Regulatory Decision Summary for Ibrance

This Supplement to a New Drug Submission (SNDS) was filed to expand the existing indication of Ibrance in combination with an aromatase inhibitor (AI) to permit use in pre/perimenopausal women, and add the final overall survival (OS) results from Study 1008 (also known as PALOMA-2) and palmar-plantar erythrodysesthesia syndrome (PPES) as a new adverse reaction to Ibrance Product Monograph (PM).

Upon review, the indication expansion was approved, and the new efficacy and safety information was added to the relevant sections of the PM.

In addition, the Marketed Health Products Directorate (MHPD) of Health Canada completed a signal assessment for Ibrance and venous thromboembolism (VTE) risk during the review of this SNDS. Based on the MHPD’s recommendation, the Ibrance PM was updated to include VTE as a new adverse reaction and to highlight this risk in the Warnings and Precautions section.

Ibrance plus an aromatase inhibitor (letrozole) previously demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with placebo plus letrozole as initial endocrine-based therapy in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer (BC) in Study 1008 (PALOMA-2; median PFS 24.8 vs. 14.5 months, hazard ratio [HR] 0.576). The totality of the evidence presented in this submission supports that pre/perimenopausal patients with adequate ovarian function suppression can derive similar clinical benefits from the treatment of Ibrance in combination with an aromatase inhibitor (AI). The evidence reviewed included:

• PFS results in a subgroup of patients with bilateral oophorectomy were consistent with the overall population and patients without oophorectomy in Study 1008.

• Patients ≤ 40 years of age with ovarian function suppression (e.g., receiving bilateral oophorectomy or a luteinizing hormone-releasing hormone [LHRH] agonist) derived similar PFS benefits from the treatment of a cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitor plus an AI or fulvestrant, compared with the overall population and patients > 40 years of age, based on a meta-analysis of seven registration trials of CDK4/6 inhibitors in combination with AI or fulvestrant for the treatment of patients with HR-positive, HER2-negative locally advanced or metastatic BC.

• Ibrance, in combination with an AI and an LHRH agonist, was efficacious for the treatment of premenopausal women with HR-positive, HER2-negative metastatic BC in a phase 2 randomized trial (Young-PEARL) and a real-world observational study (A5481159).

• The role of adequate ovarian function suppression is well established in treating hormone-sensitive BC with endocrine therapy (ET). As supported by literature and current guidelines, ovarian function suppression may be achieved by the use of bilateral oophorectomy or an LHRH agonist. Pre/perimenopausal patients with adequate ovarian function suppression have estrogen levels similar to those in postmenopausal patients and are expected to derive similar benefits from endocrine-based therapies.

• Consistent PFS benefit was observed in pre/perimenopausal women receiving an LHRH agonist vs. postmenopausal women treated with Ibrance in combination with fulvestrant in Study PALOMA-3. As palbociclib has a different mechanism of action from ET and works downstream of fulvestrant and AI, the consistent PFS improvement regardless of the menopausal status in PALOMA-3 is supportive of the extrapolation of the result from postmenopausal patients in Study 1008 to pre/perimenopausal patients.

The clinical pharmacology and safety profiles of Ibrance have been characterized in previous submissions and are deemed applicable to pre/perimenopausal patients.

The submission also contained results of the final analysis of overall survival (OS) from Study 1008. After a median follow-up of 90 months, the median OS in the Ibrance plus letrozole group was 53.8 months compared to 49.8 months in the placebo plus letrozole group (HR 0.921, 95% CI 0.755, 1.124, not statistically significant). No apparent detriment to OS was observed in the Ibrance plus letrozole group. The uncertainty regarding the OS benefit is managed through labelling. The updated safety analysis did not identify new safety concerns.

Palmar-plantar erythrodysesthesia syndrome (PPES) and venous thromboembolism (VTE) were considered new adverse reactions of Ibrance based on the post-market reviews conducted by the Marketing Authorization Holder (MAH) and the Marketed Health Products Directorate (MHPD) of Health Canada, respectively.

The Ibrance Product Monograph (PM) was updated, and the final PM adequately describes the expanded indication, the final OS results of Study 1008 and the risks of PPES and VTE.

An updated Risk Management Plan (RMP) was included in the submission. The MHPD reviewed the RMP and considered it acceptable.

Overall, the benefit-harm-uncertainty profile of Ibrance remains positive.

For further details about Ibrance, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.