SONIA: No survival benefit with first-line versus second-line CDK4/6 inhibition in metastatic breast cancer

CDK4/6 inhibition in first line compared with second line did not improve survival or quality-of-life. Instead, it extended time on the CDK4/6 inhibitor, increased the incidence of grade 3–4 toxicity, and increased drug expenditure in the randomised, phase 3 SONIA trial.

CDK4/6 inhibitors have been shown to improve the outcome of patients with advanced/metastatic ER⁺/HER2^- breast cancer in the first and second line [1,2]. 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 [3].

The (publicly funded) Dutch, nationwide, randomised, phase 3 SONIA trial (NCT03425838) compared the use of CDK4/6 inhibitors as first- or second-line treatment in patients with advanced/metastatic ER⁺/HER2^- breast cancer. Prof. Gabe Sonke (Netherlands Cancer Institute, the Netherlands) presented the results [4].

In the study, 1,050 participants were 1:1 randomised 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 favoured PFS after 1 line of therapy, PFS2 was not statistically different between arms: 31.0 versus 26.8 months (HR 0.87; P=0.10) in the first-line arm and second-line arm, respectively (see Figure). In addition, overall survival was not significantly different between arms: 45.9 versus 53.7 months (HR 0.98; P=0.83).

Figure: PFS after 2 lines of treatment in the SONIA trial [4]



CI, confidence interval; PFS, progression-free survival

First-line CDK4/6 inhibition came with 42% more grade ≥3 adverse events compared with second-line CDK4/6 inhibition (n=2,782 vs n=1,620), most likely due to an extended time on CDK4/6 inhibition. For the same reason, first-line CDK4/6 inhibition also increased drug expenditure by $200,000 per patient.

Based on these results, Prof. Sonke concluded that “CDK4/6 inhibition in first line compared with 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.”

1. Goetz MP, et al J Clin Oncol. 2017;35:3638–3646.
2. Sledge G, et al. J Clin Oncol 2017;35:2875–2884.
3. Van Ommen-Nijhof A, et al. BMC Cancer. 2018;18(1):1146.
4. Sonke GS, et al. Primary outcome of the phase 3 SONIA trial (BOOG 2017-03). Abstract LBA1000, ASCO Annual Meeting 2023, 2–6 June, Chicago, USA.

 

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Posted on 2 August, 20232 August, 2023