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

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Question for the sponsor:

  1. Please provide the breakdown of the operations as to whether they were breast versus non-breast surgery for each treatment arm. For those who underwent breast surgery, please state the number and percentage going on to receive adjuvant therapy, by treatment arm.

  2. Please provide a breakdown of the numbers of the 17.9 % patients for each arm who received no endocrine therapy following an earlier ER-positive breast cancer diagnosis.

ER-positive status was required and therefore no patients with ER-negative/PR-positive status have been recruited. The proposed population in the indication needs to be modified to reflect this that is, change from ‘hormone-receptor positive’ to ‘oestrogen receptor-positive’.

The imbalance in bone-only disease resulted from incorrect stratification at the time of randomisation, discovered subsequently. While sensitivity analyses suggest this had no impact on the study outcomes, this adds to uncertainties about the trial outcomes overall and underscores the importance of evaluating data from a more robust Phase III study (that is, Study 1008).

The low numbers of locally advanced disease is not unexpected. The wording of the indication needs to state ‘locally advanced’.

Overall, there are factors that could favour the experimental arm (higher rates of no prior treatment, less visceral disease, lower rates of PR-negative) but there are also negative prognostic factors including more patients with Grade 3 disease.

Post-study treatments

In the palbociclib+letrozole arm, 57.1% received follow-up systemic therapy for their breast cancer compared with the letrozole alone arm (76.5%) which was most commonly further endocrine therapy, but also included chemotherapy.

        1. Results for the primary efficacy outcome

The Phase I efficacy outcomes will be discussed at the end as they are non-randomised and essentially descriptive.
Phase II PFS (investigator-assessed) ITT population

By investigator assessment:

  • there were 100/165 (60.6%) PFS events (41 events [48.8%] and 59 events [72.8%] in the palbociclib plus letrozole arm and the letrozole alone arm, respectively;

  • HR 0.488 (95% CI: 0.319-0.748; stratified 1-sided p=0.0004) in favour of the combination arm;

  • median PFS was 20.2 months (95% CI: 13.8-27.5) in the palbociclib plus letrozole arm and 10.2 months (95% CI: 5.7-12.6) in the letrozole alone arm.


  • 43 and 22 patients in the palbociclib plus letrozole arm and the letrozole alone arm, respectively, were censored in the PFS analysis;

  • 19 patients and 6 patients, respectively, were still in follow-up for disease progression and had not had disease progression at the time of the final analysis

  • The most common reason for censoring in each treatment arm was due to treatment being permanently discontinued without a PFS event. There was a higher percentage of patients censored for discontinuing treatment due to AEs in the palbociclib plus letrozole arm (8 patients, 9.5%) than in the letrozole alone arm (1 patient, 1.2%), and this difference in treatment discontinuation due to AEs was observed in the Ph2P1 Cohort only.

Comment: FDA report for Investigator censoring for Study A5481003. The sponsor is requested to provide an explanation for the differences in these data, noting that this FDA table was compiled following an FDA query, 28 Feb 2014 (Clinical Question).

As previously stated, this discontinuation due to AEs in the earlier part of the study may reflect clinician experience but may also be due to the vagaries of a small sample size.

Figure 4: Study A5481003 Kaplan-Meier plot of progression-free survival Investigator assessment (ITT population)

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