The addition of the cyclin-dependent kinase (CDK)4/6 inhibitor abemaciclib (Verzenio) to standard endocrine therapy reduced the risk for invasive disease recurrence or death compared with endocrine therapy alone by almost 30% in patients with high-risk, hormone receptor (HR)-positive, human epidermal growth receptor 2 (HER2)-negative, early-stage breast cancer. These results come from the primary analysis of the phase 3 monarchE clinical trial that was presented at the virtual 2020 San Antonio Breast Cancer Symposium.
Although many patients with HR-positive early-stage breast cancer will not have disease recurrence with endocrine therapy alone, “Approximately 20% may experience disease recurrence in the first 10 years, often in the form of incurable metastatic breast cancer,” said Priya Rastogi, MD, Associate Professor, University of Pittsburgh School of Medicine, PA, who presented the new results.
At a median follow-up of 19 months, after 385 events had occurred, the invasive disease–free survival (IDFS) benefit was statistically significant and clinically meaningful (P = .0009). The 2-year IDFS rates were 92.3% with abemaciclib plus endocrine therapy versus 89.3% with endocrine therapy alone, translating to a 28.7% reduction in risk and an absolute difference of 3% favoring abemaciclib.
“Abemaciclib combined with standard endocrine therapy continued to demonstrate a reduction in the risk of developing IDFS and distant relapse–free survival events for patients with HR-positive, HER2-negative, high-risk early breast cancer, and resulted in a statistically significant improvement in IDFS in patients with high Ki-67 tumors,” said Dr Rastogi.
“Abemaciclib in combination with endocrine therapy is the first CDK4/6 inhibitor to demonstrate efficacy and tolerability” for this patient population, she added.
Abemaciclib is currently approved for the treatment of patients with HR-positive, HER2-negative advanced or metastatic breast cancer, in combination with a nonsteroidal aromatase inhibitor, fulvestrant, or as monotherapy.
The 5637 patients enrolled in the monarchE trial were divided into 2 cohorts. Cohort 1 was based on clinicopathological risk factors (ie, ≥4 positive axillary lymph nodes or 1-3 axillary lymph nodes and at least a grade 3 histology or a tumor size ≥5 cm); cohort 2 was based on Ki-67 status (ie, 1-3 axillary lymph nodes, a centrally tested Ki-67 index of ≥20%, no grade 3 histology, and a tumor size <5 cm).
Patients were randomized in a 1:1 ratio to standard endocrine therapy alone for 5 to 10 years, as clinically indicated, or to endocrine therapy plus abemaciclib at 150 mg twice daily for up to 2 years. Stratification factors were previous chemotherapy, menopausal status, and geographic region.
The study’s primary end point was IDFS; the secondary outcome measures included IDFS in the Ki-67–high (≥20%) population (N = 2498), distant relapse–free survival, overall survival, safety, patient-reported outcomes, and pharmacokinetics.
Previously presented data at the 2020 European Society for Medical Oncology meeting showed that at a median follow-up of 15.5 months, abemaciclib reduced the risk for invasive disease by 25.3% versus endocrine therapy alone (2-sided P = .0096). The 2-year IDFS rates were 92.2% in the abemaciclib arm versus 88.7% in the endocrine therapy–alone arm, for an absolute improvement of 3.5%.
At the time of the analysis presented by Dr Rastogi, 1437 (25.5%) patients had completed the 2-year treatment period.
Ki-67 was evaluated in all patients in cohort 1 and cohort 2 who had suitable untreated breast tissue. In the primary analysis, in the Ki-67–high population (N = 2498), the risk for an IDFS event was reduced by 30.9% with abemaciclib compared with endocrine therapy alone (2-sided P = .0111), which was clinically meaningful. The 2-year IDFS rates were 91.6% with abemaciclib and 87.1% with endocrine therapy alone, for an absolute difference of 4.5%.
In the intention-to-treat analysis, abemaciclib reduced the risk for distant relapse–free survival by 31.3% versus endocrine therapy alone (P = .0009), which was deemed clinically meaningful. The 2-year survival without distant relapse rates were 93.8% and 90.8%, a 3% absolute difference favoring abemaciclib.
The safety profile of abemaciclib was consistent with previous reports. Most treatment discontinuations were because of adverse effects and occurred within the first 5 months of abemaciclib treatment. In addition, most patients who required dose interruptions or reductions were able to continue with abemaciclib therapy.
The planned follow-up for the monarchE study is 10 years.
Commenting on the results of the additional 4 months of follow-up in this study, C. Kent Osborne, MD, Founding Director, Dan L. Duncan Comprehensive Cancer Center, and Dudley and Tina Sharp Chair for Cancer Research, Baylor College of Medicine, Houston, TX, said, “I think these results are encouraging, especially in the subgroup of tumors with high proliferation.”
However, he cautioned that this follow-up period is short for estrogen receptor–positive breast cancer, which can recur years later. And, he added, “This class of inhibitors is largely cytostatic rather than cytocidal, meaning that it blocks cell proliferation rather than killing the cells. An important question remains: will the invasive disease–free survival curves come together when the drug is stopped? With these caveats in mind, this is still a very important trial,” Dr Osborne concluded.