Adding the cyclin-dependent kinase (CDK) inhibitor abemaciclib to standard adjuvant endocrine therapy continued to improve invasive disease-free survival (IDFS) among patients with high-risk, node-positive, early-stage, HR-positive, HER2-negative breast cancer, according to extended follow-up data from a Phase III clinical trial.
"Abemaciclib in combination with endocrine therapy is the first CDK4 & 6 inhibitor to demonstrate efficacy and tolerability for patients with HR-positive, HER2-negative, node-positive, high-risk early breast cancer," said senior author Priya Rastogi, MD, Associate Professor at the University of Pittsburgh Department of Medicine and Medical Director of the National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation, at the 2020 San Antonio Breast Cancer Symposium (SABCS).
Many patients with HR-positive early breast cancer will not experience recurrence on endocrine therapy alone, and about 20 percent may experience disease recurrence in the first 10 years, often in the form of incurable metastatic breast cancer.
"The risk of recurrence is higher among patients whose cancer has certain clinical and/or pathological risk factors, such as a high number of positive lymph nodes, large tumor size, or a high cellular proliferation as measured by tumor grade or biomarkers," said Rastogi. "There is a significant unmet need for this patient population, and research must be done to find new treatment options to help prevent early breast cancer from returning for these patients."
The Phase III, open-label monarchE trial compared abemaciclib plus adjuvant endocrine therapy with endocrine therapy alone in 5,637 patients with high-risk, node-positive, early-stage, HR-positive, HER2-negative breast cancer. Earlier results from an interim analysis were previously reported after a median follow-up of 15.5 months and 323 invasive disease-free events. That analysis found that the addition of abemaciclib to endocrine therapy reduced the risk of invasive disease by 25 percent. The 2-year IDFS rate in the combination arm was 92.2 percent and in the endocrine therapy alone arm was 88.7 percent.
At SABCS, Rastogi reported on an extended follow-up (Abstract GS1-01) that captured results from 395 invasive disease-free events with a median follow-up time of 19 months. Following surgery, and radiotherapy and/or chemotherapy as indicated, patients were randomly assigned to receive standard of care adjuvant endocrine therapy with or without abemaciclib 150 mg twice per day for 2 years.
These patients had at least four positive lymph nodes, or 1-3 positive nodes in combination with either grade 3 disease, a tumor of at least 5 cm, or centrally assessed high Ki-67 status. High Ki-67 status was defined as at least 20 percent positivity in tumor cells. Higher levels of Ki-67 protein are indicative of a fast-growing, aggressive tumor with increased probability of recurrence, she said.
At the time of this analysis, 1,437 patients (25.5%) had completed the 2-year treatment period and 3,281 patients (58.2%) were in the 2-year treatment period.
"We found a statistically significant treatment benefit with abemaciclib plus endocrine therapy that accretes to a 28.7 percent reduction in IDFS events," said Rastogi. The 2-year IDFS rate in the combination arm was 92.3 percent and the endocrine therapy alone arm was 89.3 percent.
In addition, there was an improvement in the 2-year distant relapse-free survival (DRFS) rate among patients who received the combination treatment compared with those who received endocrine therapy alone (93.8% vs. 90.8%, respectively).
The researchers also evaluated outcomes among 2,498 patients with centrally assessed high Ki-67 status. In this cohort, those patients who received the combination treatment "demonstrated a statistically significant benefit in IDFS that corresponded to a 30.9 percent decrease in IDFS events" as compared with those who received endocrine therapy alone, she said. The 2-year IDFS rates in the combination arm and the endocrine therapy-alone arm were 91.6 percent and 87.1 percent, respectively.
"Across the spectrum of data for abemaciclib, we have observed a consistent benefit in all subgroups," said Rastogi.
Safety data from this trial were consistent with the known safety profile of abemaciclib and no new safety signals were observed. Most discontinuations due to adverse events occurred within the first 5 months of treatment. Most patients who required a dose hold or reduction were able to remain on study treatment.
"These results may mark a notable treatment advance in the last 2 decades for people living with high-risk, node-positive, HR-positive, HER2-negative early breast cancer," she said. "These clinically meaningful results have the potential to change how high-risk, HR-positive, HER2-negative early breast cancer is treated."
In conclusion, Rastogi said: "At this preplanned analysis, with 395 events and an additional 3.6 months median follow-up, abemaciclib combined with standard endocrine therapy continued to demonstrate a reduction in the risk of developing IDFS and DRFS events for patients with HR-positive, HER2-negative, high-risk early breast cancer. This resulted in a statistically significant improvement in IDFS in patients with high Ki-67 tumors."
Rastogi noted that overall survival data are immature at this time, and additional follow-up is warranted. The study will continue until the final assessment of OS.
C. Kent Osborne, MD, Professor in the Department of Medicine and Hematology Oncology at Baylor College of Medicine, commented: "The 19-month data continue to show improved IDFS with abemaciclib in a high-risk subgroup of patients. The results are particularly encouraging in the subgroup with high Ki-67 tumors. This could be a practice-changing treatment in these patients if results continue to show improvement in survival with further follow-up."
Mark L. Fuerst is a contributing writer.