Additional treatment with abemaciclib or ribociclib may prolong survival in women with advanced hormone receptor-positive and HER-2-negative breast cancer.
Endocrine therapy is considered standard for advanced hormone receptor-positive (HR+) HER2-negative breast cancer. However, promising results on the combination of endocrine therapy with CDK4/6 inhibitors are now available. For example, the MONALEESA-7 study in premenopausal women showed that the additional administration of ribociclib significantly prolonged the overall survival of patients compared to endocrine therapy alone.
In the two studies MONALEESA 3 and MONARCH 2 presented at ESMO, the CKD4/6 inhibitor was investigated in combination with fulvestrant, but different patient groups were included in different therapy lines.
In the MONALEESA 31 Phase 3 trial, ribociclib (Kisqali®) plus fulvestrant versus fulvestrant alone was evaluated as first or second-line therapy in 726 postmenopausal women with HR-positive HER2-negative advanced breast cancer. The primary endpoint, progression-free survival (PFS), was significantly longer when combined at 20.5 months than endocrine therapy alone at 12.8 months. At the ESMO Congress in Barcelona, Dennis J. Slamon, from the David Geffen School of Medicine, Los Angeles, California, USA, presented the second of three planned overall survival analyses after a median follow-up of 39.4 months. In the ribociclib group, the median survival time was not yet reached, in the fulvestrant-group it was 40 months. This means a reduction of the mortality risk by the additional administration of ribociclib of 28% (HR 0.72, p = 0.0045).
The effect was detectable in both first-line and second-line therapy. PFS was consistent with the findings reported a year ago - 20.6 months for ribociclib/vestrant and 12.8 months for fulvestrant alone (HR 0.587). The median PFS was 33.6 months versus 19.2 months (HR 0.546) for first-line therapy and 14.6 months versus 9.1 months (HR 0.571) for second-line therapy. The time to the next therapy was not yet reached after ribociclib/fulvestrant, with fulvestrant alone it was 29.5 months.
No new, previously unknown adverse effects were seen in a follow-up period of approximately 40 months.
"The combined data of MONALEESA 3 and MONALEESA 7 are the largest evidence of a survival benefit from a CDK4/6 inhibitor to date. These data show a consistent and significant prolongation of survival by ribociclib with various endocrine therapies regardless of menopause status and therapy line," concluded Slamon.
The Phase 3 MONARCH 2 study2,3 investigated abemaciclib (Verzenios®) plus fulvestrant versus fulvestrant in 669 pretreated pre-, peri- or postmenopausal women with advanced hormone receptor-positive HER2-negative breast cancer. They were resistant to endocrine therapy. The primary endpoint, PFS, was significantly extended from 9.3 to 16.9 months with the addition of abemaciclib. George W. Sledge, from Stanford University, California, USA, presented the results on the secondary endpoint OS at the ESMO Congress. After a median follow-up of 47.7 months, overall survival was 46.7 months in the abemaciclib group and 37.3 months in the control group - a difference of 9.4 months (HR 0.757, p = 0.013). The benefit of the CDK4/6 inhibitor was demonstrated in all subgroups. After an exploratory analysis, the time to chemotherapy was extended to 50.2 months in the abemaciclib group and 22.1 months in the control group, which corresponds to an extension of the interval to chemotherapy by approximately 60%.
In an ESMO press conference at the Barcelona Congress, Nadia Harbeck, from the Ludwig-Maximilians University, Munich, Germany, described the results as a "clear game-changer in metastatic breast cancer". "We see here 46 or more than 50 months of median overall survival - in our breast cancer registries, the median survival time is only two and a half years.
The MONARCH study showed for the first time a survival benefit for a CDK4/6 inhibitor in a second-line cohort. "It is the first time we have had survival data for abemaciclib", Harbeck indicated. The difference of 10 months in overall survival is truly clinically significant, according to the team.
The MONALEESA-3 study is the first to provide survival data in first and second-line therapy. This is also of great clinical importance. "So far, we were uncertain whether we should administer CDK4/6 inhibitor therapy in the first or second line," said Harbeck. "Now we know: There is also a survival advantage in the first line - and that should influence our standard of care."
These data will lead to treatment with CDK4/6 inhibitors becoming the standard of care. In Harbeck's opinion, they should also become standard in first-line therapy, because it is never known whether the patient would come back for second-line therapy. "We should give the best drugs first." Harbeck believes that CDK4/6 inhibitors will have a similar significance for women with metastatic breast cancer as HER2 inhibitors do for HER2-positive breast cancer.
1. Slamon DJ et al. Overall survival results of the phase III MONALEESA-3 trial of postmenopausal patients with hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2-) advanced breast cancer treated with fulvestrant ± ribociclib. ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, LBA7_PR.
2. sledge GW, et al. MONARCH 2: Overall survival of abemaciclib plus fulvestrant in patients with HR+, HER2- advanced breast cancer. ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, LBA6_PR.
3. Sledge GW, et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy-MONARCH 2. A randomized clinical trial. JAMA Oncol, published online on September 29, 2019.