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

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Figure 12: Study A5481008 Kaplan-Meier curves for progression-free survival (Investigator Assessment, ITT population) taken from Figure 2 Topline summary

The reasons for censorship based on the investigator assessment were summarised.

The censoring rates indicate similar absolute differences in discontinuations without disease progression across both arms. It is unclear how many patients ‘in follow up for progression’ were still on study drug (Clinical Questions) as this could include some where progression had not been established radiologically yet.

Clinical worsening in the absence of objective radiologically confirmed progression was handled differently in this study compared with Study 1003 and was required to be declared as PD only once there was radiological confirmation; clinical progression and discontinuation due to suspected progress was to be declared due to global deterioration and the numbers are even in both arms.

There were 11 (2.5%) deaths without progression in the treatment arm compared with 3 (1.4%) in the control arm. Details of these are required to understand causality (Clinical Questions), and determine if there was any link to treatment – these are not currently available.

It is noted that subgroup analyses of these data yield a non-significant PFS for the de novo metastatic population for PFS due to overlapping confidence intervals using population identified using the randomisation criteria. (HR 0.729 95% CI: 0.486, 1.093; p=0.063) compared with a HR 0.674 (95% CI: 0.457, 0.993), p=0.022) when using the CRF data.

Comment: Uncertainty exists as to whether there is a benefit for those with de novo metastatic disease. Whether this represents an increased responsiveness to the control arm which generally did better than in other subgroup analyses cannot be checked against the group who had received no prior systemic treatment for their disease (irrespective of stage of presentation) as these data could not be located in the Tables or Topline summary. Provision of these data is requested (Clinical Questions).

The results for the BICR assessment are considered important to validate the findings.

        1. Results for other efficacy outcomes

The sponsor has provided 3 ‘key secondary outcomes’ based on investigator assessment: OR, DoR, Disease control
Objective Response – Investigator assessment

Confirmed ORR for patients with measurable disease at baseline in the palbociclib plus letrozole arm was 55.3% (95% CI: 49.9-60.7) and in the placebo plus letrozole arm was 44.4% (95% CI: 36.9-52.2).

The odds ratio was 1.55 (95% CI: 1.05-2.28), significantly in favour of palbociclib plus letrozole with a 1-sided p-value of 0.0132.

The overall confirmed ORR rate for all patients in the palbociclib plus letrozole arm was 42.1% (95% CI: 37.5-46.9) and in the placebo plus letrozole arm was 34.7% (95% CI: 28.4-41.3) based on investigator assessment. The odds ratio was 1.40 (95% CI: 0.98-2.01) in favour of palbociclib plus letrozole with a 1-sided p-value of 0.0310.

In terms of the best overall tumour response, adding palbociclib to letrozole resulted in:

similar CR rate: 2% versus 2.3%

improved PR rate 40.1% versus 32.4%

lower objective progression (that is, progressive disease without a response): 7.7% versus 16.7%

Comment: Adding in palbociclib increased response rates and more than halved the clinical failure rate of first line letrozole treatment.

Duration of Response

The duration of response (DOR) in patients with measurable disease at baseline in the palbociclib plus letrozole arm was 22.5 months (95% CI: 19.8-28.0) and in the placebo plus letrozole arm was 16.8 months (95% CI: 15.4-28.5).

Comment: The confidence intervals are overlapping indicating this did not achieve statistical significance. It is unclear whether a more pronounced benefit would be seen in those previously treated where a lower response to letrozole would be anticipated.
Disease Control

The disease control rate (DCR) in the palbociclib plus letrozole arm was 84.9% (95% CI: 81.2-88.1) and in the placebo plus letrozole arm was 70.3% (95% CI: 63.8-76.2) based on investigator assessment. The odds ratio was 2.39 (95% CI: 1.58-3.59) also significantly in favour of palbociclib plus letrozole with a 1-sided p-value of <0.0001.

Comment: DCR includes stable disease which is a clinically relevant response but is difficult to interpret where radiological imaging underpins the means of determining progression. This analysis would benefit from validation by the independent review assessment of disease progression.
Biomarker assessment – Investigator assessment

No biomarker assessments were prespecified in the Protocol, and the only reported outcome is that of Retinoblastoma status.
Retinoblastoma (Rb) Protein Expression and Progression-Free Survival (Investigator Assessment)

568 of 666 enrolled patients had samples suitable for biomarker analysis (Biomarker Analysis Set)

563 patients had evaluable Rb testing results (validated assay)

    • 512 (90.9%) tumours were Rb positive:

      • 345 (92.2%) in combination arm and 167 (88.4%) patients in the placebo

      • 51 (9.1%) patients’ tumours were Rb negative.

      • 29 (7.8%) patients were in the combination arm and 22 (11.6%) patients were in the control arm

The sponsor presented the following investigator assessed median PFS rates according to Rb status.

Table 21: Study A5481008 Progression-free survival by Rb Status across treatment (Investigator assessment, Biomarker Analysis Set)

These results are immature with a median PFS in the Rb-negative population in the treatment arm not reached. The HR crosses 1 but it is difficult with the small numbers involved to make a meaningful statement about whether Rb negativity is predictive of a lesser response. These data do not preclude patients who might have their tumour status determined as negative, being offered treatment or enrolled in future palbociclib trials.

Additional information not provided in the dossier but presented at the American Society of Clinical Oncology meeting in Chicago.

The median PFS by Investigator assessment, based on there being 194 (44%) events in the treatment arm and 137 (62%) in the control arm, was 24.8 months (95% CI: 22.1, NR) versus 14.5 months (95% CI: 12.9, 17.1), respectively; HR 0.58 (0.46, 0.72); p<0.000001

The median PFS by BICR, based on 152 (34%) events in the treatment arm and 96 (43%) in the control arm was 30.5 months (95% CI: 27.4, NR) versus 19.3 months (95% CI: 16.4, 30.6) with a HR 0.65 (0.51, 0.84); p=0.0005.

Comment: These data appear to confirm the benefit but discrepancies between the figures used in the ITT population were noted for example, the de novo disease population was reported at ASCO as 37.2% of the entire population

        1. Evaluator commentary

Study A5481008 is an ongoing randomised, controlled, double blind Phase III study designed to demonstrate that adding palbociclib to letrozole improved a range of outcomes including PFS as the primary endpoint, and secondary outcome measures of OS, ORR, DoR, disease control rate, quality of life as well as provide further information about the pharmacokinetics and pharmacodynamics of palbociclib and also biomarkers and responses. The efficacy analyses were to be done with investigator assessments with a secondary assessment by a blinded independent review committee. A higher level of detail was included in this protocol regarding bone-only disease measurements, and the handling of progression without objective evidence of relapse and together with the double blind, randomised nature of the study sought to overcome the issues that affected Study 1003.

The limited data and results presented here provide support for a statistically and clinically significant improvement in PFS for those receiving palbociclib and letrozole compared with letrozole alone. This included an improvement in the response rates to treatment, with a halving of upfront treatment failure (best tumour response of objective progression), although the observed improvement in duration of response was not statistically significant.

However, while these investigator-assessed results appear to support the benefit seen in Study 1003, a large number of the study outcomes and assessments required to satisfactorily establish efficacy have not been presented – most notably, 5/10 of the efficacy endpoints, all the analyses of all outcomes by BICR assessment. It is not possible to evaluate the impact of the changes introduced in this study protocol with respect to the handling of progression without measurable disease without more information, particularly from the BICR.

Within the study, there was some discordance between the baseline information provided at randomisation which affected the stratification and has had an impact on the efficacy analyses, particularly on the subgroup analyses, depending which dataset is used for the ITT population. The full impact of these cannot be understood and contextualised without presentation of the study protocol deviations. It is not sufficient to provide the analyses for these groups according to the differing information source (that is, randomisation versus CRF). A more rigorous approach should include:

  • Presentation of the number of patients for whom there was any discordance between the randomisation information and CRF;

  • Whether these patients were from a single or limited number of investigation centres - it is noted that in Study 1003, the FDA clinical site audit identified a single site as having a significant number of protocol deviations but that analyses with these patients censored were not reported to significantly affect the outcomes;

  • Presentation of sensitivity analyses for the efficacy outcomes censoring the data from these patients incorrectly classified.

While these are included in the Clinical Questions section as a reference for the clinical evaluator when Study 1008 CSR is submitted, this clinical evaluator considers that the responses to these would not, in isolation from a full evaluation of the rest of the full CSR for Study 1008, be sufficient to demonstrate efficacy satisfactorily. However, this information and analyses are recommended to be included in the preparation of the CSR for submission to the TGA. They are listed in the Clinical Questions section so that they can be readily captured and responded to by the sponsor and checked by the evaluator.

Given this is essentially the pivotal study in support of the proposed first line indication, and the wide usage if registered in this line of treatment, there should be a full dataset, analyses and secondary analyses by the BICR submitted for evaluation. The clinical evaluator notes that this was the recommendation of the TGA at the presubmission meeting in October 2015.

It is appropriate that no information has been included regarding Study 1008 in the Product Information as the top line summary has not provided sufficient information to satisfactorily establish efficacy for the proposed first line usage. Given the first line indication is not supported on the evidence supplied to date, all information pertaining to Study 1003 and the proposed usage with letrozole should be removed from the PI. However, the clinical evaluator recommends that this be resubmitted as a new application for first line treatment with the full CSR for Study 1008.

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