Ribociclib regimen reduces recurrence risk in common breast cancer subtype
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Key takeaways:
- The regimen conferred 3-year invasive DFS event rates of 90.4% vs. 87.1% with endocrine therapy alone.
- No new adverse events occurred with the combination.
CHICAGO — The addition of ribociclib to endocrine therapy improved invasive DFS vs. endocrine therapy alone in patients with hormone receptor-positive, HER2-negative early-stage breast cancer.
Findings from the phase 3 NATALEE trial, presented during a press conference ahead of ASCO Annual Meeting, support ribociclib (Kisqali, Novartis), a cyclin-dependent kinase (CDK) 4/6 inhibitor, plus endocrine therapy as a possible new treatment option for hormone receptor-positive, HER2-negative early-stage breast cancer.
Rationale and methods
“Nearly 2 million new breast cancers are diagnosed globally each year, the majority of which are diagnosed early. The current standard of care for these patients is surgery with or without chemotherapy or radiation, followed by 5 to 10 years of adjuvant endocrine therapy,” Dennis J. Slamon, MD, PhD, director of clinical/translational research and director of the Revlon/UCLA Women’s Cancer Research Program at UCLA’s Jonsson Comprehensive Cancer Center, said during the press conference. “The goal of treatment in early breast cancer is to improve our cure rates. But we know that with our current standard of therapy, as many as one-third of patients with stage II disease and more than half of those with stage IV disease will still recur, which can occur as far out as 2 or 3 decades after diagnosis. This is the unmet need that we are trying to address in developing earlier therapies for early breast cancer.”
As Healio previously reported, the randomized, open-label phase 3 NATALEE trial included 5,101 men and premenopausal or postmenopausal women with hormone receptor-positive, HER2-negative early breast cancer.
Researchers evaluated the efficacy and safety of ribociclib plus endocrine therapy (n = 2,549) vs. endocrine therapy alone (n = 2,552). The trial tested a lower ribociclib starting dose of 400 mg to improve tolerability while maintaining efficacy.
Invasive DFS served as the primary endpoint. Secondary endpoints included recurrence-free survival, distant DFS and OS.
Median follow-up was 34 months.
“In the metastatic setting, we typically use 600 mg daily for 3 weeks on and 1 week off every 4 weeks. But in the trial, we used a lower dose, hoping for fewer side effects,” Debu Tripathy, MD, professor of medicine and chair in the department of breast medical oncology at The University of Texas MD Anderson Cancer Center, and HemOnc Today Editorial Board Member, told Healio. “Ribociclib does have some of the same side effects of the other CDK inhibitors like fatigue; it can also cause liver function test abnormalities, although that is uncommon. The duration of treatment on this trial was 3 years as opposed to 2 years. We do know that the risk for recurrence continues into 2 years and beyond, but it’s not feasible to give a CDK 4/6 inhibitor forever. The toxicity profile here was such that it might lend itself to longer therapy.”
Findings
At the time of data cutoff, 74.7% of participants remained on study treatment, with 1,984 patients on ribociclib and 1,826 patients on hormonal therapy alone. Among those assigned the ribociclib regimen, 20.2% completed 3 years of treatment and 56.8% completed 2 years of treatment.
At the prespecified interim analysis of 426 invasive DFS events, researchers observed recurrence rates of 7.4% in the ribociclib group compared with 9.2% in the endocrine therapy alone group.
“Median duration of follow-up for invasive DFS at this interim analysis was 27.7 months for both arms,” Slamon said. “We saw a difference of 25% relative reduction in the risk for invasive breast cancer when ribociclib was added to endocrine therapy. The benefit was seen across all subgroups, regardless of disease stage, menopausal status or even nodal status.”
Results showed 3-year invasive DFS event rates of 90.4% with the ribociclib regimen vs. 87.1% with endocrine therapy alone (HR = 0.748; 95% CI, 0.618-0.906).
No new adverse events occurred with the ribociclib regimen.
“The overall sense of this study is that patients are getting the same benefit they would expect with abemaciclib [Verzenio, Eli Lilly] but with fewer gastrointestinal side effects than you might see with abemaciclib,” Tripathy said. “Most of us feel that abemaciclib and ribociclib in the end are going to be perfectly adequate options. We now have the ability to change to ribociclib or start a patient on ribociclib if they have really bad gastrointestinal side effects.”
Implications
The findings support ribociclib plus endocrine therapy as a new treatment option for a broad population of patients with hormone receptor-positive, HER2-negative early breast cancer, Slamon said.
Researchers plan to continue to assess how the addition of ribociclib to hormonal therapy impacts quality of life and will follow patients to observe long-term outcomes.
“It is a big step forward to have another CDK 4/6 inhibitor that is effective in improving long-term outcomes,” Tripathy said. “Whether we start treatment later is something that is going to be looked at more closely because it may be that people do not get started on treatment right away.”
Perspective
Back to TopRita Nanda, MD
Slamon and colleagues are to be congratulated on this very important and practice-changing clinical trial.
Three CDK4/6 inhibitors are approved for the treatment of advanced hormone receptor-positive HER2-negative breast cancer — palbociclib [Ibrance, Pfizer], ribociclib and abemaciclib. All three agents have been shown in the advanced cancer setting to improve PFS when combined with endocrine therapy in the first- and second-line settings. Ribociclib and abemaciclib have also both been shown to improve OS in the advanced cancer setting. We also now have data for all three agents for the treatment of early-stage disease.
This is early but impressive data demonstrating a significant reduction in the risk for recurrence as defined by an improvement in invasive DFS for patients with high-risk node-positive and node-negative disease. We know that a substantial proportion of patients with early-stage hormone receptor-positive breast cancer can recur, and these recurrences can be quite delayed. For patients with node-negative disease, we had not previously seen any improvements with the addition of a CDK 4/6 inhibitor to endocrine therapy for early-stage breast cancer.
In the context of the NATALEE trial, ribociclib was effective and well-tolerated. I expect that these results will change practice. To now have another option for patients with high-risk node-positive disease but even more so for patients with high-risk node-negative disease will be an important contribution.
Perspective
Back to Top
Sylvia Adams, MD
Once approved by the FDA, this will offer an additional adjuvant treatment option for patients with stage II or stage III ER-positive breast cancer to reduce the risk for recurrence. There is another CDK 4/6 inhibitor, abemaciclib (Verzenio, Eli Lilly) available for patients with node-positive breast cancer that is FDA-approved for adjuvant therapy in combination with hormonal therapy. Now we will have a second option — once FDA approved — and can decide with patients which one of these two drugs to use based on their adverse event profiles, tolerability and/or treatment duration. In addition, the results of NATALEE also show benefit for patients with node-negative stage II breast cancer — a subgroup not studied in MONARCHE — and, therefore, more patients will be eligible to receive adjuvant CDK 4/6 inhibitors.
Patients with lymph-node negative, stage II ER-positive breast cancer now have a new treatment option. Adding ribociclib to endocrine therapy after surgery can decrease risk for recurrence and improve survival. In addition, for patients with lymph node-positive stage II or stage III breast cancer, there is now an additional CDK4/6 inhibitor option, allowing physicians and patients to choose the drug based on side effect profile and/or length of treatment. Both statements only apply once FDA approved.
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Slamon DJ, et al. Abstract LBA500. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
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