Ribociclib may land a spot in early breast cancer treatment

In the second interim efficacy analysis of the phase III NATALEE trial, a combination regimen comprising the CDK4/6 inhibitor ribociclib and endocrine therapy (ET) demonstrated favourable signals for the adjuvant treatment of stage II/III hormone receptor-positive, HER2-negative (HR+, HER2–) early breast cancer.

“The goal of early breast cancer treatment is curative, with the hope that the disease will not recur,” said Dr Dennis Slamon from the UCLA David Geffen School of Medicine, Los Angeles, California, US, during his presentation at ASCO 2023.

However, even with stage II disease, a third of patients recur, and for those with stage III disease, more than half experience recurrence even 2–3 decades later, he said. “And when recurrence occurs, it is often at a more advanced stage, when the disease may already be incurable. Therefore, it is critical to prevent recurrences to better achieve the original curative intent of treatment.”

“We wanted to see if we could replicate the [significant survival benefit] we saw with ribociclib in the advanced setting,” Slamon shared. “[Hence,] we designed NATALEE to see if we could address this unmet medical need of recurrences that happen in HR+, HER2– breast cancers.”

NATALEE included a broad population of men and pre- or postmenopausal women with stage IIA, IIB, or III HR+, HER2– breast cancer at risk for recurrence, including those with no nodal involvement (n=5,101; median age 52 years). Participants were randomized 1:1 to receive adjuvant ribociclib 400 mg daily for 3 years (3 weeks on, 1 week off) with or without ET* for ≥5 years. Men and premenopausal women were also given goserelin. [ASCO 2023, abstract LBA500]

 

Invasive DFS benefit

After a median follow-up of 27.7 months, the risk for invasive disease was cut by 25.2 percent with ribociclib-ET vs ET alone (hazard ratio [HR], 0.748), translating to a highly significant invasive disease-free survival (DFS) benefit (p=0.0014).

“Based on this p value, the IDMC** concluded that the results met the criteria to demonstrate statistically significant and clinically superior efficacy. It actually exceeded what was specified in the protocol,” noted Slamon.

The 3-year invasive DFS rate was 90.4 percent for ribociclib-ET and 87.1 percent for ET alone, yielding an absolute difference of 3.3 percent.

Moreover, invasive DFS benefit was consistent across clinically relevant subgroups. “All of them are trending in the right direction. We’ll see what happens as these data mature,” noted Slamon.

 

Other survival outcomes

There was consistent improvement in distant DFS with ribociclib-ET vs ET alone (HR, 0.739; p=0.0017). Three-year distant DFS rates were 90.8 percent and 88.6 percent, respectively (absolute difference 2.2 percent).

There was also a trend for improved overall survival (OS) after a median follow-up of 30.4 months (HR, 0.759; p=0.0563). “However, this is relatively immature. Additional follow-up for OS planned,” said Slamon. There may be a trend in the right direction in terms of the number of events with ribociclib-ET vs ET alone (n=61 vs 73), but statistical significance has not yet been achieved.

 

Safety

“[To improve tolerability,] we looked at a dose that was different from the approved dose for advanced disease (600 mg),” Slamon noted. [www.accessdata.fda.gov/drugsatfda_docs/label/2019/209092s004lbl.pdf, accessed June 14, 2023] Also, the team decided on a 3-year treatment duration (as opposed to 2 years in other trials) to prolong cell cycle arrest and drive more tumour cells into irreversible senescence.

No new side effects or safety signals were reported with ribociclib 400 mg. Compared with the 600-mg dose in the pooled MONALEESA studies, ribociclib 400 mg was tied to lower rates of dose-dependent toxicities such as QTc prolongation (4.2 percent vs 6.5 percent), which was unique to ribociclib, and neutropenia (62 percent vs 74 percent). [Br J Cancer 2021;125:679-686] Moreover, grade ≥3 QTc prolongation events was decreased sixfold with 400 vs 600 mg (0.2 percent vs 1.2 percent).

The most common grade ≥3 adverse event (AE) with ribociclib-ET was neutropenia (44 percent). However, this was a known side effect of ribociclib with no perceived symptoms. The most frequent all-grade AEs with ribociclib-ET leading to discontinuation were liver transaminitis (8.9 percent) and arthralgias (1.3 percent).

These findings suggest that the extended treatment duration with the reduced dose had a more favourable safety profile than the 600-mg dose approved in the metastatic setting.

 

A new treatment option for early breast cancer

“Given the broad, easily identifiable population of patients at risk of recurrence, the tolerability of ribociclib, and the clinically meaningful reduction in the risk of recurrence seen in this study … these landmark results have fundamental clinical impact and could help streamline decisions for how we treat patients with stage II/III early breast cancer,” Slamon stated in a press release.

“Our results thus support ribociclib-ET as a new treatment of choice in a broad population of patients with stage II or III HR+, HER2– early breast cancer at risk of recurrence, including patients with node-negative disease,” he concluded.