. Discontinuation owing to diarrhea was infrequent (5%) and when it did occur was mostly (84%) due to grade 1/2 diarrhea. Discontinuations occurred mainly in the first 3 months and mostly in patients without a prior dose reduction (74%) [47]. The need for dose modifications owing to diarrhea decreased over time, with ≤ 0.6% of patients receiving dose adjustments in the second year of treatment [47]. In addition, while the incidence of fatigue was also higher in the abemaciclib arm than with placebo, this was mainly low grade and infrequently associated with dose reductions or discontinuations, and patient-reported outcome data did not reflect this between-arm difference in fatigue [47].

AE management is important for an optimal patient experience on abemaciclib. In addition to appropriate use of supportive care medications, dose reductions are a key component of AE management [48]. In monarchE, dose reductions were used in 43% of patients for AE management, and did not impact treatment efficacy. More specifically, in monarchE, consistent IDFS and DRFS rates were observed regardless of relative dose intensity [21], and these findings were confirmed in a time-dependent Cox proportional hazards model which also showed no significant differences in IDFS (HR 0.91; 95% CI, 0.73–1.13) and DRFS (HR 0.94; 0.74–1.20) in patients receiving full or lower doses of abemaciclib [21]. Of note, the TRADE study in patients with HR+HER2− EBC found that an early abemaciclib dose-escalation strategy, in which patients received abemaciclib at 50 mg BID for 2 weeks, then 100mg BID for 2 weeks, then 150mg BID onward, allowed the majority of patients to reach and/or maintain target dosing and significantly reduced abemaciclib discontinuation for any reason [49]. Compared with the 40% discontinuation or dose-reduction rate at 12 weeks in monarchE, this dose-escalation strategy was associated with a discontinuation/dose reduction rate of 29.2%, with 70.8% of patients able to reach and maintain the target abemaciclib dose of 150mg twice daily at 12 weeks, and only 6.7% discontinuing abemaciclib early [49].

Long-term patient-reported outcome (PRO) data have shown preserved health-related QoL (HRQoL) with the addition of adjuvant abemaciclib to ET [50]. Patients reported that the side effect burden was low, with most reporting being bothered “a little bit” or “not at all” by side effects during treatment [50].

In summary, the monarchE trial demonstrated that adjuvant abemaciclib plus ET in patients with high-risk, node-positive HR+, HER2− EBC resulted in statistically significant improvement in IDFS and OS [11]. Importantly, the benefit extended beyond the 2-year treatment period, with a sustained reduction in IDFS and DRFS recurrence risk observed at 7 years [11, 13, 41]. These results represent the most mature efficacy data for any CDK4/6 inhibitor in the adjuvant setting. AEs were mainly low grade and manageable with supportive care and dose adjustments.

Progression From Early to Metastatic Breast Cancer

Approximately 70% of MBC cases are HR+ and patients typically receive endocrine-based therapies in the first-line setting [1]. While a minority of patients present with de novo MBC [51], the vast majority have progressed from EBC [51, 52]. When disease progresses from EBC to MBC, the therapeutic goal shifts from prevention of recurrence to control of metastatic growth and spread, prolongation of survival, and maintenance of QoL, including through delaying transition to chemotherapy for disease control [53, 54]. A substantial proportion of patients live for many years with MBC and may sequentially progress through multiple lines of ET-based systemic therapy (~60–80% from first-line to second-line, and ~60–75% from second-line to third-line).

While HR+ breast cancers in the advanced setting typically respond well to initial ET-based therapy, nearly all patients with advanced disease eventually develop resistance to ET, leading to disease progression and the need for alternative therapeutic strategies [23, 55]. Mechanisms of endocrine resistance may be mediated by a variety of mechanisms, including PIK3CA/mTOR/AKT pathway mutations or the development of mutations in the estrogen receptor (ESR1), leading to unregulated signaling [19, 56, 57]. Unlike ET-refractory disease, where tumors are no longer responsive to any form of ET, many patients with endocrine-resistant disease may still derive meaningful benefit from switching to a different ET backbone, especially when combined with targeted agents such as abemaciclib [3]. Importantly, therapies such as abemaciclib added to ET for MBC can delay the development of endocrine resistance, which has the potential to change the course of disease, delaying the need for chemotherapy, and potentially increasing OS [58, 59]. Biomarker testing (e.g., ESR1, PIK3CA/AKT) can help tailor treatment decisions in endocrine-resistant disease [19], but some therapies targeting these mutations may pose administration and toxicity challenges, and may have restricted indications [60]. These limitations underscore the value of therapies such as abemaciclib, which has demonstrated consistent benefit across patients regardless of mutational status [19].

The complexity of the HR+, HER2− MBC treatment landscape, including the evolving role of biomarker testing and the lack of clarity around optimal sequencing of both ET and non-ET therapies, makes it challenging to identify those patients most likely to derive benefit from each treatment (see Fig. 3 for a summary of the proposed place of abemaciclib in such therapy). However, the treatment goal for patients with HR+, HER2− MBC is clear: to extend survival, alleviate symptoms, and maintain QoL [53, 61].

Fig. 3

Evidence-based place of abemaciclib in the treatment of patients with HR+, HER2− breast cancer: the potential future landscape. Note, given the evolving therapeutic landscape in HR+, HER2– breast cancer, this schematic outlines the potential for abemaciclib across the disease continuum. This depiction reflects current evidence and areas under active clinical investigation; it is not intended to represent a treatment algorithm or guideline-supported sequence. *In PostMONARCH, only 8% of patients had previously received abemaciclib; most patients had previously received ribociclib or palbociclib. **This combination is not currently approved or endorsed by local guidelines

First-Line Abemaciclib in Combination with AI in Patients with Endocrine Sensitive HR+, HER2− Advanced Breast Cancer: MONARCH 3

For patients with endocrine-sensitive MBC, including those with de novo disease or late relapse, combining ET (which targets the hormonal signaling pathway) with abemaciclib (which inhibits CDK4/6 and induces sustained cell cycle arrest, senescence, and apoptosis) reduces the risk of progression by 46% and extends chemotherapy-free survival by 16 months [7]. This is important given the primary goal of first-line treatment in MBC is to prolong progression-free survival (PFS) while maintaining QoL through delaying chemotherapy treatment [62, 63]. PFS is a highly informative first-line endpoint as it directly measures the duration of disease control and is not confounded by subsequent therapies [64].

The efficacy and safety of first-line abemaciclib plus AI was investigated in postmenopausal women with ET-sensitive HR+, HER2− MBC in the phase 3 placebo-controlled MONARCH 3 study (NCT02246621), in which PFS was the primary endpoint [23]. At baseline, 41% of patients in the abemaciclib arm had de novo metastatic disease, 53% had visceral metastases, and 22% had bone-only metastases [23]. Patients were randomized 2:1 to receive abemaciclib 150 mg or placebo BID with anastrozole 1 mg or letrozole 2.5 mg once daily (QD) until disease progression (N = 493) [23]. Abemaciclib plus AI demonstrated improved PFS as well as a clinically meaningful but not statistically significant improvement in OS compared with AI alone [7, 23, 65]. At a median of 17.8 months’ follow-up, median PFS was significantly greater in the abemaciclib plus AI arm (median not reached) than in the AI plus placebo arm (14.7 months) with a HR of 0.54 (95% CI, 0.41–0.72; P = 0.000021) [23]. This improvement in median PFS was sustained after a median follow-up of 8.1 years (29.0 months in the abemaciclib arm versus 14.8 months in the placebo arm; HR 0.535, 95% CI, 0.429–0.668; P < 0.0001) corresponding to an absolute difference at this time point of 14.3 months (Fig. 2b) [7].

In the ITT population, abemaciclib + AI provided a 20% relative risk reduction for the secondary endpoint of OS with a 13.1-month improvement in median OS, although not meeting statistical significance (66.8 months in the abemaciclib plus AI arm versus 53.7 months in the AI arm; HR 0.804; 95% CI, 0.637–1.015, P = 0.0664) [7]. In subgroup analyses, OS was numerically longer with abemaciclib plus AI versus AI alone in both patients with visceral disease as well as those with bone-only disease, although statistical significance was not reached [7]. Chemotherapy-free survival (CFS) was significantly longer in the abemaciclib arm than the placebo arm (46.7 versus 30.6 months; HR 0.69; 95% CI, 0.56–0.86; P = 0.0010) [7]. Moreover, there were no clinically meaningful differences in global HRQoL, functioning, or in most symptoms (with the exception of diarrhea) for patients receiving abemaciclib plus AI compared with AI alone [66].

Several possible factors may have contributed to the substantial numerical improvement in OS not meeting statistical significance [67]. First, post-discontinuation therapies (such as CDK4/6 inhibitors) may have contributed to slight dilution of OS benefit over time. Second, suboptimal timing of the final analysis may be a potential explanation, with the greatest separation of curves at the second interim analysis at 5.8 years whereas the final OS analysis was conducted at a median follow-up of 8.1 years [67]. In addition, as OS was not a primary endpoint of the study, the sample size was not powered to detect an OS benefit, and thus the study may have been relatively underpowered for the OS analysis.

In summary, in the pivotal phase 3 MONARCH 3 trial in postmenopausal women with HR+, HER2− MBC, abemaciclib plus an AI showed a significant improvement in PFS and a clinically meaningful increase in OS. Importantly, abemaciclib plus AI delayed the initiation of chemotherapy, an important goal in MBC [7]. The HRQoL results further support treatment with abemaciclib plus AI in this patient population [66].

First-Line or Second-Line Abemaciclib in Combination with Fulvestrant in Patients with Endocrine Resistant HR+, HER2− Advanced Breast Cancer: MONARCH 2

CDK4/6 inhibition in combination with ET has become a global standard-of-care first-line option for patients with HR+, HER2− MBC [