Reducing Recurrence in High-Risk, Early Breast Cancer

breast cancer: breast cancerAbemaciclib, in combination with endocrine therapy, is the first CDK4/6 inhibitor to show a statistically significant improvement in invasive disease-free survival (IDFS) among patients with HR-positive, HER2-negative, high-risk early breast cancer, according to findings presented at the ESMO Virtual Congress 2020 (Abstract LBA5). The results were simultaneously published in the Journal of Clinical Oncology (2020; doi:10.1200/JCO.20.02514). “Many patients diagnosed with HR-positive, HER2-negative early breast cancer will not experience recurrence with standard therapies, but up to 20 percent may develop disease recurrence or distant relapse,” noted lead author Stephen Johnston, MA, PhD, FRCP, Professor of Breast Cancer Medicine at the Royal Marsden Hospital NHS Foundation Trust in London. “In the first 10 years, that risk of recurrence is greatest for those with certain high-risk clinical or pathological features, especially during the first few years on their adjuvant endocrine therapy. Novel treatments are needed to prevent early recurrence and distant metastasis. “Abemaciclib is an oral, continuously dosed CDK4/6 inhibitor approved for HR-positive, HER2-negative, advanced breast cancer in combination with endocrine therapy. And, indeed, in combination with fulvestrant, overall survival was significantly improved,” he continued. “So, based on the efficacy and safety data from the metastatic setting, abemaciclib with endocrine therapy in the adjuvant setting was explored.” Trial Design An open-label, phase III study, monarchE included patients with HR-positive, HER2-negative, high-risk early breast cancer who completed primary treatment. Eligible patients included those with four or more positive nodes, or 1-3 nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3, or central Ki-67 ≥20 percent. The study enrolled 5,637 patients between July 2017 and August 2019 who were randomized (1:1) to receive abemaciclib (150 mg BID for 2 years) plus endocrine therapy or endocrine therapy alone. The primary endpoint was IDFS per STEEP criteria. Secondary endpoints included distant relapse-free survival (DRFS), overall survival, and safety. Median follow-up at the interim analysis was approximately 15.5 months in each arm, according to Johnston, who noted that 12.5 percent of patients had completed the 2-year treatment period and over 70 percent were still in the 2-year treatment period. In terms of patient demographics, the study arms were well-balanced. The median age was 51 years, over 99 percent of patients were female, more than 40 percent were premenopausal at diagnosis, and over 95 percent had received prior chemotherapy. When discussing high-risk disease characteristics, Johnston noted that over 40 percent of patients had a grade 3 tumor and over 60 percent had four or more involved nodes. Key Findings At the time of the data cutoff, there were 323 IDFS events—136 in the abemaciclib arm and 187 in the endocrine therapy alone group, Johnston reported. The combination of abemaciclib and endocrine therapy demonstrated a statistically significant improvement in IDFS compared to endocrine therapy alone (p=.0096, HR: 0.747, 95% CI: 0.598, 0.932), corresponding to a 25.3 percent reduction in the risk of an IDFS event. The 2-year IDFS rate was 92.2 percent among patients treated with abemaciclib plus endocrine therapy versus 88.7 for endocrine therapy alone. Two-year DRFS rates were 93.6 percent in the combination arm and 90.3 in the endocrine therapy cohort. Data demonstrated a consistent benefit across all prespecified subgroups. Distance recurrences were observed in 92 patients who received abemaciclib and 142 of those who underwent endocrine therapy alone. The major differences were in bone (32 vs. 81) and liver (29 vs. 42) metastases, according to Johnston. The median duration of abemaciclib treatment was 14 months, which will increase as the study continues, noted Johnston. Sixteen percent of patients discontinued abemaciclib due to adverse events (AEs). Of those patients, 306 remained on endocrine therapy after stopping abemaciclib. Only 21 (0.8%) patients in the control arm discontinued treatment due to AEs. Safety was consistent with the known profile of abemaciclib. The most frequent AEs included diarrhea, neutropenia, and fatigue in the abemaciclib arm and arthralgia, hot flush, and fatigue in the control group. The researchers observed that the frequency and severity of diarrhea decreased over time. “Abemaciclib combined with endocrine therapy showed a statistically significant improvement in IDFS in patients with high-risk HR-positive, HER2-negative early breast cancer, with a 25 percent reduction in risk of recurrence and a 3.5 percent absolute improvement in 2-year IDFS rates,” summarized Johnston. “Moreover, the results indicate the prevention of early recurrence and the reduction in the risk of metastasis by a clinically meaningful 28 percent, particularly in bone and liver disease. “The safety was consistent with the known profile of abemaciclib and diarrhea was manageable with anti-diarrheal medication and dose adjustments. A significant reduction in arthralgia and hot flush with abemaciclib added to endocrine therapy is intriguing,” he concluded. “Abemaciclib is the first CDK4/6 inhibitor to show a significant improvement in IDFS when combined with endocrine therapy in [this patient population.]” Expert Commentary During the conference, invited discussant George W. Sledge, MD, Stanford University School of Medicine, shared his thoughts on the monarchE trial and its positive findings. “Positive trials raise as many questions as they answer and monarchE trial is no exception,” Sledge noted. “What will be the ultimate increase in disease-free and distant relapse-free survival? Will the improvement seen in disease-free survival lead to what we really care about, improved overall survival? “What is the optimal duration of therapy? There's nothing magic about 2 years of therapy. Is it more than we need or not enough?” he continued. “[These are] important questions for an expensive drug with real side effects.” Sledge, who noted that there has been a recent trend to reduce chemotherapy in the ER-positive setting, wondered if something similar could be done with CDK4/6 inhibitors. Acknowledging the high cost of these drugs, Sledge emphasized the importance of addressing financial toxicity. “Two years of adjuvant therapy is simply out of reach for the majority of patients around the globe who might be candidates for adjuvant CDK4/6 inhibitor therapy,” he said. “A patient cannot benefit from a drug she cannot take. “Adjuvant CDK4/6 inhibition with abemaciclib significantly improves IDFS and DRFS in high-risk early-stage breast cancer patients. This establishes for the first time a proof of concept for CDK4/6 inhibition in the adjuvant setting,” he concluded. “We await more mature data particularly with regard to overall survival. The decision to use adjuvant CDK4/6 inhibitor therapy is more complex than a simple perusal of disease-free survival or distant relapse-free survival data and will need to be weighed against evolving measures of benefit.” Catlin Nalley is a contributing writer.