Baseline disease characteristics and prior treatments (Table 10)
The following imbalances are noted in the Phase II combined P1+P2 populations:
Shorter median time to diagnosis in the combination arm (1.3 versus 2.4 years) – this was in part due to the larger number of de novo patients in combination arm;
Fewer patients with visceral disease in the palbociclib plus letrozole arm (44.1%) than in the letrozole alone arm (53.1%);
More patients in the combination arm had bone-only disease (20.2% versus 14.8%) due to incorrect stratification at randomisation and discovered subsequently;
There was a large discrepancy between the PR-negative status with 13.1% in the combination versus 28.4% in the letrozole alone arm;
More patients with Grade 3 disease in combination arm (36.9% versus 22.2%);
More patients had ductal carcinoma in the combination arm overall (75% versus 66.7%);
The majority had metastatic disease with only 3 patients with locally advanced disease enrolled.
Comment: Discrepancies between the CRF data and that used for randomisation identified errors with incorrect stratification factors being used to randomize patients, resulting in fewer patients with visceral disease and more with bone-only disease being randomised to the palbociclib and letrozole arms - both of these would favour a better outcome in this arm. Sensitivity analyses have not demonstrated a significant impact of these errors.
The first four imbalances in baseline disease factors would be likely to favour a better outcome in the palbociclib and letrozole arm, while the 5th would favour the letrozole alone arm – the 6th is of uncertain significance.
Table 10 continued: Study A5481003 Baseline disease characteristics – Intention-to-Treat population
De novo metastatic disease was reported in 49.1% and a higher number of these (44) were in the treatment arm versus 37 in the letrozole alone arm;
In Study 1003 there were 57 patients (67.9%) in the palbociclib plus letrozole arm and 53 (65.4%) patients inthe letrozole arm who received no prior endocrine therapy.
More patients in the combination arm compared with the letrozole alone arm had received no prior systemic therapy (52 vs. 46% in the full Phase II population, 50 vs. 41% in Part 2 cohort).
66.7% of patients presented within 12 months of any treatment or with de novo disease
49.1% of patients had de novo metastatic disease which is a much higher figure than the 5-10% that would be expected with Stage IV disease at presentation in Australia.
66.7% had either relapsed within 12 months of completion of adjuvant treatment or had de novo disease, and these two groups have been put together for stratification purposes. The latter (49.1%) would be expected to have a better prognosis than those relapsing after treatment, which makes this stratification factor likely to lead to prognostic factor imbalances; indeed this did happen with more patients with de novo disease in the palbociclib and letrozole arm;
The rates of prior antihormonal therapy indicate that 110/165 patients (67%) in the Phase II study received no prior hormonal therapy that is, 17.9% did not receive endocrine therapy following a diagnosis of ER-positive breast cancer; it is standard practice in Australia to offer endocrine therapy to women with ER-positive breast cancer, and may influence baseline response rates to any endocrine therapy commenced in the metastatic setting;
the ‘prior surgeries’ rate is 81% in both arms, although it is not clear whether this is breast surgery; it would not be usual practice in Australia to perform breast surgery on a woman presenting with metastatic disease and this rate appears very high for palliative procedures. Similarly rates of radiation are 54.8% which may have been adjuvant or palliative.