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CHICAGO -- Adding ribociclib (Kisqali) to adjuvant endocrine therapy significantly improved invasive disease-free survival (iDFS) in patients with early-stage, high-risk breast cancer and hormone receptor (HR)-positive/HER2-negative disease, an interim analysis of a large phase III study found.

In the , which included patients with node-negative disease, the CKD4/6 inhibitor plus endocrine therapy combination resulted in a 3-year iDFS rate of 90.4%, as compared to 87.1% with endocrine therapy alone (HR 0.748, 95% CI 0.618-0.906, P=0.0014), reported Dennis Slamon, MD, PhD, of the UCLA Jonsson Comprehensive Cancer Center in Los Angeles.

"Based on the number of patients that are challenged with this subtype of disease, that could result in a significant efficacy improvement," Slamon said during a press briefing in advance of the American Society of Clinical Oncology (ASCO) annual meeting.

He added that the results support the combination "as a new treatment choice" for this broad population of patients.

The iDFS benefit was seen across all subgroups, said Slamon, including in node-negative disease where CDK4/6 inhibitors are not currently indicated.

Based on results of the phase III monarchE trial, the CDK4/6 inhibitor abemaciclib (Verzenio) is in combination with adjuvant endocrine therapy for this same patient population, but only for those with node-positive disease.

In NATALEE, the addition of ribociclib was associated with a 24% reduction in the risk of invasive disease for the node-positive subgroup -- a finding that while not statistically significant, was "highly suggestive" of a benefit in patients "who are normally thought to be those with lower-risk disease," said Slamon.

ASCO-invited discussant Rita Nanda, MD, of the University of Chicago, said that although the results are early, they suggest a role for adjuvant ribociclib for stage II and higher disease.

"I do expect these trial results will change practice," Nanda said. "Having another option for patients with high-risk hormone-receptor positive/node-positive disease, but more so for patients with hormone-receptor positive/node-negative disease, will be an important contribution."

In NATALEE, 5,101 men or pre- or post-menopausal women were randomized 1:1 to ribociclib (3 years) plus endocrine therapy (letrozole or anastrozole for at least 5 years) or to endocrine therapy alone. Men and pre-menopausal women also received goserelin.

At a median follow-up of 34 months, 20% of patients in the ribociclib group had completed 3 years of treatment, while 57% had completed 2 years. Overall, 3,810 patients (74.7%) remained on treatment at data cutoff (1,984 in the ribociclib arm and 1,826 in the endocrine therapy-alone arm).

Improved Tolerability While Maintaining Efficacy

Slamon pointed out that the current standard of care for patients with HR-positive/HER2-negative early-stage breast cancer is surgery, with or without chemotherapy or radiation, followed by 5 to 10 years of adjuvant endocrine therapy. However, even after receiving adjuvant endocrine therapy, recurrence occurs in a third of patients with stage II disease and more than half of those with stage III disease, sometimes decades later.

Thus, Slamon said, there is an unmet need for tolerable treatment options that reduce the risk of recurrence in these patients.

Slamon pointed out that the approved dose of ribociclib for metastatic disease is 600 mg daily, while in NATALEE, a dose of 400 mg per day was used.

"The rationale there was that if we were hoping to improve efficacy, we also wanted to see if we could improve safety," he said. "And we had data from the metastatic trials that when patients were dose-reduced because of any adverse events, to 400 mg, it appeared to have equivalent efficacy."

That dose reduction led to improved safety signals with ribociclib, Slamon reported.

Specifically, he noted that neutropenia -- the major side effect associated with CDK4/6 inhibitors -- was seen in 62% of patients in this study, with 44% having grade ≥3 neutropenia. By comparison, when ribociclib was evaluated at 600 mg in the MONALEESA trials, neutropenia of all grades was observed in 74% of patients, while 60% had grade ≥3 events.

Slamon further noted that the incidence of QT interval prolongation associated with ribociclib was "rare" at 400 mg (5.2%), and no cases of torsade de pointes (an abnormal heart rhythm that can lead to sudden cardiac death) were reported.

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