NEW YORK – Updated analysis from the Phase III MonarchE trial has further strengthened evidence of abemaciclib's (Eli Lilly's Verzenio) efficacy as an adjuvant treatment for high-risk, early-stage, hormone receptor (HR)-positive, HER2-negative breast cancer patients.
At the San Antonio Breast Cancer Symposium on Wednesday, Priya Rastogi, associate professor of medicine at the University of Pittsburgh, said during a presentation that abemaciclib sponsor Eli Lilly is planning to submit the MonarchE data to the US Food and Drug Administration by year end. The drug is currently approved in the US as a treatment for metastatic breast cancer. An approval based on the MonarchE data would allow the company to market abemaciclib as an adjuvant treatment for early-stage breast cancer patients.
At the European Society for Medical Oncology's Virtual Congress in September, researchers reported initial data from MonarchE, showing that abemaciclib plus endocrine therapy reduced the risk of invasive disease by 25 percent at a median of 15.9 months of follow up. This marked the first time that the combination of a CDK4/6 inhibitor and endocrine therapy had significantly improved invasive disease-free survival in HR-positive, HER2-negative breast cancer patients in the adjuvant setting.
The results presented at SABCS include an additional 3.6 months of follow up and a total of 395 invasive disease-free events. Rastogi and colleagues reported that patients taking abemaciclib plus endocrine therapy had a 29 percent reduced risk of invasive disease compared to those receiving endocrine therapy alone. While the trial is still ongoing, 1,437 patients (26 percent) have completed the two-year treatment period and 3,281 patients (58 percent) were in the two-year treatment period.
The two-year invasive disease-free survival rate in the abemaciclib arm was 92 percent and 89 percent in the endocrine therapy alone arm. Researchers also saw an improvement in the two-year distant relapse-free survival rate in this updated analysis. Patients who received abemaciclib plus endocrine therapy had a distant relapse-free survival rate of 94 percent during this time compared to 91 percent for those who received endocrine therapy alone.
In the subgroup of patients with 20 percent or more cancer cells positive for Ki-67, thought to be a biomarker for high risk of relapse, the combination of abemaciclib and endocrine therapy reduced the risk of invasive disease by 30.9 percent compared to endocrine therapy alone.
However, the researchers and other experts at SABCS noted that the relatively short median follow-up time in MonarchE, which was 19.3 months, raises questions about the ability of abemaciclib plus endocrine therapy to stave off breast cancer recurrence over the long term.
"Early-stage, estrogen receptor-positive, HER2-negative breast cancer is known for a persistent recurrence rate even after 10 years," said Kent Osborne, a professor at the Baylor College of Medicine, who was not affiliated with the study. "With these caveats in mind, this is an extremely important trial and could be practice-changing in this high-risk population if the results continue to be positive and show improved survival."
Rastogi noted that the invasive disease-free survival endpoint in the present study was based on data from older breast cancer trials, like ATAC, which showed there was a higher risk of recurrence after the first few years with endocrine therapy.
"When MonarchE had been developed, we looked at historical data that [showed] there was a risk of recurrence after the first few years of endocrine therapy," Rastogi said. "As we continued with this [trial], all the analyses, both the interim analysis, as well as the primary outcome analysis, was based on [invasive disease-free survival] events that were pre-specified."
She noted that that the rate of invasive disease-free survival continues to separate between the abemaciclib arm and the endocrine therapy arm at each analysis, showing a short-term benefit for abemaciclib. However, the researchers will also continue to follow trial participants for up to 10 years after their treatment with abemaciclib and will report updated results about invasive disease-free survival and overall survival endpoints, she said.
As the final results from the PENELOPE-B study showed at this meeting, invasive disease-free survival benefits reported initially may not bear out with longer follow up. In the Phase III PENELOPE-B trial, researchers compared giving one year of palbociclib (Pfizer's Ibrance) and at least five years of endocrine therapy against five-year endocrine therapy in HR-positive, HER2-negative primary breast cancer patients who had received neoadjuvant taxane-based chemo. Earlier, with around two years of follow-up, palbociclib plus endocrine therapy appeared to delay cancer recurrence better than endocrine therapy alone.
However, at a median of 43 months of follow-up, palbociclib plus endocrine therapy did not improve invasive disease-free survival, said researcher Sibylle Loibl, head of the German Breast Group, in a presentation at SABCS. After approximately four years, the rates of invasive disease-free survival in the palbociclib and comparator arms were similar, 73 percent and 72 percent, respectively.
"This is the first study showing mature [invasive disease-free survival] results on a CDK4/6 inhibitor as part of post-neoadjuvant therapy," Loibl said. "To date, results of the PENELOPE-B study do not support the addition of one year of palbociclib to endocrine therapy."
She acknowledged that the trial may have failed to show a benefit with the addition of palbociclib because a one-year treatment duration was too short. "Long-term follow-up from all neoadjuvant CDK4/6 studies should continue and must be awaited," she said.
Although the designs of MonarchE and PENELOPE-B studies were different, Ruth O'Regan, division chief for hematology and medical oncology at the University of Wisconsin, who was not affiliated with either study, stressed that longer follow-up within MonarchE was also "critical."
O'Regan noted in her presentation that these two trials may have yielded divergent results because they employed varying criteria for determining which patients were high risk and had different durations of treatment for the CDK4/6 inhibitors.
"At two years, the [invasive disease-free survival] delta in favor of abemaciclib is 3 percent [in MonarchE], but when you look at PENELOPE-B, it was actually 4.3 percent in favor of palbociclib at two years and then the curves came together between years three and four," Regan said. "Clearly, longer follow-up for MonarchE is crucial to ensure the positive results we've seen to date remain positive at longer follow-up."