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

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Other safety issues

  1. Safety in special populations

    1. Age

Combination of palbociclib and fulvestrant Study 1023

75.2% of patients in the palbociclib and fulvestrant arm and 75.3% in the placebo and fulvestrant arm were younger than 65 years of age at baseline. The rates of TEAEs, SAEs and discontinuations were similar.


  1. Given the proposed usage is in postmenopausal women and the frequency in older women, the sponsor is requested to provide a breakdown for the events reported in the 90-day safety update for those > 75 years of age and include this in the PI (PI Comments and Clinical Question).

  2. Subgroup analyses of TEAEs by age were hampered by relatively small numbers and a lack of statistical power to determine a significant difference. It is thus not possible to provide information for the PI for these events, for example alopecia occurred more commonly in older women but there were only 22 in this arm.
        1. Race

Combination of palbociclib and fulvestrant Study 1023

Most patients participating in either treatment arm of this study were White (72.6% in the palbociclib plus fulvestrant arm and 76.4% in the placebo plus fulvestrant arm [intent-to-treat population]). The second largest race group in this study was Asian (21.3% in the palbociclib plus fulvestrant arm and 17.8% in the placebo plus fulvestrant arm [intent-to-treat population]).

While TEAE frequencies were similar between the 2 race groups (98.4% for White patients and 100% for Asian patients, Grade 3/4 TEAE frequency was much higher in Asian patients (94.5%) than in White patients (71.3%), Similarly, there was a higher overall Grade 3/4 treatment-related AE frequency in Asian patients (94.5%) than in White patients (63.7%) along with a higher overall treatment-related SAE frequency in Asian patients (9.6%) than in White patients (4.4%) were observed in the palbociclib plus fulvestrant arm. These differences were not observed in the placebo plus fulvestrant arm.

No reliable observations could be made regarding the safety profile of palbociclib plus fulvestrant treatment in patients of Black race due to small numbers: 12 in the palbociclib plus fulvestrant arm and 8 in the placebo plus fulvestrant arm.

This information was corroborated by the increase in severe TEAEs (Grade 3/4), SAEs and treatment discontinuations in those from the Asia Pacific region compared with North America and Europe.


  1. The assessment of individual AEs to inform the PI is limited by small numbers but given the overall consistently higher risk profile observed in Asian patients particularly for severe events, a heading under Special Populations is warranted. Based on current information, there appears to be a predisposition to more severe adverse events which will require closer monitoring and potentially more dose adjustments (PI and CMI Comments).

  1. Submission of the study reports for the following studies once completed may characterise this risk further: Study 1010 conducted in Japanese patients and Study 1027 in Asian (Chinese) patients may provide further information.
    1. Post marketing experience

Study A5481034 was an expanded access study of palbociclib in combination with letrozole as treatment of postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer for whom letrozole therapy is deemed appropriate.

238 women received at least one dose of palbociclib and letrozole as of 31 July 2015. Palbociclib 125 mg QD was given according to Schedule 3/1 in combination with letrozole 2.5 mg QD continuously in this study. Study objectives were to collect additional safety and efficacy data for the combination of palbociclib and letrozole in postmenopausal women with HR-positive, HER2-negative advanced breast cancer. 40 patients (16.7%) completed the study, 197 patients (82.1%) were permanently discontinued from treatment, and 1 patient (0.4%) was ongoing as of that data cutoff date.

Comment: Efficacy data were not presented, and the data for safety was descriptive.

139 patients (58.0%) were younger than 65 years of age, while 99 patients (41.6%) were 65 years of age or older; the mean age was 61.6 years, ranging from 29 years to 89 years. The majority of patients (85.3%) were White. Approximately half of patients (50.8%) had ECOG PS 0 at baseline, and 8.8% had ECOG PS 2.

8 of the 238 patients (3.4%) died on study as of 31 July 2015. Disease progression was the most frequently reported SAE (n=5) in these death cases. A clinical outcome of pancytopenia experienced by Subject [information redacted] was reported in the safety database as not resolved rather than fatal. None of the SAEs associated with deaths in Study 1034 was considered by the sponsor to be related to treatment.

Treatment emergent SAEs include febrile neutropenia, acute kidney injury, pancytopenia and hepatic enzyme abnormal and DVT. One case each of peripheral motor neuropathy and asthenia were also included. Of these, the febrile neutropenia and pancytopenia were considered treatment-related.

Comment: The evaluator is in agreement with the attribution of most of these events to disease progression after reviewing the CIOMS for the SAEs. Several patients appear to have died within a short period of commencing treatment, suggesting their disease was at a much more advanced stage than was observed in those enrolled in the clinical trials. The non-randomised nature of the data and the lack of baseline information make assessment of causality difficult. One case of pancytopenia in an 89 year old woman appeared to be treatment related and resolved and was not reported as recurring after stopping temporarily and dose reduction. No new adverse events were identified.
      1. Periodic Safety Update Report 03 February 2015-02 February 2016

        1. Cumulative Subject Exposure in Clinical Trials

Cumulatively, it is estimated that 2,461 subjects have participated in the palbociclib clinical development programme as of the DLP: 410 subjects were exposed to palbociclib alone; 661 subjects received palbociclib in combination with other drugs; 1,313 subjects received blinded-therapy; and 77 subjects received comparator drugs (that is, letrozole).
        1. Cumulative and Interval Patient Exposure from Marketing Experience

During this reporting interval, it is estimated that 22,532 patients were exposed to palbociclib worldwide since the product was first approved on 03 February 2015: 11,581 patients aged 17-65; 10,951 aged >65 years and 969 aged >75. The doses reported were 3470 patients receiving 100 mg and 18093 receiving 125 mg.

3,107 cases with 7,303 adverse events from post-marketing data sources, 65.0% of which were non-serious were reported. Of these 3,107 cases, 2,912 (93.7%) were reported from spontaneous sources and 193 (6.2%) were reported as compassionate use; the remaining 2 cases were reported from either the literature or a non-interventional study.

The most frequently reported serious and non-serious adverse events (≥ 40 events) from the marketing program cases included Product use issue (319), Fatigue (156), White blood cell count decreased (143), Disease progression (129), Nausea (85), Diarrhoea (54), Neutropenia (48), Breast cancer metastatic (46), and Death (40). Given these are all known side effects, only the cases of death will be evaluated in detail. The sponsor states there were no new, ongoing, or closed signals for palbociclib during the reporting interval.

        1. Events noted

QT prolongation was noted in one patient (QTc 700msec) and put down to a drug interaction between the patient’s medication (dofetilide) which is a CYP3A substrate and may also affect the QT interval.


  1. Direct potentiation of QT prolongation by palbociclib and dofetilide was not discussed in the narrative. This is plausible given the observed effects of palbociclib on QTc in the clinical trials.

  2. The sponsor states as a preventability measure that ‘Coadministration of palbociclib with concomitant medications known to prolong the QT interval should be avoided.’ (PSUR). This information should be included in the PI (PI Comments).

The sponsor presents data on venous thrombosis and thromboembolic events, with one fatality not able to be excluded as related to palbociclib. The sponsor indicates that the current information is adequate (in the US label) and does not warrant any changes.

Comment: This wording is not in the draft PI submitted with this application and should be, together with the changes recommended in the section of venous thromboembolism in the evaluation report.

Other events are not possible to evaluate and all are discounted by the sponsor as adding any further information to the identified risks with palbociclib.

        1. Deaths

155 deaths were reported from postmarketing sources but were no data are presented for evaluation.

  • 96 reported no cause (PT of ‘death’)

  • 59 deaths was most likely attributable to:

    • progression of the underlying malignancy (44) [32 due to breast cancer];

    • hepatic events (9);

    • infections/myelosuppression (8);

    • cardiac events (4);

    • thromboembolic events (3);

    • haemorrhagic events (2);

    • and 1 occurrence each of the following events: Circulatory collapse, Disseminated intravascular coagulation, Gastric ulcer, Haemolysis, Product use issue, and Renal failure.
        1. Use in the Elderly

The PSUR did not provide information that could be evaluated, and no additional changes for the RMP or PI can be made.
    1. Evaluator’s overall conclusions on clinical safety

There was no integrated safety summary and no single document provided a comprehensive and clear picture of the safety profile for palbociclib.The 90-day safety provided updates for an SCS prepared for the FDA and not submitted with this application, but which appears likely to have been updated by the version provided.The sponsor has been requested to provide a single, up to date comprehensive summary integrating the safety data from all studies rather than this detailing each study individually (and partially) This information should capture exposure, median duration and adverse events for all populations receiving the same treatment, not study by study.

The addition of palbociclib to either fulvestrant or letrozole is associated with a substantial increase in toxicities, most of which are haematological and in particular, neutropenia. This occurs in the vast majority of patients and is often of a Grade 3 or 4 severity. However, it does not appear to be associated with a correspondingly high risk of neutropenic fever or sepsis, and was generally manageable with treatment interruption, delays and dose reductions. No information is provided about the use of granulocyte colony stimulating factors was included and to what extent this might have reduced the incidence, severity and sequelae of the observed events. There were relatively few permanent discontinuations required due to neutropenia. Of note, the observed neutropenia occurs very early (median time to first onset 14 days) but may occur at any time during treatment (although does not appear to be a cumulative toxicity), and persists for a lengthy period after withholding treatment. This would not necessarily be anticipated by medical oncologists used to managing chemotherapy-related neutropenia which is typically of a relatively short duration, and information in the PI about this should be included (PI Comments). Leukopenia was common and often prolonged, and the potential clinical impact (PML, viral reactivation, opportunistic infection, risks with live vaccines) is not currently addressed in the dossier (Clinical Question). If no information to reassure regarding this is available, this should be included as important missing information in the RMP. Infections, sometimes fatal, occurred more commonly in patients on palbociclib including a death from neutropenic sepsis that the evaluator considers treatment-related. Thrombocytopenia also occurred commonly, and the sponsor has been asked to correlate these events to determine whether this is associated with an increased risk of bruising or bleeding events. The high level of surveillance and frequent clinical and laboratory visits required to monitor these haematological parameters, offsets some of the convenience of an oral medication.

Of note, a review of some of the investigator initiated studies on indicates they appear to be investigating a lower dose as although generally manageable, the tolerability was relatively low with 64.9%, 31% and 3.8% requiring temporary discontinuation, dose reduction or permanent discontinuation of palbociclib respectively, in Study 1023. These rates were similar to those reported for Study 1008, and in Study 1003, 15.7% discontinued permanently.

Other frequently reported TEAEs were fatigue, infections, nausea, arthralgia, stomatitis, vomiting, diarrhea and alopecia. Many of these were of Grade 1 or Grade 2 maximum severity except for neutropenia and leukopenia, which were most commonly reported as Grade 3 events. Alopecia was of both greater frequency and severity in patients receiving palbociclib in addition to fulvestrant or letrozole. The impact of these adverse events on quality of life has not been adequately assessed to date, although it was noted that palbociclib added to fulvestrant significantly delayed the time to development of pain which is an important benefit.

Of concern is the frequency of thrombotic and thromboembolic events, with one fatal pulmonary embolism reported and several Grade 4 events. Of note, there has been one case reported of ischaemic colitis in patients receiving palbociclib8 .

Other events identified as of special interest by the sponsor were pneumonitis/interstitial lung disease, QT prolongation, liver dysfunction, hyperglycaemia and cataract and visual disturbance - as well as neutropenia, thrombocytopenia and venous thrombosis, which have already been discussed. The protocol-defined method for reporting TEAEs and the presentation of AEs that occurred in ≥ 5% of the study population makes identification of the rates of these less common but potentially severe events more difficult, and for many events the narrative or CIOMS was not found or was blinded to treatment allocation. This has led to multiple clinical questions, and the responses to these questions need to be evaluated before any comments can be made. QT prolongation was observed in the clinical studies to date and has been investigated in a substudy within Study 1008, but the results were not provided in the top-line summary. In addition, although liver function test abnormalities were not common, there were cases reported of drug-induced liver injury and further details have been requested (Clinical Question).

One area of uncertainty, but where there were more reports in the palbociclib and fulvestrant arm is the risk of suicidal behaviour. This was an exclusion criterion for Studies 1023 and 1008, but not 1003 which is the subject of a clinical question (Clinical Question).

In terms of special populations, there was a signal for increased severity of adverse events in Asian patients in Study 1023 with a higher rate reported for Grade 3 or 4 events compared with non-Asian patients. Patients with Asian ethnicity make up a significant proportion of the Australian population and information alerting to this should be included in the PI. Submission, once completed, of the studies conducted solely in Japanese patients (Study 1010) and solely in China (Study 1027) may provide further information once completed.

No special safety concerns were identified in those over the age of 65, but information about the numbers of women and a breakdown of adverse events in the elderly population >75 years is awaited (Clinical Question).

  1. First round benefit-risk assessment

    1. First round assessment of benefits

The statistically significant improvement in PFS of 4.9 months observed with palbociclib and fulvestrant is considered clinically meaningful, and sustained over the 3 efficacy reports. Within the statistical limitations imposed by only a small sample being reviewed by the limited blinded independent central review of the PFS as of 5 December 2014 (first cut-off date), there appeared to be a low likelihood of bias and within the sample population reviewed, the findings were supported by the BICR. Most of this benefit is derived from stable disease and no complete responses were observed at any of the 3 time points reported. The duration of response among those who responded was not statistically significantly increased in the palbociclib and fulvestrant arm compared with those in the fulvestrant and placebo arm, but the baseline response rates were higher (that is, the treatment failure rate was lowered with the addition of palbociclib) which is clinically important. The study data are immature and no data are available for overall survival as yet. The delay in time to onset of pain in this study is also considered a clinical benefit, but no other quality of life measures were significantly improved.

Uncertainties with this proposed usage are related to whether ‘hormone receptor-positive’ describes the population treated, that is, whether there were any patients enrolled with ER- PR-positive metastatic breast cancer (Clinical Question). Similarly, the number of patients with locoregional or locally advanced inoperable disease requires clarification (Clinical Question).

The reported statistically significant improvement in PFS in Study 1003 is considered promising but due to the methodological issues, the evaluator believes no improvement in any of the reported outcomes can be asserted. Data from Study 1008 were selected for presentation for 5of the 12 planned study endpoints: PFS was reported to be statistically significantly improved by 10.3 months, but there were no data presented from the blinded independent central review in support of these findings. These were reported to be positive at a presentation in June 2016 at the American Society of Clinical Oncology annual meeting but are available in abstract form only. The overall response rate improvement was statistically significant but a relatively modest increase of 10.9%, and the level of clinical benefit rate was increased further slightly, due to additional patients having stable disease (CBR: 14.6%). These reported improvements are considered clinically significant.

There are many clinical questions arising from the evaluation of the limited information provided in the top-line data for Study 1008, with no data presented for 7/11 endpoints of the study nor the blinded independent review findings and analyses. The clinical questions address uncertainties about randomisation compared with CRF populations, and many surrounding adverse events. The clinical study report was not available at the time of this evaluation and is required to permit a full evaluation.

The convenience potentially offered by an oral medication as opposed to intravenous administration in an outpatient setting, is offset somewhat by the high level of monitoring required necessitating frequent and ongoing blood tests and clinic visits which is more akin to the monitoring level required for patients on chemotherapy than those on endocrine therapy.

    1. First round assessment of risks

Haematological toxicities, often Grade 3 or 4 neutropenia, but also thrombocytopenia and leukopenia occurred in the vast majority of patients. Although generally considered manageable from a clinician’s perspective, the high proportions of temporary discontinuations, dose reductions and discontinuations suggest that palbociclib as an add-on is not particularly well tolerated by patients.

Other concerns are the rates of thromboembolic events, which are currently not addressed in the PI. Overall, each of the studies except one very small trial (Study 1010) presented here had events of pulmonary embolism including one fatal event, with further reports of deep vein thrombosis and one event of ischaemic colitis. In Study 1008, there were 4 events which cannot be investigated further due to ongoing blinding.

Many more patients receiving palbociclib also experienced AEs associated with visual loss and impairment, the nature of which is not fully understood due to the non-specific nature of the terms used for reporting. These should be included in the PI (Clinical Question).

The extent of the risks cannot be fully established at this time without the sponsor’s responses to the clinical questions for Study 1023 which include queries/issues about cases of drug-induced liver injury12, cataract formation, ischaemic colitis, as well as suicidal ideation and behaviours.

It is not known if the clinical benefit from palbociclib is proportional to the dose received, and whether those requiring a dose reduction have comparable clinical outcomes with those maintained on the starting dose (Clinical Question).

    1. First round assessment of benefit-risk balance

The magnitude of the benefit on PFS is established and statistically significant and clinically relevant for the proposed usage in women with ER-positive metastatic breast cancer receiving palbociclib following progression on earlier endocrine therapy. There are a number of outstanding issues that prevent a benefit-risk assessment being made at this point, but satisfactory responses to the clinical questions may change this.

While the magnitude of the benefit in improving PFS appears promising in Study 1003, and the investigator assessed outcomes indicate a statistically significant improvement in the 4/12 study endpoints that were presented (PFS, ORR, CBR and DoR) in Study 1008, this could not be fully evaluated due to the very limited data presented. The blinded independent central review was not presented in the top-line summary. There are a number of serious adverse events including an increase in deaths on study in the palbociclib and letrozole arm that could not be evaluated due to ongoing blinding, with all CIOMS blinded to treatment allocation. Thus the risks of treatment cannot be fully established and the benefits could not be verified through evaluation of the full dataset and the blinded independent central review.

  1. First round recommendation regarding authorisation

No recommendation regarding authorisation for the proposed combination of palbociclib and fulvestrant can be made at this time without the responses to the clinical questions, and evaluation of those responses in the second round of the clinical evaluation.

Study 1003 is not considered to satisfactorily demonstrate safety and efficacy for the proposed indication for palbociclib and letrozole as first line treatment for a very common cancer. There are many outstanding questions arising from evaluation of the limited data provided for Study 1008, which require addressing as well as significant endpoints which have not been submitted for evaluation in this dossier. It is not considered that responses to the clinical questions raised in this evaluation alone would be sufficient to allow the evaluator to make a benefit-risk assessment (missing efficacy and safety endpoints, ongoing blinding to treatment allocation would continue to be limitations). It is recommended that the future submission of the full CSR for Study 1008 address the issues and questions raised regarding the proposed usage (that is, for both Study 1003 and 1008), and that a Product Information reflecting those data be included. Given the extensive questions already asked and those envisaged upon review of the CSR, it is considered important that this should be submitted as a separate application. It is beyond the scope of a second round evaluation to review an entire CSR and the TGA does not accept rolling submissions.

  1. Clinical questions

The following questions about efficacy and safety are to address uncertainties or provide clarification on the study data submitted. Some require responses only if the sponsor is pursuing inclusion of a statement in the PI. In such instances, if not pursuing inclusion of that information, it would be acceptable to state that and the question would no longer require an answer. Other questions pertaining to Studies 1003 and 1008 are included in this report but it is recommended by the evaluator that responses to be these be provided (if not already in the CSR for Study 1008 for those pertaining to that study) as part of a separate application for the first line indication with the full CSR for Study 1008 as the responses to these questions alone will not be sufficient to overcome the reasons for not recommending approval for the first line indication. These particular questions are included at this juncture to reflect the uncertainties about the data provided to date, but responses to them could be deferred to a subsequent application if the first line indication is no longer pursued in this application.

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