I presented the results of the SONIA trial today at ASCO. The SONIA trial was initiated after seeing that CDK4/6 inhibitors demonstrated important benefits for women with ER positive HER2 negative breast cancer. The first studies were done in second line treatment with palbociclib but soon afterwards new studies followed, both with the other CDK4/6 inhibitors, abemaciclib and ribociclib, and also studies in first line. While the results of all these studies’ benefits were seen independent of line of treatment and also independent of endocrine treatment, most guidelines adopted a first line strategy to be preferred although there was no comparative data to see which one would be better.
So, inspired by ASCO’s and ESMO’s commitment to promote sustainable and equitable healthcare, we designed the SONIA trial with the idea of specifically comparing a first-line versus a second-line strategy, remembering that the CDK4/6 inhibitors also come with quite some added toxicity and considerable costs.
The study design, it was a randomised phase III trial in 1,050 patients and women were randomised to either a first-line CDK4/6 inhibitor strategy or a second-line strategy. All patients received the same backbone endocrine therapy with an aromatase inhibitor in first line and fulvestrant in second line. The primary endpoint was progression free survival after two lines of therapy and key secondary endpoints were overall survival and quality of life. Tumour assessments were done every 12 weeks and were assessed locally according to RECIST.
After solely first-line treatment a CDK4/6 inhibitor prolongs progression free survival with a hazard ratio of 0.59 and this is very much in line with the pivotal PALOMA-2, MONALEESA-2 and MONARCH-3 studies. However, after crossover to the predefined, protocol-defined, second line treatment, this first-line benefit completely disappears. The hazard ratio for PFS2 is 0.87 and not statistically significant. When we look at overall survival the curves completely overlap with a hazard ratio of 0.98 and a p-value of 0.83.
What we do see, however, is that those who were randomised to receive a CDK4/6 inhibitor in the first line used their treatment for approximately 16.5 months longer than those who used it in second line. Consistent with this longer use they also experienced much more side effects – approximately 42% more grade 3 and 4 events.
We also looked at quality of life with validated questionnaires FACT-B and EQ-5D at several time points during the study. The completion rate of these questionnaires was 87% at baseline and remained high thereafter. We saw no improved quality of life with the first-line strategy, with a p-value of 0.4.
So we conclude that this treatment in first line does not improve your progression free survival, it does not improve your overall survival and it does not improve your quality of life. It does come with added side effects and about $200,000 per patient extra. Our conclusion is that the SONIA results seriously challenge the current paradigm of adding a CDK4/6 inhibitor in first line and that endocrine single agent remains an excellent choice for almost all patients. Of course, biomarkers are highly desirable to select the few patients that might benefit from a first-line strategy but, unfortunately, thus far these biomarkers have not been successful.
We have collected both biopsies and liquid samples and these will be studied and presented at a later stage.
What’s important to note is the active participation of the Dutch breast cancer patient organisation in this trial. They have been crucial as a member of the steering committee and have been true partners in our study. Without them this would not have been a success. What’s also important to mention is that the study was funded by the Dutch government and by health insurance companies. By funding this trial they actually saved a lot of money as the investment for performing the study was a fraction of the savings that we made by doing the study.
Post-marketing academic studies like SONIA should be performed more often to allow patients to get the best and optimal treatment and to have a much more balanced and cheaper healthcare system.