For the first time, a biomarker-based therapy approach was able to achieve prolongation of overall survival (OS) in premenopausal women with breast cancer. In the phase III study MONALEESA 7, therapy with the CDK4/6 inhibitor Ribociclib (Kisqali) in addition to endocrine therapy reduced the risk of death by 29% compared to endocrine therapy alone.
Sara Hurvitz, Director of the Breast Cancer Clinical Research Program at the UCLA Jonsson Comprehensive Cancer Center, Los Angeles, California, USA, presented the results at the American Society of Clinical Oncology (ASCO) Annual Meeting on June 4, 2019 and published them in parallel in the New England Journal of Medicine (See source 1 and 2).
According to Hurvitz, more than 268,000 women in the USA will develop breast cancer in 2019. About 20 % will be younger than 50 years. Younger women with advanced breast cancer usually have a particularly aggressive disease with a worse prognosis. MONALEESA 7 is the first Phase III study to include only premenopausal women. Efficacy and tolerability of a ribociclib-based regimen in addition to endocrine therapy in the first line compared to placebo in addition to endocrine therapy were investigated.
Ribociclib is approved in the EU for the treatment of women with HR-positive, HER2-negative, locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy or in women with prior endocrine therapy. In pre- or perimenopausal women, endocrine therapy should be combined with an LHRH agonist.
The study included 672 untreated pre- or perimenopausal women with HR-positive and HER2-negative advanced breast cancer. They were randomized and treated with Ribociclib (600 mg/day) for 3 weeks followed by 1-week break plus tamoxifen or a non-steroidal aromatase inhibitor (NSAI) plus goserelin (n = 335) or with placebo plus endocrine therapy (n = 337). The primary endpoint was progression-free survival (PFS), secondary endpoints included overall survival, overall response rate, clinical benefit, safety, and patient-reported outcomes.
As already published in Lancet Oncology, the study met its primary endpoint. Progression-free survival was significantly extended by ribociclib from 13.0 to 23.8 months in the median (HR 0.553, p < 0.0001).
Hurvitz now presented the results of a predefined interim analysis of the secondary endpoint of overall survival (OS), conducted after a follow-up period of 34.6 months and 192 deaths. These were another 15 months of follow-up after analysis of the primary endpoint. 35% of patients in the Ribociclib group continued therapy at the time of this analysis.
In the Ribociclib group 83/335 and in the placebo group 109/337 patients died. The additional administration of the CDK4/6 inhibitor reduced the relative risk of death by 29% (p = 0.00973), whereby the median OS had not yet been reached in the Ribociclib group. In the placebo group, it was 40.9 months. After a landmark analysis, 70.2 % of patients in the ribociclib group and 46.0 % in the placebo group survived after 42 months. Due to the significance of the results, they are now considered by the protocol as the final results of the study for the important secondary endpoint of overall survival.
Predefined subgroup analyses showed that patients taking aromatase inhibitors had OS rates similar to those of the whole group at 42 months with 69.7 % in the ribociclib group and 43 % in the placebo group. The relative risk of death decreased by 30% with Ribociclib. The OS rates for tamoxifen were 71.2% and 54.5%, respectively, and the relative risk of death decreased by 21%. "This is a small subgroup," Hurvitz explained the tamoxifen data. "We currently do not administer tamoxifen in combination with ribociclib. At the end of the study, tamoxifen was found to prolong the QT interval." Ribociclib is also not approved for combination with tamoxifen.
Patients were treated in the ribociclib arm for a median of 2 years and in the placebo arm for 1 year. No new, previously unknown side effects were observed during the longer follow-up period.
"This is the first time that a statistically significant improvement in overall survival with a CDK4/6 inhibitor in combination with endocrine therapy has been seen in patients with advanced HR+/HER2-negative breast cancer," concluded Hurvitz. In an ASCO press conference, the oncologist also emphasized: "It is very difficult to demonstrate a significant improvement in overall survival in trials in patients with metastatic breast cancer because patients are very often treated with other drugs after the end of the trial medication".
Discutant Angelo Di Leo, Sandro Pitigliana Medical Oncology Department, Prato, Italy, is of the opinion that the results of this study represent a new therapy standard for women without previous endocrine therapy. The MONALEESA-7 study had shown a significant extension of the OS with Ribociclib in them.
A subgroup analysis showed that the OS benefit was mainly seen in the non-endocrine pretreated group, whereas Ribociclib did not work better as a placebo in the endocrine pretreated patients. Di Leo showed parallels with the SWOG-S0266 study, in which about 700 women were also treated with anastrozole plus fulvestrant in the first line or initially only with anastrozole and after progression with fulvestrant.
At 49.8 months in the median, the OS was significantly better in the combination group than at 42 months in the sequence group (HR 0.82, p = 0.03). Here, too, a subgroup analysis showed that the positive effect on OS was predominantly seen in women who had not yet received endocrine treatment. However, since both cases are subgroup analyses, one has to be cautious with a conclusion, but at least a trend can be seen. Further support, however, would come from the survival data of the PALOMA-3 study, which showed no survival benefit in primary resistance to endocrine therapy with palbociclib.
1. Hurvitz SPS, et al. Phase III MONALEESA-7 trial of premenopausal patients with HR+/HER2- advanced breast cancer treated with endocrine therapy ± ribociclib: Overall survival results.ASCO 2019, Chicago, May 31 to June 4, 2019, Abstract LBA 1008.
2. Im SA; et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019, published online on 4 June 2019. https://www.nejm.org/doi/full/10.1056/NEJMoa1903765