Sara Tolaney, MD, MPH

Associate Director, Susan F. Smith Center for Women’s Cancers
Director, Clinical Trials, Breast Oncology
Dana-Farber Cancer Institute
Associate Professor of Medicine
Harvard Medical School

Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer
San Antonio Breast Cancer Symposium. 2020 Dec 8-11. Virtual: Abstract GS1-01.

KOL Insight and Perspective

Title: Primary outcome analysis of invasive disease-free survival for monarchE: Too soon to tell?

Background: Hormone receptor-positive (HR+) breast tumors account for the majority of breast cancer cases. Most patients with HR+ breast cancer are diagnosed with early-stage disease, and are successfully treated with surgery and radiation therapy (sometimes with the addition of chemotherapy), followed by 5-10 years of adjuvant endocrine therapy (ET). Despite this, approximately 20% of patients will experience disease recurrence within the first 10 years after diagnosis.1 Certain clinical and pathologic characteristics have been used to identify patients at high-risk of recurrence, who might benefit from additional adjuvant treatment beyond ET.

Abemaciclib is an oral inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6). In patients with advanced HR+/HER2- breast cancer, abemaciclib in combination with ET has produced significant improvements in progression-free survival (PFS) as well as overall survival (OS) 2,3,4. Accordingly, abemaciclib is FDA approved in combination with ET and as monotherapy for the treatment of advanced HR+/HER2- breast cancer. However, the efficacy of abemaciclib in the adjuvant setting has remained largely unexplored.

Study Design: The open-label, randomized phase III monarchE study5 was designed to investigate the efficacy of adjuvant abemaciclib plus ET in HR+ breast cancer patients at high-risk of recurrence. The trial recruited patients with stage II-III HR+/HER2- breast cancer who were pre- or post-menopausal, with or without prior (neo)adjuvant chemotherapy. High-risk was defined as four or more positive axillary lymph nodes or 1-3 positive axillary lymph nodes along with one of the following features: tumor size > 5 cm, histologic grade 3, or centrally assessed Ki-67 ≥ 20%.

Patients were randomized 1:1 to receive abemaciclib (150 mg twice daily) plus ET or ET alone. Protocol therapy was administered for two years (the treatment period) or until participants met the criteria for discontinuation. After the treatment period, patients continued ET for a total of five or ten years as clinically indicated. The primary study endpoint was invasive disease-free survival (IDFS) according to STEEP criteria.6 Secondary endpoints included distant relapse-free survival (DRFS), OS, safety, pharmacokinetics, and patient-reported outcomes.

The study was powered at approximately 85% to detect the superiority of abemaciclib with ET versus ET alone in terms of IDFS, assuming a hazard ratio (HR) of 0.73 at a cumulative two-sided alpha of 0.05, with a five-year IDFS rate of 82.5% in the ET arm. The threshold for detection was 390 IDFS events in the ITT population at the time of the primary analysis. There were two pre-planned efficacy interim analyses at approximately 50% and 75% of the total required events.

Results: From July 2017 to August 2019, 5,637 patients were recruited into the study. At the second pre-planned interim analysis,5 707 patients (12.5%) had completed the two-year treatment period and 4,101 patients (72.8%) were still in the two-year treatment period. The median follow-up time was approximately 15.5 months in both arms. The 2-year IDFS was significantly higher in the abemaciclib plus ET arm (92.2%) than in the ET arm (88.7%; p = 0.01; HR: 0.75; 95% CI: 0.60-0.93). DRFS was also significantly higher in the abemaciclib plus ET arm (93.6%) than the ET arm (90.3%; nominal p = 0.01; HR: 0.72; 95% CI: 0.56-0.92).

At SABCS 2020, Dr. Priya Rastogi7 presented the results of the primary efficacy analysis, which was triggered by the occurrence of 395 IDFS events in the ITT population (with a data cutoff of July 8, 2020). After a median follow-up of 19.1 months, 1,437 patients (25.5%) had completed the two-year treatment period, and 3,281 patients (58.2%) were still within the two-year treatment period. The 2-year IDFS was 92.3% in the abemaciclib plus ET arm versus 89.3% in the ET arm (nominal 2-sided p = 0009; HR: 0.713; 95% CI: 0.583-0.871). The 2-year DRFS was 93.8% in the abemaciclib plus ET arm versus 90.8% in the ET arm (nominal 2-sided p = 0.0009; HR: 0.687; 95% CI: 0.551-0.858). The 2-year IDFS in the Ki-67-high (≥ 20%) population was 91.6% for patients on abemaciclib plus ET versus 87.1% for ET (2-sided p = 0.0111; HR: 0.691; 95% CI: 0.519-0.920). Safety was consistent with the known profile of abemaciclib and the results from the second interim analysis.5

Conclusions: At the pre-planned primary outcome analysis, the addition of abemaciclib to standard adjuvant ET significantly improved IDFS and DRFS for patients with high-risk HR+/HER2- breast cancer.

Discussion: The positive results from the monarchE trial stand in contrast to two other studies of adjuvant CDK4/6 inhibitors plus ET in HR+/HER2- breast cancer: PALLAS and PENELOPE-B. PALLAS8 is an open-label randomized phase III trial of adjuvant palbociclib plus ET versus ET alone in 5,600 patients with high-risk stage II-III HR+/HER2- breast cancer. The treatment duration was two years, after which patients received standard adjuvant ET. The primary efficacy endpoint was 3-year IDFS in the ITT population. The planned second interim analysis occurred at a median follow-up of 23.7 months, at which point the 3-year IDFS was 88.2% in the palbociclib plus ET arm versus 88.5% for ET alone (log-rank p = 0.51; HR: 0.93; 95% CI: 0.76-1.15). Moreover, the DRFS was 89.3% in the palbociclib plus ET arm versus 90.7% in the ET arm (HR: 1.00; 95% CI: 0.79-1.27; p = 0.9997).

The phase III PENELOPE-B trial9 recruited 1,250 patients with early-stage HR+/HER2- breast cancer without a pathologic complete response (pCR) after neoadjuvant chemotherapy, and at high-risk of recurrence (CPS-EG score ≥ 3 or 2 with one or more positive lymph nodes). Patients were randomized 1:1 to receive one year of palbociclib or placebo plus adjuvant ET, followed by standard adjuvant ET. After a median follow-up of 42.8 months, there were 152 IDFS events in the palbociclib plus ET group versus 156 events in the ET group, for a stratified HR of 0.93 (95% CI: 0.74-1.17; p = 0.525).

There are several factors that could explain the different results between these trials. Abemaciclib is a more potent inhibitor of CDK4 and CDK6 than palbociclib.10 Moreover, abemaciclib is dosed continuously versus a 21-day on, 7-day off schedule for palbociclib. The continuous dosing of abemaciclib might provide an advantage in the form of constant cell cycle inhibition. However, abemaciclib and palbociclib demonstrated fairly similar efficacy in metastatic trials when combined with endocrine therapy, so it is unknown why their activity would be different in the adjuvant setting.10

The discontinuation rate for abemaciclib was 27.7% in monarchE (17.2% due to AEs), which was higher than the discontinuation rate of 19.5% for palbociclib in PENELOPE-B (5.2% due to AEs). In comparison, the PALLAS trial had a much higher palbociclib discontinuation rate of 42.2%.8 This might suggest that a shorter duration of CDK4/6 inhibitor therapy, whether by design (one year of therapy in PENELOPE-B) or early discontinuation (PALLAS), could partially explain the lower efficacy of palbociclib in these two trials. However, additional PALLAS results presented at SABCS 2020 by Dr. Erica Mayer demonstrated a slight but non-significant positive association between palbociclib dose exposure and IDFS.11 This analysis indicates that duration of exposure is not sufficient to explain the lack of efficacy of palbociclib in PALLAS.

The definition of high-risk disease also varies between the studies. For instance, only 58.7% of the patients in the PALLAS trial met the eligibility criteria for inclusion in the monarchE trial. However, palbociclib plus ET did not produce any additional benefit in this high-risk subgroup in the PALLAS trial, which suggests that patient selection does not entirely explain the differences between studies. Moreover, the PENELOPE-B trial uses different criteria to define high-risk (no pCR and the CPS-EG score), which makes it difficult to directly compare these patients to the study populations of monarchE and PALLAS.

The duration of follow-up must also be considered. In the PENELOPE-B trial, at a follow-up of two years, there was a significant difference of 4.3% in IDFS between the palbociclib plus ET arm (88.3%) and the ET arm (84.0%). However, by three years of follow-up the differences were no longer significant, and by four years the IDFS curves had almost completely merged (73.0% for palbociclib plus ET; 72.4% for ET).  At 19.1 months of follow-up, the IDFS difference between the two groups in monarchE is 3.0%, and while it is possible that these curves may remain separated given the perhaps more potent inhibition of cdk4 and the longer duration of treatment, longer follow-up is needed to determine if abemaciclib will have sustained long term benefits even after abemaciclib has been discontinued.12 


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