The phase III SONIA trial challenges the universal need for CDK4/6 inhibition in the first-line treatment of patients with hormone-receptor positive advanced breast cancer

In recent years, CDK4/6 inhibitors have become an essential part of the first-line treatment for patients with hormone-receptor positive, HER2-negative advanced breast cancer. However, controversial results of the phase III SONIA trial, presented at ASCO 2023, challenge this paradigm by showing that using a CDK4/6 inhibitor in first- rather than second-line does not improve the overall survival, progression-free survival, or quality of life of patients. Furthermore, first-line CDK4/6 inhibition increased the incidence of grade ≥3 adverse events by 42% with a marked increase in treatment costs.

Background

Over the last decade, numerous clinical trials have demonstrated improved outcomes with CDK4/6 inhibitors in the first- and second-line treatment of patients with hormone-receptor positive (HR+), HER2 negative (HER2-) advanced breast cancer (ABC). Based on these results, most international treatment guidelines recommend to routinely include a CDK4/6 inhibitor as part of the first-line treatment regimen for these patients. However, this recommendation is made in the absence of comparative evidence between the use of these agent in first- or second-line. Furthermore, first-line use of these agents is associated with a prolonged drug exposure, leading to more toxicity and higher costs. The SONIA trial was a nationwide, phase III study conducted in the Netherlands which compared the use of CDK4/6 inhibitors in the first- and second-line treatment of patients with HR+/HER2- ABC.

Study design

SONIA enrolled a total of 1,050 pre- or postmenopausal women with HR+/HER2- ABC who did not receive prior therapy in the advanced setting and had measurable or evaluable disease at study entry. Patients had to have a WHO performance status of 0-2 and (neo)adjuvant therapy was allowed as long as the disease-free interval after non-steroidal aromatase inhibitor (NSAI) was longer than 12 months. Patients in the study were randomised (1:1) to receive a first-line treatment with an NSAI in combination with a CDK4/6 inhibitor, followed by fulvestrant (F) at the time of progression (strategy A), or first-line treatment with an NSAI, followed by F plus a CDK4/6 inhibitor at progression (strategy B). The choice for a specific CDK4/6 inhibitor (abemaciclib, palbociclib, ribociclib) was left to the discretion of the treating physician and was used as a stratification factor in the randomisation. The primary endpoint of this study was the time from randomisation until the second objective disease progression, or death (PFS2), with overall survival (OS), safety, quality of life (QoL), and cost-effectiveness as secondary study objectives.

Results

The median age of patients in the study was 64 years and about 85% of patients was postmenopausal at study entry. A third of patients in the study had newly diagnosed ABC, 56% had visceral metastases and 17% had bone-only disease at study entry. Furthermore, 40% of patients received (neo)adjuvant chemotherapy, whereas about 48% received endocrine therapy in the (neo)adjuvant setting. The vast majority (91%) of patients was treated with palbociclib, with ribociclib and abemaciclib being used in 8% and 1% of patients, respectively. After a median follow-up of 37.3 months, the median CDK4/6 inhibitor treatment duration was 24.6 months with strategy A as compared to 8.1 months with strategy B.

The PFS2 did not differ significantly between both treatment arms, with a median of 31.0 months for strategy A and 26.8 months with strategy B (HR[95%CI]: 0.87[0.74-1.03]; p= 0.10). This observation was similar across all investigated subgroups, irrespective of the prior use of (neo)adjuvant endocrine therapy or chemotherapy, the presence of visceral metastases or bone only disease, the CDK4/6 inhibitor that was used and whether or not the patient had de novo metastatic disease. Also in terms of OS there was no significant difference between both treatment arms, with a median OS of 45.9 months with strategy A and 53.7 months with strategy B (HR[95%CI]: 0.98[0.80-1.20]; p= 0.83). Furthermore, no difference was seen between both arms in terms of QoL (FACt-B total score, p= 0.4).

The safety profile in both arms was characteristic for CDK4/6 inhibition, with neutropenia, liver abnormalities, anemia and thrombocytopenia as the most prominent AEs. Interestingly, however, strategy A proved to be associated with 42% more grade ≥3 AEs than strategy B.

Conclusions

Results of the phase III SONIA trial show that CDK4/6 inhibition in first- rather than second- line does not improve the PFS, OS or QoL of patients. Moreover, the first-line strategy extends the time on the CDK4/6 inhibitor by 16.5 months, resulting in a 42% increase in the incidence of grade ≥3 AEs. A further cost-effectiveness analysis showed that the first-line strategy also comes with an additional cost of 200,000$ compared to the use of CDK4/6 inhibition in second line. As such, the investigators conclude that the SONIA data challenge the need for a CDK4/6 inhibitor in the first-line treatment of patients with HR+/HER2- ABC. For them, endocrine monotherapy remains to be an excellent first-line treatment option for these patients.

Reference

Sonke G, et al. Primary outcome analysis of the phase 3 SONIA trial (BOOG 2017-03) on selecting the optimal position of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). Presented at ASCO 2023; Abstract LBA1000.