Real-world data for a CDK4/6 inhibitor, Palbociclib, as 1st- or 2nd-line therapy in HR+/HER2− metastatic breast cancer: A multicenter prospective cohort study

Background Palbociclib (PAL), the first CDK4/6 inhibitor approved for breast cancer, improves progression-free survival (PFS) in hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) when added to an aromatase inhibitor or fulvestrant, but also increases toxicity compared to endocrine therapy alone. Use of PAL in 1st-line treatment increases the burden on patients and adds to costs compared to use as 2nd-line treatment, due to the longer period of 1st-line treatment. Therefore, data on use of PAL in a real-world setting are required to assess the merits of 1st- and 2nd-line therapy in the sequence of treatment for MBC. Methods A prospective observational study was performed in patients with postmenopausal metastatic or unresectable breast cancer using PAL in 1st-, 2nd-, or 3rd-line treatment. The primary endpoint was PFS (start of PAL to progression or death). Secondary endpoints included PFS2 (start of 1st-line endocrine treatment to second progression) and adverse events. Results The study included 593 patients treated with PAL (246 1st-line, 282 2nd-line, 65 3rd-line) from April 2019 to January 2023. Median PFS was 25.8 (95%CI: 21.4), 18.0 (14.0-22.7), and 12.0 (7.7–17.4) months, for 1st-, 2nd- and 3rd-line use respectively. Median PFS2 was 36.9 (27.7-not reached) and 57.9 (43.4–65.3) months in the 1st- and 2nd-line cohorts. Neutropenia of grade ≥ 3 occurred in 70% of patients, and > 80% required dose reductions. Conclusions PFS for the 1st-line cohort was similar to that in PALOMA-2, while the 2nd-line cohort had better outcomes than those in PALOMA-3, even when modelled for potential bias since some patients on 1st-line endocrine monotherapy would have received chemotherapy rather than 2nd-line PAL. Overall, the findings in this study of real-life treatment of patients with HR+/HER2- MBC support randomized control trial data that challenge the need to use a CDK4/6 inhibitor in the 1st-line setting for all patients. Clinical Trial Registration: UMIN000035863