Date of first round report: 1 September 2016 Date of second round report: 30 January 2017

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Question 6 for sponsor

6. Please point to a tabulation in the CSR (or create a tabulation) of the use of commoner prohibited concomitant medications (capturing type of medication, typical reason/s for use and extent of use), allowing comparison across arms.

Baseline data

Demographic characteristics were balanced across arms. Median age was 62.0 years, and 40.8% (palbociclib arm) versus 36.5% (placebo arm) were ≥ 65 yrs of age. 77.5% across arms were of White race, and 14.3% were of Asian race.

Baseline disease characteristics were reasonably balanced. A prominent imbalance was in ECOG performance status: 58% had ECOG PS = 0 in the palbociclib-containing arm, versus 46% in the placebo-containing arm. Median duration since breast cancer diagnosis was 4.5 yrs (palbociclib-containing arm) versus 4.0 yrs (placebo-containing arm).

Measurable disease was present at baseline in 76.1% and 77% respectively. Based on sensitivity analysis 11.3, it appears 103/444 (23.2%) versus 48/222 (21.6%) had bone-only disease at baseline – these figures may account for the extent of non-measurable disease noted above. However, bone disease was present in 73% of patients.

Almost all patients had metastatic disease; and about a third of patients had de novo metastatic disease.

About half of patients had visceral disease. 1-2 patients per arm had brain disease.

Comment: Initial presentation of breast cancer with metastatic disease (i.e. de novo metastatic disease) may be less common in the community than was the case in PALOMA-2, where a third of patients had de novo metastatic disease. This might be due in part to exclusion criteria such as the exclusion of patients with recurrence inside 12 months of neoadjuvant / adjuvant NSAI therapy.

Arms were balanced for prior systemic therapies used to treat breast cancer. Also:

  • 167/444 (37.6%; palbociclib + letrozole) versus 81/222 (36.5%; placebo + letrozole) had no prior systemic therapy (median age 64 yrs). Presumably, this group would overlap considerably with patients with ‘de novo metastatic disease’ but it seems likely there remains a group of patients without de novo metastatic disease who had not received prior systemic therapy; see below.

  • 99/444 (22.3%) versus 48/222 (21.6%) had a disease-free interval of ≤12 months after last systemic therapy (these patients tended to be younger; median age 53 yrs)

  • 178/444 (40.1%) versus 93/222 (41.2%) had a disease-free interval of >12 months (median age 62 yrs)

A further breakdown is provided in the EMA Second JRAR, Table 2, that notes:

Table 54: From EMA Second JRAR (Table 2)

This indicates that 28/167 palbociclib-arm patients described as ‘de novo’ actually had a recurrence, implying existence of an earlier diagnosis of breast cancer so not truly ‘de novo’ advanced disease.

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