Professor Sherene Loi

The addition of the CDK4/6 inhibitor ribociclib to standard aromatase inhibitor therapy significantly improves invasive disease–free survival in patients with HR-positive, HER2-negative stage II or III early breast cancer.

The international NATALEE study, published in the NEJM [link here], randomised 5,101 patients to either ribociclib (400 mg per day) plus a non-steroidal aromatase inhibitor (letrozole or anastrozole) or an NSAI alone.

All premenopausal women in the trial received goserelin as ovarian function suppression therapy.

A prespecified interim analysis after three years of the RCT found ribociclib plus an NSAI was statistically and clinically superior to an NSAI alone.

Invasive disease–free survival was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone (hazard ratio for invasive disease, recurrence, or death, 0.75; 95% confidence interval, 0.62 to 0.91; P=0.003).

Distant recurrences were the most commonly reported type of event in the analysis of invasive disease–free survival, occurring in 120 patients (4.7%) in the ribociclib–NSAI group and in 170 patients (6.7%) in the NSAI group.

In secondary endpoints, distant disease–free survival (90.8% v 88.6%; HR 0.74), and recurrence-free survival (91.7% v 88.6%; HR 0.72) also showed a consistent benefit with ribociclib.

There were no new safety signals with ribociclib or the NSAIs.

“The most common adverse events of any grade that led to discontinuation of any trial treatment were liver-related events (in 8.9% of the patients in the ribociclib–NSAI group and in 0.1% of those in the NSAI group) and arthralgia (in 1.3% and 1.9%, respectively).

The investigators, including Professor Sherene Loi from Melbourne’s Peter MacCallum Cancer Centre, said the 400-mg ribociclib dose was associated with a lower incidence of toxic effects — namely, neutropenia and QT prolongation — than that seen with the 600-mg dose used in patients with advanced breast cancer.

Overall, “The results of this trial showed a significant invasive disease–free survival benefit over NSAI alone as adjuvant therapy in stage II or III HR-positive, HER2-negative early breast cancer; a 25.2% lower risk of invasive disease, recurrence, or death; and an absolute invasive disease–free survival benefit of 3.3 percentage points at 3 years.”

The study, funded by Novartis, said overall survival data remain immature.