Study 1008 findings relevant to the round 2 evaluation
The following is a list of findings from Study 1008, which were assumed to be accurate in reviewing the above clinical and PK/PD questions (including those related to the PI/CMI) or in reviewing the second round product documentation.
A sensitivity analysis was performed to evaluate whether there was a difference when using CRF data for Disease Site as the stratification factor, compared to Impala data (sensitivity analysis #4 in Study A5481008 CSR). The results showed a HR of 0.572 with 95% CI (0.459, 0.713) similar to the primary PFS analysis which showed a HR of 0.576 with 95% CI (0.463, 0.718).
Relevant to Efficacy question 7
Pre-specified efficacy subgroup analyses were in the SAP, which specified the effect of age, ethnic origin, ECOG performance status, geographical region, selected biomarkers, and stratification factors on the primary PFS, OS, and OR endpoints may be evaluated. In addition, to assess the impact of the concomitant use of proton pump inhibitors and the impact of palbociclib administered under fasting conditions, PFS was also evaluated in the population excluding patients who took proton-pump inhibitors and/or any other antacid medications concomitantly with study drug under fasting conditions during the active treatment phase.’
Relevant to Efficacy question 8
As of the data cutoff date 26 February 2016 a total of 257 patients were still on study drug: 199 patients in the palbociclib + letrozole arm and 58 in the placebo + letrozole arm.
Relevant to Efficacy question 9
In describing some of the subjects who were censored in Study 1008 in the primary efficacy (PFS) analysis, the phrase/category ‘in follow up for progression’ is presumed to refer to subjects in whom progression has not yet occurred, and they are being followed up ‘for progression’ in that they are being followed up to see when progression will occur. The first round evaluator had thought this category potentially included subjects in whom progression had occurred, who remained on treatment and were being followed up due to diagnosis of progression not yet having been radiologically established. The sponsor’s response indicates that all subjects in that category remained on treatment at the time of analysis, suggesting the former definition is correct.
Relevant to Efficacy question 9
The sponsor indicates that CIOMS narratives for all cases in which a patient died without evidence of disease progression have been included in the CSR document in Section 143.3.1 of the CSR, whilst details and causality are summarised in Tables 50 and 51 of that document. There were more such cases in the active arm (7: 1.6%) than the control arm (2: 0.9%).
Relevant to Efficacy question 10.
The HR for the subgroup of patients with metastatic disease at diagnosis (de novo) for the active versus placebo arm falls just inside nominal statistical significance (0.674 [95% CI: 0.457, 0.993]) and was above 1 prior to data cleaning. However, given the natural history of de novo metastatic disease (no prior treatment, thus generally better response to initial treatment), it is possible that PFS in this group is a less mature dataset than other subgroups. Given that the data cut-off date for Study 1008 was ten months ago, is it possible to request an updated efficacy analysis in the de novo subgroup with a later cut-off date? Alternatively, the submission of further data to this point when available could be made a condition of registration, as this subgroup analysis should not be considered an absolute barrier to registration.
Relevant to Efficacy question 11.
The sponsor in response to an s31 question provided efficacy data for all ER-/PR-positive subjects in Study 1023. There were 16 such subjects in total. Only one had an objective response, which lasted 3.71 months. This subject was in the placebo arm. There is no evidence for efficacy in this subgroup from this trial. Restriction of the indication to ‘ER-positive’ rather than ‘HR+’ disease may be appropriate if there is no evidence of efficacy in ER-/PR-positive disease seen Study 1008.
Relevant to Efficacy question 19.
An imbalance in psychiatric disorders was seen between the palbociclib and placebo arm in trial 1023. The absolute number of cases was small enough that it is statistically not significant. However, if this trend was also seen in Study 1008 this would raise concerns for a safety signal.
Relevant to Safety question 2 and Safety question 4
Is there evidence of an increased risk of bleeding in Study 1008?
Relevant to Safety question 14 and the case of subarachnoid haemorrhage noted in study 1010
Does Study 1008 support the proposed indication in the PI?
Relevant to PI text.
Does the ECG sub-study of Study 1008 provide adequate evidence that QT prolongation is not a clinical concern, and support the proposed PI text?
Relevant to PI textError: Reference source not found
PI text has been proposed that describes Study 1008 and its findings.
The second round evaluator is not able to make a full assessment of the treatment benefits due to the necessarily limited nature of the second round evaluation. However, the following has been noted in review of the sponsor’s responses:
Efficacy in ER-/PR-positive disease has not been separately established, but this is not considered a clinically relevant subgroup for the purposes of hormone-receptor based treatment.
Evidence for efficacy in de novo disease only reaches statistical significance after data cleaning activities were carried out, with a HR of 0.674 [95% CI: 0.457, 0.993]. However, the results are concordant with those for patients with other durations of remission prior to diagnosis of metastatic recurrence, and data maturity may improve with more time. The Delegate may wish to consider requiring submission of more mature data to this point as a condition of registration.
Second round assessment of risks
The second round evaluator is not able to make a full assessment of the treatment risks due to the necessarily limited nature of the second round evaluation. However, the following has been noted in review of the sponsor’s responses:
Consistent with palbociclib’s mechanism of action, myelosuppression is the predominant adverse effect seen throughout clinical trials.
Secondary susceptibility to infections also features, and it is worth considering that other events downstream of haematological insufficiencies should be monitored for in safety updates – particularly bleeding. The isolated case of a fatal sub-arachnoid haemorrhage in a Japanese subject in one of the supporting trials (Study 1010) appears to have been reported newly since the initial dossier was received, and is the principal reason for concern around monitoring for bleeding safety events. It is perfectly plausible that in subjects with other risk factors, palbociclib might elevate the risk of such events occurring.
Other adverse effects are described adequately in the PI and include stomatitis, gastrointestinal symptomatology, mild vision disturbances, and skin-related symptoms.
Second round assessment of benefit-risk balance
The second round evaluator is not able to make a full assessment of the benefit-risk balance of this treatment due to process-related resource limitations.
Second round recommendation regarding authorisation
The second round evaluator is not able to make a recommendation regarding authorisation due to process-related resource limitations.
Clinical Evaluation Report for Study A5481008 (PALOMA-2)
This supplementary clinical evaluation focuses on evaluation of the PALOMA-2 study (A5481008). This study is pivotal in support of one the two indications proposed by the sponsor for this product, namely:
Ibrance in combination with endocrine therapy is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer:
with letrozole as initial endocrine-based therapy in postmenopausal women
Top-line results from PALOMA-2 were included in the initial dossier, with the following documents included:
The top-line summary document extended to 38 pages, plus Tables.
There are two first round clinical evaluation reports for this submission:
The first round evaluation of efficacy and safety (‘CER-ES’) did consider the top-line data noted above. In the sponsor’s response to questions asked in that first round report, the full Clinical Study Report (CSR) for PALOMA-2 was supplied.
A single second round report has been written (by a different evaluator), addressing the sponsor’s response to questions asked in both first round reports. The second round evaluator has not been asked to evaluate the full CSR for PALOMA-2; instead, it is being evaluated separately, by the Delegate, in this document.
This supplementary CER should be read in conjunction with the first round and second round reports mentioned above.
Only the full CSR for PALOMA-2 will be evaluated in this report. Other components of the sponsor’s response are being evaluated in a second round report as noted earlier.
A supplemental Clinical Overview (date: ‘Approved On: 14-Oct-2016’) and summaries of efficacy and safety were also submitted in the later dossier version. These have been consulted only with regard to specific issues in PALOMA-2.
The following information within the CSR for PALOMA-2 is considered relevant from a PK perspective:
Study 1008 used palbociclib free base capsules that were intended for commercialisation and have subsequently been approved for the use by multiple regulatory bodies including the United States (US) Food and Drug Administration (FDA). Initially, the administration instructions for the free base capsules in Study 1008 were consistent with the instructions provided for the isethionate capsules used in Study 1003, namely that patients were to be fasting from at least 1 hour before to at least 2 hours after administration of palbociclib / placebo capsules, referred to as ‘minimally fasted conditions,’ and there were no restrictions in the Study 1008 protocol with regard to the use of agents that suppress gastric acid production.
During study conduct, the results across several clinical pharmacology studies showed that approximately 13% of all PK profiles observed after palbociclib free base capsule formulations were administered in healthy subjects under an overnight fasted condition (single dose) were associated with substantially lower palbociclib exposure, compared with that seen with PK profiles from the rest of subjects. These profiles with substantially lower exposure, referred to as ‘low-liers’, were not observed when palbociclib free base capsules were administered with high-fat and low-fat meals or in between meals (that is, moderate-fat meal 1 hour before and 2 hours after dosing) in the food effect study (Study 1021). The administration of palbociclib with or in between meals eliminates the occurrence of low liers and significantly reduced the intersubject variability of AUCinf and Cmax, from 39% for AUCinf and 73% for Cmax under overnight fasted conditions to 23% to 27% for AUCinf and 21% to 24% for Cmax under fed conditions, irrespective of the timing or the fat and calorie content of the food. Additionally, the supplemental analysis excluding low-liers from the overnight fasted treatment showed bioequivalence between palbociclib given under each of the fed conditions and palbociclib given under overnight fasted condition, indicating that food intake did not change the exposure of subjects who were not low-liers. In addition, the results from Study 1018 showed that palbociclib exposure was substantially decreased when palbociclib free base capsules were administered under fasted conditions concomitantly with PPIs. Therefore, protocol Amendment 2 of Study 1008 revised the study drug administration instructions from administration in a minimally fasted state to administration with food and also to prohibit the concomitant use of PPIs.
Taking into account the results from Studies 1018 and 1021, it was assumed that drug exposures in Study 1008 would be different in patients who took palbociclib in a minimally fasted state or in patients who took palbociclib under fasted conditions concomitantly with antacids (including local antacids and H2RAs in addition to PPIs, under the assumption that these agents would have a similar effect as PPIs when given concomitantly with palbociclib under fasted conditions) relative to those patients who did not. This assumed difference in drug exposure could potentially affect the efficacy outcome in these patients and thus the ability to estimate the treatment effect of palbociclib in the ITT population under the original study design. After the discussion with the US FDA, protocol Amendment 3 of Study 1008 was distributed to the study sites prior to the planned interim analysis to increase the sample size from 450 patients to 650 patients to preserve the desired statistical power and an alternative analysis population for the primary endpoint was included in the Statistical Analysis Plan (SAP) to assess the efficacy of palbociclib in the sub-population of patients who were administered palbociclib under fed conditions (that is, patients randomised after Amendment 2 of Study 1008 protocol was distributed to the study sites).
PK assessment in PALOMA-2
There was a PK assessment component to PALOMA-2. Palbociclib concentrations were measured to assess the following:
(Group 1 refers to the QTc monitoring subset, where ECGs were time-matched to serial PK draws.)
Given the evidence of a food effect, and also of PPIs in the fasted state, PK datasets were sub-grouped into Group A (fasting with antacid use), Group B (fasting without antacid use), Group C (fed regardless of antacid use) and Group D (Groups B + C), based on an assumption that patients were taking palbociclib fasted (as instructed) until 21 January 2014 (when directives were issued about food / PPI effects).
PK outcomes in PALOMA-2
In the ‘fasted’ dose-compliant group, steady-state PK outcomes were as follows:
Table 49: Pharmacokinetic outcomes in the fasted group
Trough levels were also measured, across a larger number of patients. Trough levels did not vary drastically according to ‘group’ as defined above, with Ctrough of 64.9 ng/mL across n=243 subjects (based on cycle 1 day 14 and cycle 2 day 14 data), although Ctrough was higher in fed than fasted patients (67.4 versus 58.1-58.6 ng/mL).
The CSR notes in this regard (emphasis added):
The differences in reported palbociclib PK parameters observed in this study between administration conditions were directionally consistent with those reported in prior clinical pharmacology studies dedicated to assessing the impact of these conditions on palbociclib PK but the differences observed in this study were less pronounced. This is presumably due to the PK data being collected in a less controlled and less extreme setting in this study than in the prior dedicated clinical pharmacology studies (eg, minimal fasting administration instructions in this study in place of the overnight fasting conditions used in clinical pharmacology studies, using a real-world selection of antacids of varying potency without controls on relative dosing times that maximize potential effects when palbociclib was still instructed to be administered under minimal fasting conditions).
In PALOMA-2, blood was also taken pre-dose at the cycle 1 day 1 visit ‘to be retained for potential pharmacogenomics analyses related to drug response or adverse drug reactions’ and possibly other research.
Tissue sample from 568 of the 666 randomised patients had biomarker results. ER, Rb, CCND1, p16 and Ki67 expression was assessed; see below.
Dosage selection for the pivotal studies
The CSR for PALOMA-2 states that dose escalation Study 1001 (n=74 patients with advanced cancer) examined two dosing schedules: 3/1 (daily dosing with 3 weeks on, 1 week off) and 2/1 (daily dosing with 2 weeks on, 1 week off):
Based on the relatively improved safety profile of Schedule 3/1, and the efficacy results from this study, Schedule 3/1 was selected for further clinical development and the recommended Phase II dose (RP2D) for this schedule was determined to be 125 mg QD.
The 125 mg QD 3/1 schedule was further tested in the Phase 1I/II Study 1003.