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

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Clinical efficacy

  1. Pivotal or main efficacy studies

A5481008 ‘PALOMA-2’

Study design, objectives, locations and dates


PALOMA-2 is a multicentre, randomised, double-blind, placebo-controlled, Phase III study of palbociclib + letrozole versus placebo + letrozole in postmenopausal women with ER-positive / HER2-negative advanced breast cancer, previously untreated with systemic anti-cancer therapy for locoregionally recurrent or metastatic disease.


The CSR for PALOMA-2 states (Study Rationale):

The Phase III double-blind study, Study 1008, was initiated to confirm the favourable benefit / risk profile observed with the combination of palbociclib with letrozole in the open label Phase 1/2 Study 1003 in a similar patient population. This Phase III study was designed to demonstrate that palbociclib in combination with letrozole provides superior clinical benefit compared to letrozole in combination with placebo in postmenopausal women with ER-positive/HER2-negative locoregionally recurrent or metastatic BC who have not received any prior systemic anti-cancer therapies for their advanced disease.

The formal primary objective of the study was:

To demonstrate that the combination of palbociclib with letrozole is superior to placebo plus letrozole in prolonging PFS in postmenopausal women with ER-positive/HER2-negative ABC who have not received any prior systemic anti-cancer therapies for their advanced/metastatic disease.


666 women enrolled at 186 sites in 17 countries, mainly in Europe and North America. The largest study site in any country had 34 enrolees; this was Russian site 1056.

Region / Country

Number of sites

Patients (number in palbociclib arm; percent of n=444 total)

Patients (number in placebo arm; percent of n=222 total)

North America

168 (37.8%)

99 (44.6%)



126 (28.4%)

71 (32.0%)



42 (9.5%)

28 (12.6%)


212 (47.7%)

95 (42.8%)

Russian Federation


38 (8.6%)

22 (9.9%)



38 (8.6%)

19 (8.6%)



27 (6.1%)

12 (5.4%)



19 (4.3%)

14 (6.3%)



22 (5.0%)

6 (2.7%)



20 (4.5%)

7 (3.2%)



15 (3.4%)

7 (3.2%)



14 (3.2%)

4 (1.8%)



9 (2.0%)

2 (0.9%)



5 (1.1%)

2 (0.9%)



5 (1.1%)



64 (14.4%)

28 (12.6%)



32 (7.2%)

14 (6.3%)



15 (3.4%)

9 (4.1%)



15 (3.4%)

5 (2.3%)



2 (0.5%)



The 666 women were randomised between 28 February 2013 and 29 July 2014.

Interim analysis of efficacy and safety was performed by the External Data Monitoring Committee (E-DMC) on 12 September 2015 (data cutoff 1 May 2015), with 236 PFS events. The recommendation was for the study to continue as planned.

The CSR evaluated here presents the final progression-free survival (PFS) analysis. The CSR states:

A data cutoff date (26 February 2016) was applied for this final analysis. Data reported in this CSR occurred on or before 26 February 2016, with the snapshot of the active clinical database for the purpose of final analysis made on 08 April 2016.

(The Topline Summary presented earlier to the TGA also used the 26 February 2016 cutoff date.)

The CSR was dated 4 October 2016. The study is ongoing (subjects are being followed up for the purpose of a final overall survival [OS] analysis).

      1. Questions 1-2 for sponsor

  1. It is noted in the EMA’s Second Joint Rapporteur’s Assessment Report (JRAR) that:

The sponsor also commits to submit the final OS results from Study 1008 when they become available. Based on current projections, the readout is estimated to occur in May 2020 and the final report would be submitted by November 2020, as a type 2 variation.

Please provide an update about when the final OS outcomes are anticipated, and when the CSR reporting final OS outcomes will be available.

  1. Beyond the OS analyses conducted at the time of the initial and final PFS analysis, are any OS analyses to be conducted (by the E-DMC, sponsor, or any other party) prior to the final OS analysis?

Inclusion and exclusion criteria


  1. Adult women (≥ 18 years of age) with proven diagnosis of adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent and for whom chemotherapy was not clinically indicated;

  2. Documentation of histologically or cytologically confirmed diagnosis of ER-positive BC based on local laboratory results;

  3. Previously untreated with any systemic anti-cancer therapy for their locoregionally recurrent or metastatic ER-positive disease;

  4. Postmenopausal women defined as women with:

    • Prior bilateral surgical oophorectomy, or

    • Medically confirmed postmenopausal status defined as spontaneous cessation of regular menses for at least 12 consecutive months or follicle-stimulating hormone (FSH) and estradiol blood levels in their respective postmenopausal ranges with no alternative pathological or physiological cause;

  1. Measurable disease as defined per RECIST v 1.1 or bone-only disease (with bone lesions confirmed by CT, MRI or bone X-ray). Tumor lesions previously irradiated or subjected to other locoregional therapy were only deemed measurable if disease progression at the treated site after completion of therapy was clearly documented;

  2. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2;

  3. Adequate organ and marrow function defined as follows:

    • Absolute neutrophil count (ANC) ≥ 1,500/mm3 (1.5 x 109/L),

    • Platelets ≥ 100,000/mm3 (100 x 109/L)

    • Haemoglobin ≥ 9 g/dL (90 g/L),

    • Serum creatinine ≤1.5 x Upper limit of normal (ULN) or estimated creatinine clearance ≥ 60 mL/min as calculated using the method standard for the institution,

    • Total serum bilirubin ≤1.5 x ULN (≤3.0 x ULN if Gilbert’s disease),

    • AST and/or ALT ≤3 x ULN (≤5.0 x ULN if liver metastases present),

    • Alkaline phosphatase ≤2.5 x ULN (≤5.0 x ULN if bone or liver metastases present);

  1. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v 4.0 Grade ≤1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion);

  2. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures;

  3. All patients had to agree to provide tumor tissues for centralized retrospective confirmation of estrogen receptor (ER) status and to evaluate correlation between genes, proteins, and RNAs relevant to the cell cycle pathways and sensitivity / resistance to the investigational agents. Freshly biopsied, recurrent/metastatic tumor samples had to be provided whenever possible. If such a biopsy was not feasible or could not be safely performed, then an archived tumor sample could be accepted. In either case a formalin fixed, paraffin embedded (FFPE) block or 12 unstained FFPE slides were required for patient participation;

  4. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legal representative) was informed of all pertinent aspects of the study before any study-specific activity was performed.

  1. HER2-positive tumor as defined by documentation of erbB-2 gene amplification by Fluorescent In Situ hybridization (FISH) (as defined by a HER2/CEP17 ratio ≥ 2) or chromogenic in situ hybridization (CISH, as defined by the manufacturer’s kit instruction) or INFORM HER2 dual ISH (as defined by manufacturer’s kit instruction) or documentation of HER2-overexpression by immunohistochemistry (IHC) (defined as IHC3+ or IHC2+ with FISH or CISH confirmation) based on local laboratory results utilizing one of the Sponsor-approved assays (Appendix 2 of the protocol, provided in Section 16.1.1). If HER2 status is unavailable or was determined using a test other than a Sponsor-approved assay, then testing had to have been performed/repeated using one of these assays prior to randomization. If tissue sample from both primary and recurrent/metastatic tumors were available, HER2 assessment from the most recent sample (ie, recurrent/metastatic sample) should be used to define eligibility whenever feasible;

  2. Patients with advanced, symptomatic, visceral spread, who were at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver involvement);

  3. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Patients with a history of CNS metastases or cord compression were eligible if they had been definitively treated with local therapy (eg, radiotherapy, stereotactic surgery) and were clinically stable off anticonvulsants and steroids for at least 4 weeks before randomization;

  4. Prior neoadjuvant or adjuvant treatment with a nonsteroidal aromatase inhibitor (ie, anastrozole or letrozole) with disease recurrence while on or within 12 months of completing treatment;

  5. Prior treatment with any CDK4/6 inhibitor;

  6. Patients treated within the last 7 days prior to randomization with:

    • Food or drugs known to be CYP3A4 inhibitors (ie, amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole, and grapefruit or grapefruit juice),

    • Drugs known to be CYP3A4 inducers (ie, carbamazepine, felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and St. John’s wort),

    • Drugs known to prolong the QT interval;

  1. Major surgery, chemotherapy, radiotherapy, any investigational agents, or other anti-cancer therapy within 2 weeks before randomization. Patients who received prior radiotherapy to ≥ 25% of bone marrow were not eligible independent of when it was received;

  2. Diagnosis of any other malignancy within 3 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix;

  3. QTc >480 msec (based on the mean value of the triplicate ECGs), family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes;

  4. Uncontrolled electrolyte disorders that could compound the effects of a QTc-prolonging drug (eg, hypocalcaemia, hypokalaemia, hypomagnesaemia);

  5. Any of the following within 6 months of randomization: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE v 4.0 Grade ≥ 2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism;

  6. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any upper gastrointestinal surgery including gastric resection;

  7. Known hypersensitivity to letrozole, or any of its excipients, or to any palbociclib / placebo excipients;

  8. Known human immunodeficiency virus infection;

  9. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that could increase the risk associated with study participation or study drug administration or could interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into the study;

  10. Patients who were investigational site staff members or relatives of those site staff members or patients who were Pfizer employees directly involved in the conduct of the study;

  11. Participation in other studies involving investigational drug (s) (Phases 1-4) within 2 weeks before randomization and/or during participation in the active treatment phase of the study;

  12. Recent or active suicidal ideation or behaviour.

Study treatments

The CSR for PALOMA-2 states:

Patients randomised to Arm A (experimental arm) received:

    • Palbociclib, 125 mg, orally QD on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment; in combination with

    • Letrozole, 2.5 mg, orally QD (continuously).

Patients randomized to Arm B (control arm) received:

    • Placebo orally QD on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment; in combination with

    • Letrozole, 2.5 mg, orally QD (continuously).

Palbociclib was supplied as capsules containing 75 mg, 100 mg (each for use in the case of dose reductions) or 125 mg equivalents of palbociclib free base. Patients were instructed to swallow palbociclib / placebo capsules whole and not to chew them prior to swallowing. The CSR also states:

Patients were to continue receiving assigned treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first. However, patients could continue treatment as assigned at randomization beyond the time of RECIST-defined PD at the discretion of the investigator if that was considered to be in the best interest of the patient and as long as no new anti-cancer treatment was initiated.

      1. Question 3 for sponsor

3. How many patients continued to receive palbociclib beyond RECIST-defined PD? Provide a summary of the benefits (if any) observed in PALOMA-2 with such treatment, e.g. median duration of treatment post-progression; PFS relative to others with PD who did not receive palbociclib post-PD; evidence of any tumour response after progression.

Crossover between treatment arms was not allowed in the study.

Dosing interruption was required by protocol in the following circumstances:

  • Uncomplicated Grade 3 neutropenia (ANC<1000/mm3);

  • Grade 3 neutropenia (ANC<1000/mm3) associated with a documented infection or fever ≥ 38.5°C;

  • Grade 4 neutropenia (ANC<500/mm3);

  • Grade 4 thrombocytopenia (platelet count <25,000/mm3);

  • Grade ≥ 3 non-hematologic toxicity (including, nausea, vomiting, diarrhea, and hypertension only if persisting despite optimal medical treatment);

  • Grade 3 QTc prolongation (QTc ≥ 501 msec on at least 2 separate ECGs).

Retreatment following treatment interruption for treatment-related toxicity or at the start of any new cycle required platelet count ≥ 50 000/mm3, ANC ≥ 1000/mm3 and no fever, recovery of severe AEs to grades 0-1 (or grade 2 if not a ‘safety risk’) and QTc <501 msec with reversible causes corrected. If these parameters were not met after 2 weeks of treatment interruption, permanent discontinuation was to be considered, but this was at the investigator’s discretion.

Dose reduction criteria were specified, with re-escalation not allowed. Reductions were for treatment-related toxicities requiring treatment interruption / delay or persisting despite optimal medical treatment:

Table 50: Dose reduction criteria

There were specific criteria for relating to QT prolongation:

Efficacy variables and assessments

Disease assessment was performed every 12 weeks; patients with baseline bone lesions were to have repeat bone scans every 24 weeks. The CSR states:

Efficacy analyses were to be performed using the local radiologist’s/investigator’s tumor assessments as primary data source. However, a blinded independent third-party core imaging laboratory completed a retrospective review of all radiographic images and clinical information collected on-study to verify the protocol-defined endpoints of tumor response and disease progression as assessed by the investigator.

Tumour assessments involved CT or MRI, radionuclide bone scan and correlative bone imaging, and photographs of superficial lesions (CSR page 80). Baseline brain scans were only required if signs and symptoms suggested metastatic brain disease. Detailed special rules applied to interpretation of response for bone-only disease.

RECIST v1.1 was used to determine objective response to treatment.

Patient-reported outcomes were assessed with FACT-B and EuroQol-5D questionnaires, completed pre-dose on day 1 of selected cycles. The CSR states:

The FACT-B consists of the Functional Assessment of Cancer Therapy-General (FACT-G) (27-items) and a breast-specific module: a 10-item instrument designed to assess patient concerns relating to BC. The FACT-G is a 27-item compilation of general questions divided into 4 domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. Patients were asked to respond to a Likert scale where 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, and 4=very much.

The EQ-5D is a 6-item instrument designed to assess health status in terms of a single index value or utility score. It contains 5 descriptors of current health state (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression) with each dimension having 3 levels of function (1=no problem, 2=some problem, and 3=extreme problem). The scores on the 5 descriptors are summarized to create a single summary score. The EQ-5D also includes a visual analog scale (EQ-VAS), in which the patients self-rate their overall health status on a scale from 0 (worst imaginable) to 100 (best imaginable).

After the active treatment phase, patients were followed up with FACT-B questionnaire, survival and new anti-cancer therapy information.

In addition to the above, the study was to include:

  • QTc monitoring to evaluate the effect of palbociclib on QT interval via triplicate ECGs time-matched with select serial PK draws (subset study in at least 60 patients enrolled at selected sites, Group 1);

  • Quantification of trough palbociclib plasma concentration;

  • A molecular profiling component aimed at assessing the relationship between breast tumour sensitivity and resistance to palbociclib and the alteration of cell cycle pathway-related genes and proteins in tumour tissues.

Randomisation and blinding methods

The CSR for PALOMA-2 states:

At least 650 eligible patients were to be randomized 2:1 to receive either palbociclib plus letrozole (Arm A: at least 433 patients) or placebo plus letrozole (Arm B: at least 217 patients).

Patients were to be stratified by site of disease (visceral, non-visceral), by disease-free interval since completion of prior (neo) adjuvant therapy (de novo metastatic, ≤12 months, >12 months), and by the nature of prior (neo) adjuvant anti-cancer treatment received (prior hormonal therapy, no prior hormonal therapy).

Of note, ‘visceral’ referred to any lung (including pleura) and/or liver involvement and ‘non-visceral’ referred to absence of lung (including pleura) and/or liver involvement.

The study was double-blind, and placebo capsules matched palbociclib ones.

Tumour assessments were performed by investigators, but there was also a blinded independent central review (BICR) by a third-party imaging laboratory, with these data used for supportive analyses. ECG data were sent to a core laboratory for blinded manual measurement. The CSR also states:

The Sponsor study team was blinded from study treatments for each patient. All data review and data cleaning activities were performed in a blinded fashion until the database was released after the database snapshot (08 April 2016).

Analysis populations

All efficacy analyses were conducted on the ITT population. Numbers in key populations are described below:

Table 51: Analysis populations

Sample size

Sample size of ~650 patients assumed median PFS for letrozole of 9 months, and risk reduction of 31% (HR 0.69) with addition of palbociclib, or improvement to 13 months for median PFS, along with various other assumptions.

This sample size would also allow assessment of differences in OS; no crossover was permitted to palbociclib. The CSR states:

The OS outcome of a reported Phase III clinical study with a similar patient population was 34 months for the arm receiving letrozole. Using this value as an assumption with a hypothesized 26% reduction risk (a HR of 0.74) of 35% improvement in median OS (from 34 months to 46 months) in patients randomized to receive palbociclib plus letrozole and follow-up period of approximately 68 months, evaluation of 390 events using a 1-sided, unstratified log-rank test was required for a significance level of 0.025 and power of 80% to detect the difference.

Protocol amendment 3 (21 March 2014) increased sample size from 450 to 650 due to a concern that drug exposure prior to amendment 2 (stipulating that palbociclib should be taken with food and without PPI use) might be different. This increase in sample size reflected a shift in assumed PFS HR from 0.64 to 0.69, resulting in an increase of PFS events required for the final analysis by 108 events (from 239 to 347 events).

Statistical methods

Statistical Analysis Plan (SAP) version 3.0 (updated for study Protocol Amendment 7, and titled in Docubridge ‘Statistical Methods Interim Analysis Plan’) was provided in the s31 response.

Primary efficacy evaluation

The primary endpoint was PFS based on investigator assessment. In this regard the CSR also explains:

The primary and secondary analyses of endpoints dependent on disease assessments (PFS, objective response [OR], duration of response [DOR], and disease control/clinical benefit response [DC/CBR]) were based on the target lesion measurements, non-target lesion assessments, and new lesion records provided by the investigator, independent of the overall response category provided by the investigator, and hereafter are referred to as the investigator assessments of tumor response and progression.

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