Episode 3: The SONIA Trial – First vs. Second-Line CDK4/6 Inhibition
The SONIA trial, a phase III study conducted by a Dutch academic group, focused on comparing first-line to second-line CDK4/6 inhibition in the treatment of endocrine-sensitive breast cancer. Recruiting over 1,000 patients in the Netherlands, the trial primarily investigated progression-free survival at second progression (PFS2) as the primary endpoint.
In the experimental arm, patients received a first-line aromatase inhibitor (AI) plus a CDK4/6 inhibitor, followed by second-line fulvestrant single-agent. The comparator arm received first-line endocrine single-agent with an aromatase inhibitor, followed by the combination of fulvestrant and CDK4/6 inhibitor in the second line. All patients were endocrine-sensitive, either endocrine-naive or having relapsed after discontinuing adjuvant AI.
While the trial demonstrated a statistically significant improvement in first progression-free survival (PFS1) with the addition of a CDK4/6 inhibitor, the difference in PFS2 narrowly missed statistical significance. Subgroup analyses failed to identify specific patient groups with significant differences in PFS2. Quality of life and overall survival showed no improvement with first-line CDK4/6 inhibition. Notably, the safety analysis revealed a higher likelihood of adverse events, including grade 3 and 4, in patients treated with upfront CDK4/6 inhibitors.
Despite the trial’s design as a superiority study, it yielded negative results. The authors concluded that providing a CDK4/6 inhibitor in the first line does not offer benefits compared to second-line use while posing a higher risk of adverse events and increased societal costs.
The discussion raised concerns about the trial’s design, suggesting that a non-inferiority design might have been more appropriate for assessing de-escalation strategies. However, the constraints within the Netherlands influenced the choice of a superiority design. The robust overall survival benefits seen with some CDK4/6 inhibitors in the first-line setting were not convincingly challenged by SONIA.
In conclusion, while SONIA provides confidence in sparing CDK4/6 inhibitors for select patients with comorbidities or patient preferences, it does not significantly alter the preference for a combination in the first-line treatment of the majority of patients. The trial’s findings may be relevant for low-income countries facing resource constraints but reaffirm the continued use of CDK4/6 inhibitors with endocrine therapy as the first-line approach in well-resourced settings.
Ref : Gabe S. Sonke et al., Primary outcome analysis of the phase 3 SONIA trial (BOOG 2017-03) on selecting the optimal position of CDK4/6 inhibitors for patients with HR+, HER2 advanced breast cancer (ABC); Meeting Abstract LBA1000, 2023 ASCO Annual Meeting.