Discussion
PALOMA-3
ADVERSE EVENTS, DISEASE
This study reports data on the first experience of treating HR-positive/HER2-negative locally advanced/MBC patients with palbociclib within routine NHS clinical practice, where the patient populations are more heterogeneous. At the time of the IPP, no CDK4/6i was routinely available within the NHS in the first-line setting as per regulatory approval. Prior compassionate use programmes have provided access prior to licencing and outside of the labelled indication in a heavily pre-treated population [We presented a cohort where 30% of patients had de novo MBC, which is consistent with the rate within PALOMA-2 (37.6%) [The IPP was established to give first-line access in the advanced setting in combination with an AI as per the licensed indication in the UK; however, not all patients met these criteria, as some clinicians accessed palbociclib for their patients outside of the first-line setting. Patients receiving first-line treatment with palbociclib had a median PFS of 22.8 months (95% CI 16.5–NR), which is consistent with findings from the PALOMA-2 (24.8 months 95% CI 22.1–NR [Two recently published real-world observational studies assessed OS rates in HR-positive/HER2-negative MBC patients. In the P-REALITY study of first-line patients treated with palbociclib plus letrozole, the 24-month OS rate was 78.3%, and 64.8% remained alive at 36 months [In those patients where palbociclib was initiated within the first-line setting >3 months (Median [range] of 168 [92–3760] days) after letrozole had been initiated, the PFS was 11.8 months (95% CI 10.0–NR), suggesting that early initiation of palbociclib with ET attain the most benefit. The use of palbociclib as a second or subsequent line of therapy with ET was associated with a median PFS of 7.8 months (95% CI 6.8–NR); this is comparable to that reported by PALOMA-3 within the second-line setting with palbociclib (9.5 months (95% CI 9.2–11.0) [Whilst the vast majority of patients initiated on the recommended dose of 125 mg/day palbociclib [This study remains subject to limitations. First, patients were recruited from larger centres enrolled in the IPP, which may differ from smaller centres in terms of demographic and clinical characteristics, and therefore may not be representative of all patients treated with palbociclib in routine clinical practice as part of the IPP. Furthermore, differences in requirements for patient consent for living patients at different centres may have introduced bias in the interpretation of study outcomes. Second, common to all retrospective study designs, the interpretation of study outcomes is dependent on the completeness and quality of the medical records and the reliability of the abstraction of data from the medical records, although source data verification was employed to identify and correct any abstraction errors. Standard imputation of dates and menopause status were required in a few instances, which may have introduced bias in the interpretation of the study outcomes. Furthermore, confounding factors cannot be ruled out; although information regarding prior treatment history, disease severity and comorbidities (17% of the patient population had comorbidities [data not presented]) were collected, concomitant therapy was not. Thirdly, due to the nature of routine clinical practice in the UK, data on quality of life is not routinely collected, which means we are unable to compare outcomes reported by PALOMA-2. Furthermore, this study only reports on common adverse events from palbociclib treatment and therefore does not represent the true incidence of rarer adverse events in a real-world setting. Despite these limitations, this study provides important insights into the characteristics and clinical outcomes of the first cohort of patients with HR-positive/HER2-negative MBC treated with palbociclib according to routine clinical practice in centres across the UK prior to it being made widely available by NICE and SMC.