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



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Background

  1. Information on the condition being treated


In Australia in 2016, breast cancer is predicted to be the 3rd most commonly diagnosed cancer overall, and the most common cancer diagnosed in Australian women (based on an analysis of the Australian Cancer Registry by the Australian Institute of Health and Welfare). In 2016, it was estimated that 3,073 Australian people will die from breast cancer (27 men and 3,046 women), making it the 4th most common cause of death from cancer.

Breast cancer is a heterogeneous disease and comprises several subtypes. Treatment options are determined mainly by whether the cancer is hormone receptor-positive (oestrogen receptor [ER] and/or progesterone receptor [PR]-positive) and whether or not human epidermal growth factor 2 (HER2) is overexpressed (‘HER2-positive’). No Australian-specific data are available, but from the US SEER database, of breast cancers assessable for ER status, 73% were ER-positive/HER2-negative1). Women with metastatic disease will present either following relapse after diagnosis and treatment at an earlier stage (potentially including adjuvant endocrine or chemotherapy and/or radiotherapy) or with metastatic disease at diagnosis. Recent figures are not available, but the estimated rate of presentation with de novo metastatic disease is 6-10% (Harris et al, 1993).

Despite the use of systemic therapies which have resulted in improvements in overall survival, metastatic breast cancer is still regarded as an incurable condition, with a median survival after diagnosis of approximately 18-24 months (Wood et al, 2005). The aims of treatment are to improve survival, and to improve or maintain quality of life.

This application seeks registration for the treatment of postmenopausal women with advanced or metastatic HR-positive, HER2-negative breast cancer therefore the remainder of this background section will focus on agents available to treat this population with this particular subtype and stage of disease. Those with ER-positive/HER2-positivedisease have a different prognosis and treatment options.

The main treatment options for patients with metastatic ER-positive, HER2-negative breast cancer are systemic: endocrine therapy, chemotherapy, and targeted therapies (in combination). Additional modalities include palliative radiation therapy, surgery and supportive care measures such as analgesia. The choice of therapy depends upon the extent and location of metastases, the rate of disease progression and also symptom burden. For those with rapidly progressing disease and/or significant disease burden especially visceral metastases, chemotherapy (single agent or in combination) is usually commenced. Where there is no pending visceral crisis, endocrine therapy is the treatment of choice.

      1. Endocrine therapies


Postmenopausal women have low levels of endogenous oestrogen, with the main source being derived from androgen conversion by aromatase enzymatic activity. Endocrine therapies aim to reduce or stop oestrogen production (for example, ovarian suppression, aromatase inhibitors), block signaling through the oestrogen receptor (for example, tamoxifen and fulvestrant) or antagonize ER (for example, fulvestrant). For women who are pre- or perimenopausal, suppression of ovarian function, either with LHRH analogues or bilateral oophorectomy, is required before commencing agents such as aromatase inhibitors and fulvestrant.

The choice of treatment incorporates consideration of any prior adjuvant therapies used/in use at the time relapse is identified. Generally those with de novo metastatic breast cancer or those relapsing >12 months after completion of adjuvant endocrine therapy would be offered first line endocrine therapy; while those relapsing within 12 months of completing adjuvant endocrine therapy or progressing on first line endocrine therapy would be eligible for second line endocrine therapy.

An aromatase inhibitor, either letrozole or anastrozole, is the initial treatment of choice. Exemestane is approved for second line use, either alone or in combination with everolimus (see below). Tamoxifen was demonstrated to be inferior to letrozole (Phase III Study 025- see TGA PI) but can be used first line where there are significant co-morbidities or prior intolerance preventing use of an aromatase inhibitor.

    1. Current treatment options


The following list is confined to endocrine therapy-based regimens approved for use in postmenopausal women, either endocrine therapy alone or in combination with targeted therapies, as this is the population in whom registration is being sought, with palbociclib being proposed as an add-on to two currently approved endocrine therapies (letrozole in the first line setting; fulvestrant after progression on prior endocrine therapy).

Currently approved endocrine treatment options in Australia for postmenopausal women with metastatic ER-positive, HER2-negativebreast cancer are:


      1. First line (all approved for first line usage and beyond except toremifene)

        1. Non-steroidal aromatase inhibitors


Letrozole is indicated for the ‘treatment of advanced breast cancer in postmenopausal women with oestrogen/progesterone-receptor-positive disease’ (TGA PI)

Anastrozole is indicated for the ‘treatment of advanced breast cancer in postmenopausal women with oestrogen/progesterone-receptor-positive disease’ (TGA PI)


        1. Selective oestrogen receptor modulators (SERMs)


‘Tamoxifen is indicated for the treatment of breast cancer. ‘(TGA PI)

Toremifene Fareston is indicated for first line treatment of hormone-dependent metastatic breast cancer in postmenopausal patients. Fareston is not recommended for patients with oestrogen receptor negative tumours. (TGA PI)



Comment: Toremifene is seldom used in Australia.

LHRH analogue

Goserelin is approved in Australia for the treatment of women with ‘locally advanced or metastatic breast cancer in pre-menopausal women suitable for hormonal manipulation.’ (TGA PI)

Comment:


  1. The initial treatment of choice in postmenopausal women would be an aromatase inhibitor, either letrozole or anastrozole. If neither of these were tolerated then tamoxifen can be used.

  2. Goserelin is not used as a single agent in this setting due to its limited efficacy, but is used in combination with tamoxifen in premenopausal women and also permits these women to commence aromatase inhibitors and fulvestrant which all require postmenopausal oestradiol levels to be efficacious. Comparisons of LHRH analog alone and in combination with aromatase inhibitors have not been studied. Caution has to be exercised to ensure that postmenopausal oestradiol levels are actually achieved.
        1. Second line or beyond


Selection of second line endocrine therapy, subject to this being still the most appropriate option, may include the steroidal aromatase inhibitor, exemestane, alone or in combination with the mammalian target of rapamycin (mTOR) inhibitor, everolimus. Further options include fulvestrant monotherapy – combination therapies are being investigated within clinical trials.
Steroidal aromatase inhibitor

Exemestane is approved for the following indication: ‘Aromasin is indicated for the treatment of oestrogen receptor-positive advanced breast cancer in women with natural or induced postmenopausal status whose disease has progressed following anti-oestrogen therapy.’ (TGA PI)

Everolimus, was approved as second line therapy for ‘Postmenopausal women with hormone receptor-positive, HER2 negative advanced breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole.’ (TGA PI)



Comment: Everolimus and exemestane in combination are associated with significant toxicities including pneumonitis, nausea, vomiting, stomatitis, diarrhoea as well as neutropenia, anaemia, thrombocytopenia and the risk of infection. Hyperglycaemia also may occur. These may be severe, dose-limiting and also have a detrimental effect on quality of life.

Fulvestrant was approved by the TGA on 6 March 2006 with the following indication: ‘Faslodex is indicated for the treatment of postmenopausal women with hormone-receptor positive, locally advanced or metastatic breast cancer who have progressive disease following prior tamoxifen therapy.’ (TGA PI). Fulvestrant is an oestrogen receptor antagonist that blocks ER dimerization and DNA binding, increases ER turnover, and inhibits nuclear uptake of the receptor.



Comments:

  1. From a clinical perspective, this could include women who have received tamoxifen in the last 12 months in the adjuvant setting, or as treatment for their metastatic disease. In clinical practice in Australia, fulvestrant is usually offered following progression on an aromatase inhibitor as this is considered the standard of care for the treatment of metastatic ER-positive disease in postmenopausal women.

  1. Initial trials submitted for registration compared a regimen using 250 mg of fulvestrant versus anastrozole and demonstrated comparable clinical outcomes; the EFECT study (not submitted for TGA evaluation) demonstrated comparability with the steroidal aromatase inhibitor, exemestane (Chia et al, 2008) As the results from the CONFIRM study comparing 250 mg versus 500 mg demonstrated improved PFS and OS with 500 mg (TGA Product Information), this is the dose used. 500 mg is the fulvestrant dose proposed for use in combination with palbociclib in the indication being sought in this submission.
Progestins

Megestrol acetate is approved as follows: ‘Palliative treatment of recurrent inoperable or metastatic carcinoma of the breast (see DOSAGE). It should not be used in lieu of currently accepted procedures such as surgery, radiation or chemotherapy.’ (TGA PI)

Comment: This is used occasionally as a palliative treatment after progression on all other treatments. There are significant side effects including the risk of thrombo-embolic events, fluid retention and weight gain.
        1. Other


The use of oestrogens and androgens is not standard practice. Numerous clinical trials are underway comparing the addition of targeted therapies with endocrine therapies.
    1. Clinical rationale


Despite improvements in overall survival with the use of systemic therapies, metastatic breast cancer is still regarded as an incurable condition, with a median survival after diagnosis of approximately 18-24 months (Wood et al, 2005). The goal of therapy in any setting is prolongation of progression-free and overall survival, and improvement in quality of life as well as to defer the need for subsequent treatments, which include chemotherapy with its associated toxicities and limited clinical benefit.

ER-positive tumours make up 65% of tumours in women aged 35 to 65 years and 82% of tumours in women older than 65 years (Harvey et al, 1999), and the role of oestrogens in breast cancer aetiology and progression is well established. Even with the use of letrozole and other endocrine therapies, progression-free survival for postmenopausal women with hormone receptor-positive, HER2-negative breast cancer at first relapse is generally less than one year, and less than eight months upon progression after prior therapy. Resistance to endocrine treatment may be present from the outset, or emerge during endocrine treatment. Once this occurs, the mainstay is chemotherapy with its relatively low response rates and significant toxicities and for most agents the patient requires regular trips to an outpatient setting for intravenous administration. Thus there is significant unmet need for an agent that improves response rates, duration of response, progression-free survival and overall survival and maintains quality of life for patients with this common cancer.

Palbociclib is a first in class CDK4/6 inhibitor and is stated to inhibit G1 to S phase progression of the cell cycle. Cyclin D1 and CDK4/6 are downstream of signaling pathways which lead to cellular proliferation. In vitro studies demonstrate that palbociclib reduces cellular proliferation of oestrogen receptor (ER)-positive breast cancer cell lines by blocking progression of the cell from G1 into S phase of the cell cycle. In ER-positive breast cancer cell lines, sensitivity to palbociclib and its effects upon cell cycle and growth inhibition were associated with the presence of retinoblastoma (Rb) and upregulation of cyclin D1 as well as decreased CDKN2A. These gene expression findings are also associated with the luminal (ER positive) versus basal-like subtypes (ER-negative/PR-negative/HER2-ve) of breast cancer.

These results, together with published data about the interaction of oestrogens and CDKs and the important role of cell cycle-related proteins in the genesis and maintenance of breast cancer, provided a rationale for testing palbociclib in combination with agents such as letrozole. The clinical exploration of this combination is also supported by the safety profile of palbociclib.

Studies A5481010, A5481003 and A5481008 examined palbociclib in combination with letrozole for the treatment of postmenopausal patients with ER-positive, HER2-negative advanced (locally advanced or metastatic) breast cancer. Letrozole has been selected as background treatment as it is approved, considered a standard of care and commercially available for first line endocrine treatment. The combination with fulvestrant is proposed for those whose disease has progressed after initial endocrine therapy, and seeking to utilise the different mechanism of action of fulvestrant compared with aromatase inhibitors and improve the progression-free survival observed with fulvestrant alone.

There are no approved therapies for use in combination with aromatase inhibitors, nor in combination with fulvestrant in the first line and subsequent settings, respectively; thus this constitutes a novel treatment approach for the treatment of women diagnosed with metastatic HR-positive breast cancer.


    1. Formulation

      1. Formulation development


The Clinical Overview stated the following:

‘The commercial formulation of palbociclib is an immediate-release free base capsule for oral administration at 3 palbociclib dosage strengths of 75 mg, 100 mg, and 125 mg. This formulation is being used in ongoing Phase III clinical trials and is administered under fed conditions. During the clinical development program, early clinical trials (Studies 1001, 1002, 1003, 1004, and 1010 [Phase I portion]) used hand-filled capsules containing the palbociclib isethionate salt drug substance (hereafter referred to as the isethionate capsule) at 5-mg , 25-mg , and 100-mg strengths. In these early trials, including Study 1003, the isethionate capsule was administered under minimal fasting conditions. The isethionate salt and drug product was not designed to be commercialized. Furthermore, their pharmaceutical properties were not acceptable for the commercial product. Additionally, an intravenous solution, an oral suspension, an oral solution, and capsule formulations with different dissolution levels and active pharmaceutical ingredient particle sizes were developed to support bioavailability and clinical pharmacology studies, but not used in efficacy studies.’

Comment: It is noted that the ‘pivotal’ Phase I/II Study being submitted in support of the first line proposed usage used a formulation that differs from that used in the later Phase III trials, and also that the administration in that study was under ‘minimally fasted conditions’ - the recommendation, following results of 2 pharmacokinetic studies and resulting in a protocol amendment during Study 1008, now is to take palbociclib with food as this apparently ‘eliminated the occurrence of low-liers’ (Clinical Overview).

      1. Excipients


Ibrance is supplied as hard gelatin capsules containing 75 mg, 100 mg or 125 mg of palbociclib as the freebase and the following excipients: microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, silicon dioxide and magnesium stearate.

The sponsor states in the following in the letter of application

The Ibrance formulation excipient lactose monohydrate is produced from bovine milk. The magnesium stearate is of vegetable origin. Gelatin in the capsule shells is produced from bovine bones and bovine hides. Module 3.2.A provides statements and declarations from the capsule shell, lactose and magnesium stearate suppliers. Module 3.2 .R. provides information on the ingredients of animal origin including the summary tables and EDQM TSE Certificates of Suitability for gelatin, compliant to the Ph. Eur monograph 1483: Products with risk of transmitting agents of animal spongiform encephalopathies.

    1. Regulatory history

      1. Australian regulatory history


This is the first submission for registration of palbociclib, a first in class CDK4/6 inhibitor, in Australia.

A presubmission meeting was held with the sponsor in October 2015, followed by subsequent communications. A review of the agreed minutes and letter from the sponsor dated 20 November 2015 indicates that there was extensive discussion between the TGA and the sponsor about possible strategies for efficient evaluation of the data

At the time of undertaking this evaluation and preparing this clinical evaluation report, according to the timelines provided by the sponsor in the cover letter, no regulatory agency would have received the full CSR for Study 1008 evaluation and all existing approvals for the first line usage at this time are conditional in nature, requiring confirmation from this Study (see below).

      1. Orphan drug designation


Consistent with metastatic ER-positive breast cancer not being a rare disease, no orphan drug designation was sought.
      1. Related submissions


N/A
      1. Overseas regulatory history

        1. USA


The current FDA label for Ibrance is as follows:

Ibrance is a kinase inhibitor indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with:



  • letrozole as initial endocrine based therapy in postmenopausal women (1), or

  • fulvestrant in women with disease progression following endocrine therapy.

The indication in combination with letrozole is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Timeline of regulatory approval and postmarketing requirements by the FDA

The Food and Drug Administration (FDA) granted palbociclib breakthrough therapy designation in April, 2013 based on preliminary evidence of clinical activity in women with metastatic ER-positive breast cancer.

On 3 February, 2015, the FDA granted accelerated approval for the following indication (taken from the FDA label):

Ibrance is a kinase inhibitor indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. This indication is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

The following postmarketing commitment was required by the FDA (taken from the approval letter dated 3 February 2015).

‘Submit the final report for your ongoing drug interaction trial (A5481039) entitled, ‘A phase 1, open-label, fixed-sequence, 2-cohort, 2-period study to investigate the effect of modafinil and pioglitazone given as multiple doses on single dose pharmacokinetics of palbociclib (PD-0332991) in healthy volunteers’, to assess the effect of modafinil (a moderate CYP3A inducer) on the pharmacokinetics of palbociclib in healthy volunteers.’

‘Conduct analysis from the ongoing Trial A5481008, PALOMA-2, ‘A Randomized, Multicenter, Double-blind Phase III Study of PD-0332991 (Oral CDK 4/6 Inhibitor) Plus Letrozole Versus Placebo Plus Letrozole for the Treatment of Postmenopausal Women with ER (+), HER2 (-) Breast Cancer Who Have Not Received Any Prior Systemic Anti-Cancer Treatment For Advanced Disease’ to determine the prognostic or predictive significance of genetic alterations in the Cyclin D1/CDK4/6/p16/retinoblastoma pathway in ER (+), HER2 (-) breast cancer, specifically the prognostic/predictive significance of the genetic alteration to the safety and efficacy of palbociclib.’

On 19 February, 2016 the FDA granted approval for Ibrance as indicated for the treatment of hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer in combination with fulvestrant in women with disease progression following endocrine therapy

The following postmarketing commitment was required by the FDA (taken from the approval letter dated 19 February 2016).

3040-1 Submit the final overall survival analysis with datasets from Trial A5481023, PALOMA-3 A double-blind, phase III trial of fulvestrant with or without palbociclib in pre- and post-menopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy.

        1. Canada


On 16 March 2016, Health Canada approved the use of Ibrance as follows:

Ibrance, indicated:

in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease.

has been issued marketing authorization with conditions, pending the results of trials to verify its clinical benefit. Patients should be advised of the nature of the authorization. For further information for Ibrance please refer to Health Canada’s Notice of Compliance with conditions – drug products web site: http//www.hc-sc.gc.ca/dhp-mps/prodpharma/notices-avis/conditions/index-eng.php

The following is taken from the Health Canada Summary Basis of Decision, accessed from the Health Canada website 25 July 2016 http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd-smd-2016-Ibrance-182048-eng.php.

On March 16, 2016, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Pfizer Canada Inc. for the drug product Ibrance. The product was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit. Patients should be advised of the fact that the market authorization was issued with conditions.



Confirmatory studies

Study 1008 (PALOMA-2): A randomised, multi centre, double-blind, Phase III Study of Ibrance plus letrozole versus placebo plus letrozole for the treatment of postmenopausal women with ER-positive, HER2-negative breast cancer who have not received any prior systemic anti-cancer treatment for advanced disease.

To confirm the clinical benefit of Ibrance for the treatment of these patients, as initial endocrine-based therapy for their metastatic disease, Pfizer Canada Inc. will submit the following:

The sponsor will submit as a Supplemental New Drug Submission-Confirmatory (SNDS-C) Study:


  • High level results for Study 1008 (PALOMA-2). These results will be provided at their earliest availability. Pfizer has indicated that it will withdraw the indication should the primary endpoint of the Phase III trial not reach statistical significance.

The final study report for Study 1008 (PALOMA-2). This report will be submitted at its earliest availability.’

Comment: This conditional approval is restricted to those with metastatic ER-positive breast cancer that is, not locally advanced disease or hormone receptor-positive disease.
        1. European Union


An application was lodged with the EMA on 30 July 2015 for the following indications:

Ibrance in combination with endocrine therapy is indicated for the treatment of

HR-positive, HER2-negative advanced/metastatic breast cancer:


  • with letrozole as initial endocrine-based therapy in postmenopausal women;

  • with fulvestrant in women who have received prior therapy.

The sponsor provided an updated indication under consideration by the Rapporteurs pending assessment of the top-line summary of Study 1008 as providing adequate support.

Ibrance is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or with fulvestrant in postmenopausal women, and with an aromatase inhibitor or with fulvestrant plus a luteinizing hormone-releasing hormone (LHRH) agonist in pre- or perimenopausal women.

A recommendation regarding marketing authorization by the Committee for Medicinal Products for Human Use (CHMP) is awaited.

        1. Switzerland


An application was lodged with SwissMedic on 8 December 2015 for the same indication as sought in this application. No further details were provided.
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