Should CDK4/6 Inhibitors Be Used First or Second Line in Breast Cancer?

Breast cancer has become the most common cancer worldwide, and advances in its treatment exceed those in other cancers. CDK4/6 inhibitors first received FDA approval in 2015; 3 drugs in this class are currently approved: palbociclib, ribociclib and abemaciclib. They have substantially expanded treatment options and improved survival. However, adverse effects and costs must be considered alongside effectiveness, as they influence patients’ treatment experience and how long they can continue therapy. A new study examined the effects of this widely used drug class on survival, costs, adverse effects and quality of life.

The SONIA Study Attracted Attention at ASCO 2023

According to the phase 3 SONIA study presented at the American Society of Clinical Oncology annual meeting, ASCO 2023, using CDK4/6 inhibitors in the first line of treatment offers almost the same benefit as reserving them for second-line treatment.

CDK4/6 inhibitors are a newer treatment taken as oral tablets and used in first- and second-line therapy for advanced oestrogen receptor-positive, HER-negative breast cancer. In recent years, we have tended to use CDK4/6 inhibitors first line in metastatic, stage 4, breast cancer. However, SONIA showed that first-line CDK4/6 inhibitor use did not confer a progression-free or overall survival advantage.

The First Study Comparing First- and Second-Line Use

Until this trial, there had been no direct comparison between first- and second-line treatment. Presenting the study at ASCO 2023, Dr Sonke said, "Many patients do very well with endocrine therapy alone in the first line. Combination treatment with CDK4/6 inhibitors leads to resistant patterns such as ESR1 mutations. CDK4/6 inhibitors also bring additional costs and adverse effects. We designed SONIA because comparative first- versus second-line data were lacking."

Study Details

The study randomly assigned 1050 premenopausal and postmenopausal women to two groups:

• Experimental group: an aromatase inhibitor (AI) first line, followed by CDK4/6i plus the oestrogen receptor antagonist fulvestrant second line
• Control group: AI plus CDK4/6i first line, followed by fulvestrant second line.

The most widely used CDK4/6 inhibitor was palbociclib (Reampla), at 91%, followed by ribociclib (Valamor), at 8%, and abemaciclib (Verzenios), at 1%.

Results

• After two treatment lines, there was no significant difference in progression-free survival (PFS), the time during which treatment kept the disease under control: 31 months in the experimental group versus 26.8 months in the control group (HR, 0.87; P =0.10). This PFS outcome was the study’s primary endpoint.
• Overall survival was a secondary endpoint. Median overall survival was 45.9 months when CDK4/6 inhibitors were used first line, compared with 53.7 months when CDK4/6 inhibitors were used second line.

The first-line CDK4/6 inhibitor group experienced 42% more grade 3 or higher adverse effects than the group receiving this treatment second line. The increase in costs associated with adverse effects was reported as approximately 200 thousand US dollars for each patient receiving first-line CDK4/6i.

There were no significant differences in quality of life between the groups.

After 37.3 months of follow-up, CDK4/6 inhibitor exposure lasted 24.6 months in patients treated first line, compared with 8.1 months of CDK4/6i exposure in patients treated second line.

Commentary

These findings call for a reassessment of the need to use CDK4/6 inhibitors first line in advanced hormone-positive, HER2-negative breast cancer. Further studies are expected to identify subgroups that may benefit more from first-line CDK4/6 inhibitors. Publication of the full study in a scientific journal is important before firm conclusions are drawn, allowing more detailed assessment of subgroups, such as patients with visceral metastases, whose results may differ. Nevertheless, first-line CDK4/6 inhibitors are highly effective at extending disease control, and many oncologists may continue to consider them the initial option.

The results suggest that patients and healthcare professionals should consider not only effectiveness but also costs and potential adverse effects when evaluating treatment options. Considering all these factors helps inform the best treatment decision.