News > First- or second-line CDK 4/6 inhibitor: New study compares outcomes | ASCO 2023

First- or second-line CDK 4/6 inhibitor: New study compares outcomes | ASCO 2023



CDK4/6 inhibitors improve outcomes for many people with HR+ breast cancer. When used with endocrine therapy, the three targeted drugs in this family have shown benefit in clinical trials and in real-world use. Yet, questions remain about when it is best to give these drugs–as a first- or second-line treatment.

Some guidelines recommend using a CDK 4/6 inhibitor–along with anti-estrogen therapy–as the first course of treatment for advanced and metastatic breast cancer, even with limited evidence for this approach. Yet as a first-line therapy, these drugs can lead to prolonged side effects and higher cost of care. With this in mind, some doctors favor adding the CDK 4/6 inhibitor in the second line and starting with anti-estrogen therapy alone. The SONIA clinical trial is the first study to directly compare these two approaches.


The phase III, randomized SONIA trial found no benefit to giving a CDK4/6 inhibitor as a first-line therapy compared to giving it as second-line therapy. Based in the Netherlands, the study included 1,050 women with hormone receptor-positive, HER2-negative metastatic or advanced breast cancer, following them for an average of 37.7 months through two lines of treatment.

Everyone on the clinical trial received two lines of therapy, including a non-steroidal aromatase inhibitor (NSAI), a CDK4/6 inhibitor chosen by the doctor, and fulvestrant. The trial had two arms, or groups, that received treatment:

First-line treatment Second-line treatment
Arm 1 NSAI + CDK4/6i Fulvestrant
Arm 2 NSAI Fulvestrant + CDK4/6i

Trial participants ranged in age from 24 to 88 years with a median age of 63-64 years. Most were postmenopausal. The study included people who were newly diagnosed with advanced breast cancer and those whose cancers had returned as metastatic.

Most doctors chose palbociclib (Ibrance) as the CDK 4/6 inhibitor because it was the most readily available in the Netherlands. The data thus far do not show better outcomes with ribociclib (Kisqali), also represented in the trial.

The study team looked at time without cancer growth, overall survival, quality of life, time on CDK 4/6 inhibitor, serious side effects, and cost. They found no differences in cancer outcomes, survival, or quality of life.

Earlier use of a CDK 4/6 inhibitor extends time on the drug by 16.5 months and increases incidence of serious (grade 3 or 4) side effects by 42%. The researchers also found that first-line use increased the cost per person by $200,000. For these reasons, the study authors favor anti-estrogen therapy alone as the first-line treatment for advanced or metastatic HR+, HER2-negative breast cancer.

This study was funded by the Dutch government. The research team worked closely with patient advocates, who served on the steering committee, on the planning and execution of the trial.

What does this mean for you?

If you are facing an advanced or metastatic breast cancer diagnosis for the first time, this study offers new information for consideration and discussion with your doctor. The response to this study varied among doctors onstage and in the audience. Most would like to see more information on who might benefit from first-line treatment with a CDK 4/6 inhibitor before abandoning this approach. Some welcomed these findings and expressed concerns about the cost and side effects associated with early use of these drugs.

A key theme at this year’s ASCO meeting was the importance of listening to people with cancer. As you explore your options, let your doctor know what’s important to you both in your daily life and in your future goals. Discuss potential side effects in detail to consider what you might be able to live with more or less easily.


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