A recent retrospective study presented at the 2024 San Antonio Breast Cancer Symposium (SABCS) found no significant difference in overall survival (OS) among three CDK4/6 inhibitor combinations used as first-line treatments for hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer. The study, which analyzed real-world data from 9,146 patients across 280 US sites, challenges the notion of superior OS benefit with any single CDK4/6 inhibitor in this setting. These findings have implications for treatment selection and sequencing strategies in HR+ metastatic breast cancer.
The P-VERIFY study (NCT06495164) utilized the Flatiron Health electronic health record database to compare the effectiveness of palbociclib (Ibrance) plus an aromatase inhibitor (AI) (PAL+AI), ribociclib (Kisqali) plus AI (RIB+AI), and abemaciclib (Verzenio) plus AI (ABE+AI) in patients with HR+/HER2- metastatic breast cancer. The primary outcome was overall survival, determined using Kaplan-Meier estimates and adjusted for potential confounders using standardized inverse probability of treatment weighting (sIPTW).
Key Findings
The study revealed no statistically significant difference in OS among the three treatment groups, both before and after adjusting for confounding factors. The median OS prior to sIPTW adjustment was 54.4 months for PAL+AI, 60.3 months for RIB+AI, and not reached for ABE+AI. After adjustment, the median OS was 54.6 months for PAL+AI, 59.0 months for RIB+AI, and 64.5 months for ABE+AI. Hazard ratios for OS comparing ABE+AI vs PAL+AI, RIB+AI vs PAL+AI, and ABE+AI vs RIB+AI were not statistically significant in both unadjusted and adjusted analyses.
According to Kari B. Wisinski, MD, professor of medicine at the University of Wisconsin Carbone Cancer Center, "There was no difference in OS both in the unadjusted and adjusted methodologies."
Adverse Events
Regarding adverse events (AEs), the study found higher rates of neutropenia in the PAL+AI group (67%) compared to RIB+AI (60%) and ABE+AI (21.9%). Anemia rates were greater in the PAL+AI (5.4%) and ABE+AI (6%) groups compared to RIB+AI (0.9%). Thrombocytopenia rates were consistent across all three groups.
Limitations and Interpretations
Dr. Wisinski acknowledged several limitations of the study, including smaller sample sizes and shorter follow-up durations for the RIB+AI and ABE+AI cohorts. She also noted the potential for unmeasured confounders inherent in real-world data analyses. Despite these limitations, Dr. Wisinski concluded that "The P-VERIFY study suggests that there is no difference in OS among first-line CDK4/6 inhibitors and this would align with the PFS data that we have from those first-line studies; However, the statistically OS beneficent that we have seen as only been with ribociclib. I think that longer follow-up would be very valuable and although real-world analyses have limitations it is unlikely that we will have a head-to-head study, and thus, these data add to the information that we have."
Implications for Clinical Practice
While phase 3 trials have demonstrated progression-free survival (PFS) benefits for all three CDK4/6 inhibitors, the P-VERIFY study suggests that the statistically significant OS benefit observed with ribociclib in clinical trials may not translate to a significant difference in real-world clinical practice. These findings highlight the importance of considering individual patient characteristics, tolerability, and cost when selecting a first-line CDK4/6 inhibitor for HR+/HER2- metastatic breast cancer. Further research, including longer-term follow-up and head-to-head comparisons, is needed to validate these findings and refine treatment strategies.
