SONIA: No Survival Benefit of First-Line CDK4/6 Inhibition in Metastatic Breast Cancer

Jun 12, 2023

First-line CDK4/6 inhibition did not boost survival or QOL but did prolong CDK4/6 inhibitor use and increased grade 3-4 toxicity and drug costs.

CDK4/6 inhibitors improve the outcome of patients with advanced/metastatic ER-positive/HER2-negative breast cancer in the first and second line. Most guidelines advise using it as a first-line treatment despite a lack of comparative evidence. However, first-line use is associated with prolonged side effects and higher drug costs.

The nationwide Dutch phase 3 SONIA trial (NCT03425838) compared the use of CDK4/6 inhibitors as first- or second-line treatment in patients with advanced/metastatic ER-positive/HER2-negative breast cancer. Gabe Sonke, MD, presented the results at the 2023 ASCO Annual Meeting, held June 2-6 in Chicago.

In the study, 1,050 participants were randomly assigned 1:1 to first-line non-steroidal aromatase inhibitor plus a CDK4/6 inhibitor followed by second-line fulvestrant (first-line arm) or to first-line non-steroidal aromatase inhibitor followed by second-line fulvestrant plus a CDK4/6 inhibitor (second-line arm). The primary endpoint was progression-free survival after 2 lines of treatment (PFS2).

Although first-line CDK4/6 inhibition favored progression-free survival after one line of therapy, PFS2 was not statistically different between arms: 31.0 versus 26.8 months (HR, 0.87; P=0.10) in first-line arm and second-line arm, respectively. In addition, overall survival was not statistically significantly different between arms: 45.9 versus 53.7 months (HR, 0.98; P=0.83).

First-line CDK4/6 inhibition came with 42% more grade 3 or greater adverse events compared with second-line CDK4/6 inhibition (n=2,782 vs n=1,620), due to extended time on CDK4/6 inhibition. First-line CDK4/6 inhibition also increased drug cost by $200,000 per patient.

Based on these results, Dr. Sonke concluded that “CDK4/6 inhibition in first line compared to second line does not improve survival, does not improve quality of life, increases toxicity, and increases costs. Therefore, second-line CDK4/6 inhibition should be standard of care until we know which patients benefit from first-line CDK4/6 inhibition over second-line CDK4/6 inhibition.”