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

Analyses performed across trials: pooled and meta analyses

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Analyses performed across trials: pooled and meta analyses

None performed.
    1. Evaluator’s conclusions on clinical efficacy

The sponsor indicates that the currently promising efficacy data for use of palbociclib added to letrozole, and the improvement in PFS in combination with fulvestrant justifies that the indication should be broadened to allow approval of palbociclib in combination with ‘endocrine therapy’. Currently registered endocrine therapies in Australia include tamoxifen, the non-steroidal aromatase inhibitors letrozole and anastrozole, and the steroidal aromatase inhibitor, exemestane as well as toremifene and megestrol acetate; these last two are not commonly used in clinical practice in Australia.

However, the clinical evaluator does not currently support registration for the combination with letrozole; this may change with each of the following addressed:

  • future submission of the Study 1008 CSR for evaluation (incorporating the issues raised in this evaluation report);

  • satisfactory responses to the clinical questions arising from the studies submitted in support of this usage;

  • submission with the 1008 CSR of a PI providing up to date information that satisfactorily supports the safe and effective use of this combination.

Should each and all of the above be satisfied, and safety and efficacy demonstrated satisfactorily for the proposed usage in combination with letrozole, then consideration could be given at that time to extending the usage to anastrozole. Exemestane is not currently approved as a first line therapy for the treatment of metastatic breast cancer in Australia, and with the ready availability of letrozole and anastrozole (both approved as first line), extrapolation to first line usage seems unnecessary as these would be used in the first instance. It is noted that there is a study underway investigating the use of exemestane with palbociclib, which should address safety and efficacy for this usage and the sponsor can consider whether the GEICAM study investigating exemestane and palbociclib adequately supports an application for an extension of indications.

There are no data submitted in support of the safety and efficacy in combination with tamoxifen. Notable adverse events in the studies presented here were thrombosis and thromboembolic events. Given both tamoxifen and megestrol acetate are known to increase the risk for such events, data from randomised controlled, preferably blinded studies are required to support the safety of each in combination with palbociclib in the metastatic setting (another independent risk factor for thrombosis). Furthermore, tamoxifen is associated with inferior outcomes in the treatment of metastatic breast cancer compared with the nonsteroidal aromatase inhibitors as monotherapy; this, taken together with the known risk of venous thrombosis and thromboembolism with tamoxifen, and now of palbociclib treatment, means neither the safety nor the efficacy in combination with palbociclib is known and a benefit-risk assessment cannot be made. This combination is currently being studied in the metastatic setting by independent researchers but only open label Phase II studies were identified. It is being studied in a different disease setting as part of the randomised, controlled Phase III study ‘PENELOPE B’, where palbociclib or placebo is an add-on to standard adjuvant therapy, including tamoxifen, for women with ER-positive breast cancer at high risk of relapse following completion of neoadjuvant therapy. However, this study may not provide sufficient safety data (noting that thrombotic risk is higher in metastatic disease) and is subject to there being sufficient numbers enrolled taking tamoxifen to allow a subgroup analysis of safety and efficacy, as well as whether this is a prespecified subgroup and the study powered for such an analysis. Furthermore, any efficacy data generated will not support usage in a potentially more heavily pretreated metastatic population.

  1. Clinical safety

There is no integrated safety summary incorporating the data from the latest cut-off dates for all studies, and the populations in the SCS in the TGA dossier and the 90-day safety update overlap are different such that the latter document updates some, but not all studies in the SCS.

Comment and clinical question:

The sponsor is requested to provide a table which integrates exposure from all clinical studies (referencing the source studies) and presents:

  1. the total number of patients treated to date:

  1. at the proposed dose level and regimen (palbociclib 125 mg QD 3/1)

        1. in combination with fulvestrant

        2. in combination with letrozole at the proposed dose

        3. in combination with letrozole at any dose level

  2. as monotherapy

        1. at the proposed dose and schedule

        2. at any other dose

  3. the median duration of treatment for all those patients and an interquartile range

  4. in combination with fulvestrant

  5. in combination with letrozole at the proposed dose

  6. in combination with letrozole at any dose level

The data provided included the main CSR for 2 studies (1023 and 1003) with limited updates provided in 2 subsequent safety summaries both of which has overlapping datasets that is, neither had the same dataset and the cut-off dates were different:

The Module 2 Summary of Clinical Safety data (SCS), dated as approved on 26 Oct 2015 including data up to a cut-off of 2 January 2015

This document does not appear to be the SCS referred to by the 90-day safety update given none of the hyperlinks from the 90-day safety update link to the corresponding sections and datasets in that document. Continuity between the datasets, and any certainty that the references are indeed updates for the datasets provided in the SCS provided, are thus lost. The sponsor is requested to state whether a different SCS was provided to the US.

Studies included in this were drawn from Phase I, II and III studies in range of cancers, although most commonly, breast cancer. Additional sources included PK studies in healthy volunteers, postmarketing reports from the US (equivalent of PSUR) and an access program.

The following is taken from the Module 2 Summary of Clinical Efficacy:

Overall, a total of 1640 patients with malignant disease, including advanced breast cancer, were evaluated for safety in 8 Pfizer-sponsored Phase I-III clinical studies of palbociclib included in this SCS. Of these 1640 patients, 725 (44.2%) received at least 1 dose of palbociclib either given alone (N=103 [Studies 1001, 1002, and 1010 Phase I Part 1 {Ph1P1}]) or as a component of combination therapy (N=622 [Studies 1003, 1023, 1004, 1010 Phase I Part 2 {Ph1P2} and Phase II, and 1034]); 77 (4.7%) received a comparator drug (letrozole alone in Study 1003); 172 (10.5%) received placebo (in combination with fulvestrant [Faslodex®] with or without goserelin in Study 1023); and 666 (40.6%) received blinded treatment, palbociclib or placebo (in combination with letrozole in ongoing double blind Phase III Study 1008)….This SCS primarily focuses on safety results reported in Study 1003, Study 1023, and the completed Phase I portion of Study 1010.

Comment: Study 1002 was conducted in patients with mantle cell lymphoma using a different dosing strategy and Study 1004 was conducted in patients with multiple myeloma in a different dosing strategy and combination. These are not considered to contribute to the understanding of safety for the proposed usage. Very limited, but more recent data are available from the Top-line summary for Study 1008 and this will be used for the evaluation.

In addition, a total of 407 healthy subjects were evaluated for safety in 16 Pfizer-sponsored Phase I clinical studies of palbociclib. Further, safety data reported for a total of 505 patients participating in 17 ongoing Investigator-Initiated Research (IIR) studies in which palbociclib was given either alone in patients with malignant solid tumours, including breast cancer, or as a component of combination therapy in patients with breast cancer were summarised in the SCS.

90-day US safety update

This A5481023 supplemental New Drug Application (sNDA) 90-Day Safety Update (SU) provides a comprehensive review of updated cumulative safety data of palbociclib reported in completed Phase III Study A5481023 as of the 31 July 2015 data cutoff date’. No formal report date could be located but the date on the side of the report is 30 December 2015.

The 90-day safety update incorporated 7 Pfizer-sponsored studies representing 1503 patients (that is, different number of patients from the SCS) provided updates for cancer studies using a later cut-off (31 July 2015), and also for Study 1027, a randomised Phase III trial investigating the effect of adding palbociclib to letrozole therapy in Asian postmenopausal women with metastatic breast cancer; Study 1039, a drug-drug interaction study in healthy subjects receiving modafinil and palbociclib monotherapy.

Table 22: List of studies included in the 90-day safety update provided to the US for sNDA for Study 1023.

The clinical evaluator notes that the data cut-off dates for the Studies for the 90-day safety update, the Summary of Clinical Safety and the actual CSR are as follows:

  • Study 1003

    • 90-day safety update: cut-off date of 31 July 2015;

    • Module 2 SCS: cut-off date 2 January 2015;

    • CSR cut-off of 29 November 2013;

  • Study 1023

    • 90-day safety update: cut-off date of 31 July 2015;

    • CSR cut-off date: 05 December 2014 (same as main SCS);

    • Module 2 SCS cut-off date: 05 December 2014 (same as main CSR);

    • PI data: cut-off date: 5 December 2014;

  • Study 1008

    • Top-line summary: data cut-off date 26 February 2016;

    • 90-day safety update: cut-off date of 31 July 2015 that is updated by the more recent, limited data (from data cut-off date 26 February 2016) provided with the Study 1008 ‘top-line summary’);

    • PI data – no data or text included for efficacy or safety of this proposed usage;

  • In addition, 2 ongoing Pfizer-sponsored clinical studies of palbociclib, Phase III Study 1027 in Asian patients with advanced breast cancer and Phase I Study 1013 in subjects with hepatic impairment who were otherwise healthy, are included in this SU for the first time;

  • A postmarketing access program in the US and Canada, Study 1034, with an updated cut-off compared with the SCS;

The clinical evaluator notes the following about the 90-day safety update:

  • data for Study 1008 has been updated by the top line summary’s later cut-off date;

  • adverse events but not the full CSR for a study of palbociclib in volunteers without cancer with hepatic impairment (Study 1013) is included that is, providing limited supportive information relevant to the proposed usage;

  • Although postmarketing adverse event data are incorporated in this report (6 months from 03 February 2015-31 July 2015), a more complete 1-year report has been provided and this will be evaluated and presented separately.

25 studies of Investigator-initiated studies of palbociclib in solid tumours including breast cancer, used alone or in combination are presented.

  • CIOMS and detailed narratives are said to be provided: there are no hyperlinks from the text to these directly, and for many, these could not be located; no detailed narratives were located, only draft CIOMS and line listings;

  • Deaths and other SAEs reported in these studies are summarised by the following patient populations:

Patients with breast cancer receiving palbociclib monotherapy

Patients with breast cancer receiving palbociclib plus nonchemotherapy (endocrine therapy)

Patients with non-breast malignant solid tumours receiving palbociclib monotherapy

Patients with breast cancer receiving palbociclib plus chemotherapy


  1. The PI contains no safety data from Study 10082, and therefore cannot be evaluated with respect to this usage (See Clinical Questions).

  2. The most relevant population providing safety data for the proposed usage are those 1015 women (61.9%) who had advanced or metastatic breast cancer and received at least 1 dose of palbociclib 125 mg QD on Schedule 3/1 in combination with endocrine therapy (either letrozole, or fulvestrant +/- goserelin). See ‘Exposure’ below.

  3. All data from Study 1027 is still blinded therefore the safety data are summarised blinded for treatment. Thus, this does not offer evaluable data for the proposed usage and will not be summarised or considered further.

  4. Of the investigator-initiated studies, the first 3 patient populations above might yield supportive data for the proposed indications but the toxicities arising from chemotherapy will confound any assessments of safety for palbociclib.

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