Regulatory Decision Summary for Ibrance

Ibrance (palbociclib) has previously demonstrated a positive benefit/risk profile in the following combination treatment indications: in combination with letrozole or fulvestrant for the treatment of advanced breast cancer, in combination with letrozole in the first-line setting for metastatic disease, and in combination with fulvestrant for the treatment of disease that has progressed after prior endocrine therapy.

Ibrance in combination with letrozole was previously indicated for patients with estrogen receptor (ER)-positive breast cancer. There are no clinical trial data for Ibrance in combination with letrozole in patients with ER-negative disease, regardless of progesterone receptor (PR) status. However, the ER-negative/PR-positive subgroup is rare. There are limitations in the accuracy of testing ER and PR status, and clinical guidelines recommend that all patients with hormone receptor (HR)-positive disease should be treated with endocrine therapy. Therefore, to align with current clinical practice, the sponsor proposed to broaden the indication to include all HR-positive disease. From a mechanistic perspective, palbociclib acts downstream of the ER pathway; therefore, as with the approved combination of Ibrance and fulvestrant, the hormonal status of the indicated patient population should reflect the indicated population of letrozole, which is approved for the treatment of HR-positive advanced breast cancer. In summary, it was determined that it was acceptable to expand Ibrances indication to include patients with all HR-positive advanced breast cancer disease for the following reasons: the Clinical Trials section of the Product Monograph clearly states the hormone receptor status of all studied patients, the treatment recommendations made in the current clinical practice guidelines, the scientific rationale regarding the drugs mechanism of action, and needing to ensure that eligible patients are not deprived of endocrine therapy.

The previously-approved use of Ibrance in the first-line treatment of metastatic breast cancer is supported by clinical studies performed with Ibrance in combination with the aromatase inhibitor (AI) letrozole. There are no data of Ibrance in combination with other AIs (anastrozole or exemestane). However, published literature suggests that all 3 AIs are used interchangeably in clinical practice, which is a recommendation that is supported by current clinical practice guidelines. This is due in part to the consistent effectiveness reported across the drug class, as well as the tolerable (and similar) safety profiles. Palbociclib acts downstream of the ER and can be considered as add-on therapy to currently approved aromatase inhibitor monotherapies for the hormonal treatment of advanced or metastatic breast cancer. Additionally, the risk of drug-drug interactions between palbociclib and any of the AIs is considered low. All AIs were shown to be safe and efficacious in the same patient population, and Ibrance was shown to increase the benefit of letrozole in this target patient population when they were administered together. Therefore, from a biological perspective, Ibrance would have a synergistic effect when combined with any AI, and restricting of the Ibrance indication to letrozole may result in limiting access to a beneficial add-on therapy. An expansion of the previously-approved indication of Ibrance in combination with letrozole to indicate Ibrance in combination with an aromatase inhibitor for the first-line treatment of postmenopausal women with advanced breast cancer is considered reasonable and acceptable.

As hepatic metabolism is the major route of elimination for palbociclib, a study was conducted to evaluate the impact of varying degrees of chronic hepatic impairment on the pharmacokinetics (PK) of a single oral 75 mg dose of palbociclib. The study enrolled a total of 28 subjects: 7 with normal hepatic function, and 7 in each cohort of hepatic impairment (mild, moderate, or severe hepatic impairment, according to the Child-Pugh classification). Plasma unbound exposure decreased by approximately 17% in subjects with mild hepatic impairment, and increased by approximately 34% and 77% in subjects with moderate and severe hepatic impairment, respectively, relative to subjects with normal hepatic function. Peak palbociclib unbound exposure increased by approximately 7%, 38%, and 72% for mild, moderate, and severe impairment, respectively, relative to subjects with normal hepatic function. Based on these exposure data, no Ibrance dose adjustment is required for patients with mild or moderate hepatic impairment; however, a dose reduction from 125 mg to 75 mg once daily on Schedule 3/1 is recommended for patients with severe hepatic impairment.

Although renal routes of excretion play only a minor role in the elimination of unchanged palbociclib, a renal impairment study was designed to evaluate the impact of renal impairment on the PK of a single oral 125 mg dose of palbociclib in subjects with mild, moderate, and severe renal impairment compared to those with normal renal function. Peak plasma palbociclib concentrations were reached at about the same time in all subjects, with median Tmax of 7-8 hours. Plasma palbociclib total exposure increased, ranging from 31% to 42% for each renal impairment group, with an increase in peak exposure ranging from 12% to 17% in subjects with mild, moderate, and severe renal impairment relative to subjects with normal renal function. In summary, while there was an increase in palbociclib exposure in patients with renal impairment compared to those with normal renal function, changes in exposure did not correlate to the severity of the impairment. Therefore, no dosing recommendations were considered warranted for patients with varying degrees of renal impairment.

The Product Monograph is the primary strategy to manage the risks associated with Ibrance, as it includes a description of the studied patient population for whom benefit has been demonstrated, recommendations for the monitoring of adverse events, and criteria for dose modifications. Therefore, the Product Monograph is considered an appropriate and sufficient measure for the risk management of Ibrance.