Add-on ribociclib continues to triumph in early breast cancer

Coming on the heels of the second interim analysis, the protocol-specified final invasive disease-free survival (iDFS) analysis of the phase III NATALEE trial continues to show a highly significant iDFS benefit with the combination of the CDK 4/6 inhibitor ribociclib and a nonsteroidal aromatase inhibitor (NSAI) in individuals with HR+/HER2- early breast cancer.

“At a median follow-up of 33.3 months – which is an additional 5.6 months from the second interim efficacy analysis – the iDFS survival curves continued to diverge, confirming the superior efficacy of the ribociclib combination,” said presenting author Dr Gabriel Hortobagyi from The University of Texas MD Anderson Cancer Center, Houston, Texas, US, at SABCS 2023.

Ribociclib + NSAI conferred a significant iDFS benefit over NSAI alone (hazard ratio [HR], 0.749, 95 percent confidence interval [CI], 0.628–0.892; p_nominal=0.0006), representing a 25-percent reduction in the risk of invasive disease recurrence. [SABCS 2023, presentation ID GS03-03]

The 3-year iDFS rates with ribociclib + NSAI vs NSAI alone were 90.7 percent vs 87.6 percent, respectively, corresponding to an absolute iDFS benefit of 3.1 percent in favour of the former regimen.

This benefit was observed consistently across key prespecified subgroups, including AJCC* anatomical stage (HRs, 0.700 and 0.755 for stage II and III disease, respectively) and nodal status (HRs, 0.723 and 0.759 for node-negative [N0] and node-positive [N1-N3] disease, respectively).

Distant DFS, OS, safety

The 3-year distant DFS (dDFS) rates in the ribociclib + NSAI vs NSAI-alone arm were 92.9 percent and 90.2 percent, respectively, yielding a statistically and clinically significant absolute dDFS benefit of 2.7 years favouring the experimental regimen. Risk of distant disease was slashed by 25.1 percent with ribociclib + NSAI vs NSAI alone (HR, 0.749, 95 percent CI, 0.623–0.900; p_nominal=0.0010).

Hortobagyi stressed that dDFS is a critical endpoint as this is associated with the potential lethality of breast cancer.

Data on overall survival (OS) were immature at the time of analysis, with similar OS events between the ribociclib + NSAI and NSAI-alone arms (3.3 percent and 3.4 percent; HR, 0.892, 95 percent CI, 0.661–1.203). “At the final analysis, median follow-up for OS was 35.9 months. The OS data require longer-term follow-up,” said Hortobagyi.

About 20 percent discontinued ribociclib prematurely mostly on account of adverse events (AEs), with liver-enzyme elevation being the most common; however, Hortobagyi noted that this only represented a 0.8-percent increase from the previous interim analysis. There were no grade 4/5 AEs. Neutropenia was the most common grade ≥3 AE of special interest (44.3 percent).

Continued benefit with long-term treatment

NATALEE comprised over 5,000 participants that included men and pre- and postmenopausal women with nonmetastatic HR+/HER2- breast cancer. They were randomized 1:1 to receive NSAI (letrozole 2.5 mg daily or anastrozole 1.0 mg daily for ≥5 years) either alone or with ribociclib 400 mg daily (3 weeks on/1 week off for 3 years). Men and premenopausal women were also given goserelin 3.6 mg once every 28 days for ovarian suppression.

More than three-quarters (78.3 percent) of ribociclib recipients were no longer receiving the drug at data cutoff of the final iDFS analysis.

“Most breast cancers are diagnosed at stages I–III, and while many patients are cured with the current standard of care including surgery, radiotherapy, chemotherapy, and endocrine therapy (ET), a significant segment of this patient population will face disease recurrence,” said Hortobagyi.

Earlier work showed that the addition of ribociclib to ET led to significant improvement in progression-free survival and OS in patients with HR+/HER2- advanced breast cancer in the first- and second-line settings while maintaining and improving quality of life, he continued.

“Median OS with this combination now exceeds 5 years,” he said. Earlier this year, the initial NATALEE results demonstrated a significant iDFS benefit favouring the combo regimen over NSAI alone in patients with stage II/III HR+/HER2- early breast cancer. [ASCO 2023, abstract LBA500]

“We used a ribociclib dose that was lower than that used in the MONALEESA trials to improve tolerability and treatment adherence and extended the duration of treatment to 3 years to prolong cell cycle arrest and induce irreversible senescence,” Hortobagyi explained.

With a substantial proportion of patients completing 3 years of ribociclib treatment, the current NATALEE findings underpin the value of adding ribociclib to standard adjuvant ET, Hortobagyi noted. The efficacy findings confirm continued benefit across different prognostic subgroups, and the safety results support the manageable toxicity profile of ribociclib at the starting dose (400 mg) in early breast cancer.

“Taken together, these results further emphasize the benefit and tolerability of adjuvant ribociclib in a broad population of patients with HR+/HER2- early breast cancer at risk of recurrence,” said Hortobagyi.