Study: CDK inhibitors may increase survival for ER-positive metastatic breast cancer patients

IN-DEPTH REVIEW OF RESEARCH
Study background:

In MONALEESA-2, ribociclib plus the aromatase inhibitor letrozole showed improved progression-free survival compared with letrozole alone as first-line treatment for postmenopausal patients with hormone receptor-positive, HER2-negative, advanced breast cancer. However, the impact on premenopausal women was not determined.

Young women with breast cancer tend to have poorer prognoses and more aggressive cancer compared to older women. Premenopausal women are underrepresented in clinical trials. MONALEESA-7 is the first Phase III trial with a CDK4/6 inhibitor exclusively in premenopausal patients. This allows researchers to more directly ask whether CDK4/6 inhibitors may benefit premenopausal women who are often also on endocrine therapy.

Researchers of this study wanted to know:

Building on the MONALEESA-2 results, the MONALEESA-7 trial aimed to assess the usefulness and safety of ribociclib plus endocrine therapy for premenopausal women with advanced, hormone receptor-positive, HER2-negative advanced breast cancer.

Population(s) looked at in the study:

Patients in each group of the study had similar average characteristics. The average age of the 335 participants who received ribociclib was 43 (ages ranged from 25-58).  Most of these participants were white (56%) and did not have prior neoadjuvant or adjuvant endodcrine therapy (62%).  Only 14% had prior chemotherapy for advanced disease.  Similarly, most patients who received placebo were white (60%) and did not have prior neoadjuvant or adjuvant endocrine therapy (48%).  Identical to the ribociclib group, 14% of control patients had prior chemotherapy for advanced disease.   

Study design:

A total of 672 women who had pre- or perimenopausal advanced breast cancer before the age of 59 and who had only up to one prior line of chemotherapy and had not received endocrine therapy for metastatic disease were randomized to receive endocrine therapy with either ribociclib or placebo. The primary endpoint was progression free survival with a secondary endpoint of overall survival.

Study findings:

• Median progression-free survival was almost 24 months in the group that took ribociclib with endocrine therapy compared to 13 months in the group that received endocrine therapy only.
• Overall survival was analyzed at a pre-specified time; 192 deaths occurred before that time. 
  • Ribociclib plus endocrine therapy resulted in statistically significant longer overall survival than endocrine therapy alone.
    • Estimated overall survival at 42 months was 70.2% in the ribociclib group and 46.0% in the placebo group.

At the interim analysis point (median follow-up was 35 months), 35% of patients receiving ribociclib were still on the trial while only 17% of the patients who received a placebo remained. The predominant reason for ending treatment in both groups was disease progression.

Progression-free survival 2 (PFS2) time from when individuals were randomized to when they progressed to the next line of therapy or died differed between the two groups. Patients in the ribociclib group showed a 31% improvement in PFS2 compared to patients who received placebo.

The time to first subsequent chemotherapy differed by treatment group.  It was longer for the ribociclib group than it was for the group of patients who received placebo. At 42 months, 66% of patient in the ribociclib group had not received chemotherapy compared to 49% of patients in the placebo group. The most common subsequent therapies in both groups after treatment was discontinued were chemotherapy alone and endocrine therapy alone.  

Grade 3 (severe) or 4 (life-threatening) adverse events reported in more than 10% of patients in either group were neutropenia (low white blood cell count), hepatobiliary toxicity (chronic liver disease), and long QT interval (erratic heatbeat). Serious adverse events occurred in 18% of patients in the ribociclib group and in 12% of patients in the placebo group, of which 4% and 2%, respectively, were attributed to the study regimen. Adverse events lead to discontinued treatment in 4% of patients in the ribociclib group and 3% of patients in the placebo group.

Limitations:

Few data are available from large studies of targeted therapy for young women with breast cancer. Because ribociclib is four times more selective for the CDK4 enzyme than CDK6 enzyme, more research is needed to determine if the effect observed in this trial was due to ribociclib or if other CDK4/6 inhibitors would be as effective. 

Conclusions:

The results of the MONALEESA-7 trial show that there is substantial clinical benefit with ribociclib and endocrine therapy compared to endocrine therapy alone for young pre- or perimenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.

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Posted 7/22/19