Adjuvant Ribociclib Revamps HR+/HER2– Breast Cancer Management

The addition of ribociclib (Kisqali) to the hormone receptor–positive, HER2-negative early breast cancer treatment paradigm underscores that the choice between this agent and abemaciclib (Verzenio) is far from straightforward, instead hinging on individual patient characteristics and preferences, according to Jairam Krishnamurthy, MD, FACP.

On September 17, 2024, the FDA approved adjuvant ribociclib in combination with an aromatase inhibitor (AI) for the treatment of patients with hormone receptor–positive, HER2-negative stage II and III early breast cancer at high risk of recurrence, including those who have node-negative disease.¹ This regulatory decision was supported by findings from the phase 3 NATALEE trial (NCT03701334). In NATALEE, the combination generated a significant and clinically meaningful 25.1% (HR, 0.749; 95% CI, 0.628-0.892; P = .0006) reduction in the risk of disease recurrence vs endocrine therapy alone in this population. This invasive disease–free survival (iDFS) benefit was seen across all prespecified patient subgroups.

In the adjuvant setting, ribociclib joined the ranks of abemaciclib, which is FDA approved in combination with endocrine therapy for the treatment of adult patients with hormone receptor­–positive, HER2-negative, node-positive early breast cancer at high risk of recurrence, regardless of Ki-67 score.² In the pivotal phase 3 monarchE trial (NCT03155997), at a median follow-up of 54 months (IQR, 49-59), abemaciclib plus endocrine therapy sustained an iDFS benefit over endocrine therapy alone (HR, 0.680; 95% CI, 0.599-0.772; nominal P < .001).³

“A lot of shared decision-making will come into play between the patient and the oncologist,” Krishnamurthy said in an interview with OncLive^® following a State of the Science Summit™ on breast cancer, which he chaired. “However, it is heartening to see more treatment options come up for patients.”

In the interview, Krishnamurthy discussed factors that influence his choice between available CDK4/6 inhibitors in the metastatic breast cancer setting; challenges that may arise with the use of adjuvant ribociclib for patients with hormone receptor–positive, HER2-negative disease; and how the adverse effect profiles of ribociclib and abemaciclib inform patient-centered care in the adjuvant setting.

Krishnamurthy is an associate professor in the Division of Oncology & Hematology and the codirector of the Breast Cancer Program at the University of Nebraska Medical Center in Omaha.

OncLive: What data inform your choice of CDK4/6 inhibitor in the frontline metastatic setting?

Krishnamurthy: All 3 CDK4/6 inhibitors [that are approved in the metastatic setting] have similar progression-free survival [PFS] curves. The primary outcome of all the [pivotal studies that investigated these agents in patients] was PFS, so it is still reasonable to use any of those agents. However, between them, ribociclib has demonstrated a consistent overall survival benefit, so it is preferred by most oncologists at this time.

[Additionally], it is not always necessary to go to chemotherapy or antibody-drug conjugates right away in patients, even in those with visceral disease. Trials like the phase 2 RIGHT Choice study [NCT03839823] have shown that a CDK4/6 inhibitor plus an AI can yield similar, if not better, outcomes than chemotherapy. In the phase 2 Young-PEARL study [NCT02592746], where capecitabine was compared with a CDK4/6 inhibitor plus an AI, outcomes were similar [between the 2 arms] if not better [in the palbociclib (Ibrance) arm], which shows that you don’t have to give chemotherapy to these patients until you’ve exhausted endocrine therapy options. At the same time, [CDK4/6 inhibitors] are better tolerated than chemotherapy drugs.

What is the significance of the FDA approval of adjuvant ribociclib for patients with HR-positive, HER2-negative breast cancer? How will this agent fill an unmet need for this population?

In the NATALEE trial, we saw significant improvement [with ribociclib plus endocrine therapy vs endocrine therapy alone] in higher-risk patients, [a finding that was] somewhat similar to [data from] the monarchE trial with abemaciclib. This [approval] expands the horizon for adjuvant CDK4/6 inhibitors, particularly ribociclib, in this setting. It helps us give the opportunity to patients to have better outcomes and a reduced risk of recurrence.

The challenging part [of the NATALEE regimen is] to convince patients to take it for 3 years as the trial did because convincing them to take 2 years of abemaciclib on top of all they’ve gone through in terms of surgery, radiation, chemotherapy, and [more] is already challenging. The logistic challenge is going to be that patients will need to come [to the clinic] monthly to get laboratory tests done because this drug can cause neutropenia. You also need to check their EKG results for the first 2 cycles because the drug can cause QT prolongation.

How do you choose between ribociclib and abemaciclib in the adjuvant setting?

If a patient has pre-existing gastrointestinal issues such as inflammatory bowel disease or diarrhea, I would probably avoid abemaciclib because it can cause diarrhea. If a patient already has heart rhythm issues and they are on medications for that, especially drugs like amiodarone, which can prolong QT intervals, I would probably avoid ribociclib.

We will have to individualize therapy based on patients’ pre-existing conditions. For patients who meet the criteria for both ribociclib and abemaciclib, it’s going to be a question of whether they want to be on a drug for 3 years vs 2 years, and whether they want to be on [abemaciclib], a drug that can potentially cause diarrhea, as opposed to ribociclib, which can cause fatigue and nausea. In any case, blood counts need to be checked, so it’s a bit of give or take for both drugs.

References

1. FDA approves Novartis Kisqali to reduce risk of recurrence in people with HR+/HER2- early breast cancer. News release. Novartis. September 17, 2024. Accessed October 23, 2024. https://www.novartis.com/news/media-releases/fda-approves-novartis-kisqali-reduce-risk-recurrence-people-hrher2-early-breast-cancer
2. US FDA broadens indication for Verzenio (abemaciclib) in HR+, HER2-, node-positive, high risk early breast cancer. News release. Eli Lilly and Company. March 3, 2023. Accessed October 23, 2024. https://investor.lilly.com/news-releases/news-release-details/
3. Rastogi P, O’Shaughnessy J, Martin M, et al. Adjuvant abemaciclib plus endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative, high-risk early breast cancer: results from a preplanned monarchE overall survival interim analysis, including 5-year efficacy outcomes. J Clin Oncol. 2024;42(9):987-993. doi:10.1200/JCO.23.01994