Finding the RIGHT Choice in patients with clinically aggressive ER-positive HER2-negative metastatic breast cancer

According to global statistics, breast cancer (BC) is the most common malignant neoplasm among women and a leading cause of cancer-related mortality (1). Estrogen receptor-positive (ER⁺) and HER2-negative (HER2⁻) tumors represent the most common subtype. Around 20 to 30 percent of patients develop metastatic disease—including a considerable proportion with visceral metastases—despite progress in early diagnosis and enhancements in treatments aimed at cure (2).

For decades, endocrine therapy (ET) has been the mainstay of systemic treatment for ER⁺ HER2⁻ BC at all stages. In the metastatic setting, recent guidelines recommend the sequential use of endocrine agents, and switching to chemotherapy (CT) is only recommended when there is established endocrine resistance or visceral crisis (VC) (3).

VC, a condition that occurs in 10% to 18% of advanced breast cancers (ABC), is characterized by rapid organ deterioration due to high tumor burden, resulting in imminent risk to life (2). Traditionally, the management of this condition has been based on polychemotherapy, aiming for a rapid response in a short period of time (4). However, choosing the ideal regimen is challenging due to the frailty of patients, contraindications to the use of certain drugs, and even concerns about the safety of the regimen (4). The presence of VC is an exclusion criterion for most clinical trials, limiting the available evidence to prospective series with an estimated overall survival (OS) of less than 10 months (4).

Recently, cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have revolutionized the treatment of ABC, with increased objective response rates (ORR) and benefits in survival outcomes (5-10). Cyclin-dependent kinases play a crucial role in regulating the cell cycle and its interactions with a variety of complex mechanisms of ET resistance, and three CDK4/6i are currently available—palbociclib, ribociclib, and abemaciclib (11). With the availability of these agents, there is a question as to whether the dogma of indicating CT in the setting of VC remains valid since ER⁺ HER2⁻ tumors usually have a chemo-resistance and hormone-sensitivity phenotype. Therefore, patients could benefit from using the best possible ET instead of CT regimens that may be less effective and more toxic.

In this scenario, the RIGHT Choice study was developed and conducted. This clinical trial compared polychemotherapy (docetaxel plus capecitabine, paclitaxel plus gemcitabine, capecitabine plus vinorelbine), an approach that has been consolidated for years, with ET combined with the CDK4/6i ribociclib in pre- or peri-menopausal women with clinically aggressive ER⁺ HER2⁻ ABC. The patients selected for the study had not received prior treatment for advanced disease and presented symptomatic visceral metastases, rapid disease progression, or imminent visceral involvement, but didn’t have bilirubin levels exceeding 1.5 times the upper limit of normal (ULN) (12). Notably, ribociclib is the only CDK4/6i approved for first-line treatment in premenopausal patients, based on data from the MONALEESA-7 trial (5).

Of the 222 randomized patients, 64.4% had de novo metastatic disease, 47.7% had VC determined by the investigator, and 55.9% had three or more sites of metastatic disease. The median progression-free survival (PFS) was 21.8 months in the ribociclib group and 12.8 months with polychemotherapy [hazard ratio (HR) 0.61; P=0.003], with a more significant benefit in the subgroup of patients who had a considerable volume of disease without VC and who did not have liver metastases. Similar benefits were seen in time to treatment failure. The ORR was 66.1% in the ribociclib arm and 61.8% in the CT arm. There was no statistically significant difference in time to response (TTR) evaluation. The OS was not reached in either arm of the study (12).

Ribociclib was associated with more hematologic events, such as neutropenia and leukopenia, while CT caused more vomiting, diarrhea, and fatigue. The treatment discontinuation rate due to adverse events was 6.3% in the ribociclib group and 27% in the CT group, suggesting that ET may be a better alternative in terms of toxicity (12).

This clinical trial has limitations, such as the impossibility of treatment blinding implementation and the exclusion of some CT regimens commonly used in ABC clinical settings from the comparator arm. In addition, most patients in this study were diagnosed with de novo metastatic BC, and the population consisted only of pre- or peri-menopausal women. Therefore, further investigation is needed to confirm the validity of these findings in recurrent disease.

Another important consideration is related to the relatively arbitrary definition of VC in ABC. There is a difficult-to-delimit continuum between the presence of visceral metastases, the presence of visceral metastases with significant disease burden and symptoms, and the most severe situation when the metastatic disease rapidly impairs organ functions, leading to a life-threatening condition known as VC (2). Because widely accepted objective clinical criteria for defining VC are lacking, various studies have identified diverse clinical conditions as VC. In this context, it is important to emphasize that although the RIGHT Choice study is mentioned and discussed as a study of ABC patients with VC, this condition had been confirmed by the investigators in only 47% of the patients. In this study, a preliminary subgroup examination of participants diagnosed with investigator-evaluated VC revealed that both treatment groups had comparable lengths of PFS and TTR. Nevertheless, the frequency of side effects was reduced among patients receiving ribociclib compared to those undergoing CT.

Nonetheless, this clinical trial has several strengths, such as having a key objective of evaluating a question of extreme relevance in the field of breast oncology at a global level, having a scientific methodology and correct and objective design, presenting results with extreme significance from a clinical and statistical point of view and that are well aligned with the literature and other studies that have demonstrated benefits with the use of ET associated with CDK4/6i. Importantly, it is essential to highlight the great challenge of conducting studies in patients with VC, which is a relatively uncommon condition, especially at the beginning of the patient’s journey with ABC, and that requires rapid flows and alignments, both in the clinical practice setting and in clinical research. Finally, we must congratulate the initiative of the investigators, sponsors, and others involved in a high-quality clinical study with significant impact and benefit for the breast oncology field conducted exclusively in countries outside North America and Western Europe—an important step towards advancing breast oncology research globally (13).

Although the study did not evaluate induction CT in patients with aggressive disease behavior, the recently presented phase II ABIGAIL study addressed this question. The ABIGAIL study compared 12 weeks of paclitaxel as induction CT followed by abemaciclib plus ET vs. frontline abemaciclib plus ET without induction CT. The results demonstrated that ORR was higher in patients who did not receive induction CT (59% without induction vs. 40% with induction) (14). Currently, there are no data comparing antibody-drug conjugates (ADCs) with CDK4/6 inhibitors in first line.

The RIGHT Choice study is the first prospective clinical trial with a head-to-head comparison between a CDK4/6i plus ET and combination CT and showed improved PFS, similar response rates, and lower symptomatic adverse event rates with ribociclib plus ET versus combination CT in patients with clinically aggressive ER⁺/HER2⁻ ABC. It is a significant and practice-changing study in the treatment of women with metastatic BC, already included in some guidelines (3). However, as previously mentioned, it cannot be applied to patients with elevated bilirubin levels.

According to remarks from the editor of the Journal of Clinical Oncology, the importance of this research is that it calls for discarding the long-standing notion that individuals with visceral illness must undergo CT even when they are ER⁺. Identifying prognostic and predictive biomarkers is a priority in this and other breast oncology settings. Continued support for clinical trials is essential to improve the use of innovative agents in patients with aggressive presentations of ABC, thus ensuring that new evidence is rapidly integrated into clinical practice.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-170/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-170/coif). M.M.P. reports payments from AstraZeneca, Knight Therapeutics, Libbs. T.R. reports grants from AstraZeneca, Libbs, consulting fees from AstraZeneca, Lilly, Libbs, Novartis, MSD, Daiichi-Sankyo, Gilead, payments from AstraZeneca, Lilly, Libbs, Novartis, MSD, Daiichi-Sankyo, Gilead. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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