A combination of endocrine therapy and the targeted therapy Kisqali (ribociclib) is more effective than endocrine therapy alone at prolonging the survival of premenopausal women who have metastatic hormone receptor-positive breast cancer, a Phase 3 clinical trial suggests.

Findings from the MONALEESA-7 trial (NCT02278120) were presented during the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in the late-breaking presentation, “Phase III MONALEESA-7 trial of premenopausal patients with HR+/HER2− advanced breast cancer (ABC) treated with endocrine therapy ± ribociclib: Overall survival (OS) results.”

They were published simultaneously in The New England Journal of Medicine.

Kisqali is a targeted therapy developed by Novartis. It blocks the activity of cyclin-dependent kinases (CDKs), specifically CDK4 and CDK6. CDKs are proteins that help control the process of cell division; in the case of cancer, these proteins can spur tumor growth.

“Kisqali has characteristics that make it distinct from other CDK4/6 inhibitors,” Jeff Engelman, MD, global head of oncology research, Novartis Institutes for BioMedical Research, explained in a press release. “For one, Kisqali shows especially strong inhibition against CDK4. In pre-clinical data, Kisqali is four- to five-fold more potent against CDK4 compared to CDK6. CDK4 is likely the dominant CDK in breast cancer and a pivotal driver of disease progression,” he said.

Previously published data from the same clinical trial demonstrated that the addition of Kisqali to endocrine therapy (which deprives the tumor of hormones that can drive growth, most notably estrogen) prolonged progression-free survival (the time patients lives without disease worsening). The new data show this addition also extends overall survival.

MONALEESA-7 enrolled 672 women ages 25 to 58 with advanced or metastatic breast cancer whose tumors were positive for the hormone receptor (HR), but negative for the human epidermal growth factor receptor-2 (HER2).

Patients had not received any prior endocrine therapy for their advanced disease and were assigned randomly to receive Kisqali in combination with endocrine therapy or endocrine therapy plus a placebo. Kisqali was given orally at a dose of 600 mg daily for 21 days, then stopped for a week, for each 28-week cycle of treatment.

Endocrine therapy took the form of an aromatase inhibitor — Femara (letrozole) or Arimidex (anastrozole) — or tamoxifen plus goserelin.

The analysis of overall survival was done at a pre-specified timepoint when 192 deaths had occurred. At this time, patients had been followed for a median of 34.6 months, and deaths had occurred in 24.8% and 32.3% of the Kisqali and placebo groups, respectively.

Using statistical models, the researchers calculated an estimated overall survival rate of 70.2% in the Kisqali group and 46.0% in the placebo group at 42 months. Put another way, patients in the Kisqali group had a 29% lower risk of death than those in the placebo group.

A subgroup analysis then revealed that Kisqali in combination with an aromatase inhibitor cut the risk of death by 30% compared to an aromatase inhibitor alone, but the combination of Kisqali plus tamoxifen reduced this risk by only 20.9% compared to tamoxifen alone.

In other words, Kisqali worked better with an aromatase inhibitor than with tamoxifen, supporting last year’s MONALLESA-7-based approval of Kisqali plus an aromatase inhibitor as first-line therapy for women with metastatic breast cancer.

“Overall survival benefit is considered the ‘gold standard’ in cancer trials but is challenging to achieve in HR+/HER2- [hormone receptor-positive] metastatic breast cancer. MONALEESA-7 reached this important endpoint earlier than anticipated,” said Sara Hurvitz, MD, director of the Breast Cancer Clinical Trials Program at UCLA. “Impactful results like these ribociclib findings are what we wish for in every clinical trial, and to achieve overall survival improvement in an incurable disease, like metastatic breast cancer, is truly an outstanding advancement for patients.”

“Kisqali is the only CDK4/6 inhibitor to achieve statistically significant overall survival benefit in combination with endocrine therapy,” added Susanne Schaffert, PhD, CEO of Novartis Oncology.

Adverse side effects reported in this analysis were similar to those in previous analyses of the same trial. Common adverse reactions included low neutrophil levels (in 63.5% of the Kisqali group and 4.5% of the placebo group) and liver toxicity (in 11% and 6.8% of each group, respectively).