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Recent clinical trial data suggested a new first-line treatment option for patients with clinically aggressive and advanced HER+/HER2- breast cancer.

In the phase II RIGHT Choice trial, Nagi El Saghir, MD, of the American University of Beirut Medical Center in Lebanon, and colleagues randomized patients to first-line treatment with the cyclin-dependent kinase 4/6 inhibitor ribociclib plus endocrine therapy or investigator's choice of combination chemotherapy.

At a median 3 years of follow-up, median progression-free survival (PFS) was significantly better in the ribociclib plus endocrine therapy group (21.8 vs 12.8 months, HR 0.61, P=0.003), the researchers said, reporting the final results in the

"The data show PFS superiority with ribociclib plus endocrine therapy over combination chemotherapy, with similar response rates, lower symptomatic adverse event rates, and fewer discontinuations because of treatment-related adverse events. Thus, ribociclib plus endocrine therapy could be considered a first-line treatment option in this patient population," the team concluded.

El Saghir, director of the Breast Center of Excellence at the university's Naef K. Basile Cancer Institute, elaborated on the findings and the implications in the following interview.

Why did you undertake this study? Is there an unmet medical need in patients with HER+/HER2- advanced breast cancer?

El Saghir: We thought of this study and designed it after we had the results of , where we showed that endocrine therapy plus ribociclib produced PFS rates of 23.8 months in premenopausal patients with HR+ HER2- advanced breast cancer. Most prior studies using chemotherapy in those settings reported median PFS in the range of 6-9 months only.

All international guidelines recommended endocrine therapy plus CDK4/6i for patients with HR+ HER2- ABC [advanced breast cancer] except for patients requiring a rapid response where chemotherapy, or even combination chemotherapy, is still recommended. Patients with clinically aggressive disease, impending visceral crisis, or visceral crisis were not included in all clinical trials of endocrine therapy plus either of the three approved CDK4/6 inhibitors, and there has never been a study comparing endocrine therapy plus CDK4/6i versus combination chemotherapy.

Therefore, in light of the advances with using CDK4/6i, we decided that there is an unmet need in patients with HR+ HER2 ABC who are usually treated with chemotherapy for a limited benefit and who are exposed to all its related toxicities,

How do your results compare with other studies of cyclin-dependent kinase 4/6 inhibitor treatment in this patient population?

El Saghir: Unlike all other studies of CDK4/6i in HR+ HER2- ABC, the RIGHT Choice study enrolled patients with significant disease burden, symptomatic visceral disease, rapidly progressive disease, impending visceral crisis, and investigator-assessed visceral crisis according to ABC2 Guidelines available at the time of the study. Rather than comparing a CDK4/6i plus ET [endocrine therapy] with placebo + ET, RIGHT Choice compared CDK4/6i ribociclib plus ET with combination chemotherapy and showed improved median PFS of 21.8 months versus 12.8 months with HR 0.61.

Because patients enrolled in RIGHT Choice were relatively sick or very sick from ABC disease, we required very close evaluation and RECIST v1.1 criteria imaging every 6 and then every 8 and then every 12 weeks, in an effort to make sure we do no harm to patients who are thought to require a rapid response to treatment.

The 3-month treatment failure rate was 11.6% in the RIBO [ribociclib]+ET arm versus 21.8 months in the combination chemo arm. That was important and reassuring for us to continue with the study. Time to treatment response and overall response rates were equivalent.

We also noted in an exploratory analysis presented at ASCO23 that results in the ITT [intent-to-treat] population are seen both in patients age 40-50 and those younger than 40. We noted that patients younger than 40 had an even more significant benefit with an HR ratio of 0.38 for favoring ET plus RIBO.

Approximately 47% of patients in this trial were determined to have visceral crisis. What did your exploratory analysis of this patient subgroup find?

El Saghir: In an exploratory analysis that we presented at ESMO23 of 57 patients who had clinically aggressive disease and were in visceral crisis treated with ET+RIBO vs 49 patients treated with combination chemo, median PFS was similar at 13.2 months vs 15.4 months respectively (HR 0.95). Also, 3-month treatment failure rates were similar.

As for patients with clinically aggressive disease not in visceral crisis, median PFS was 24.0 months vs 12.8 months with an HR of 0.42 favoring ET+RIBO, and the 3-month treatment failure rate was 3.6% vs 16% favoring the ET+RIBO arm.

This exploratory analysis showed that results with ET+RIBO vs combination chemo were similar in patients with clinically aggressive disease in visceral crisis, and were better in those with clinically aggressive disease not in visceral crisis. It supports that ET+RIBO could be considered as a valid first-line treatment option in premenopausal patients with clinically aggressive HR+/HER2− ABC, including those with visceral crisis.

When choosing a first-line therapy for patients with HER+/HER2- advanced breast cancer, what are the most important clinical factors or patient characteristics to consider?

El Saghir: Endocrine therapy plus CDK4/6 inhibitor is recommended as first-line therapy for most patients with HR+ HER2- ABC. RIGHT Choice shows that this recommendation is applicable to patients with clinically aggressive and symptomatic extensive visceral disease.

The RIGHT Choice trial was conducted in pre- and peri-menopausal women using ribociclib with ET consisting of LHRHa [luteinizing hormone-releasing hormone agonist] and AI [aromatase inhibitor]. The ABC7 International Consensus Panel believes that results also apply to postmenopausal women and men with similar characteristics.

In the RIGHT Choice trial, patients with bilirubin levels over 1.5 were not included, for the sake of being able to randomize patients for ET+RIBO versus the combination chemotherapy drugs used (docetaxel plus capecitabine, paclitaxel plus gemcitabine, or vinorelbine plus capecitabine), and 85% of the patients enrolled in RIGHT Choice had tumors with ER [estrogen receptor] positivity in more than 50% of the cells.

Therefore patients with high bilirubin levels and those whose tumors have low ER positivity would probably best be treated with an appropriate chemotherapy course before switching them to endocrine therapy and ribociclib.

Is there anything else you want to make sure oncologists understand about this study or this patient group?

El Saghir: This is the first-ever prospective head-to-head comparison of a CDK4/6i plus ET versus combination chemotherapy, and it showed improved progression-free survival, similar response rates, and lower symptomatic adverse event rates with ribociclib plus ET versus combination chemotherapy in patients with clinically aggressive HR+/HER2− ABC.

The overall results of RIGHT Choice reinforce the role of CDK4/6 inhibitors as first-line therapy for patients with HR+ HER2- advanced breast cancer. The traditional thinking that chemotherapy is better than endocrine therapy plus CDK4/6 inhibitors in patients with HR+ HER2- should be laid to rest. And as Kathy Miller, MD, Associate Editor of JCO wrote in an , the "conventional wisdom" that patients with visceral disease need chemotherapy even if ER+ should be retired.

Read the study here.