The addition of the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy continues to offer improved event-free survival in women with high-risk hormone receptor-positive (HR+), HER2-negative breast cancer, indicate updated results, which now extend to about a year and a half, from the landmark monarchE trial.
However, experts warned that longer follow-up – at least to 5 years – will be required to understand the impact of the combination treatment on survival, particularly as HR+ breast cancer is associated with a high rate of late recurrences.
The research was presented Dec. 9 at the 2020 San Antonio Breast Cancer Symposium, being held online this year because of the pandemic.
An earlier preplanned interim analysis the phase 3 trial of over 5600 patients was presented at the ESMO Virtual Congress 2020, and simultaneously published in the Journal of Clinical Oncology.
As previously reported by Medscape Medical News, this showed that, after a median follow-up of 15.5 months, abemaciclib plus endocrine therapy was associated with a 25% relative risk reduction in the primary endpoint of invasive disease-free survival (IDFS) vs endocrine therapy alone.
At the time, the findings were hailed as practice changing and, once approved for high-risk HR+ HER2-negative early breast cancer, as the “new standard of care” by one expert.
Now, with median follow-up extended to 19.1 months, Priya Rastogi, MD, associate professor at the University of Pittsburgh Department of Medicine, Pittsburgh, Pennsylvania, presented new study data, including additional results on patients with a Ki-67 index ≥20%, which is indicative of fast tumor growth.
Abemaciclib plus endocrine therapy was associated with a significant 28.7% reduction in the relative risk of developing an IDFS event vs endocrine therapy alone across the whole patient population, and with a 30.9% risk reduction in those with a Ki-67 index ≥20%.
Moreover, patients taking the drug combination had a significant 31.3% reduction in the relative risk of a distant relapse-free survival (DRFS) event.
Crucially, these improvements, which were deemed clinically meaningful, were not gained at the expense of additional safety concerns, although high rates of any grade diarrhea, fatigue, and neutropenia were noted.
Rastogi said the findings underline that abemaciclib combined with standard endocrine therapy “is the first CDK4/6 inhibitor to demonstrate efficacy and tolerability for patients with HR+ HER2-negative, node-positive, high-risk early breast cancer.”
Longer follow-up is ‘reassuring’ but still ‘quite short’
George W. Sledge Jr, MD, professor of medicine at Stanford University Medical Center, Palo Alto, California, was the study discussant for the earlier interim analysis presented at ESMO 2020.
At the time, he said that the study had “very, very short follow-up,” and it was consequently unclear whether the improvements will “lead to what we really care about: improved overall survival.”
Approached to comment on the current analysis, Sledge told Medscape Medical News the data “appear quite consistent” with those presented earlier this year, “which is certainly reassuring.”
Referring to the analysis in patients with a Ki-67 index ≥20%, he added the results “show a higher absolute benefit in patients with more rapidly proliferating tumors, as might be expected for a drug affecting cell-cycle division.”
However, Sledge underlined that the median follow-up time “is still quite short for a study of ER-positive adjuvant therapy, where the majority of recurrences and deaths occur after 5 years in many studies”.
Consequently, “we still have a long way to go to understand the ultimate effects of CDK4/6 inhibition on early-stage, ER-positive breast cancer, particularly on late recurrences.”
Agreed, said C. Kent Osborne, MD, codirector of SABCS and founding director of the Duncan Cancer Center at Baylor College of Medicine, Houston, Texas.
Commenting in a press conference, he said the results are “very encouraging, especially in the subgroup of tumors with high proliferation.”
However, Osborne also urged “caution” in the interpretation of the results “given the still rather short follow-up [and] given that ER+ disease is known for its persistent recurrence rate, even past 10 years.”
He also noted “this class of inhibitors is likely cytostatic, rather than cytocidal, meaning that it blocks cell proliferation rather than killing the cells.” Questions therefore remain over whether the survival curves for combination therapy will come together with those for endocrine therapy alone once the drug is stopped.
Osborne nevertheless said that, “with these caveats in mind, this is still an extremely important trial that could be practice changing in this very high-risk patient population…if the results continue to be positive and show improved overall survival with longer follow-up.”
During the press conference, Rastogi confirmed that the study will indeed to continue out to 10 years until the final assessment of overall survival.